Synopsis of Pathology

Synopsis of
Pathology
Synopsis of
Pathology
Anoop N
Government Medical College
Thrissur, Kerala, India
Jaypee Brothers Medical Publishers (P) Ltd

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Synopsis of Pathology
First Edition: 2013
ISBN 978-93-5090-475-6
Printed at
Dedicated to
‘Pratheeksha’, the charity wing of
Government Medical College,
Thrissur, Kerala, India
Preface
Synopsis of Pathology is a one-of-a-kind book that aims to equip its readers with a
comprehensive knowledge of this vast subject from a single read. It is mostly based on
Robbins Basic Pathology and other standard textbooks. Synopsis has been presented in
a manner that would help its readers to confront the new second MBBS examination
pattern with confidence. The simple but precise text has been supplemented with
several flow charts, illustrations and essential pictures that expedite understanding
of the subject. Clinical pathology notes and a set of 50 clinical essay questions mostly
from previous university question papers is also a unique feature to this book.
Although every effort has been made to make the book error free, I acknowledge
that some mistakes might have crept in. I request the readers to point out any error—
factual or otherwise—that they notice and also to send your feedback and invaluable
suggestions towards improving future editions of this book.
Anoop N
Acknowledgments
I wish to express the deepest gratitude to Dr Joy Augustine, Professor and Head, and
all the other faculty members of the Department of Pathology, Government Medical
College, Thrissur, Kerala, India. Without their guidance and help, the completion of
this book could never have been realized. I also thank College Union 2011 to 2012 for
their support in publishing this book.
I thank my friend Jithesh R for drawing diagrams in this book. My friends
particularly; Achyuth Ajith, Ameesh M, Anto Anand G, Aseel KP, Gautham Rajan,
Gokul ED, Habeeb Rehman, Jijo Joseph, Monish Mohan and Rony Mathew of 27th
Batch; Ashna KK, Anamika Ummer, Chandini Sundar, Emil Ebin Saji, Harikrishnan
AR and Vishnu VM of 29th Batch; Benson Benchamin, Sadhik V and Vineeth of 30th
Batch, who gave me selfless support for preparing the manuscript of this book, deserve
special mention. I also thank my beloved little sister Navaneetha for her help and
support in completion of this book.
I am also thankful to Shri Jitendar P Vij (Group Chairman), Mr Ankit Vij (Managing
Director) and Mr Tarun Duneja (Director-Publishing) of M/s Jaypee Brothers Medical
Publishers (P) Ltd, New Delhi, India for the efforts they took to publish and bring out
the book in its present form.
Last but not least, I thank my parents, my sister, all my teachers, friends and God
Almighty, without whose blessings and support this book would still be only a dream.
Contents
Part 1: General Pathology

1. Cell Injury, Cell Death and Adaptations 3
•• Cellular response 3
•• Cellular adaptations 3
•• Subcellular alterations 4
•• Necrosis 4
•• Mechanisms of cell injury 5
•• Apoptosis 6
•• Intracellular accumulations 8
•• Calcification 9
•• Aging 10
2. Acute and Chronic Inflammation 11

•• Acute inflammation 11
•• Chemical mediators of inflammation 14
•• Chronic inflammation 16
•• Granulomatous inflammation 16
•• Systemic effects of inflammation 17
3. Tissue Repair, Regeneration, Healing and Fibrosis 18

•• Cell cycle 18
•• Signaling mechanisms of growth factor receptors 18
•• Angiogenesis 19
•• Cutaneous wound healing 20
4. Hemodynamic Disorders, Thrombosis and Shock 24
•• Edema 24
•• Thrombosis 25
•• Embolism 27
•• Infarction 28
•• Shock 29
5. Diseases of the Immune System 32

•• Hypersensitivity 32
•• Graft rejection 36
•• Immunological tolerance 37
•• Mechanisms of autoimmunity 38
•• Systemic lupus erythematosus 38
•• Rheumatoid arthritis 42
xii Synopsis of Pathology
•• Amylodosis 42
•• Scleroderma 45
•• Pathogenesis of human immunodeficiency virus 47
6. Neoplasia 48
•• Neoplasm 48
•• Anaplasia 48
•• Metastasis 48
•• Preneoplastic disorders 51
•• Carcinogenesis: molecular basis or genetic mechanism 51
•• RB gene 52
•• p53 gene 53
•• Chemical carcinogens 55
•• Chemical carcinogenesis 56
•• Dna viral oncogenesis 58
•• Rna viral oncogenesis 60
•• Tumor antigens 61
•• Paraneoplastic syndromes 63
7. Genetic and Pediatric Diseases 64

•• Mutations 64
•• Marfan syndrome 65
•• Lysosomal storage disease 65
•• Glycogen storage diseases (glycogenosis) 67
•• Autosomal genetic disorders 67
•• Sex chromosomal disorders 68
•• Respiratory distress syndrome of the newborn 69
•• Cystic fibrosis 70
•• Neuroblastoma 71
•• Retinoblastoma 72
8. Environmental and Nutritional Diseases 74

•• Protein-energy malnutrition 74
•• Vitamin A deficiency 75
•• Vitamin D deficiency 75
•• Effects of tobacco 75
•• Effects of alcohol 76
•• Effects of obesity 76
9. General Pathology of Infectious Diseases 77
•• Mechanisms of viral injury 77
•• Mechanisms of bacterial injury 77
•• Tuberculosis 78
•• Leprosy (Hansen disease) 78
•• Syphilis 81
Clinical Pathology 82
•• Exfoliative cytology 82
•• Fine-needle aspiration cytology 83
•• Histopathology 84
•• Urine examination 85
Contents xiii
•• Packed cell volume 88

•• Erythrocyte sedimentation rate 89
Part 2: Systemic Pathology
10. Blood Vessels 93

•• Response to injury 93
•• Atherosclerosis 93
•• Hypertension 95
•• Aneurisms 97
•• Dissection 98
•• Vasculitis 99
•• Tumors 101
•• Kaposi sarcoma 102
•• Raynaud phenomenon 102
11. Heart 103

•• Heart failure 103
•• Ischemic heart diseases 104
•• Hypertensive heart diseases 108
•• Rheumatic valvular disease or rheumatic heart disease 109
•• Infective endocarditis 110
•• Cardiomyopathies 111
12. Hematopoietic and Lymphoid Systems 114

•• Classification of anemia 114
•• Hereditary spherocytosis 115
•• Sickle cell anemia 115
•• G6pd deficiency 116
•• Paroxysmal nocturnal hemoglobinuria 117
•• Thalassemia 117
•• Iron deficiency anemia 119
•• Megaloblastic anemia 120
•• Pernicious anemia 121
•• Aplastic anemia 122
•• Microcytic hypochromic anemias 123
•• Polycythemia 123
•• Leukemoid reaction 124
•• Infectious mononucleosis 125
•• Acute myelogenous leukemia 126
•• Chronic myelogenous leukemia 127
•• Acute lymphoblastic leukemia 128
•• Chronic lymphocytic leukemia 130
•• Burkitt lymphoma 131
•• Multiple myeloma 131
•• Hodgkin lymphoma 133
•• Disseminated intravascular coagulation 136
•• Idiopathic or immune thrombocytopenic purpura 138
•• Thrombotic thrombocytopenic purpura 138
xiv Synopsis of Pathology
•• Hemophilia 139
•• Von Willebrand disease 140
13. Lungs 141
•• Acute restrictive lung disease 141
•• Alveoli in acute respiratory distress syndrome 141
•• Emphysema 142
•• Asthma 144
•• Bronchiectasis 145
•• Pneumoconiosis 147
•• Silicosis 148
•• Asbestosis and related diseases 148
•• Sarcoidosis 149
•• Pneumonia 150
•• Tuberculosis 151
•• Lung carcinomas 154
•• Malignant mesothelioma 156
14. Kidney and its Collecting System 157
•• Nephrotic syndrome 157
•• Nephritic syndrome 160
•• Rapidly progressive gn (cresentic gn) 161
•• Acute pyelonephritis 162
•• Chronic pyelonephritis 163
•• Drug induced nephritis 163
•• Acute tubular necrosis 163
•• Morphology 164
•• Benign nephrosclerosis 165
•• Malignant nephrosclerosis 165
•• Polycystic kidney disease 165
•• Renal stones 167
•• Hydronephrosis 168
•• Renal cell carcinoma 169
•• Wilms tumor 170
15. Oral Cavity and Gastrointestinal Tract 171
•• Leukoplakia 171
•• Erythroplakia 171
•• Barrett esophagus 171
•• Esophageal carcinoma 172
•• Peptic ulcer 173
•• Gastric carcinoma 174
•• Colonic diverticulosis 176
•• Malabsorption syndromes 176
•• Inflammatory bowel disease 177
•• Adenomas 179
•• Colorectal carcinoma 179
•• Familial polyposis syndromes 181
16. Liver, Gallbladder and Biliary Tract 183
•• Hepatic failure 183
•• Cirrhosis 183
Contents xv
•• Portal hypertension 184

•• Viral hepatitis 185
•• Alcoholic liver disease 188
•• Drug-induced liver disease 190
•• Hemochromatosis 191
•• Wilson’s disease 192
•• Alpha 1-antitrypsin deficiency 192
•• Hepatocellular carcinoma 193
•• Cholelithiasis (gallstones) 193
•• Cholecystitis 194
17. Pancreas 195
•• Acute pancreatitis 195
•• Chronic pancreatitis 196
18. Male Genital System 198
•• Testicular neoplasms 198
•• Nodular hyperplasia of the prostate 199
•• Prostatic carcinoma 200
•• Syphilis 201
19. Female Genital System and Breast 204
•• Cervical intraepithelial neoplasia 204
•• Invasive carcinoma of cervix 205
•• Endometrial carcinoma 205
•• Ovarian tumors 206
•• Hydatidiform mole 208
•• Benign tumors of breast 210
•• Carcinoma of breast 210
•• Fibrocystic changes 213
20. Endocrine System 215
•• Hashimoto’s thyroiditis 215
•• Graves’ disease 215
•• Diffuse and multinodular goiter 216
•• Adenoma of thyroid (follicular adenoma) 217
•• Papillary carcinoma of thyroid 218
•• Follicular carcinoma of thyoroid 218
•• Medullary carcinoma 219
•• Anaplastic carcinoma 219
•• Hyperparathyroidism 220
•• Diabetes mellitus 220
•• Cushing syndrome 222
•• Hyperaldosteronism 223
•• Adrenal insufficiency 224
•• Pheochromocytoma 224
•• Multiple endocrine neoplasia syndromes 225
21. Musculoskeletal System 226

•• Congenital diseases of bone 226
•• Paget disease (osteitis deformans) 228
•• Rickets and osteomalacia 229
xvi Synopsis of Pathology
•• Hyperparathyroidism 230
•• Osteomyelitis 230
•• Osteoarthritis 233
•• Gout 234
•• Fatty tumors 236
•• Smooth-muscle tumors 237
22. Skin 238

•• Squamous cell carcinoma 238
•• Basal cell carcinoma 238
•• Malignant melanoma 239
23. Nervous System 241

•• Berry aneurysm 241
•• Meningitis 241
•• Brain tumors 243
•• Alzheimer disease 246
•• Neuroblastoma 246
Essays 247
Diagnosis 256
Most Important Topics 257
Important Laboratory Values 259
Bibliography 261
Index 263
Abbreviations
AA Amino acid B Basophils

AA Aortic aneurysm BC Bowman’s capsule
AAA Abdominal aortic aneurysm BCC Basal cell carcinoma
AAH Atypical adenomatous BF Blood flow
hyperplasia BI Bacterial index
AA protein Amyloid-associated protein BM Basement membrane
Ab Antibody BM Bone marrow
Aβ2M Amyloid β2-microglobulin
BMR Basal metabolic rate
Aβ protein Amyloid β-protein
BT Bleeding time
ACA Anterior cerebral artery
BV Blood volume
ACE Angiotensin-converting enzyme
C Complement
ACh Acetylcholine
CA Carcinoma
AD Autosomal dominant
CAD Coronary artery disease
ADP Adenosine diphosphate
CAM Cell adhesion molecules
AF Atrial fibrillation
cAMP Cyclic adenosine
AFP Alpha fetoprotein
monophosphate
Ag Antigen
CCB Calcium channel blocker
AL protein Amyloid light-chain protein
CCF Congestive cardiac failure
ANCA Anti-neutrophil cytoplasmic
antibody CD Crohn disease
ANF Atrial natriuretic factor CDK Cyclin-dependent kinase
APC Antigen-presenting cell cDNA Cytoplasmic deoxyribonucleic
acid
APP Amyloid precursor protein
CEA Carcinoembryonic antigen
APTT Activated partial
thromboplastin time CF Cystic fibrosis
AR Autosomal recessive CFTR Cystic fibrosis transconductance
AS Aortic stenosis factor
AT2 Angiotensin-2 CHF Congestive heart failure
ATM Ataxia telangiectasia mutated CHO Carbohydrate
ATR Ataxia telangiectasia and Rad3 CIN Cervical intraepithelial neoplasia
related CK Creatine kinase
ATTR Amyloid transthyretin CMI Cell-mediated immunity
AV Aortic valve CMV Cytomegalovirus
xviii Synopsis of Pathology
CO Cardiac output FFP Fresh frozen plasma

COX Cyclo-oxygenase FGF Fibroblast growth factor
CPE Cytopathic effect FGFR Fibroblast growth factor receptor
CPZ Chlorpromazine FIGLU Formiminoglutamate
CRP C-reactive protein FISH Fluorescent in situ hybridization
CT Clotting time FMTC Familial medullary thyroid
CT Collecting tubule carcinoma
CTL Cytotoxic lymphocytes GADD Growth arrest and
CV Cardiovascular deoxyribonucleic acid damage
CVD Cerebrovascular disease GB Gallbladder
CVP Central venous pressure GBM Glomerular basement membrane
DBP Diastolic blood pressure GCA Gastric carcinoma
DCIS Ductal carcinoma in situ GF Growth factor
DCT Distal convoluted tubule GFR Glomerular filtration rate
DDS Denys-Drash syndrome GH Growth hormone
DHC Dihydrocalciferol GN Glomerulonephritis
DHFA Dihydrofolate GP Glycoprotein
DHT Dihydrotestosterone GS Glomerular sclerosis
DM Diabetes mellitus GVHR Graft-versus-host reaction
DMT Divalent metal transporter Hb Hemoglobin
ds DNA Double-stranded
HBV, HCV,
deoxyribonucleic acid
HDV, HEV Hepatitis B, C, D, E viruses
DTH Delayed-type hereditary
sensory neuropathy HCC Hepatocellular carcinoma
DVT Deep vein thrombosis hCG Human chorionic gonadotropin
E Eosinophils H and E Hematoxylin and eosin
EBV Epstein-Barr virus HF Heart failure
EC Endothelial cells HGF Hepatocyte growth factor
EC Extracellular HHV 8 Human herpesvirus-8
ECF Extracellular fluid HL Hodgkin lymphoma
ECM Extracellular matrix HLA Human leukocyte antigen
ECP Eosinophilic cationic protein HNPCC Hereditary nonpolyposis colon
EF-2 Elongation factor 2 cancer
EGF Epidermal growth factor HP Hydrostatic pressure
EM Electron microscopy HPOA Hypertrophic pulmonary
EPC Endothelial precursor cells osteoarthropathy
ER Endoplasmic reticulum HPV Human papillomavirus
FAP Familial adenomatous polyposis HR Heart rate
Fc Fraction crystallizable of Ig HSN Hypersensitivity
FDP Fibrin degraded products HTN Hypertension
FFA Free fatty acid IBD Inflammatory bowel disease
Abbreviations xix
IC Immune complex LVH Left ventricular hypertrophy

IC Intracellular M Monocytes
ICA Internal carotid artery MAC Mycobacterium avium complex
ICAM Intercellular adhesion molecule MAP Mitogen-activated protein
ICF Intracellular fluid MBP Major basic protein
ICP Intracranial pressure MC 1R Melanocortin-1 receptor gene
IDDM Insulin dependent diabetes MCA Middle cerebral artery
mellitus MCH Mean corpuscular hemoglobin
IE Infective endocarditis MCHC Mean corpuscular hemoglobin
concentration
IF Intrinsic factor
M CSF Macrophage colony-stimulating
IFN Interferon
factor
Ig Immunoglobulin
MCV Mean corpuscular volume
IHD Ischemic heart disease MEN Multiple endocrine neoplasia
IL Interleukin MHC Major histocompatibility
IMN Infectious mononucleosis complex
iNOS Inducible nitric oxide synthase MI Myocardial infarction
gene MM Multiple myeloma
ITP Idiopathic thrombocytopenic MMP Matrix metalloproteinases
purpura MNG Multinodular goiter
IUGR Intrauterine growth restriction MOA Mechanism of action
IVFV Intravascular fluid volume MPO Myeloperoxidase
IV space Intravascular space MPS Mucopolysaccharides
KS Kaposi sarcoma MR Mitral regurgitation
L Lymphocytes MV Mitral valve
LA Left atrium N Neutrophils
LAD Leukocyte adhesion deficiency NA Noradrenaline
LCIS Lobular carcinoma in situ NAD Nicotinamide dinucleotide
LDL Low-density cholesterol NAP (N) acid phosphatase
LM Light microscopy NBTE Nonbacterial thrombotic
endocarditis
LN Lymph node
NF-kB Nuclear factor kappa B
LOX Lipoxygenase
NHL Non-Hodgkin lymphoma
LP Lipoprotein
NIDDM Non-insulin dependent diabetes
LPS Lipopolysaccharides mellitus
LSE Libman-Sacks endocarditis NK cells Natural killer cells
LT Leukotriene NO Nitric oxide
LV Left ventricle NRAMP Natural resistance associated
LVEDP Left ventricular end-diastolic macrophage protein
pressure NSCLC Nonsmall cell lung carcinoma
LVEDV Left ventricular end-diastolic NSE Nonspecific esterase
volume NTRK Neurotrophic tyrosine receptor
LVF Left ventricular failure kinase
xx Synopsis of Pathology
OCP Oral contraceptive pills RNP Ribonucleoproteins

OP Osmotic pressure ROS Reactive oxygen species
OPG Osteoprotegerin RT Respiratory tract
PAF Platelet-activating factor RT Reverse transcriptase
PAN Polyarteritis nodosa RVH Right ventricular hypertrophy
PAS Periodic acid-schiff SAA Serum amyloid A
PCA Posterior cerebral artery SABE Subacute bacterial endocarditis
PCT Proximal convoluted tubule SAH Subarachnoid hemorrhage
PDA Patent ductus arteriosus SCC Squamous cell carcinoma
PDGF Platelet-derived growth factor SCD Sudden cardiac death
PECAM Platelet-endothelial cell SER Smooth endoplasmic reticulum
adhesion molecule
SI Small intestine
PG Prostaglandin
SIL Squamous intraepithelial lesion
PIH Pregnancy-induced hypertension
SLE Systemic lupus erythematosus
PIN Prostatic intraepithelial neoplasia
SMC Smooth muscle cell
PKC Protein kinase-C
SOD Superoxide dismutase
PL Phospholipid
SV40 Simian virus-40
PMF Progressive massive fibrosis
TAG Triglycerides
PMN Polymorphonuclear cell
TGF Transforming growth factor
PND Paroxysmal nocturnal dyspnea
THFA Tetrahydrofolic acid
PPD Purified protein derivative
Th cells Helper T cells
PR Peripheral resistance
TIBC Total iron-binding capacity
PR-3 Proteinase 3
TNF Tumor necrosis factor
PSA Prostate-specific antigen
PSGN Post-streptococcal TPA Tissue plasminogen activator
glomerulonephritis TSH Thyroid-stimulating hormone
PT Prothrombin time TT Thromboplastin time
PTH Parathyroid hormone TTP Thrombotic thrombocytopenia
PVD Peripheral vascular disease TXA2 Thromboxane A2
RA Rheumatoid arthritis UC Ulcerative colitis
RANK Receptor activator of NF-kB URTI Upper respiratory tract infection
RBF Renal blood flow VCAM Vascular cell adhesion molecule
RB gene Retinoblastoma gene VEGF Vascular endothelial growth
RCC Renal cell carcinoma factor
RDS Respiratory distress syndrome VF Ventricular fibrillation
RER Rough endoplasmic reticulum VHL Von Hippel-Lindau
RET Tyrosine kinase receptor gene VIP Vasoactive intestinal peptide
RF Rheumatic fever VP Venous pressure
RF Rheumatoid factor vWF von Willebrand factor
RHD Rheumatic heart disease ZES Zollinger-Ellison syndrome
P
A General
R Pathology
T
1
1 Cell Injury, Cell Death
and Adaptations
Chapter
CELLULAR RESPONSE Hypertrophy

Cellular response to stress/stimuli is 1. Increase in size of the cells.
shown in Figure 1.1. 2. Resulting in increased size of the or-
gan.
3. Increased amount of structural pro-
teins and organelles.
4. Physiological:
a. Uterine enlargement during preg-
nancy (hypertrophy + hyperplasia).
b. Breast enlargement during lacta-
tion.
5. Pathological:
Fig. 1.1: Cellular response a. Cardiac hypertrophy in HTN and
AS.
CELLULAR ADAPTATIONS b. Cardiac hypertrophy is due to:
•• Mechanical—stress
1. Cellular adaptations are reversible
changes in size, number, phenotype, •• Trophic—a-adrenergic stimu-
metabolic activity or function of cells lation.
in response to changes in the envi-
ronment. Hyperplasia
2. Physiological:
1. Increase in number of cells.
a. Response to normal stimulation by
2. Resulting in hypertrophy of the organ.
hormones or endogenous chemical
mediators. 3. Physiological:
3. Pathological: a. Breast glands during puberty and
a. Response to environmental stress, pregnancy (hormonal).
which helps them to escape from b. Liver regrowth after a part is re-
injury. sected (compensatory).
4 Part 1 u General Pathology
4. Pathological: b. Stratified squamous epithelium of

a. Endometrial hyperplasia after esophagus replaced by columnar
menstruation (hormonal). epithelium in C/c gastric reflux.
b. Wound healing (due to growth
factors). Mesenchymal Metaplasia
1. Osseous metaplasia.
Atrophy a. Bone in fibrous tissues.
1. Decrease in cell size. •• In arterial wall
2. Loss of intracellular substance. •• Myositis ossificans.
3. Atrophied cells have diminished 2. Cartilaginous metaplasia:
function. a. Cartilage deposit in fracture heal-
4. Sometimes, accompanied by au- ing.
tophagy.
5. Decreased protein synthesis and in- SUBCELLULAR ALTERATIONS
creasse protein degradation.
1. Autophagy—self-eating by lysosom-
6. Causes may be:
al enzymes.
a. Decreased work load.
2. Hypertrophy of SER.
b. Denervation.
3. Mitochondrial alterations.
c. Decreased blood supply.
4. Cytoskeletal abnormalities—loss of
d. Malnutrition. integrity, cell mobility, phagocytosis,
e. Senility. etc.
f. Pressure.
g. Decreased functioning. NECROSIS
7. Seen in cancer cachexia.
1. Irreversible cell injury.
2. Resulting from degenerative actions
Metaplasia
of enzymes.
1. Reversible change of one adult cell 3. The enzymes are either from
type by another. self-lysosomes or from lysosomes of
2. Metaplasia is in order to withstand leukocytes.
certain conditions.
Morphology
Epithelial Metaplasia
1. Increased eosinophilic staining to the
1. Squamous metaplasia: cells.
a. Columnar epithelium of respira- 2. Cytoplasm become vacuolated and
tory tract is replaced by stratified appears moth-eaten.
squamous epithelium in cigarette 3. Large phospholipid masses called
smoking. myelin figures that are derived from
2. Intestinal metaplasia: damaged cell membranes.
Chapter 1 u Cell Injury, Cell Death and Adaptations 5
4. These myelin figures may get de- 4. Wet gangrene—dry gangrene + bac-
graded into fatty acids and become terial infection.
calcified to form calcium soaps.
5. Marked dilatation of mitochondria, Caseous Necrosis
damage of cell membrane, lysosomal
disruption, etc. can be seen. 1. Friable yellow white (cheesy like)
6. Nuclear changes: appearance.
a. Karyolysis—digestion of DNA. 2. Complete distortion of the architec-
b. Pyknosis—nuclear shrinkage. ture.
c. Karyorrhexis—fragmentation of 3. Within a well-defined border (granu-
pyknosed nuclei. loma). For example, TB.
Classification Fat Necrosis

Coagulative Necrosis 1. Focal areas of fat destruction.
1. Basic architecture is maintained for 2. Calcified to produce chalky white
some days. areas.
2. Denaturation of all proteins. 3. Necrotic fat cells with calcium depos-
3. Its own lysosomal enzymes are also its and surrounded by an inflamma-
denatured. tory border. For example, acute pan-
4. Later digested by leukocytes. creatitis.
5. For example, all infarcts except that
in brain. Fibrinoid Necrosis
1. Commonly seen in immune complex-
Liquefactive Necrosis mediated vasculitis.
1. The tissue get converted into liquid 2. These complexes along with fibrin
viscous mass. deposits form the fibrinoid necrosis.
2. The tissue is digested completely. For example, PAN.
3. Sometimes, the material will be
creamy yellow-pus. Mechanisms of Cell Injury
4. Certain bacterial and fungal infec-
tions. For example, brain infarcts. 1. Adenosine triphosphate ATP deple-
tion (Fig. 1.2).
2. Mitochondrial damage (Fig. 1.3).
Gangrenous Necrosis
3. Increased Ca2+ influx (Fig. 1.4).
1. Due to ischemia. 4. Defects in membrane permeability
2. Usually lower limb is affected. (Fig. 1.5).
3. Actually this is a type of coagulative 5. Accumulation of reactive O2 species
necrosis. (Fig. 1.6).
a. Antioxidant mechanisms: APOPTOSIS

Tightly regulated suicide program by ac-
tivating the degrading enzymes.
Causes
Physiologic Situations

6. Damage to DNA and proteins 1. Programed destruction of cells dur-
(Fig. 1.7). ing embryogenesis.
Fig. 1.2: ATP depletion Fig. 1.3: Mitochondrial damage
Fig. 1.4: Increased Ca2+ influx Fig. 1.5: Defects in membrane permeability
2. Involution of hormone-dependant 4. Atrophy due to duct obstruction.

tissues upon hormone deprivation. 5. Deprivation of GFs.
3. In proliferating cell populations.
4. After completion of their work. Morphology
5. Elimination of self-reactive T-cell 1.
Round or oval masses.
clones.
2.
Eosinophilic cytoplasm.
6. Cell death by cytotoxic T cells.
3.
Karyorrhexis of nucleus.
4.
Later, those cells get shrinked to form
Pathologic Situations cytoplasmic buds and fragmented
1. DNA damage. into apoptotic bodies.
5. The cell membrane will be usually
intact.
*FLIP—a caspase antagonist.
Mechanisms
1. Intrinsic/mitochondrial pathway is
shown in Figure 1.8.
2. Extrinsic/death receptor pathway is
3. Final common pathway and clearing
mechanism is shown in Figure 1.10.
Fig. 1.6: Accumulation of reactive O2 species
Fig. 1.8: Intrinsic/mitochondrial pathway
Fig. 1.7: Damage to DNA proteins
2. Accumulation of misfolded proteins

(results in ER stress).
3. Certain infections. Fig. 1.9: Extrinsic/death receptor pathway
•• Decreased fatty acid oxidation,

decreased mobilization of fat
from liver and increased mo-
bilization of fat from periphery
are the important pathways
leading to fatty liver.
Morphology
•• Bright yellow, soft and en-
larged
Fig. 1.10: Final common pathway and clearing •• Firstly small fat vacuoles
around nucleus
•• Then large fat globules and pe-
Intracellular ripheral nucleus
Accumulations •• At last ruptures and form fatty
Pathways cysts.
b. Fat in heart
1. Normal or increased production of a
normal substance, but decreased re- •• Prolonged moderate hypoxia
moval. For example, fatty change in causes anemia and focal fat
liver. droplets
2. Normal or abnormal substance accu- •• Appear as yellow bands within
mulates due to defect in packaging, brown colored muscle tissue—
transportation, etc. For example, α1- thrush breast appearance.
antitrypsin deficiency.
3. Decreased degrading enzymes. For Cholesterol Accumulation
example, glycogen storage diseases.
4. Ingestion of indigestible materials. For 1. Macrophages get filled with mem-
example, pneumoconiosis, silicosis, brane bound lipid vacuoles and
etc. forms foam cells. For example, in ath-
erosclerosis.
Fatty Change (Steatosis) 2. A cluster of foam cells beneath the
skin and tendons is called xanthoma.
1. Accumulation of TAGs in parenchy-
mal organs.
2. Mostly in liver.
Proteins
3. Also in heart, skeletal muscle, kidney, 1. Mallory bodies: Eosinophilic hyaline
etc. inclusions within the cytoplasm of
a. Fatty liver degenerating hepatocytes in alcohol-
•• Alcohol abuse and DM associ- ic liver disease—contains intermedi-
ated obesity are the most im- ate filaments.
portant causes 2. Russell bodies: Round eosinophilic
•• Hepatotoxins decrease fatty inclusions within the RER of plasma
acid oxidation cells and is composed of new Ig.
Glycogen 3. Normal levels of serum calcium. For

example, in atheromas (advanced
1. See glycogen storage diseases in the
cases), in aged or damaged heart
Chapter 7 (Genetic and Pediatric Dis-
eases). valves.
4. Seen as fine white granules felt as
Pigments gritty deposits.
5. These are microscopically seen as in-
1. Lipofuscin.
tracellular or extracellular basophilic
a. Wear and tear pigment.
deposits.
b. Insoluble brownish yellow granu-
6. Sometimes, tuberculous LNs may
lar material.
also get involved.
c. Intracellularly accumulates in the
heart, liver and brain. 7. Occurs as two processes:
d. Produced after lipid peroxidation a. Initiation—in mitochondria and in
of membranes. membrane-bound vesicles.
e. Causes brown atrophy of heart. b. Propagation—depends on other fac-
f. PAS stain is used and will give a tors too.
brown color. 8. The end product is calcium
2. Carbon. phosphate.
a. Mainly in the lung (anthracosis). 9. Extracellular initiation in membrane-
3. Melanin. bound vesicles.
a. In freckles and in dermal mac- 10. Intracellular initiation in mitochon-

rophages. dria.
b. Masson-Fontana stain is used.
11. Propagation depends on Ca2+ and

4. Iron. PO4– concentration, mineral inhibi-
a. Hemosiderosis and hemochroma- tors, collagen content, etc.
tosis.
5. Human granulocytic anaplasmosis.
Metastatic Calcification
a. In alkaptonuria.
b. Produces ochronosis. 1. Occur in normal tissues.
6. Bilirubin. 2. Derangement in the calcium metabo-
a. In jaundice. lism.
3. Causes are:
CALCIFICATION a. Increased parathyroid hormone
(1° or 2°).
Dystrophic Calcification b. Increased bone destruction.
1. Occurring in the dead and decaying c. Vitamin D intoxication and sarcoi-
tissues. dosis.
2. There is no derangements in calcium d. Renal failure—causes 2° hyper-
metabolism. parathyroidism.
4. Usually in vasculature of kidneys, e. Lifestyle.

lungs and gastric mucosa. f. Diseases.
5. White granules with gritty feeling.
6. Nephrocalcinosis is common finding. Mechanism
The mechanism of aging is shown in Fig-
AGING ure 1.11.
1. Aging is a result of progressive de-
cline in the proliferative capacity and
lifespan of cells and continuous expo-
sure to exogenous factors that cause
cellular and molecular damage.
2. The causes are:
a. DNA damage.
b. Decreased replication.
c. Decreased GFs.
d. Decreased regenerative capacity. Fig. 1.11: Mechanism of aging
2 Acute and Chronic
Inflammation
Chapter
ACUTE INFLAMMATION b. The mechanisms leading to in-

creased permeability are:
Cells involved are polymorphonuclear
•• Endothelial cell contraction and
cells (neutrophils).
retraction.
– Reversible, transient and im-
Stimuli mediate
1. Infections. – Forms intercellular gaps
2. Trauma. – Contraction is by histamine,
3. Tissue necrosis. bradykinin (15–30 min) and
4. Foreign bodies. leukotrienes
5. Immune reactions. – Retraction is by TNF and
interleukin 1 (IL-1) (4–24
Vascular Changes hours).
•• Endothelial injury.
1. Changes in vascular caliber and flow
are: – Immediate and sustained
a. Transient vasoconstriction. – Cell necrosis and detachment
b. Arteriolar dilatation: occurs
•• Increased flow and engorged – Occur in burns and infections
capillary bed – Develop within 2–12 hours
•• Causes erythema and warmth. and persists longer.
c. Increased oozing of fluid (transu- •• Leukocyte-mediated endothe-
date). lial injury.
d. Increased viscosity and stasis. – Due to the release of toxic
e. Margination. mediators from accumulated
2. Increased vascular permeability. leukocytes
a. Increased oozing out of pro- – Injury or detachment occurs.
tein-rich fluids along with cells •• Increased transcytosis of pro-
(exudate). teins.
– Via newly formed channels •• Selectins.

by VEGF. – E on ECs
•• Leakage from newly formed – P on ECs and platelets
vessels. – L on leukocytes.
– Mediated by VEGF. b. Adhesion and transmigration.
3. Responses of lymphatic vessels. •• Here, firm adhesion to endothe-
a. Increased ECF is drained by lym- lial surface is mediated by the
phatics and leads to ↑ lymphatic integrins on the leukocytes
flow. •• These intergrins attach onto the
b. Leukocytes and cell debris may ligands only after leukocyte ac-
also be found in the lymph. tivation by chemokines
c. Sometimes, lymphangitis and •• The main ligands are ICAM-1
lymphadenitis can be seen. and VCAM-1
d. Lymph nodes may become en- •• After adhesion, leukocytes mi-
larged due to hyperplasia. grate into interstitium by mov-
e. Lymphangitis is seen as inflamed ing in between the endothelial
lymphatic vessels as red streaks cells called transmigration or
near the skin wound. diapedesis
f. The enlarged lymph nodes may be •• The main adhesion molecule
that helps in the diapedesis
tender.
is CD31 (PECAM-1), which is
present on leukocytes, as well
Cellular Changes as ECs.
1. Leukocyte recruitment. c. Chemotaxis.
a. Margination and rolling. •• After extravasating from the
•• When blood flows from capil- blood, leukocytes migrate to-
laries to venule, the RBCs move wards sites of infection or inju-
faster and leukocytes pushed ry along a chemical gradient by
out of the central cellular col- a process called chemotaxis
umn •• The main chemotactic agents
•• As a result, leukocytes accu- are:
mulate at the periphery of the – Bacterial products
vessels and the process is called – Chemokines
margination – Components of complement
•• These leukocytes move on the system (C5a)
endothelial surface by sticking – Products of LOX pathway
transiently along the way and (LTB4).
is called rolling •• Mediated through G-protein
•• This weak transient adhesion is coupled receptors
mediated via selectins (present •• Leukocytes move by extending
on both leukocytes and ECs) pseudopods
Chapter 2 u Acute and Chronic Inflammation 13
•• Cells: b. These opsonins are produced in

– Neutrophils predominate host cells to coat the microbes (op-
first 6–24 hours sonization).
– Monocytes predominate next c. These coated microbes are then
24–48 hours. attached to leukocytes through
•• Reason: special receptors on leukocyte sur-
– Neutrophils are more preface.
dominant in blood 2. Engulfment.
– Respond more rapidly a. Engulfment is triggered after the
– Attach more firmly. attachment process.
2. Leukocyte activation. b. After attachment, pseudopods are
a. Stimuli: formed around the attached par-
•• Microbes ticle and eventually phagosome is
•• Products of necrosis formed.
•• Mediators. c. Then the phagosomal and lyso-
b. Result: somal membrane fuses to form
•• Phagocytosis of particles phagolysosome.
•• Production of substances that
destroy phagocytosed particles,
e.g. lysosomal enzymes, ROS,
nitrogen radicals, etc.
•• Production of mediators that
increases inflammation, e.g.
cytokines, arachidonic acid me-
tabolites.
Phagocytosis
Phagocytosis is the process of killing and
degradation of a foreign particle by leu-
kocytes (Fig. 2.1).
Steps
1. Recognition and attachment of par-
ticle on leukocyte.
a. Mediators are: Fig. 2.1: Phagocytosis
•• Opsonins on microbes or dead
cells 3. Killing and degradation.
•• IgG, C3 breakdown products a. By ROS and lysosome enzymes.
and collectins are major op- b. The ROS is produced by oxidative
sonins. burst in leukocyte.
CHEMICAL MEDIATORS
Phagocyte oxidase
O2 O2ֹ (superox- OF INFLAMMATION
ide)
1. Chemical mediators are special chemi-
cal molecules that mediate the process
Dismutation
O2ֹ + 2H+ H 2O 2 of acute and chronic inflammation.
2. The action of these mediators are
MPO tightly regulated.
H 2O 2 HOCl (Hypochlorous
radical)
c. These ROS and NO kill the bac- Classification
teria (MOA of ROS mentioned in The classification of chemical mediators
chapter-1). is illustrated in Figure 2.2.
d. These killed particles are degraded
by lysosomal acid hydrolases.
e. Other mediators involved in kill-
ing and degradation are lysozyme,
MBP, defensins.
Defects
1. Defect in leukocyte adhesion (LAD-1
and LAD-2).
2. Defect in mitochondrial activity as in
chronic granulomatous inflammation.
3. Defect in phagolysosome formation Fig. 2.2: Classification of mediators
as in Chediak-Higashi syndrome.
Cell-derived Mediators
Outcomes of Acute Inflammation Tissue macrophages, mast cells, endothe-
1. Resolution or healing. lial cells and recruited leukocytes are the
2. Progression to chronic inflammation. main cells capable of producing different
mediators.
3. Scarring or fibrosis.
Vasoactive Amines
Morphological Patterns of
Acute Inflammation 1. For example, histamine and serotonin.
2. These are the first mediators to be re-
1. Serous. leased in acute inflammatory reactions.
2. Fibrinous. 3. Mainly produced by mast cells and
3. Suppurative. platelets.
4. Actions are vasodilatation, ↑ vascular Reactive Oxygen Species

permeability.
1. Produced by (N) and macrophages
via NADPH oxidase pathway (Dis-
Arachidonic Acid Metabolites cussed in detail in Chapter-1).
1. Arachidonic acid metabolites are 2. Response for tissue injury by en-
PGs, LTs, TXs and lipoxins. dothelial damage, ↑ vascular perme-
2. Mainly produced by mast cells, leu- ability, protease activation and by
kocytes and platelets. direct injury.
3. Actions: 3. These ROS are inactivated by various
a. PGs—vasodilatation, pain, fever. antioxidant mechanisms.
b. LTs—vasoconstriction, ↑ vascular
permeability, chemotaxis, leuko- Nitric Oxide
cyte adhesion. 1. Produced by macrophages and ECs
c. TXs—vasoconstriction. by NO synthase enzyme.
2. Actions: Killing microbes and tumor
Platelet-activating Factor cells, smooth muscle relaxation, va-
sodilation, inhibit platelet activation
1. Produced from (N), (M), (B), ECs and
and reduce leukocyte recruitment.
platelets by the action of phospholi-
pase-A2.
2. PAF acts via ‘G’ protein-coupled Lysosomal Enzymes of Leukocytes
receptor. 1. Lysosomal enzymes are acid proteas-
3. Actions: Platelet aggregation and de- es and neutral proteases.
granulation, vasodilatation, ↑ vascu- 2. These are mainly concerned with de-
lar permeability, chemotaxis, leuko- struction of proteins like collagen,
cyte adhesion, etc. elastin, etc.
3. These enzymes are inhibited by anti-
Cytokines proteases.
1. Cytokines are polypeptide products
of many cell types. Neuropeptides
a. Tumor necrosis factor and inter- Mainly produced by nerve fibers (e.g.
leukin 1.
substance P).
•• Produced by macrophages,
mast cells, ECs, etc.
•• Actions: Endothelial activation, Plasma Protein-derived
systemic acute phase response, Mediators
fibroblast proliferation, etc.
b. Chemokines.
Complement System
•• Produced by macrophages and 1. Activated by various stimuli.
leukocytes 2. Activation occurs through classical
•• Actions: Chemotaxis, leukocyte pathway, alternate pathway and lec-
activation. tin pathway.
3. Actions: Opsonization, vasodilata- 3. Prolonged toxic exposure in silicosis

tion, ↑ vascular permeability, leu- and atherosclerosis.
kocyte activation, chemotaxis and
phagocytosis. Mediators
Kinin System 1. Macrophages (produce protease,
ROS, NO, AA metabolites, cytok-
1. Main molecules in this system are ines).
bradykinin and kallikrein.
2. Lymphocytes.
2. Bradykinin causes vasodilatation, ↑
vascular permeability, bronchial con- 3. Plasma cells.
striction. 4. Eosinophils.
3. Kallikrein causes chemotaxis and ac- 5. Mast cells.
tivation of Hageman factor.
Mechanism
Coagulation/Fibrinolytic System The mechanism of chronic inflammation
1. Factor Xa and thrombin are the main is shown in Figure 2.3.
mediators from coagulation system.
2. Actions: Increased vascular permea-
bility and recruitment of leukocytes.
3. From fibrinolytic system, the fibrin
degradation products ↑ vascular per-
meability and plasmin causes com-
plement activation.
CHRONIC INFLAMMATION
Inflammation of prolonged duration in
which active inflammation, tissue injury
and healing proceed simultaneously.
Characterized by:
1. Mononuclear infiltrate (macrophag-
es, plasma cells, etc).
2. Tissue destruction.
Fig. 2.3: Mechanism of chronic inflammation
3. Healing by angiogenesis and fibrosis.
Conditions giving rise to chronic in- GRANULOMATOUS
flammation:
INFLAMMATION
1. Persistent infections (delayed-type
hypersensitivity). 1. A pattern of chronic inflammation.
2. Immune-mediated diseases (hyper- 2. Characterized by aggregates of acti-
sensitivity disease) like RA, IBD and vated macrophages with epitheliod
asthma. appearance.
Conditions 2. TNF, IL-1 are the most important me-

diators.
1. Tuberculosis: Both caseating and
a. Fever.
non-caseating granuloma.
•• Increased in body temperature
2. Leprosy: Non-caseating granuloma. by 1°C–40°C
3. Syphilis: Non-caseating granuloma. •• The substances producing fever
4. Sarcoidosis: Non-caseating granulo- are pyrogens
ma. •• Pyrogens act by stimulating PG
5. Crohn disease: Non-caseating granu- synthesis in hypothalamus
loma. •• PGs stimulate production of
6. Cat-scratch disease: Rounded stellate neurotransmitter, which resets
granuloma. the temperature set point to
higher level
Morphology •• Pyrogens are:
– Exogenous (bacterial prod-
1. Central caseous necrosis (cheesy like), ucts—LPs)
sometimes, non-caseating as well.
– Endogenous (cytokines like
2. Central necrosis is surrounded by IL-1, TNF).
large multinucleated giant cells. 2. Elevated acute phase proteins.
3. Then aggregates of epithelioid mac- a. Most important are CRP, fibrino-
rophages, which are characteristic. gen and SAA.
4. This is surrounded by a rim of lym- b. Production of these proteins in liv-
phocytic infiltrate, which continually er is mainly induced by IL-6.
activate macrophages. 3. Leukocytosis.
5. In older lesions, a peripheral rim of a. Leukemoid reaction may occur.
fibroblast and connective tissue can b. More immature cells in blood.
be seen.
4. Others.
6. The healing of granuloma is accom- a. ↑ HR and BP.
panied by extensive fibrosis.
b. ↓ sweating, chills and rigor.
c. Anorexia, malaise, cachexia, sleep.
SYSTEMIC EFFECTS OF 5. Sepsis.
INFLAMMATION a. In severe infection.
1. The severe form is called acute phase b. Disseminated intravascular coagu-
reaction or systemic inflammatory relation DIC, hypoglycemia and hy-
sponse syndrome (SIRS). potension (septic shock).
3 Tissue Repair,
Regeneration,
Chapter Healing and Fibrosis
CELL CYCLE Paracrine Signaling

Phases of cell cycle are shown in the A substance acts on the cells, which are
Figure 3.1. in the vicinity of the secreting cell. For ex-
ample, recruiting cells for inflammation
wound healing.
SIGNALING MECHANISMS
OF GROWTH FACTOR Endocrine Signaling
RECEPTORS A regulatory substance like hormone is
released into blood and acts on distant
Autocrine Signaling target cells. For example, insulin secre-
A substance acts predominantly on the tion as a response to hyperglycemia.
tissue that secretes it. For example, T-cell
proliferation increased by cytokines. Receptors
Compensatory epithelial hyperplasia 1. With intrinsic enzyme activity (VEGF,
(liver regeneration). FGF, HGF, EGF).
Fig. 3.1: Cell cycle

Chapter 3 u Tissue Repair, Regeneration, Healing and Fibrosis 19
2. Without intrinsic enzyme activity

(IFN, GH, erythropoetin).
3.
G-protein coupled (epinephrine,
ADH, serotonin, histamine, gluca-
gon).
ANGIOGENESIS
1. Angiogenesis is the first process in
the sequence of repair by connective
tissue.
2. This repair occurs when the injury is
severe or chronic and results in pa-
renchymal damage, epithelia or stro- Figs 3.2A and B: Angiogenesis. A. By
ma, etc. mobilization of EPCs from BM; B. From pre-
3. Occur in four processes: existing vessels.
a. Angiogenesis. 3. Migration of angioblasts, EPCs to the
b. Fibroblast proliferation. injury site or migration of ECs and
c. Scar formation by ECM. their proliferation.
d. Remodeling (reorganization of fi- 4. Increased proliferation and remodel-
brous tissue). ing into capillary tubes.
4. Angiogenesis starts within 24 hours 5. Recruitment of periendothelial cells.
of injury. a. Pericytes for capillaries (small).
5. Occur by two processes: b. SMCs for larger vessels.
a. Vasculogenesis: Primitive vascular 6. New vessels will be leaky due to in-
network is assembled from angio- completely formed endothelial junc-
blasts. tions and accounts for edematous
b. Angiogenesis: Capillary sprouts granulation tissue.
from pre-existing vessels and for- 7. The leakage is also due to ↑ perme-
mation of new vessels. ability by VEGF.
6. The angioblasts are migrating from 8. Structural ECM participate through
BM to the site (Fig. 3.2A). integrin receptors.
7. Important process in healing and tu- 9. Non-structural ECM participate by
mor growth. ↑ cell migration, remodeling and in-
growth of vessels.
Steps
1. Vasodilatation by NO. Involvement of Growth Factors
2. Increased permeability of pre-exist- Most importent growth factors are VEGF
ing vessels by VEGF (Fig. 3.2B). and FGF-2.
Vascular Endothelial Growth Factors

1. VEGF—A, B, C and D.
2. VEGF receptors—VEGFR 1, 2 and 3.
3. Most important in angiogenesis is
VEGFR-2 (in ECs only).
4. The inducers for VEGFs are hypoxia,
PDGF, TGF-α, TGF-b.
Fig. 3.3: Phases of wound healing
5. VEGF induces proliferation and mo-
tility of ECs and thus ↑ permeability.
Steps
6. VEGFR-2—migration of angioblasts
from BM. 1. Epithelial proliferation—EGF, HGF.
2. Monocyte chemotaxis—PDGF, TGF-b,
Fibroblast Growth Factor FGF.
3. Fibroblast migration—PDGF, TGF-b,

1. FGF-2—increased proliferation of FGF.
ECM. 4. Fibroblast proliferation—PDGF, FGF.
a. ↑ migration of macrophages and 5. Angiogenesis—VEGF, FGF.
fibroblasts. 6. Collagen synthesis—PDGF, TGF-b.
b. ↑ migration of epithelial cells. 7. Collagenase secretion ↓ —PDGF,
TGF-b, FGF.
2. FGF-7—keratinocyte GF.
a. Cutaneous wound healing. Phases of Cutaneous
b. Also in oral cavity and gastrointes- Wound Healing
tinal tract (GIT) lesions.
It has mainly three phases, they are:
1. Inflammation.
Others
2. Granulation tissue formation.
1. Angioprotein 1 and 2—recruit pe- 3. Collagen (ECM) deposition and re-
riendothelial cells. modeling.
2. PDGF—recruit smooth-muscle cells
(SMCs). Healing by First Intention
3. TGF-b—increase in production of (Healing by 1° Union)
ECM. 1. Healing of a clean (Fig. 3.4A) unin-
fected, incised wound approximated
CUTANEOUS WOUND HEALING by sutures (surgically).
2. In incised wound, only less amount
Phases of wound healing is shown in the of cell death. So, epithelial regenera-
Figure 3.3. tion predominates over fibrosis.
3. Small scar and minimum wound con- a. Inflammatory reaction is much

traction. more intense.
4. Within 24 hours—fibrin clot forma- b. Granulation tissue is abundant.
tion and invaded by (N). c. Wound contracts by the action of
a. Basal cells proliferate and a thin myofibroblasts.
epithelium below scab (24–48 d. Accumulation of ECM and forma-
hour). tion of large scar.
5. Within/by 3 days—(N) replaced by 2. Wound contraction occurs by 6 weeks
macrophages. is the main additional feature from
a. Granulation tissue invades into first intention healing.
incision space.
b. Vertical collagen fibers along mar- Factors Affecting Wound
gins. Healing Process
6. By 5th day:
1. Infection, nutrition, steroids, diabe-
a. Increased proliferation and thick
tes, poor perfusion, foreign bodies,
epithelial layer.
etc.
b. Neovascularization and more
2. The type of tissue injured—efficient
granulation tissue.
healing with labile cells.
c. Bridging of space by collagen fi-
bers. 3. The location of injury—healing be-
comes prolonged in tissue spaces.
d. Epidermis attains normal thick-
ness and keratinization.
7. By 2nd week:
Fracture Healing
a. More collagen and fibroblasts pro- 1. Depends on whether the fracture is:
liferation. a. Traumatic or pathological.
b. Blanching with regression of ↑ vas- b. Complete or incomplete.
cular channels. c. Simple, comminuted or com-
8. By 1 month: pound.
a. Scar comprised of more collagen 2. Primary union.
and falls off. a. Occurs when the ends of fracture
b. Normal epithelium and strength ↑ are approximated.
progressively. b. Union takes place by medullary
callus formation.
Healing by Second Intention c. Patient can be made ambulatory
(Healing by 2° Union) early.
1. Occurs when cell (Fig. 3.4B) or tissue d. Extensive bone necrosis and slow
loss is more extensive such as in large healing.
wounds, abscess formation, ulcer- 3. Secondary union.
ation, etc. Here: i. More common.
ii. Takes place by procallus forma-

tion, osseous callus formation, re-
modeling.
a. Procallus formation.
•• Hematoma formation (Fig.
3.5A).
– Due to bleeding from the
torn blood vessels
– Loose meshwork is
formed by blood and fibrin
clot, which acts as a frame-
work for subsequent gran-
ulation tissue formation.
•• Local inflammation.
– By PMNs and macro-
phages Figs 3.5A to D: Steps of fracture healing. A.
Hematoma (inflammation); B. Soft callus; C.
– Macrophages clear away Hard callus; D. Remodeling.
the fibrin, red blood cells
(RBCs), inflammatory ex- •• Ingrowth of granulation tis-
udate and debris sue.
– Necrosed bone is lysed by – Begins with neovascular-
ization and mesenchymal
macrophages and osteo-
cell proliferation from pe-
clasts.
riosteum and endosteum
– A soft tissue callus ( Fig.
3.5B) is thus formed.
•• Procallus formation.
– This is the callus com-
posed of woven bone and
cartilage
– The cells of inner layer of
the periosteum have os-
teogenic potential and lay
down collagen as well as
osteoid matrix in the gran-
ulation tissue
– This osteoid undergoes
calcification to form wo-
ven bone callus (Fig. 3.5C)
– The woven bone cal-
Figs 3.4A and B: Wound healing. A. Healing by lus bridges the gap and
first intension; B. Healing by second intension gives rise to a spindle-
shaped or fusiform ap- Remodeling

pearance
1. By osteoblastic and osteoclastic activity.
– In poorly immobilized 2. External callus cleared away, cortex
fracture, the osteoblasts is formed in place of intermediate
form cartilage at the site. callus and BM develops in internal
Osseous callus formation.
b. callus (Fig. 3.5D).
•• The woven bone and carti-
lage get cleared off Complications
•• Newly formed blood vessels 1. Fibrous union.
and osteoblasts invade and 2. Delayed union.
lay down osteoid, which cal- 3. Malunion.
cified to form lamellar bone. 4. Non-union.
4 Hemodynamic
Disorders, Thrombosis
Chapter and Shock
EDEMA a. Increased salt intake with renal in-

sufficiency.
Increased amount of fluid in interstitial
b. Increased tubular reabsorption of
tissue spaces.
sodium.
•• Renal hypoperfusion and in-
Causes creased RAAS activity.
1. Increased hydrostatic pressure. 5. Inflammatory.
a. Impaired venous return. a. Acute inflammation.
•• CCF b. Chronic inflammation.
•• Constrictive pericarditis c. Angiogenesis.
•• Liver cirrhosis One and two are the main pathologies
•• Venous obstruction like DVT. leading to edema.
b. Arteriolar dilatation.
•• Heat Mechanism
•• Neurohormonal dysregulation.
The formation of edema-mechanism is
2. Decreased osmotic pressure. shown in Figure 4.1.
a. Protein losing glomerulopathies—
nephrotic syndrome.
Notes
b. Liver cirrhosis.
c. Protein losing gastroenteropathy. 1. Heart failure can lead to edema in
d. Malnutrition. two ways:
3. Lymphatic obstruction. a. By increasing CVP.
a. Inflammatory. b. By reducing cardiac output (CD).
b. Neoplastic. 2. Decreased in arterial blood volume
can leads to edema in three ways:
c. Postsurgical and postirradiation.
a. By renal hyperperfusion.
4. Sodium and water retention (causes
both increased hydrostatic [HP] and b. By ↑ production of renin.
decreased plasma OP). c. By ↑ production of ADH.
Chapter 4 u Hemodynamic Disorders, Thrombosis and Shock 25
Fig. 4.1: Mechanism of formation of edema
THROMBOSIS
Thrombosis is the process of thrombus
formation in our blood circulation.
Pathogenesis
Virchow’s triad (Fig. 4.2) explains the pri-
mary mechanism.
1. Endothelial injury (Fig. 4.3).
a. Most important factor.
b. Important role in heart and arteries. Fig. 4.2: Virchow’s triad
2. Abnormal blood flow (Fig. 4.4). •• Hypercholesterolemia
a. Conditions producing endothelial •• Radiation
dysfunction are: •• Cigarette smoking.
•• Polycythemia and sickle cell

anemia.
3. Hypercoagulability.
a. Contributes less frequently to
thrombosis.
b. Conditions producing hypercoag-
ulability are:
i. Primary.
•• Common.
– Mutation in factor V
gene
– Mutation in prothrombin
gene
Fig. 4.3: Endothelial injury producing – Mutation in methyl THFA
thrombosis gene
•• Rare.
– Antithrombin-III defi-
ciency
– Protein C and protein S
deficiency
Fig. 4.4: Abnormal blood flow producing •• Very rare.
thrombosis – Defects in fibrinolysis
b. Abnormal blood flow leads to ii. Secondary (acquired).
thrombus formation by: •• High risk.
•• Bringing platelets in contact – Prolonged immobiliza-
with endothelium tion
•• Preventing dilution of activated – MI, AF and DIC
clotting factors
– Tissue damage
•• Reducing the inflow of clotting
factor inhibitors – Cancer
•• Promoting endothelial cell acti- – Prosthetic heart valves
vation. – Heparin-induced throm-
c. Conditions producing abnormal bocytopenia (HIT) due
blood flow are: to use of unfractionated
•• The ulcerated atherosclerotic heparin
plaques – Antiphospholipid anti-
•• Aneurysms body syndrome
•• Mitral stenosis •• Low risk.
•• Atrial fibrillation resulting in – Cardiomyopathy
atrial dilatation – Nephrotic syndrome
– Hyperestrogenic state— 3. Dissolution—by fibrinolytic system.

pregnancy 4. Organization and recanalization—
– OCPs organized by inflammation and fi-
– Sickle cell anemia brosis.
– Smoking. a. Recanalized to establish some de-
gree of flow.
Morphology
EMBOLISM
1. Alternate pale platelets and fi-
brin rich layer and dark eryth- 1. Embolus is a detached intravascular
rocyte rich layer can be seen solid, liquid or gaseous mass that is
macroscopically and microscopi- carried by blood to a distant site from
cally. These are called lines of Zahn. its point of origin.
These lines represent antemortem 2. The main embolisms are:
thrombus and which are absent in a. Pulmonary thromboembolism.
postmortem clots. •• In pulmonary circulation
2. Mural thrombi—cardiac and aortic •• Originate from deep vein
thrombi. thrombi (mostly).
3. Arterial thrombi—frequently occlu- b. Systemic thromboembolism.
sive.
•• In systemic circulation
a. Grow in a retrograde manner.
•• Originate from arterial or mu-
b. Produced by platelets and coagu- ral thrombi.
lation activation.
c. Air embolism.
c. Also called white thrombi.
•• Originate from gaseous mass
4. Venous thrombi—invariably occlu-
•• Generally more than 100 mL
sive.
gas required. For example, de-
a. Grow in an anterograde manner. compression sickness charac-
b. Produced mainly by coagulation terized by bends and chocks.
cascade. d. Fat embolism (Fig. 4.5).
c. Also called red thrombi. •• Originate from fat globules
5. Vegetations—thrombi on heart
valves.
a. Seen in infective IE and NBTE.
Fate of Thrombus
1. Propagation—accumulate more plate-
lets and fibrin, eventually causing ves-
sel obstruction.
2. Embolization—get dislodged and
transported through blood vessels. Fig. 4.5: Effects of fat emboli
•• Occur usually after fracture of – Lanugo hair

long bones or soft tissue trau- – Fat from vernix caseosa
ma – Mucin from fetal respiratory
•• Enters the circulation by rup- and GI tract.
ture of vascular sinusoids in
marrow or rupture of venules INFARCTION
•• Characterized by:
1. An infarct is an area of ischemic ne-
– Pulmonary insufficiency crosis caused by occlusion of either
– Neurologic symptoms the arterial supply or venous drain-
– Anemia and thrombocytope- age in a particular tissue.
nia 2. Mainly results from thromboembolic
•• Typically the symptoms appear phenomenon in arteries.
1–3 days after injury 3. Other causes include vasospasm,
•• Symptoms start with tachyp- atheroma, external compression, ves-
nea, dyspnea, tachycardia and sel twisting, etc.
can progress to delirium and
coma
•• Demonstration of fat emboli re-
quires special methods like fro- 4. Red infarct occurs:
zen sections and fat stains. a. In venous occlusion.
e. Amniotic fluid embolism. b. In loose tissues like lung.
•• Uncommon complication of c. In tissues with dual circulation like
labor and immediate complica- lung and small intestine.
tion of postpartum period d. In tissues that were previously
•• Initial phase—severe dyspnea, congested.
cyanosis, hypotensive shock, e. When flow is previously re-estab-
seizures and coma lished to a site of previous arterial
•• Late phase—pulmonary ede- occlusion.
ma, alveolar damage and DIC 5. White infarct occurs:
•• DIC occurs due to release of a. In arterial occlusion.
thrombogenic substances from b. In solid organs like heart and kidney.
amniotic fluid 6. Septic infarct occurs.
•• Amniotic fluid enters into ma- a. After microbial seeding in an in-
ternal circulation via a tear in farct or can occur after emboliza-
the placental membranes or tion of bacterial vegetations.
rupture of uterine veins
•• Pulmonary microcirculation Morphology
contains: 1. Wedge shaped with occluded vessel
– Squamous cells from fetal at the apex and periphery of organ
skin forming the base.
2. Histologically: b. Caused by hemorrhage and fluid

a. Peripheral inflammatory response. loss like vomiting, diarrhea, burns
b. Central ischemic coagulative ne- or trauma.
crosis except in brain. 3. Neurogenic shock.
c. Liquifactive necrosis in brain in- a. Results from loss of vascular tone
farct. and pooling of blood.
b. Caused by anesthetic accident or
spinal cord injury.
Factors Influencing Infarction
4. Septic shock.
1. Nature of vascular supply (presence a. Results mainly from peripheral va-
of alternate supply). sodilatation and pooling of blood.
2. Rate of development of occlusion. b. Caused by Gram-negative infec-
3. Vulnerability to hypoxia (neurons are tions (endotoxic shock), Gram-
most susceptible). positive infections, fungal infec-
4. Oxygen content of the blood. tions, super antigens, etc.
5. Anaphylactic shock
a. Results from systemic va-
SHOCK sodilatation and ↑ vascular
1. Shock is the final common pathway permeability.
for a number of potentially lethal b. Caused by IgE hypersensitivity.
events charecterized by systemic
hypoperfusion caused either by re- Stages of Shock
duced cardiac output or by reduced
effective circulatory blood volume. 1. Initial non-progressive stage.
2. The end results are hypotension, im- a. Reflex neurohormonal pathways
paired tissue perfusion and cellular work and maintain CO and BP and
hypoxia. thus perfusion of vital organs.
3. Persistent shock can produce irre- b. The neurohormonal pathways ac-
versible tissue injury and death of the tivated are baroreceptor reflexes,
patient. RAAS, ADH release, sympathetic
stimulation and release of cate-
cholamines.
Types of Shock
c. Produces cutaneous vasoconstric-
1. Cardiogenic shock. tion.
a. Results from failure of cardiac d. Coronary and cerebral vessels are
pump. spared.
b. Caused by MI, ventricular arrhyth- 2. Progressive stage.
mias, cardiac tamponade, pulmo- a. If the underlying causes are not
nary embolism, etc. corrected, the shock persists to
2. Hypovolemic shock. cause tissue hypoperfusion.
a. Results from loss of blood or plas- b. Anaerobic glycolysis occur more
ma volume. and produce lactic acidosis.
c. This acidic pH blunts the vasomo- b. Activation of endothelial cell.

tor response, which causes periph- c. Activation of complement.
eral pooling of blood.
d. Production of TNF, IL1, IL6 and
d. Later leads to reduced CO, en-
dothelial injury and DIC. IL8.
e. Vital organs are affected and begin e. No secondary mediators.
to fail. f. Local inflammation.
3. Irreversible stage. 2. The LPS in moderate amounts.
a. Widespread cell injury leads to a. Production of TNF, IL1, IL6, IL8,
lysosomal enzyme leakage and ag-
gravation of shock. NO and PAF.
b. The CO further worsens. b. Fever.
c. Ischemic bowel allows intestinal c. Release of acute phase proteins
flora to enter into circulation and from liver.
leads to endotoxic shock. d. Release of more WBCs from BM.
d. Complete renal failure due to acute
e. Systemic effects.
tubular necrosis.
3. The LPS in high quantities.
e. Eventually leads to death.
a. Increased TNF, IL1, IL6, IL8, NO
Pathogenesis of Septic Shock and PAF.
b. Low CO.
The production of mediators in septic
shock is shown in Figure 4.6. c. Low PR.
d. Thrombosis and DIC.
Production of Mediators e. ARDS.
1. The LPS in low quantities. f. Multisystem failure (liver, kidney,
a. Activation of macrophages, (M) CNS and others).
and (N). g. Septic shock.
Fig. 4.6: Production of mediators in septic shock

Morphology 4. Adrenals—cortical cell lipid deple-

tion, cells become more active to pro-
1. Fibrin thrombi can be identified at duce steroids.
any site. 5. GIT—focal mucosal hemorrhage and
2. More evident changes occur in brain, necrosis.
heart, kidney, adrenals and GIT. 6. Lung—diffuse alveolar damage
3. Kidney—acute tubular necrosis. (shock lung) in septic shock.
5 Diseases of the
Immune System
Chapter
HYPERSENSITIVITY c. Formation of immune complexes

and inflammation (PSGN).
Increased immune responses against an
3. Reaction against environmental Ag.
antigen, which can cause tissue injury
a. Shown by only a minor population.
and diseases.
b. Increase immune response against
common Ag (pollen, dust).
Causes
1. Autoimmunity—if self-tolerance fails. Type I
2. Reaction against microbes. 1. Type I is immediate hypersensitivity
a. T cell-mediated injury of the af- (Fig. 5.1).
fected cell (TB). 2. Occurs after the interaction of Ag with
b. Ab to the microbe cross-reacts with IgE, which is bound to the mast cell
host Ag (RHD). surface in a previously sensitized host.
Fig. 5.1: Immediate hypersensitivity

Chapter 5 u Diseases of the Immune System 33
Fig. 5.2: Type I hypersensitivity mediators
Clinical and Pathologic

Manifestations
1. Systemic.
a. By systemic administration of Ag Mediators
(bee sting) or drugs (penicillin).
The mediators involved in type I hyper-
b. This is called systemic anaphylaxis.
sensitivity is shown in Figure 5.2.
c. Urticaria and skin erythema; then
respiratory difficulty and larynge- Type II
al edema; then vasodilatation and
1. Type II is antibody-mediated hyper-
hypotension → CV collapse and sensitivity.
death (anaphylactic shock). 2. The Ag may be endogenous or exog-
2. Localized. enous.
a. By Ag exposure through skin con-
tact, ingestion or inhalation. For Opsonization and
example, skin and food allergy, Phagocytosis (Fig. 5.3)
hay fever, asthma, etc. 1. Autoimmune hemolytic anemia.
b. If the susceptibility is genetically 2. Autoimmune thrombocytopenic pur-
controlled → atopy. pura.
2. The increased deposition act as patho-

genic mechanism.
3. The immune complexes may formed
in circulation and deposit in blood
Fig. 5.3: Opsonization and phagocytosis vessels or in specific organs, where
the Ag is implanted.
Compliment and FC Receptor-mediated
Systemic (Serum Sickness—Acute)
Inflammation (Fig. 5.4)
1. First described in persons when large
amounts of serum (foreign) is intro-
duced for passive immunization.
2. Within 5 days → Ab formation.
3. Within 10 days → inflammatory fea-
tures.
Fig. 5.4: Compliment-mediated inflammation
4. Very large complexes (Ab excess) →
1. Vasculitis by ANCA. easily phagocytosed.
2. Goodpasture syndrome. 5. Small complexes (Ag excess) → harm-
ful (remain in circulation).
Antibody-mediated Cellular 6. Blood vessels, kidney, joints are
Dysfunction mostly affected (Fig. 5.7).
7. Mainly IgG and IgM are involve.
Fig. 5.5: Antibody-mediated cellular dysfunction
Morphology
1. Graves disease—Ab-mediated stim-
ulation of thyroid receptors and in- 1. A/c necrotizing vasculitis.
creased hormone release. 2. Microthrombi and fibrinoid necrosis.
2. Myasthenia gravis—Ab to Ach re- 3. Other example is SLE (C/c).
ceptor inhibits binding of Ach to re-
ceptor and cause paralysis. The An- Local (Arthus Reaction—Acute)
tibody-mediated cellular dysfunction
is shown in Figure 5.5. 1. Cutaneous reaction.
2. By injecting Ag to a previously sensi-
Type III tized animal.
3. Immune complexes are formed and
1. Immune complex mediated (Fig. 5.6). deposited at the site of injection.
4. Results in inflammation and tissue
damage.
5. Other examples are PSGN, PAN, re-
Fig. 5.6: Serum sickness active arthritis.
Fig. 5.7: Mechanism of serum sickness
Type IV a. Increased vasodilatation (↑ NO,

PGI2).
T cell-mediated hypersensitivity.
b. Increased expression of selectins
and integrins.
Delayed-type Hypersensitivity c. Secretion of chemokines like IL-8.
CD4 T cell-mediated hypersensitivity is 4. Prolonged DTH leads to granuloma
shown in Figure 5.8. formation.
Tuberculin test Contact dermatitis type
1. ID injection of PPD in previously sen- a. Exposure of a sensitized host in-
sitized host. duces inflammation mainly as ve-
2. Local area of erythema and indura- sicular dermatitis.
tion reach peak in 24–72 hours (de- b. Mechanism similar to that of tu-
layed). berculin type.
3. TNF and lymphotoxin are cytokines, c. CD4+ T cell-mediated.
which causes: d. Contact to metals, radiations, etc.
Fig. 5.8: Delayed-tuberculin type hypersensitivity

T cell-mediated Cytotoxicity Mechanisms

1. CD8+ T cells are causing this type of 1. T cell-mediated rejection.
cytotoxicity. a. Cytotoxic T cells → killing of graft
2. These cytotoxic cells kill the antigen- cells.
bearing target cells. b. CD4+ T cells → DTH → dam-
3. Recognition is through class I MHC age and destruction of graft due
to ischemia (mediated by mac-
receptors.
rophages and cytokines).
4. Typical role in viral infections and
2. Ab-mediated rejection (Fig. 5.9).
some tumors.
5. Killing is by perforin and granzyme
Types of Rejection
system.
6. Perforin binds to cell membrane and Hyperacute Rejection
allows the granzyme (protease) to en- 1. In those conditions, where preformed
ter the cell. antidonor antibodies are present in
the host. For example, prior blood
GRAFT REJECTION transfusions (Ab to platelets and
WBCs) previous organ rejection.
Immune Recognition of Allograft
2. Immediate rejection (within minute
1. Rejection is a response to MHC to hour).
molecules. 3. Morphology.
2. No two individuals (except identical a. Cyanotic, mottled and flaccid.
twins) have same MHC.
b. A/c arteritis, thrombosis.
a. Direct recognition.
c. Fibrinoid necrosis.
•• The host T cells directly recog-
nize the foreign MHC d. Narrowing or complete occlusion
of vessel lumen.
•• Through MHC class II → DTH
(CD4+ T cells)
•• Through MHC class I → cyto- Acute Rejection
toxicity (CD8+ T cells) 1. Within days to weeks.
•• Violation of MHC restriction 2. In a non-immunosuppressed host.
rule.
Types of acute rejection
b. Indirect recognition.
1. Acute cellular rejection.
•• The host T cells identify the
a. First months.
foreign Ag and MHC after pro-
cessing and presentation by b. Extensive CD4 and CD8 T cell in-
host’s APCs filtration.
•• According to MHC restriction c. Edema and hemorrhage.
rule d. Necrosis and arthritis.
•• Mainly DTH and Ab to foreign e. Not much response to immuno-
Ag are involved in rejection. suppressive therapy.
3. Also with some solid organs rich in

lymphoid cells (e.g. liver) with irradi-
ated blood.
4. Here the host cannot reject the trans-
plant.
5. Graft will induce DTH and CTL re-
sponses against host.
6. A/c → epithelial cell necrosis mainly
in liver, gut and skin.
7. C/c → mainly skin, like in systemic
Fig. 5.9: Antibody-mediated graft rejection
sclerosis.
2. Acute humoral rejection. 8. GVHR decreased by HLA matching
a. Rejection vasculitis. and T cell suppression → increased
b. Antidonor Ab may present. chance of failure.
c. Necrotizing vasculitis and cell ne-
crosis. IMMUNOLOGICAL TOLERANCE
d. N, deposition of complement, Ab
1. Unresponsiveness to an antigen that
and fibrin.
is induced by exposure of specific
e. Vasculitis and ischemic necrosis lymphocytes to that Ag.
and atrophy.
2. Self-tolerance means lack of immune
f. Mimics arteriosclerotic thickening. responsiveness to one’s own tissue
antigens.
Chronic Rejection 3. There will be specific receptors on
1. Months to years. lymphocytes for self-antigens for rec-
2. Progressive deterioration. ognition.
3. Vascular changes, fibrosis, atrophy,
etc. Central Tolerance Mechanism
4. (L) infiltrate.
5. SMC proliferation of arteries and ar- In Thymus
terioles. The central tolerance mechanism in thy-
6. Increased ECM synthesis. mus is given in Figure 5.10.
7. Not respond to standard immuno-
suppressive therapy.
Graft-versus-host Reaction
1. Occurs when immunologically com-
petent T cells are transplanted into an
immunocompromised host.
2. Occurs usually with BM transplanta- Fig. 5.10: Central tolerance mechanism in
tion. thymus
Fig. 5.11: Central tolerance mechanism in bone marrow
In Bone Marrow SYSTEMIC LUPUS

The central tolerance mechanism in bone ERYTHEMATOSUS
marrow is given in Figure 5.11. 1. Multisystem autoimmune system
disease.
Peripheral Tolerance Mechanism 2. Remitting and relapsing disease. May
The peripheral tolerance mechanism is be A/c or insidious.
shown in Figure 5.12. 3. Has a female preponderance (20–40).
MECHANISMS OF Etiopathogenesis
AUTOIMMUNITY Defect in maintenance of self-tolerance.
Genetic Susceptibility
Immunologic Variables
The active immunity by genetic suscepti-
bility is given in Figure 5.13. 1. Increased generation of nuclear Ag
by apoptosis.
Infections and Tissue Injury 2. Decreased clearance of nuclear Ag
from apoptotic cells.
The autoimmunity by infections and tis-
3. Failure of self-tolerance.
sue injury is given in Figure 5.14.
4. C/c B cell hyperactivity.
1. A single autoimmune can leads to
further attack by epitope spreading.
2. Epitopes (specific by determining Genetic Variables
sites) are present on every self-Ag. 1. Increased incidence rate in monozy-
3. This epitope will stimulate self-reac- gotic twins.
tive clones.
2. Familial inheritance.
4. These self-reactive clones spread im-
mune responses to other epitopes, 3. Association with HLA class II genes.
which are not recognized initially. 4. Association with complement defect.
Fig. 5.12: Peripheral tolerance mechanism
2. Anticytoplasmic Ab.
3. Antiblood cell Ab.
a. To red cells.
b. To platelets.
c. To lymphocytes.
Fig. 5.13: Autoimmunity by genetic susceptibility
4. Antiphospholipid Ab.
Non-genetic variables Morphology

1. Ultraviolet (UV) exposure. 1. Blood vessels.
2. Drugs like hydralazine and procain- a. A/c necrotizing vasculitis.
amide. b. Fibrinoid necrosis with lumen
3. Sex hormones. narrowing.
c. Deposits of immune complex (IC),
Autoantibodies in Systemic C, fibrin and leukocytes.
Lupus Erythematosus 2. Skin.
a. Erythematous maculopapular le-
1. Antinuclear Ab.
sions.
a. To DNA. b. Malar rashes (butterfly pattern)
b. To histones. and discoid rashes.
c. To non-histone proteins attached c. Photosensitivity.
to RNA (RNPs). d. Degeneration of basal layer with
d. To nucleolar Ag. infiltrate.
Fig. 5.14: Autoimmunity by infections and tissue injury
e. IC deposition at the dermo-epider- b. Neuropsychiatric illness.

mal junction. c. Due to ischemia and cerebral
3. Joints. microinfarcts.
a. Swelling with infiltrate. 5. Kidney.
b. Arthritis, even destruction of ar- a. Most important.
ticular cartilage (rare). b. Mainly glomerular pathology.
4. Central nervous system (CNS). c. Interstitial and tubal lesions also
a. Focal neurologic deficits. seen (Fig. 5.15).
Fig. 5.15: Pathogenesis of systemic lupus erythematosus

Grades – Non-bacterial verrucous en-

docarditis
Grade I
– Increased CAD due to ath-
a. Almost normal by LM and EM erosclerosis.
(5%).
•• Spleen
Grade II
– Enlarged and capsular fi-
a. Mesangial lupus GN (10%–25%). brous thickening
b. Mild symptoms with IC in mesan- – Follicular hyperplasia with
gium. plasma cells
Grade III – Arteries—onion like lesions.
a. Focal proliferative GN (20%–35%). •• Serosa
b. Proliferation of endothelial and – Pleuritis, pericarditis
mesangial cells.
– Fibrinous exudates and fi-
c. (N) and fibrinoid deposits and brosis.
microthrombi.
•• Liver
d. Mild microscopic hematuria and
– Enlarged.
proteinuria.
Grade IV
Clinical Course
a. Diffuse proliferative GN (35%–
60%). 1. Butterfly rashes on face.
b. Most serious in SLE and most 2. Fever, arthritis, pleuritic chest pain.
common. 3. Neuropsychiatric illness.
c. Diffuse proliferation of cells. 4. Hematuria, proteinuria.
d. Some crescents in Bowman’s cap-
sule. Diagnosis
e. Capillary wall thickening → wire-
loop appearance. The code is ‘SOAP BRAIN MD’.
f. Proteinuria, HTN and renal insuf- 1. Any four features out of 11.
ficiency. a. Serositis.
Grade V b. Oral ulcers.
a. Membranous GN (10%–15%). c. Arthritis.
b. Capillary wall thickening. d. Photosensitivity.
c. Severe proteinuria and nephrotic e. Blood related disorder.
syndrome.
f. Renal disorder.
•• Heart
g. Antinuclear Ab.
– Pericarditis
h. Immunologic disorder.
– Myocarditis with non-specif-
ic infiltrate i. Neurologic disorders.
– Libman-Sacks endocarditis j. Malar rash.
(valvular lesions) k. Discoid rash.
2. Specific Ab in SLE diagnosis. b. Inflammatory infiltrate—mainly

a. Ab to dsDNA. (L), plasma cells, macrophages.
b. Ab to Smith Ag. c. Increased vascularity due to an-
giogenesis.
Treatment d. (N) and fibrin aggregates in syn-
ovial membrane.
The systemic lupus erythematosus is
e. Bone erosion.
treated with corticosteroids.
5. Appearance of pannus formed by:
a. Synovial cells.
RHEUMATOID ARTHRITIS
b. Inflammatory cells.
1. Systemic C/c inflammatory disease.
c. Granulation tissue.
2. Principally affecting joints.
d. Fibrous connective tissue.
3. Non-suppurative progressive and
proliferative synovitis that frequent- 6. C/c → thinning of synovial mem-
ly results in destruction of articular brane.
cartilage and underlying bone and 7. Continuous pannus deposition leads
ultimately disabling arthritis. to permanent ankylosis by fibrosis
4. Common in women than in men. and calcification.
8. Destruction of articular cartilage.
Clinical Course 9. Destruction of tendons and ligaments
→ swan neck deformity of fingers.
1. Fever, malaise, weakness.
10. Rheumatoid S/c nodules.
2. Joint-ache, stiffness and swelling.
a. Extensor aspect of fore arm mainly
3. Raynaud phenomenon and C/c leg
(also in many organs).
ulcers (vascular).
b. Central fibrinoid necrosis.
Pathogenesis c. Macrophage palisading.
d. Rimmed by granulation tissue.
Pathogenesis of rheumatoid arthritis is
11. Heart, lung, bloodvessels, skin and
muscles also affected.
Morphology
Diagnosis
1. Systemic arthritis—mainly affecting
1. Characteristic radiographic features.
small joints.
2. Sterile, turbid and thin synovial fluid.
2. Mainly proximal interphalangeal and
metacarpophalangeal joints. 3. RA factor.
3. Axial skeletal involvements—mainly
cervical vertebrae. AMYLODOSIS
4. C/c synovitis. Amylodosis is a condition of systemic in-
a. Synovial cell hyperplasia and pro- flammation caused by abnormal extracel-
liferation. lular deposition of fibrillar proteins.
Fig. 5.16: Pathogenesis of rheumatoid arthritis
Classification 3. Dialysis induced.

a. C/c renal failure (Aβ2m protein in-
Systemic Amyloidosis creases).
1. Primary amyloidosis.
a. Associated with multiple myeloma Hereditary Amyloidosis
and other conditions of monoclo- 1. Familial Mediterranean fever.
nal B cell proliferation. a. AA protein increases.
b. AL protein accumulated. 2. Familial amyloidotic neuropathies.
2. Secondary amyloidosis. a. ATTR proteins increases.
a. C/c inflammatory conditions (AA 3. Senile amyloidosis.
protein increases). a. ATTR protein ↑.
Localized Amyloidosis 1. Amyloid associated protein and AL

proteins are accumulated due to lim-
1. Senile cerebral. ited proteolysis.
a. Assosiated with Aizheimer’s. 2. Aβ2M is deposited due to limited
b. Aβ protein increases. excretion.
2. Endocrine.
Morphology
a. Medullary CA thyroid associat-
ed—a cal protein ↑ (calcitonin). 1. Many organs are affected (grey
pale waxy).
b. Type II DM–AIAPP ↑ (islet amy-
2. Deposition of amyloid proteins (ex-
loid peptide—IAP). tracellular).
3. Atrial amyloidosis. 3. Stains.
a. AANF ↑ (ANF precursor). • Brown with I2 and sulfuric acid
(H2SO4)
• Red green with congo red.
Pathogenesis 4. Kidney.
The pathogenesis of amyloidosis is shown a. Most common and most serious.
in Figure 5.17. b. Enlarged, pale green and firm.
Fig. 5.17: Pathogenesis of amyloidosis

c. Amyloid deposits mainly in glom- Limited Scleroderma

eruli.
1. Limited skin involvement.
d. Also in interstitium, blood vessels
and tubules. 2. Visceral involvement occurs only
5. Spleen. late.
a. Moderate or marked enlargement. 3. Also called CREST syndrome.
b. Sago spleen—tapioca-like granules a. Calcinosis.
(deposit in follicles). b. Raynaud phenomenon.
c. Lardaceous spleen—sheet-like de- c. Esophageal dysmotility.
posits (in sinuses and pulp).
d. Sclerodactyly.
6. Liver.
e. Telangiectasia.
a. Massive hepatomegaly.
b. First deposit in space of Disse and
then progress. Etiopathogenesis
7. Heart. 1. B-cell activation also occurs and so
a. Subendocardial elevations, myo- two Abs are specific for SS diagnosis.
cardial deposits and atrophy. a. Ab to DNA topoisomerase-I.
b. Ab to centromere.
Clinical Course 2. B-cell activation → not much role in
1. Multiorgan damage. pathogenesis (Fig. 5.18).
2. Macroglossia (deposition on tongue).
3. Carpal tunnel syndrome (deposition Morphology
on carpal ligament). 1. Skin (100%).
4. Poor prognosis.
a. Sclerotic atrophy (begins from fin-
gers).
SCLERODERMA b. Edema and infiltrate containing
1. Better described as systemic sclerosis. CD4 + T cells.
2. Excessive fibrosis throughout the c. Small vessels show wall thickening.
body. d. Increased collagen and fibrosis.
3. Mainly involves skin. e. Later calcification, ulceration and
4. Lungs, kidneys, heart, GIT and skel- atrophy.
etal muscles also affected.
Types of Scleroderma
Diffuse Scleroderma
1. Initial skin involvement (wide
spread).
2. Rapid progression with early visceral
involvement. Fig. 5.18: Pathogenesis of scleroderma
Fig. 5.19: Entry of the virus into the cell
Fig. 5.20: Viral replication in the host cell
2. Gastrointestinal tract. 5. Kidneys (60%).

a. In 90% patients. a. Fibrinoid necrosis, thrombosis and
b. At any part (more severe in esoph- infarction.
agus). b. Thickening of blood vessels.
c. Mucosa is thinned and ulcerated. c. Malignant HTN may occur.
d. Collagen deposition and fibrosis 6. Heart.
of lamina propria, submucosa and
muscularis. a. Myocardial fibrosis.
3. Musculoskeletal. b. Ischemia (cardiac Raynaud).
a. Synovial hyperplasia and inflam-
mation (10%). Clinical Course
b. Later fibrosis and joint destruction. 1. More in women than in men.
c. Polymyositis may develop. 2. Overlapped with RA, SLE, etc.
4. Lungs. 3. Raynaud phenomenon.
a. Pulmonary fibrosis and pulmo- 4. CREST syndrome.
nary HTN. 5. Features of multiorgan damage.
Fig. 5.21: Progression of disease
PATHOGENESIS OF HUMAN Progression of infection

IMMUNODEFICIENCY VIRUS The progression of infection in the body
is given in Figure 5.21.
1. Involves five steps:
a. Entry of virus into cells.
Depletion of T cells
b. Viral replication.
c. Progression of infection. 1. Infected CD4+ T cells.
• Death by CPE of virus.
d. Depletion of T cells.
2. Uninfected CD4+ T cells.
e. Alteration in other cell types.
• Activation and activation-induced
2. HIV principally affect CD4+ T cells, cell death.
macrophages and dendritic cells. 3. Expression of HIV peptides on infect-
ed CD4+ T cells and killing by virus
Entry of Virus into Cell (Fig. 5.19) specific cytotoxic T cells.
Requires CD4 and chemokine receptors.

Other Alterations
1. Decreased T cell functioning.
Viral replication
2. Defective monocyte or macrophage
The viral replication in the host cell is and dendritic cell functioning.
given in Figure 5.20. 3. Polyclonal B cell proliferation.
6 Neoplasia
Chapter
NEOPLASM •• Gliomas of CNS

Neoplasm is defined as an abnormal mass •• Basal cell carcinoma of skin.
of tissue, the growth of which exceeds and
is uncoordinated with that of the normal Routes of Metastasis
tissues and persists in the same excessive
manner after the cessation of the stimuli, Lymphatic Spread
which evoked the change. 1. In general, carcinomas metastasize
by lymphatic route, while sarcomas
Features of Tumors favor hematogenous routes.
2. Two forms of involvement of lym-
Features of tumors, both benign and ma- phatics are given below.
lignat are listed in Table 6.1. a. Lymphatic permeation: The walls
of lymphatics are invaded and
ANAPLASIA form a continuous growth in the
lymphatic channels.
1. Anaplasia is lack of differentiation. b. Lymphatic emboli: The detached
2. This is characteristic of many malig- tumor emboli get carried along the
nant tumors. lymph to lymph node. The tumor
3. The features of anaplasia are: cells start growing in lymph node
Microscopic features of malignant tu- and later lymph node may replaced
mors is given in Table 6.1. by enlarged metastatic tumor.
3. Generally regional lymph nodes
draining the tumor site are invari-
METASTASIS ably involved producing regional
1. Metastasis is the spread of malignant nodal metastasis. For example, CA
tumor by invasion in such a way that breast to axillary nodes. CA thyroid
discontinuous secondary tumor mass- to lateral cervical nodes.
es are formed at the site of lodgement. 4. Sometimes, metastases do not develop
2. This is a major characteristic feature first in the regional lymph nodes, but
of most of malignant tumors with a affect distant nodes due to venous-
few exceptions like: lymphatic anastomoses or due to
Chapter 6 u Neoplasia 49
Table 6.1: Difference between benign and malignant tumor
Feature Benign Malignant

Gross features
Boundaries Well-circumscribed or Irregular and pseudo-
encapsulated encapsulated
Surrounding tissue Often compressed Usually invaded
Size Usually small Often larger
Secondary changes Less often More often
Microscopy
Pattern Resembles tissue of origin closely Resembles tissue of origin
poorly
Basal polarity Retained Often lost
Pleomorphism Usually absent Usually present
Nucleo-cytoplasmic ratio Normal Increased
Anisonucleosis Absent Generally present
Hyperchromatism Absent Often present
Mitoses May present, but normal Increased and abnormal
Tumor giant cells May present, but without nuclear Present with nuclear atypia
atypia
Chromosomal abnormalities Infrequent Always present
Function Maintained Retained, lost or absent
Growth rate Usually slow Usually rapid
Local invasion No invasion Invades surrounding
Metastasis Absent Frequently present
Prognosis Local complications Local and metastatic
complications
obliteration of lymphatics by inflam- produced by sinus histiocytosis in-

mation and is called skip metastasis. duced by tumor cells.
5. Some other times, due to obstruc-
tion of lymphatics by tumor cells
spread against the flow of lymph Hematogenous Spread
causing retrograde metastases. 1. Hematogenous spread is the com-
For example, CA prostate to su-
praclavicular lymph nodes. CA mon route of spread for sarcomas,
lung to axillary lymph nodes. but also for certain carcinomas like
6. Regional lymphadenitis is not always carcinoma of lungs, breasts, thyroid,
due to nodal metastasis and is also kidneys, liver, prostate and ovary.
2. The sites mainly involved by he- Mechanism of Metastasis

matogenous spread are: Liver, lungs,
brain, bones, kidneys and adrenals. 1. Aggressive clonal proliferation and
3. The sites like spleen, heart and skel- angiogenesis.
etal muscles are rarely involved. a. Aggressive clonal proliferation of
4. Cancers of limbs, head, neck and pel- a subgroup of monoclonal tumor
vis are more often metastasis to lungs cells is the first step in metastasis.
through systemic veins. b. This nature of tumor cells that sub-
5. Cancers of bowel, spleen and pan- population can involve completely
creas usually spread to liver through in the development of metastasis is
portal veins. on the basis of tumor heterogeneity.
6. Systemic arterial spread is rare be- c. Tumor angiogenicity plays a ma-
cause they are thick walled and resis- jor role, because the new vessels
tant to invasion. formed are more vulnerable to in-
7. Cancers of lung may metastasis to vasion.
kidneys, adrenals, bones, brain, etc.
2. Tumor cell loosening.
through pulmonary artery.
a. Normal cells are held together by
8. Retrograde spread may occur due to
venous obstructions. For example, CAMs.
CA thyroid and CA prostate to verte- b. In tumors, these adhesion mol-
bral column. ecules get inactivated and this re-
sults in loosening.
Spread Along Body 3. Tumor cell/ECM interaction.
Cavities and Others a. Loosened tumor cells are then at-
tached to ECM proteins mainly
1. Transcoelomic spread, e.g. CA stom- laminin and fibronectin through
ach to ovaries (Krukenberg tumor). the receptors on the cancer cells.
a. Carcinoma ovary to peritoneal b. Facilitated by lose of integrins.
cavity, pseudomyxoma peritonei
(from CA ovary and appendix). 4. Degradation of ECM.
CA lung and breast to pleura and a. Tumor cells induce proteases and
pericardium. metalloproteinases like gelatinase
2. Along epithelial lined surfaces (rare), and collagenase.
e.g. through fallopian tube from en- b. Also the metalloproteinase inhibi-
dometrium to ovary and vice versa. tors are decreased.
Through bronchus to alveoli. c. All these results in dissolution of
Through ureter to lower urinary tract ECM (BM of tumor cells, intersti-
from kidneys. tial matrix and BM of vessel wall).
3. Via CSF, e.g. malignancy of ependy- 5. Entry of tumor cells into capillary
ma and leptomeninges. lumen.
4. Direct implantation. By surgeon’s a. A cytokine AMF stimulates recep-
scalpel, needles, sutures of direct tormediated motility of tumor cells
contact. into the lumen.
b. Matrix degradation products have 2. Benign lesions.

properties of chemotaxis, growth a. For example, multiple villous ad-
promotion and angiogenesis. enoma of large intestine may de-
6. Thrombus formation. velop into adenocarcinoma.
a. Tumor cells in the lumen get trans- •• Neurofibromatosis may devel-
formed into a thrombus. op into sarcoma.
b. The thrombus provides nutrition 3. Miscellaneous.
and protects tumor cells from im- a. Certain inflammatory and hyper-
mune attack. plastic conditions predispose to
7. Extravasation of tumor cells. cancer.
a. This occurs at the site of metastasis. •• Long-standing ulcerative colitis
to colorectal ulcer
b. Just reversal of steps of tumor cell
•• Cirrhosis liver to hepatocellular
entry into lumen.
carcinoma
8. Survival of growth of metastatic de-
•• Chronic bronchitis to carcino-
posit.
ma bronchus
a. The main growth factors acting
•• Chronic irritation from jagged
here are PDGF, FGF, TGF and tooth may lead to oral cancer
VEGF.
•• Old burn scar (Marjolin’s ulcer)
b. These deposits can further metas- to squamous cell carcinoma
tasize also.
•• Chronic atrophic gastritis to
CA stomach
PRENEOPLASTIC DISORDERS •• A typical endometrial hyper-
Preneoplastic disorders are group of con- plasia to endometrial cancer.
ditions, which predispose to the subse-
quent development of cancer. Many of CARCINOGENESIS:
these conditions are characterized by fea- MOLECULAR BASIS OR
tures like increased nuclear-cytoplasmic
GENETIC MECHANISM
ratio, pleomorphism, increased mitotic
activity, etc. The major types are: 1. Carcinogenesis or oncogenesis is the
1. Carcinoma in situ mechanism by which the tumor de-
velops from a normal tissue by the
a. Here the cytological features of ma-
action of carcinogens.
lignancy are present, but the ma-
2. The major non-lethal mutations ac-
lignant cells are confined to epithe-
count for cancer are on the following
lium without invasion across BM.
targets:
b. The common sites are: a. Growth promoting proto-onco-
•• Uterine cervix at the junction of genes.
ecto- and endocervix b. Growth inhibiting tumor suppres-
•• Bowens disease of skin sor genes.
•• Oral leukoplakia c. Genes that regulate apoptosis.
•• LCIS and DCIS of breast. d. Genes involved in DNA repair.
3. The major mechanisms by which a j. Oncomirs.

cancer develops are: •• These are microRNAs in cer-
a. Self-sufficiency in growth signals tain cancers
and excessive growth. •• These leads to certain mutations.
•• By the action of oncogenes, e.g.
RAS, BCR-ABL, MYC, CDK4, Mechanism
etc.
The genetic mechanism is given in the
b. Insensitivity to growth inhibitory Figure 6.1.
signals.
•• By mutation of tumor suppres-
RB GENE
sor genes, e.g. mutation of RB
gene, p53 gene, etc. 1. Located on long arm of chromosome
c. Evasion of apoptosis. 13.
•• By mutation of genes like BCL2, 2. This is the first tumor suppressor
CD95, etc. gene discovered.
d. Avoiding cellular ageing and in- 3. The RB gene product is a DNA bind-
ing protein expressed in two forms:
creased replicative potential.
a. A hypophosphorylated active
•• By the action of increased te-
form.
lomerase.
b. A hyperphosphorylated inactive
e. Tumor angiogenesis.
form.
•• Due to increased angiogenic
factors (VEGF and FGF) and
Mechanism of Functioning
decreased antiangiogenic fac-
tors (thrombospondin and an- 1. The active form blocks E2F mediated
giostatin). transcription in two ways (Fig. 6.2).
f. Invasion and distant metastasis. •• Sequesters E2F and prevent
•• By a series of events (already it from interacting with other
discussed). transcriptional factors
g. Genetic instability. •• Recruits chromatin remodeling
•• Mainly by DNA damage due to proteins which bind to promot-
defective repair, e.g. HNPCC, ers of E2F responsive genes.
xeroderma pigmentosum, CA 2. During M-phase, the phosphate
breast. groups are removed by phosphatases
h. Clonal aggressiveness. and make RB gene active.
•• By cancer progression and het- 3. In tumors, the mutations inactivate
erogenicity. RB gene and leads to increased cell
i. Multistep molecular phenomenon. growth, e.g. retinoblastoma, osteo-
•• Mutation at different genes to- sarcoma, CA lung, CA colon and CA
gether. breast.
Fig. 6.1: Genetic mechanism
Knudson’s Two-hit Hypothesis 3. p53 gene is an exception for this hy-

pothesis.
1. RB gene functioning, is a classical
example for Knudson’s two-hit hy-
pothesis, which states that “a tumor p53 GENE
suppressor gene transforms to a can-
cer producing oncogene usually after 1. p53 gene is one of the most commonly
two different mutations”. mutated genes in human cancers and
2. Other examples are neurofibromin is called ‘protector of the genome’.
gene in neurofibromatosis and APC 2. p53 induces neoplastic transformation
gene in FAP. by three interlocking mechanisms:
Fig. 6.2: Mechanism of RB gene functioning
a. Activation of temporary cell cycle 3. The p53 is normally seen in associa-

arrest (quiescence). tion with MDM2, which targets the
b. Induction of permanent cell cycle destruction of p53.
arrest (senescence). 4. On stress, p53 undergo certain post-
c. Triggering of programmed cell transcriptional modifications and get
death (apoptosis). released from MDM2.
3. The p53 is triggered by anoxia, inap-
5. On release from MDM2, p53 induce
propriate oncogene expression and
DNA repair.
damage to integrity of DNA.
6. After DNA repair, p53 upregulates
4. The p53 gene is located on the short
arm of chromosome 17. the transcription of MDM2 leading
to destruction of p53 and relief of cell
cycle block.
Mechanism of Functioning
7. Many tumor show p53 mutation, e.g.
1. The key initiators of DNA damage sarcomas, CA breast, leukemia, brain
are the ATM and ATR genes, those are tumor, etc.
seen in ataxia telengectasia patients
8. Patients with Li-Fraumeni syndrome
and that patients have an increased risk
of malignancy due to p53 mutation. has inherited p53 mutation and has
2. p53 brings about the G1 arrest through 25-fold increased risk for cancer.
p21 (CDK inhibitor) and the DNA re- 9. p53 is inactivated by certain DNA vi-
pair GADD 45. ruses like HPV, HBV,EBV, etc.
Fig. 6.3: Effect of carcinogens on cells
CHEMICAL CARCINOGENS •• β-propionolactone

•• Epoxides
Chemicals, which induces cancer.
•• These are weakly carcinogenic
•• Causes lymphomas and leuke-
Initiator Carcinogens mias.
Carcinogens (Fig. 6.3), which can initiate b. Acylating agents.
the process of carcinogenesis. •• Acetylimidazole
•• Dimethylcarbamoyl chloride.
Directly Acting
1. Directly acting agents do not need Indirectly Acting
metabolic activation to become carci- 1. Indirectly acting agents require prior
nogenic. metabolic activation to become carci-
a. Alkylating agents. nogenic.
•• Anticancer drugs (cyclophosh- 2. Also called procarcinogens.
phamide, busulfan, melphalan, a. Poly cyclic aromatic hydrocarbons.
etc.) •• Anthracenes
•• Benzpyrene 2. But their exposure subsequent to ini-

•• Methylcholanthrene tiator helps the initiated cell to prolif-
•• Largest group erate further, e.g. phorbol esters, phe-
•• Causes skin cancer by topical nols, certain hormones and drugs,
application, sarcomas by sub- dietary fat, etc.
cutaneous injections and lung 3. Hormones include.
cancer by inhalation a. Estrogen: Carcinoma endometri-
•• The sources are tobacco, smoke, um, CA breast.
fossil fuel, soot, tar, mineral oil,
b. Diethyl stillbestrol: Postmeno-
smoked animal foods, industrial
and atmospheric pollutants, etc. pausal CA endometrium.
b. Aromatic amines and azo dyes. c. Adolescent vaginal cancer in fe-
•• β-naphthalene: Bladder cancer male child if mother exposed dur-
ing pregnancy.
•• Benzidine: Bladder cancer
•• Azo-dyes (margarine, scarlet 4. Dietary fat causes CA colon.
red): Hepatocellular carcinoma.
c. Naturally occurring products. CHEMICAL CARCINOGENESIS
•• Aflatoxin-B1, actinomycin-D, 1. Chemical carcinogenesis is the pro-
mitomycin-C, safrol and cess by which carcinogens induce the
batel nuts
cancer.
•• All these are known to cause
2. The factors influencing are:
hepatocellular carcinoma.
d. Miscellaneous. a. Dose and mode of administration
of carcinogens.
•• Nitrosamines and nitrosamides:
CA stomach b. Individual susceptibility.
•• Vinyl chloride monomer: He- c. Various predisposing factors.
mangiosarcoma of liver 3. Following are the stages.
•• Asbestos: Bronchogenic carci-
noma, mesothelioma Initiation
•• Arsenical compounds: Basal
cell carcinoma of skin 1. Initiation is the first stage and in-
•• Metals like nickel, cobalt: Lung duced by initiators.
cancer 2. The induced change is sudden, irre-
•• Insecticides and fungicides: versible and permanent.
Cancer in experimental animals 3. Initiation is brought about by both di-
•• Saccharin and cyclamates: Can- rect and indirect acting carcinogens.
cer in experimental animals. 4. The steps involved are given below.
Promoter Carcinogens Metabolic Activation

1. Promoter carcinogen agents lack the 1. Metabolic activation step is only re-
intrinsic carcinogenic potential. quired for indirect-acting carcinogens
and not required for direct-acting car- Promotion

cinogens.
2. Activation occurs in ER of liver by 1. The main promoter carcinogens are
mono-oxygenases of cyt-p450 system. phorbol esters, phenols, hormones,
3. Sometimes the procarcinogen get in- artificial sweetners and certain drugs.
activated. 2. The promoters differ from initiators
4. The carcinogenic potential is deter- in the following aspects:
mined by. a. Do not produce sudden change.
a. Balance between activation and in- b. Require application or administra-
activation. tion in sufficient time and dose.
b. Genes that code for cyt-p450 de- c. The induced change may be re-
pendent enzymes. versible.
c. Age, sex and nutritional status of d. Do not damage DNA as such, but
the host. enhance the damage caused by
initiators.
Reactive Electrophiles Formation e. Act by further proliferation of ini-
1. Direct acting agents are intrinsical- tiated cell.
ly electrophilic and indirect acting 3. Initiator alone can also result in can-
agents become electrophilic after ac- cer, but promoter alone cannot cause
tivation. cancer.
2. These reactive electrophiles bind to
electron-rich portions of DNA, RNA Progression
and other proteins.
1. This is the stage in which the mutated
proliferated cell shows phenotypic
Target Molecule Attack features of malignancy.
1. The primary target molecules are 2. Features pertain to morphology, bio-
DNA. chemical composition and molecular
2. Several genes are affected. features.
3. The commonly affected growth pro- 3. Throughout this process, the cells ac-
moter oncogene is RAS gene and an- cumulate more and more mutations.
ti-oncogene is p53 gene.
4. RNA and proteins are also targets. Tests for Carcinogenicity
1. Experimental induction.
Formation of Initiated Cells a. Expose experimental animals to
specific chemicals.
1. The cells with sudden, irreversible,
permanent DNA damage is called b. Prolonged and expensive.
initiated cell. 2. Ames’ test.
2. These are vulnerable to the action of a. Evaluates the carcinogenetic po-
promoters. tential of a chemical in the mutant
strain of Salmonella typhimurium, DNA VIRAL ONCOGENESIS

which cannot produce histidine.
b. The mutant strains are incubated The DNA viral oncogenesis steps is
with carcinogen and liver homo- shown in Figure 6.5.
genate. 1. DNA oncogenesis viruses have three
c. Liver homogenate is to activate special genes:
carcinogen.
a. ‘gag’ gene—codes for group anti-
d. If the carcinogen is potent, that
gen.
will cause mutation in Salmonella
strains and thus those strains can b. ‘pol’ gene—codes for polymerase
produce histidine. enzyme.
e. So these strains can grow in histi- c. ‘env’ gene—codes for envelope
dine free medium. protein.
2. Persistence of DNA virus in the host
Sequential Stages cell act as one step in the multistep
in Chemical Carcinogenesis process of cancer development.
The Sequential stages in chemical car- 3. These viruses induce clonal prolifera-
cinogenesis is shown in Figure 6.4. tion of cells by:
Fig. 6.4: Chemical carcinogenesis

Fig. 6.5: Steps in DNA virus oncogenesis
a. Activation of growth promoting d. SV-40

pathways. •• Animals → sarcoma
b. Inhibition of tumor suppressor •• Humans → mesothelioma.
genes. 2. Herpes virus
4. This oncogenetic mechanism involves a. EBV (humans) → Burkitt’s lym-
two steps: phoma.
a. Replication of virus in the host b. HHV-8 (humans) → Kaposi sarco-
cells and release of virions. ma, pleural effusion, lymphoma.
b. Integration of viral DNA with host c. Lucke frog virus (frog) → RCC.
cell DNA. d. Marek’s disease virus (chicken) →
5. The replication leads to host cell death, T cell leukemia, lymphoma.
but no neoplastic transformation. 3. Adenoviruses.
6. Integration induces mutation and thus a. Animals → sarcomas.
leads to neoplastic transformation. 4. Poxviruses.
a. Rabbits → myxomatosis.
Specific DNA Oncogenic Viruses b. Humans → molluscum contagio-
sum.
1. Papovaviruses
5. Hepadna viruses.
a. HPV (humans) → cervical cancer,
SCC at other sites, skin cancer and a. Hepatitis B virus (humans) → he-
papillomas (warts). patocellular carcinoma.
•• Cervical → HPV 16, 18, 31 and 33
•• Warts → HPV 6 and 11 Mechanism in four Important
•• Skin → HPV 5 and 8. DNA Viral Oncogenesis
b. Papilloma virus (animals) → pap- 1. Human papilloma virus.
illomas, alimentary tract cancer. a. Refer pathogenesis of CIN given
c. Polyoma virus (mice) → various in the chapter 19, the FGS and
carcinomas and sarcomas. breast.
Fig. 6.6: Steps in EBV oncogenesis
2. Epstein-barr virus (EBV) (Fig. 6.6). 2. The RNA oncogenic viruses are
a. Causes Burkitt’s lymphoma, na- mainly retroviruses that having re-
sopharyngeal carcinoma, a subset verse transcriptase enzyme.
of Hodgkin lymphoma and B cell 3. This enzyme (RT) helps the viral
lymphomas in AIDS. RNA to synthesize viral DNA.
3. Human herpes virus-8 (HHV-8)(Fig.
6.7).
Specific RNA Oncogenic Viruses
4. Hepatitis virus (Fig. 6.8). 1. Acute transforming viruses (rapidly
acting) (by viral oncogenes).
a. Rous sarcoma virus (animals) →
sarcomas.
b. Leukemia sarcoma virus (animals)
→ leukemia, sarcomas.
Fig. 6.7: Steps in HHV oncogenesis 2. Slow transforming viruses (slowing
acting) (by mutagenesis).
a. Mouse mammary tumor virus (an-
RNA VIRAL ONCOGENESIS imals) → leukemia, lymphomas
1. These viruses also have three typical and breast cancer.
genes (gag, pol and env) as DNA onco- 3. Human T cell lymphotropic virus
genic viruses. (HTLV) (Fig. 6.9):
Fig. 6.8: Steps in hepatitis virus oncogenesis
a. HTLV-I (humans) → adult T-cell TUMOR ANTIGENS

leukemia lymphoma (ATLL).
1. Tumor are certain surface antigens
b. HTLV-II (humans) → T-cell vari-
ant of hairy cell leukemia. on tumor cells.
4. Hepatitis–C (HCV) (humans) → he- 2. Tumor specific antigens are those,
patocellular carcinoma. which are seen only on tumor, but
not on normal cells. These are specific
antigens for particular tumor.
HTLV Oncogenesis
3. Tumor associated antigens are those,
Human T cell lymphotropic virus does which are present both on tumor cells
not have viral oncogenes and have no and normal cell from which the tu-
fixed site for interstitial mutagenesis. mor originated.
Fig. 6.9: Steps in HTLV oncogenesis

Table 6.2: Paraneoplastic syndromes
Clinical syndrome Underlying cancer Mechanism

Endocrine syndrome
Hypercalcemia SCC of lung, RCC, CA breast, Parathormone like protein ,
ATLL TGF-α, TNF, IL-1
Cushing syndrome SCC of lung, CA pancreas, ACTH or ACTH like substance
neural tumors
Hypoglycemia CA pancreas, mesothelioma, Insulin or insulin like substance
fibrosarcoma
Inappropriate antidiuresis SCC of lung, CA prostate, ADH or ANF
Intracranial tumor
Carcinoid syndrome Bronchial carcinoid, CA Serotonin, bradykinin
pancreas, CA stomach
Polycythemia RCC, HCC, cerebellar Erythropoietin
hemangioma
Neuromuscular
Myasthenia gravis Thymoma Immunologic
Neuromuscular disorders SCC of lung, CA breast Immunologic
Bone, joint, soft tissue
HPOA and clubbing CA lung Not known
Hematologic
Thrombophlebitis CA pancreas, lung, GIT Hypercoagulability
NBTE Advanced cancers Hypercoagulability
DIC AML, adenocarcinoma Chronic thrombotic
phenomenon
Anemia Thymoma Unknown
GIT and renal
Malabsorption Lymphoma of small bowel Hypoalbuminemia
Nephrotic syndrome Advanced cancers Renal vein thrombosis
Cutaneous
Acanthosis nigricans CA stomach, large bowel Immunologic
Seborrheic dermatitis CA bowel Immunologic
Exfoliative dermatitis Lymphoma Immunologic
Dermatomyositis Bronchogenic CA, CA breast Immunologic
Amyloidosis
Primary Multiple myeloma AL protein
Secondary RCC, lymphoma AA protein
a. Oncoproteins from mutated protein of EBV in Burkitt’s lym-

oncogene. phoma.
•• Oncoproteins express certain g. Cell specific differentiation anti-
cell surface antigens, e.g. RAS, gens.
BCR/ABL, CDK4. •• Tumor cells express antigens
b. Products of tumor suppressor due to varying degree of differ-
genes. entiation
•• Mutated tumor suppressor •• For example, CD markers in
genes also express tumor anti- lymphoma, PSA in CA prostate.
gens, e.g. p53, β-catenin. h. Oncofetal antigens.
c. Products of other mutated genes. •• These are normal in embry-
•• Various random mutations onic life, but later appear as tu-
elaborate tumor antigens and mor antigens, e.g. AFP in liver
protein products which are tar- cancer, CEA in colon cancer.
geted by cytotoxic T cells. i. Abnormal cell surface molecules.
d. Overexpressed cellular proteins. •• For example, abnormal expres-
•• Here the cellular proteins are sion of mucin in CA ovary (CA-
normal, but overexpressed and 125), abnormal mucin (MUC-1)
elaborate tumor antigens, e.g. in breast cancer.
HER/NEU protein in breast
cancer, melanoma specific pro- PARANEOPLASTIC
tein in melanoma.
SYNDROMES
e. Abnormally expressed cellular
proteins. 1. Paraneoplastic syndromes (Table 6.2)
are a group of conditions that occur
•• Her abnormal proteins are seen
in patients with advanced cancer,
on tumor cells, e.g. MAGE gene which are neither explained by direct
in CA lungs, CA liver and CA or distant spread of tumor nor by the
stomach. usual hormone elaboration by the tis-
f. Tumor antigens from viral onco- sue of origin of tumor.
proteins. 2. These represent significant clinical
•• For example, oncoproteins of problems, sometimes occult neo-
HPV in cervical cancer, EBNA plasm and may mimic metastases.
7 Genetic and
Pediatric Diseases
Chapter
MUTATIONS ●● Trinucleotide expansion (Hunting-

ton’s chorea) or
Mutations are the permanent changes in
DNA, which may be inherited if affect the ●● Duplication (Duchenne muscular
germ cells. Point mutation is the change dystrophy).
in a single nucleotide.
Effects of Mutation
Types of Mutation Silent Mutation
Substitution Silent mutation has no effect.
Resulting from the substitution of a sin-
gle nucleotide base by a different base, Mis-sense Mutation
resulting in the replacement of one amino
acid by another in the protein structure. An abnormal amino acid or protein is
formed.
For example, sickle cell anemia—glu-
tamic acid in the 6th position of β-globin 1. Acceptable (functionally normal).
chain is replaced by valine. 2. Partially acceptable (partial loss of
1. Transition—substitution of purine by function).
another purine (A and G) or pyrimi- 3. Unacceptable (non-functional).
dine by another pyrimidine (T and C).
2. Transversion—substitution of a pu- Nonsense/Terminator
rine by a pyrimidine or vice versa. Codon Mutation
Deletion 1. Leads to premature termination of
proteins.
●● Deletion of a single nucleotide or
●● Deletion of a codon (cystic fibrosis) or Frame Shift Mutation
●● Deletion of a large gene (hemophilia).
1. Due to deletion or insertion of nucle-
otides.
Insertion 2. A completely irrelevant protein is
●● Insertion of a single nucleotide or formed.
Chapter 7 u Genetic and Pediatric Diseases 65
Conditional Mutation Morphology

1. Become manifested under certain cir- Morphological features mainly confined
cumstances only. to three systems, they are skeleton, CVS
and eyes.
Manifestations
1. Lethal—alteration is incompatible Skeletal Abnormalities
with life. a. These are the most obvious features.
2. Silent—no functional effect. b. Slender elongated habitus.
3. Beneficial—beneficial to life. c. Abnormally long legs, arms and
4. Carcinogenic—results in neoplasms. fingers (arachnodactyly).
d. High arched palate.
Mutagens e. Hyper extensibility of joints.
The substances, which produce muta- f. Spinal deformities-like kyphosco-
tions are called mutagens. liosis.
g. Pectus excavatum or pigeon chest
For example, X-ray, ultraviolet (UV)
deformity.
ray, γ-ray, acridine orange dye, etc.
Ocular Features
MARFAN SYNDROME
a. Bilateral dislocation or subluxation
1. An autosomal dominant disorder of of lens.
connective tissues. b. Ciliary zonule is devoid of elastin.
2. Basically affect fibrillin-1.
3. Fibrillin-1 is a glycoprotein secreted Cardiovascular Features
by fibroblasts, which is a major com-
a. Most serious.
ponent of myofibrils in ECM.
b. Predisposition to aortic aneurysm
4. Myofibrils are integral part of elastin and dissection.
and elastic fibers. c. Aortic valve incompetence.
5. Fibrillin-1 is encoded by FBN-1 gene d. Mitral and tricuspid regurgitation
on chromosome 15q21. (floppy valve syndrome).
6. Marfan syndrome is almost always e. Leads to congestive cardiac failure
associated with FBN-1 mutations, but (CCF).
FBN-1 mutations are not always as- f. Most common cause of death in
sociated with Marfan syndrome. Marfan syndrome is aortic rupture.
7. Recently an additional dysregulation
of transforming growth factor-beta LYSOSOMAL STORAGE DISEASE
(TGF-β) production, which leads to 1. Resulting from the inherited lack of
increased TGF-β production and con- lysosomal enzymes, which leads to
nective tissue overgrowth. accumulation of partly degraded in-
soluble metabolites within the lyso- Gaucher Disease

somes.
1. Accumulation of glucosylceramide
2. An autosomal recessive condition.
in phagocytic cell.
3. Commonly affects infants and young
2. Due to deficiency of glucosylcerami-
children.
dase.
4. Usually this produce hepatospleno- 3. C/f—hepatosplenomegaly, bone
megaly. erosion due to deposition in BM and
5. Frequent CNS involvement is seen. neuronal involvement.
4. Accumulation leads to the formation
Main Types of large phagocytic cells (Gaucher
cells) with pathognomonic wrinkled
Tay-Sachs Disease tissue paper appearance of cyto-
1. Resulting from the accumulation of plasm.
gangliosides. 5. High levels of IL-2, IL-6 and TNF can
2. Due to deficiency of hexosamini- be seen.
dase-A. 6. Type I non-neuropathic form is char-
3. Mainly GM2 gangliosides are accu- acterized by hepatosplenomegaly
mulated in the neurons and glial cells and bone erosion.
of CNS, autonomic nervous system 7. Type II and III forms predominantly
(ANS) and peripheral nerves. shows neuronal involvement.
4. Sometimes retina also involved.
5. C/f—motor weakness, mental retar- Mucopolysaccharides
dation, blindness, etc. 1. Accumulation of mucopolysaccha-
rides (MPS) in liver, spleen, heart,
Niemann-Pick Disease Type A and B brain, blood vessels, cornea, joints, etc.
1. Accumulation of sphingomyelin. 2. Several types (I–VII) are reported and
each due to deficiency of one specific
2. Due to deficiency of acid sphingomy-
lysosomal degrading enzyme.
elinase.
3. The MPS accumulated are dermatan
3. Accumulation mainly in the phago-
sulfate, heparan sulfate and chon-
cytic cells and neurons.
droitin sulfate.
4. Spleen, liver, BM, LNs and lungs are
4. C/f—coarse facial features, joint stiff-
severely affected.
ness, clouding of cornea and mental
5. C/f—massive visceromegaly and retardation.
neurologic deterioration.
5. Hurler syndrome (type I) is severe
and Hunter syndrome (type II) has a
Niemann-Pick disease Type C milder course.
1. Accumulation of cholesterol and gan- 6. Six types are AR except hunter syn-
gliosides (GM1 and GM2). drome, which is X-linked recessive.
2. C/f-ataxia, dystonia, dysarthria and 7. Death is commonly due to cardiac
psychomotor regression. complications.
GLYCOGEN STORAGE 2. Deficient enzyme is lysosomal glu-

DISEASES (GLYCOGENOSIS) cosidase or acid maltase.
3. C/f—mild hepatomegaly with bal-
1. Due to inherited deficiency of any looning of lysosomes.
one enzyme involved in glycogen
4. Cardiomegaly, cardiorespiratory fail-
synthesis or degradation, glycogen
ure.
accumulates in excessive amount or
in abnormal form. 5. Muscle hypertonia and chronic
myopathy.
2. Most glycogen storage diseases are
autosomal recessive (AR).
3. One of the glycogen storage disease, AUTOSOMAL GENETIC
i.e. Pompe disease is not only a gly- DISORDERS
cogenosis, but also a lysosomal stor-
age disease, because the enzyme de-
Autosomal Trisomies
ficient is a lysosomal enzyme and is Down Syndrome
involved in glycogen metabolism.
1. Most common chromosomal disorder.
2. This is the trisomy of chromosome 21.
Hepatic Form
3. The chromosome count will be 47.
1. Also called von Gierke disease (type I).
4. It occurs due to meiotic non-disjunc-
2. Deficient enzyme is glucose-6-phos- tion of chromosomes.
phatase.
5. Maternal age has a strong influence
3. C/f—Hepatomegaly and renomegaly. on the incidence of Down syndrome.
a. Hypoglycemia due to failure of 6. 95%—trisomy 21.
glucose mobilization.
7. 4%—extrachromosome is seen as a
b. Hyperlipidemia and hyperurice- translocation of the long arm of chro-
mia. mosome 21 to chromosome 22 or 14.
c. Bleeding tendency due to platelet 8. 1%—mosaics mixture of cells with 47
dysfunction. and 46 chromosomes.
Clinical features
Myopathic Form
1. Mental retardation and dementia.
1. Also called McArdle syndrome 2. Epicanthic folds.
(type V).
3. Flat facial profile.
2. Deficient enzyme is muscle
phosphorylase. 4. Abundant neck skin.
3. C/f—painful cramps with exercise, 5. Simian crease.
myoglobinuria, failure of increased 6. Cardiac defects.
lactate level in exercise. 7. Intestinal stenosis.
8. Umbilical hernia.
Generalized Form 9. Hypotonia.
1. Also called Pompe disease (type II). 10. Increased gap between 1st and 2nd toe.
11. Predisposition to leukemia and seri- Clinical features:

ous infections. 1. Facial dimorphism.
Diagnosis—demonstration by FISH tech- 2. Palatal abnormalities.
nique. 3. Thymic hypoplasia and impaired
CMI.
Edward Syndrome 4. Parathyroid hyperplasia and hy-
Edward syndrome is trisomy 18. pocalcemia.
Clinical features: 5. Heart defects.
1. Prominent occiput.
2. Mental retardation.
Cri du Chat Syndrome
3. Low set ears. Due to partial deletion of short arm of
4. Micrognathia. chromosome 5.
5. Short neck.
6. Overlapping fingers. SEX CHROMOSOMAL
7. Cardiac defects. DISORDERS
8. Renal malformations. Even a large variation in the sex chro-
9. Limited hip abduction. mosomal pattern is compatiable with life
10. Rocker-bottom feet. because:
1. Lyonization of X chromosomes.
Patau Syndrome a. All the X chromosomes except one
are inactivated in the developmen-
This is trisomy 13.
tal period.
Clinical features: b. Only a small amount of genetic in-
1. Microcephaly. formation is carried by Y chromo-
2. Mental retardation. somes.
3. Microphthalmia.
4. Cleft palate and lip. Klinefelter Syndrome
5. Polydactyly. 1. Best defined as male hypogonadism.
6. Cardiac defects. 2. Develops when there are at least two
7. Umbilical hernia. X chromosomes and one or more Y
8. Renal defects. chromosomes.
9. Rocker-bottom feet. 3. Most patients are 47 XXY.
4. Results from non-disjunction of sex
Deletion Syndromes chromosome during meiosis.
5. The extra X chromosome may be ma-
Chromosome 22q 11.2 Syndrome ternal or paternal.
Due to small interstitial deletion of band 6. Advanced maternal age of irradiation
11 on the long arm of chromosome 22. may contribute to this anomaly.
7. This is the most common cause of hy- 8. Bicuspid aortic valve.

pogonadism in males. 9. Coarctation of the aorta.
8. Mosaics have a less severity of the 10. Horseshoe kidney.
disease. 11. Pigmented nevi all over the body.
12. Subnormal secondary sexual charac-
Clinical Features ters:
1. Increased length between soles and a. Genitalia remain infantile.
pubic bones. b. Minimal breast development.
2. Decreased facial, body and pubic hair. c. Little pubic hair.
3. Gynecomastia. d. Primary amenorrhea.
4. Testicular atrophy and decrease in e. Transformation of ovaries to white
size. fibrous streaks.
5. Decreased testosterone levels. f. Ovaries are devoid of follicles.
6. Impaired spermatogenesis.
7. Mild mental retardation. RESPIRATORY DISTRESS
8. Increased predisposition to breast SYNDROME OF THE NEWBORN
cancers, extragonadal germ cell tu-
mors, autoimmune diseases like SLE.
Etiology of Respiratory Distress
1. Excessive sedation of the mother.
Turner Syndrome 2. Fetal head injury during delivery.
1. Primary hypogonadism in phenotyp- 3. Aspiration of blood or amniotic fluid.
ic females. 4. Intrauterine hypoxia.
2. Results from partial or complete 5. Respiratory distress syndrome (RDS)
monosomy of short arm of X chromo- or hyaline membrane disease.
some.
3. Commonly 45-XO genotype. Pathogenesis
4. Mosaics are also seen and have a less
1. Basically RDS is a disease of prema-
severe course of the disease.
ture infants (Fig. 7.1).
2. Other contributing factors are mater-
Clinical Features
nal diabetes, cesarian section before
1. Growth retardation (short stature). the onset of labor and twin gestation.
2. High-arched palate. 3. Fundamental defect is the inability
3. Low-posterior hairline. of type II pneumocytes of immature
4. Webbed neck. lung to produce surfactant.
5. Hypothyroidism. 4. Function of surfactant is to coat the
6. Cubitus valgus. alveolar surface to reduce the surface
7. Shield-like chest with widely spaced tension and thus decrease the pres-
nipple. sure required to keep alveoli open.
5. The surfactant production is stimu-

lated by steroids. So RDS is less likely
to develop in intrauterine fetal stress
and IUGR.
Morphology
1. Lungs are of normal size, but are
heavy and airless.
2. Have a mottled purple color.
3. Collapsed alveoli (atelectasis).
4. Necrotic cellular debris in alveoli
(early phase).
5. Eosinophilic hyaline membranes (late
phase) in the respiratory bronchioles,
alveolar ducts and alveoli.
6. (N) infiltration also seen.
Clinical Features
1. Respiratory distress.
2. Retrolental fibroplasia or retinopathy
of prematurity due to angiogenic fac-
tors like VEGF.
3. Bronchopulmonary dysplasia (BPD)
is a disease in mature alveoli and due
to several cytokines.
4. Increased risk for PDA, intraventric-
ular hemorrhage and necrotizing en-
terocolitis.
CYSTIC FIBROSIS
Fig. 7.1: Pathogenesis of respiratory distress
1. An AR condition. syndrome
2. This is a disorder of epithelial trans-
port affecting the fluid secretion in
exocrine glands and the epithelial Pathogenesis
lining of the respiratory, GI and re- 1. The primary defect is abnormal func-
productive tracts.
tioning of an epithelial chloride chan-
3. Most important manifestations are
chronic pulmonary infections and nel protein encoded by CFTR gene.
pancreatic insufficiency. 2. CFTR gene is located on chromosome
4. We can see a high level of NaCl in the 7q 31.2 and is get mutated in cystic
sweat. fibrosis.
In Sweat Gland 3. Liver:

a. Bile canaliculi are plugged with
1. Normally CFTR protein reabsorb
mucus.
chloride ions and augment reabsorp-
tion of Na ions from lumen to cells. b. Ductular proliferation and portal
inflammation.
2. In CF, the reabsorption of Na+ and
Cl- get reduced and hypertonic sweat c. Hepatic steatosis in biopsy.
is produced. d. Cirrhosis in late stages.
4. Small intertine
In Respiratory Tract and Pancreas a. Small bowel obstruction and meco-
nium ileus.
1. Active luminal secretion of Cl- ions
reduced and luminal Na+ ions ab- 5. Genital system:
sorption increased. a. Azoospermia and infertility.
2. This leads to increased passive water b. Bilateral absence of vas deferens.
reabsorption from lumen into epithe-
lial cells. Clinical Features
3. As a result, mucous become dehy-
drated and impairs the mucociliary a. Malabsorption of protein, fat and
clearance. fat-soluble vitamins.
4. This also leads to obstruction of air b. Persistent diarrhea.
passages by viscid secretions and c. Chronic pancreatitis.
predispose to recurrent pulmonary d. C/c cough, lung infections, ob-
infections. structive pulmonary diseases, cor
5. In pancreas, mucus obstructs the pulmonale, liver disease, etc.
ducts.
NEUROBLASTOMA
Morphology
1. Affecting the sympathetic ganglia
1. Pancreas: and adrenal medulla, which are de-
a. Accumulation of mucus and dila- rived from the primordial neural
tation of glands. crest cells.
b. Later the ducts become totally 2. This is a malignant neoplasm, which
plugged and leads to atrophy is a second most common solid malig-
and fibrosis. nancy of childhood after brain tumors.
c. Impaired fat absorption and avi- 3. Mainly sporadic, but familial also (AD).
taminosis A leads to squamous 4. Demonstrate certain unique features
metaplasia. in history including spontaneous re-
2. Pulmonary: gression and spontaneous maturation.
a. Obstruction of air passages.
b. Hyperplasia and hypertrophy of
Morphology
mucous secreting cells. Most commonly occcurs in adrenal me-
c. Bronchitis and bronchiectasis. dulla (40%), paravertebral sympathetic
chain of abdomen (25%) and sympathet- Clinical Features

ic chain in posterior mediastinum (15%).
1. Protuberant abdomen with mass, fe-
ver and weight loss.
Gross 2. Metastasis leads to hepatomegaly, as-
1. Size varies from minute nodules to cites and bone pain.
large masses. 3. In infants, deep blue discoloration
2. Some are well-encapsulated and some of skin due to metastasis (blueberry
others are extensively infiltrative. muffin baby).
3. They are composed of soft, grey tan,
brain-like tissue. Prognosis
4. Some large tumors show areas of necro- Most important factors influencing prog-
sis, cystic softening and hemorrhage. nosis are:
1. Stage of tumor.
Microscopy
2. Age of patient.
1. Small, primitive appearing cells with 3. Metastasis worsens the prognosis.
dark nucleus and scanty cytoplasm.
4. Younger age group will have a good
2. Cells are arranged as rosettes (Hom-
prognosis.
er-Wright pseudorosettes) in which
cells are seen concentrically around a 5. Amplification of MYCN oncogene
central space filled with neurofibril- again worsens the prognosis.
lary material. 6. Expression of TrKA (a receptor for
3. Mitotic activity, karyorrhexis and nerve growth factor) favors the prog-
pleomorphism are prominent. nosis.
4. Neuron specific enolase can be dem- 7. Over expression of telomerase wors-
onstrated. ens the prognosis.
5. Some neoplasms show signs of mat-
uration, which are the larger cells
with abundant cytoplasm and large RETINOBLASTOMA
vesicular nucleus with a prominent 1. Most common malignant eye tumor
nucleolus. of childhood.
6. These large cells are called ganglion 2. Usually develop as a congenital tumor.
cells.
3. Usually undergo spontaneous re-
7. In some tumors (ganglioneuroblas-
gression.
tomas), these ganglion cells are seen
admixed with primitive cells and in 4. Familial cases are mostly multifocal
some others (ganglioneuroma), these and bilateral, where as sporadic cases
large cells are seen alone. are mostly unilateral and unifocal.
8. The maturation usually accompanied 5. Almost always results from RB-1
by the appearance of Schwann cells. gene mutation.
Morphology are arranged around a central lumen

are seen.
1. Usually in the posterior retina, from a
cell of neuroepithelial origin.
Clinical Features
2. Composed of small round cells with
1. Poor vision and strabismus.
hyperchromatic nuclei and scanty
2. A whitish hue to pupil (cats eye
cytoplasm resembling undifferenti-
reflex).
ated retinoblasts. 3. Pain and tenderness in the eye.
3. Characteristic true rosette (Flexner- 4. Increased risk for developing osteo-
Wintersteiner rosette) in which cells sarcoma.
8 Environmental and
Nutritional Diseases
Chapter
PROTEIN-ENERGY •• The muscle proteins and sub-

cutaneous fat are relatively
MALNUTRITION spared
Inadequate consumption of protein and •• Their minute loss is marked by
energy as a result of primary dietary de- edema
ficiency or conditioned deficiency that •• Flaky paint skin lesions →
leads to loss of body mass (protein and alternate bands of hyperpig-
adipose tissue). mentation, desquamation and
hypopigmentation
Primary •• Flag sign → alternate bands of
light and dark hair
1. Occurs in children due to dietary de-
•• Growth is retarded
ficiency or increased loss.
•• Liver is fatty and enlarged (↑
a. Kwashiorkor (between 6 months LPs)
and 3 years of age).
•• Small bowel shows mucosal
•• Protein deficiency with suffi- atrophy and loss of villi, 7
cient calorie intake microvilli
•• Can occur due to dietary de- •• BM will be hypoplastic
ficiency of proteins or due to •• Anemia is present (usually mi-
protein-losing enteropathies, crocytic hypochromic)
severe nephrotic syndrome, etc. •• Brain and lymphoid organs
•• Here, severe loss of protein show atrophy
from the visceral protein •• Deficiency of other vitamins
compartment and hence, re- and minimal muscle wasting
duced level of serum albumin •• Decreased immunity and in-
(hypoalbuminemia) creased infections.
•• This hypoalbuminemia leads b. Marasmus (< 1 year age)
to generalized and dependant •• Starvation in infants with over-
edema all lack of calories
Chapter 8 u Environmental and Nutritional Diseases 75
•• Muscle protein and adipose tis- c. Maintenance of cartilaginous and

sue are extensively reduced bone growth.
•• Severe muscle wasting, ema- d. Antioxidant action.
ciation and thinning of skin are 3. Lesions in deficiency.
present a. Ocular.
•• Growth is retarded •• Night blindness (1st sign)
•• Xerophthalmia (dry and scaly
•• Edema and hepatic involve-
conjunctiva)
ment are absent
•• Corneal ulcers
•• Reduction in serum protein •• Keratomalacia (infected corneal
level is minimal ulcers—keratinization)
•• Decreased immunity (T cell) •• Bitot spots (small opaque
and increased infections plaques on cornea)
•• Lipolysis is due to ↓ leptin and •• Blindness.
thus ↑ cortisol b. Cutaneous.
•• Xeroderma (due to hyperkera-
•• Monkey-like face, abdominal
tosis papules).
protuberance and anemia are
c. Epithelial.
present
•• Squamous metaplasia of:
•• Hypoplastic BM, atrophy of – Respiratory epithelium (↑ in-
brain and lymphoid organs. fections)
– Pancreatic ductal epithelium
Secondary (obstruction)
1. Secondary to certain diseases. – Urothelium (stones and
pyelonephritis).
2. Commonly in advanced cancers.
d. Decreased bone and cartilaginous
3. Severe form is called cachexia. growth.
VITAMIN A DEFICIENCY VITAMIN D DEFICIENCY

1. Vitamin A is available in two forms: Rickets and Osteomalacia
a. Retinol. Refer Chapter 21, Musculoskeletal Sys-
b. Retinoid (precursor). tem.
2. Normal functions:
a. Normal vision in dim light. EFFECTS OF TOBACCO
b. Maintenance of structure and func- 1. Carcinoma (CA) of oral cavity.
tion of epithelium. 2. Carcinoma of larynx.
3. Carcinoma of esophagus. EFFECTS OF ALCOHOL

4. Lung carcinoma.
1. Fatty liver, hepatitis, cirrhosis, HCC.
5. C/c bronchitis and emphysema.
2. Portal HTN and systemic HTN.
6. MI and systemic atherosclerosis.
3. Metabolic acidosis.
7. Peptic ulcer. 4. Gastric ulcers and C/c gastritis.
8. Pancreatic carcinoma. 5. Peripheral neuropathy and Wernicke-
9. Carcinoma of bladder. Korsakoff syndrome (↓ pyridoxine).
6. A/c and C/c pancreatitis.
Toxic Components 7. Atherosclerosis and cardiomyopathy.
of Tobacco Smoke 8. Fetal alcoholic syndrome.
9. CA of oral cavity, pharynx, larynx,
1. Tar.
esophagus, etc.
2. Nicotine.
3. Phenol. EFFECTS OF OBESITY
4. CO.
1. Hyperlipidemia, HTN, DM.
5. Formaldehyde.
2. Atherosclerosis, CAD, stroke.
6. N2 oxides. 3. Hyperventilation syndrome.
7. Nitrosamine. 4. Fatty liver and cholelithiasis.
8. Benzopyrine. 5. Osteoarthritis.
9 General Pathology of
Infectious Diseases
Chapter
MECHANISMS OF 3. Alteration of apoptosis pathway. For

VIRAL INJURY example, apoptosis induced by gp
120 of HIV, apoptosis inhibited by
The predilection of virus to infect certain Bcl-2 homologous.
cells and not others (tissue tropism) is de-
4. Introduction of cell proliferation and
termined by:
transformation—resulting in cancer.
1. Host cell receptors for a particular vi-
For example, EBV, HPV, HBV, HCV.
rus, e.g. human immunodefeciency
virus (HIV) gp120 binds to CD4 cells. 5. Inhibition of host cell DNA, RNA or
2. Cell type specific transcription factors protein synthesis. For example, po-
that recognize viral enhancer and pro- liovirus inhibits translation of host’s
moter sequences, e.g. John cunning- mRNA.
ham (JC) virus active only in oligo- 6. Damage to plasma membranes. For
dendroglia due to presence of specific example, HIV, measles virus, herpes
transcription factors in glial cells. virus.
3. Physical barriers, e.g. enterovirus rep- 7. Damage to cells involved in antimi-
licate in intestine, because they can re- crobial defense. For example, influ-
sist acidic pH, bile, enzymes, etc. enza damages respiratory epithelium
and leads to bacterial pneumonia,
Mechanism HIV damages CD4+ TH2 cells and
leads to opportunistic infections.
After entry into host cells, virus injure the
cells by:
1. Lysis of host cells. For example, influ-
MECHANISMS OF
enza virus kills the respiratory epithe- BACTERIAL INJURY
lium, rabies virus kills the neurons. The bacterial injury on a cell depends on:
2. Immune cell-mediated killing—by 1. Adherence to host cells—with the
stimulation of cytotoxic T cells. For help of adhesins on bacterial surface.
example, HBV destroys hepatocytes. For example, fibrillae on Streptococcus
pyogenes are composed of lipoteicho- •• Diphtheria toxin: Inactivating

ic acids and M-protein, which help protein synthesis by transfer-
in adherence as well as resistance ring ADP-ribose to EF-2
against host immune response. •• Cholera toxin: Generates excess
2. Virulence is the ability of a bacteria of cAMP by transfer of ADP-
to cause a disease and is depending ribose from NAD.
upon: c. Inhibiting the release of neu-
a. Entry into cells. rotransmitters. For example, C. tet-
ani, C. botulinum.
For example, Mycobacterium tuber-
culosis enters into macrophages by d. Stimulating T lymphocytes—re-
sults in a cytokine storm. For ex-
inducing an alternate compliment
ample, superantigens by S. aureus
pathway.
and S. pyogenes.
b. Intracellular survival.
•• Superantigens bind with MHC-
For example, Escherichia coli and class I
Shigella survive by inhibiting host •• Then binds with T-cell receptors
protein synthesis.
•• Thus activates T cells.
M. tuberculosis survives by block-
ing the phagosome formation.
TUBERCULOSIS
3. Bacterial endotoxins.
a. This is a LPS, which forms a ma- Refer Chapter 13, Lungs.
jor component of outer cell wall of
gram-negative bacteria. LEPROSY (HANSEN DISEASE)
b. The LPS attaches to LPS bind-
Leprosy is a chronic non-fatal granu-
ing protein and then the complex lomatous infectious diseases principally
binds to CD14 on macrophages, affecting the skin and nerves.
(M), (N).
c. CD14 causes signaling through tall-
Causative Organism
like receptor 4 (TLR-4) and leads to
production of various cytokines. By M. leprae.
d. Effects of LPS (Refer Pathogenesis
of Septic Shock). Mode of Transmission
4. Bacterial exotoxins: These are secret- 1. Direct contact—commonest.
ed proteins.
2. Transplacental.
a. Directly acting
3. Through breast milk.
For example, proteases of Staphylo-
coccus aureus helps in cutaneous in-
vasion, lecithinase of Clostridium per-
Pathogenesis
fringens disrupt plasma membrane. 1. The main pathogenesis is by cell-me-
b. Altering the regulatory pathways. diated delayed hypersensitivity reac-
For example, tion (type IV).
Chapter 9 u General Pathology of Infectious Diseases 79
2. The determinants of immune reac- 2. Modified Ridley and Jopling

tion are: classification.
a. Antigens of lepra bacilli. a. TT → tuberculoid polar.
•• Specific phenolic glycolipid b. BT → borderline tuberculoid.
(PGL-1) and lipoarabinoman- c. BB → mid borderline.
nan (LAMN) determine the d. BL → borderline lepromatous.
host immune response e. LL → lepromatous polar.
•• Trisaccharide Ag helps to in- 3. Lepromin test is mainly used to clas-
vade nerves by binding with sify the clinic-pathologic groups of
basal lamina of Schwann cells. leprosy.
b. Genotype of the host.
•• Major histocompatibility com- Lepromin Test
plex (MHC) class in host deter-
1. Intradermal injection of lep-
mines the immune response in romin (an antigenic extract of
different hosts. M. leprae) reveals delayed HSN
c. T cell response. reaction in patients with TT.
•• Activation of both CD4+ T cells 2. Fernandez reaction—early positive
and CD8+ T cells reaction (24–48 h).
•• CD4+ T cells elaborate promot- 3. Mitsuda reaction—delayed reac-
er as well as cytotoxic functions tion with granulomatous lesion (3–4
•• CD4+ TH1 and CD4+ TH2 cells weeks).
produce different types of 4. This shows that CMI is suppressed in
cytokines LL and good CMI response in TT.
•• In TT, the response is largely by Difference between lepromatous lep-
CD4+ T cells and in LL, the re- rosy and tuberculoid leprosy is given in
sponse is mainly by CD4+ T cells. Table 9.1.
d. Humoral response.
•• Mainly in LL Lepra Reaction
•• High levels of IgG, IgM and 1. Type I (reversal reaction).
IgA can be seen a. This is shown by patients with bor-
•• But no protective role. derline leprosy.
b. Upgrading reaction.
Classification •• In BL type on treatment
•• Increase in CMI
1. Types. •• Shows ↑ (L), edema and ↓ bac-
a. Lepromatous type (low resistance). terial index (BI).
b. Tuberculoid type (high resistance). c. Downgrading reaction.
c. Borderline type. •• In BT type
d. Indeterminate type. •• Decrease in CMI
Table 9.1: Differences between lepromatous leprosy (LL) and tuberculoid leprosy (TT)
Feature LL TT
Skin lesions Symmetrical and multiple Asymmetrical and single
Nerve involvement Less severe More severe
Histopathology Collection of foamy macrophages in Hard tubercles eroding into
dermis separated from epidermis by a epidermis; no clear zone
clear zone
Bacteriology Numerous bacilli; mainly in skin lesions A few bacilli; mainly in
destroyed nerves
Lepromin test Negative Positive
•• Shows spread of granuloma c. The collection of lepra cells sepa-

and ↑ BI. rated from the epidermis by a clear
2. Type II (erythema nodosum lepro- zone.
sum—ENL). d. The epidermis is thinned out and
may ulcerate.
a. ENL occurs in lepromatous pa-
2. Tuberculoid leprosy.
tients after treatment.
a. Granulomas made of epitheloid
b. Characterized by tender cutane- cells, giant cells and (L) in the dermis.
ous nodules, fever, iridocyclitis, b. Lepra bacilli are few and seen in
synovitis and LN involvement. destroyed nerves.
c. Lesions show infiltration by (N) c. Dermal nerves are infiltrated by
and (E) and vasculitis. epitheloid cells and lymphocytes.
d. Inflammation extends to subcuta- d. Tubercles erode into epidermis
neous fat. and no clear zone.
e. Bacillary load is increased. 3. Borderline leprosy.
f. Repeated attacks of ENL can lead a. BT form.
to 2° amyloidosis. •• Epitheloid cells and numerous
(L)
•• A narrow clear zone
Histopathology
•• Scanty bacilli in nerves.
1. Lepromatous leprosy. b. BL form.
a. Foamy macrophages (lepra cells) •• Predominant histiocytes
in the dermis. •• A few epithelioid cells and (L)
b. Lepra bacilli are seen in lepra •• Numerous lepra bacilli.
cells as globi or cigarettes in pack c. BB form.
appearance. •• Epithelioid cells and some (L)
Chapter 9 u General Pathology of Infectious Diseases 81
•• No giant cells Clinical Types

•• Lepra bacilli present mainly in 1. Multibacillary.
nerves. a. More than five lesions.
d. Indeterminate leprosy. b.
Lepromatous and borderline
•• Features are non-specific leprosy.
•• (L) infiltration particularly 2. Paucibacillary.
around hair follicles, sweat a. Less than or equal to five lesions.
glands, blood vessels, etc. b. Tuberculoid and indeterminate
•• Nerve involvement may be leprosy.
seen
•• Lepra bacilli can be demon- SYPHILIS
strated. Refer Chapter 18, Male Genital System.
23 Clinical Pathology
EXFOLIATIVE CYTOLOGY •• Taken in suspected conditions

of TB, Ca lung.
1. Exfoliative cytology is the branch
d. Buccal mucosa.
of diagnostic medicine, which deals
•• By using glass slide, scrape the
with the study of cells that shed off.
mucosa
2. The material is obtained by scraping, •• For Barr body (sex chromatin)
brushing or washing (lavage). examination.
3. The various sites commonly studied
under this technique are: Fixation
a. Uterine cervix.
1. The commonly used fixatives are:
•• Smear is taken by using bifid
end of Ayre spatula a. Equal parts of ether and 95% alco-
•• Smear is called Pap smear hol.
•• To assess dysplasia and neopla- b. 95% ethanol.
sia. c. 85% isopropyl alcohol.
b. Vaginal mucosa. 2. Fixation time is usually 30 min.
•• Taken by using round end of 3. For long transport, we will use Car-
Ayre spatula bowax spray.
•• This smear is also called Pap 4. If there is a delay, use refrigerator.
smear 5. Some specimens are air dried and
•• To diagnose infections and neo- some others are wet fixed.
plasia. 6. For body fluids, we will use 10% for-
c. Sputum. mal or 50% ethanol. Then centrifuge
•• Usually, early morning sam- and concentrate is used for smear
ples are taken in clean wide- preparation.
mouthed bottles 7. Body fluids like urine, spinal fluid,
•• Sputum expectoration increased etc. are coated with Mayer’s egg al-
by steam inhalation bumin on slide.
Staining 2. 21 G needle gives better and adequate

material.
1. For wet-dried specimens, we use Pa-
3. clean glass slides about 4–6.
panicolaou stain H and E stain.
4. Spirit as skin disinfectant.
2. For air-dried specimens, we use
Leishman and Giemsa stains. 5. Coplin jar with 85% isopropyl alco-
hol.
3. After staining mount on DPX.
6. Papanicolaou and Romanowsky stains.
FINE-NEEDLE Biopsy Procedure

ASPIRATION CYTOLOGY
1. Clean the skin with spirit.
1. Fine-needle aspiration cytology 2. Immobilize the area to be aspirated.
(FNAC) is one of the invasive tech- 3. Insert needle and take aspirate (if
niques in diagnostic cytology. blood is present, discard the sam-
2. Commonly aspirated organs are thy- ple).
roid, breast, soft tissue swellings and 4. Blow the aspirate on to the slide.
LNs.
5. Deep-seated lesions are aspirated
with the help of USG or CT.
Advantages
1. One of the cheapest and easiest tools. Fixation and Staining
2. Any superficial or deep structures 1. After transferring on to the slide,
(with image guidance) can be aspi- crush the thick portion.
rated. 2. Then fix it rapidly by wet fixing or air
3. This is an OP procedure and can be drying.
done without anesthesia. 3. Air-dried specimens are stained by
4. Quick, safe and less painful. Leishmania-giemsa staining.
5. Repeated aspirations are possible. 4. Wet fixes are stained by Pap H and E
6. Complications are rare. stains.
5. Morphologic details are seen better
Limitations in wet-fixed Pap smears.
1. Cannot depend completely for con-

Complications
firmation of diagnosis.
2. Difficulty in reaching lesion. 1. Hematoma (thyroid, breast).
3. Absence of imaging facilities. 2. Infection.
4. Inadequate confidence of physician. 3. Pneumothorax (lung).
4. Dissemination of malignancy.
Equipments
Contraindication
1. Disposable 20–25 G needle with 5– 10
mL syringe. Coagulopathies like hemophilia.
HISTOPATHOLOGY 6. At last, do section cutting in micro-

tome and then place in warm water
Histopathology is the study of tissues af-
ter a series of processes. at 45˚C.
7. Then coating the section with egg
Fixation albumin and glycerine and kept for
overnight incubation.
1. Most important step.
2. Should be fixed as soon as the mate-
Staining
rial is removed from the body.
3. This process will prevent putrefac- The steps for staining are:
tion and autolysis. 1. Deparaffinization with xylol and hy-
4. Preserve the cell architecture by co- drate with descending grades of alco-
agulating the proteins. hol.
5. Routinely, we use 10% formalin for 2. Then wash in running water.
12–24 hours. 3. Staining with H and E stain.
6. The best thickness is 3–5 mm. 4. Bluing in ammonia water—pink col-
7. For complete fixation, we inject formol or changes to blue.
saline in addition to the immersion.
5. Counterstaining with 1% aqueous
8. Other fixatives are: eosin.
a. Bouin fluid (BM and tes-
6. Differentiation by treating with acid
ticular biopsy, skin, gastric).
alcohol.
b. Helly fluid (hematopoietic tissue).
7. Dehydration and clearing with as-
c. Formol HNO3, Gooding and Stew-
cending grades of alcohol and xylol.
art fluid (bone).
8. Mounting in Canada balsam or DPX.
d. Formol saline, Zenker fluid, etc.
Frozen Section Technique

Paraffin Embedding
1. Cryostat or a freezing microtome is
1. Before the proper procedure, do the
used.
fixation.
2. This is used for rapid preparation of
2. Then dehydration by serial passage
through 70%, 90% and absolute alco- special tissue parts.
hol for 2–4 hours or 12–24 hours. 3. Used for the demonstration of fats
3. Then clearing with xylol for half an and lipids.
hour to 1 hour or 2–4 hours. 4. Fixation is done in 10% formol saline
4. After that do impregnation with par- at 60˚C for 10–20 minutes.
affin for 2–3 hours at 58˚C–60˚C in 5. Then put in gum syrup and then cut
two changes. by freezing microtome (CO2 cooling
5. Then casting or blocking in molten system type).
wax and cool. 6. Staining.
URINE EXAMINATION 3. Other tests.

a. Correlate with leukocyte esterase.
Physical Examination
b. Urine microscopic examination
1. Color: (bacteria).
a. Straw colored normally (due to c. Urine culture.
urochrome).
4. Inference.
b. Colorless in polyuria.
a. Negative or positive.
c. Dark brown in oliguria.
2. Transparency:
For Leukocyte Esterase
a. Normally clear.
b. Turbid if pus, blood or bacteria. 1. Significance.
3. Odor: a. Pyuria.
a. No smell or aromatic smell normally. b. Acute inflammation.
b. Ammoniacal smell—decomposed c. Renal calculus.
urine. 2. Limitations.
c. Acetone smell—ketonuria. a. Interference: Oxidizing agents,
4. pH reaction: menstrual contamination.
a. Normally litmus blue to red (pH 3. Other tests.
around 6).
a. Urine microscopic examination
b. Alkaline pH—vegetarian diet, cit- (WBCs and bacteria).
rate, bicarbonates.
b. Urine culture.
c. Highly acidic—high-protein diet,
ketonuria. 4. Inference.
5. Specific gravity: a. Negative/trace/mild positive/
a. Normal is around 1.025. moderate positive/strong positive.
b. Temperature variation is ± 0.001
for every 3˚C. Chemical Examination
Proteinuria
Urine Dipstick Test
1. Seen in CCF, cystitis, prostatitis,
For Nitrite nephrotic syndrome, etc.
1. Significance. 2. Laboratory tests are based on precipi-
a. Gram-negative bacteriuria. tation of protein by chemical agents
b. Dependant on the conversion of or coagulation by heat.
dietary nitrate to nitrite by gram- 3. The commonly used tests are:
negative bacteria. a. Heat and acetic acid test.
2. Limitations. •• Precipitate increases on adding
a. Interference: Bacterial overgrowth. acetic acid in proteinuria
b. Only able to detect bacteria that re- •• Precipitate disappear on add-
duce nitrate to nitrite. ing acetic acid in phosphaturia.
b. Sulphosalicylic acid test. Hematuria

c. Esbach test—quantitative test. 1. The test is benzidine test.
2. In multiple myeloma—Bence-Jones 2. It will give a blue color in hematuria.
proteinuria.
3. False positive results by myoglobin,
a. These are light chain of Ig precipi- iron and peroxidase.
tated at 50˚C–60˚C.
Microscopic Examination
Glycosuria
1. Done in proteinuria, suspected UTI,
1. Seen in diabetes mellitus. etc.
2. Based on reduction of CuSO4 to yel- 2. Fresh morning sample of urine is ex-
low or red cuprous oxide. amined within 6 hours of voiding.
3. The main test is Benedict test (semi- 3. The urine sample is centrifuged for
quantitative). 3,000 rpm for 5 minutes and sedi-
a. False positive in alkaptonuria, urine ment is obtained.
with uric acid and creatinine. 4. Place a drop of sediment on a glass
slide and cover it with a coverslip.
Ketonuria 5. First look under low power and then
1. Seen in diabetes mellitus. in high power.
2. The ketone bodies are acetoacetic acid, 6. At least look 10 high power fields.
acetone and β-hydroxybutyric acid. 7. Examination without staining is
3. The main test is Rothera test will get enough, but if needed, we can do
a purple ring in ketonuria. staining also.
Bilirubinuria Organized Sediments

1. In hepatocellular and obstructive Organized sediments include various
jaundice. cells and urinary casts.
2. The tests are: Cells
a. Fouchet test. 1. Red blood cells: Appear as pale discs
•• Green color for biliverdin and may show crenated margins.
•• Blue color for bilicyanin. 2. Pus cells: These are neutrophils,
which appear as round, granular
b. Ehrlich test:
spheres larger than RBCs.
•• For urobilinogen—pink color 3. Epithelial cells: Have a single round
from top, if positive.
nucleus.
a. Renal tubular epithelial cells.
Bile Salt
b. Bladder epithelial cells.
a. In obstructive jaundice. c. Squamous epithelial cells.
b. The test is Hay’s sulfur test. 4. Bacteria: Usually seen better in gram-
c. The sulfur powder sinks, if positive. stained smear.
5. Fungus: Yeast cells can be seen in UTI 5. Tubular epithelial casts.

in DM. a. Two rows of cells in a narrow cast.
6. Parasites: Like Schistosoma, Trichomo- b. Seen in acute GN, tubular necro-
nas, etc. sis, CMV infection and transplant
7. Spermatozoa and foreign bodies. rejection.
Urinary casts: These are formed by coag- 6. RBC casts.
ulation of albuminous material and cells a. Yellow to orange.
in renal tubules (Fig. 1).
b. Seen as bundle of coins.
1. Hyaline casts.
c. Adherent to hyaline or granular
a. Colorless, homogenous and trans-
casts.
parent.
d. Seen in acute GN, SABE, renal in-
b. Most common and seen in many
farction and lupus nephritis.
renal diseases, diabetic retinopa-
thy and CCF. 7. WBC casts
2. Granular casts. a. Small granular casts in a clear matrix.
a. Fine and coarse granular casts. b. Admixed with RBCs and epithelial
b. Seen in chronic GN, nephrotic syn- cells.
drome, pyelonephritis, lead toxic- c. These are also adherent to hyaline
ity, etc. or granular casts.
3. Fatty casts. d. Seen in acute GN, acute pyelone-
a. Contain highly refractile globules. phritis and lupus nephritis.
b. Have epithelial cells and fat.
4. Waxy casts. Unorganized Sediments
a. Yellow and homogenous with 1. Unorganized sediments have little
irregular margins seen in tubu- diagnostic and prognostic value.
lar degeneration, renal failure or 2. May be crystalline or amorphous
transplant rejection. (Fig. 2).
Fig. 1: Different types of urinary casts

Fig. 2: Different unorganized sediments
In normal acidic urine: PACKED CELL VOLUME

1. Sodium and potassium urates: Amor-
1. Also called hematocrit.
phous yellow-red granules.
2. This is the volume of red cells ex-
2. Uric acid crystals: Yellow or red pressed as a percentage of the volume
brown and irregular. of the whole blood in the sample.
3. Calcium oxalate crystals: Refractile 3. Dried heparin, EDTA or double ox-
and octahedral. alate are satisfactory anticoagulants.
In normal alkaline urine: 4. Double oxalate mixture containing
1. Amorphous phosphate: Fine precipi- ammonium and potassium oxalates
tate. in the ratio 3:2 is commonly used.
This mixture does not alter the cell
2. Triple phosphate: Ammonium mag- morphology, because ammonium ox-
nesium phosphate. alate causes swelling and potassium
3. Calcium phosphate: Stellate prisms. oxalate causes shrinkage of RBCs.
4. Calcium carbonate: Colorless spheres 5. The common methods employed are:
or dumbbells. a. Wintrobe tube.
5. Ammonium biurate: Yellow brown •• Fill up to 10 mark by using a
spheres like thornapple. Pasteur pipette without any air
In abnormal urine: bubbles
1. Cysteine: Colorless and refractile. •• Then centrifuge for 30 minute
at 3,000 rpm
2. Tyrosine: Yellow fine needles.
•• Measure the length of RBC
3. Leucine: Yellow oily spheres. column and expressed as
4. Sulfonamide: Yellow brown and percentage
asymmetrical. •• Errors are due to inadequate
5. Cholesterol: Flat, notched plates. mixing and incomplete packing.
b. Microhematocrit. ERYTHROCYTE
•• By using capillary tubes coated SEDIMENTATION RATE
with heparin
1. Erythrocyte sedimentation rate (ESR)
•• Take capillary blood and cen-
is the rate at which RBCs sediment on
trifuge at high rates for 3 min.
their own weight, when anticoagulat-
ed blood is held in vertical column.
Values 2. It is expressed as the fall of RBCs in
1. Normal. mm at the end of 1 hour.
a. Men: 42%–52% (47%). 3. The whole process occurs in three
b. Women: 37%–47% (42%). stages.
2. Abnormal values. a. Stage 1 of aggregation (rouleaux
formation)—first 10 minutes.
a. High PCV.
b. Stage 2 of elimination (falling of
•• Newborns, high altitude, exer-
cells)—next 40 minutes.
cise (physiological)
c. Stage 3 of packing—last 10 minutes.
•• Dehydration, polycythemia,
burns (pathological). 4. ESR is measured as the length of the
plasma column above the red cell col-
b. Low PCV—pregnancy (physiolog-
umn at the end of 1 hour.
ical).
5. ESR is mainly determined by roule-
•• Anemias (pathological).
aux formation; which inturn is influ-
enced by fibrinogen (main), globulin,
Plasma Column albumin and lipid content of plasma.
1. Normally straw colored.
2. Yellow color—jaundice. Method
3. Pink or reddish—hemolysis. Westergren Method
4. Creamy white—hyperlipidemia.
1. Tube is 30 cm long and 2.5 mm bore
5. Brown—methemoglolbinemia.
diameter. Both ends are open.
2. Lower 20 cm is marked from 0 to 200
Buffy Coat and will have 2 mL blood.
1. Buffy coat is the thin middle zone 3. The anticoagulant used is 0.4 mL 3.8%
between RBC column and plasma sodium citrate for 1–6 mL of venous
column. blood.
2. Normal thickness is about 0.5–1 mm. 4. Fill upto zero mark and keep it vertical.
3. Used for estimation of WBC and 5. Take reading at the end of 1 hour.
platelets. 6. Normal value:
4. Increased thickness—leukocytosis a. Male: 1–5 mm at the end of 1
and thrombocytosis. hour.
5. Decreased thickness—leukopenia b. Female: 1–7 mm at the end of 1
and thrombocytopenia. hour.
Wintrobe Method Factors Influencing Erythrocyte

1. Wintrobe method is 11 cm long with Sedimentation Rate
2.5 mm bore diameter. 1. Plasma factors:
2. Fill anticoagulated blood (with dou- a. Fibrinogen and globulin (increase
ble oxalate mixture) up to zero mark
ESR).
and keep it undisturbed for 1 hour.
b. Plasma lipid content (decrease
3. Normal value:
ESR).
a. Male: 1–9 mm at the end of 1
hour. c. Albumin (decrease ESR).
b. Female: 1–20 mm at the end of 1 2. Red cell factors:
hour. a. Anemia (decrease ESR).
b. Shape and size of RBC’s.
Esrite Method 3. Anticoagulants:
1. This ESR pipette has a volume of 1.25 a. Oxalates and heparin may affect.
mL with 0.25 mL sodium citrate and 4. Products of tissue destruction and
1 mL blood.
inflammation.
2. The pipette is not graduated, but an
aluminium sheet with marking is
kept as background. Variations in Erythrocyte
3. This is better because easy to use, Sedimentation Rate
elimination of risk of infection, more 1. Rapid ESR.
accurate and highly convenient.
a. Pregnancy, menstruation (physi-
4. Normal values same as Westergren
ological).
method.
b. Anemia (except sickle cell), infec-
tion (pathological).
Sources of Error
c. Septicemia, RF, RA less than TB,
1. Improper anticoagulant. MI, shock, etc.
2. Inclination of tube. 2. Slow ESR.
3. Dirty tube. a. Newborn (physiological).
4. Air bubble. b. Sickle cell anemia, polycythemia,
5. Prolonged blood storage. allergy, CCF (pathological).
P
A Systemic
R Pathology
T
2
10 Blood Vessels
Chapter
RESPONSE TO INJURY 2. Release of several molecules.

3. Vasodilatation, hypercoagulable states,
Functions of Endothelial Cells leukocyte adhesion.
1. Maintenance of permeability. 4. Stimulation of smooth muscle cell
2. Elaboration of anticoagulants, anti- proliferation.
thrombotic and fibrinolytic regulators. a. Increased ECM collagen, elastin, etc.
a. Thrombomodulin, PGI2, TPA. b. Proteoglycans, GFs, cytokines.
b. Heparin-like molecules. 5. Intimal thickening.
3. Elaboration of prothrombotic mol-
ecules. Intimal Thickening (Stereotyped)
a. Tissue factor, VWF, TPA inhibitor.
4. Production of ECM. 1. Vascular injury → EC loss and EC
dysfunction → SMC proliferation
5. Modulation BF and reactivity.
and matrix production.
a. Vasoconstrictors—endothelins,
2. Injury → SMCs or their precursors
ACE.
move into intima → proliferate → in-
b. Vasodilators—NO, PGI2.
crease ECM production.
6. Regulation of inflammation and im-
a. The various stimuli are infection, in-
munity.
flammation, immuneinjury, phys-
a. Chemokines, IL-1, IL-6. ical trauma, toxic exposure, etc.
b. Selectins, VCAM-1, ICAM. b. Neointimal SMCs → cannot con-
c. Histocompatibility Ag. tract. Capacity to divide. Organ-
7. Regulation of cell growth. elles for protein synthesis—more.
a. Stimulators—PDGF, FGF. c. Repeat injury → lumen narrowing
b. Inhibitors—heparin, TGF-β. as in atherosclerosis.
8. Oxidation of LDL.
ATHEROSCLEROSIS
Responses 1. Presence of intimal lesions—athero-
1. Thrombosis, atherosclerosis, hyper- mas/atheromatous plaques/athero-
tensive vascular disorders. sclerotic plaques.
94 Part 2 u Systemic Pathology
2. Protrude into vascular lumen.

3. Atheroma—raised, soft and yellow
with lipid core. It is made up of four
layers.
•• Lipid core (IC/EC)
•• Cell debris
•• Macrophages, SMCs, foam cells,
lymphocytes, etc.
•• Outer fibrous cap—collagen,
proteoglycans, elastin, etc (Fig.
10.1).
Risk Factors
1. Major.
a. Non-modifiable.
•• Increased age
•• Male
•• Genetic abnormalities
•• Postmenopausal and family
history.
b. Modifiable.
•• Hyperlipidemia (hypercholes-
trolemia)
•• Hypertension (HTN)
•• Cigarette smoking
•• Diabetes mellitus (DM)
•• C-reactive proteins
•• Increased inflammation.
Fig. 10.1: Steps in atherosclerosis
2. Minor.
a. Homocyteinemia.
Pathogenesis
•• Increased LP-a
•• Thrombotic factors 1. Chronic(C/c) endotheFlialinjurydueto:
•• Obesity a. Hyperlipidemia.
•• Physical inactivity and stress b. HTN.
•• Chlamydia pneumonia infec- c. Smoking.
tion d. Hemodynamic factors.
•• Increased CHO diet and in- e. Infections, immune response and
creased saturated fat in body. toxins.
Chapter 10 u Blood Vessels 95
2. Endothelial dysfunction. f. Hemorrhage and thrombosis.

a. Increased permeability and accu- g. Can produce atheroembolism and
mulation of LPs. occlusion.
b. Leukocyte adhesion. h. Can leads to aneurysm and fissuring.
c. Monocyte adhesion.
3. Macrophage activation, foam cell for- Consequences
mation and platelet adhesion.
4. Release of factors and SMC re- Myocardial infarction (MI), cerebral
cruitment. strokes, aortic aneurysm, PVDs.
5. Smooth muscle cells engulf lipids and
also foam cells. Prevention
6. Smooth muscle cell proliferation and
1. Primary.
ECM production, collagen and EC lip-
id deposition. a. Delaying atheroma formation.
a. Early stages → plaques are aggre- b. Regressing established lesions.
gates of SMCs, foam cells, mac- c. Risk factor identification and elim-
rophages and EC lipids. ination.
b. Late stages → more connective tis- 2. Secondary.
sue (collagen and proteoglycans).
a. Prevention of recurrent conse-
Calcification also.
quences.
b. Use of aspirin (antiplatelets).
Morphology
c. Statins (hypocholesterolemic).
1. Fatty streaks. d. Beta blockers (anti-HTN).
a. Composed of lipid filled foam
e. Surgeries (bypass).
cells.
b. Not much raised.
c. Multiple minute yellow flat spots HYPERTENSION
can coalesce. Causes
d. Acts as precursors for atheroma.
2. Atheromas ( fibro-fatty plaques). 1. Essential HTN (90%–95%)—idiopathic.
a. Abdominal aorta is more involved. 2. Secondary HTN.
b. Preference of involvement. a. Renal—A/c GN, C/c renal dis-
•• Lower abdominal aorta > coro- ease, polycystic kidney, renal A
naries > popliteal artery (A) > stenosis and renin producing tu-
ICA > circle of Willis. mors.
c. At the periphery—neurovascular- b. Endocrine—adrenal hyperfunc-
ization. tion (Cushing syndrome and 10
d. Can undergo calcification and ne- aldosteronism), exogenous hor-
crosis. mones (glucocorticoids, OCPs),
e. Rupture, ulceration or erosion can pheochromocytoma, acromegaly,
occur. myxedema and thyrotoxicosis.
c. Cardiovascular—coarctation of Morphology
aorta, PAN, increased IVFV and
increased CO. 1. Hyaline arteriosclerosis.
d. Neurological—psychogenic, in- a. Pink, homogenous, hyaline thick-
creased ICT and A/c stress. ening.
b. Loss of underlying structure.
Pathogenesis
c. Narrowing of lumen.
1. Reduced renal Na+ excretion → in-
d. More generalized.
creased BV → increased CO → in-
creased BP. e. Due to leakage of plasma compo-
2. Vasoconstriction → increased periph- nents and increased ECM.
eral resistance (PR) → increased BP. f. In benign HTN.
3. Defects in vascular SM growth → in-
2. Hyperplastic arteriosclerosis.
creased vessel thickness → increased
PR → increased BP. a. In malignant HTN DBP > 120 mm
Hg with cerebral or renal injury).
Regulation of Blood Pressure b. Onion skin like concentric lami-
Mechanism Regulation of BP is given in nated thickening.
Fig. 10.2. c. Narrowing of lumen.
Fig. 10.2: Mechanism of regulation of BP

d. Increased SCMs and duplicated Aortic Aneurysm

basement membrane (BM).
1. Causes are atherosclerosis and tunica
e. Fibrinoid deposits and wall ne-
media degeneration.
crosis (necrotizing arteriolitis)—
prominent in kidney.
2. Commonly abdominal aorta is
invoved.
ANEURISMS
Pathogenesis
1. Localized abnormal dilatation of
blood vessel or heart. Thoracic AA produces—encroachment
2. True → involves all the layers. For of mediastinum, respiratory difficulty,
example, atherosclerotic, syphylitic, dysphagia, persistent cough (laryngeal
congenital and ventricular that fol- nerve), pain due to bone erosion, cardiac
low MI. problems and aortic rupture. Pathogene-
3. False → breach in vessel wall leads sis of atherosclerosis in given in Fig. 10.3.
extravascular hematoma, which com-
municates with IV space pulsating
hematoma. For example, ventricular
Morphology
rupture after MI and leak at the junc- 1. Usual position is below renal artery
tion of vascular graft. and above aortic bifurcation.
2. Inflammatory AA—dense periaor-
Classification tic fibrosis, abundant L, plasmacytes
a. Saccular—spherical outpouchings and macrophages, giant cells also.
involves small portion and contain 3. Mycotic AA—Bacteria primarily
thrombi. from Salmonella gastroenteritis, sup-
b. Fusiform—diffuse circumferential puration and destruction of media.
dilatation, involves long vascular
segment. Clinical Consequences
1. Rupture into peritoneal cavity and
Etiology retroperitoneum and leads to fatal
1. Atherosclerosis. hemorrhage.
2. Cystic degeneration of tunica media. 2. Obstruction of a branch and causes
3. Trauma. ischemic tissue injury.
4. Congenital defects (Berry aneu- a. Iliac artery—leg.
rysm). b. Renal artery—kidney.
5. Infections (mycotic and syphilitic). c. Mesenteric artery—GIT.
6. Mycotic infection through, d. Vertebral artery—spinal cord.
a. Embolization of septic thrombi. 3. Embolism from atheroma or mural
Extension of adjacent suppuration. thrombus.
Circulating pathogens. 4. Compression on adjacent structures.
Fig. 10.3: Pathogensis of aortic aneurism
5. Abdominal mass, which can stimu- DISSECTION

late a tumor.
1. Often aneurysmal and can rupture.
2. Tearing of wall and extravasation of
Syphilitic Aneurysm blood into wall.
1. In 3° syphilis—obliterative endarteri-
tis of vasa vasorum. Aortic Dissection
2. Ischemic injury of tunica media—
1. Blood filled channel within the aortic
leads to AA. wall.
2. Can rupture through adventitia.
Morphology 3. Can cause massive hemorrhage or
1. Obliteration and lumen narrowing. cardiac tamponade.
2. Scarring of wall. 4. Commonly in males (40–60) with se-
vere HTN and younger patients with
3. Inflammatory infiltrate of (L) and connective tissue disorders (Marfan).
plasma cells, which extending to me-
dia—syphilitic endarteritis.
Morphology
4. Patchy loss of medial fibers and mus-
cle cells. 1. Intimal tear usually in ascending aor-
ta with sharp edges.
5. Wrinkling of aortic intima—tree bark
2. Tear progress towards heart or dis-
appearance tally.
6. Leads to valvular insufficiency and 3. Hematoma usually spreads along
volume overload and hypertrophy of laminar plane (B/n middle and outer
left ventricle thirds).
7. This dilated heart is called cor bovi- 4. Sometimes hematoma into the lumen
num (cow heart). double-barreled aorta.
Fig. 10.4: Pathogensis of aortic dissection
5. Cystic medial degeneration without Clinical Course

inflammation.
1. Sudden excruciating pain.
2. Begin in anterior chest and radiates
Pathogenesis to back.
Pathogensis of aortic dissection is given 3. Cause of death—hemorrhage into
pericardial/pleural/peritoneal cavi-
as Fig. 10.4.
ties.
4. Retrograde progression leads to car-
Classification diac tamponade, aortic insufficiency
1. Type A—common and dangerous and MI.
5. Involvement of other arteries also.
(DeBakey—I and II).
a. Ascending only or both ascending
VASCULITIS
and descending.
Inflammation of blood vessel walls.
2. Type B—Not involving ascending
(DeBakey III) (Fig. 10.5).
Infectious Vasculitis
1. By Aspergillus, Mucor, bacterial pneu-
monia.
2. Syphilitic endarteritis.
3. Mycotic arteries and aneurysm.
Non-infectious Vasculitis
1. Immune-complex associated (Both
local and circulating complex).
a. In SLE (DNA –anti-DNA complex).
b. Associated with drug hypersensi-
Fig. 10.5: Classification of aortic dissection tivity (e.g. penicillin).
c. Associated secondarily with viral 3. Associated with helper T cells and

infections (e.g. Hep.B). MHC.
2. Anti-neutrophil cytoplasmic Ab (AN- 4. Responds to steroids (Fig. 10.6).
CAs). Morphology
a. Cytoplasmic localization.
1. Nodular intimal thickening with
•• Target Ag is proteinase 3 (PRs)
thrombosis.
•• Wegener granulomatosis.
2. Granulomatous inflammation in in-
b. Perinuclear localization ner media.
•• Target is myeloperoxidase
3. Fragmentation of internal elastic
(MPO)
lamina.
•• Microscopic polyangitis.
4. Heal by collagenous thickening and
c. Circulating Ab might not be present.
become fibrous cord.
3. Anti-endothelial cell Ab (AECAs).
Clinical features
a. Kawasaki disease.
1. Fever, fatigue, weight loss.
2. Facial pain or head ache, along with
Types of Non-infectious Vasculitis
polymyalgia rheumatica.
1. Large vessel vasculitis. 3. Tender temporal artery.
2. Medium vessel vasculitis. 4. Diplopia and loss of vision.
3. Small vessel vasculitis. Treatment
Large vessel vasculitis—giant cell ar-
Corticosteroids.
teritis.
Medium vessel vasculitis—PAN.
1. C/c granulomatous inflammation
(Not affect < 50 age). 1. Systemic vasculitis (Younger age
2. Affect mainly the cranial vessels, es- group).
pecially temporal. 2. Typically involves renal and visceral
3. Also affect vertibral, ophthalmic and arteries.
aorta. 3. Not involving pulmonary circula-
Pathogenesis tion.
1. T cell-mediated. Pathogenesis
2. Immune response against a vessel 1. Immune transmural necrotizing in-
wall Ag. flammation.
Fig. 10.6: Pathogenesis of non-infections vasculitis

2. Only one part of vessel circumference 2. Persistent pneumonitis, C/c sinusitis

involved. and ulcerations.
3. Aneurysmal dilatation. 3. Renal disease.
4. Ulceration, infarct, ischemia and 4. Fever, rashes, muscle and joint pain,
hemorrhage of those areas supplied neuritic pain.
by affected vessels.
5. Fibrinoid necrosis + (N), (E), (M), etc. TUMORS
6. Later fibrosis.
Hemangioma
Clinical features
1. Fever, malaise, weight loss, HTN. 1. Increased number of normal or ab-
normal vessels with blood.
2. Abdominal pain, melena, neurotic
2. Most are present from birth.
pain.
3. Most are localized and superficial.
Treatment
4. Extensive angiomatosis.
Cyclophosphamide and corticosteroids.
Small vessel vasculitis—Wegener gran- Capillary Hemangioma
ulomatosis.
1. In skin, s/c tissue, mucos membrane
1. Necrotizing vasculitis. of oral cavities, lips, liver, spleen and
2. Triad of: kidneys.
a. A/c necrotizing granulomas of RT. 2. Very common at birth and usually re-
gress by age 7.
b. Necrotizing/granulomatous vas-
3. Strawberry type/juvenile hemangio-
culitis of RT.
ma.
c. Necrotizing vasculitis of renal A
Morphology
and GN.
1. Bright red to blue, raised with intact
Pathogenesis
epithelium.
C-ANCAs associated. 2. Aggregates of thin walled capillaries.
Morphology 3. Blood filled and lined by flat EC.
1. Inflammatory sinusitis with granulo- 4. Stroma is only scanty.
mas. 5. Focal scarring and hemosiderin pig-
2. Ulcerative lesions of nose, palate, ment due to rupture.
pharynx rimmed by granulomas with 6. Pyogenic granuloma—a form of capil-
central necrosis. lary HA, which occur usually after trau-
3. Parenchymal granuloma and alveo- ma and with edema and inflammation.
lar hemorrhage.
4. Segmental necrotizing GN and cre- Cavernous Hemangioma
sentic GN.
1. Large dialated vascular channels.
Clinical features 2. Less circumscribed and deeper than
1. Males—more affected, age around 40. capillary HA.
Morphology 2. Sometimes viscera also.

1.
Red-blue, soft spongy masses. 3. Aggressive.
2.
Large blood filled cavernous spaces.
3.
Moderate amount of stroma. Transplant-associated KS
4.
Thrombosis and dystrophic calcifica- 1. Due to associate immunosuppressive
tion. therapy.
5. Vulnerable to traumatic ulceration 2. Mucosal, nodal and visceral involve-
and bleeding. ment.
6. Component of Von-Hippel-Lindau
disease (neoplasm of pancreas, liver AIDS-associated KS (Epidemic KS )
and kidney). 1. Particularly male homosexuals with
HIV.
KAPOSI SARCOMA 2. Involves nodes and viscera.
3. Wide spread.
1. Boderline or low grade malignant tu-
mors.
2. Common in AIDS patients. RAYNAUD PHENOMENON
1. Increased vasoconstriction of digital
Types of Kaposi Sarcoma arteries and arterioles.
2. Digits, toes, nose, ear lobes and lips
Chronic Kaposi sarcoma (KS) are involved.
(Classic KS) 3. Show red, white and blue from proxi-
1. Associated with underlying malig- mal to distal.
nancy/altered immunity. 4. Due to vasodilatation, constriction
and cyanosis respectively.
2. Multiple red to purple plaques or
5. Primary.
nodules.
a. Increased vasomotor response
3. In distal lower extremities and grad- (central/local).
ually progress.
b. Cold or emotion.
6. Secondary.
Lymphadenopathic KS (Endemic KS) a. Vascular insufficiency.
1. Skin and lymph node (LN) involve- b. Due to SLE, Buerger disease and
ment. atherosclerosis.
11 Heart
Chapter
HEART FAILURE b. Late → increased O2 demand →

myocardial failure → decompen-
1. Heart failure (HF) also called conges- sated HF.
tive heart failure (CHF). 3. Myocardial structural changes like
2. Commonly due to systolic dysfunc- hypertrophy.
tion (contractility). It can also be due a. Concentric.
to diastolic dysfunction.
•• In pressure overload (HTN,
3. Causes are IHD, HTN, DM, valve stenosis)
failure, overload, etc. •• Increased diameter of muscle
4. Cannot pump blood to meet the fibers
needs of body. •• Increase in wall thickness with-
5. Heart cannot pump the blood that de- out chamber size.
livered to it by venous circulation → b. Eccentric.
forward failure and is accompanied •• In volume overload (regurgita-
by venous congestion → backward tion, shunts)
failure. •• Increased length
6. Increased LVEDV → increased •• Increased wall thickness and
LVEDP → increased (VP). chamber size.
c. Increased O2 demand and tension.
Pathogenesis d. Myocardium becomes vulnerable
Pathways to ischemic injury.
1. Activation of neurohormonal systems.

Left-sided Heart Failure
a. Increased release of NA.
Left-sided heart failure is due to dam-
b. Increased RAAS working.
ming of blood in pulmonary circulation.
c. Increased ANF.
2. Frank-Starling mechanism.
Causes
a. Early → increased fiber length
→ increased force → increased CO 1. Ischemic heart disease.
→ compensated HF. 2. Hypertension.
3. Mitral or aortic valve disease. Morphology

4. Primary (1o) disease of myocardium.
1. Congestive hepatomegaly with nut-
meg appearance.
Morphology 2. Congested red centers of liver lobules
1. Myocardial infraction and valvular surrounded by pallor.
deformities. 3. With LVF—centrilobular necrosis.
2. Usually LV is dilated and hypertro- 4. Long standing—cardiac cirrhosis.
phied.
5. Congestive splenomegaly (increased
3. Hypertrophy and fibrosis of myocar-
dium. pressure in portal system).
4. Secondary (2o) enlargement of LA and 6. Sinusoidal dilatation of spleen.
AF → thrombosis. 7. Edema of bowel wall and ascites.
5. Increased pressure in pulmonary 8. Pleural and pericardial effusions.
veins → pulmonary congestion and 9. Ankle and pretibial edema (also ana-
edema. sarca).
6. Lungs are heavy and boggy with tran-
sudate, alveolar septal edema and al-
veolar edema. Clinical Features
7. Hemosiderin-laden macrophages in 1. Hepatomegaly.
alveoli (heart failure cells). 2. Splenomegaly.
3. Ascites.
Clinical Features 4. Pleural and pericardial effusions.
1. Dyspnea, cough, orthopnea, PND, 5. Edema.
tachycardia.
2. Systolic murmer, MR, S3, AF, cardio- ISCHEMIC HEART DISEASES
megaly.
Ischemic heart diseases (IHD) are caused
Right-sided Heart Failure due to imbalance between cardiac perfu-
sion and myocardial oxygen demand.
Right-sided heart failure (RSHF) alone is
very rare.
Causes
Causes 1. Increased demand—increased HR
and HTN.
1. Left ventricular failure—increased
pressure in pulmonary circulation. 2. Decreased O2 carrying capacity—
2. Tricuspid valve disease, left (L) to anemia, CO poisoning.
right (R) shunt (chronic pressure and 3. Decreased O2 of coronary blood flow
volume overload). BF—atherosclerosis.
3. Intrinsic lung parenchymal disease 4. Acute coronary syndrome—unstable
(cor pulmonale). angina, acute MI, SCD.
Chapter 11 u Heart 105
Pathogenesis 1. Typical or stable angina.

a. Episodic chest pain due to in-
The followings plays an important role in
creased myocardial O2 demand.
pathogenesis:
b. Squeezing/crushing retrosternal
1. Acute changes in plaque.
pain radiates to left arm or left jaw
2. Inflammation. or to back.
3. Thrombosis and emboli. c. Due to fixed coronary obstruction.
4. Vasoconstriction (Fig. 11.1). d. Treatment is adequate rest or ni-
troglycerine.
Plaque Disruption 2. Prinzmetal or variant angina.
1. By intraplaque hemorrhage, erosion, a. Occurring at rest due to coronary
ulceration, rupture, fissuring, etc. vasospasm.
2. Platelets release 2o molecules—TX- b. Responds to nitroglycerine or
A2, ADP, serotonin. CCBs.
3. Unstable angina or crescendo angina.
Acute Coronary Syndromes a. Increasing frequency of pain with
less exertion progressively.
Evolution of coronary artery disease is
b. Episode will be more intense and
long lasting.
Angina Pectoris c. Mural thrombus with variable ob-
Intermittent chest pain caused by tran- struction/vasospasm.
sient reversible myocardial ischemia. d. Also called preinfarction angina.
Fig. 11.1: Pathogenesis of coronary artery disease

Fig. 11.2: Diagram showing evolution of coronary artery disease
Myocardial Infarction Morphology

1. Necrosis of myocardium due to Mophological features of MI is listed in
ischemia. Table 11.1.
2. Caused by acute coronary thrombo- Clinical features
sis from atherosclerosis. 1. Severe crushing retrosternal pain ra-
3. Vasospasm and platelet aggression diates to neck, jaw, left arm epigas-
can contribute. trium, etc.
Response to ischemia 2. Long lasting (20 min) and not relived
Response to ischemia is shown in Figure by nitroglycerine.
11.3. 3. Sometimes asymptomatic.
Fig. 11.3: Response of myocardium to ischemia
4. Rapid and weak pulse. ** Markers are the cardiac troponins T

5. Dyspnea, pulmonary congestion and and I and creatine kinase-MB (CK-MB).
edema.
Complications
6. Cardiogenic shock in massive MIs.
7. Q and ST abnormalities and T-wave 1. Contractile dysfunction.
inversion. 2. Arrhythmias.
Table 11.1: Sequential changes in myocardium after MI
Time Gross features Microscopy

0–1/2 h None *Electron microscopy (EM)—myofibril relaxation,
mitochondrial swelling and glycogen decreases
½–4 h None *EM—sarcolemmal description
4–12 h Dark mottling starts *Coagulation necrosis, edema, hemorrhage.
Wavy bands at the rim.
12–24 h Dark mottling *Pyknosis of nuclei
Marginal contraction band necrosis.
Beginning of (N) infiltrate
1–3 day Yellow-tan infarct *Completed coagulation necrosis
Loss of nuclei and striations
(N) infiltrate ↑
3–7 day Hyperemic border *Early phagocytosis of dead cells by macrophages
Central yellow-tan
7–10 day Maximum yellow-tan center *Well developed phagocytosis
Red-tan margins Granulation tissue formation
10–14 day Red-grey depressed margins * ↑ Granulation tissue and collagen
New blood vessels
2–8 week Grey-white scar * ↑ Collagen and ↓ cellularity
> 2 month Complete scar *Dense collagen
3. Myocardial rupture. c. Mital valve (MV) prolapse.

4. Pericarditis. d. Myocarditis.
5. Infarct expansion. e. Dilated or hypertrophic cardiac
6. Mural thrombus and thromboembo- myopathy.
lism. f. Pulmonary HTN.
7. Ventricular aneurysm. g. Abnormalities of conducting sys-
8. Papillary muscle dysfunction. tem.
9. Progressive late HF. h. Myocardial hypertrophy.
Reperfusion i. Cause of death is VF.
1. Achieved by:
a. Thrombolysis (streptokinase, TPA). HYPERTENSIVE HEART
b. Balloon angioplasty. DISEASES
c. Coronary artery bypass graft. Cardiac Hypertrophy
2. Reperfusion injury can occur due to
O2 free radicals liberated by leuko- 1. Increased muscle mass.
cytes. This injury even occlude the 2. HTN → pressure overload → concen-
vessel → no reflow. tric hypertrophy.
3. Reperfusion site shows hemorrhage 3. AS, MR → volume overload → eccen-
and contraction band necrosis. tric hypertrophy.
4. In the absence of ATP, contraction 4. Hypertrophy → increased O2 demand
persists. → ischemia → HF.
5. Do not affect on stunned myocardi-
um (the myocardium failed to con- Systemic Hypertensive
tract due to injury of cells). Heart Disease
Left ventricular hypertrophy (LVH) (con-
Chronic Ischemic Heart Disease centric) with h/o HTN, impairs diastolic
1. Can be with or without previous in- filling.
farction.
2. Enlarged heart with LV dilatation Morphology
and hypertrophy. 1. Left ventricular hypertrophy and LA
3. Grey-white healed scar can be seen. enlargement.
4. Fibrous thickening and mural thrombi. 2. Increased interstitial fibrosis.
3. Irregular, enlarged and prominent
Sudden Cardiac Death nuclei with hyperchromasia → box-
car nuclei.
1. Within 24 hours of symptom onset.
2. Causes are:
Clinical Features
a. Congenital coronary artery abnor-
malities. 1. AF and CHF and IHD.
b. Aortic valve (AV), stenosis (AS). 2. Renal damage and stroke.
Pulmonary Hypertensive Heart 3. RHD—inflammation of pericardium,

Disease (Cor Pulmonale) myocardium and valves.
4. Chronic valvular deformities are
1. Right ventricular hypertrophy (RVH) most important consequences.
and dilatation due to pulmonary HTN 5. Diffuse and dense scarring of valves
caused by primary disease of lung pa- (most common mitral stenosis [MS]).
renchyma or pulmonary vasculature.
2. Acute → from massive pulmonary Morphology
embolism.
3. Chronic → RVH and dilatation. 1. Discrete inflammatory lesions—As-
choff bodies are present.
a. Aschoff bodies—central degen-
Morphology erating ECM, infiltrate of (L), (P)
1. Acute → may not show RVH, but and plump activated macrophages
show dilatation. (Anitschkow cells).
2. Chronic → RVH and dilatation. b. Anitschkow cells—abundant cyto-
plasm and central nucleus, wavy
ribbon like chromatin (caterpillar
Predisposing Diseases for cells).
Cor Pulmonale 2. Pancarditis with exudates.
1. Lung parenchymal diseases → 3. Valve.
COPD, fibrosis, pneumoconiosis, a. Fibrinoid necrosis along lines of
bronchiectasis. closure.
2. Pulmonary vessel diseases → throm- b. Verrucae formation (due to fibrin
boembolism, primary pulmonary precipitate).
HTN, arteritis. c. Inflammation and collagen degra-
3. Chest movement diseases → dation.
kyphoscoliosis, neuromuscular 4. C/c.
disease. a. Fibrosis and scarring.
4. Diseases inducing pulmonary artery b. Thickening of leaflets and chordae
constriction → metabolic acidosis, tendineae.
hypoxemia, C/c altitude sickness, c. Fibrous bridging and calcification →
idiopathic. fish mouth or buttonhole stenosis.
d. Obliteration of normal leaflet ar-
RHEUMATIC VALVULAR chitecture.
5. Valvular stenosis and regurgitation.
DISEASE OR RHEUMATIC
a. Involvement—mitral—aortic —tri-
HEART DISEASE cuspid—tricuspid—pulmonary.
1. Rheumatic heart disease (RHD) is the 6. MS.
cardiac manifestation of RF. a. LA dilates with mural thrombi
2. RF is a multisystem disease sequelae inside.
of poststreptococcal pharyngitis. b. Chronic → RVH.
Pathogenesis INFECTIVE ENDOCARDITIS

1. Streptococcal antigen (Ag) induces 1. Microbial invasion into valves and
antistreptococcal antibody (Ab). mural endocardium.
2. This antibody reacts with glycopep- 2. Destruction of cardiac tissue and form
tide (GP) Ag in heart, joint and other vegetations composed of necrotic de-
sites. bris, thrombosis and organisms.
3. Mainly caused by bacteria.
Clinical Features
1. Occur 3 weeks after streptococcal Acute Endocarditis
pharyngitis. 1. By highly virulent organisms affect-
2. Arthritis and carditis. ing normal heart.
3. Swollen and painful joint. 2. Fatal within 2–3 weeks.
4. Pericardial exudates and arrhythmias.
5. Cardiac dilatation and MS and CHF. Subacute Endocarditis
6. Stenosis, murmers, hypertrophy, etc. 1. By low virulent organisms affecting
abnormal heart.
Jone’s Major Criteria 2. Most will recover after antibiotic
1. Carditis. therapy.
2. Polyarthritis.
3. Subcutaneous nodules. Etiopathogenesis
4. Erythema marginatum of skin. 1. Heart lesions like RHD and indwell-
5. Sydenham chorea. ing catheters predispose to this by
seeding of bacteria and platelet ag-
Jone’s Minor Criteria gregation induction (prosthetic
valves also).
1. Fever.
2. Arthralgia. 2. Mainly by Streptococcus viridans.
3. Increased A/c phase reactants. 3. Also by Staphylococcus aureus, Haemo-
4. Leukocytosis. philus, etc.
5. Previous RF.
6. First degree AV block.
Clinical Features
1. Fever (most consistent).
Diagnosis 2. Fatigue, weight loss and flu-like syn-
Two major manifestations/one major and drome.
two minor manifestations with evidence 3. Splenomegaly subacute bacterial en-
of preceding streptococcal infection. docarditis (SABE) and murmers.
Complications CARDIOMYOPATHIES
1. Glomerulonephritis. 1. Intrinsic myocardial dysfunction.
2. Septicemia. 2. Includes (causes):
3. Arrhythmias. a. Inflammatory → myocarditis (1°).
4. Systemic embolization. b. Immunologic → sarcoidosis (2°).
c. Systemic metabolic diseases →
Libman-Sacks Endocarditis hemochromatosis (2o).
d. Muscular dystrophies.
1. Usually affect normal valves.
e. Idiopathic.
2. Sterile vegetation. 3. Primary—involves heart muscle only.
3. On both sides of valves. 4. Secondary—involves heart muscle as
4. As a part of SLE. a part of another disease.
Non-bacterial Thrombotic Dilated Cardiomyopathies

Endocarditis 1. Most common.
1. Sterile vegetations. 2. Progressive cardiac dilatation and
2. Caused by hypercoagulable states, systolic dysfunction.
endocardial trauma, etc. 3. Usually with hypertrophy.
3. Also called marantic endocarditis.
Pathogenesis
Major Forms of Vegetative Endocarditis 1. Viral.
Forms of vegetative endocardities are a. Virus → infection → myocarditis →
shown in Figure 11.4. dilated cardiomyopathy (DCM).
Fig. 11.4: Major forms of vegetative endocarditis

2. Alcohol and other toxic exposure. 2. Usually autosomal dominant (AD)

a. Alcohol → acetaldehyde → DCM. inheritance.
b. Alcohol → thiamine deficiency→ 3. Beta-myosin heavy chain is common-
DCM. ly affected.
c. Doxorubicin → DCM. 4. Myosin binding protein-C and tro-
3. Genetic and familial. ponin-T are also affected.
a. AD inheritance (X-linked and AR 5. Mutation → defective contractility
also seen). GF release compensatory hyper-
b. X-linked—dystrophin gene trophy and fibrosis later.
mutation defective cytoskeleton
due to defective dystrophin gene
Morphology
→ DCM.
c. Mitochondrial—decreased ATP → 1. Thick walled, heavy and hypercon-
DCM. tracting heart.
4. Peripartum. 2. Without ventricular dilatation.
a. Volume increase, PIH, nutritional 3. Disproportionate increase in thick-
deficiency and immunologic reac- ness of septal wall with respect to
tions leads to DCM. free wall. It is called asymmetrical
septal hypertrophy.
Morphology 4. Concentric hypertrophy of walls.
5. MS and plaque in the LV outflow.
1. Enlarged, flabby heart with dilatation
of all chambers. 6. Severe myocyte hypertrophy and in-
terstitial fibrosis.
2. Mural thrombi and valvular damage.
3. Myocytes are hypertrophied and en-
larged nuclei. Clinical Features
4. Fibrosis and scarring. 1. Dyspnea, harsh systolic ejection mur-
mer.
Clinical Features 2. Thrombus, IE, CHF, arrythmias.
Dyspnea on exertion, murmers.
Restrictive Cardiomyopathy
Hypertrophic Cardiomyopathy 1. Diastolic dysfunction and impaired
ventricular filling.
Hypertrophic cardiomyopathy (HCM)
involves myocardial hypertrophy, dia- 2. Causes are idiopathic, fibrosis, amy-
stolic dysfunction and ventricular out- loidosis, sarcoidosis, etc.
flow obstruction. 3. Genetic involvement is less defined.
Pathogenesis Morphology
1. Mutations (missense point muta- 1. Ventricles usually normal in size and
tions) of several genes encoding for cavities not enlarged.
sarcomere proteins. 2. Interstitial fibrosis are two forms.
a. Endomyocardial fibrosis (common). •• Endocardial fibrosis and with

••Fibrosis of endocardium and sub- mural thrombi
endocardium •• ↑ (E) → (E) degranulation →
↑ MBP release → endocardial
•• Decreased volume and compliance. damage necrosis → scarring
b. Loeffler endomyocarditis. and fibrosis.
12 Hematopoietic and
Lymphoid Systems
Chapter
CLASSIFICATION OF ANEMIA •• Autoantibodies—idiopathic,

drug induced, SLE.
Etiological b. Mechanical trauma to red cells.
Blood Loss •• Microangiopathic hemolytic
anemias—TTP, DIC
1. Acute—trauma.
•• Infections—malaria.
2. Chronic—GIT lesions, gynecological
disturbances.
Impaired Red Blood Cell Production
Increased Destruction of RBCs 1. Disturbance of stem cell proliferation
and differentiation.
1. Intrinsic abnormalities. a. Aplastic anemia, pure red cell
a. Hereditary. aplasia, anemia due to renal and
•• Membrane abnormalities— endocrine disorder.
spherocytosis, elliptocytosis, 2. Disturbance of proliferation and mat-
etc. uration of erythroblasts.
•• Enzyme deficiencies—deficiency a. Defective DNA synthesis.
of pyruvate kinase, G6PD, etc. •• Vitamin B12 and folate deficiency.
•• Disorders of Hb synthesis b. Defective Hb synthesis.
– Deficient globin—thalas- •• Deficient heme—iron-deficiency
semia anemia
– Abnormal globin—sickle cell •• Deficient globin—thalassemia
anemia. •• Anemia of renal failure.
b. Acquired. c. Unknown or multiple factors.
•• Membrane defect—PNH. •• Myelodysplastic syndrome and
anemia of chronic inflammation.
2. Extrinsic abnormalities.
a. Antibody mediated.
Morphological
•• Isohemagglutinins—transfu-
sion reactions, erythroblastosis 1. Normochromic normocytic.
fetalis 2. Hypochromic microcytic.
Chapter 12 u Hematopoietic and Lymphoid Systems 115
3. Macrocytic. 3. Hyperplasia of marrow red cell pro-

4. Others—spherocytosis, elliptocyto- genitors.
sis, sickle cell anemia. 4. Reticulocytosis in peripheral blood.
5. Splenomegaly is very common.
HEREDITARY SPHEROCYTOSIS 6. Congestion of cords of Billroth in
1. Inherited disorder characterized by an spleen.
intrinsic defect in the RBC membrane. 7. Increased phagocytes in spleen.
2. Autosomal dominant (75%) or auto- 8. Later cases—hemosiderosis due to
somal recessive (25%) inheritance. increased hemolysis.
9. Cholelithiasis may be also seen due
Pathogenesis to increased hemolysis.
1. The basic abnormality is with the ma-
jor membrane protein spectrin. Clinical Features
2. The spectrin is attached to membrane 1. Anemia, splenomegaly and jaundice.
at two points. 2. Increased osmotic fragility.
a. Through ankyrin and band 4.2 to 3. Splenectomy can correct anemia to
band 3.
a major extent, because the RBC de-
b. Through band 4.1 to glycophorin. struction mainly occurs in spleen.
3. The normal membrane stability is
maintained by spectrin—spectrin as
well as spectrin-intrinsic membrane SICKLE CELL ANEMIA
protein interactions. Sickle cell anemia is one of the major
4. In HS, mainly the spectrin-intrinsic hemoglobinopathies characterized by the
membrane protein interactions are presence of structurally abnormal hemo-
affected due to mutation of ankyrin, globins.
band 3 or spectrin genes.
5. As a result, the integrity of RBC mem-
brane is lost and certain fragments Etiopathogenesis
are separated off without much loss 1. Caused by a mutation in the beta-
in volume. globin chain.
6. Thus, RBCs assume a spherical shape 2. Results in the substitution of valine
to maintain the maximum volume.
for glutamic acid at the 6th position
7. These spherical RBCs because of their in the β-chain.
limited deformability get sequestrat-
ed in the splenic cords and eventually 3. Thus, the normal HbA is replaced by
destroyed by macrophages. HbS completely in homozygous and
half in heterozygous individuals.
4. These HbS molecules undergo po-
Morphology
lymerization on deoxygenation and
1. In smear—RBCs lack central pallor. these polymers distort the red cells,
2. Spherocytes are seen, but not diag- which assume a cresentic or sickle
nostic. shape.
5. The sickling is initially reversible by 9. Splenomegaly and congestion of red

reoxygenation. pulp.
6. Later the cells accumulate calcium, 10. Later, spleen undergoes hypoxic tis-
lose K+ and water and become irre- sue damage and eventually become a
versibly sickled. useless fibrous tissue. This process is
7. The determinants of sickling are: called autosplenectomy.
a. Presence of other Hb. 11. Many organs are affected by vascular
•• HbA and HbF reduce sickling congestion, thrombosis and infarction.
•• HbC increases sickling. 12. Bone marrow and penis are more

vulnerable to ischemic injury.
b. Concentration of HbS in the cell.
13. Hemosiderosis and gallstones are

•• HbS concentration increases
common.
sickling.
c. The duration of hypoxia.
Clinical Features
8. These sickled RBCs are recognized
and destroyed by mononuclear 1. Anemia, jaundice.
phagocytes. 2. Vaso-occlusive pain crisis.
9. Thus, produces a chronic extravascu- 3. Acute chest syndrome.
lar hemolytic anemia. a. Due to fat emboli from necrotic
10. Also produces microvascular ob-
marrow.
struction and leads to tissue damage b. Worsening of pulmonary and sys-
and pain crisis. temic hypoxemia.
4. CNS stroke.
Morphology 5. Aplastic crisis.
1. Chronic hemolytic anemia and pe- 6. Prone to infections.
ripheral reticulocytosis.
2. Increased bilirubin. G6PD DEFICIENCY
3. Microvascular obstruction. 1. X-linked disorder.
4. Sickled cells are seen in peripheral 2. G6PD deficiency leads to decreased
smear. production of reduced glutathione
5. Fatty changes in heart, liver and renal (GSH).
tubules. 3. This GSH is essential for RBCs to get
6. Hyperplasia of marrow erythroid protected from endogenous and ex-
progenitors. ogenous oxidants.
7. Bone resorption and new bone for- 4. G6PD deficiency becomes manifest-
mation may occur and leads to prom- ed when the patient is exposed to
inent cheek bones and skull changes. increased oxidant stress by infections
8. Extramedullary hematopoiesis in liv- and drugs like antimalarials, sulfon-
er and spleen. amides, nitrofurantoin, aspirin, etc.
5. Infections and certain drugs induce 6. Increased susceptibility to infections

phagocytes to produce oxidants like and intravascular thrombosis.
hydrogen peroxide. 7. The term paroxysmal is not explained.
6. This peroxide and other free radicals
attack the sulfhydryl group of Hb.
7. These oxidized Hb get denatured and
THALASSEMIA
precipitated to form intracellular in- 1. A group of disorders that resulting
clusions called Heinz bodies, which from mutations that decrease the rate
will damage the RBC membrane to of synthesis of α or β-globin chains.
cause intravascular hemolysis.
2 So, there is a deficiency of normal Hb
8. The affected RBCs again get damaged with secondary red cell abnormalities
in spleen, when the splenic phago-
caused by relative excess of the unaf-
cytes pluck out the Heinz bodies. As
fected globin chains.
a result, deformed RBCs are called
bite cells, are formed.
9. These bite cells are destroyed by Etiopathogenesis
splenic phagocytes and produce ex- 1. HbA is a tetramer composed of 2α
travascular hemolysis. and 2β chains.
10. Thus, produces anemia and a com-
2. Each α-chain is encoded by 2α-
pensatory reticulocytosis.
globin genes on chromosome 11 and
each β-chain is encoded by a single
PAROXYSMAL NOCTURNAL β-globin gene on chromosome 16.
HEMOGLOBINURIA
1. Paroxysmal nocturnal hemoglobinu- β-thalassemia
ria is the only hemolytic anemia re- Here, the defects can be in:
sulting from an acquired membrane
•• Transcription of beta-globin gene (β+)
defect secondary to a mutation that
affects myeloid stem cells. •• Translation of beta-globin mRNA
2. An X-linked disorder, which is rare (β°)
in community. •• Processing of mRNA (β+ or β0).
3. In this, PIGA gene which is respon- 1. β-thalassemia major.
sible for an intramembranous glyco- a. β°/β° or β°/β+ (homozygous or
lipid anchor—PIG, is get mutated. compound heterozygous).
4. As a result, the PIG deficient RBCs b. Severe symptoms.
get lysed by the activated comple- 2. β-thalassemia intermedia.
ment system.
a. β+/β+.
5. Here, the hemolysis occurs nocturnal-
b. Moderately severe course.
ly because the blood becomes acidic
during sleep due to carbon dioxide 3. β-thalassemia minor (trait).
retention and an acidic pH promotes a. β/β+ or β/β0 (Box 12.1).
hemolysis. b. Asymptomatic or mildly anemic.
•• β—normal β-globin chain Box 12.1: WHO classification of acute leukemia

•• β+—reduced β-globin synthesis 1. AML with recurrent chromosomal
•• β0—no β-globin synthesis. translocations
•• AML with t(8;21)(q22;q22); CBFa/ETO
4. The anemia in β-thalassemia is due to:
fusion gene
a. Reduced β-globin and inadequate •• AML with inv(16)(p13;q22); CBFb/
HbA. Thus, MCHC decreases and MYH11 fusion gene
cells become microcytic and hypo- •• AML with t(15;17)(q22;21.1); PML/RARa
chromic. •• AML with t(11q23;variant)
b. Excess of α-chains stand as un- 2. AML with multilineage dysplasia
•• With prior myelodysplastic syndrome
paired and form insoluble precipi-
•• Without prior myelodysplastic
tates, which damage RBC mem- syndrome
brane and induce extravascular 3. AML, therapy related
hemolysis in spleen. •• Alkylating agent related
5. Also leads to destruction of erythro- •• Epipodophyllotoxin related
blasts in bone marrow and this inef- 4. AML, not otherwise classified
fective erythropoiesis leads to: •• Subclasses M0-M7
a. Increased iron absorption and sec- Here, the abnormal Hb produces less
ondary hemochromatosis. damage to RBC membrane, so that anemia
b. Increased erythropoietin levels and is less when compared to β-thalassemia.
BM expansion, which ultimately
results in skeletal abnormalities.
Morphology
a-thalassemia 1. b-thalassemia minor.
a. Features confined to peripheral
a-thalassemia results from deletions of
blood.
α-globin genes.
•• Microcytic and hypochromic
1. Hydrops fetalis.
RBCs
a. --/-- (all the 4 genes deleted).
•• Normal shape
b. Fetus die in utero.
•• Target cells may be seen.
2. HbH disease.
a. --/-α (3 genes deleted). 2. β-thalassemia major.
b. Moderately severe anemia due to a. Peripheral smear.
ineffective oxygen delivery. •• Microcytosis and hypochromia
3. Alpha thalassemia trait. •• Anisopoikilocytosis
a. --/αα or -α/-α (2 genes deleted). •• Reticulocytosis.
b. Asymptomatic or mild symptoms. b. Bone marrow.
4. Silent carrier. •• Hyperplasia of erythroid pro-
a. -α/αα (only 1 gene deleted). genitors
b. Asymptomatic, normal RBCs. •• BM expansion.
c. Others. Morphology
•• Skeletal deformities
1. Red blood cells are microcytic and
•• Hepatosplenomegaly
hypochromic.
•• Lymphadenopathy
2. Decreased MCV, MCH and MCHC.
•• Hemochromatosis
3. Increased erythropoietin levels and
•• Growth retardation and cachexia.
decreased Hb.
4. Marrow response is blunted due to
IRON DEFICIENCY ANEMIA Fe deficiency, so that marrow cellu-
Iron deficiency anemia is most common larity is only slightly elevated.
form of anemia. 5. Reticulocyte count is usually normal.
Iron metabolism is given in Figure 12.1.
Etiology
1. Low dietary intake—poor economy, Clinical Features
anorexia. 1. Weakness, restlessness and pallor.
2. Malabsorption syndromes—sprue, 2. Thinning, flattening and eventually
celiac disease, etc. spooning of fingernails (koilonychia).
3. Increased demand not met by normal
3. Pica—a neurobehavioral problem
intake.
characterized by consumption of
a. Pregnancy and infancy.
non-foodstuffs like dirt or clay.
4. Chronic blood loss.
a. GIT bleeds.
Biochemistry
b. Female genital tract bleeding.
1. Low serum ferritin and low serum
Pathogenesis iron levels.
2. Low transferrin saturation.
Decreased iron leads to decreased heme
3. Increased TIBC.
synthesis, decreased Hb and anemia.
Fig. 12.1: Iron metabolism

4. Response to iron therapy. and thus results in a delay in nuclear

5. Decreased marrow iron. maturation and cell division.
2. But the cytoplasm and RNA synthe-
Treatment (Rx) sis occurs normally, which leads to
nuclear-cytoplasmic asynchrony.
1. Correction of the disorder.
3. This leads to anemia by:
2. Correction of the deficiency—oral
and parenteral therapy. a. Destruction of megaloblasts in
marrow.
b. Decreased number of macrocytes
MEGALOBLASTIC ANEMIA
(RBCs) in blood.
Etiology
Folate Deficiency Morphology
1. Peripheral blood.
1. Inadequate dietary intake.
a. Hypersegmented neutrophils (ear-
a. Alcoholics, infants, old age.
ly changes).
2. Malabsorption.
b. Macrocytic RBCs.
a. Tropical sprue, Crohn disease, ce-
liac disease, gastrectomy. c. Giant metamyelocytes.
3. Excess demand. d. Anemia, thrombocytopenia and
granulocytopenia.
a. Pregnancy, lactation, infancy.
2. BM.
b. Malignancy, tuberculosis, RA.
a. Hypercellular.
4. Excess urinary loss.
b. Megaloblasts (large RBC precur-
a. Alcoholic liver disease, CCF.
sors).
5. Drugs.
•• Fine chromatin and abundant
a. Phenytoin and methotrexate.
basophilic cytoplasm.
c. Giant metamyelocytes.
Vitamin B12 deficiency
d. Giant megakaryocytes with bizarre
1. Inadequate dietary intake. multilobed nuclei.
a. Strict vegetarians, breastfed infants.
2. Malabsorption. Vitamin B12 Metabolism
a. Gastric causes—pernicious ane- 1. Vitamin B12 combines with IF in
mia, gastrectomy. stomach and reaches distal ileum.
b. Intestinal causes—topical sprue, 2. Then vitamin B12-IF complex is taken
Crohn disease.
to the mucosal cells and there the IF
get destroyed.
Pathogenesis 3. Later the vitamin B12 complex is
1. Folate and vitamin B12 deficiencies coupled with a transporter protein
leads to impaired DNA synthesis transcobalamin-2.
4. Then the vitamin B12-TC2 complex a. Microbiological.

transported to liver, BM and other b. Radioasssay.
cells by circulation. 3. Red cell folate assay.
Folate Metabolism Treatment (Rx)

Absorbed directly from small intestine a. Hydroxocobalamin injection and fo-
(Fig. 12.2). lic acid tablets.
b. Blood transfusion should be avoided.
PERNICIOUS ANEMIA
Anemia due to vitamin B12 deficiency re-
sulting from inadequate gastric produc-
tion or defective functioning of IF.
Etiology
1. Circulating autoantibodies like antipa-
rietal cell Ab and anti-IF Ab are seen.
2. Increased occurrence in autoimmune
diseases like Grave disease, thyroidi-
tis, vitiligo, DM, etc.
3. Increased incidence in families.
Fig. 12.2: Folate metabolism
4. Corticosteroids are found to be use-
ful in treatment.
Lab Diagnosis
Tests for Vitamin B12 Deficiency Pathogenesis
1. Serum vitamin B12 assay. 1. Vitamin B12 metabolism and role of
IF is mentioned previously.
a. Microbiological.
2. So when the IF becomes defective,
b. Radioassay.
the absorption of vitamin B12 willnot
2. Schilling test. occur properly and which leads to a
a. 24 hour urinary excretion test. vitamin B12 deficient state.
3. Enzyme levels.
a. These enzymes with vitamin B12 Morphology
as cofactor are estimated.
1. Blood and BM similar as megaloblas-
tic anemia.
Tests for Folate Deficiency
2. Gastric atrophy of acid and pepsin
1. Urinary excretion of FIGLU. secreting portion.
2. Serum folate assay. 3. Cellular atypia of gastric secretion.
4. Peripheral neuropathy and spinal APLASTIC ANEMIA

cord damage.
In aplastic anemia, the multipotent my-
eloid stem cells are suppressed, leading
Diagnostic Criteria to marrow failure and pancytopenia.
1. Major criteria.
a. Low serum B12 level. Etiopathogenesis
b. Megaloblastic anemia. 1. Primary aplastic anemia.
c. Presence of IF Ab. a. Fanconi’s anemia—congenital and
2. Minor lab criteria. AR inheritance.
a. Anemia and macrocytosis. b. Immune causes—acquired.
2. Secondary aplastic anemia.
b. Hypergastrinemia.
a. Drugs.
c. Presence of parietal cell Ab.
••Dose related.
d. Gastric pH above 6. – Antimetabolites (methotrexate)
3. Minor clinical criteria. – Mitotic inhibitors (daunorubi-
a. Neuropathy. cin)
b. Hypothyroidism. – Alkylating agents (busulfan)
c. Family history. – Anthracyclines.
4. Reference standard criteria. ••Idiosyncratic.
– Chloramphenicol
a. Schilling test showing malabsorp-
– Phenylbutazone
tion of oral vitamin B12, which is
corrected by IF administration. – Chlorpromazine
– Sulpha drugs.
b. Toxic chemicals—benzene deriva-
Clinical Features
tives, arsenic compounds.
1. Anemia, glossitis, gastric atrophy. c. Infections—hepatitis, EBV, AIDS.
2. Peripheral neuropathy and retrobul- d. Others associated with SLE and X-
bar neuritis. ray medications.
3. Spinal cord degeneration.
4. Hepatosplenomegaly, CCF, hemor- Clinical Features
rhages, etc. Anemia, hemorrhage and infections.
Treatment (Rx) Morphology

1. Parenteral vitamin B12 supplementa- 1. Peripheral blood.
tion. a. Normochromic normocytic anemia.
2. Corticosteroids for autoantibodies. b. Reticulocyte count is highly re-
3. Treatment of neuropathy and duced.
gastric atrophy. c. Decreased WBC count (leukopenia).
Table 12.1: Microcytic hypochromic anemias
Features Iron deficiency Anemia due to Thalassemia Sideroblastic

anemia C/c disorders anemia
MCV, MCH, MCHC ↓ ↓ ↓↓ ↓↓
Serum iron ↓ ↓ Normal ↑
TIBC ↑ Normal or ↓ Normal Normal
Serum ferritin ↓ ↑ Normal ↑
Marrow iron Absent Present ↑ ↑
Iron in normoblast Absent Absent Present Ring sideroblast
Hb electrophoresis Normal Normal Abnormal Normal
d. Decreased platelet count (throm- Types

bocytopenia).
1. Relative.
2. BM.
a. Due to hemoconcentration—in
a. Hypocellular.
prolonged dehydration.
b. Pancytopenia.
2. Absolute.
c. Stem cells also decrease.
a. Primary—polycythemia vera.
d. Increased amount of fat. ••
Mutations in erythropoietin
receptor.
Treatment (Rx) b. Secondary—increased erythropoi-
1. Elimination of cause. etin levels.
2. Blood transfusion. ••Appropriate—lung diseases,
high altitude, cyanotic heart dis-
3. Prevent infections.
ease, etc.
4. BM stimulators.
••Inappropriate—erythropoietin
5. Immunosuppressive therapy. secreting tumors (RCC, hepa-
6. BM transplantation. toma).
— Increased erythropoietin use
MICROCYTIC HYPOCHROMIC (athletes).
ANEMIAS
Polycythemia Vera
The different types of microcytic hypochro-
mic anemias are explained in Table 12.1. 1. Due to excessive neoplastic prolifera-
tion and maturation of myeloid ele-
ments (erythroid, granulocytic and
POLYCYTHEMIA megakaryocytic) and producing a
1. Also called erythrocytosis. panmyelosis.
2. Denotes an increase in the blood con- 2. Low erythropoietin level is a charac-
centration of red cells. teristic feature.
3. Hb concentration also increases. 3. Have a mutation in JAK2.
Morphology 2. The clinical features of leukemia like

splenomegaly, lymphadenopathy
1. Increased blood volume and viscosity.
and hemorrhages are usually absent.
2. Plethoric congestion of all organs.
3. Thrombosis and infarctions can be seen
Myeloid Leukemoid Reaction
mainly in heart, spleen and kidneys.
4. Hepatosplenomegaly can be seen. Much more common.
5. Hemorrhages usually from GIT,
oropharynx and brain. Etiology
6. Basophilia can be seen in peripheral 1. Infections—Staphylococcus pneumonia,
blood. disseminated TB, sepsis, meningitis,
7. Hypercellular BM. endocarditis, etc.
8. Some degree of marrow fibrosis can 2. Intoxications—eclampsia, mercury-
also be seen. poisoning, severe hemolysis, etc.
Clinical Features Morphology

1. Patients will be plethoric and often 1. Leukocytosis (not exceeding 1,00,000/
cyanotic.
µL).
2. Pruritis and peptic ulcer due to hista-
2. Increased immature cells (meta-my-
mine from basophils.
elocytes, myelocytes, blasts).
3. Headache, dizziness, hematemesis,
melena. 3. Similar to CML.
4. Hyperuricemia. 4. Toxic granulation and Dohle bodies
5. Spent phase—myelofibrosis occurs. in (N) cytoplasm.
6. Blast crisis may occur. 5. Anemia and thrombocytosis.
Treatment (Rx) Lymphoid Leukemoid Reaction

1. Phlebotomy. Etiology
2. Anticoagulants. 1. Infections—IMN, CMV infection,
3. Chemotherapy. chickenpox, measles, TB.
4. Interferon-alpha. 2. Malignancies like bone metastasis.
LEUKEMOID REACTION Morphology

1. Leukemoid reaction is defined as a 1. Leukocytosis not exceeding 1,00,000/
reactive excessive leukocytosis in the
µL.
peripheral blood resembling that of
leukemia in a subject, who does not 2. Increased mature lymphocytes.
have leukemia. 3. Similar to CLL.
Fig. 12.3: Etiopathogenesis of IMN
Myeloid Leukemoid Reaction Morphology

vs CML 1. Peripheral blood leukocytosis.
1. NAP score is high in leukemoid reac- 2. More than half of WBCs will be atypi-
tion. cal lymphocytes, which are large cells
2. Philadelphia chromosome is absent with abundant cytoplasm contain-
in leukemoid reaction. ing azurophilic granules and folded
nucleus.
INFECTIOUS 3. Generalized lymphadenopathy.
MONONUCLEOSIS 4. Cells resembling RS cells may be
seen.
1. Acute self-limiting disease.
5. Enlarged spleen infiltrated with atyp-
2. Mainly affecting the adolescents and
ical lymphocytes.
young adults.
6. Liver is enlarged and with parenchy-
3. Caused by B-lymphotropic EBV.
mal necrosis.
4. Characterized by:
7. Abundant atypical lymphocytes are
a. Fever, sore throat and generalized
seen in liver also.
lymphadenopathy.
b. Atypical lymphocytes. Clinical Features
c. Ab and T-cell response to EBV.
1. Prodromal period (3–5 days).
a. Mild symtoms.
Pathogenesis
b. Malaise, myalgia, headache, fatigue.
Usually, transmitted by direct oral con- 2. Frank clinical features (7–21 days).
tact and so it is also called kissing cousin a. Fever, sorethroat, generalized
syndrome. Etiopathogenesis of IMN is lymphadenopathy.
shown in Figure 12.3. b. Hepatosplenomegaly and splenitis.
c. Erythematous and maculopapular 2. Basic defect is acquired mutations in

skin eruptions. transcription factors that inhibit nor-
d. Neurologic manifestations (men- mal myeloid differentiation and lead
ingitis, encephalitis). to accumulation of cells at early stag-
e. Pneumonia and cardiac involve- es. For example, (15:17) translocation
ment.
in acute promyelocytic leukemia.
3. Can progress to Burkitt lymphoma
and B cell NHL. Classification of acute myelogenous
leukemia is shown in Table 12.2.
ACUTE MYELOGENOUS Morphology

LEUKEMIA
Peripheral Blood
Primarily, affects older adults with the
median age being 50 years. 1. Anemia.
2. Thrombocytopenia (< 50,000/µL).
Pathophysiology 3. WBC—may be subnormal or highly
1. Arise from myeloid stem cells and elevated.
give rise to monoclonal proliferations 4. Increase myeloblasts and promyelo-
that replace the normal BM cells. cytes.
Table 12.2: Classification of acute myelogenous leukemia
FAB class Morphology Cytochemistry

M0—minimally differentiated Blasts without differentiation. MPO –ve
Have myeloid lineage antigens.
M1—AML without Myeloblasts predominate. MPO +ve
maturation Auer rods are seen.
M2—AML with maturation Promyelocyte predominate. MPO+++
Auer rods may be seen.
M3—acute promyelocytic Hypergranular promyelocytes. MPO+++
leukemia Multiple Auer rods per cell.
M4—acute myelomonocytic Both myeloid and monocytic series MPO++
leukemia in peripheral blood. Non-specific esterace +ve
M5—acute monocytic M5A—poorly differentiated Non-specific esterace++
leukemia monoblasts M5b—differenciated
promonocytes and monocytes
M6—acute erythrocytic Erythroblast predominant. PAS +ve
leukemia Myeloblasts and promyelocytes MPO +ve
also seen
M7—acute megakaryocytic Undifferentiated blasts react with Platelet peroxidase +ve
leukemia antiplatelet Ab.
BM 8. Gum hypertrophy.
9. Chloroma.
1. Marrow is hypercellular.
10. Meningeal involvement.
2. BM tightly packed with leukemic
blast cell.
Treatment (Rx)
3. Myeloblasts are large cells with deli-
cate chromatin, 3–5 nucleoli and 1. Treatment of anemia and hemorrhage.
azurophilic granules in cytoplasm. 2. Treatment of infection.

4. Distinctive red staining rod-like 3. Cytotoxic drug therapy.
structures called Auer rods can be a. Combination of cytosine arbinoside,
seen in myeloblasts. anthracycline and 6-thioguanine.
5. Decreased erythropoiesis. b. Amsacrine can be added.
6. Decreased megakaryocytes. 4. BM transplantation.
Immunophenotype Prognosis
Most express some combination of myel- 1. AML is most malignant of all leu-
oid associated antigens like CD13, CD14, kemias with a median survival with
CD15, CD64, CD117 and CD33. treatment is 12–18 months.
2. Remission rate is low and shorter du-
Histochemistry ration of remission.
1. Positive for enzyme myeloperoxidase. CHRONIC MYELOGENOUS

2. Auer rods are positive for peroxidase. LEUKEMIA
3. Monocytic differentiation is dem-
1. Primarily affect adults between 25
onstrated by staining for lysosomal and 60 years of age with peak inci-
non-specific esterase (NSC). dence in the 4th and 6th decades of
4. Positive for Sudan black. life.
5. PAS positive in M6 and acid phos- 2. Marked by hyperproliferation of
phatase positive in M4 and M5. neoplastic myeloid progenitors that
retain the capacity for terminal dif-
ferentiation.
Clinical Features
1. Pallor, fatigue, lethargy. Pathophysiology
2. Petechiae, bleeding gums.
1. Caused by the effect of reciprocal
3. Infections and fever.
translocation between chromosomes
4. Bone pain and tenderness. 9 and 22 forming the Philadelphia
5. Lymphadenopathy. chromosomes (t9;22).
6. Hepatosplenomegaly. 2. Involves the fusion of BCR gene with
7. Leukemic infiltration of kidney. the ABL gene.
3. BCR/ABL fusion brings about the fol- Cytochemistry

lowing changes.
1. Reduced NAP score.
ABL protein activates some kinas-
a. 2. Elevated serum B12 and B12 binding
es, which inhibits apoptosis. capacity.
b. Ability of ABL protein to act as a 3. Hyperuricemia.
DNA binding protein is altered.
c. Binding of ABL to actin filaments Clinical Features
is increased. 1. Weakness, pallor, tachycardia (ane-
4. Mechanisms leading to blast phase are: mia).
a. Structural alterations in p53 gene. 2. Weight loss, anorexia, night sweats
b. Structural alterations RB gene. (increase BMR).
c. Alterations in RAS oncogene. 3. Splenomegaly.
4. Bleeding tendencies like easy bruis-
d. Alterations in MYC oncogene.
ing, epistaxis.
e. Release of cytokine IL-1β. 5. Gout, visual disturbances and lymph-
f. Inactivation of tumor suppressor— adenopathy.
phosphatase A2.
Treatment (Rx)
Morphology
1. Removal of all clones with BCR/ABL
1. Blood. fusion protein.
a. Anemia (normocytic normochro- a. Imatinib oral therapy.
mic). b. BM transplantation.
b. Marked leukocytosis (2,00,000/µL). c. IFN-alpha.
c. Promyelocytes, myelocytes, d. Chemotherapy.
metamyelocytes and band forms e. Splenectomy, splenic radiation, etc.
can be seen.
d. Platelets : Normal or raised (throm- Prognosis
bocytosis).
•• Chronic phase—myelocytes and Better than AML, but worse than CLL.
metamyelocytes
•• Accelerated phase—increased ACUTE LYMPHOBLASTIC
basophils and thrombocytopenia LEUKEMIA
•• Blastic phase—basophilia.
1. Also called precursor (immature) B
2. BM. and T cell leukemia.
a. Hypercellular. 2. Most common malignancy of chil-
b. Predominantly myeloid cells. dren under 4 years of age.
c. Decreased erythropoiesis. 3. B-cell acute lymphoblastic leukemia
d. Megakaryocytes usually normal. (ALL) is more common (80%) than
Table 12.3: Classification of acute lymphoblastic leukemia
FAB class Morphology Cytochemistry

L1—Childhood ALL (B-ALL Homogenous lymphoblasts PAS +/-
and T-ALL) —scanty cytoplasm, round nucleus Acid phosphatase +/-
and inconspicuous nucleoli
L2—Adult ALL (T-ALL) Heterogenous lymphoblasts PAS +/-
—irregular nucleolus and large Acid phosphatase +/-
nucleoli
L3—Burkitt type ALL (B-ALL) Large homogenous PAS -ve
lymphoblasts—cytoplasmic Acid phosphatase -ve
vacuolation
Table 12.4: Subtypes of ALL
Subtype FAB class Markers

Pre B-ALL L1, L2 CD10 and TdT
B-cell ALL L3 CD10 and TdT
T-cell ALL L1, L2 CD10 and TdT
T-cell ALL (20%). Classification of Cytochemistry

acute lymphoblastic leukemia is
shown in Table 12.3 and subtypes of 1. Positive for:
ALL is shown in Table 12.4. a. PAS.
b. Acid phosphatase.
Pathophysiology 2. Negative for:
Block in differentiation and accumulation a. MPO.
of blasts in BM and peripheral blood. b. Sudan black.
c. NSE.
Morphology
1. Peripheral blood. Immunophenotype
a. Anemia.
1. Express TdT.
b. Thrombocytopenia.
c. WBC—variable. 2. B-cell ALL—positive for CD19, CD10
d. Increased lymphoblasts. and CD9a.
2. BM. 3. T-cell ALL—positive for CD1, CD2,
a. Malignant undifferentiated pre- CD3, CD5 and CD7.
cursors of B or T cells. 4. Pre B-cell ALL shows Philadelphia
b. Megakaryocytes reduced or absent. chromosome.
Clinical Features 2. More commonly in middle and older

age groups with a male preponder-
1. B-cell ALL. ance.
a. In children.
b. Lymphadenopathy, hepatospleno- Pathophysiology
megaly.
c. CNS infiltration. 1. Suppression of normal B cell function.
d. Testicular and cutaneous involve- 2. Later normal marrow elements are
ment. replaced by neoplastic B cells.
2. T-cell ALL.
a. In adults. Morphology
b. Mediastinal mass or pleural effu- 1. Peripheral blood:
sion. a. Anemia and mild reticulocytosis.
c. Anemia, neutropenia, thrombocy- b. Marked leukocytosis (50,000–
topenia. 2,00,000/µL).
d. Lymphadenopathy, hepatospleno- c. About 90% of WBCs are mature
megaly and CNS infiltration. small lymphocytes.
d. Smudge or basket cells may be
Treatment (Rx) present.
1. Chemotherapy. e. Later neutropenia.
a. Combination of vincristine, pred- f. Thrombocytopenia.
nisolone, anthracyclines and L-as- 2. BM:
paraginase. a. Increased lymphocyte count.
2. BM transplantation. b. Decreased myeloid and erythroid
precursors.
Prognosis 3. LNs:
a. Certain foci of mitotically active
1. High remission rate and prolonged
cells-proliferation center.
duration of remission.
b. Increased number of small lym-
2. Survival.
phocytes.
a. Adults: 12–18 months.
b. Children: 33 months (if CNS in- Cytochemistry
volved) or 60 months (if CNS not
involved). 1. Coomb’s test +ve.
2. Decreased serum Ig levels.
CHRONIC LYMPHOCYTIC
LEUKEMIA Immunophenotype
1. Also called B-cell chronic lymphocyt- 1. Typically +ve for CD5.
ic leukemia (CLL) or small lympho- 2. Trisomy 12 can be seen.
cytic lymphoma. 3. Also CD19, CD20 and CD23.
Clinical Features Morphology

1. Weakness, fatigue. 1. Cells are round and uniform with
2. Lymphadenopathy, hepatosplenom- round or oval nuclei containing two
egaly. to five prominent nucleoli and mod-
3. Hemorrhagic manifestations, in- erate amount of basophilic cytoplasm
creased infections. with lipid vacuolation.
2. High mitotic rate.
Treatment (Rx) 3. Numerous macrophages containing
nuclear debris are often surrounded
1. Palliative and symptomatic. by a clear space to produce a starry
2. Cyclophosphamide, steroids, radio- sky pattern.
therapy and splenectomy.
Immunophenotype
Prognosis
1. Positive for CD10, CD19 and CD20.
1. Stage A: Lymphocytosis alone—10 2. Express surface IgM.
years.
3. Traslocations of MYC gene on chro-
2. Stage B: Lymphocytosis, LNs, hepa- mosome-8.
tosplenomegaly—5 years.
4. t(8;14) and t(8;22) are seen.
3. Stage C: Lymphocytosis, anemia,
thrombocytopenia—less than 2 years.
Clinical Features
BURKITT LYMPHOMA 1. Jaw, bowel, retroperitoneum, ovaries
are involved.
1. Although this is a rare tumor, this com- 2. LNs, BM and CNS are involved.
prises about 30% of childhood NLHs. 3. Most of the patients can be cured.
2. Burkitt lymphoma corresponds to
L3-ALL. MULTIPLE MYELOMA
1. Originates from a single clone of B
Types
cells (monoclonal) that differentiate
1. African endemic Burkitt lymphoma. into plasma cells.
a. Some relation to EBV. 2. Also called monoclonal gammopathy
b. Usually present as a jaw tumor. due to increased serum Ig.
c. Extranodal sites like BM and me- 3. Usually affects the elderly.
ninges are involved.
2. Sporadic Burkitt lymphoma. Etiopathogenesis
a. More aggressive. 1. Radiation exposure and epidemio-
b. Infiltrate CNS. logical factors have an influence on
3. Immunodeficiency associated. the occurrence of multiple myeloma.
a. Usually in association with HIV. 2. Karyotypic abnormalities like:
a. Translocations-t (11;14) (q13;q32) tex and radiographically appear as

and t(4;14) (p16;q32). punched out round defects.
b. Deletion of 13q. c. The normal marrow is replaced by
3. Oncogene-antioncogene mutations. soft, gelatinous reddish-grey tu-
a. Over expression of MYC and RAS mors.
oncogenes. d. Often leads to pathological frac-
b. Mutation of P53 and RB genes. tures.
e. Microscopy.
Molecular Pathogenesis •• Marrow is hypercellular with
myeloma cells greater than or
1. Plasma cells bind with BM stromal equal to 10%
cells and ECM proteins with the help
•• Myeloma cells are usually large
of adhesion molecules.
oval cells with a rounded nucleus
2. This adhesion leads to production of and slightly basophilic cytoplasm
cytokines. with vacuolation. Usually have
3. The cytokines like IL-1, lymphotoxin, a cartwheel chromatin pattern.
RANK ligand and TNF-α leads to osteo-
2. Extraosseous lesions.
clast activation and bone destruction.
a. Peripheral blood.
4. The cytokine IL-6 leads to prolifera-
tion of tumor cells through its anti- •• Anemia and ↑ ESR
apoptotic effects. •• Atypical plasma cells can be
5. All these again lead to drug resistance seen.
and migration of tumor cells. b. Myeloma kidney.
•• The Bence-Jones proteins are
Immunochemistry precipitated in DCT along with
Tamm-Horsfall proteins.
1. The Ig in multiple myeloma is re-
c. Myeloma neuropathy.
ferred to as ‘M’ component.
•• Tumor cells infiltrate the nerve
2. The ‘M’ component is commonly IgG
trunks to produce non-specific
(60%), followed by IgA (20%–25%)
polyneuropathy.
and rarely IgM, IgD or IgE.
d. Systemic amyloidosis.
3. In some cases, there is only kappa or
lambda light chains and these are ex- •• AL amyloid get deposited.
creted through urine and are called e. Hepatosplenomegaly.
Bence-Jones proteins.
Clinical Features
Morphology 1. Bone pain and multifocal destructive
1. Osseous (BM) lesions. bone lesions.
a. Most commonly involved bones 2. Increased susceptibility to infections
are skull, spine, ribs and pelvis. (pyelonephritis, pneumonia).
b. Lesions erode the medullary cav- 3. Renal failure.
ity and ultimately destroys the cor- 4. Anemia.
5. Bleeding tendencies. Reed-Sternberg Cells or RS Cells

6. Hyperviscosity syndrome.
Classic RS Cell
7. Neurologic symptoms.
8. Hypercalcemia, hyperuricemia. 1. A large cell with bilobed nucleus.
9. POEMS syndrome (polyneuropa- 2. Each lobe is a mirror image of the
thy, organomegaly, endocrinopathy, other.
multiple myeloma and skin changes). 3. Each lobe is a prominent, eosinophilic
nucleolus.
Diagnosis 4. A clear halo around the nucleolus,
giving an owl eye appearance.
1. Triad of:
5. Abundant amphophilic cytoplasm.
a. Marrow plasmacytosis greater
than 10%.
Lacunar Type RS Cell
b. Radiological evidence of lytic bony
lesions. 1. Smaller than classic RS cell.
c. Demonstration of serum and urine 2. Similar to classic RS cell except that
‘M’ component. these lie in a pericellular space or lacuna.
Treatment (Rx) Popcorn RS Cell

1. Chemotherapy—alkylating agents. 1. Larger with lobulated nucleus.
2. Symptomatic treatment. 2. Have a popcorn shape.
3. Stem cell transplantation.
4. IFN-α. Pleomorphic RS Cell
Pleomorphic atypical nucleus.
Prognosis (Refer Fig. 14.16, Harshmohan 6th edi-
1. Poor prognosis, if there is: tion).
a. Secretion of lambda light chain.
b. Increased cytogenic abnormalities. Etiopathogenesis
c. Increased β2 microglobulin. 1. Arising from germinal center of B
cells (Fig. 12.3)
HODGKIN LYMPHOMA 2. A close association with EBV.
1. Hodgkin lymphoma is a group of 3. The RS cells contain high levels of
neoplasms that arise almost invari- activated NF-κB, which stimulates B
ably in a single lymph node or chain cell proliferation and protect B cells
of LNs and spread characteristically
from apoptosis.
in a stepwise pattern to the anatomi-
cally contiguous nodes. 4. The EBV protein activates this NF-κB.
2. This is characterized by the presence 5. Certain cytokines like IL-5, IL-13 and
of RS cells. TGF-β have a role in pathogenesis of
Table 12.5: WHO classification
Subtypes Incidence Immunophenotype of RS Prognosis

cells
Classic
•• (L) predominance 5% CD15-, CD30- and CD20+ Excellent
•• Nodular sclerosis 70% CD15+, CD30+ Very good
•• Mixed cellularity 22% CD15+, CD30+ Good
•• (L) depletion 1% CD15+, CD30+ Poor
Nodular
•• (L) predominant 2% CD15-, CD30 - and CD45+ Chronic relapsing
Hodgkin lymphoma. These cytokines Nodular Sclerosing Type

are produced by RS cells.
1. Presence of lacunar type of RS cells.
Classification 2. Presence of collagen bands.
3. Classic RS cells are infrequent.
Rye Classification
4. Some (L), (E) and histiocytes are seen.
1. (L) predominance type.
2. Nodular sclerosing type. Mixed Cellularity Type
3. Mixed cellularity type.
1. Typical RS cells are frequent.
4. (L) depletion type.
2. Presence of infiltrate, which in-
WHO Classification cludes (L), (E), (N), histiocytes and
plasma cells.
The WHO classification is shown in the
Table 12.5.
(L) Depletion Type
Morphology 1. Diffuse fibrotic variant.
a. Hypocellular and diffuse fibrosis.
(L) Predominance Type
b. Numerous classic and pleomor-
1. Proliferation of small (L) admixed phic RS cells.
with histiocytes.
c. Some (L) and atypical histiocytes
2. Increased number of classic RS cells. (Hodgkin cells).
3. Popcorn RS cells can also be seen.
2. Reticular variant.
4. Nodular form—replacement of nodal
a. More cellular.
architecture by numerous neoplastic
nodules. b. Few classic RS cells.
5. Diffuse form—diffuse proliferation c. Large number of atypical histio-
of cells and number of nodules. cytes and some (L).
Nodular (L) Predominant Type 7. Moderate leukemoid reaction.

1. Have a nodular growth pattern. 8. Increased ESR.
2. Predominance of small (L) and a few 9. Decreased CMI, but humeral immu-
RS cells. nity is normal.
10. Immunophenotyping.
Immunophenotype
Staging
Refer the classification.
•• Stage 1: Involvement of a single LN
Clinical Features region
•• Stage 1E: A single extralymphatic
1. Lymphadenopathy (mainly cervical
and mediastinal). site
2. Splenomegaly and sometimes he- •• Stage 2: Two or more LN region on
patomegaly. the same side of the diaphragm
3. Constitutional symptoms. •• Stage 2E: Stage 2 with contiguous ex-
tranodal site
Diagnosis •• Stage 3: LN regions on the both sides
1. Clinical features. of the diaphragm
2. Demonstration of RS cells. •• Stage 3E: Stage 3 with contiguous ex-
3. In Hodgkin lymphoma, the neoplas- tranodal site
tic cells are RS cells, but these are •• Stage 3S: Stage 3 with spleen involve-
only less than 5% of total cellularity. ment
4. Anemia. •• Stage 3ES: Stage 3E + stage 3S
5. Serum iron and TIBC are low. •• Stage 4: Multiple disseminated in-
6. Marrow infiltration. volvement of extranodal sites.
Table 12.6: Hodgkin lymphoma (HL) VS non-Hodgkin lymphoma (NHL)
Features HL NHL
Cells Mostly B cells 90% B cell, 10% T cell
LN involvement Localized Disseminated
Extranodal involvement Uncommon Common
BM involvement Uncommon Common
Constitutional symptoms Common Uncommon
Chromosomal defect Aneuploidy Translocation, deletion
Spill-over Never May spread to blood
Prognosis Better (75%–85%) Bad (30%–40%)
Prognosis Massive Tissue Injury

1. Stage 1 and 2 have 100%, 5 year survival. 1. Trauma.
2. Advanced stages have 50%, 5 year 2. Burns.
survival.
3. Refer classification. Miscellaneous
The Hodgkin lymphoma vs non-
Hodgkin lymphoma is given in Table Snakebite, shock, heat stroke, vasculitis,
12.6. aortic aneurysm, liver disease, etc.
DISSEMINATED Pathogenesis
INTRAVASCULAR 1. The two major mechanisms, which
COAGULATION starts the DIC process are:
a. Release of thromboplastic sub-
1. Also called defibrillation syndrome stances.
or consumption coagulopathy.
b. Widespread endothelial damage.
2. As the name indicates DIC is char-
2. The steps of pathogenesis of DIC are:
acterized by formation of thrombi
throughout the microvasculature. a. Coagulation activation by the two
mechanism mentioned above.
b. Thrombotic phase.
Etiology
•• The activation of coagulation
Obstructive Complications leads to formation of platelet ag-
1. Abruption placenta. gregates and thus deposition of
thrombi.
2. Septic abortion.
c. Consumption phase.
3. Amniotic fluid embolism.
4. Retained dead fetus. •• The thrombus consumes coagu-
lation factors and platelets.
5. Toxemia.
d. Secondary fibrinolysis.
•• As a protective mechanism, the
Infections
fibrinolysis get activated and
1. Sepsis (gram -ve and gram +ve). FDPs are formed in circulation.
2. Meningococcemia. 3. As a result of thrombus formation,
3. Histoplasmosis. there occurs microvascular occlusion,
4. Aspergillosis. which in turn leads to ischemic tissue
5. Malaria. injury and microangiopathic hemo-
lytic anemia.
Neoplasms 4. Severe bleeding occurs as a result
consumption of coagulation factors
1. CA pancreas, CA prostate, CA lung, and platelets and inhibition of plate-
CA stomach. let aggregation. Pathogenesis of DIC
2. Acute promyelocytic leukemia. is given in Figure 12.4.
Fig. 12.4: Pathogenesis of DIC
Morphology 8. Hemorrhages, petechiae and ecchy-

moses.
1. Microthrombi in arterioles and capil-
laries.
Clinical Features
2. Kidneys, adrenals, brain and heart
are mostly affected. 1. Bleeding and organ damage.
3. A focal glomerulitis. 2. Shock, acute renal failure, dyspnea,
4. Renal cortical infarcts. cyanosis, convulsion and coma.
5. Sometimes, renal cortical necrosis.
Lab Findings
6. Adrenals—Waterhouse-Friderichsen
syndrome. 1. Thrombocytopenia.
7. Contributes to Sheehan postpartum 2. Microangiopathic hemolytic anemia.
pituitary necrosis. 3. PT, TT, APTT are prolonged.
4. Decreased fibrinogen levels. 3. These antibodies are mainly pro-

5. Increased FDPs. duced in spleen.
4. Ab are targeted against platelet gly-
Treatment (Rx) coproteins 2b-3a and 1b-9 complexes.
5. Ab to platelet surface antigens are
1. Treat the cause. also seen.
2. Treat with anticoagulants or coagu- 6. The antibodies are of IgG type.
lants in FFP.
7. The Ab-mediated platelet destruction
mainly in spleen.
IDIOPATHIC OR IMMUNE
THROMBOCYTOPENIC Clinical Features
PURPURA 1. Petechial hemorrhages, early bruis-
Idiopathic or immune thrombocytopenic ing, mucosal bleeding.
purpura (ITP) is characterized by immu- 2. Melena and hematuria.
nologic destruction of platelets and nor- 3. Hepatosplenomegaly.
mal or increased megakaryocytes in BM. 4. Lymphadenopathy.
Etiology Lab Findings

An autoimmune condition. 1. Thrombocytopenia (10,000–50,000/
µL).
Pathogenesis 2. Increased megakaryocytes in BM.
3. Antiplatelet IgG Ab can be detected.
Acute ITP
4. Increased bleeding time.
1. Self-limiting condition usually affects
children after a viral illness (hepatitis
C, IMN, CMV, HIV) or a URTI.
Treatment (Rx)
2. In this, immune complexes are 1. Shows 90% spontaneous recovery.
formed (viral Ag and Ab) and they 2. Steroids and immune suppressants.
crossreact with platelets leading to 3. Splenectomy.
their destruction. 4. Platelet transfusions.
3. Usually have a severe thrombocy-
topenia.
4. Recovery within a few weeks to 6
THROMBOTIC
months. THROMBOCYTOPENIC
PURPURA
Chronic ITP Thrombotic thrombocytopenic purpura
1. More commonly in young females (TTP) is a thrombotic microangiopathy
(20–40 years). characterized by the pentad of:
2. Here, antiplatelet autoantibodies are 1. Fever.
found. 2. Thrombocytopenia.
3. Microangiopathic hemolytic anemia. HEMOPHILIA

4. Transient neurologic deficits.
Hemophilia-A
5. Renal failure.
1. Also called classic hemophilia.
Pathogenesis 2. Due to deficiency or reduced activity
1. Deficiency of a metalloprotease AD- of factor-VIII (antihemophilic factor).
AMTS-13 is the underlying cause of 3. This is an X-linked recessive disorder.
TTP. 4. Clinically affected are mainly males.
2. Either this can be congenital or ac-
5. Females are usually asymptom-
quired due to an autoantibody against
atic carriers, but sometimes become
the metalloprotease.
symptomatic if factor VIII is less than
3. This enzyme is essential for the degra-
50% of normal.
dation of very high molecular weight
multimers of vWF.
4. So the enzyme deficiency leads to Pathogenesis
accumulation of vWF multimers in 1. About 90% due to reduced level of
plasma, which in turn stimulates the factor-VIII and other 10% due to re-
formation of platelet aggregates. duced activity of factor-VIII.
5. These platelet aggregates and later 2. Factor-VIII is essential for activation
get surrounded by fibrin to form mi- of factor-X in intrinsic coagulation
crothrombi. pathway.
6. These microthrombi consume plate- 3. So in hemophilia-A, the intrinsic coag-
lets and leads to thrombocytopenia. ulation pathway becomes defective.
7. An endothelial injury can trigger the 4. At least 25% factor-VIII activity is
process. needed for normal coagulation.
5. In symptomatic patients, the factor-
Clinical Features VIII concentration will be less than
5%.
1. Pentad of symptoms—mentioned.
2. Spleen may be palpable.
Clinical Features
Lab Findings 1. Petechiae are absent.
2. Prolonged bleeding after injury.
1. Thrombocytopenia and increased
bleeding time. 3. Increased TT, but normal PT.
2. Negative Coomb’s test. 4. Decreased factor-VIII level.
3. Leukocytes.
4. Increased megakaryocytes in BM. Treatment (Rx)
5. Slight myeloid hyperplasia in BM. 1. Factor-VIII replacement therapy.
6. Microthrombi in capillaries, arteri- 2. Factor-VIII concentrates or cryopre-
oles and venules. cipitates.
Hemophilia-B Clinical Features

1. Also called Christmas disease. 1. Bleeding from mucous membrane.
2. Due to factor-IX deficiency. 2. Excessive bleeding from injuries.
3. Type I.
3. Inheritance and C/F are similar to
hemophilia-A. a. Most common.
b. Mild-to-moderate.
4. BT is normal and APTT is prolonged.
c. Synthesis of vWF is normal release
of its multimers get inhibited.
Treatment (Rx) 4. Type II.
Infusion of FFP or plasma enriched in a. Less common.
factor-IX. b. vWF is functionally defective.
5. Type III.
VON WILLEBRAND DISEASE a. Rare and most severe.
b. Low activity and reduced activity
1. Most common inherited coagulation of vWF.
disorder.
2. Due to qualitative or quantitative de- Lab Findings
fect in vWF.
1. Prolonged BT, TT and APTT.
3. The vWF circulates in blood as a com- 2. Normal platelet count.
plex of factor-VIII-vWF. 3. Decreased vWF level.
4. An autosomal dominant inheritance. 4. Reduced factor-VIII activity.
5. Mutation of gene for vWF on chromo- 5. Defective platelet aggregation.
some-12 is responsible for this disease.
6. The main function of vWF is to fa- Treatment (Rx)
cilitate the adhesion of platelets to Cryoprecipitates or factor-VIII concen-
subendothelial collagen and thus to trates are used to treat the bleeding
induce coagulation. episodes.
13 Lungs
Chapter
ACUTE RESTRICTIVE Pathogenesis

LUNG DISEASE 1. The main events are:
Acute restrictive lung disease is caused a. Epithelial damage.
by diffuse alveolar capillary and epithe- b. Necrosis of type I pneumocytes.
lial damage. c. ↑ edema fluid.
d. ↓ surfactant → due to damage of
Causes type II pneumocytes.
e. Hyaline membrane formation.
Direct Lung Injury 2. Basically results from the imbalance
1. Common: between protective and destructive
a. Pneumonia. molecules.
b. Aspiration of gastric content.
2. Uncommon: ALVEOLI IN ACUTE
a. Pulmonary contusion. RESPIRATORY DISTRESS
b. Fat embolism. SYNDROME
c. Near drowning. The pathogenesis of ARDS is shown in
d. Inhalational injury. Figure 13.1.
Morphology
Indirect Lung Injury
1. Dark red, firm, airless and heavy.
1. Common:
2. Alveolar edema, hemorrhage and ne-
a. Sepsis. crotic cells.
b. Shock (trauma). 3. Hyaline membrane lining the dis-
2. Uncommon: tended alveolar ducts.
a. Cardiopulmonary bypass. 4. Organizing stage → ↑ proliferation of
b. A/c pancreatitis. pneumocytes.
c. Blood transfusion. 5. Healing by alveolar fibrosis due to
d. Drug overdose and uremia. collagen deposition.
Fig. 13.1: Pathogenesis of ARDS
Clinical Course 3. α-1 antitrypsin—encoded by genes

on Pi locus on chromosome-14.
1. Respiratory insufficiency and cy- 4. Smoking—functional α-1 antitrypsin
anosis. deficiency (Fig. 13.2).
2. Poor prognosis—if increased age,
sepsis and multisystem failure.
Centriacinar (Centrilobular)
3. If healed by alveolar fibrosis, the lung
function gets compromised. 1. Central or proximal part of the acini
are involved.
2. Distal alveoli are spared.
EMPHYSEMA
3. More common and significant in api-
Emphysema is a abnormal permanent cal segments.
dilation of air spaces distal to terminal 4. Mainly occur as a consequence of
bronchioles (alveoli) along with destruc- smoking in people who do not have
tion of their walls without much fibrosis. α-1 antitrypsin deficiency.
5. Most significant obstruction clinically.
Pathogenesis
1. Protease—antiprotease imbalance Panacinar (Panlobular)
(α-1 antitrypsin deficiency). 1. Whole acini are involved.
2. Oxidant—antioxidant imbalance 2. Common in lower lobe.
(smoking related). 3. Common in α-1 antitrypsin deficiency.
Chapter 13 u Lungs 143
Fig. 13.2: Pathogenesis of emphysema
Distal Acinar (Paraseptal) 2. Terminal and respiratory bronchioles

are deformed.
1. Distal acini are involved.
3. Loss of elastic tissue from alveolar
2. Commonly adjacent to pleura, septa septae.
and margins. 4. ↓ alveolar capillaries.
3. More severe in the upper half.
4. Cyst-like structures (bullae) can be seen. Clinical Course
1. Dyspnea, cough, wheezing.
Irregular
2. Barrel-shaped chest and prolonged
Most common type. expiration.
3. Sitting preferably in leaning forward
Morphology position.
1. Panacinar—lungs will be pale and 4. Sometimes weight loss.
voluminous. 5. Pink puffers (emphysema only).
2. Centriacinar—lungs will be pink and 6. Blue blotters (emphysema + bronchi-
less voluminous. tis → cyanosis).
7. Death due to:
Histology a. Pulmonary failure → acidosis, hy-
1. Thinning and destruction of alveolar poxia and coma.
walls. b. Right heart failure (cor pulmonale).
Conditions Related to Emphysema Pathogenesis

1. Compensatory overinflation. The pathogenesis of chronic bronchitis is
2. Obstructive overinflation. shown in Figure 13.3.
3. Bullous emphysema.
4. Mediastinal emphysema. Morphology
1. Hyperemic and swollen mucosa.
CHRONIC BRONCHITIS
2. Mucoid or mucopurulent discharge.
Definition 3. Hypertrophy of mucous glands.
Persistent productive cough for at least 3 4. ↑ inflammatory infiltrate.
consecutive months in at least 2 consecu- 5. ↑ goblet cells and obliteration of lumen.
tive years.
Clinical Course
Types 1. Cough and sputum, recurrent infec-
1. Simple chronic (C/c) bronchitis. tion.
•• Mucoid sputum, but airflow is not 2. Blue blotters (severe cases).
obstructed.
2. C/c asthmatic bronchitis. ASTHMA
•• Sputum, bronchospasm and wheez- 1. Asthma is a chronic inflammatory
ing intermittently. disorder of the airway that causes re-
3. C/c obstructive bronchitis. current episode of wheezing, breath-
•• Sputum, outflow obstruction (in lessness, chest tightness and cough
heavy smokers). (at night and early morning).
Fig. 13.3: Pathogenesis of chronic bronchities

2. Characterized by triad of: 2. Drug-induced asthma (Fig. 13.5).

a. Intermittent and reversible airway 3. Atopic (allergic) asthma (Fig. 13.6).
obstruction.
b. C/c bronchial inflammation with Morphology
eosinophilia.
1. Overinflated lung with areas of at-
c. Bronchial smooth muscle hyper-
electasis.
trophy and hyper-reactivity.
2. Occlusion of bronchi and bronchioles
with mucus plugs.
Main Mediators of
Bronchoconstriction and 3. Curschmann spirals—whorls of epi-
Increased Permeability thelial cells in mucus plugs.
4. Charcot-leyden crystals—eosino-
1. LTC4, LTD4, LTE4.
philic crystalloids.
2. Ach.
5. Airway remodeling—thickening of
3. Histamine.
basement membrane, edema and in-
4. PG-D2.
flammatory infiltrate, hypertrophy of
5. PAF → ↑ histamine.
glands and smooth muscles.
Pathogenesis
Clinical Course
1. Non-atopic asthma (Fig. 13.4).
1. Dyspnea and wheezing.
2. More difficulty in expiration.
3. Intermittent attacks respond to corti-
costeroids and bronchodilators.
4. Status asthmaticus—persistent and
not respond to treatment.
5. The disease is disabling than lethal.
BRONCHIECTASIS
Bronchiectasis abnormal permanent dila-
tation of bronchi and bronchioles caused
by destruction of muscle and elastic sup-
porting tissue due to C/c necrotizing in-
Fig. 13.4: Pathogenesis of non-atopic asthma fections.
Fig. 13.5: Pathogenesis of drug-induced asthma

Fig. 13.6: Pathogenesis of atopic (allergic) asthma

Causes
1. Bronchial obstruction.
a. Tumors, foreign body, mucous
plug, etc.
2. Congenital or hereditary condition.
a. Cystic fibrosis—obstruction and
infections.
b. Ig deficiencies—infections.
c. Kartagener syndrome—infections.
3. Necrotizing or the suppurative pneu-
monia.
Fig. 13.7: Pathogenesis of bronchiectasis
Pathogenesis
The pathogenesis of bronchiectasis is Clinical Course
shown in Figure 13.7. 1. Severe persistent cough.
Morphology 2. Copious amount of mucopurulent
sputum.
1. Usually bilateral lower lobes are af- 3. Hemoptysis and clubbing.
fected.
4. Respiratory failure and cor pulmonale.
2. Mostly affect vertical air passages.
3. Dilated bronchioles and distal bron-
chi (4 times).
PNEUMOCONIOSIS
4. A/c and C/c inflammatory infiltrate 1. Pneumoconiosis is a chronic restric-
(exudate). tive lung disease.
5. Desquamation and ulceration. 2. This is a non-neoplastic lung reaction
6. Bacterial infections usually in- to inhalation of mineral dust particles.
creased.
7. Fibrosis of walls and peribronchiolar Pathogenesis (Fig. 13.8)
fibrosis (C/c). 1. Depending on size, shape, solubility,
8. Sometimes necrosis and abscess. reactivity, etc.
Fig. 13.8: Pathogenesis of pneumoconiosis

2. More than 5 µm—cannot reach distal 2. PMF—pulmonary dysfunction, pul-

airway. monary hypertension, cor pulmonale.
3. Less than 0.5 µm—reach distal air-
way without much effect.
SILICOSIS
4. 1–5 µm—dangerous and lodged at
the bifurcation of distal airways. 1. Currently most prevalent C/c occu-
5. Coal dust—inert and need large pational disease.
amount. 2. By inhalation of crystalline silica
6. Silica and asbestos—relatively reac- (mainly quartz).
tive. 3. Release of TNF is very important in
silicosis.
Coal Worker’s Pneumonia 4. Anti-TNF, Ab can reduce collagen ac-
1. Asymptomatic anthracosis. cumulation in silicosis.
•• Pigment deposition only. 5. Quartz with other minerals → de-
2. Simple coal worker’s pneumoconio- creases fibrogenic effect.
sis (CWP).
•• Macrophage accumulation, but no Morphology
pulmonary dysfunction.
1. Silicotic nodules.
3. Complicated CWP or PMF.
a. Pale to black in upper zone.
•• Pulmonary function compro-
mised. b. Concentric collagen bundles.
c. Central amorphous area (birefrin-
gent silica particles).
Morphology
2. May coalesce to form hard collagen
1. Pulmonary anthracosis—carbon par- scar.
ticles are engulfed by macrophages
and deposited in connective tissues. 3. Fibrotic lesion in pleura and hilar
LNs.
2. CWP—coal macules and coal nodules:
4. Eggshell calcification in lymph
a. Coal macules—dust laden mac-
rophages. node—Ca surrounding a zone with-
out calcification.
b. Coal nodules—coal macules + col-
lagen fibers.
3. Upper lobe and upper part of lower Clinical Course
lobe involved. 1. Fine nodularity in radiographs.
4. Centriacinar emphysema can be seen.
2. PMF—dyspnea, pulmonary HTN,
5. PMF—coal nodules coalesce to form cor pulmonale.
larger lesions.
3. ↑ incidence of TB.
a. Dense collagen fiber bundles are
seen.
ASBESTOSIS AND RELATED
Clinical Course DISEASES
1. Coal worker’s pneumoconiosis—be- 1. Asbestosis—parenchymal interstitial
nign black lungs. fibrosis.
2. Localized fibrotic plaques, pleural ef- Pathogenesis

fusion, mesothelioma, bronchogenic
carcinoma and laryngeal carcinoma. 1. Mainly due to dysregulation of im-
3. Two forms of asbestos fibers—ser- mune system.
pentine and amphibole fibers. 2. Genetic predisposition with certain
4. Amphibole is more pathogenic HLA are also seen.
(straight fibers). 3. Intra-alveolar and interstitial accu-
5. Beyond its fibrogenic effect, it induc- mulation of CD4 TH1 cells (Fig. 13.9).
es carcinogenesis by:
a. Reactive free radicals—initiator Morphology
and promoter.
b. Adsorbing toxins onto its surface. 1. Non-caseating epithelioid granulo-
ma—discrete collection of epithelioid
Morphology cells and gaint cells rimmed by CD4
TH1 cells and outer fibroblast.
1. Diffuse parenchymal interstitial fi-
brosis with asbestos bodies. 2. Schaumann bodies—laminated bod-
2. Asbestos bodies are: ies of Ca and proteins.
a. Golden brown bodies with trans- 3. Asteroid bodies—stellate inclusions
lucent center. within gaint cells.
b. Its fibers coated with iron contain-
4. Sometimes central necrosis sugges-
ing proteinaceous material.
tive of infection.
3. Begins in lower lobe.
4. Distortion of normal architecture
with enlarged air spaces.
5. Thickening of visceral pleura and ad-
hesion with chest wall.
6. Pleural plaque of collagen and Ca on
partial pleura.
Clinical Course
1. Dyspnea, cough with sputum, bloody
effusion.
2. Cor pulmonale and CHF.
SARCOIDOSIS
1. C/c restrictive lung disease.
2. Multisystem disease of unknown eti-
ology characterized by non-caseating
granuloma in many tissues.
3. More in age group of less than 40 and
non-smokers. Fig. 13.9: Pathogenesis of sarcoidosis
5. Lungs. 2. Dyspnea and dry cough.

a. Granulomas mainly in interstitium. 3. Fever, fatigue, weight loss, anorexia,
b. Later diffuse interstitial fibrosis. etc.
c. Hilar and parenchymal LNs in-
volved. PNEUMONIA
d. Sometimes peripheral lymphade- 1. Community acquired acute pneumo-
nopathy (non-matted). nia.
6. Skin. 2. Community acquired atypical pneu-
a. Erythema nodosum (hallmark of monia.
A/c sarcoidosis). 3. Nosocomial pneumonia (Klebsiella,
•• Red tender nodules on anterior Escherichia coli, Pseudomonas).
aspect of legs. 4. Aspiration pneumonia (necrotizing).
b. Lupus pernio. 5. Chronic pneumonia (Nocardia, Actino-
•• Indurated plaques with viola- mycetes, Histoplasma, Mycobacterium).
ceous discoloration in the re- 6. Necrotizing pneumonia (mainly an-
gion of nose, lip and cheeks. aerobic bacteria).
7. Eyes and lacrimal glands. 7. Pneumonia in immunocompromised
a. Iritis or iridocyclitis. (CMV, MAC, Aspergillus, Cryptococ-
b. Choroiditis, retinitis and optic cus).
nerve involvement.
c. Sicca syndrome—lacrimal gland Acute Pneumonia
inflammation and suppression of
lacrimation. 1. Abrupt onset, high fever, shaking
chills, pleuritic chest pain, cough
8. Painful enlargement of parotids (xe-
rostomia). with mucopurulent sputum and oc-
casional hemoptysis.
9. Combined uveoparotid involve-
ment— Mikulicz syndrome. 2. Streptococcus pneumoniae is most com-
10. Spleen—enlarged and granulomas mon cause.
can be seen. 3. Examination of gram stained sputum
11. Liver—sometimes enlarged and gran- for diagnosis.
ulomas often seen. 4. Numerous (N) and bacteria in sputum.
12. Bone marrow is involved sometimes: 5. Also caused by Haemophilus influ-
a. Hypercalcemia and hypercalciuria enza, Moraxella, Staphylococcus aureus
due to ↑ calcium absorption (not (abscess), Klebsiella (in C/c alcohol-
due to bone destruction). ics), Legionella, Pseudomonas, etc.
Clinical Course Morphology

1. Skin lesions, hepatosplenomegaly, The lower lobes or right middle lobes are
lymphadenopathy, etc. mostly affected.
Stage of Congestion (1–2 Day) 4. Meningitis, arthritis and infective

endocarditis (due to bacterial dis-
1. Affected lobe is heavy, red and boggy.
semination).
2. Exudate of bloody frothy fluid (CS).
3. Vascular congestion and dilatation.
Atypical Pneumonia
4. Proteinaceous fluid, (N) and bacteria
in alveoli. 1. A/c febrile respiratory disease with
patchy inflammatory lesions in the
Stage of Red Hepatization (2–4 Day, lungs confined to septa and intersti-
Early Consolidation) tium.
2. Most common causative organism is
1. Liver-like consistency, firm and red.
Mycoplasma pneumoniae.
2. (N), red cells and fibrin in alveoli.
3. Also by Chlamydia, Coxiella burnetii
3. (N) shows ingested RBCs.
and some viruses.
Stage of Grey Hepatization (5–7 Day, Morphology

Late Consolidation)
1. Red-blue and congested lobes.
1. Dry, grey and firm.
2. Confined within alveolar walls.
2. Granular and liver-like consistency.
3. Septa are widened and edematous.
3. Red cells are lysed and ↓ bacteria.
4. ↓ (N) and macrophage appear. 4. Infiltrate of (L) and plasma cells.
5. More dense fibrin strands. 5. Lack of alveolar exudates and con-
solidation findings.
Stage of Resolution (8–20 Day) 6. Moderate amount of sputum.
1. The exudate (fibrinous) in alveoli Clinical Course

is enzymatically lysed to produce
granular semi fluid debris, which is
1. Upper respiretory tract infection
ingested by macrophages. (URTI).
2. Dirty brown creamy fluid on present- 2. Fever, headache, malaise and cough.
ing.
3. ↑ macrophages, ↓ (N). Nosocomial Pneumonia
4. Fragmented fibrin strands. Most common by Enterobacteriaceae,
5. Engorged alveolar capillaries. Pseudomonas, S. aureus, etc.
Complications TUBERCULOSIS
1. Lung abscess. Tuberculosis (TB) is communicable
2. Empysema. chronic granulomatous disease caused
3. Fibrosis. by Mycobacterium tuberculosis.
Epidemiology Primary Tuberculosis

Risk Factors 1. Occur in unsensitized person.
2. Fate of primary TB.
1. Diabetes mellitus (DM).
a. Induces hypersensitivity and in-
2. Hodgkin disease.
creases resistance.
3. C/c lung disease (silicosis).
b. Reactivation and cause secondary
4. C/c renal failure. TB.
5. Malnutrition. c. Progressive primary TB (without
6. Alcoholism. interruption—mainly in HIV).
7. Immunosuppression (HIV). 3. Complication—TB meningitis, mil-
iary TB.
Etiology
Pathogenesis
1. Mycobacterium tuberculosis, Mycoplas-
ma hominis (mainly). 1. An example for cell-mediated (de-
layed) hypersensitivity.
2. Mycobacterium bovis and M. avium-
2. Figures 13.10 and 13.11 gives the sche-
intracellulare (rarely).
matic representation of delayed hy-
3. Transmission is air borne. persensitivity at the age of ‘0’–3 weeks
and more than 3 weeks respectively.
Clinical Course
Morphology
1. Low grade fever (evening rise of tem-
perature), malaise, anorexia, weight 1. Mainly lower part of upper lobe and
upper part of lower lobe is affected.
loss, night sweats.
2. Grey white inflammatory consolida-
2. Hemoptysis, pleuritic chest pain. tion (granuloma of 1–1.5 cm)—Ghon
3. Consolidation and cavitation (X-ray). focus.
Fig. 13.10: Pathogenesis of primary pulmonary TB (0–3 week)

Fig. 13.11: Pathogenesis of primary pulmonary TB (> 3week)
3. Spread to LNs and the combination Pathogenesis

of parenchymal and nodular lesion
1. Occur in re-exposure or previously
—Ghon complex.
sensitized host.
4. Granuloma. 2. The mechanism is same.
a. Central caseous necrosis. 3. But the defensive reaction is more
b. Epithelioid and gaint cells. and hence, the necrosis will be more
c. Few fibroblasts and inflammatory intense and rapid.
cells (L). 4. There will be false negative for tubercu-
5. Later Ghon complex regresses and lin test due to loss of hypersensitivity.
fibrosed, which is followed by calci-
fication—Ranke complex. Morphology
The initial small granuloma can regress
Secondary Tuberculosis by fibrosis and leaving only fibrotic scars
1. Occur in previously sensitized host. at different sites.
2. Occur usually by reactivation.
3. More localized to apex of upper lobes Later (Disseminated) Stages
(↑ O2 tension). of Secondary Tuberculosis
4. Regional LNs are less involved. Progressive pulmonary TB
5. Decreases bacilli in sputum HIV pa- 1. Enlargement of the apical lesion with
tients. ↑ caseation.
2. Erosion into bronchus and an irregu- 2. Inflammatory enlargement and ul-

lar cavity lined by caseous material ceration.
can be seen. Pleural involvement
3. Erosion into blood vessels leads to 1. Effusion, tuberculosis, empyema, fi-
hemoptysis. brous pleuritis, etc.
4. With adequate treatment—healing
by fibrosis.
LUNG CARCINOMAS
5. Inadequate treatment—dissemina-
tion. 1. Small cell lung carcinoma (SCLC).
Miliary TB 2. Squamous cell carcinoma.
1. Organism → lymphatics → venacava 3. Adenocarcinoma. NSCLC
→ right heart → pulmonary arteries 4. Large cell carcinoma.
→ lungs. 5. Mixed → adenosquamous carcinoma,
2. Multiple small (2 mm) yellow white squamous-small cell carcinoma.
consolidation spots in lung paren- 6. Most commonest—squamous cell
chyma. carcinoma (smokers).
Endobronchial, endotracheal and laryngeal
7. Most commonest in non-smokers—
TB
adenocarcinoma.
1. Occur when spreads through lym-
8. SCLC:
phatics or expectorated material.
a. Metastasized by the time of diag-
Systemic miliary TB
nosis.
1. Organism → pulmonary veins → left
b. Better treated by chemotherapy.
heart → other tissues.
c. RB gene mutations are usually
2. Mainly in liver, BM, spleen, adrenals,
seen.
kidney, meninges, epididymis and
fallopian tube. 9. Non-small cell lung carcinoma
(NSCLC):
Isolated Organ TB a. Better treated by surgery.
b. p16 gene mutation is usually seen.
1. Hematogenous spread.
2. Meninges, kidney, adrenals and Etiopathogenesis
bones are mainly involved.
3. TB of vertebrae—Pott disease (leads The etiopathogenesis of CA lungs is
to cold abscess). shown in Figure 13.12.
Lymph nodes Morphology
1. Lymphadenitis—most frequent ex- 1. Begins as a small grey white mucosal
trapulmonary TB. lesion.
2. Cervical LNs—scrofula (commonest). 2. Later enlarges and invade bronchi
Intestinal TB and air spaces.
1. By intake of contaminated milk or 3. Large masses push adjacent lung
other products. parenchyma.
Fig. 13.12: Etiopthogenesis of CA lung
4. May lead to cavitation and hemor- 4. AAH—hyperplasia of epithelial cells

rhage. resembling type II pneumocytes with
5. May undergo necrosis. ↑ atypia (hyperchromasia, pleomor-
6. May invade pleura and chest wall. phism and prominent nucleoli).
7. Distant spread through hematog- 5. Three types—acinar (gland forming),
enous and lymphatic route. papillary and solid.
Squamous Cell Carcinoma Bronchioalveolar Carcinoma

1. Arise centrally in major bronchus. 1. Bronchioalveolar carcinoma (BAC) is
a subtype of adenocarcinoma.
2. Dissemination is more.
2. Growth along pre-existing structures
3. This is usually preceded by metapla- without altering the alveolar structure.
sia and dysplasia. Later transform
3. Pneumonia-like consolidation.
into carcinoma in situ.
4. Mucinous and non-mucinous type.
4. Well differentiated—with keratin
pearls and intercellular bridges with 5. The ↑ proliferation of BA stem cells
well-defined squamous cell features. leads to BAC.
5. Poorly differentiated—with minimal 6. Sometimes the sequence will be, AAH
squamous cell features. → BAC → invasive adenocarcinoma.
Adenocarcinoma Large Cell Carcinoma

Undifferentiated and cells have large nu-
1. Usually more peripherally located
clei and prominent nucleoli.
near the scars.
2. Grow slowly, but metastasize at an
early stage. Small Cell Lung Carcinoma
3. Precursor lesions are atypical ade- 1. Pale grey central masses invade into
nomatous hyperplasia (AAH). parenchyma and nodes.
2. Small cells with scanty cytoplasm 2. Cushing syndrome due to ↑ ACTH-

and granular chromatin. like peptide.
3. Mitotic figures can be seen. 3. Syndrome of inappropriate secretion
4. Extensive necrosis. of ADH.
5. Shows cellular fragmentation and 4. Neuromuscular syndrome (myasthe-
nuclear molding.
nia gravis, peripheral neuropathy).
6. Derived from neuroendocrine cells
of lung and show neuroendocrine
5. Hypertrophic pulmonary osteoar-
markers. thropathy (HPOA).
6. Hematologic—like DIC, NBTE, etc.
Clinical Course
1. The chain of spread involves nodes in MALIGNANT MESOTHELIOMA
the order of: 1. Carcinoma of mesothelial cells aris-
a. Hilar nodes → mediastinal → neck ing from pleura.
(scalene) → clavicular (Virchow) 2. Also occur rarely from pericardium
→ distant metastasis.
and peritoneum.
2. Pancoast tumor—apical tumors com-
press on: 3. Close relation with asbestosis:
a. Brachial plexus—pain along ulnar a. Asbestos accumulate mainly near
nerve distribution. the pleura.
b. Cervical sympathetic plexus b. Release reactive O2 species → DNA
—Horner syndrome (endopthal- damage and oncogenic mutation.
mos, ptosis, miosis, anhydrosis). c. Mutation of p16 and NF2.
3. Often accompanied by destruction of
first and second ribs and sometimes
thoracic vertebrae also. Morphology
4. C/c cough with expectoration and 1. Preceded by extensive pleural fibro-
hemoptysis. sis and plaque formation.
5. Hoarseness of voice, chest pain, effu- 2. Lung is en-sheathed by a yellow
sion, atelectasis. -white gelatinous layer of tumor.
6. Superior venacaval syndrome due to 3. Distant metastasis is rare.
compression.
4. Spreads to parenchyma of chest wall.
7. Metastasis to bone liver and bones.
8. SCLC has less prognosis compared to 5. Epithelial pattern.
NSCLC. a. Lining of cuboidal cells.
b. Small papillary projections.
Paraneoplastic Syndromes 6. Sarcomatoid pattern.
in Carcinoma Lung a. Fibroblast like spindle cells.
1. Hypercalcemia due to parathormone- 7. Biphasic.
like peptide. a. Both pattern mixed.
14 Kidney and its
Collecting System
Chapter
NEPHROTIC SYNDROME Secondary Causes (Systemic Diseases)

1. Nephrotic syndrome is a clinical com- 1. Diabetes.
plex including:
2. Amyloidosis.
a. Massive proteinuria (> 3.5 g/day).
3. Systemic lupus erythematosus (SLE).
b. Hypoalbuminemia (< 3 g/dL).
c. Generalized edema. 4. Drugs (gold, penicillamine).
d. Hyperlipidemia and lipiduria. 5. Infections (malaria, HIV, hepatitis-B).
2. The principal derangement is in the 6. Malignancy (carcinoma, melanoma).
capillaries of glomeruli, which leads
to ↑ permeability → proteinuria and 7. Others (bee sting, allergy, hereditary).
lipiduria.
3. Hypoalbuminemia → edema. Membranous Glomerulonephritis
4. Fluid escapes from vascular compart- Membranous glomerulonephritis is com-
ment into tissue → ↓ plasma volume
→ ↑ aldosterone → ↓ GFR and ↓ ANF mon in adults.
→ salt and water retention → aggre- 1. Characterized by the presence of
gation of edema → anasarca. subepithelial Ig containing deposits
along GBM.
Causes of Nephrotic Syndrome 2. Diffuse thickening of capillary wall
Primary Causes (Glomerular Diseases) in late stage.
1. The membranous glomerulonephri- 3. It is usually idiopathic and sometimes
tis (GN). secondary.
2. Minimal change disease (lipoid neph-
rosis). Pathogenesis
3. Focal segmental glomerulosclerosis 1. C/c immune complex-mediated ne-
(FSAS). phritis.
4. Membranoproliferative GN. 2. Antibodies against endogenous or
5. Immunoglobulin (IgA) nephropathy. planted glomerular Ag (Fig. 14.1).
Fig. 14.1: Pathogenesis of membranous GN
Morphology 3. Uniform and diffuse effacement of

podocyte foot processes in electron
1. Diffuse thickening of GBM. microscopy.
2. Subepithelial complex deposits and 4. Microvillus formation and focal de-
GBM spikes for separating these derangements may be seen.
posits (spikes and dome pattern).
3. Granular deposits on GBM.
Clinical Course
4. With progression, sclerosing of GBM
and ↑ thickening. 1. Selective proteinuria (mainly albu-
5. Effacement of foot processes of podo- min).
cytes. 2. Prognosis is good with corticosteroids.
Clinical Course Focal Segmental

Non-selective and less proteinuria; bad
Glomerulosclerosis
prognosis. 1. Focal segmental glomerulosclerosis
(FSGS) is most common in adults.
Minimal Change Disease 2. Sclerosis of some glomeruli (focal).
(Lipoid Nephrosis) 3. Only some segments in each glom-
eruli are affected (segmental).
Minimal change disease is most com-
monly seen in children. 4. Primary or secondary to some other
diseases like HIV, IgA nephropathy.
Pathogenesis
Pathogenesis
Injury to podocytes and effacement of foot
processes caused by T cell derived factors. 1. Clearly not known.
2. Believed to be resulting from MCD.
Morphology 3. Podocyte injury is the initiating
event.
1. Glomeruli appears normal in light
microscopy.
Morphology
2. Proximal convoluted tubule (PCT)—
cells laden with protein droplets and 1. Focal and segmental involvement of
lipids. glomeruli.
Chapter 14 u Kidney and its Collecting System 159
2. Affected glomeruli have increased 2. Proliferation of glomerular cells and

matrix, capillary lumen obliteration ↑ leukocytes.
and deposition of hyaline masses and 3. Thickening and splitting of GBM.
lipids. 4. Type I—subendothelial deposition of
3. Global sclerosis → completely sclero- C3 and IgG.
sed glomeruli (late). 5. Type II—subendothelial deposition
4. Effacement of foot processes and IgM of C3, but not IgG.
deposition.
5. Tubular atrophy and interstitial fi- Clinical Course
brosis.
1. Hematuria and protenuria.
6. Collapsing glomerulopathy → severe
manifestation of FSGS. 2. Poor prognosis.
Clinical Course IgA Nephropathy (Berger Disease)

1. Hematuria, HTN, non-selective pro- Immunoglobulin A (IgA) deposition in
teinuria. mesangium.
2. Prognosis with corticosteroid—poor.
Pathogenesis
Membranoproliferative 1. Increased IgA production and de-
Glomerulonephritis creased clearance.
1. Hematuria, HTN, non-selective pro- 2. Abnormal glycosylation of IgA leads
to decreased clearance.
teinuria.
3. Increased deposition of IgA and IgA
2. Proliferation of glomerular cells.
immune complexes in the mesan-
gium trigger alternate complement
Pathogenesis pathway leads to glomerular injury.
1. Membranoproliferative glomerulo-
nephritis-1 (MPGN-1). Morphology
a. Caused by circulating immune 1. Mesangial widening (deposits of IgA,
complex. IgG, IgM and C3).
2. MPGN-2. 2. Focal segmental inflammation.
a. Not much clear. 3. Diffuse mesangial proliferation
b. Due to ↑ complement activation. (MPGN).
c. Ab against C3 convertase → activa- 4. Subendothelial deposits.
tion of alternate complement path-
way.
Clinical Course
Morphology 1. Gross hematuria usually after some
systemic infection.
1. Large glomeruli of lobular appear-
ance. 2. With or without proteinuria.
NEPHRITIC SYNDROME 2. ↑ (N) and (M) infiltrate.

1. Clinical complex of acute onset char- 3. Necrosis of capillary wall.
acterized by: 4. Crescents may be seen in glomeruli.
a. Hematuria with RBC and RBC 5. Subepithelial humps (immune com-
casts. plexes) on GBM.
b. Oliguria and azotemia (↑ N2 con- 6. Granular deposits of IgG and C3 com-
taining compound). plement.
c. Hypertension (HTN).
d. Some proteinuria and edema. Clinical Course
2. Proliferation of glomerular cells fol-
1. Abrupt onset fever, malaise.
lowed by leukocyte infiltrate.
2. Oliguria, azotemia, hematuria and
3. Inflammatory reaction injuries the
HTN.
capillaries and leads to hematuria
and ↑ GFR (oliguria and azotemia). 3. Smoky brown urine.
5. As a result, Na+ and water retention
→ HTN. Hereditary Nephritis
1. Caused by mutations in GBM protein
Acute Postinfectious genes.
Glomerulonephritis 2. Alport syndrome → nephritis + nerve
(Poststreptococcal deafness + eye disorders.
glomerulonephritis or PSGN)
1. Glomerular deposits of immune com- Pathogenesis
plexes. 1. Type IV collagen is made of het-
2. Glomerular proliferation and (N) in- erotrimers of α3, α4 and α5.
filtrate. 2. Mutation in any one α-chain → de-
3. Exogenous antigen → streptococcal, fective type IV collagen → alport syn-
pneumococcal, staphylococcal, etc. drome.
4. Endogenous antigen → in SLE.
5. PSGN occurs 4–8 weeks after recov- Morphology
ery from infection.
1. Glomerular basement membrane
(GBM), lens, cochlea are affected.
Pathogenesis
2. Interstitial cells accumulate fats cells
Accumulation of immune complex, IgG, to form foam cells.
C3 complement on GBM and leads to 3. With progress → glomerular sclero-
glomerular injury. sis, tubular atrophy and fibrosis.
4. GBM—thinned, attenuated and split-
Morphology ted.
1. Uniformly ↑ cellularity of all glom- 5. Later GBM—basket weave appear-
eruli (diffuse). ance.
Clinical Course Type I RPGN

1. X-linked (α5) mainly. 1. IgA and C3 deposits on GBM.
2. α3 and α4 → AR/AD. 2. Idiopathic → renal involvement
• Familial hematuria/thin BM le- only.
sions. 3. Goodpasture syndrome →
a. Renal failure + pulmonary hemor-
IgA Nephropathy rhage.
Already discussed. b. Anti-GBM Ab react with pulmo-
nary alveolar capillary membrane.
Morphology
RAPIDLY PROGRESSIVE GN
1. Enlarged and pale kidneys.
(CRESENTIC GN)
2. Petechial hemorrhages on cortical
1. Characterized by rapid loss of renal surface.
function with features nephritic syn- 3. Segmental necrosis and crescents in
drome (severe oliguria) and death Bowman’s capsule.
due to renal failure, if untreated.
4. IgA and C3 deposit on GBM.
2. Presence of crescents in the glomeruli.
3. Proliferation of parietal epithelial
Type II RPGN
cells of Bowman’s capsule and (M)
and macrophage infiltrate and exu- 1. Deposition of immune complex on
dates of plasma protein → formation GBM.
of crescents. 2. Lumpy bumpy appearance of GBM.
Morphology
Etiopathogenesis 1. Segmental necrosis and GBM breaks.
Type I 2. Crescents in BC.
1. Anti-GBM Ab-mediated. 3. Granular pattern of immune complex.
2. Idiopathic.
Type III RPGN
3. Good pasture syndrome.
Type II 1. Lack of anti-GBM Ab and immune
complex.
1. Immune complex mediated.
2. ANCAs in serum.
2. Postinfectious.
Morphology
3. IgA nephropathy.
1. Segmental necrosis and crescents.
4. Systemic lupus erythematosus (SLE).
Type III 2. No detectable deposits.
Clinical Course
1. Pauci-immune, ANCA associated.
2. Idiopathic. 1. Rapid onset.
3. Wegener’s granulomatosis. 2. More severe oliguria and azotemia.
4. Microscopic angiitis. 3. Death due to renal failure, if untreated.
4. Prognosis becomes worse with in- 3. Female urethra.

crease in crescents. a. Short urethra, proximity to rectum.
4. Urinary tract obstruction (easy bacte-
ACUTE PYELONEPHRITIS rial multiplication).
1. Suppurative inflammation of kidney a. BPH, uterine prolapse in pregnancy.
and renal pelvis caused by bacterial 5. Diabetes.
infection. a. ↑ susceptibility infections, neuro-
2. Majority are associated with lower UTI. genic bladder.
6. Incompetence of vesicourethral valve
Pathogenesis and previous renal lesions.
1. Hematogenous infection (Staphylo-
coccus, Escherichia coli). Morphology
a. Bacteria in blood → reach kidneys 1. Yellowish discrete raised abscess on
→ acutepyelonephritis (APN). the surface.
2. Ascending infection (E. coli, Klebsiella, 2. Suppurative necrosis within the pa-
Proteus, Enterobacter) (Fig. 14.2). renchyma.
3. Intratubular (N) infiltrate and WBC
Risk Factors casts in urine.
1. Genetic factors. 4. Sometimes pyelonephrosis → pus in
a. Abnormal urinary tract, immuno- pelvis, calyces and ureter.
deficiency. 5. Renal papillary necrosis (in DM, an-
2. Instrumentation. algesic abuse) and coagulative necro-
a. Cystoscopy, catheterization. sis with (N).
Fig. 14.2: Pathogenesis of acute pyelonephritis

6. Cystitis → urine obstruction → hy- 4. Infiltrate of (L) and plasma cells.

pertrophic bladder. 5. Dilation or contraction of tubules.
6. Epithelial atrophy and fibrosis.
Clinical Course 7. Vascular changes.
1. Sudden onset chill, fever, malaise. 8. Glomerulosclerosis.
2. Pain at costovertebral angle.
3. Pyuria and bacteriuria. Clinical Course
4. Dysuria and ↑ frequency and urgen- 1. Gradual onset.
cy of micturition. 2. HTN and renal failure.
5. Better treated with antibiotic. 3. Kidneys are asymmetrically con-
6. Papillary necrosis → poor prognosis. tracted.
4. Secondary FSGS → Proteinuria.
C/c PYELONEPHRITIS
1. Interstitial inflammation and paren- DRUG INDUCED NEPHRITIS
chymal scarring. 1. Penicillin (ampicillin, methicillin).
2. Visible scarring and deformity of 2. Other antibiotics (Rifampin).
calyces.
3. Diuretics (Thiazides).
3. Important cause of C/c renal failure.
4. Analgesics (aspirin, paracetamol, caf-
feine, codeine).
Types 5. Others (phenindione, cimetidine).
C/c Obstructive Pyelonephritis
1. C/c obstructive lesions and recurrent A/c TUBULAR NECROSIS
infection. 1. Damaged tubular epithelial cells.
2. C/c inflammation and scarring → 2. A/c suppression of tubular function.
C/c pyelonephritis. 3. Most common cause of A/c renal failure.
4. A/c renal failure → oliguria (< 400
C/c Reflex Associated Pyelonephritis mL/day) within 24 hours of onset of
1. More common form. disease.
2. UTI + vesicoureteral reflux and intra- a. Ischemic ATN → associated with
renal reflex. shock and hypotension.
3. Leads to scarring and C/c renal in- b. Nephrotic ATN → caused by
sufficiency. poions like Hg, CCl4, drugs (gen-
tamicin).
Morphology
1. Uneven scarring of kidney. Clinical Course
2. Scarring of pelvis and calyces. 1. Initiation phase.
3. Uneven scarring of interstitium. a. 0–36 hours.
b. ↓ urine output. Pathogenesis

c. ↑ Serum creatinine.
Pathogenesis of ATN in shown in Fig. 14.3.
2. Maintenance phase.
a. 2–6 days.
MORPHOLOGY
b. Oliguria (50–400 mL/day).
c. Uremia and fluid overload. 1. Necrosis of short segments of tubules.
3. Recovery phase. 2. Tubular injury with cell detachment
leads to formation of casts.
a. ↑ urine output.
3. Proteinaceous casts,
b. Serious electrolyte imbalances.
a. Tamm-Horsfall protein + Hb +
c. ↑ vulnerability to infections. plasma protein.
d. Later urine output comes to normal. b. Sometimes myoglobin.
Fig. 14.3: Pathogenesis of ATN

4. Edema and inflammation infiltrate in MALIGNANT

interstitium. NEPHROSCLEROSIS
5. But in toxic ATN,
Kidney changes in malignant HTN (hy-
a. The tubular BM is generally
perplastic arteriosclerosis).
spared.
b. Necrosis prominent in PCT.
Morphology
BENIGN NEPHROSCLEROSIS 1. Small pinpoint petechial hemorrhag-
es on cortical surface → flea-bitten
Hyaline arteriosclerosis in kidney that
appearance.
occurs in benign HTN.
2. Fibrinoid necrosis and thrombi in
glomerular capillaries.
Pathogenesis 3. Homogeneous eosinophilic granular
1. Clear pathogenesis is not known. appearance of vessels.
2. HTN is associated with renal vascu- 4. Hyperplastic arteriosclerosis.
lar changes, which together induces 5. Some vessel wall → onion skin ap-
sclerosis. pearance.
Morphology Pathogenesis
1. Kidneys are symmetrically atrophied. Pathogenesis of malignant nephrosclero-
2. Fine granularity on surface. sis in shown in Fig. 14.4.
3. Hyaline arteriolosclerosis.
a. Hyaline thickening of walls of Clinical Course
small arteries and arterioles.
1. DBP is > 120 mm Hg.
b. Homogenous pink hyaline thick-
2. Papilledema, encephalopathy, CV
ening of walls with the loss of
abnormalities, renal failure.
underlying cellular details.
4. ↓ lumen width → ↓ blood flow → 3. ↑ ICP → headache, nausea, vomiting,
ischemia → sclerosis. visual impairment.
5. Diffuse tubular atrophy and intersti- 4. Microscopic hematuria.
tial fibrosis. 5. Mainly death is due to uremia.
6. Larger arteries show reduplication
of elastic lamina along with fibrous POLYCYSTIC KIDNEY DISEASE
thickening of media → fibroelastic
hyperplasia. Adult Polycystic Kidney Disease
1. Multiple expanding cyst, which ul-
Clinical Course timately destroy the intervening pa-
1. Impairment of kidney function. renchyma.
2. ↓ GFR → ↓ urine output. 2. Leads to C/c renal failure.
Fig. 14.4: Pathogenesis of malignant nephrosclerosis
1. Autosomal dominant. 1. Enlarged kidneys, readily palpable
abdominally.
2. Usually the defective gene is PKD-1
2. Multiple cyst with destruction of in-
(on chromosome-16).
tervening parenchyma.

3. Adult polycystic kidney disease 3. Cyst are filled with clear/turbid/
(APKD) develops usually by loss of 2 hemorrhagic fluid.
alleles of PKD-1 gene. 4. Pressure atrophy of surrounding
4. PKD-2 mutation is minor. parenchyma.
5. Superimposed HTN or infection is
5. PKD-2 is on chromosome-4.
common.
6. Polycystin-2 → Ca permeable mem- 6. Liver cysts are also seen (asymptom-
brane channel (Figs 14.5 and 14.6). atic).
Fig. 14.5: Pathogenesis of adult PKD-1
Fig. 14.6: Pathogenesis of adult PKD-2
Clinical Course Clinical Course

1. Does not produce symptoms until 1. Perinatal and neonatal forms are
4th decade. common.
2. Flank pain (usually), intermittent 2. Dies in infancy due to hepatic and re-
gross hematuria. nal failure.
3. HTN and urinary infection. 3. If survive infancy—develop liver cir-
rhosis later.
4. Death due to uremia and hyperten-
sive complications.
RENAL STONES
Childhood Polycystic The important cause is increased urine
Kidney Disease concentration of constituents, so that it
exceeds their solubility in urine (super-
1. Autosomal recessive. saturation) and leads to precipitation.
2. Mutation in the PKHD-1 gene (chro- 1. Calcium stones (75%) → alkaline pH.
mosome-6p) → defective receptor 2. Struvite stones (15%) → urea splitting
protein-fibrocystin → defective func- organism, alkaline pH.
tion of cilia in tubular epithelial cells. 3. Uric acid stones (6%) → acidic urine.
3. Subcategories—perinatal, neonatal, 4. Cysteine stones (2%) → cystinuria.
infantile and juvenile. 5. Others (2%) → xanthinuria.
Morphology Etiopathogenesis
1. Numerous small cysts. Calcium stones (phosphate and oxalates)
2. Sponge like appearance. 1. Idiopathic hypercalciuria without
3. Cuboidal lining of the cysts (origin hypercalcemia (↑ absorption).
from CT). 2. Hypercalciuria with hypercalcemia
4. Invariably bilateral. (hyperparathyroidism, ↑ vitamin D).
5. Cyst in liver—symptomatic. 3. Hyperoxaluria.
4. Hyperuricosuria. 2. Obstruction may be sudden or

5. Without any known metabolic abnor- insidious.
mality. 3. Obstruction can occur at any level
Struvite stones (Mg, -NH3, -PO-4) from urethra upto pelvis.
1. UTI (due to alkaline urine).
Uric acid stone Causes
1. With hyperurecemia (gout, leuke- 1. Congenital:
mia).
a. Atresia of urethra.
2. With hyperuricosuria (gout, leuke-
mia). b. Valve formations.
3. Idiopathic. c. Renal ptosis with torsion.
Cysteine stone d. Kinking of ureter.
1. Inborn error of metabolism. 2. Acquired:
a. Staghorn calculi → branching a. Foreign bodies (calculi, necrotic
structures on calculi. papillae).
b. Tumors (BPH, CA prostrate, CA
Inhibitors of Crystal bladder)
Formation in Urine c. Inflammation (prostatitis, urethri-
1. Tamm-horsfall proteins. tis, ureteritis).
2. Osteopontins. d. Neurogenic—spinal cord damage
3. Pyrophosphate. with bladder palsy.
4. Diphosphonates. e. Normal pregnancy—due to mild
5. Mucopolysaccharides. compression.
6. Nephrocalcin (GP).
Pathogenesis
Clinical Course Pathogenesis of hydronephrosis is shown
1. Intense pain (renal or ureteric colic) in Fig. 14.7.
→ Flank pain radiating to groin (loin
to groin). Morphology
2. Hematuria.
1. Dilated pelvis and calyces.
3. Ulceration and bleeding.
2. Parenchymal atrophy.
4. ↑ urinary infection.
3. ↓ GFR and renal function impair-
5. Renal failure at later stage. ment.
4. Sometimes hydroureter (dilatation of
HYDRONEPHROSIS ureter).
1. Dilatation of pelvis and calyces with 5. Tubular dilatation followed by atro-
accompanying parenchymal atrophy phy and fibrosis.
caused by obstruction to urine outflow. 6. Sometimes coagulation necrosis also.
Fig. 14.7: Pathogenesis of hydronephrosis
Clinical Course Morphology

1. Bilateral—if the obstruction is below 1. Usually solitary and large.
ureter.
2. CS—yellow to grey-white with cystic
2. Unilateral—if the obstruction is in
softening or hemorrhage.
ureter or above.
3. Oliguria and anuria. 3. Well defined margins.
4. Decreased GFR and renal function im- 4. Aggressive and surrounding paren-
pairment. chyma affected.
5. Tumor invades pelvis, calyses, ureter
and renal vein.
RENAL CELL CARCINOMA
6. Invasion into perinephric fat and
1. Derived from the renal tubular epi- adrenals.
thelium. 7. Tumor cells appear vacuolated (lipid-
2. Located predominantly in the cortex. laden) or solid with granular or clear
cytoplasm.
Risk Factors 8. Sometimes anaplasia (mitotic figures,
hyperchromasia, pleomorphism).
1. Smoking.
9. Scanty, but vascularized stroma.
2. HTN and obesity.
3. Cadmium exposure (occupation).
4. APKD as a result of dialysis. Papillary Renal Cell Carcinoma
1. Second most common type of RCC.
Clear Cell Carcinoma 2. Papillary growth pattern.
1. Renal cell carcinoma (RCC). 3. Usually multifocal and bilateral.
2. Occur sporadically and familial. 4. Both sporadic and familial.
3. Occur in association with von-Hip- 5. No mutation.
pel-Lindau disease.
6. Duplication of MET proto-oncogene
4. Mutation of VHL gene (tumor sup-
pressor gene)—clear cell RCC (chro- on chromosome-7q31.
mosome-3p25). 7. Associated with trisomy 7.
Morphology WILMS TUMOR

1. Numerous papillae with fibrovascu- 1. One of the major cancers in children
lar core. (2–5 year).
2. Necrosis, hemorrhage and cystic de- 2. Derived from mesoderm.
generation. 3. Also called nephroblastoma.
3. Orange-yellow color due to less lipid 4. Sporadic and familial occurrence.
content. 5. Patients with WAGR and DDS show
4. Tumor cells have pink cytoplasm. ↑ occurrence of Wilms tumor.
6. Associated with the abnormality of
Chromophobe Renal WT1 gene (chromosome-11p13).
Cell Carcinoma 7. WAGR—deletion of WT1.
8. DDS—mutation of WT1.
1. Least common type of RCC. 9. BWS also predispose to Wilms tu-
2. Arise from intercalated cells of col- mor—mutation of WT2 locus (chro-
lecting duct. mosome-11).
3. Multiple losses of entire chromo-
somes—1, 2, 6, 10, 13, 17 and 21. Morphology
4. Have good prognosis.
1. Large, solitary, well circumscribed
mass.
Morphology 2. CS—homogenous, soft, tan grey col-
1. Grossly tan brown. ored.
2. Darkly stained tumor cells. a. Cystic degeneration, hemorrhage
and necrosis are seen.
3. Distinct cell membrane. 3. Triphasic combination.
4. Perinuclear hallow. a. Blastemal (sheets of blue cells) cells.
5. Microvesicles are seen. b. Stromal (fibrocystic or myxoid) cells.
c. Epithelial (tubules or glomeruli)
Clinical Course of Renal cells.
Cell Carcinoma 4. Rarely heterogenous—SMCs, epithe-
lial cells, adipose tissue, cartilage, os-
1. Hematuria (most frequent) teoid, etc.
2. Large tumor—flank pain with pal- 5. Rarely shows anaplasia.
pable mass. 6. Nephrogenic rests.
3. Fever and polycythemia. a. Precussor lesions of Wilms tumor.
4. Hypercalcemia, HTN, Cushing syn- b. Hyperplastic or sclerotic.
drome (paraneoplastic syndromes).
5. Metastasis to bone and lungs. Clinical Course
6. Triad of:
1. Palpable abdominal mass.
a. Painless hematuria.
2. Fever, abdominal pain with hematuria.
b. Palpable abdominal mass. 3. Good prognosis with nephrectomy
c. Dull flank pain. and chemotherapy.
15 Oral Cavity and
Gastrointestinal Tract
Chapter
Leukoplakia 2. May be elevated or hot.

1. Whitish well-defined mucosal patch 3. Marked dysplasia.
or plaque by epidermal thickening or 4. Chance of transformation to carci-
hyperkeratosis. noma.
2. Cannot be scraped off easily.
3. Commonly seen on the vermilion BARREtT ESOPHAGuS
border of lower lip, buccal mucosa,
1. Replacement of normal distal strati-
hard and soft palate.
fied squamous mucosa by metaplas-
4. Localized, smooth or roughened, tic columnar epithelium containing
leathery, white discrete areas. goblet cells.
5. May be without epithelial dysplasia
2. Occurring as a complication of long-
or with severe dysplasia (carcinoma
standing gastroesophageal reflux dis-
in situ).
ease (GERD).
6. Close association with tobacco abuse.
3. More common in males than in fe-
7. More seen in older men. males (4:1).
8. Can be transformed to squamous cell
4. More common in white race.
carcinoma.
5. The re-epithelialization by columnar
9. Lip and tongue lesions—more chance
epithelium is due to the induction by
of transformation.
low pH.
10. Hairy leukoplakia (only in AIDS) and
verrucous leukoplakia are different 6. This metaplastic columnar epithe-
lium is more resistant acidic pH (not
from classical leukoplakia.
typical intestinal variety).
7. Complications are ulceration and
Erythroplakia strictures.
1. Red, velvety, granular, circumscribed 8. More risk of developing adenocarci-
areas of irregular borders. noma.
Fig. 15.1: Schematic representation of various diseases affecting esophagus
9. Due to high grade dysplasia. The Squamous Cell Carcinoma

schematic representation of vari-
1. Common (90% of esophageal can-
ous diseases affecting esophagus is cers).
shown in the Figure 15.1. 2. Mutation of tumor suppressor gene
p16 and p53.
Morphology 3. Mutation of EGFR, KRAS and APC
1. Salmon-pink velvety mucosa. also seen.
2. Exist as tongue extending into the
junction. Risk Factors
3. Metaplastic columnar epithelium 1. Esophageal disorders—esophagi-
with globlet cells. tis, achalasia, Plummer-Vinson
syndrome.
4. Dysplastic changes may be present.
2. Habits—alcoholism and tobacco abuse.
5. Repeated endoscopy and biopsy is 3. Dietary.
needed for definitive diagnosis. The a. Deficiencies of vitamins (A,C),
sequence of events in Barrett esophagi- trace metals (Zn, Mb).
tis is shown in the Figure 15.2. b. Fungal contamination.
c. Increased nitrites and nitrosamines.
4. Genetic predisposition.
a. Familial, associated with tylosis.
Fig. 15.2: Sequence of events in Barret

Morphology
esophagitis 1. Epithelial dysplasia → CA in situ →
invasive CA.
2. At first: Grey-white small thickenings
ESOPHAGeAL CARCINOMA (plaque like).
1. Arise from both mucosa and under- 3. Later transformed to one of three
lying mesenchyme. forms.
Chapter 15 u Oral Cavity and Gastrointestinal Tract 173
a. Polypoid masses. Etiology

b. Ulcerations into depth (sometimes
1. Increased damage to mucosa.
erode outside structures).
a. Helicobacter pylori infection (Fig.
c. Diffuse infiltrative—wall thicken-
15.3).
ing and lumen narrowing.
b. NSAIDS (Fig. 15.4).
c. Cigarette smoking (Fig. 15.5).
Adenocarcinoma
d. Alcoholism.
1. Complication of Barrett esophagus. e. Hyperacidity.
2. High grade dysplasia easily leads to 2. Decreased defence mechanisms.
adenocarcinoma. a. Ischemia.
3. Aneuploidy and p53 mutation is com- b. Shock.
monly associated.
c. Delayed gastric emptying.
d. Host factors.
Morphology
1. Usually located in distal one-third Normal Defence Mechainsms
and may invade into stomach.
1. Surface mucus secretion.
2. Large nodular masses/ulcerative/
diffuse infiltrative. 2. Bicarbonate secretion.
3. Mostly these are mucin-producing 3. Mucosal blood flow.
glandular tumors. 4. Apical surface membrane transport.
5. Epithelial regenerative capacity.
Clinical Course 6. Elaboration of PGs.
1. Dysphagia, weight loss, anorexia, fa-
tigue, weakness, etc.
2. Often pain and obstruction also.
PEPTIC ULCER
1. Discontinuity in the epithelial lining.
2. Most common sites are first part of
duodenum and lesser curvature of
stomach (4:1).
3. Duodenal ulcer—male is more affect- Fig. 15.3: Helicobactor pylori leading onto
ed than female (3:1). peptic ulcer
4. Remitting and relapsing disease.
Definition
Lesions or defects in the mucosa that pen-
etrate at least into the submcucosa and
often to muscularis propria or deeper. Fig. 15.4: NSAIDs leading onto peptic ulcer
Pathogenesis
1. Helicobacter pylori infection is the ma-
jor etiology of peptic ulcer. Fig. 15.5: Smoking leading onto peptic ulcer
a. H. pylori strains producing (vacuolat-
ing toxin) and CagA (cytotoxin asso-
ciated gene-A) are more virulent.
2. NSAIDs are the second most impor-
tant etiological factor.
3. Cigarette smoking.
Morphology
1. Round, sharply punched out lesions
(2–4 cm diameter).
Fig. 15.6: Microscopy of peptic ulcer
2. Usually, sites are anterior and poste-
rior walls of first part of duodenum 3. G—granulation tissue.
and lesser curvature of stomach. 4. S—fibrous, collagenous material.
3. Associated with antral gastritis. The microscopy of peptic ulcer is
4. Duodenal—smaller lesions. shown in the Figure 15.6.
5. Gastric—larger lesions.
6. The edges of the craters are perpen- Clinical Course
dicular to the surface. 1. Epigastric pain (burning sensation).
7. Mild edema of adjacent mucosa. 2. Hemorrhage and perforation (com-
8. There is no significant elevation. plication).
9. Surrounding mucosal folds may be 3. Nausea, vomiting, bloating, belch-
flat or radiating like spokes of wheel. ing, etc.
1 0. The base of the lesion is clean due to 4. Can be transformed to malignancy.
peptic digestion. 5. Usually pain worsens at night.
11. Perforation can leads to peritonitis. 6. Usually pain.
12. Healing—granulation tissue and re- a. Relieved on taking food—gastric
epithelialization. ulcer.
b. Aggravating on taking food—duo-
13. C/c gastritis is common. The micros-
denal ulcer.
copy of peptic ulcer is shown in the
Figure 15.6.
GASTRIC CARCINOMA
Histology (Superficial to Deep) Intestinal Type Adenocarcinoma
1. N—base and margins have thin layer 1. Arise from gastric mucous cells that
of necrotic debris. have undergone intestinal metapla-
2. I—inflammatory infiltrate, mainly (N). sia after long-term C/c gastritis.
2. Better differentiated. Pathogenesis

3. Occur more in older males.
1. Mutation of E-cadherin in 50% indi-
viduals.
Risk Factors
2. Some other mutations are also present.
1. C/c gastritis with intestinal meta-
plasia. 3. FGFR2 mutation.
2. H. pylori infection. 4. Expression of MMPs.
3. Nitrites and nitrosamines in food.
4. Reduced intake of vegetables and Morphology
fruits.
5. Partial gastrectomy. 1. More in pylorus and antrum.
6. Pernicious anemia. 2. Followed by cardia, body, fundus,
lesser and greater curvature.
Pathogenesis 3. The most favored site is lesser curva-
Pathogenesis of gastric carcinoma is ture of antropyloric region.
shown in the Figure 15.7.
4. Early GCA.
a. Confined to mucosa and submucosa.
b. Perigastric LNS may or may not
involved.
5. Advanced GCA.
a. Extend into muscularis.
b. Had spread more widely.
6. Dysplasia is the precursor lesion.
7. Three growth patterns.
Fig. 15.7: Pathogenesis of gastric carcinoma
a. Exophytic (polyp-like and contain
adenoma).
Diffuse Type Adenocarcinoma
b. Flat or depressed.
1. Arise from gastric mucous cells not
c. Excavated (shallow or deep
with C/c gastritis.
crater)—mimic peptic ulcer.
2. Poorly differentiated.
3. Occur more in younger females. 8. If the entire stomach is involved, then
the stomach become rigid and thick-
Risk Factors ened—leather bottle stomach (linitis
1. Undefined. plastica).
2. H. pylori infection and C/c gastritis 9. Intestinal—gastric cells and intestinal
often absent. type glands.
10. Diffused—only gastric cells, but no Morphology

glands.
1. Small, flask-like or spherical out-
11. Spread to LNs—commonly left su-
pouchings.
praclavicular LN (Virchow’s node).
2. Most commonly in sigmoid colon.
12. Spread intraperitoneally to ovaries—
Krukenberg tumor. 3. Isolated cecal diverticula are also
seen.
4. Muscular hypertrophy and promi-
Clinical Course nent Taenia.
1. Asymptomatic early stages. 5. Frequently dissecting into appendi-
2. Abdominal discomfort and weight ces epiploicae.
loss later. 6. Uninflamed state—thin walls.
3. Fatigue and anorexia. 7. Perforation leads to peritonitis and
4. Dysphagia rarely. abscesses.
8. Later—lumen narrowing and fibrosis.
COLONIC DIVERTICULOSIS
Clinical Features
1. A diverticulum means a blind pouch
that communicates with the gut lumen. 1. Mostly asymptomatic.
2. All the three layers of gut wall are 2. Feeling of incompleteness of rectum.
present. 3. Bleeding, peritonitis, abscesses, etc.
3. Congenital.
a. Distinctly three layers. MALABSORPTION
b. Most common site is Meckel diver- SYNDROMES
ticulum. 1. Defective absorption of fats, CHO,
4. Acquired. proteins, vitamins, minerals, electro-
a. Muscularis propria is attenuated. lytes and water.
b. Most common site is colon (due to 2. Most common presentation is C/c di-
Taenia). arrhea.
5. Focal defects are created in the mus- 3. Hallmark is steatorrhea.
cle wall.
6. Nerves and arteries penetrate the Pathogenesis
muscle coat through the defects.
Defective Intraluminal Digestion
7. The connective tissue sheath accom-
panying these nerves and arteries 1. Defective digestion of fats and pro-
provide potential sites for herniation. teins.
8. Low fiber diet predisposes to diver- a. Pancreatic insufficiency (C/c alco-
ticulosis. holism, Crohn disease).
9. Exaggerated peristaltic contractions b. ZES.
(segmentation) also lead to herniation 2. Defective solubilization of fat (due to
through anatomical site of weakness. ↓ bile secretion).
a. Ileac dysfunction. 6. Skin—purpura, petichia, edema, der-

b. Biliary obstruction. matitis.
3. Total or subtotal gastrectomy. 7. Nervous system—peripheral neu-
ropathy.
Defective Mucosal Absorption
Inflammatory Bowel
1. Primary mucosal cell abnormalities.
Disease
a. Defective terminal digestion (lac-
tose intolerance, bacterial over- 1. Crohn disease (CD).
growth). 2. Ulcerative colitis (UC).
b. Defective transepithelial transport
(abetalipoproteinemia). Etiopathogenesis
2. Reduced SI surface area. 1. Mainly idiopathic.
a. Celiac disease (gluten sensitive 2. Result from abnormal local immune re-
enteropathy)—destruction of villi. sponses against normal flora of gut and
b. Crohn disease. probably against some self-antigens.
c. Surgical resections.
Genetic Predisposition
3. Infections.
a. A/c infectious enteritis, parasitic 1. Related to MHC-II alleles.
infestation, tropical sprue, Whip- 2. CD—HLA-DR7, HLA-DQ4, NOD2,
ple disease. IL-23R genes.
3. UC—HLA-DRB1, IL-23R genes.
Defective Nutritional Delivery
Immunologic Factors
Lymphatic obstruction
1. Mainly CD4+ TH cells associated.
1. Lymphoma.
2. CD—IFN producing TH1 cells are as-
2. TB and tuberculous lymphadenitis.
sociated.
3. Recently TH17 subset is seems to be
Clinical Course associated, which produces IL-17.
1. Bulky, frothy, greasy, yellow-gray 4. CD—association with TNF.
stools.
2. Weight loss, anorexia, abdominal dis- Microbial Factors
tension, flatus, muscle wasting. 1. Triggers the immune response and
3. Hematopoietic system—vitamin B12 inflammation.
and vitamin K deficiency. 2. The final common pathway in IBD
4. Musculoskeletal—osteopenia, tetany, pathogenesis is inflammation.
muscle wasting. 3. Mucosal destruction with loss of in-
5. Endocrine—amenorrhea, impotence, tegrity of epithelial barrier and ab-
hyperparathyroidism. sorptive function.
Crohn Disease 2. Uveitis, polyarthritis, erythema no-

dosum, obstructive uropathy.
1. May affect any level of the alimenta-
ry tract from mouth to anus, but most 3. Relapses are very common.
commonly the terminal ileum. 4. Complications are fistulae, abscesses,
2. This is a systemic inflammatory dis- strictures, carcinoma.
ease with predominant gastrointesti-
nal involvement. Ulcerative Colitis
3. Occur at any age.
1. Ulceroinflammatory disease of colon,
4. Characterized by the triad of:
usually limited to mucosa and sub-
a. Mucosal damage and transmural
mucosa.
involvement.
b. Non-caseating granulomas. 2. A systemic disease, primarily involv-
ing the colon.
c. Fistula formation.
3. A non-granulomatous disease.
Morphology 4. No skip lesions.
5. Usually not extending beyond sub-
1. SI alone—30%. mucosa.
2. Colon alone—30%.
6. Mural thickening usually absent.
3. SI and colon—40%.
7. Risk of carcinoma development.
a. Triad—already mentioned.
8. Start in rectum and extending proxi-
b. Intestinal wall will be rubbery and
thick due to edema, inflammation, mally to involve entire colon.
fibrosis and hypertrophy. 9. Peak incidence between 20 and 25
c. Narrow lumen—string sign radio- years of age.
graphically.
d. Serosal extension into mesentric Morphology
fat—creeping fat.
1. Continuous colonic lesion.
e. Sharp demarcation between in-
2. Mucosal destruction with hyperemia,
volved and non-involved areas.
edema, etc.
f. Presence of skip lesions.
3. Easy bleeding and presence of ulcer-
g. Small ulcers large ulcers
ations.
fissuring fistula.
h. (N) infiltrate and granulomas. 4. Pseudopolyps are present—extend-
ing upwards.
i. Crypt abscesses, ulceration and
C/c mucosal damage. 5. Rarely perforation, abscesses and
j. Mucosal metaplasia and dysplasia peritonitis.
may occur. 6. Sometimes expose muscularis pro-
pria and neural plexus to fecal mat-
ter, which leads to complete arrest of
Clinical Course
neuromuscular junction. This results
1. Diarrhea, abdominal pain, fever, in swelling and gangrene of colon—
melena. toxic megacolon.
7. Healing leads to fibrosis and atrophy c. Greater with dysplasia.

(granulation). d. Greater with diameter.
8. (L) infiltrate in lamina propria.
9. (N) and crypt abscesses may present. Morphology
1 0. Most serious complication is carci- 1. Tubular adenomas.
noma colon. a. Usually in rectosigmoid junction.
b. Has usually a slender stalk and a
Clinical Course head.
c. Stalk—normal epithelium.
1. Bloody diarrhea, abdominal cramps,
d. Head—Neoplastic cells.
tenesmus, colicky abdominal pain.
e. Shows slight dysplasia and atypia.
2. Relapse is common.
f. Leads to intramucosal or invasive
3. Uveitis, polyarthritis, erythema no- carcinoma.
dosum, etc. 2. Villous adenomas.
4. Mucosal metaplasia and dysplasia. a. Commonly in rectum and rectosig-
moid junction.
ADENOMAS b. Generally sessile cauliflower-like
masses.
1. Neoplastic polyps. c. High degree of dysplasia.
2. Small pedunculated or large sessile
lesions. Clinical Course
3. Lesser in SI and more in large intes-
1. Bleeding and anemia.
tine.
2. Smaller ones are asymptomatic.
4. Resulting from epithelial prolifera-
tion and dysplasia.
5. Shows genetic and familial predispo- COLORECTAL CARCINOMA
sition. 1. About 98% is constituted by adeno-
6. Four subtypes. They are: carcinomas.
a. Tubular adenomas (mostly tubular 2. Adenomas are the precursor lesions.
glands—pedunculated). 3. Males are more affected than females.
b. Villous adenomas (villous projec-
tions—sessile). Pathogenesis
c. Tubulovillous adenomas (mixed Pathogenesis of colorectal carcinoma is
type). shown in the Figure 15.8. The NSAIDs
d. Sessile serrated adenomas (lining vs colorectal carcinoma are shown in the
of serrated epithelium). Figure 15.9.
7. Carcinoma incidence is:
a. Lesser in small pedunculated tu- Carcinogenesis
bular adenomas. 1. Adenoma—carcinoma sequence (Fig.
b. Greater in large sessile villous ad- 15.10) or APC/β-catenin pathway or
enomas. chromosomal instability pathway.
Fig. 15.8: Pathogenesis of colorectal carcinoma
Fig. 15.9: NSAIDs vs colorectal carcinoma
Fig. 15.10: Adenoma-carcinoma sequence
Fig. 15.11: Mismatch repair pathway

2. Mismatch repair pathway as shown 3. Metastasis.

in the Figure 15.11 (microsatellite in- a. Regional LNS, liver, lungs and bones.
stability [MSI]).
a. Apoptosis regulating genes. TNM Staging
•• TGF-β, BAX, IGF2R, etc.
1. Tumor.
b. DNA repair genes.
a. T0—none evident.
•• MLH1, MSH2 (main)
b. Tis—in situ.
•• MSH6, PMS1, PMS2. c. T1—invasion into lamina propria
c. Adenoma-carcinoma sequence. or submucosa.
•• Hereditary—FAP d. T2—invasion into muscularis pro-
•• Sporadic—left-sided predomi- pria.
nant cancers. e. T3—invasion into subserosa and
d. Mismatch repair pathway. serosa.
•• Hereditary—HNPCC f. T4—invasion into other structures
•• Sporadic—right-sided predom- or organs.
inant cancers. 2. Lymph nodes.
a. L0—none evident.
Morphology b. L1—1 to 3 pericolic LNs.
c. L2—greater than four pericolic LNs.
1. Mostly single.
d. L3—any positive node along a
2. Proximal tumor. named blood vessel.
a. Occur as polypoid masses. 3. Metastasis.
b. Not much obstructive. a. M0—none evident.
3. Distal tumor. b. M1—any distant metastasis.
a. Occur as encircling lesions (nap-
kin ring).
Familial Polyposis
b. Narrowing of lumen.
Syndromes
4. Adenomatous change.
5. May be well differentiated or ana- 1. Autosomal dominant.
plastic. 2. Can transform into malignancy.
6. Many tumors secrete mucin. 3. Peutz-Jeghers (PJ) polyposis and fa-
7. Mucin facilitate extension and thus ↓ milial adenomatous polyposis.
prognosis.
Peutz-Jeghers Polyposis
Clinical Course 1. Uncommon hamartomatous polyps.
1. Right sided—fatigue, iron-deficiency 2. Autosomal dominant.
anemia. 3. As a part of PJ syndrome.
2. Left sided—bleeding, changes in 4. Germ line mutations in PTEN are as-
bowel habit. sociated.
Familial Adenomatous Polyposis 4. Mostly tubular.

5. Usually become evident in early
1. Defect in APC gene.
childhood and adolescence.
2. 500–2,500 colonic adenomas. 6. There is 100% chance for malignant
3. Minimum 100 number is required for transformation unless colonectomy
diagnosis. has done.
16 Liver, Gallbladder
and Biliary Tract
Chapter
HEPATIC FAILURE a. This leads to exposure of brain to

NH3 (A/c) and neuronal dysfunc-
Complications tion and brain edema.
1. Coagulopathy. b. C/c—disturbance in AA metabo-
2. Hepatic encephalopathy. lism in brain.
3. Hepatorenal syndrome.
Hepatorenal Syndrome
Hepatic Encephalopathy 1. Renal failure without primary renal
disease and associated with hepatic
1. Disturbances in brain functioning. failure.
2. Symptoms ranging from subtle be- 2. Kidney function will improve, if the
havior abnormalities to marked liver failure reversed.
confusion and stupor to coma and 3. Oliguria, ↑ blood urea, ↑ blood N2, ↑
death. serum creatinine.
3. Rigidity, hyper reflexia, non-specific 4. Hyperosmolar urine with ↓ Na+ and
EEG changes and rarely seizure are no proteins.
also seen. Pathogenesis
4. Characteristics asterixis (flapping Splanchnic vasodilatation and systemic
tremor). vasoconstriction leads to decreased RBF
5. Non-rhythmic rapid flexion—exten- and renal failure.
sion movements of head and extrem-
ities; best elicited when the arms are CIRRHOSIS
held in extension with dorsiflexion of
wrist. Definition
Pathogenesis A diffuse process characterized by fibrosis
1. Severe loss of hepatocellular function. and convertion of normal liver architecture
2. Shunting of blood from portal to sys- into abnormal structure characterized by:
temic circulation. 1. Bridging fibrous septae.
2. Parenchymal nodules. PORTAL Hypertension

3. Disruption of the architecture. 1. Increased resistance to portal blood
flow.
Causes a. Intrahepatic causes—cirrhosis, fat-
ty liver, sarcoidosis, etc.
1. Alcoholism.
b. Prehepatic causes.
2. Chronic infection.
c. Posthepatic causes.
3. Autoimmune hepatitis. 2. The main consequences are detailed
4. Biliary disease. below.
5. Iron overload.
Ascites
Vascular Changes in Cirrhosis 1. Collection of excess fluid in the peri-
toneal cavity (Fig. 16.3).
1. Hepatic artery to portal vein and por-
2. Clinically detectable if volume more
tal vein to hepatic vein shunts.
than 500 mL.
2. Loss of fenestration between EC. 3. The fluid is usually serous with low
proteins, glucose, Na+ and K+.
Pathogenesis 4. Some mesothelial cells and leuko-
cytes are also seen.
Figure 16.1 shows the pathogenesis of
cirrhosis.
Portosystemic Shunt
Fibrogenesis 1. Due to ↑ pressure, there will be porto-
systemic shunt and manifests as:
The fibrogenesis is shown in Figure 16.2. a. Hemorrhoids (rectum).
b. Esophageal varices (esophagus).
Clinical Course c. Caput medusa (umbilicus).
1. Progressive liver failure.
2. Leads to portal HTN. Congestive Splenomegaly
3. Lead to HCC. Due to long-standing congestion.
Fig. 16.1: Schematic representation of pathogenesis of cirrhosis

Chapter 16 u Liver, Gallbladder and Biliary Tract 185
Fig. 16.2: Fibrogenesis (*Ito cells are normally vitamin A or fat storing cells)
Hepatic Encephalopathy 5. Does not cause C/c hepatitis or a car-

rier state.
Described earlier. 6. Seems to be results from T cell-medi-
ated injury of infected hepatocytes.
VIRAL HEPATITIS
Diagnosis
Hepatitis A Virus
Diagnosis is by detection of IgM Ab.
1. Benign self-limited disease.
2. ssRNA virus of incubation period Prevention
15–50 days.
1. Hygiene.
3. Feco-oral route of transmission.
2. Passive immunization.
4. Largest potential of causing epidem- 3. Pre-exposure prophylaxis with HAV
ics. vaccine.
Fig. 16.3: Mechanism of formation of ascites in portal hypertension

Hepatitis B Virus Diagnosis

1. Double-stranded DNA virus. 1. Diagnosis
2. Transmission through sexual contact, a. PCR for HCV RNA.
parenteral and perinatal. b. ELISA for Ab.
3. High rate of producing chronic illness.
4. Incubation period is 1–4 months. Hepatitis D Virus
5. CD4+ T cells and CD8+ T cells act on
the affected hepatocytes and cause 1. Single-stranded RNA virus with
hepatocellular injury. The outcomes multiplication defect.
of hepatitis B is shown in the Figure 2. Become infective when multiplica-
16.4. tion defects.
3. Always dependent on HBV infection.
Diagnosis and Prevention 4. Can cause A/c coinfection or super-
1. Diagnosis is by detection of HBSAg infection.
and Ab to HBcAg. 5. Parenterally transmitted.
2. Prevention is by screening and vac-
cination. Diagnosis
1. Detection of IgG and IgM.
Hepatitis C Virus
2. Detection of HDV RNA in blood.
1. Single-stranded RNA virus. 3. Detection of HDV Ag in liver.
2. Parenterally transmitted.
3. Intranasal use of cocaine is a risk factor. Hepatitis E Virus
4. Incubation period is 6–12 weeks.
5. Persistent infection is the hallmark. 1. Enterically transmitted, waterborne
The outcomes of hepatitis C virus is disease.
shown in Figure 16.5. 2. ssRNA virus.
Fig. 16.4: Outcomes of hepatitis B infection

Fig. 16.5: Outcomes of hepatitis C infection
3. Not producing C/c infection or per- 4. Fulminant hepatitis.

sistent viremia. a. A/c liver failure (only a small pro-
portion).
Diagnosis b. Massive hepatic necrosis.
1. HEV PCR for RNA. c. Massive necrosis and regenerative
2. IgM and IgG Abs. hyperplasia.
5. Chronic hepatitis.
Clinical Outcomes a. Hepatocyte injury, apoptosis, cy-
1. HAV, HCV, HEV—no carrier state. tolysis, regeneration, etc.
2. HAV, HEV—no C/c hepatitis. b. Portal tract inflammation and in-
1. Asymptomatic terphase hepatitis.
c. Bridging inflammation and necro-
a. No external symptoms, but infec-
tion is there. sis.
2. A/c viral hepatitis d. Fibrous collagen deposition in por-
tal tracts.
a. Caused by all hepatitis viruses.
e. Later bridging fibrosis (p-p, c-c, p-c).
b. Four phases.
f. At last—endstage cirrhosis.
•• Incubation period
•• Symptomatic preicteric phase g. Occurs when persistent more than
6 months.
•• Symptomatic icteric phase
h. Many causes are there like viral, au-
•• Convalescence.
toimmune, drugs, Wilson disease,
c. Peak infectivity is noticed during
α1-AT deficiency, alcoholism, etc.
last days of incubation period and
early days of preicteric phase.
3. Carrier state
Morphology
a. Caused by HBV and HDV only. 1. Liver is enlarged, red or green.
b. Can transmit the disease, but no 2. Hepatocytes undergo swelling—bal-
symptoms. looning degeneration.
3. Hepatocytes undergo fatty changes—

ground-glass cell.
4. Hepatocyte injury and necrosis.
5. Cytolysis or apoptosis of hepato-
cytes.
6. Sometimes bridging necrosis (p-p,
c-c, p-c).
7. Lobular disarray (loss of architec-
ture).
8. Hepatocyte proliferation. Fig. 16.6: Hepatitis A serology

9. Hypertrophy and hyperplasia of Hepatitis C: The hepatitis C serology is
Kupffer cells. shown in Figure 16.8.
10. Mononuclear infiltrate (mainly in
portal tracts). ALCOHOLIC LIVER DISEASE
11. Interphase hepatitis—inflammation 1. Three diseases are coexisting with al-
spill over to adjacent parenchyma. cohol abuse.
a. Fatty liver.
Diagnosis of Hepatitis with b. Alcoholic hepatitis.
Reference to Ag and Ab c. Alcoholic cirrhosis.
Hepatitis A: The hepatitis A serology is
shown in Figure 16.6. Pathogenesis
Hepatitis B: The hepatitis B serology is The pathogenesis of alcoholic liver dis-
shown in Figure 16.7. ease is shown in Figure 16.9.
Fig. 16.7: Hepatitis B Serology

3. First centrilobular change, then entire

lobule.
4. Grossly the liver is enlarged, soft, yel-
low and greasy.
5. No fibrosis, if not progressing.
Alcoholic Hepatitis
Fig. 16.8: Hepatitis C serology
1. Hepatocyte swelling and necrosis
(ballooning degeneration).
Morphology 2. Mallory bodies—tangled intermedi-
Fatty Liver ate filaments and some proteins to-
gether form eosinophillic inclusion
1. Moderate alcohol intake—microve- bodies in the degenerating hepato-
sicular fat droplets (Fig. 16.10). cytes.
2. C/c intake—macrovesicular fat drop- 3. (N) infiltration; also (L) and mac-
lets. rophages.
Fig. 16.9: Pathogenesis of alcoholic liver disease

Fig. 16.10: Sequence of liver changes in alcoholism (*AE-Alcohol exposure; **AA-Alcohol abstinence)
4. Fibrosis—sinusoidal and perivenular c. Hepatorenal syndrome.

fibrosis. d. Massive GI bleeding.
5. Sometimes hemosiderin deposits e. HCC.
also.
DRUG-INDUcED LIVER DISEASE
Alcoholic Cirrhosis
Intrinsic (Predictable)
1. Enlarged liver with yellow–tan color.
1. Occur in anyone who accumulates a
2. Micronodules are formed (micronod-
large dose.
ular cirrhosis).
2. Examples for these drugs are parac-
3. Hobnail appearance—nodularity on etamol, tetracycline, antineoplastic
the surface. drugs, amanitin toxin, etc.
4. Progressive necrosis and fibrosis
(bridging fibrosis). Idiosyncratic (Unpredictable)
5. Bile stasis and loss of architecture.
1. Depend upon the host’s immune re-
6. Nodules are formed by aggregation sponse, metabolic capacity, etc.
of degenerating hepatocytes.
2. Drugs like CPZ, halothane, sulpho-
namide, allopurinol, α-methyl dopa,
Clinical Course etc. causes this type of reaction.
1. Mild to severe hepatomegaly.
2. Progressive anorexia and weight Mechanism
loss. 1. Direct
3. Progressive impairment of liver func- a. Acetaminophan, CCl4, mushroom
tion. toxins, etc.
4. May progress to complications like, 2. Mediated through several inflamma-
a. Liver failure. tory reactions and immune-mediated
b. Hepatic encephalopathy. destruction.
a. Halothane, sulfonamide. Pathogenesis (Hereditary)

b. A/c liver failure—acetaminophen, 1. Net iron accumulation of 0.5–1 g/
CCl4 and halothane. year.
2. Total iron content will become > 50 g
Morphology over years (normal is 2–6 g).
3. Hereditary hemochromatosis—
1. Massive hepatic necrosis.
atleast 20 g Fe.
2. Liver may get shrinked. 4. Excess Fe causes toxicity by:
3. Capsule may get wrinkled. a. Lipid peroxidation.
4. Complete destruction of hepatocytes. b. Collagen formation.
5. Only a little inflammatory reaction. c. Direct DNA damage (Fig. 16.11).
6. Shows some regeneration.
7. Macronodular cirrhosis (similar to vi- Morphology
ral hepatitis). 1. Deposit of hemosiderin in liver, pan-
creas, myocardium, etc.
Pattern of Injury a. Triad.
1. Cholestasic and cholestatic hepatitis. •• Cirrhosis (micronodular), in-
flammation is absent
2. Hepatocellular necrosis (mainly by
•• Pancreatic fibrosis and DM
acetaminophen).
•• Skin pigmentation (due to ↑
3. Steatosis and steatonecrosis. melanin production).
4. Fibrosis and cirrhosis. 2. Heart is enlarged and with brown
5. Granulomas and vascular lesions. discoloration.
6. Neoplasms. 3. A/c synovitis with hemosiderin de-
position.
HEMOCHROMATOSIS 4. Testes may get atrophied.
1. Excessive accumulation of body Clinical Course

iron most of which is deposited in
parenchymal organs like liver and 1. Male predominance.
pancreas. 2. Hepatomegaly, abdominal pain and
skin pigmentation.
2. Hereditary and acquired are there.
3. Atypical arthritis, DM.
3. Most common among hereditary is
4. May leads to HCC due to DNA dam-
an AR disease.
age.
a. Adult onset.
b. Caused by mutation in HFE gene.
4. Acquired form is 2° to repeated trans-
fusions, ↑ Fe intake, infective erythro-
poiesis, C/c liver disease, etc. Fig. 16.11: Pathogenesis of hemochromatosis
WILSON’S DISEASE Clinical Course

1. AR disease. 1. Younger age.
2. Increased copper accumulation in 2. A/c or C/c hepatitis.
many organs and tissues; principally 3. Neuropsychiatric illness.
in liver, brain and eye. 4. Kayser-Fleischer ring.
3. Due to mutation in ATP7B gene on
chromosome 13. Diagnosis
4. This leads to defective ATPase metal- 1. Decreased serum ceruloplasmin level.
ion transporter in liver. 2. Increased urinary Cu.
5. Thus, the cooperation of Cu into ceru- 3. Increased hepatic Cu.
loplasmin and ceruloplasmin secre-
tion into plasma gets arrested, which Treatment
in turn leads to defective excretion of
D-penicillamine.
Cu into bile.
7. So Cu gets accumulated primarily in
liver and later in brain, eyes, etc.
ALPHA1-ANTITRyPSIN
8. The accumulated Cu exerts toxicity
DEFICIENCY
through. 1. Autosomal recessive disease.
a. Free radical generation. 2. Decreased levels of AAT (antiprotease).
3. AAT is predominantly synthesized
b. Binding to cellular proteins.
by hepatocytes.
c. Replacing metals from hepatic 4. Due to mutation of AAT gene on
metalloenzymes. chromosome 14.
5. Increased lysosomal destruction of
Morphology liver parenchyma.
1. Fatty change.
2. A/c hepatitis. Morphology
3. C/c hepatitis. 1. Globular inclusion in hepatocytes
(+ve with PAS stain).
4. Massive liver necrosis.
2. Cholestasis and hepatocyte necrosis
5. Fibrosis and cirrhosis. in newborn.
6. Cholestasis. 3. Childhood cirrhosis.
7. Brain—mainly the basal ganglia (pu-
tamen) is affected. Clinical Course
a. Atrophy and even cavitation.
1. Presenting with hepatic failure or
8. Eyes—Kayser-Fleischer rings. pulmonary disease.
a. Green-brown Cu deposits in De- 2. Closely associated with pathogenesis
scemet membrane of cornea. of emphysema.
HEPATOCELLULAR 7. Another form—fibrolamellar carci-

CARCINOMA noma (no association with cirrhosis).
Risk Factors Clinical Course

1. Sex (male predominance). 1. Hepatomegaly.
2. HBV and HCV infection. 2. Increases ascites and even with blood.
3. Aflatoxin and C/c alcoholism. 3. Fever.
4. Cirrhosis. 4. Cirrhotic features.
5. Poor prognosis.
6. Death by.
Pathogenesis
a. Profound cachexia.
1. Most of cases arise from high-grade b. GI bleed.
dysplasa nodules (Fig. 16.12). c. Liver failure and hepatic coma.
d. Rupture of tumor with hemor-
rhage.
CHOLELITHIASIS
(GALLSTONES)
Risk Factors
Fig. 16.12: Pathogenesis of hepatocellular
carcinoma 1. Cholesterol stones.
a. Demography and advancing age.
2. Tumor may arise from mature hepa-
b. Female sex hormones.
tocytes or progenitor cells.
c. Obesity.
3. Characterized by numerical or struc- d. Gallbladder stasis.
tural chromosomal abnormalities. e. Hyperlipidemia.
2. Pigment stones.
Morphology a. Demography.
1. Three patterns. b. C/c hemolytic syndromes.
a. Unifocal (usually massive). c. Biliary infection.
d. GI disorders like Crohn’s disease.
b. Multifocal.
c. Diffusely infiltrative.
Pathogenesis
2. Areas of hemorrhage and necrosis.
3. Increases tendency for invasion of 1. Cholesterol stones are four condi-
tions are predisposing:
vascular channels.
a. Supersaturation of bile with cho-
4. Well differentiated and with bile lesterol.
globules. b. Microprecipitates of calcium.
5. Large multinucleated anaplastic tu- c. Gallbladder stasis.
mor cells. d. Mucus hypersecretion—trap the
6. Mallory bodies-like inclusions. crystals.
2. Pigment stones. 5. If the exudate is purely pus—empye-

a. Bilirubin in biliary tree get usually ma of GB.
precipitated as calcium salts. 6. GB wall may get edematous and hy-
peremic.
Morphology 7. Sometimes gangrenous cholecystitis.
1. Cholesterol stones.
Chronic
a. Mainly in gallbladder.
b. Pure-pale yellow, mostly radiolu- 1. GB may be shrinked/normal/en-
cent. larged.
c. Mixed with other substances— 2. GB wall is often thickened by fibrosis.
gray-white. 3. (L) infiltrate—less amount.
d. Usually multiple, firm and faceted. A/c calculus cholecystitis
2. Pigment stones—anywhere in the 1. Commonly seen.
biliary tree. 2. Most common indication for emer-
a. Black—mainly in gallbladder gency cholecystectomy.
small, firm and radio-opaque. 3. Due to chemical irritation and
b. Brown—in biliary ducts soft, soap inflammation.
like and mostly radiolucent. phospholipase
4. Lecithin lysoleci-
Clinical Course thin (toxic to GB mucosa).
1. Colicky pain. 5. PGs are produced and accounts for

inflammation.
2. Complication—empyema, perfora-
6. May leads to ↓ blood flow and later
tion, fistulae, etc.
bacterial infection.
A/c non-calculus cholecystitis
CHOLECYSTITIS 1. Postoperatively, severe trauma, se-
1. Inflammation of gallbladder. vere burns and sepsis.
2. Can be A/c, C/c or A/c superim- 2. GB stasis, dehydration, vascular com-
posed on C/c. promise also contributes.
3. Almost always associated with chole- C/c cholecystitis
lithiasis. 1. Usually associated with GB stones.
2. Symptoms are similar to A/c.
Morphology 3. Not usually associated with
obstruction.
Acute 4. Not much inflammation.
1. Gallbladder sometimes violaceous or
green colored. Clinical Course
2. It is 90% associated with stones.
3. Obstruction of neck or cystic duct 1. Colicky pain.
usually. 2. Tender distended GB.
4. GB contains turbid bile even with pus 3. Nausea, vomiting, less tenderness
or blood. (chronic stage).
17 Pancreas
Chapter
ACUTE PANCREATITIS b. Coxsackie virus.

Mycoplasma pneumoniae.
c.
1. A group of reversible lesions char-
acterized by inflammation of the
pancreas. Morpholgy
2. Can range from focal edema and fat 1. Microvascular leakage and edema.
necrosis to parenchymal necrosis and 2. Fat necrosis and acute inflammation.
hemorrhage. Pathogenesis of acute 3. Necrosis and destruction of pancre-
pancreatitis is shown in Figure 17.1. atic parenchyma.
4. Hemorrhage due to destruction of
Etiology blood vessels.
1. Metabolic. 5. Red black hemorrhagic spots.
a. Alcoholism. 6. Yellow-white chalky fat necrosis.
b. Hypercalcemia and hyperlipopro- 7. Fat globules in peritoneal fluid.
teinemia. 8. Necrotizing pancreatitis (moderately
c. Genetic (hereditary pancreatitis— severe).
AD). a. Hemorrhagic pancreatitis (severe).
d. Drugs like thiazide, furosemide,
methyldopa. Clinical Course
2. Mechanical. 1. Abdominal pain (cardinal symptom).
a. Trauma, gallstones and iatrogenic 2. Explosive inflammatory reaction
injury. (ARDS and even shock).
3. Vascular. 3. Markedly elevated serum amylase.
a. Shock, arterioembolism and PAN. 4. DDS.
4. Infection. a. Ruptured A/c appendicitis.
a. Mumps. b. Ruptured A/c cholecystitis.
Fig. 17.1: Pathogenesis of acute pancreatitis
c. Perforated peptic ulcer. 2. Destruction of exocrine parenchyma

d. Occlusion of mesenteric vessels. followed by destruction of endocrine
5. Complication/sequelae is pancreatic parenchyma later.
pseudocyst. 3. Results from recurrent bouts of A/c
pancreatitis.
CHRONIC PANCREATITIS
Etiology
1. Long-standing inflammation with ir-
reversible lesion. 1. Long-term alcohol abuse.
Chapter 17 u Pancreas 197
2. Long-term standing pancreatic duct Morphology

obstruction.
1. Parenchymal fibrosis.
3. Tropical pancreatitis due to malnutri-
tion. 2. Acinar atrophy and loss.
4. Hereditary pancreatitis. 3. Dilatation of pancreatic ducts.
5. Cystic fibrosis (CFTR gene muta- 4. Epithelium may be hyperplastic or
tion). show squamous metaplasia.
5. First exocrine sclerosis.
Pathogenesis 6. Later endocrine sclerosis and loss of
islets.
1. Similar to that of A/c pancreatitis.
2. Can result from:
Clinical Course
a. Ductal obstruction and acinar cell
injury. 1. Persistent abdominal or back pain.
b. Direct acinar cell injury by toxins. 2. Recurrent jaundice and indigestion.
c. Acinar cell injury by oxidative 3. Pancreatic insufficiency and DM only
stress. later.
d. Necrosis, fibrosis—due to repeated 4. Can lead to chronic malabsorption.
A/c pancreatitis. 5. Predisposing to pancreatic carcinoma.
18 Male Genital System
Chapter
TESTICULAR NEOPLASMS 2. Counter part of ovarian dysgermi-

noma.
Most common cause of painless enlarge-
3. Also related to germinomas of ex-
ment of the testes.
tragonadal sites (CNS).
4. Large soft well-demarcated homog-
Risk Factors enous gray-white tumors that bulge
The risk factors of testicular neoplasms from the cut surface.
are: 5. Typically confined to the testes by an
1. Cryptorchidism. intact tunica albuginea.
2. Gonadal dysgenesis. 6. Foci of coagulation necrosis usually
3. CA of other testis. without hemorrhage.
4. Isochromosome of short arm of chro- 7. If hemorrhage, there will be a compo-
mosome 12. nent of non-seminomatous tumor.
8. Large cells with distinct borders, gly-
Classification cogen-rich clear cytoplasm and round
nuclei with conspicuous nucleoli.
1. Seminomatous germ cell tumor.
9. Intratubular neoplasia is seen.
a. Seminoma.
10. Tumor cells are arranged in separate
2. Non-seminomatous germ cell tumors. lobules.
a. Embryonal carcinoma. 11. (L) infiltrate and granulomatous in-
b. Yolk sac tumor (extraembryonic). flammation.
c. Choriocarcinoma (extraembryonic). 12. Cells staining positive for hCG.
d. Teratoma (somatic cell line). Spermatocytic seminoma
3. Sex cord/stromal tumors (rare). 1. A less frequent morphologic variant
of seminoma.
Seminoma (Only hCG Elevated) 2. Occur usually in older patients.
1. The commonest form is referred to as 3. Small, medium and large cells are
classical. seen.
Chapter 18 u Male Genital System 199
4. May be uninucleate or multinucleate. 3. Tumor cells—eosinophilic cytoplasm

5. The relation with intratubular meta- and pleomorphic nuclei.
plasia is less. 4. Well-formed placental villi are not seen.
6. Less metastatic potential. 5. Increased hCG can be demonstrated.
Embryonal Carcinomas (Both Teratoma (Both

hCG and AFP Elevated) hCG and AFP Elevated)
1. Ill-defined invasive masses. 1. Differentiation towards somatic cell
2. Foci of necrosis and hemorrhage are line.
seen. 2. Mature teratoma—fully differenti-
3. Larger lesions may invade spermatic ated tissues seen.
cord and epididymis. 3. Immature somatic elements are seen.
4. Large cells with ill-defined borders, 4. With malignant somatic elements—
basophilic cytoplasm with large nu- frank malignancies arise in pre-exist-
clei and prominent nucleoli. ing teratoma.
5. Usually undifferentiated. 5. For example, adenocarcinoma,
6. Intratubular neoplasia is seen. squamous cell carcinoma.
6. Main somatic elements are cyst, car-
Yolk Sac Tumors (Only AFP Elevated) tilage, bone, epithelium, fat, neural
1. Also called endodermal sinus tumors. tissue, glands, etc.
2. Usually affect children with less than 7. Mixed germ cell tumors are also seen.
3 years of age.
3. Large and well demarcated. Clinical Course
4. Differentiated towards endodermal 1. Painless enlargement of testes.
sinus.
5. Tumor cells arranged in different pat- 2. Metastasis commonly to iliac and pa-
terns. ra-aortic LNs.
6. Characteristic presence of primitive 3. Both lymphatic and hematogenous
glomeruli-like structures called Schil- route.
ler-Duval bodies. 4. hCG and AFP are markers for diag-
7. Alpha-fetoprotein (AFP) with tumor nosis.
cell cytoplasm.
NODULAR HYPERPLASIA
Choriocarcinomas
(Only hCG Elevated) OF THE PROSTATE
1. Differentiation of stem cells towards 1. Also called benign prostatic hyper-
trophoblastic cells. trophy (BPH) as misnomer.
2. Small, but extensive metastatic po- 2. BPH is more in central and transi-
tential. tional zones.
3. Carcinomas are more in peripheral PROSTATIC CARCINOMA

zone.
1. Most common visceral cancer in
4. Both stromal and glandular hyper-
males.
plasia occurs.
2. Peak incidence between the ages of
5. Males are affected after the age of 40.
65 and 75.
6. Risk increases with increase in age.
3. Does not occur before puberty.
7. Androgens (specific DHT) have a
central role in BPH.
a. DHT → increased DNA, RNA, GFs,
Etiology
cellular proteins → hyperplasia. 1. Hormonal, genetic and environmen-
tal factors contributed.
Clinical Course 2. Androgen increases the risk and es-
1. Lower urinary tract obstruction. trogen decreases the risk.
2. Difficulty in starting urination and 3. Genetic.
also intermittently get arrested. a. Susceptible foci in chromosome 1
3. Painful distension of bladder and is identified.
sometimes hydronephrosis. b. Certain mutations and telomere
4. Urinary, urgency, frequency and noc- shortening.
turia.
5. Increased chance of UTI. Morphology
1. Mainly in the peripheral zones.
Morphology 2. Palpable by rectal examination.
1. Nodularity, mainly in inner zone. 3. Not much urethral obstruction in the
2. Enlarged prostate. initial stages.
3. Nodules bulge out from cut surface. 4. Grey white masses infiltrating the ad-
4. Nodules may be cystic or solid ap- jacent glands and ill defined.
pearance. 5. Early metastasis to regional lymph
5. May produce compressive obstruc- nodes.
tion or ball-valve type of obstruction 6. May invade into seminal vesicle,
(projecting into the bladder). bladder, adjacent soft tissues and rec-
6. Proliferating stroma and glandular tum.
elements.
7. Most of these are adenocarcinomas.
7. Glands are lined by columnar epithe-
lium and the lumen contains protein- 8. Variable degree of differentiation and
aceous secretory material—corpora anaplasia.
amylacea. 9. Neoplastic glands are lined by cuboi-
8. Some glands show squamous meta- dal cells.
plasia. 10. Gland adjacent to cancer shows aty-
pia (PIN).
11. This PIN acts as a precursor for carci- SYPHILIS (LUES)

noma.
1. C/c veneral infection caused by
12. There is a high-grade and low-grade Treponema pallidum.
PIN (according to degree of atypia).
2. Sexually transmitted disease through
the cutaneous mucosal lesions.
Clinical Course 3. Transmission mainly occurs at the
1. Early lesions—usually asymptomatic. primary and secondary stages.
2. Late—metastasis. 4. Congenital syphilis—transmission
3. Bone metastasis—both osteoclastic through placenta.
and osteoblastic lesions. 5. Rapid dissemination of the organ-
4. Diagnosis by assay of PSA and imag- ism occurs through lymphatics and
ing techniques. bloodstream.
5. Treated with surgery and chemother- 6. Incubation period is 9–90 days (mean
apy. 21 days).
7. Primary lesion is a chancre at the site
Anatomical Staging of entry.
8. Two antibodies are developed.
Tumor Extent a. Ab to non-treponemal Ag.
1. T1: Clinically apparent (T1a, T1b, T1c). b. Ab to specific treponemal Ag.
2. T2: Palpable or visible imaging and
cancer confined to prostate (T2a, T2b, Morphology
T2c).
1. Macroscopic lesions vary with stages.
3. T3: Local extraprostatic invasion
(T3a, T3b). 2. Microscopic lesions are common fun-
damentally.
4. T4: Invasion of contagious organs
(bladder, rectum). a. Proliferative endarteritis.
b. Inflammatory infiltrate rich in
plasma cells.
Regional Lymph Nodes
3. Hypertrophy and proliferation of ECs.
1. N0: No metastasis to regional LNs. 4. Lumen narrowing.
2. N1: Metastasis to regional LNs. 5. Local ischemia, cell death and fibrosis.
Distant Metastasis Primary Syphilis

1. M0: No distant metastasis. 1. Chancre/hard chancre at the point of
2. M1: Distant metastasis. entry.
•• M1a: Distant LNs metastasis 2. The chancre develops usually on
•• M1b: Bone metastasis (more os- the penis (on vagina and cervix in
teoblastic lesion) females).
•• M1c: Other organs. 3. Begins as a firm papule.
4. Progress into painless ulcer with in- Tertiary Syphilis

durated well-defined edges and clear
1. In about one-third of untreated pa-
base.
tients.
5. Regional LNs usually enlarged, but
2. Usually after a latent period of 5 days.
painless.
These are three forms that are given
6. Infiltrate of (L) and plasma cells with as.
arteritis.
7. Usually resolves without any treat- Cardiovascular Syphilis
ment leaving a scar.
1. Syphilitic aortitis (common).
Secondary Syphilis 2. Endarteritis of vasa vasorum of aor-
ta.
1. Occur within 2 months of resolution 3. Occlusion of vasa vasorum leads to
of chancre (25%). scarring of media.
2. Combination of generalized lymph- 4. So aortic insufficiency and aneurysms
adenopathy and various mucocuta- occurs.
neous lesions. 5. Mainly the proximal aorta is in-
3. Lesions may be maculopapular, scaly volved.
or pustular. 6. Sometimes, coronary artery occlusion
4. Mainly palms and soles are involved. also.
5. Condyloma lata.
a. Broad based elevated lesions in Neurosyphilis
moist skin areas like anogenital re-
1. Chronic meningovascular disease
gion, thighs and axilla.
and tabes dorsalis.
6. Mucosal lesions are common in oral
2. General paresis (parenchyma affect-
cavity, pharynx and external genitalia.
ed).
7. Endarteritis and plasma-lymphocytic
3. Increased frequency in HIV patients.
infiltrate.
8. LNs enlargement mainly in neck and
Benign Tertiary syphilis
inguinal region.
a. Non-specific hyperplasia of germi- 1. Uncommon .
nal centers with increased plasma 2. Deposition of gumma at various
cells. sites—commonly in bones and mu-
9. Hepatitis, renal involvement and iri- cocutaneous areas.
tis are also seen. 3. This results from delayed type of hy-
10. Then 2° syphilis resolves as 1° at
persensitivity.
which the patient enters early latent Gumma
phase. 1. Irregular firm mass of necrotic tissue.
11. Most infective stage. 2. Surrounded by connective tissue.
3. Central coagulation necrosis. •• Notched central incisors

a. Surrounded by infiltrate of (L), •• Keratitis with blindness
plasma cells, macrophages and gi- •• Nerve injury (8th) and deafness.
ant cells.
c. Saber shin deformity.
b. Peripheral zone of fibrous tissue.
d. Mulberry molars.
e. Saddle nose deformity.
Congenital Syphilis
f. Chronic meningitis.
1. Stillbirth with syphilis.
g. Chorioretinitis.
a. Hepatomegaly, bone abnormali-
ties, pneumonitis and pancreatic
Diagnosis
fibrosis.
b. Liver shows extramedullary he- 1. Primary syphilis.
matopoiesis and portal tract in- a. Dark ground microscopy of T. pal-
flammation. lidum.
2. Infantile syphilis. 2. Secondary syphilis.
a. Clinically manifests at birth or a. Dark ground microscopy of T. pal-
within a few months after birth. lidum.
b. Chronic rhinitis and mucocutane- b. Non-treponemal and antitrepone-
ous lesions. mal Ab detection.
3. Late/tardive syphilis. 3. Tertiary syphilis.
a. Untreated congenital syphilis of a. Antitreponemal Ab detection.
more than 2 years duration. 4. VDRL and RPR are done for Ab de-
b. Hutchinson triad. tection.
19 Female Genital
System and Breast
Chapter
CERVICAL INTRAEPITHELIAL 3. Men have multiple sexual partners.

NEOPLASIA 4. Persistent infection with high risk
HPV (high risk HPV—HPV 16, 18, 31
1. Precursor of invasive cervical carci- and 45).
noma. 5. Cigarette smoking.
2. All cervical intraepithelial neoplasia 6. Immunodeficiency.
(CIN) does not progress to CA cervix.
3. But all CA cervix develop from CIN. Pathogenesis
4. Peak age is 30 years.
The pathogenesis of cervical intraepithe-
5. High grade SIL. lial neoplasia is shown in the Figure 19.1.
a. CIN-I: Mild dysplasia (low grade
SIL). Morphology
b. CIN-II: Moderate dysplasia.
1. CIN-I.
c. CIN-III: Severe dysplasia and car-
a. Mild dysplasia (flat condyloma).
cinoma in situ.
b. Koilocytosis.
•• Nuclear hyperchromasia
Risk Factors
•• Angulation with perinuclear
1. Early age of first intercourse. vacuolization due to cytopathic
2. Multiple sexual partners. effect of HPV.
Fig. 19.1: Pathogenesis of cervical intraepithelial neoplasia

Chapter 19 u Female Genital System and Breast 205
2. CIN-II. 6. Nodal and distant metastasis as pro-

a. Moderate dysplasia. gresses.
b. Variation in nuclear and cell size. 7. Grades (1–3) based on cellular differ-
c. Heterogenicity of nuclear chroma- entiation.
tin. 8. Stages (1–4) based on clinical spread.
d. Superficial cells show differentia-
tion and koilocytosis. Clinical Course
e. Increased mitosis.
1. Vaginal bleeding, leukorrhea, painful
3. CIN-III.
coitus.
a. Marked severe dysplasia.
2. Dysuria.
b. Marked size variation and marked
heterogenecity. 3. Pap smear is for diagnosis.
c. Normal or abnormal mitosis. 4. Treated with chemotherapy.
d. Loss of maturation and differentia-
tion. ENDOMETRIAL CARCINOMA
e. Loss of koilocytosis. Mostly seen in peak age of 60 (55–65).
f. Confined to epithelium and its
glands, so called carcinoma in
situ. Risk Factors
1. Obesity (↑ estrogen synthesis).
INVASIVE CARCINOMA 2. DM, HTM.
OF CERVIX 3. Infertility.
4. Increased exposure to estrogen.
1. Squamous cell CA (75%).
2. Adenocarcinoma (20%).
Endometrioid Carcinoma
3. Small cell neuroendocrine CA (5%).
4. Always arise from CIN. 1. Usually seen in perimenopausal
5. Peak age is 45 years. women with excess estrogen.
2. Usually arise in the background of
Morphology endometrial hyperplasia and is high-
ly glandular.
1. Usually occurring in the squamoco- 3. These tumors are usually associated
lumnar junction. with breast carcinoma.
2. Begin as early stromal invasion. 4. Close association with HNPCC (mis-
3. Late stage tumor—encircling the match repair) and also microsatellite
overall survival (OS). instability.
4. Late stage tumor penetrates into un- 5. Seen in association with Cowden
derlying stroma and produce barrel syndrome (hematoma of breast, thy-
cervix. roid and endometrium) in which
5. Extension to parametrium—fixes the mutation of PTEN is seen (suppres-
uterus. sor gene).
6. This tumor closely resembles normal OVARIAN TUMORS

endometrium.
Classification
7. May be exophytic or infiltrative.
8. They show mucinous, tubal and 1. Surface epithelial-stromal tumors
(70%) (> 20 years).
squamous patterns.
a. Serous tumor.
9. Arise in the mucosa of uterus.
b. Mucinous tumor.
10. Sometimes arises simultaneously in
c. Endometrioid tumor.
uterus and ovary.
d. Clear cell tumor.
11. Grading (1–3) according to local in- e. Brenner tumor.
vasion. f. Cystadenofibroma.
12. Staging: 2. Germ cell tumors (20%) (0–30 years
Stage I—limited to corpus. arise from totipotent germ cells).
Stage II—extending to cervix. a. Teratoma.
Stage III—beyond uterus, but within b. Dysgerminoma.
true pelvis. c. Endodermal sinus tumor.
Stage IV—distant metastasis. d. Choriocarcinoma.
3. Sex cord-stromal tumors (10%) (any
age arise from multipotent cells).
Serous Carcinoma
a. Fibroma-thecoma.
1. Usually arise in the background of b. Granulosa-theca cell tumor.
endometrial atrophy in an old age c. Sertoli-Leydig cell tumor.
women. 4. Metastasis to ovary (< 5%) (older age).
2. p53 mutations are usually seen.
3. This forms small tufts or papillae, Box 19.1: Multipotent cells
rather than glands. •• Arises from coelomic mesothelium that
4. Much greater cytological atypia. covers the ovarian surface
•• Due to repeated ovulation, small epithelial
5. These are poorly differentiated and cysts are formed
aggressive. •• This undergoes metaplasia and neoplasia.
6. Glandular element is less.
Serous Tumors
Clinical Course
1. Most frequent ovarian tumors.
1. Marked leukorrhea and irregular 2. Benign, low malignant and malig-
bleeding. nant tumors.
2. With progression, the uterus will en- 3. Benign: 30–40 years (60%).
large. 4. Malignant: 45–60 years.
3. Local invasion also seen. 5. Can be unilateral or bilateral.
6. Serosal covering will be smooth and Krukenberg Tumors

glistening for benign and nodular for
1. Metastasis of mucinous tumor from
malignant tumors.
GIT mimics the primary mucinous
7. Contains cystic spaces usually filled ovarian tumor.
with clear serous fluid.
2. Usually bilateral involvement.
8. Benign.
3. Infiltration of stroma.
a. Lined by ciliated columnar epithe-
4. Dirty necrosis (necrosis with cellular
lium.
debris).
b. Psammoma bodies in papillae.
9. Low malignant.
Endometrioid Tumors
a. Mild cellular atypia.
b. Usually non-invasive. 1. May be solid or cystic.
10. Malignant. 2. Cyst contains chocolate-colored fluid.
a. Anaplastic and undifferentiated 3. Tubular glands similar to those in en-
dometrium.
cells.
4. Mostly malignant.
b. Locally invasive and regional LN
metastasis. 5. PTEN mutation is usually observed.
c. Distant metastasis is rare.
d. Poor prognosis. Brenner Tumors
1. Usually unilateral and uncommon.
Mucinous Tumors 2. Consisting of abundant stroma.
1. Consisting of mucin secreting cells. 3. Nests of transitional-like epithelium.
2. Benign (80%), low malignant and 4. Cysts are lined by columnar mucin
malignant tumors. secreting cells.
3. Can be unilateral (major) and bilateral. 5. Usually smooth and encapsulated.
4. Cystic spaces are filled with mucino-
us material. Teratoma
5. Most of these are larger and multio- 1. Differentiation towards somatic cell
cular. line.
6. Papillary formations are less. 2. Younger the age of the patient, more
7. Psammoma bodies are not seen. chances to be malignant.
8. Endocervical, intestinal and endome- a. Benign mature cystic teratoma.
trial type of lining epithelia are seen. •• Most common (90%)
9. The rupture of mucinous cyst results •• Mature somatic elements are
in release of mucin into peritoneum formed
and mucin production in the peri- •• Cysts are lined by epidermis
toneum by mucinous cells leads to (dermoid cyst)
pseudomyxoma peritonei. •• Mostly unilateral (more often
10. Prognosis is better than serous tumor. in right ovary)
•• Filed with sebaceous secretion. 4. Metastasize widely and resistant to

•• Hair, teeth, bone, cartilage and chemotherapy.
epithelium are seen.
•• Can produce infertility. Granulosa-theca Cell Tumors
•• Can produce torsion. 1. Usually postmenopausal, unilateral
•• Rarely malignant transforma- and cystic.
tion of somatic element can oc- 2. Cuboidal granulosa cells → usually
cur (usually SCC). malignant.
b. Immature malignant teratoma. 3. Lipid-laden thecal cells → secrete es-
•• Found early in life (18 years) trogen and induce endometrial and
•• Bulky and predominantly solid breast Ca.
•• The somatic elements are im-
mature Thecoma-fibroma Tumors
•• Areas of necrosis
1. Solid grey fibrous cells and lipid-lad-
•• Foci of neuroepithelial lesions—
en thecal cells.
metastatic
2. Produce hydrothorax and ascites
•• Late stages—poor prognosis.
(Meigs syndrome).
c. Specialized teratoma.
3. Rarely malignant and elaborate es-
•• Only certain specialized tissues trogen.
are seen
•• Struma ovarii → thyroid tissue
(hyperthyroidism)
Sertoli-Leydig Cell Tumors
•• Ovarian carcinoid → carcnoid 1. Grey to yellow masses and usually
syndrome. solid.
2. Masculinizing or defeminizing effect.
Dysgerminoma 3. Rarely malignant.
1. Usually unilateral and malignant.
2. Counterpart of testicular seminoma. HYDATIDIFORM MOLE
3. Grey-white masses and has less 1. One of gestational trophoblastic dis-
amount of stroma. ease.
4. (L) infiltration and granuloma can be 2. This is a voluminous mass of swollen
seen. chorionic villi appearing as grape-
like structures.
Choriocarcinoma 3. These swollen chorionic villi are cov-
ered by atypical chorionic epithelium.
1. Unilateral and identical to placental
tumor.
Complete Mole
2. Small and foci of hemorrhage.
3. Cytotrophoblastic and syncytiotro- 1. Diploid (46 XX/46 XY).
phoblastic differentiation. 2. All villi are edematous.
3. Does not produce embryogenesis (no 2. The enlarged villi penetrate the uter-
fetal parts). ine wall and sometimes cause rup-
4. Diffuse trophoblastic proliferation. ture and hemorrhage.
5. Highly elevated β-hCG levels. 3. Local invasion to broad ligament and
6. Atypia is often present. vagina also.
7. Some progresses to choriocarcinoma. 4. The villi epithelium will be hyper-
8. In this, an empty egg is fertilized by plastic.
two spermatozoa or a diploid sper- 5. The villi can embolize and reach
matozoon. lungs or brain.
9. Delicate friable mass of translucent 6. Not possible to remove completely
cystic structure. by curettage.
10. Absence of vascularization of villi. 7. Possible to cure by chemotherapy.
11. Myxomatous and edematous stroma.
12. Can be removed by curettage. Choriocarcinoma
1. Another gestational trophoblastic
Partial Mole
disease.
1. Triploid (69 XXY). 2. Aggressive malignant tumor.
2. In this, a normal egg is fertilized by 3. Arises usually from chorionic epithe-
two spermatozoa or a diploid sper- lium.
matozoon.
4. 50% from complete mole, 25% arise
3. Allows some embryogenesis (fetal
after abortion, 25% arise after normal
parts present).
pregnancy.
4. Only focal trophoblastic proliferation
(mild). 5. Bloody brownish discharge (hemor-
rhagic and necrotic).
5. b-hCG is less elevated.
6. Elevated HCG level (β-subunit) in
6. Only some villi are affected.
blood and urine.
7. Atypia is absent.
7. Originates due to abnormal ovum.
8. Rarely progresses to choriocarcinoma.
8. Hematogenous spread mainly to
9. Villi have an irregular scalloped mar-
gin. lungs (50%).
10. Fetal parts are seen in villi. 9. Also spreads to vagina, brain, liver
11. Can be removed by curettage. and kidneys.
10. Hemorrhagic and necrotic mass.
Invasive Mole 11. No chorionic villi.
12. Purely epithelial.
1. Invasive mole is a complete mole,
which is more invasive locally, but 13. Cuboidal cytotrophoblast and syncy-
do not have the aggressive metastatic tiotrophoblast, which are anaplastic.
potential as that of choriocarcinoma. 14. Lymphatic spread is uncommon.
BENIGN TUMORS OF BREAST 3. Clinically.

a. Serous or bloody nipple dis-
Fibroadenoma charge.
1. Most common benign neoplasm of b. Small subareolar tumor.
breast. c. Nipple retraction rarely.
2. Almost always benign. 4. Solitary or multiple papillae.
3. Usually in young women (20–30 5. Papillae have a connective tissue axis
years).
and epithelial lining.
4. Due to ↑ estrogen activity.
6. Multiple.
5. Usually small, solitary, discrete and
freely movable within the breast. a. Intraductal papillomatosis.
6. Rarely may be multiple or giant fi- b. Can leads to carcinoma.
broadenoma.
7. Can easily shell out. CARCINOMA OF BREAST
8. Glandular elements are seen. Usually occur in women after 50 years.
9. Loose fibroblastic stroma and ductal
spaces.
Risk Factors
10. Pericanalicular pattern—the ducts

may be open, regular, round/oval. Well-established
11. Intracanalicular pattern—the ducts
1. Geographic factors.
are compressed, slit like and irregular.
2. Age.
12. The stromal cells secrete GFs for epi-
a. Usually after 50 years.
thelium.
b. Uncommon before 30 years.
3. Family history.
Phyllodes Tumor a. First degree relative with breast
1. Arise from periductal stroma. carcinoma.
2. Usually massive and distending the b. Mutation of BRCA 1 and BRCA 2
breast. genes.
3. Some become lobulated, cystic or leaf 4. Menstrual history.
like. a. Menarche before 12.
4. Increased stromal cellularity with b. Menopause after 55.
anaplasia and increased mitosis. 5. Pregnancy.
5. Rapid increased in size and leads to a. Risk for late pregnancy and nulli-
carcinoma. para.
6. Most are cured by excision. 6. Benign breast disease.
Intraductal Papilloma Less Well-established

1. Always benign. 1. Exogenous estrogens.
2. Neoplastic papillary growth within a. Estrogen replacement therapy.
the duct. 2. Oral contraceptives.
3. Obesity. 3. Lower outer quadrant—10%.

4. High fat diet. 4. Lower inner quadrant—10%.
5. Alcoholism. 5. Central portion—20%.
6. Cigarette smoking.
7. Ionizing radiation. Ductal Carcinoma in Situ
1. Does not invade beyond basement
Pathogenesis membrane.
Genetic Changes 2. Arises within the ducts.
1. Mutation in BRCA 1 and 2 (Familial). 3. Involve distorted duct like space.
2. Overexpression of RAS and MYC 4. Many patterns like solid, cribriform,
genes and HER2/NEU. papillary, etc.
3. Inhibition of p53 and RB genes. 5. Necrosis may be present.
6. Nuclei may be monotonous or pleo-
Hormonal Factors morphic.
7. Comedo subtype has toothpaste-like
1. Estrogen stimulates production of
GFs like TGF-α, FGF, PDGF. necrosis.
2. Autocrine mechanism. 8. Calcifications are seen.
9. Late stage—palpable masses or nip-
ple discharge.
Environmental Factors
10. Express estrogen and progesterone

Ionizing radiation. receptors.
11. Very good prognosis with mastec-

Classification tomy.
Non-invasive
Paget Disease of the Nipple
1. Ductal carcinoma in situ (DCIS).
1. Due to expression of DCIS into lactif-
2. Lobular carcinoma in situ (LCIS). erous duct and into skin and nipple.
2. Exudate is coming out due to disrup-
Invasive tion of epidermal barrier by tumor
1. Invasive ductal carcinoma. cells.
2. Invasive lobular carcinoma. 3. Prognosis depends upon underlying
3. Medullary carcinoma. DCIS.
4. Colloid carcinoma.
5. Tubular carcinoma. Lobular Carcinoma in Situ
6. Other types.
1. Uniform appearance with monomor-
phic nuclei.
Sites 2. Signet ring cells are seen (intracellu-
1. Upper outer quadrant—50%. lar mucin).
2. Upper inner quadrant—10%. 3. Calcification is rare.
4. Expanded ducts, but does not disrupt 2. Large anaplastic cells.

the architecture. 3. Increased lymphoplasmacystic infil-
5. This is a marker of ↑ risk of CA in ei- trates.
ther breast. 4. Increased BRAC 1 mutations and no
6. Radiologic follow-up of both breasts hormone receptors.
and prophylactic bilateral mastecto-
my.
7. Does not extend beyond the base-
Colloid (Mucinous) Carcinoma
ment membrane. 1. Rare subtype with ↑ mucin produc-
tion.
Invasive Ductal Carcinoma 2. Well circumscribed and express hor-
(Scirrhous Carcinoma) mone receptors.
1. These are carcinomas of no special
type. Tubular Carcinoma
2. Not essentially arising from ducts.
1. Well-formed tubules with low grade
3. Majority of breast carcinomas (70%–
nuclei.
80%).
4. Usually associated with DCIS, but 2. Express hormone receptors and good
rarely with LCIS. prognosis.
5. Desmoplastic and replacing the nor-
mal breast fat. Inflammatory Carcinoma
6. May be well differentiated or poorly
differentiated. 1. Enlarged swollen erythematous
7. Invasion of lymphovascular spaces breast with palpable mass.
and along nerves. 2. Poorly differentiated and diffusely
8. Express estrogen and progesterone infiltrating.
receptors.
3. True inflammation is absent.
9. Advanced cancers show dimpling of
skin, nipple, retraction and fixation of 4. Poor prognosis.
chest wall. 5. Blockade of dermal lymphatics leads
to the clinical picture.
Invasive Lobular Carcinoma
1. Associated with LCIS.
Spread
2. The cells surrounding the acini or 1. Outer quadrant and central lesions—
ducts to form Bull’s eye pattern. axillary lymph nodes.
3. Express hormone receptors and more 2. Inner quadrant lesions—lymph nodes
metastatic power. along internal mammary artery.
3. Supra clavicular lymph nodes are
Medullary Carcinoma also involved.
1. Rare subtype, which will clinically 4. Metastasis to lungs, bone, liver, brain,
mistaken for fibroadenoma. adrenals, spleen and pituitary.
Prognosis FIBROCYSTIC CHANGES

Depends on: Non-proliferative Changes
1. Size of primary carcinoma (< 1 cm—
1. Cysts and fibrosis.
good prognosis).
2. Without epithelial cell hyperplasia.
2. Nodal involvement and number of
lymph nodes involved. 3. Also called simple fibrocystic change.
3. Distant metastasis. 4. Very common.
4. Grade of the carcinoma (well differ- 5. Increase in fibrous stroma and dilata-
entiated → good prognosis). tion of ducts with formation of cysts.
5. The histologic type of carcinoma → 6. Usually multifocal and bilateral.
specialized types have good progno- 7. The cysts are brown to blue color and
sis than non-specialized types. contains serous/turbid fluid.
6. Hormone receptors → presence of 8. Small areas of calcification can be
receptors—slightly better prognosis. seen.
7. Proliferative rate of cancer. 9. Smaller cysts are lined by polygonal
8. Aneuploidy—worsens the progno- cells with abundant granular eosino-
sis. philic cytoplasm and small, round,
hyperchromatic nuclei → apocrine
9. Overexpression of HER2/NEU—
metaplasia.
worsens the prognosis.
10. Virtually always benign.
11. Cysts are surrounded by compressed
Stages
fibrous tissue, which had lost its myx-
Stage 0: DCIS or LCIS. omatous appearance.
Stage I: Invasive CA ≤ 2 cm without nod- 12. Stromal lymphocytic infiltrate is seen.
al involvement.
Stage II: Proliferative Changes
a. Invasive CA ≤ 5 cm with 3 axillary 1. Epithelial hyperplasia
LNs or. a. Some are only mild hyperplasia.
b. Invasive CA > 5 cm without nodes. b. On the other extent, some are se-
Stage III: vere hyperplasia with ↑ atypia.
a. ≤ 5 cm with 4 or more axillary c. Often accompanied by other fibro-
nodes. cystic changes.
b. > 5 cm with axillary nodes. d. The ductules or lobules are filled
c. Invasive CA with mammary with hyperplastic cuboidal cells.
lymph nodes. e. Some glandular patterns can be
d. With skin involvement or chest seen—fenestrations.
wall fixation. f. Sometimes papillary projections
Stage IV: Invasive CA with distant me- into ductal lumen—ductal papil-
tastasis. lomatosis.
g. Atypical ductal hyperplasia— sim- g. Not much risk of progressing to

ilar to DCIS. carcinoma.
h. Atypical lobular hyperplasia—
similar to LCIS. Fibrocystic Changes and
i. Usually do not produce palpable Breast Carcinoma
breast mass. 1. Minimal or no risk of carcinoma.
j. Microcalcifications can be seen. a. Cysts and fibrosis.
2. Sclerosing adenosis. b. Apocrine metaplasia.
a. Similar to carcinoma. c. Mild hyperplasia.
b. Produce intralobular fibrosis and d. Fibroadenoma.
ductular proliferation. 2. Slightly higher risk of carcinoma.
a. Moderate to severe hyperplasia
c. Hard and rubbery mass.
without atypia.
d. Proliferation of epithelial and myo- b. Ductal papillomatosis.
epithelial cells. c. Sclerosing adenosis.
e. Small glandular elements in mark- 3. Significantly higher risk of carcinoma.
edly fibrosed stroma. a. Atypical hyperplasia (ductular or
f. Compression of acini and ductules lobular).
leads to the appearance of solid *A family history of breast carcinoma in-
cords of cells. creases the risk in all cases.
20 Endocrine System
Chapter
HASHIMOTO’S THYROiditis Morphology

1. A common cause of hypothyroidism. 1. Diffuse enlargement of thyroid.
2. An autoimmune disease. 2. The capsule is intact.
3. Common in women than men. 3. Cut surface is pale and firm.
4. Mononuclear inflammatory infiltrate
Pathogenesis (lymphocytes and plasma cells)
1. Autoimmune destruction of thyro- 5. Well-developed germinal centers.
cytes and replaced by mononuclear 6. Thyroid follicles are atrophied.
inflammatory infiltrate and fibrosis.
7. Some follicles lined by cells with
a. Activation of CD+ T cells against
abundant eosinophilic granular cyto-
thyroid Ag.
plasm—Hürthle/oxyphilic cells.
•• Release of IFN-ϒ and activation
of macrophages. 8. Hurthle cells have numerous mito-
•• Inflammation, tissue injury and chondria in them.
phagocytosis. 9. Interstitial fibrous tissue is increased.
b. Activation of CD8+ T cells and di- 10. Fibrosing variant—sometimes atro-

rect killing of thyrocytes. phic due to increased fibrosis.
c. Ab against thyroid Ag produced
by B cells. Clinical Course
•• Ab-dependant cell-mediated
1. Painless enlargement of the thyroid.
cytotoxicity by natural killer
(NK) cells. 2. Features of hypothyroidism (some-
2. Association with HLA-DR3 and times preceded by transient toxicosis).
HLA-DR5 mutations. 3. Increased risk for B cell NHL.
3. Three antibodies are detected:
a. Ab to TSH receptor. GRAVES’ DISEASE
b. Ab to thyroglobulin. 1. Most common cause of endogenous
c. Ab to thyroid peroxisome. hyperthyroidism.
2. Characterized by: Morphology

a. Hyperthyroidism—diffuse the en-
1. Diffusely enlarged due to hypertro-
largement and hyperfunctional.
phy and hyperplasia.
b. Ophthalmopathy—exophthalmos.
2. Smooth and soft with intact capsule.
c. Dermopathy—pretibial myxede-
3. Crowded columnar cells lining the
ma.
follicles.
3. Women more affected than men. 4. Small papillae formation and project
into follicular lumen.
Pathogenesis 5. These papillae lack fibrovascular
1. Autoimmune disease with mainly core.
three Abs. 6. Infiltrate of T cells (mainly), B cells
a. Ab to TSH receptor. and plasma cells.
7. Well-developed germinal centers.
b. Ab to thyroglobulin.
8. Generalized lymphoid hyperplasia.
c. Ab to thyroid peroxisome.
9. Orbital tissues will be edematous.
2. The Ab to TSH receptor is central to
pathogenesis. 10. Thickening of dermis in dermopathy
(increased infiltrate).
a. Thyroid stimulating Ig.
•• Binds to TSH receptor and
stimulates it. Clinical Course
b. Thyroid growth stimulating Ig. 1. Hyperthyroidism, exophthalmos,
•• Binds to TSH receptor and in- dermopathy.
creases proliferation. 2. Diffuse enlargement of the gland.
c. TSH–binding inhibitor Ig (TBII).
•• Actually these are inhibitors of DIFFUSE AND
thyroid MULTINODULAR GOITER
•• Some TBII mimics TSH and in-
Most commonly caused by I2 deficiency.
duce thyroid.
Ophthalmopathy Types
1. T cell-mediated autoimmunity. Endemic Goiter

2. Volume of retro-orbital connective 1. In geographic areas, where the soil,
tissue and extraocular muscles is in- water and food supply has little I2,
creased by: especially in mountain areas.
a. Marked infiltration by mononu- 2. Declined by increasing I2 availability.
clear cells.
b. Inflammatory edema and swelling. Sporadic Goiter
c. Accumulation of ECM compo- 1. There is an increase demand for T4.
nents. 2. Occur by ingestion of certain sub-
d. Increased adipocytes. stances, which interferes with
Chapter 20 u Endocrine System 217
Fig. 20.1: Pathogenesis of goiter
thyroid hormone synthesis, like in- 6. This may be non-toxic or produce

creased Ca and vegetables like cab- thyrotoxicosis (toxic MNG).
bage, cauliflower, etc. 7. Colloid will be brown and gelati-
3. Occur more in younger females. nous.
8. Long-standing MNG necrosis, hem-
Dyshormonogenetic Goiter orrhage, cystic change, fibrosis, calci-
fication, etc. can be seen.
Hereditary enzyme defects.
9. The nodules will be similar to those
in follicular adenoma.
Pathogenesis
1. Goiter with euthyroid—here the hor- Clinical Course
mone deficiency is overcome by in-
crease in thyroid mass. 1. Airway obstruction, dysphagia, com-
2. Goitrous hypothyroidism—here the pression of neck vessels.
hormone deficiency is severe and 2. Sometimes hyperthyroidism (Plum-
cannot be overcome by increased mer syndrome).
thyroid mass (Fig. 20.1). a. Not associated with ophthalmopa-
thy or dermopathy.
Morphology 3. Less commonly hypothyroidism.
1. Mostly the hypertrophy and hyper-
plasia of follicles result in diffuse en- ADENOMA OF THYROID
largement initially.
(FOLLICULAR ADENOMA)
2. There will be papillary projection of
crowded columnar epithelium. 1. Benign neoplasm derived from folli-
3. If I2 increases and hormone demand cular epithelium.
decreases, the follicles become col- 2. Nodularity is usually observed.
loid rich and enlarged to form colloid 3. Nodules will be usually neoplastic if:
goiter. a. Solitary nodule (usually benign).
4. Now the epithelium will be cuboidal b. Nodules in younger patients.
(involution).
c. Nodules in males.
5. With recurrent hyperplasia and invo-
d. Nodules after radiation exposure.
lution, the gland becomes irregularly
enlarged to form multinodular goiter e. Nodules taking radioactive I2, which
(MNG). are usually benign (hot nodules).
Pathogenesis gene) and NTRK 1 gene (neurotropic

tyrosine kinase receptor gene).
1. The mutations in TSH receptor sig-
nalling pathway. 2. Point mutations BRAF proto-onco-
gene.
2. Activating mutation in:
3. Leads to activation of MAP kinase
a. TSH receptor (common).
signalling pathway and ultimately to
b. Alpha-subunit of stimulatory G
(GS) protein leads to increased pro- papillary carcinoma.
duction of cAMP (chronic).
3. This results in clonal expansion of ep- Environmental Variables
ithelial cells of follicles and increased
thyroid hormone production. Exposure to ionising radiations.
4. Point mutations in RAS family of on-
cogenes are also observed. Morphology
1. Can be solitary of multifocal.
Morphology
2. May be well-encapsulated or with ill-
1. Usually solitary and well-encapsu- defined margins.
lated nodule often compressing adja-
3. Foci of cystic change, fibrosis and cal-
cent non-neoplastic thyroid.
cification are seen.
2. The neoplastic cells are uniform
round cells. 4. Papillary projections with fibrovas-
3. Some cells will be like oxyphil cells. cular core.
4. Some follicular adenoma shows aty- 5. The cells have nuclei with finely dis-
pia, pleomorphism and prominent persed chromatin—ground glass nu-
nucleoli. clei/Orphan Annie eye nuclei.
6. Cytoplasmic invaginations look like
nuclear inclusions in CS and called
Clinical Course
pseudoinclusions.
1. Toxic nodules—if features of thyro- 7. Concentrically calcified structures—
toxicosis. psammoma bodies are seen often
2. Cold or hot nodules—in radioactive within the papillae.
I2 imaging.
Clinical Course
PAPILLARY CARCINOMA
1. Painless mass in the neck with cervi-
OF THYROID cal lymph node (LN) metastasis.
1. Most common thyroid carcinoma 2. Rarely hematogenous spread to lungs.
(75%–85%). 3. Good prognosis.
2. Derived from follicular epithelium.
FOLLICULAR CARCINOMA
Pathogenesis OF THYORoID
Genetic Variables 1. Second most common (10%–20%) and

1. Chromosomal rearrangements in arising from follicular epithelium.
RET gene (tyrosine kinase receptor 2. Usually in older age.
1. Mutation in RAS family of proto-on- 1. Solitary or multiple nodules.
cogene (HRAS, KRAS, NRAS). 2. Multiple is common in familial variety.
2. Translocation between PAX-8 and 3. C-cell hyperplasia in the surrounding
thyroid is also seen in familial cases.
PPAR-ϒ-1.
4. These hyperplastic zones are the pre-
3. Associated with dietary I2 deficiency cursor lesions.
and follicular adenomas. 5. Polygonal to spindle-shaped cells
form nests, trabeculae or follicles.
Morphology 6. Acellular amyloid deposits derived
from calcitonin.
1. Uniform cells forming small follicles.
7. Calcitonin can be demonstrated in
2. Well demarcated—minimally inva- tumor cells and in amyloid bodies.
sive. 8. This tumor also secretes somatosta-
3. Infiltrating—show infiltration of cap- tin, serotonin and VIP.
sules and vessels.
4. The early stage resembles normal Clinical Course
thyroid or follicular adenoma.
1. Mass in the neck, sometimes produc-
ing dysphagia.
Clinical Course 2. VIP causes diarrhea, but calcitonin
1. Usually solitary and cold nodules. does not cause hypocalcemia.
2. Regional LN metastasis is rare.
3. Hematogenously metastasize to liver, ANAPLASTIC CARCINOMA
lungs and bones. 1. Only less than 5%.
2. Aggressive tumor arising in older age.
MEDULLARY CARCINOMA
1. Five percent of thyroid carcinoma. Pathogenesis
2. This is a neuroendocrine neoplasm 1. Usually arise by dedifferentiation of
derived from parafollicular cells or well-differentiated papillary or folli-
‘C’ cells . cular carcinoma.
2. As a result of one or more genetic al-
Pathogenesis terations.
3. p53 mutation is usually observed.
1. Mutation in RET proto-oncogene and
leads to activation of TSH receptor. Morphology
2. Occur sporadically in 80%.
1. Bulky masses invade the capsule to
3. Familial 20%. reach neck structures.
a. Associated with MEN 2A or 2B or 2. Highly anaplastic cells and shows
FMTC without MEN. four patterns:
a. Pleomorphic giant cells. Pathogenesis of

b. Spindle cells. Type II DM (NIDDM)
c. Mixed giant cells and spindle cells.
1. Insulin resistance and progressive
d. Small cells as in small cell carcinoma. beta-cell dysfunctioning.
3. Foci of papillae or follicles some times. 2. Here relative insulin deficiency only
(Fig. 20.2).
Clinical Features
Highly aggressive and metastasize rap- Insulin Resistance
idly (death in 1 year). 1. This is the resistance to the effects of
insulin on glucose uptake, metabo-
lism or storage.
HYPERPARATHYROIDISM 2. Caused by:
Refer Chapter 21 (Musculoskeletal System). a. Genetic defects of insulin receptor
and insulin signalling pathways.
b. Obesity:
DIABETES MELLITUS •• Increased free fatty acid
Pathogenesis of Type I DM (IDDM) (FFAs)—decreased sensitivity
to insulin
1. An autoimmune disease. •• Adipocytokines.
2. T cell-mediated destruction of islets – ↓ leptin
(β cells) and results in reduction of – ↓ adiponectin
beta-cell mass. – ↑ resisitin.
3. There is absolute insulin deficiency. •• Decreased activity of thiazoli-
4. Genetic predisposition and environ- dinediones (TZD) and loss of
mental factors play a role in patho- activation of PPAR-ϒ (insulin
genesis. resistance)
5. Commonly develops in childhood, •• Decreased sirtuins (a family of
manifests at puberty and progressive proteins)
with age. •• Insulin resistance.
6. Responds to exogenous insulin. – Decreased beta-cell stimula-
tion.
7. The mechanisms of destruction are:
– Decreased adiponectin insu-
a. CD4+ T cells activate macrophages. lin resistance.
b. Release of IL-1, IL-6 and TNF by
macrophages.
Beta-cell Dysfuncion
c. Results in inflammation and tissue
injury. 1. Develops after several years of hy-
d. CD8+ T cells causes direct cyto- peractivity to compensate insulin re-
toxicity. sistance.
e. Ab-mediated beta-cell destruction. 2. May be due to:
8. The susceptibility locus is HLA–D on a. Lipotoxicty by ↑ FFAs.
chromosome-6, which is encoding for b. Glucotoxicity by chronic hyperg-
class-2 MHC molecules. lycemia.
Fig. 20.2: Pathogenesis of type II DM
3. Qualitative β-cell dysfunction. 3. IC hyperglycemia with disturbance

4. Quantitative β-cell dysfunction. in polyol pathway.
a. Decrease in β-cell mass. a. By this, accumulation of sorbitol
b. Islet degeneration. and fructose get increased, which
in turn increases the susceptibility
c. Deposition of amyloid in islet. of cells towards oxidative stress.
b. This is due to decrease in antioxi-
Pathogenesis of dants (IC) by sorbitol metabolism.
DM Complications
Morphology
1. Non-enzymatic glycosylation.
a. This is the process by which glu- Pancreas
cose is attached to free amino ac- 1. Reduction in number and size of islets.
ids of proteins without the aid of 2. Leukocytic infiltration of islets (insu-
enzymes. litis).
b. This results in the formation of ad- 3. Amyloid replacement of islets in
vanced glycosylation end products long-standing type II DM.
(AGEs). 4. Increase in number and size of islets
in non-diabetic newborn of a diabetic
c. The AGEs of collagen in vascular
mother.
wall leads to accumulation of cho-
lesterol (atherosclerosis).
Diabetic Macrovascular Disease
d. AGEs modify the plasma proteins
and these modified proteins get at- 1. Atherosclerosis.
tached to AGE receptor and induce: 2. If coronaries involved—(1st cause of
death in DM).
•• Release of cytokines
3. Gangrene of lower extremities can
•• Proliferation of ECM occur.
•• Increased membrane perme- 4. Severe hyaline arteriosclerosis of HTN.
ability, etc.
e. All these contributes to complica- Diabetic Microangiopathy
tions. 1. Thickening of basement membrane
2. Activation of protein kinase-C (Fig. (BM) due to deposition of AGEs and
20.3). proliferation of fibroblasts.
2. Occur in skin, skeletal muscle, retina, •• Neovascularization and fibrosis

renal glomeruli, renal medulla and •• Vitreous hemorrhages from
cerebrum. new vessels
•• Retinal detachment.
Diabetic Nephropathy 2. Cataract.
1. Second cause of death in DM. 3. Glaucoma.
a. Capillary BM thickening (glom-
erular lesion). Diabetic Neuropathy
b. Diffuse mesangial sclerosis (glom- 1. Peripheral neuropathy of extremities
erular lesion). mainly affecting the sensory function.
•• Increased mesangial matrix 2. Autonomic neuropathy affecting
and BM thickening bowel and bladder functioning.
•• Can manifest as nephrotic syn- 3. This is due to microangiopathy, in-
drome. creased capillary permeability and
c. Nodular glomerulosclerosis. direct axonal damage caused by sor-
•• Increased deposition of matrix bitol accumulation.
•• Leads to renal ischemia.
d. Renal atherosclerosis and arterio- Clinical Course
sclerosis.
1. Hyperglycemia.
•• Both afferent and efferent arte-
rioles are affected. 2. Polyuria, polyphagia, polydipsia.
e. Pyelonephritis. 3. Diabetic ketoacidosis and diabetic
coma.
•• More severe and with necrotiz-
ing papillitis. 4. Hyperosmolar non-ketotic coma.
Ocular Complications CUSHING SYNDROME

1. Diabetic retinopathy. 1. Also called hypercortisolism.
a. Non-proliferative. 2. Caused by any condition that produc-
•• Retinal hemorrhages and exu- es elevation in glucocorticoids level.
dates
•• Microaneurysms Etiology
•• Retinal edema 1. Primary hypothalamic-pituitary
•• Microangiopathy (BM thicken- diseases, which increases ACTH se-
ing). cretion.
b. Proliferative. a. Cushing disease (50%).
Fig. 20.3: Pathogenesis of DM complications (activation of protein kinase-C)

2. Primary adrenocortical hyperplasia Clinical Course

or neoplasia.
1. Hypertension (HTN) and weight
3. Secretion of ectopic ACTH by non- gain.
endocrine tumors (paraneoplastic).
2. Moon facies and buffalo hump.
a. Small cell carcinoma of lung. 3. Osteoporosis and decrease muscle
b. Carcinoid tumors. mass.
c. Medullary carcinoma of thyroid. 4. Hyperglycemia, glycosuria, polydip-
d. Islet cell tumors of pancreas. sia.
4. Exogenous glucocorticoids (clinically 5. Purple abdominal striae.
most common). 6. Hirsutism and menstrual disturbances.
7. Mental problems.
Morphology
Pituitary HYPERALDOSTERONISM
1. Crooke hyaline change. Primary
a. The normal basophilic granular 1. Overproduction of aldosterone au-
cytoplasm of ACTH producing tonomously and there will be:
cells is replaced by homogenous a. Suppression of RAAS.
hyaline material. b. Increased plasma renin activity.
b. Due to deposition of keratin fila- 2. By primary adrenocortical hyperpla-
ments. sia or adrenocortical neoplasms.
Adrenal Gland Secondary

1. Depends on the cause: 1. Extra-adrenal cause and there will be
a. Cortical atrophy—in exogenous stimulation of RAAS and increased
hypercortisolism. plasma renin activity.
•• Atrophy of zona fasciculata and 2. Caused by:
reticularis a. Decreased renal perfusion (renal
•• Zona glomerulosa will be artery stenosis).
normal. b. Arterial hypovolemia and edema
b. Diffuse hyperplasia—in endog- (CCF, cirrhosis).
enous hypercortisolism. c. Pregnancy (induced by estrogen).
c. Nodular hyperplasia—an exten-
sion of diffuse hyperplasia. Morphology
d. Adrenocortical neoplasms. 1. The 80% of primary hyperaldoster-
•• Adenoma—benign and well onism is by aldosterone secreting ad-
encapsulated enoma (Conn syndrome).
•• Carcinoma—malignant and 2. There will be cortical hyperplasia
unencapsulated. also.
3. Eosinophilic lamellated cytoplasmic •• Non-infectious (Kaposi sarco-

inclusions called aldosterone bodies ma).
are seen. d. Metastatic neoplasms:
4. In most cases, adrenocortical hyper- •• CA breast and CA lung com-
plasia will be there. monly.
Clinical Course Secondary Insufficiency

1. Na+ retention and K+ excretion— 1. Disease of pituitary and hypothala-
HTN and hypokalemia. mus.
2. Primary—treated with spironolac- 2. Decreased ACTH level.
tone or surgery.
3. Secondary—treated according to the Morphology
course. 1. Depending upon cause.
2. Primary autoimmune adrenalitis—
ADRENAL INSUFFICIENCY irregularly shrunken.
3. Secondary—small and atrophic.
Primary Acute
4. Tuberculous—granulomatous in-
1. Waterhouse-Friderichsen syndrome. flammation.
2. Sudden withdrawal of long-term cor-
ticosteroid therapy. PHEOCHROMOCYTOMA
3. Stress in patients with underlying
1. Neoplasms composed of chromaf-
C/c insufficiency.
fin cells capable of synthesizing and
4. Massive adrenal hemorrhage. releasing catecholamines and some-
times other peptide hormones also.
Primary Chronic
2. Neoplasm of adrenal medulla and is
(Addison Disease) surgically correctable.
1. Due to progressive destruction of ad- 3. Rule of 10:
renal cortex:
a. 10% occur in association with Fa-
a. Autoimmune adrenalitis (60%–70%).
milial syndromes like MEN-2A,
•• Isolated autoimmune Addison
MEN-2B, VHL and neurofibroma-
disease or
tosis.
•• Autoimmune polyendocrinop-
athy syndrome. b. 10% occur extra-adrenal in sites
b. Infections such as: like carotid body (paraganglioma).
•• Tuberculosis. c. 10% adrenal pheochromocytoma
•• Fungal infections also. are bilateral.
c. AIDS: d. 10% adrenal pheochromocytoma
•• Infections (CMV, MAC). are malignant.
Morphology 4. Usually preceded by asymptomatic

endocrine hyperplasia.
1. Can be small circumscribed or large
hemorrhagic.
MEN1
2. Incubation with potassium dichro-
mate produces dark brown color. 1. Autosomal dominant (AD) involving
3. Polygonal or spindle-shaped chroma- MEN1 gene on chromosome 11q 13.
ffin cells and supporting cells form 2. Affected organs are:
nests. a. Parathyroid—primary hyperpara-
4. Chromaffin cells have granules con- thyroidism due to hyperplasia.
taining CAs and highlighted by sil- b. Pancreas—leading cause of death
ver stains. in MEN1, ZES, gastrinomas, hypo-
5. Pleomorphic nuclei. glycemia (insulinoma).
6. Invasion and mitotic figures are pres- c. Pituitary—prolactinoma (mainly),
ent in both benign and malignant le- GH secreting tumors also.
sions.
7. Malignancy is identified by metastasis. MEN2
Mutation of RET proto-oncogene on
Clinical Course 10q 11.
1. Sudden onset of HTN (episodes) with
tachycardia, palpitation, headache, MEN2A
sweating, tremor, etc.
1. Thyroid:
2. Sense of apprehension. a. Medullary carcinoma.
3. Chronic sustained HTN also. 2. Adrenal medulla:
4. Increased risk of MI, cardiac failure, b. Pheochromocytoma.
renal failure, CVD, etc.
3. Parathyroid:
c. Hyperplasia with primary hyper-
Multiple endocrine parathyroidism.
neoplasia SYNDROMES
1. A group of inherited diseases result- MEN2B
ing in proliferative lesions of multiple 1. Thyroid and adrenal medulla are in-
endocrine organs. volved as in MEN2A.
2. Usually in younger age with In- 2. Do not develop primary hyperpara-
creased aggressiveness and more thyroidism.
chance of recurrence. 3. Develop extraendocrine manifesta-
3. Usually multifocal and may arise si- tions like ganglioneuromas of mu-
multaneously or one by one. cosa and Marfan syndrome.
21 Musculoskeletal
System
Chapter
CONGENITAL DISEASES Achondroplasia

OF BONE 1. Autosomal dominant and a major
The defect is in migration of mesenchy- cause of dwarfism.
mal cells during development leads to 2. Point mutation in FGFR-3 leads to its
the formation of condensations—dysos- activation.
tosis. For example, 3. Activated FGFR-3 inhibits chondro-
1. Aplasia—absence of a digit. cyte proliferation.
2. Formation of extra digit. 4. So normal epiphyseal growth plate
expansion is suppressed and long
3. Fusion of two bones. bone growth is severely stunted.
5. In homozygous condition, abnor-
Osteogenesis Imperfecta malities in chest leads to respiratory
1. Osteogenesis imperfecta is also called arrest and death.
brittle bone disease. 6. Features are shortening of extremi-
2. Due to defective formation of type I ties, bowing of legs and a lordotic
collagen. posture.
3. Autosomal dominant. 7. Thanatotropic dwarfism severe and
also FGFR-3 mutation:
4. Mutations in genes for α-1 or α-2 sub-
unit of collagen 1 leads to defective a. Shortening of limbs.
extracellular matrix (ECM) produc- b. Bossing of forehead.
tion and its early degradation. c. Extremely small thorax.
5. Too little bone resulting in extreme
fragility. Osteopetrosis
6. Type I: Normal lifespan with ↑ frac- 1. Rare.
tures, blue sclera, hearing loss, mis- 2. Reduced osteoclast-mediated resorp-
shapen teeth. tion and thus defective bone remod-
7. Type II: Fatal due to fractures in utero. eling.
Chapter 21 u Musculoskeletal System 227
3. Affected bone is dense and stone a. Endocrine disorders—hyperpara-

like. thyroidism, hypogonadism, pitu-
4. Readily leads to fractures as a chalk itary tumors.
piece. b. Neoplasia—multiple myeloma,
5. The decalcification and digestion of carcinomatosis.
bone matrix get affected. c. Gastrointestinal (GI) disorders—
6. The decalcification needs an acidic malnutrition, malabsorption.
environment and so the associated d. Drugs—anticoagulants, anticon-
deficiency of (CA-II) also contributes vulsants, alcohol, corticosteroids
to pathogenesis.
and cancer chemotherapy.
7. Easy fracture, cranial nerve problems
e. Others—immobilization, pulmo-
and increased infections.
nary disease, homocystinuria, ane-
8. Hepatosplenomegaly due to extra mia.
medullary hematopoiesis.
Pathogenesis
Osteoporosis
Due to loss of balance between bone for-
1. Characterized by increased porosity
mation and resorption (Fig. 21.1).
of bones due to reduced bone mass.
2. This is an acquired disease of bone.
3. Increased bone fragility and suscepti- Determinants
bility to fractures. 1. Increased age.
4. Localized: Disuse osteoporosis of a a. Decreased replication of osteopro-
limb. genitor cells.
5. Generalized: Metabolic bone diseases b. Decreased synthetic activity of os-
(primary or secondary). teoblasts.
c. Decreased activity of GFs.
Causes d. Decreased physical activity.
1. Primary: Senile and postmenopausal 2. Menopause as shown in the Figure
(common). 21.2 (hormonal).
2. Secondary: 3. Physical activity.
Fig. 21.1: Pathogenesis of osteoporosis

4. Genetic factors. b. Mixed osteoclastic.

5. Nutrition (especially Ca2+). •• Osteoblastic stage—exuberant
bone formation.
Morphology c. Osteosclerotic stage.
1. Vertebrae and femoral neck is more •• Exhaustion of cellular activity.
affected, because there is increased 2. There will be a net gain in bone mass,
resorption rate in our body. which lacks strength.
2. Loss of bone is more conspicuous,
where there is abundant trabecular Pathogenesis
bone.
Occur as a result of hyper-responsive-
3. Thinning of trabeculae and widening
ness to vitamin D and RANK ligand (Fig.
of Haversian canals.
21.3).
Treatment
Morphology
1. Vitamin D3 and Ca.
1. May be unifocal or multifocal.
2. Bisphosphonates.
3. Selective estrogen receptor agonists. 2. Lytic phase.
4. Parathyroid hormone (in ineffective a. Increased osteoclasts and of in-
estrogen therapy). creased size.
3. Mixed phase.
a. Both osteoclasts and osteoblasts.
PAGET DISEASE
b. Marrow contains increased con-
(OSTEITIS DEFORMANS) nective tissue and vessels.
1. Paget disease is characterized by: c. Mosaic pattern of lamellar bone.
a. Osteolytic stage. 4. Sclerotic phase.
•• Regional osteoclastic activity a. Normal marrow, but increased
and bone resorption. fragile bone mass.
Fig. 21.2: Menopause leading onto osteoporosis
Fig. 21.3: Pathogenesis of Paget disease

Clinical Course 4. Deposition of osteoid matrix and re-

placement of cartilage with lateral ex-
1. Can be mono-ostotic or polyostotic.
pansion of osteochondral junction.
2. Symptoms depend on the site.
5. Abnormal overgrowth of capillaries
3. Back pain, cranial nerve involve-
and fibroblast.
ment.
4. Special chalk-stick fractures of long 6. Deformed skeleton due to loss of ri-
bones. gidity.
5. Treatment by calcitonin and bisphos- 7. Occipital bone flattening and buck-
phonates. ling of parietal bones due to pressure
and regains normal, if pressure is re-
RICKETS AND OSTEOMALACIA moved.
8. Frontal bossing.
1. Rickets—affects growing children.
9. Rachitic rosary—prominent costo-
2. Osteomalacia—adult counterpart.
chondral junction.
3. Both results from diet deficient in Ca
10. Pigeon chest—anterior protrusion of
and vitamin D.
sternum.
4. Decreased sunlight exposure, renal
disorders (decreased 1, 25-DHC). 11. Harrison’s groove—due to inward

pull by diaphragm.
5. Phosphate depletion and malabsorp-
tion are also leading to rickets and 12. Lumbar lordosis.
osteomalacia. 13. Bowing of legs.
Pathogenesis of Rickets Pathogenesis of Osteomalacia

1. Overgrowth of epiphyseal cartilage 1. Inadequately mineralized excess os-
due to inadequate calcification. teoid.
2. Failure of maturation of cartilage cells. 2. Defective remodeling.
3. Persistence of distorted irregular The Figure 21.4 shows the pathogen-
masses of cartilage. esis of both rickets and osteomalacia.
Fig. 21.4: Pathogenesis of rickets and osteomalacia

HYPERPARATHYROIDISM 6. Contain cystic spaces and so called

osteitis fibrosa cystica.
1. Parathyroid hormone (PTH) causes
hypercalcemia and increased bone
resorption. OSTEOMYELITIS
2. PTH acts on bone metabolism
through: Inflammation of bone and bone marrow.
Increasing
a. RANKL production by osteo- Pyogenic Osteomyelitis
blasts.
1. Pyogenic osteomyelitis caused by
b. Osteoclasts and bone resorption. bacteria.
c. Ca mobilization from bones.
2. The infection occurs through three
d. Ca reabsorption from kidney. routes:
e. 1,25-DHC production in kidney.
a. The hematogenous dissemination
Decreasing (common).
a. Ca excretion.
b. Extension from adjacent site.
b. Phosphate excretion.
c. Traumatic implantation (com-
3. Primary—increased autonomous
parathyroid secretion. pound fracture, orthopedic surger-
ies).
4. Secondary—due to C/c renal diseas-
es (Fig. 21.5). 3. Staphylococcus aureus is the most com-
mon organism.
4. Escherichia coli, Group-B Streptococ-
Morphology cus, Salmonella are also common.
1. Increased osteoclastic activity.
2. Cortical and trabecular bone are lost Morphology
and replaced by loose connective tissue.
3. Bone resorption mainly in the subpe- 1. Depend on the stage—acute, sub-
riosteal region. acute or chronic.
4. Marrow contain fibrovascular tissue 2. The affected bone undergoes necrosis
and hemosiderin. and the dead bone is called seques-
5. The mass of osteoclasts, giant cells and trum.
hemorrhagic debris is called brown 3. Subperiosteal abscess in children due
tumor of hyperparathyroidism. to loosely attached periosteum.
Fig. 21.5: Events in secondary hyperthyroidism

4. Rupture of periosteum leads to ab- Osteosarcoma

scess formation in surrounding soft
1. A bone producing malignant mesen-
tissue—draining sinus.
chymal tumor.
5. Usually in infants, the epiphyseal 2. Primary—younger age group (< 20).
infection spreads to adjacent joint to
3. Secondary—older age group (> 40).
produce suppurative arthritis.
a. Secondary to Paget disease, bone
6. After the 1st week, chronic inflamma- infarcts, etc.
tory cells will get deposited. 4. Usually affects metaphysis of distal
7. The cytokines induce bone resorp- femur, proximal tibia, humerus, pel-
tion, fibrous tissue ingrowth and new vis, jaw, etc.
bone formation.
8. This reactive new bone surrounded by Pathogenesis
the dead bone is called involucrum.
Mutations in RB gene and p53 are associ-
ated.
Clinical course
1. Fever, malaise, leukocytosis. Morphology
2. Throbbing pain.
1. Gritty and grey-white tumors.
3. Typical radiological features.
2. Hemorrhage and cystic degeneration.
4. Treatment with draining and antibi- 3. Destroy the surrounding cortex and
otics. produce soft tissue masses.
4. They invade through the medullary
Tuberculous Osteomyelitis canal and replace the marrow.
5. Involvement of joint space is rare.
1. Tuberculous osteomyelitis is caused
6. Large bizarre tumor giant cells have
by Mycobacterium tuberculosis.
hyperchromatic nuclei.
2. Occur mainly by hematogenous 7. Increased unmineralized osteoid pro-
spread and also by direct extension. duction.
3. Hematogenously spreads mainly to 8. Cartilage and fibrous tissue are also
long bones and vertebrae. seen.
4. Granulomatous inflammation with 9. If there is increased amount of carti-
caseous necrosis and extensive bone lage—chondroblastic osteosarcoma.
destruction. 10. There will be spontaneous necrosis of
tumor.
5. Tuberculosis of vertebral bodies (Pott
11. Can go outward to periosteum or go
disease) leads to:
inward to medullary cavity.
a. Compression fractures.
b. Psoas abscess.
Clinical course
1. Painful enlarging mass.
Bone Tumors
2. Pathologic fractures.
Primary bone tumors are less compared 3. Periosteal new bone formation.
to bone metastasis. 4. A triangular shadow in X-ray be-
The classificaton of bone tumors (Ta- tween cortex and raised periosteum
ble 21.1) are as given below: —Codman’s triangle.
Table 21.1: Classification of bone tumors
Tumor type Common locations Age (year) Morphology

Bone forming
Benign
•• Osteoma Facial bones, skull 40–50 Exophytic growth attached
to bone surface
•• Osteoid osteoma Metaphysis of femur 10–20 Cortical tumors with
and tibia interlacing trabeculae of
woven bone
•• Osteoblastoma Vertebral column 10–20 Arise in transverse and
spinous processes.
Histologically similar to
osteoid osteoma
Malignant
•• 10 osteosarcoma Given below Given below Given below
•• 20 osteosarcoma Given below Given below
Cartilage forming
Benign
•• Osteochondroma Metaphysis of long 10–30 Bony excrescences with
bones a cartilaginous cap, may
be solitary or multiple.
Hereditary.
•• Chondroma Small bones of hand 30–50 Well circumscribed single
and feet tumors arising in medullary
cavity. Uncommonly
multiple.
Malignant
•• Chondrosarcoma Given below Given below Given below
Miscellaneous
•• Giant cell tumor Given below Given below Given below
•• Ewing tumor Given below Given below
5. Typically spread hematogenously. Morphology

6. Amputation and chemotherapy is the
treatment. 1. Conventional.
a. Expansile glistening mass.
Chondrosarcoma b. Arise in the medullary cavity and
erodes the cortex.
1. These are cartilage producing ma-
c. Exhibit malignant hyaline and
lignant tumor (mainly in 40–60 age
group). myxoid cartilage.
2. According to site they are intramed- 2. Myxoid.
ullary and juxtacortical. a. Viscous and gelatinous.
b. Spotty calcifications. 5. Homer-Wright rosettes.

c. Necrosis and cystic degeneration. a. Tumor cells circled around a cen-
3. Dedifferentiated. tral fibrillary space—neural differ-
a. High grade poorly-differentiated entiation.
variety. 6. Mainly seen in diaphysis as a mass.
b. Foci of fibrosis or osteosarcomas.
7. Mainly in femur and pelvis.
4. Clear cell chondrosarcoma.
5. Mesenchymal chondrosarcoma.
a. Low grade—cartilage will be nor- Giant Cell Tumor (Osteoclastoma)
mal. 1. Mainly affect epiphysis of long bone
b. High grade—pleomorphic chon- (especially around knee).
drocytes with mitotic figures. 2. Multinucleated osteoclast-like giant
cells (reactive cells).
Clinical course 3. Usually benign, but locally aggres-
1. Mainly in shoulder, pelvis, ribs and sive.
femur. 4. Frequently cystic degeneration, hem-
2. Metastasize hematogenously to lungs orrhage and necrosis.
and other bones.
5. Small round, spindle-shaped mononu-
3. Surgical excision and chemotherapy clear cells are seen (neoplastic cells).
as treatment.
6. Bulging soft-tissue mass and reactive
bone formation are seen.
Ewing Sarcoma
1. Primary malignant small round cell OSTEOARTHRITIS
tumors of bone and soft tissue.
2. Undifferentiated tumor and usually 1. Degenerative joint disease.
affect below 20 year of age group. 2. The fundamental feature is degenera-
3. Second most common pediatric bone tion of articular cartilage.
tumor after osteosarcoma. 3. Primary:
4. The chromosomal abnormality is fu- a. Occurs insidiously with age.
sion of EWS gene on ETS family of
transcription factors (FL1 and ERG). b. Oligoarticular (affecting a few
5. The resultant gene induces cell prolif- joints).
eration. 4. Secondary:
a. In youth due to predisposing con-
Morphology ditions like:
•• Trauma
1. Arise in the medullary cavity.
•• Developmental deformity
2. Erodes cortex and periosteum to form
soft-tissue mass. •• Obesity
3. Hemorrhage, necrosis and periosteal •• Systemic diseases like DM,
reaction. hemochromatosis
4. Small round tumor cells with glyco- •• Affecting the predisposed
gen-rich cytoplasm. joints.
5. Female—mainly knees and hands are 7. Fractures lead to dislodging small

affected. pieces of cartilage and bone into joint
6. Male—mainly hip. space—loose bodies.
8. The synovial fluid forced into sub-
chondral region to form fibrous
Pathogenesis walled cysts.
The pathogenesis of osteoarthritis is 9. Osteophytes (bone outgrowths) de-
shown in the Figure 21.6. velop at the margins of articular sur-
face.
Morphology 10. Severe cases—pannus formation also.
11. No ankylosis as in RA.
1. Proliferation and disorganization of
chondrocytes in the superficial part
Clinical Course
of articular cartilage (as a response to
increased chondrocyte apoptosis). 1. Deep aching pain.
2. Increased water content and ↓ pro- 2. Morning stiffness.
teoglycans in the matrix. 3. Crepitus.
3. Cracking of matrix. 4. Neurological symptoms due to com-
pression by osteophyte.
4. Soft-granular articular cartilage.
5. Heberden nodes on distal interpha-
5. The bone surface get exposed and
langeal joints.
due to friction, polished surfaces are
formed—bone eburnation.
6. The underlying cancellous bone get
GOUT
thickened and becomes sclerotic 1. Gout is caused by tissue accumula-
(subchondral sclerosis). tion of uric acid crystals.
Fig. 21.6: Pathogenesis of osteoarthritis

2. Monosodium urate crystals are accu- c. Chronic renal disease—normal

mulated. production and ↓ excretion.
3. Primary:
a. Due to inborn errors in uric acid Pathogenesis
metabolism.
b. ↑ production with normal or ↑ ex- 1. Increased uric acid synthesis (HG-
cretion. PRTase deficiency).
c. Normal production with ↓ excre- a. Abnormal ‘de novo’ pathway.
tion. b. Abnormal ‘salvage’ pathway.
d. Constitutes 90% and this is idio-
pathic. 2. Decreased uric acid excretion.
4. Secondary: a.
Renal disorder (by thiazide
a. Constitutes 10%. diuretic).
b. ↑ nucleic acid turn over—↑ pro- The pathogenesis of gout is shown in
duction and ↑ excretion. the Figure 21.7.
Fig. 21.7: Pathogenesis of gout

Morphology c. Intercritical gout (resolved stage

without treatment).
1. Acute arthritis.
d. Chronic tophaceous gout.
a. Dense (N) infiltrate.
b. Long needle-shaped monosodium
urate crystals in the cytoplasm. Pseudogout
c. The synovium is congested and 1. Pseudogout is also called chondro-
edematous. calcinosis.
2. Chronic tophaceous arthritis. 2. Deposition of calcium pyrophosphate
a. Repeated precipitation of urate crystals in various joints.
crystals leads to the formation of 3. Produce inflammation and joint de-
visible deposits—tophi. struction.
b. Synovium becomes hyperplastic,
fibrotic and thickened with in- FATTY TUMORS
creased inflammatory cells.
c. Forms a pannus, which destroys Lipoma
the cartilage. 1. Benign tumors of fat.
d. Bone erosions and ankylosis may 2. Commonest soft-tissue tumor in
occur. adults.
3. Tophi at various sites. 3. Mostly are unifocal.
a. Tophi are large aggregations of
4. Types.
urate crystals surrounded by (L),
macrophages and foreign body gi- a. Conventional lipoma—only fat.
ant cells. b. Myolipoma—fat + muscle.
b. Deposit in joints, ligaments, ten- c. Neurolipoma—fat + neural tissue.
dons, soft tissues like ear lobes, na- d. Myelolipoma—fat + marrow ele-
sal cartilage, finger tips, etc. ments.
c. Tophi can lead to draining ulcer- e. Angiolipoma—fat + blood vessels.
ations. f. Fibrolipoma—fat + fibrous tissue.
4. Gouty nephropathy. g. Pleomorphic lipoma—mixed vari-
a. Medullary tophi, intra tubular to- ety.
phi and renal calculi. 5. Conventional lipomas are soft, yel-
b. Can leads to obstruction and pyelo- low, well-encapsulated masses of
nephritis. mature adipocytes.
Clinical Course Liposarcoma

1. More in men after 30 years. 1. Malignant neoplasms of adipocytes
2. Four stages. (mainly in old age).
a. Asymptomatic hyperuricemia. 2. Arise in deep soft tissues or in viscer-
b. Acute gouty arthritis. al sites.
3. Well-differentiated and myxoid vari- a. Intramural, submucosal and sub-

eties—good prognosis. serosal.
4. Aggressive round cell and pleomor- 11. Some are attached to adjacent struc-
phic types—bad prognosis. tures—parasitic fibroids.
5. MDM2 gene mutation and p53 sup- 12. Foci of hemorrhage, necrosis, cystic
pression are seen. change, fibrosis and calcification can
be seen.
6. t(12,16) translocation also seen.
13. Manifest as menorrhagia with or

7. Well-circumscribed lesions. without metrorrhagia.
8. Abundant mucoid ECM.
9. Lipoblasts are seen. Leiomyosarcoma
a. Adipocytes precursors. 1. Most commonly in uterus (retroperi-
b. Lipid vacuoles in cytoplasm. toneal).
2. Arise from the mesenchymal cells of
SMOOTH-MUSCLE TUMORS myometrium and not from pre-exist-
ing leiomyoma.
Leiomyoma 3. Can form bulky masses infiltrating
1. Benign smooth-muscle tumor. myometrium or form polyps pro-
2. Well-circumscribed lesions (grey truding into uterine cavity.
white masses). 4. Usually solitary, soft, hemorrhagic
3. Occurs anywhere in the body. and necrotic.
5. Range from well-differentiated to
4. Mostly in the uterus (fibroid uterus).
highly anaplastic.
5. Most common benign tumor in fe-
6. Cytologic atypia and increased mito-
males. sis are observed.
6. Estrogen and oral contraceptives 7. Metastasize typically to lungs.
(OCP) induces the growth.
8. Occurs also in skin and deep soft tissue.
7. They shrink postmenopausally. 9. The cutaneous lesions are easy to
8. The cut surface is typically whorled. excise.
9. Usually solitary. 10. The retroperitoneal lesions cannot be
10. Types. excised completely.
22 Skin
Chapter
SQUAMOUS CELL CARCINOMA a. Invade through BM.

b. Highly anaplastic cells and ulcer-
1. Squamous cell carcinoma (SCC) is a
ations.
common skin tumor arising mainly
on sun-exposed areas in older people. c. Foci of necrosis seen.
2. Predisposing factors include sunlight, 5. Keratin horn pearls typically seen.
industrial carcinogen, chronic ulcers,
old burn scars, arsenic, ionizing ra- Clinical Course
diation, immunosuppression, etc. 1. Metastasis is uncommon for cutane-
ous SCC.
Pathogenesis 2. Mucosal SCC is aggressive.
The pathogensis of squamous cell carci-
noma is shown in Figure 22.1. BASAL CELL CARCINOMA
1. Most common human cancer.
2. Slow growing tumor that rarely me-
tastasizes.
3. Occur at chronically sun exposed sites
and in lightly pigmented people.
Fig. 22.1: Pathogenesis of squamous cell
4. Risk increases in immunosuppres-
carcinoma sion and in persons with inherited
DNA repair defect.
Morphology
1. Highly atypical cells. Pathogenesis
2. Squamous dysplasia. 1. Dysregulation of sonic hedgehog
3. Carcinoma in situ → well demarcat- pathway (PTCH pathway) due to
ed, red plaques. mutation in PTCH gene.
4. Invasive SCC. 2. p53 muptation also seen.
Chapter 22 u Skin 239
Morphology 5. Activating mutations of NRAS or

BRAF are also seen.
1. Tumor cell resemble normal epider-
mal basal cells. 6. Suppression of PTEN gene.
2. Not seen in mucous cell surfaces. 7. Polymorphism of MC1R gene (mel-
anocortin receptor gene).
3. Two patterns:
8. All these leads to increased melano-
a. Multifocal → superficial type.
cyte production.
b. Nodular.
•• Goes deep into dermis as spe-
cial tumor islands
Morphology
•• The tumor cells are basophilic 1. Radial growth.
with hyperchromatic nuclei a. Grow horizontally within the epi-
•• The peripheral tumor cells in dermis and superficial layers of
the islands are in a palisading dermis.
arrangement. b. Initial stage.
c. No ability to metastasize.
Clinical Course d. No angiogenesis observed.
1. Present as pearly papules contain- 2. Vertical.
ing prominent dilated subepidermal a. Grows into the depth of dermis.
blood vessels (telangiectasia). b. As an expansile mass (angiogen-
2. Some contain melanin pigment. esis).
3. Advanced lesions may ulcerate or c. Lack cellular maturation.
invade the underlining tissue exten- d. Have metastatic potential.
sively (often bone).
e. Metastasize to LNs and hematog-
4. When ulcerate, it is called rodent ulcer.
enously to lungs, liver, brain, etc.
3. Malignant cells are larger.
MALIGNANT MELANOMA 4. The nuclei have clumped chromatin
Less common, but much more deadly at periphery and eosinophilic nucleo-
than SCC. li (cherry red).
5. May arranged as nests or nodules in ra-
Pathogenesis dial and vertical growth respectively.
1. Sunlight exposure plays an impor- 6. Melanin pigment can be seen.
tant role.
2. Previous nevi and heredity are also Clinical Course
risk factors. 1. Occur mostly in skin.
3. Occur mostly sporadically. 2. Also in mucosa of mouth, anogeni-
4. Mutation in CDKN2A gene—this reg- tal region, esophagus, meninges and
ulates the G1-S transition. even eye.
3. May be itching or painful. a. Asymmetry.

4. Suggestive of MM. b. Border—irregular.
a. Increase in size of lesion. c. Color—change.
b. Change on color of the lesion. d. Diameter—increase.
5. The borders are irregular. e. Evolution of new nevus during
6. ABCDEs of melanoma. adulthood.
23 Nervous System
Chapter
BERRY ANEURYSM MENINGITIS

1. Also called saccular aneurysm. 1. Inflammation of leptomeninges and
2. The rupture of this aneurysm is the CSF within the subarachnoid space.
most common cause of SAH. Sites of 2. If both meninges and underlying
berry aneurysms is shown in Figure brain parenchyma are involved—
23.1. that is called meningoencephalitis.
3. The rupture can occur at any time, 3. Meningitis will be usually infectious.
but particularly during increased ICT
with straining stools and sexual or-
gasm. Acute Pyogenic Meningitis
4. The blood then rapidly leaks into 1. Also called bacterial meningitis.
subarachnoid space and the patients 2. Neonates—Escherichia coli, group B-
will be having sudden excruciating streptococci.
headache (described as the worst
3. Adolescent and young adults—Neis-
headache that I have ever had) and
loss of consciousness. seria, Haemophilus.
5. The aneurysm means abnormal dila- 4. Older age—Streptococcus pneumoniae,
tation of blood vessel due to the de- Listeria monocytogenes.
fect in tunica media.
6. Sites → occuring typically around the
circle of Willis.
7. Berry aneurysm is the most common
intracranial aneurysm.
8. The unruptured saccular aneu-
rysm is a thin walled outpouching.
9. The sac is composed of hyalinized
intima.
10. The media and elastic lamina are

absent.
11. Rupture usually occurs at the apex. Fig. 23.1: Sites of berry aneurysm
5. Meningeal irritation and neurologi- Tuberculous Meningitis

cal impairment
1. Usually presents with headache, mal-
6. Symptoms are headache, photopho- aise, vomiting and mental confusion.
bia, irritability, cloudiness, neck stiff- 2. Highly purulant and thick exudate—
ness, etc. gelatinous or fibrinoid.
7. CSF studies show increased in ICT, 3. Increased CSF cellularity (pleocyto-
N, protein and decreased glucose. sis) either (L) alone or (L) and (N) to-
8. Bacteria demonstrated by CSF gether.
smear. 4. Increased protein level and decreased
9. Pyogenic (purulent) exudate is seen glucose level.
within the leptomeninges and brain 5. A well-circumscribed intraparnchy-
mal granulomatous lesion (tubercu-
parenchyma.
loma) is present.
10. In Fulminant meningitis: (N) in-
6. Arteries in the subarachnoid space
creased in CSF and may spreads to shows obliterating endarteritis.
brain producing focal cerebritis. 7. May spreads to choroid plexus or
11. Sometimes, produces ventriculitis. ependymal surface.
12. Bacterial meningitis may be associ- 8. Well-developed granulomas on me-
ated with brain abscess too. ninges with central caseous necrosis,
13. Phlebitis may be produced and can macrophages, plasma cells and giant
leads to venous occlusion and hem- cells.
orrhagic infarction of brain. 9. Can lead to arachnoid fibrosis and
hydrocephalous.
Aseptic Meningitis
Neurosyphilis
1. Also called viral meningitis.
1. Tertiary stage of syphilis in untreated
2. Signs of meningeal irritation, fever, patients.
alteration of consciousness, etc. with- 2. One of the manifestation is menin-
out recognizable organisms and of gitis and is called meningovascular
acute onset. neurosyphilis.
3. Usually self-limiting. 3. Parenchymal involvement due to in-
4. CSF study shows increased (L), mod- vasion of Treponema pallidum leads to
erate elevation of proteins and nearly progressive loss of mental and phys-
ical function and terminating in se-
normal glucose level. vere dementia (paretic neurosyphilis).
5. Some swelling of the site can be seen. 4. If the meninges of spinal cord is in-
6. Not much other finding. volved it can invade into sensory
nerves in the dorsal root, which leads
Chronic Meningitis to tabes dorsalis. This develops due
to pallor and atrophy of axons and
A paranchymal component is also myelin sheath.
present. 5. HIV is predisposing to neurosyphilis.
Chapter 23 u Nervous System 243
6. Usually involves the base of brain. 3. Poorly differentiated.

7. Obliterating endarteritis with a. Medulloblastoma.
perivascular infiltrate of (L) and plas- 4. Other parenchymal tumors.
ma cells.
a. Primary CNS lymphoma.
8. Cerebral gummas are also seen.
b. Germ cell tumors.
9. Paretic neurosyphilis mainly in-
5. Meningiomas.
volves the frontal lobe and gliosis is
observed along with loss of neurons. 6. Metastatic tumors.
a. Five common primary sites for
Neuroborreliosis brain metastasis are lung, breast,
skin, kidney and GIT.
1. By Borrelia burgdorferi. b. Usually at the grey-white matter
2. Aseptic meningitis is caused. junction and surrounded by glio-
3. Facial nerve palsy and encephalopa- sis.
thy are also observed. c. Paraneoplastic syndromes may in-
volve CNS also.
BRAIN TUMORS d. Subacute cerebellar degeneration
1. Histologic distinction between be- (ataxia).
nign and malignant is more subtle e. Limbic encephalitis (dementia).
than in other sites. f. Subacute sensory neuropathy (al-
2. Even low grade tumors can infiltrate tered pain).
large areas.
3. Even benign lesions can be life threat- Astrocytoma
ening by compression at various sites.
Fibrillary astrocytoma
4. The metastasis outside CNS is rare
1. About 80% of adult primary brain tu-
and the main route is through CSF.
mors.
2. Usually found in cerebral hemi-
Classification spheres.
1. Gliomas—tumors of brain parenchy- 3. Seizures, headache, focal neurologi-
ma. cal deficit, etc. occurs.
a. Astrocytoma. 4. These are three types.
b. Oligodendroglioma. a. Well differentiated (mild pleomor-
c. Ependymoma. phism).
2. Neuronal tumors. b. Anaplastic (highly pleomorphic).
a. Central neurocytoma. c. Glioblastoma multiforme (highest
b. Ganglioglioma. grade).
c. Dysembryoplastic neuroepithelial Morphology
tumors. 1. Poorly defined gray, infiltrative tumor.
2. Firm or soft gelatinous mass. Ependymoma

3. Cystic change and necrosis may be
1. Usually arise in ependyma lined ven-
seen. tricles and spinal central canal.
4. Glioblastoma shows highly anaplas- 2. Early age—fourth ventricle.
tic cells with additional features of
3. Adults—central canal of spinal cord.
necrosis and vascular or EC prolifera-
tion and pseudopalisading nuclei. 4. CSF dissemination is common.
5. High-grade tumors have leaky ves- 5. Relatively good prognosis with com-
sels. plete excision.
Pilocytic astrocytoma Morphology
1. Benign tumors usually affecting 1. Usually small cells with round-oval
children. nuclei containing finely granular
chromatin.
2. Usually located in cerebellum.
2. The tumor in fourth ventricle usually
3. Also appear in third ventricle, optic arises from the floor as a solid mass
nerves and cerebrum. or papille.
4. Tumors extending into hypothalamic 3. The tumor cell arrange to form ro-
region have more complicated clini- sette or canal with projecting delicate
cal course. process into lumen.
5. Usually cystic tumors. 4. Sometimes pseudorosettes by ar-
6. Bipolar cells with long hair-like pro- range around the blood vessels.
cesses (rosenthal fibers), eosinophilic 5. Anaplastic—increased mitosis, ne-
granules and microcytes are present. crosis and decreased differentiation.
7. Necrosis and mitosis are absent.
Medulloblastoma
Oligodendroglioma
1. Predominantly in children.
1. Several years of neurologic com- 2. Exclusively in cerebellum (midline).
plaints including seizures.
3. Often undifferentiated and highly
2. Usually seen in cerebral hemispheres
malignant.
predominantly white matter.
4. Origin from neuroectodermal cells.
3. Better prognosis than astrocytoma.
Morphology
Morphology
1. Often well-circumscribed gray masses.
1. Gelatinous grey infiltrative masses.
2. May show cystic changes, hemor- 2. Infiltrate into leptomeninges.
rhage and calcification. 3. Small blue cells, which are highly
3. Tumor cells are similar to normal oli- anaplastic and with hyperchromatic
godendrocytes with finally granular nuclei.
chromatin. 4. Abundant mitoses.
4. High grade—anaplastic oligodendro- 5. Laterally occurring tumors are more
glioma. in adults.
Chapter 23 u Nervous System 245
Meningioma b. Fibroblastic → elongated cells and

abundant collagen in between.
1. Predominantly benign tumors of
adults. c. Transitional → features of both
syncitial and fibroblastic.
2. Arising from the meningothelial cells
of arachanoid space and usually at- d. Psammomatous → with numer-
tached to dura. ous psammoma bodies.
3. Usually producing symptoms of e. Secretory → with PAS positive in-
brain compression. tracytoplasmic droplets.
Morphology f. Microcystic → loose spongy ap-
1. Well-defined masses on dura may ex- pearance.
tend into over lying bone also. 3. Atypical → highly infiltrative and
2. Differential types. highly mitotic.
a. Syncitial clusters → of cells in tight 4. Anaplastic → highly aggressive and
groups. malignant, high metastatic potential.
Fig. 23.2: Pathogenesis of Alzheimer disease

ALZHEIMER DISEASE 2. Widening of sulci—more in frontal,

temporal and pariteal.
1. Most common cause of dementia in
elderly. 3. Plaques (EC) and neurofibrillary tan-
2. Insidious impairment of intellectual gles (IC).
function with alteration in mood and 4. First seen in entorhinal cortex, then in
behavior. isocortex and finally in neocortex.
3. Later progressive disorientation, 5. Neuritic plaques.
memory loss and aphasia. a. Collections of neuritic processes
4. Finally become disabled, mute and (dystrophic).
immobile.
b. Central amyloid core.
5. Mostly sporadic and rarely familial.
c. Peripheral astrocytes and glial cells.
d. Seen in cortex, amygdale, hip-
Pathogenesis pocampus, cerebellum, basal gan-
The pathogenesis alzheimer disease is glia, etc.
shown in Figure 23.2. 6. Neurofibrillary tangles.
a. Bundles of paired helical filaments.
Predisposition b. Seen as basophilic fibrillary struc-
1. Trisomy 21. tures.
2. Mutation of Apo E4 gene. c. Especially seen in entorhinal cortex.
3. Mutation in SORL1 gene. d. The major component is abnor-
4. Mutations in APP or enzymes in- mally hyperphosphorylated forms
volved. of Tau protein.
Morphology NEUROBLASTOMA
1. Cortical atrophy and compensatory Refer Chapter 7, Genetic and Pediatric
ventricular enlargement. Diseases.
23 Essays
CLINICAL QUESTIONS b. Explain the reason for his:

•• Anemia
1. A 29-year-old man hospitalized
for AIDS is found to have bilateral •• Proteinuria
patchy pulmonary lesions. He had fe- •• Fever.
ver with evening rise of temperature. c. How are urinary casts formed?
Liver also showed multiple lesions d. Describe the pathogenesis of ede-
with central necrosis. ma in this patient.
a. What is your complete diagnosis? e. Enumerate the etiology of edema.
b. Which type of tissue reaction is ex- 3. A 25-year-old man from leprosy sana-
pected in the lung? torium presented with severe edema.
c. Which type of necrosis is seen in O/E proteinuria, hyperlipidemia and
these lesions? lipiduria.
d. Indicate the special stains useful in a. What is your diagnosis?
confirming the diagnosis. b. Name the dye used to diagnose the
e. Name the commonest lung pathol- condition in biopsy section.
ogy seen in AIDS. c. Pathology of kidney in this condi-
2. A 74-year-old diabetic man presented tion.
with fever with chills, pallor and dim- d. Other organs involved.
ness of vision. Investigations revealed 4. A 60-year-old man presented with
Hb was 4 g%, reticulocyte count was bone pain, pallor and backache. O/E
0.5%. Urine showed—sugar ++, pro- he had localized tenderness in L1, L2
tein +++ with plenty of hyaline casts and L3 levels and paraparesis. Inves-
and pus cells. O/E pedal edema was tigations revealed Hb was 8 g% and
present. His BP was 200/110 mm of ESR was 140 mm/1st hour. X-ray re-
Hg. Blood glucose was 350 mg%, vealed destructive bony lesions.
blood urea was 109 mg% and serum a. What is your diagnosis?
creatinine was 3.4 mg%. b. Explain the reason for his anemia
a. What is your complete diagnosis? and paraplegia.
248 Synopsis of Pathology
c. Name the two investigations, giant cells with prominent nucleoli.

which will be diagnostic in this pa- Some of the atypical cells are seen,
tient. surrounded by a clear space.
d. Describe the blood picture in this a. What is your diagnosis?
condition. b. What are her symptoms described?
5. A 40-year-old woman died after a c. What is the name of the two type
long history of an illness character- of cells described?
ized by dyspnea, orthopnea, hepato- d. What would the histopathology in
megaly, distended neck veins and addition to the above cells?
peripheral edema. The cut surface e. What is the natural history of this
of the liver showed alternating dark disease?
and yellowish appearance. 8. A 55-year-old strict vegetarian pre-
a. What is the most likely diagnosis? sented with weakness and easy fa-
b. What is the appearance of the liver? tigue. O/E he was having pallor.
c. What is the most likely appearance His Hb was 8.5 g%. He had under-
of her heart? gone surgery for CA stomach 2 years
d. Describe the pathogenesis of the back.
condition. a. What is the probable diagnosis?
6. A 26-year-old man developed dys- b. What is the etiology?
pnea and cough with blood-tinged c. What will be the morphology?
sputum. On enquiry, he indicated d. How will you diagnose?
that he had right-sided chest pain 2 e. How will you treat?
days before and was intermittent and 9. Within minutes of a bee sting, a 23-
varying with respiration. O/E he was year-old woman develops general-
febrile and had a pulse rate of 102/ ized pruritus and hyperemia of the
min. skin, followed shortly by swelling of
a. What is your diagnosis? the face and eyelids and stridor.
b. What is the significance of his chest a. What is your diagnosis?
pain? b. What is the pathogenesis of this
c. Explain the pathogenesis and nat- condition?
ural history of his disease. c. What are the other diseases with
d. What would his chest X-ray the same pathology?
show? d. Name one inherited disorder that
e. What are the complications of this could cause a similar reaction.
condition? e. Will this problem recur?
7. A 22-year-old woman presented 10. A 59-year-old patient received che-
with intermittent fever, weight loss, motherapy with the anthracycline—
sweating and painless supraclavicu- Adriamycin for breast carcinoma.
lar lymph nodes. A biopsy of one of 2 years later, she developed severe
the lymph nodes showed binucleated refractory heart failure. No specific
Essays 249
cause could be immediately identi- onset of periorbital edema, hematu-

fied for the cardiac failure. The pa- ria, malaise, nausea and headache.
tient died 3 days later. An autopsy ASO titer was 700 Todd units. Urine
was performed. Her heart was found was positive for blood, blood cell
to be flabby and dilated. casts and protein.
•• What is your diagnosis? a. What is your complete diagnosis?
•• What is the pathogenesis of this b. Explain the reason for her.
condition?
•• Hematuria
•• What is the diagnostic test?
•• Proteinuria
•• Describe the histopathology of
•• Casts.
the heart in this condition.
11. A 23-year-old African-American man c. Indicate the probable cause for her
with a history of severe lifelong ane- headache and nausea.
mia requiring many transfusions. He d. How are urinary casts formed?
has non-healing leg ulcers and recur- e. What type of cast will be diagnos-
rent episodes of joint, abdominal and tic in this patient?
chest pain. f. Describe the pathogenesis of ede-
a. What is your diagnosis? ma in this patient.
b. How will you confirm the diagno- 14. A 60-year-old man presented in a der-
sis? matology OP with a hypopigmented
c. What will the peripheral smear anesthetic patch on his face. O/E pe-
show? ripheral nerves are thickened.
d. Name two other diseases with the a. What is your diagnosis?
similar pathology?
b. What are the investigations you
e. What is the significance of his ab- want to do in this case?
dominal and chest pain?
c. What is the pathology of the dis-
12. A 5-year-old boy developed a mas- ease?
sive hemarthrosis. The platelet count
is normal. The PT and bleeding time d. What are the morphological types?
are normal, but the APTT is pro- e. How can you identify the disease
longed. according to immunological status?
a. What is your diagnosis? 15. A 24-year-old man came to STD clinic
b. How will you confirm the diagno- with complaints of low grade fever,
sis? malaise and mucocutaneous rash.
c. Name one other disease with a He gives a past history of sexual con-
similar pathology? tact following which he developed a
d. What is the significance of clinical painless ulcer over glans. O/E he has
history in this patient? generalized lymphadenopathy.
13. Two weeks after recovery from a se- a. What is your diagnosis?
vere bout of pharyngitis, a 11-year- b. What are the modes of transmis-
old girl is seen because of the acute sion?
c. Describe the various stages of was present. Urine: Albumin +++,

disease. granular casts are present.
16. A 14-year-old boy presented with
a. What is your provisional diagnosis?
yellowish discoloration of the eyes b. What is the etiology?
and abdominal pain. Investigation
c. What is the pathogenesis?
revealed Hb was 6 g%, reticulocyte
count was 11%. O/E splenomegaly d. Enumerate two relevant investiga-
was present, patient was jaundiced tions for confirmation.
and USG revealed gallstones. Mater- e. Mention the most serious renal le-
nal uncle gave history of similar com- sion in this condition.
plaints. f. What are the cardiac lesions seen
a. What is your diagnosis? in this disease?
b. Name two investigations to con- 19. A 5-year-old male presented with

firm your diagnosis (other than pain and swelling of right thigh. His-
blood picture). tory of rapid increase in size. On ex-
c. Describe the blood picture in this amination, X-ray revealed an ‘onion
condition. peel’ appearance in the shaft of femur.
d. Mention three similar diseases. a. What is your diagnosis?
e. What is the likely cause of the gall- b. Mention two relevant investiga-
stones? tions.
17. A 48-year-old male was admitted to c. What is the reason for the radio-
hospital because of hematemesis. O/E logical appearance of this lesion?
he has jaundice, ascites, splenomega- d. What is the histopathology of this
ly and a nodular hepatomegaly. USG lesion?
showed multiple nodules. One nod-
e. Name any two conditions with
ule was larger with central necrosis.
similar histology.
a. What is the most likely diagnosis?
20. A 40-year-old male presented with

b. Indicate four investigations you pallor, ecchymotic patches and hepa-
will do in this patient.
tosplenomegaly. O/E he was found
c. Describe the pathogenesis of his to have gum hypertrophy and cervi-
problem. cal lymph node enlargement.
FNAC was unsuccessful from the a. What is the clinical diagnosis?
large nodule. Hence, finally a liver
biopsy was done. b. Describe the blood smear in this
patient.
a. Mention why this was done?
c. Mention one important investiga-
b. What is the histopathology likely
tion for diagnosis.
to be, in this patient?
d. How will you confirm the diagno-
18. A 25-year-old female presented with
sis?
fever, joint pain and edema since 4
weeks. On examination, butterfly e. What serum test can be done to
rash on face and oral ulcer. No joint confirm the diagnosis?
deformity. Bilateral pleural effusion f. How will you classify this disease?
Essays 251
21. A 15-year-old boy presented with

painful swelling above knee. X-ray b. What is the clinical significance of
revealed a metaphyseal lesion with this finding?
characteristic sunray spicules. c. Indicate two tests you would do to
a. What is your diagnosis? confirm the diagnosis.
b. Radiographic and histological fea- d. What are the features to assess the
tures. prognosis of this condition?
c. Common site and age group. 25. A 35-year-old woman complains of
d. Most common malignancy of bone? shortness of breath and cough for
e. Most common site of metastasis? the last 2 months. She also has had
22. A 2-year-old child presented with
fatigue and mild fever. A chest radio-
high fever, prostration and vomiting. graph shows bilateral hilar lymph-
His pulse is rapid and thready. BP is adenopathy. O/E two cervical nodes
recorded at 60/40. A diffuse general- were palpable. She also had hyper-
ized hemorrhagic rash is noted. calcemia.
a. What is your diagnosis? a. What is your provisional diagnosis?
b. Mention one important investiga- b. What would her cervical node bi-
tion and its diagnostic features. opsy show?
c. What immediate test should you c. What type of pathology is likely to
do? explain her shortness of breath?
d. Mention two etiological factors. d. What serum blood test can help to
23. A 24-year-old man has shortness of confirm the diagnosis?
breath and ascites. USG revealed cir- 26. A 60-year-old woman has pain in her
rhosis of liver. A sister and several lower back upon bending over in her
close relatives also have had similar kitchen. A radiograph of the spine
findings. shows a compression fracture of the
a. What is the clinical diagnosis? lumbar vertebrae at L2–L3. Further
evaluation reveals normocytic ane-
b. How will you confirm the diagno-
mia, hypercalcemia and a high ESR.
sis?
a. What is the diagnosis?
c. What is the cause of his shortness
of breath? b. Indicate one test you would do to
confirm the diagnosis
d. How will you classify his lung con-
dition? c. What would you expect to find in
her urine?
24. A 60-year-old woman seeks medi-

cal attention for soreness and ooz- d. What other tests might be contribu-
ing from the nipple of her left breast. tory to her diagnosis and follow-up?
She denies trauma to the breast. O/E, e. In the context of this patient, what
there is fissuring and ulceration of the would the term ‘CRAB’ mean?
areola and nipple. A lump 1.5 × 1.5 27. A 55-year-old man complaining of

cm was palpable below the areola. gross hematuria and right loin pain.
Physical examination reveals a flank c. What are the underlying mecha-

mass. The complete blood count nisms involved?
(CBC) reveals a Hb level of 21 g/dL. d. What other disorders may cause
Ultrasound shows a 6 cm mass at the similar clinical findings?
upper pole of the right kidney. 30. A 4-year-old boy is seen by his pe-
a. What is the most likely diagnosis? diatrician for easy bruising, joint pain
b. What is the brain lesion associated and leg pain; red dots on the skin that
with this condition? do not blanch and hepatosplenom-
c. What is the most likely explanation egaly. CBC reveals an elevated white
for this patient’s polycythemia? blood cell count of 50,000/mm3, Hb
of 4 g% and thrombocytopenia. Pe-
d. What is the likely microscopy of
ripheral smear showed numerous
this lesion?
cells with a high nuclear to cytoplas-
28.
A 48-year-old man complains of mic ratio and fine chromatin.
weakness, fatigue and bleeding from
the gums when he brushes his teeth.
O/E no organomegaly was present. b. What other investigations need to
His WBC—1000/mm3, Hb—8 g/dL be done to confirm it?
and platelets—30,000/mm3. Reticu- c. How do you classify this condition?
locyte count was less than 0.5%. d. What is the prognosis?
a. What is the most likely diagnosis? 31. A 45-year-old lady with a history of
b. If the patient had hepatosplenom- fracture shaft of femur 2 days back,
egaly, what differential diagnosis had a sudden onset of tachypnea,
would you entertain? tachycardia and petechial skin rash-
es. She was restless and irritable.
c. What test need to be done to con-
firm the diagnosis? a. What is your provisional diagnosis?
d. Indicate three etiological factors. b. How will you confirm your diag-
nosis?
29. A 57-year-old man complains of fa-
c. Pathogenesis of symptom complex.
tigue, weakness and weight gain,
particularly around the abdomen. 32. A 25-year-old lady suddenly devel-
O/E, he is found to have hyperten- oped profound respiratory difficulty
sion, fullness over the upper back and with deep cyanosis immediately after
abdominal striae. Laboratory studies delivery.
include an elevated serum cortisol a. What is your provisional diagnosis?
level that is not suppressed with dex- b. Mention two important causes of
amethasone. Imaging studies reveal death in this condition.
no pituitary or adrenal masses, but c. What will be the microscopic pic-
a CT scan of the chest shows a right ture of lung in this condition?
lung mass arising near the hilum. d. Describe the pathogenesis of this
a. What is the most likely diagnosis? condition.
b. What test would be useful in con- 33. A 42-year-old male was admitted

firming the diagnosis? with history of head injury following
Essays 253
RTA. On the 3rd day, he developed c. Is splenomegaly possible in this

progressive dyspnea with tachypnea case?
and hypoxia refractory to therapy. X- d. What are the causes of this condi-
ray showed diffuse bilateral pulmo- tion and what is the commonest
nary infiltrates. He became comatose cause?
and died on 6th day.
e. What is the treatment ideally?
a. Give the most possible cause of
f. What are the causes of pancytope-
death.
nia?
b. Describe the microscopy of lung in
this condition. 36. A 80-year-old man presented with

pathological fracture. X-ray revealed
c. Mention two important events in
osteoblastic metastatic deposits in the
pathogenesis.
bones.
d. State two other causes, which can
lead to this event. a. What will be the most likely pri-
mary malignancy is?
34. A 35-year-old woman was admitted
due to snakebite in MCH. She later b. What type of clinical manifesta-
developed bleeding from gums, pur- tions will you do to confirm the
puric and ecchymotic patches over diagnosis?
the body. Her BP was 90/60 mm Hg. c. Tumor marker associated with
Renal O/P for first 24 hours was 75 malignancy and its importance in
mL. clinical evaluation?
a. What is your diagnosis? d. What is the staging system for this
b. What lab investigation would you malignancy?
suggest? e. Describe the gross and microscopy?
c. What are the major disorders asso- f. What are hormonal, genetic and
ciated with this condition? environmental factors?
d. Is it true that in hospital, snakebite 37. A 60-year-old man presented with

is the commonest cause of this con- fever with chills. Routine blood ex-
dition? amination revealed neutrophilic leu-
35. A 10-year-old boy presented in the kocytosis. Urine analysis revealed
OP with features suggestive of men- pyuria and bacteriuria. Patient gives
ingitis. CSF culture yielded Haemo- history of urinary hesitancy, urgency
philus influenzae. Doctor prescribed a and increased frequency for months.
course of chloramphenicol. Later the
a. Which condition was the predis-
boy developed pallor and dyspnea.
posing factor to the present illness?
Petechiae and ecchymosis appeared
on his trunk. There was also high b. How the commonly used term for
grade fever. Blood investigation re- this condition is a misnomer?
vealed Hb was 4.5 g%. c. What is the role of hormone in this
a. What is your diagnosis? condition?
b. How will you confirm your diag- d. Why is it most commonly in elderly?
nosis? e. Microscopic features of the lesion.
38.
A 56-year-old woman came with necomastia, increased SGPT and re-
complains of irregular vaginal bleed- versal of S/G ratio.
ing, leukorrhea, painful coitus and a. What is your diagnosis?
dysuria. On examination a fungating b. Give gross and microscopy of af-
mass at cevix. fected organ.
a. Give your diagnosis. c. What is the pathogenesis of ascitis?
b. Explain the cytological grading. 42. A 55-year-old male presenting with
c. Staging of the disease. dry cough, hemoptysis and chest
d. What are macroscopic forms? pain. X-ray chest showed a well-
e. Describe the risk factors and patho- circumscribed round opacity in the
genesis. right middle lobe.
39. A 45-year-old women presented with a. What is your diagnosis?
a painless movable mass on the up- b. Give five investigations that will
per outer quadrant of her right breast. confirm diagnosis.
Axillary LNs are enlarged. Mammog- c. What are the histological types?
raphy revealed microcalcification in d. What are the risk factors associated?
the lesion. 43. A 48-year-old male presenting with
a. What is your diagnosis? dyspepsia, hard palpable mass in the
b. What other lesions can produce epigastrium. A hard fixed palpable
calcification in the mammogram? supraclavicular node also.
c. What are the factors that determine a. What is your diagnosis?
the prognosis? b. How will you confirm?
d. Explain the staging system? c. Gross and microscopy of this con-
e. Genetic factors involved in the dition.
pathogenesis? d. Two predisposing factors of this
f. Hormonal and environmental in- condition.
fluence? 44. A 40-year-old male presented with

40. A 55-year-old man with a habit of history of fatigue and weight loss for
heavy cigar smoking came to OP with the last 6 months. O/E large spleen
a history of cough and blood stained was present. On lab investigations,
sputum and loss of weight. X-ray re- Hb—9 g%, TC—95,000/cm with shift
veals Hilar shadows. to left and platelet count—6 lakhs/cm.
a. What is your diagnosis? a. What is your diagnosis?
b. What are the etiological factors of b. What is the common genetic and
this condition? cytogenetic abnormality expected?
c. Microscopic picture of this condi- c. Describe the blood and bone mar-
tion. row findings.
41. A 50-year-old man came to OP with d. What is the outcome and prognosis?
distension of abdomen and weight 45. A 32-year-old female from Wayanad
loss. O/E he was having ascitis, gy- admitted with fever, dyspnea and
Essays 255
abdominal pain. O/E she has pallor 48. A mother came to OP with the com-
and mild icterus. No hepatosplenom- pliant that her child is eating non-
egaly. No lymphadenopathy. There food stuffs like dirt. The child was
is a scar of a healed ulcer on leg. Hb restless and pale. O/E the child was
—4.8 g% TC—26000, ESR—30 mm found to have koilonychia.
and reticulocyte count—6%. Urine
a. What is your diagnosis?
albumin—nil, sugar—nil and uro-
bilinogen ++. b. What will be the morphology of
a. What is your diagnosis? Give rea- peripheral blood?
sons. c. What are the etiological factors?
b. What will be the blood picture? d. How will you treat this condition?
c. Name two investigations to con- e. DDs of microcytic hypochromic
firm and explain. anemia.
d. Name two common complications 49. A male patient presented with con-
that can occur here. vulsions and vomiting. CT scan
46. A 42-year-old male taken to casualty shows a well-circumscribed mass in
with acute onset of left-sided chest parasagittal sinus arising from me-
pain radiating to left arm, dyspnea ninges.
and died after 2 hours. a. What is your diagnosis?
a. What is your probable diagnosis? b. Describe the gross and microscop-
b. What is the cause of death in this ic features.
case?
50. A 12-year-old male child presented
c. Outline the complication of this with fever, sore throat and cervical
case.
lymphadenopathy. O/E mild he-
d. Name two serum enzymes useful patosplenomegaly, Hb—13 g% and
in the diagnosis of this condition. TC—20000/cm with lymphocytosis.
47. A 55-year-old male presented with

a. What is your diagnosis?
retrosternal chest pain. Coronary
angiogram shows narrowing of de- b. Name one investigation to confirm
scending branch of left coronary ar- diagnosis.
tery. Serum cholesterol elevated. c. Describe the blood picture.
a. What is your diagnosis? d. What is the etiology of this condi-
b. What will be the likely outcome? tion?
c. Enumerate the risk factors and e. Name the special type of cells seen
complications. in peripheral smear.
Diagnosis
1. Tuberculosis. 25. Sarcoidosis.

2. DM nephropathy, UTI, anemia of 26. Multiple myeloma.
CRF. 27. Renal cell carcinoma.
3. 2° Amyloidosis. 28. Aplastic anemia.
4. Multiple myeloma. 29. Small cell lung carcinoma.
5. COPD and CCF. 30. Acute lymphatic leukemia.
6. Lobar pneumonia. 31. Fat embolism.
7. Hodgkin disease—nodular sclerosis. 32. Amniotic fluid embolism.
8. Megaloblastic anemia. 33. ARDS.
9. Anaphylactic reaction. 34. DIC.
10. Adriamycin cardiomyopathy. 35. Aplastic anemia.
11. Sickle cell anemia. 36. CA prostate.
12. Hemophilia A. 37. Nodular hyperplasia of prostate.
13. Acute poststreptococcal glomerulo-
38. Cervical carcinoma.
nephritis. 39. Breast carcinoma.
14. Leprosy. 40. Bronchogenic carcinoma.
15. Syphilis. 41. Chronic hepatic failure due to cirrho-
16. Hereditary spherocytosus. sis.
17. Cirrhosis with hepatocellular carci-
42. Bronchogenic carcinoma.
noma. 43. Stomach carcinoma.
18. Systemic lupus erythematosus. 44. Chronic myeloid leukemia.
19. Ewing sarcoma. 45. Sickle cell anemia.
20. Acute myeloid leukemia . 46. MI.
21. Primary osteosarcoma. 47. Angina.
22. Acute pyogenic meningitis. 48. Iron deficiency anemia.
23. a-1 antitrypsin deficiency. 49. Meningioma.
24. Breast carcinoma with Paget disease. 50. IMN.
23 Important Laboratory Values
Test Name Values Test Name Values

Blood routine Osmotic fragility 0.35%–0.45%
Hb Red cell distribution < 14.5%
•• Male 13.3–16.2 g/dL width
•• Female 12–15.8 g/dL
TC 4–11 × 103 Reticulocyte count
DC •• Male 0.8%–2.3% red cells
•• Neutrophils 40%–70% •• Female 0.8%–2.0% red cells
•• Bands 0%–5% LFT
•• Lymphocytes 20%–50%
•• Monocytes 4%–8% Bilirubin
•• Eosinophils 0%–6% •• Total 0.3–1.3 mg/dL
•• Basophils 0%–2% •• Direct 0.1–0.4 mg/dL
ESR •• Indirect 0.2–0.9 mg/dL
•• Male 0–15 mm/h SGOT 12–38 U/L
•• Female 0–20 mm/h SGPT 7-41 U/L
Platelet count 165–415 × 109/mm3 GGT 9-58 U/L
Erythrocyte count Albumin
•• Male 4.30–5.60 × 106 mm3
•• Male 4.1–5.3 g/dL
•• Female 4.00–5.20 × 106 mm3
•• Female 4.0–5.0 g/L
PCV
Total protein 6.7–8.6 g/dL
•• Male 38.8–46.4 mm
•• Female 35.4–44.4 mm Amylase 20–96 IU/L
Erythrocyte life-span 120 day RFT
Bleeding time 2–7 min S urea 15–40 mg/dL
Clotting time 5–8 min S uric acid
Prothrombin time 12.7–15.4 s •• Male 3.1–7.0 mg/dL
Erythropoietin 4–27 U/L •• Female 2.5–5.6 mg/dL
MCH 26.7–31.9 pg S creatinine
MCHC 32.3–35.9 g/dL •• Male 0.6–1.2 ng/mL
MCV 78–98 fl •• Female 0.5–0.9 ng/mL
Test Name Values Test Name Values

S electrolytes •• Borderline high 130–159 mg/dL
S Na 136–146 mEq/L •• High 160–189 mg/dL
SK 3.5–5.0 mEq/L •• Very high > 190 mg/dL
S Ca 8.7–10.2 mg/dL HDL
S Cl 102–109 mEq/L •• Low < 40 mg/dL
Glucose •• High > 60 mg/dL
Fasting TFT
•• Normal 75–110 mg/dL TSH 0.3–3.3 mU/mL
•• Impaired 111–125 mg/dL T4
tolerance •• Free 0.8–1.7 ng/dL
•• Diabetes mellitus > 125 •• Total 5.4–11.7 ug/dL
2 h postprandial 70–120 mg/dL T3
Total cholesterol •• Free 2.4–4.2 pg/dL
•• Desirable < 200 mg/dL •• Total 77–135 ng/dL
•• Borderline high 200–239 mg/dL Rheumatoid factor < 30 IU/mL
•• High > 240 mg/dL Urine albumin
LDL •• Normal < 0.03 g/24 h
•• Optimum < 100 mg/dL •• Microalbuminuria 0–30 mg/24 h
•• Near optimum 100–129 mg/dL •• Nephrotic range > 3.5 g/24 h
Index
Page numbers followed by f refer to figure and t refer to table, respectively.
A hepatitis 188, 189

liver disease 188
Abnormal cell surface molecules 63
Alpha1-antitrypsin deficiency 192
Abnormally expressed cellular proteins 63
Alzheimer disease 246
Abruption placenta 136
Amniotic fluid 69
Abundant neck skin 67
embolism 136
Acanthosis nigricans 62 Amylodosis 42
Achondroplasia 226 Anaphylactic shock 29
Acute Anaplasia 48
and chronic inflammation 11 Anaplastic carcinoma 219
arthritis 236 Anemia 62
cellular rejection 36 Angiogenesis 19
coronary syndromes 105 Antibody-mediated
endocarditis 110 cellular dysfunction 34, 34f
humoral rejection 37 graft rejection 37f
inflammation 11, 14 Aortic
ITP 138 aneurysm 97
lymphoblastic leukemia 128 dissection 98
myelogenous leukemia 126 Aplastic anemia 122
pancreatitis 195 Apoptosis 6
pneumonia 150 Arachidonic acid metabolites 15
postinfectious glomerulonephritis 160 Aromatic amines 56
pyelonephritis 162 Arteriolar dilatation 11
pyogenic meningitis 241 Arthralgia 110
respiratory distress syndrome 141 Arthus reaction 34
restrictive lung disease 141 Ascites 184
Addison disease 224 Aseptic meningitis 242
Adenocarcinoma 154, 155, 173 Aspergillosis 136
Adenoma 179 Aspiration of
of thyroid 217 blood 69
Adrenal gastric content 141
gland 223 Asthma 144
insufficiency 224 Atherosclerosis 93, 94f, 97
Adult polycystic kidney disease 165 Atresia of urethra 168
Aggressive clonal proliferation and Atrial amyloidosis 44
angiogenesis 50 Atrophy 4
Alcoholic Atypical pneumonia 151
cirrhosis 188, 190 Autocrine signaling 18
Autosomal Cardiac
dominant 181 defects 67, 68
genetic disorders 67 hypertrophy 108
trisomies 67 Cardiogenic shock 29
Cardiopulmonary bypass 141
B Cardiovascular syphilis 202
Carditis 110
Bacterial
Cartilaginous metaplasia 4
endotoxins 78
Caseous necrosis 5
exotoxins 78 Causes of nephrotic syndrome 157
Barrett esophagus 171 Cavernous hemangioma 101
Basal cell carcinoma 238 Cell
Benign cycle 18, 18f
and malignant tumor 49t derived mediators 14
nephrosclerosis 165 Cellular adaptations 3
tertiary syphilis 202 Central tolerance mechanism 37
tumors of breast 210 in bone marrow 38f
Berger disease 159 in thymus 37f
Berry aneurysm 241 Centriacinar 142
Beta-cell dysfunction 220 Cervical intraepithelial neoplasia 204
Bicuspid aortic valve 69 Chemokines 15
Bilirubin 9 Chemotaxis 12
Bitot spots 75 Childhood polycystic kidney disease 167
Blindness 75 Cholecystitis 194
Blood Cholelithiasis 193
loss 114 Cholesterol accumulation 8
transfusion 141 Chondrosarcoma 232
vessels 39, 93 Choriocarcinoma 199, 208, 209
Bone tumors 231 Chromophobe renal cell carcinoma 170
Borrelia burgdorferi 243 Chronic
Brain tumors 243 bronchitis 144
Brenner tumors 207 endothelial injury 94
Bronchiectasis 145 hepatitis 187
Bronchioalveolar carcinoma 155 inflammation 16
Burkitt lymphoma 131 ischemic heart disease 108
ITP 138
Kaposi sarcoma 102
C
lymphocytic leukemia 130
Calcinosis 45 meningitis 242
Calcium stones 167 myelogenous leukemia 127
Calculus cholecystitis 194 pancreatitis 196
Capillary hemangioma 101 rejection 37
Carcinogenesis 51, 179 tophaceous arthritis 236
Carcinoid syndrome 62 Cirrhosis 183
Carcinoma of Classification of
bladder 76 acute
breast 210 lymphoblastic leukemia 129t
esophagus 76 myelogenous leukemia 126t
Index 265
anemia 114 Diffuse

aortic dissection 99f scleroderma 45
bone tumors 232t type adenocarcinoma 175
mediators 14f Dilated cardiomyopathies 111
Clear cell carcinoma 169 Diphosphonates 168
Cleft palate and lip 68 Direct lung injury 141
Clonal aggressiveness 52 Diseases of immune system 32
Clostridium perfringens 78 Disseminated intravascular coagulation 136
Coagulative necrosis 5 Distal acinar 143
Coal worker’s pneumonia 148 Distant metastasis 201
Coarctation of aorta 69 Down syndrome 67
Colloid carcinoma 212 Drug induced liver disease 190
Colonic diverticulosis 176 Dry and scaly conjunctiva 75
Colorectal carcinoma 179 Ductal carcinoma in situ 211
Complement system 15 Dysgerminoma 208
Dyshormonogenetic goiter 217
Complete
Dystrophic calcification 9
destruction of hepatocytes 191
mole 208
Compliment and FC receptor-mediated E
inflammation 34 Edema 24
Congenital Edward syndrome 68
diseases of bone 226 Elevated acute phase proteins 17
syphilis 203 Embryonal carcinomas 199
Corneal ulcers 75 Emphysema 142, 151
Coronary artery disease 106f Endemic goiter 216
Cri Du Chat syndrome 68 Endocrine 44
Crohn disease 177, 178 syndrome 62
Cubitus valgus 69 system 215
Cushing syndrome 62, 222 Endometrial carcinoma 205
Cutaneous wound healing 20 Endometrioid
Cystic fibrosis 70 carcinoma 205
tumors 207
D Endothelial
dysfunction 95
Defective injury 11
intraluminal digestion 176 producing thrombosis 26f
mucosal absorption 177 Eosinophils 16
nutritional delivery 177 Ependymoma 244
Degradation of ECM 50 Epicanthic folds 67
Deletion syndromes 68 Epithelial metaplasia 4
Depletion of T cells 47 Epstein-Barr virus 60
Dermatomyositis 62 Erythema marginatum of skin 110
Diabetes mellitus 220 Erythroplakia 171
Diabetic Escherichia coli 78, 150, 230, 241
macrovascular disease 221 Esophageal
nephropathy 222 carcinoma 172
neuropathy 222 dysmotility 45
Evasion of apoptosis 52 Gastric carcinoma 174

Ewing sarcoma 233 Gastrointestinal tract 46
Excessive sedation of mother 69 Gaucher disease 66
Exfoliative dermatitis 62 General pathology of infectious diseases 77
Extravasation of tumor cells 51 Genitalia remain infantile 69
Eyes and lacrimal glands 150 Genotype of host 79
Giant cell
F arteritis 100
tumor 233
Facial dimorphism 68
Glomerular diseases 157
Familial
Glycogen 9
adenomatous polyposis 181, 182
storage diseases 67
amyloidotic neuropathies 43
Glycogenosis 67
mediterranean fever 43
Gout 234
polyposis syndromes 181
Gouty nephropathy 236
Fat necrosis 5
Graft
Fate of thrombus 27
rejection 36
Fatty versus-host reaction 37
liver 8, 188, 189 Granulomatous inflammation 16
tumors 236 Granulosa-theca cell tumors 208
Female genital system and breast 204 Graves’ disease 215
Fetal head injury during delivery 69 Growth retardation 69
Fever 110
Fibrillary astrocytoma 243
Fibrinoid necrosis 5
H
Fibrinolytic system 16 Haemophilus influenzae 150
Fibroadenoma 210 Hansen disease 78
Fibroblast growth factor 20 Hashimoto’s thyroiditis 215
Fibrogenesis 184 Heart failure 103
Fibrosis 151 Helicobacter pylori 173, 174
Flat facial profile 67 Hemangioma 49, 101
Focal segmental glomerulosclerosis 158 Hematoma 22f
Folate Hemochromatosis 191
deficiency 120, 121 Hemodynamic disorders 24
metabolism 121f Hemophilia
Follicular A 139
adenoma 217 B 140
carcinoma of thyoroid 218 Heparin-induced thrombocytopenia 26
Formation of initiated cells 57 Hepatic
Fracture healing 21 encephalopathy 183, 185
Frame shift mutation 64 failure 183
Hepatitis
Fulminant hepatitis 187
A 188
Functions of endothelial cells 93
serology 188f
virus 185
G B 188
Gallstones 193 serology 188f
Gangrenous necrosis 5 virus 186
Index 267
C 188 Impaired red blood cell production 114

serology 189f Indeterminate leprosy 81
virus 186 Indirect lung injury 141
E virus 186 Infarct expansion 108
virus 60 Infected corneal ulcers 75
Hepatocellular carcinoma 193 Infectious
Hepatorenal syndrome 183 mononucleosis 125
Hereditary vasculitis 99
amyloidosis 43 Infective endocarditis 110
nephritis 160 Inflammatory
spherocytosis 115 bowel disease 177
Herpes virus 59 carcinoma 212
High-arched palate 69
Ingrowth of granulation tissue 22
Histoplasmosis 136
Inhalational injury 141
Hodgkin lymphoma 133, 135t
Inhibitors of crystal formation in urine 168
Horseshoe kidney 69
Intestinal
Human
metaplasia 4
granulocytic anaplasmosis 9
herpesvirus 60 stenosis 67
papilloma virus 59 TB 154
T cell lymphotropic virus 60 type adenocarcinoma 174
Hyaline Intracellular accumulations 8
arteriosclerosis 96 Intraductal papilloma 210
membrane disease 69 Intrauterine hypoxia 69
Hydatidiform mole 208 Invasive
Hydronephrosis 168 carcinoma of cervix 205
Hyperacute rejection 36 ductal carcinoma 212
Hypercalcemia 62 lobular carcinoma 212
Hyperkeratosis papules 75 mole 209
Hyperparathyroidism 220, 230 Involvement of growth factors 19
Hyperplasia 3 Iron deficiency anemia 119
Hyperplastic arteriosclerosis 96 Ischemic heart diseases 104
Hypertension 95 Isolated organ TB 154
Hypertensive heart diseases 108
Hypertrophic cardiomyopathy 112 J
Hypertrophy 3
Hypoalbuminemia 62 Jone’s major criteria 110
Hypoglycemia 62
Hypotonia 67 K
Hypovolemic shock 29 Kaposi sarcoma 102
Keratinization 75
I Keratomalacia 75
IgA nephropathy 159, 161 Kinin system 16
Immature malignant teratoma 208 Kinking of ureter 168
Immune Klinefelter syndrome 68
recognition of allograft 36 Knudson’s two-hit hypothesis 53
thrombocytopenic purpura 138 Krukenberg tumors 207
L M
Large Malabsorption syndromes 176
cell carcinoma 154, 155 Malaria 136
vessel vasculitis 100 Male genital system 198
Later stages of secondary tuberculosis 153 Malignant
Leiomyoma 237 melanoma 239
Leiomyosarcoma 237 mesothelioma 156
nephrosclerosis 165
Lepra reaction 79
Mallory bodies 8
Lepromatous leprosy 80t
Marasmus 74
Lepromin test 79, 80
Marfan syndrome 65
Leprosy 78 Massive
Leukemia sarcoma virus 60 hepatic necrosis 191
Leukemoid reaction 124 tissue injury 136
Leukocyte Mast cells 16
activation 13 Mechanisms of
mediated endothelial injury 11 autoimmunity 38
recruitment 12 bacterial injury 77
Leukocytosis 17, 110 cell injury 5
Leukoplakia 171 chronic inflammation 16f
Libman-Sacks endocarditis 111 formation of
Limited hip abduction 68 ascites in portal hypertension 185f
edema 25t
Lipofuscin 9
metastasis 50
Lipoid nephrosis 158
serum sickness 35f
Lipoma 236 viral injury 77
Liposarcoma 236 Medium vessel vasculitis 100
Liquefactive necrosis 5 Medullary carcinoma 212, 219
Listeria monocytogenes 241 Medulloblastoma 244
Little pubic hair 69 Megaloblastic anemia 120
Lobular carcinoma in situ 211 Membranoproliferative glomerulonephritis
Low-posterior hairline 69 159
Lung Membranous glomerulonephritis 157
abscess 151 Meningioma 245
carcinoma 76, 154 Meningitis 241
Lymph nodes 154 Meningococcemia 136
Lymphadenopathic KS 102 Mental retardation 68
and dementia 67
Lymphatic spread 48
Mesenchymal metaplasia 4
Lymphocytes 16
Metaplasia 4
Lymphoid Metastatic calcification 9
leukemoid reaction 124 Microcytic hypochromic anemias 123, 123t
systems 114 Micrognathia 68
Lymphoma of small bowel 62 Microphthalmia 68
Lysosomal Microscopy of peptic ulcer 174f
enzymes of leukocytes 15 Miliary TB 154
storage disease 65 Minimal breast development 69
Index 269
Mitochondrial damage 6f Oral cavity and git 171

Mucinous tumors 207 Osseous
Mucopolysaccharides 66, 168 callus formation 23
Multiple metaplasia 4
endocrine neoplasia syndromes 225 Osteitis deformans 228
myeloma 62, 131 Osteoarthritis 233
Multistep molecular phenomenon 52
Osteoblastoma 232
Musculoskeletal system 226
Osteogenesis imperfecta 226
Myasthenia gravis 62
Osteoid osteoma 232
Mycobacterium
bovis 152 Osteoma 232
tuberculosis 78, 152, 231 Osteomalacia 75, 229
Mycoplasma Osteomyelitis 230
hominis 152 Osteopetrosis 226
pneumoniae 151, 195 Osteopontins 168
Myeloid leukemoid reaction 124, 125 Osteoporosis 227
Myocardial Osteosarcoma 231
infarction 106 Outcomes of
rupture 108 acute inflammation 14
hepatitis
N B infection 186f
Necrosis 4 C infection 187f
Neoplasm 48 Ovarian tumors 206
Nephritic syndrome 160 Overlapping fingers 68
Nephrocalcin 168t
Nervous system 241 P
Neuroblastoma 71, 246
Paget disease 228
Neuroborreliosis 243
of nipple 211
Neurogenic shock 29
Pancreas 195
Neuromuscular disorders 62
Neuropeptides 15 Pancreatic carcinoma 76
Neurosyphilis 202, 242 Pancreatitis 141
Niemann-Pick disease 66 Papillary
Night blindness 75 carcinoma of thyroid 218
Nitric oxide 15 muscle dysfunction 108
Nodular hyperplasia of prostate 199 renal cell carcinoma 169
Non-bacterial thrombotic endocarditis 111 Papilloma virus 59
Non-calculus cholecystitis 194 Papovaviruses 59
Non-Hodgkin lymphoma 135t Paracrine signaling 18
Non-infectious vasculitis 99 Paraneoplastic syndromes 62t, 63
Nosocomial pneumonia 151 in carcinoma lung 156
Parathyroid hyperplasia and hypocalcemia
O 68
Obstructive pyelonephritis 163 Paroxysmal nocturnal hemoglobinuria 117
Oligodendroglioma 244 Partial mole 209
Oncofetal antigens 63 Patau syndrome 68
Pathogenesis of Paucibacillary 81
acute Pediatric diseases 64
pancreatitis 196f Peptic ulcer 76, 173f, 174
pyelonephritis 162f Pericarditis 108
alcoholic liver disease 189f Peripheral
Alzheimer disease 245f blood 126
amyloidosis 44f tolerance mechanism 38, 39f
aortic Pernicious anemia 121
aneurism 98f Peutz-Jeghers polyposis 181
dissection 99f Phagocytosis 13, 13f
ARDS 142f Pheochromocytoma 224
ATN 164f Phyllodes tumor 210
atopic asthma 146f Pigmented nevi 69
bronchiectasis 147f Pilocytic astrocytoma 244
cervical intraepithelial neoplasia 204f Plasma
chronic bronchitis 144f cells 16
cirrhosis 184f protein-derived mediators 15
colorectal carcinoma 180f Pneumoconiosis 147
coronary artery disease 105f Pneumonia 141, 150
DIC 137f Polyarthritis 110
DM complications 221 Polycystic kidney disease 165
emphysema 143f Polycythemia 62, 123
gastric carcinoma 175f vera 123
goiter 217f Polyoma virus 59
gout 235f Popcorn RS cell 133
hemochromatosis 191f Portal hypertension 184
hepatocellular carcinoma 193f Portosystemic shunt 184
human immunodeficiency virus 47 Poststreptococcal glomerulonephritis 160
hydronephrosis 169f Preneoplastic disorders 51
malignant nephrosclerosis 166f Primary
non-atopic asthma 145f amenorrhea 69
non-infections vasculitis 100f amyloidosis 43
osteoarthritis 234f aplastic anemia 122
osteomalacia 229 syphilis 201
osteoporosis 227f tuberculosis 152
Paget disease 228f Production of mediators in septic shock 30f
pneumoconiosis 147f Products of tumor suppressor genes 63
primary pulmonary TB 153f Progression of
respiratory distress syndrome 70f disease 47f
rheumatoid arthritis 43f infection 47
rickets 229 Prostatic carcinoma 200
and osteomalacia 229f Protein energy malnutrition 74
sarcoidosis 149f Pseudogout 236
scleroderma 45f Pulmonary hypertensive heart disease 109
septic shock 30 Pyelonephritis 163
squamous cell carcinoma 238f Pyogenic osteomyelitis 230
systemic lupus erythematosus 40f Pyrophosphate 168
Index 271
R Septic
abortion 136
Rapidly progressive GN 161
shock 29
Raynaud phenomenon 45, 102
Serous
Reactive electrophiles formation 57
carcinoma 206
Reed-Sternberg cells 133
tumors 206
Reflex associated pyelonephritis 163
Sertoli-Leydig cell tumors 208
Regional lymph nodes 201
Serum sickness 34f
Regulation of blood pressure 96
Sex chromosomal disorders 68
Renal
Shock 29
cell carcinoma 169, 170
Sickle cell anemia 115
defects 68
Silicosis 148
malformations 68
Simian crease 67
ptosis with torsion 168
Slow transforming viruses 60
stones 167
Small
vein thrombosis 62
cell lung carcinoma 154, 155
Respiratory
vessel vasculitis 101
distress 69
Smooth muscle tumors 237
syndrome 69
Spermatocytic seminoma 198
tract and pancreas 71
Sporadic goiter 216
Restrictive cardiomyopathy 112
Squamous
Retained dead fetus 136
cell carcinoma 154, 155, 172, 238
Retinoblastoma 72
metaplasia 4, 75
Rheumatic
Stage of
heart disease 109
congestion 151
valvular disease 109
gray hepatization 151
Rickets 75, 229
red hepatization 151
RNA viral oncogenesis 60
resolution 151
Rocker-bottom feet 68
shock 29
Rous sarcoma virus 60
Staphylococcus aureus 78, 150, 230
Russell bodies 8
Steps in
Rye classification 134
DNA virus oncogenesis 59f
EBV oncogenesis 60f
S HHV oncogenesis 60t
Salmonella typhimurium 58 HTLV oncogenesis 61f
Sarcoidosis 149 Streptococcus pneumoniae 150, 241
Scleroderma 45 Subacute endocarditis 110
Seborrheic dermatitis 62 Subcellular alterations 4
Secondary Subcutaneous nodules 110
amyloidosis 43 Subtypes of ALL 129t
aplastic anemia 122 Sudden cardiac death 108
insufficiency 224 Sweat gland 71
syphilis 202 Sydenham chorea 110
tuberculosis 153 Syphilis 81, 201
Seminoma 198 Syphilitic aneurysm 98
Senile amyloidosis 43 Systemic
Sepsis 17, 136 amyloidosis 43
diseases 157 U
hypertensive heart disease 108
Ulcerative colitis 177, 178
inflammatory response syndrome 17
lupus erythematosus 38, 39 Umbilical hernia 67, 68
miliary TB 154 Underlying cancer 62
T V
T cell-mediated Valve formations 168
cytotoxicity 36 Vascular endothelial growth factors 20
rejection 36 Vasoactive amines 14
Tamm-Horsfall proteins 168 Ventricular aneurysm 108
Tay-Sachs disease 66 Viral
Telangiectasia 45
hepatitis 185, 187
Teratoma 199
oncoproteins 63
Tertiary syphilis 202
Testicular neoplasms 198 replication 47
Thalassemia 117 in host cell 46f
Thrombophlebitis 62 Virchow’s triad 25f
Thrombotic thrombocytopenic purpura 138 Vitamin
Thymic hypoplasia 68 A deficiency 75
Toxemia 136 B12
Transformation of ovaries 69 deficiency 120
Treponema pallidum 201, 242 metabolism 120
Tuberculin test 35 D deficiency 75
Tuberculoid leprosy 80t von Willebrand disease 140
Tuberculosis 78, 151
Tuberculous
meningitis 242 W
osteomyelitis 231 Webbed neck 69
Tubular
Wegener granulomatosis 101
carcinoma 212
White fibrous streaks 69
necrosis 163
Tumor WHO classification of acute leukemia 118
angiogenesis 52 Wilms tumor 170
antigens 61 Wilsons disease 192
cell loosening 50 Wound healing 22
Turner syndrome 69
Types of X
acute rejection 36
Kaposi sarcoma 102 Xeroderma 75
mutation 64 Xerophthalmia 75
non-infectious vasculitis 100
rejection 36
Y
scleroderma 45
shock 29 Yolk sac tumors 199

Synopsis of Pathology

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Synopsis of

Jaypee Brothers Medical Publishers (P) Ltd

Jaypee Brothers Medical Publishers (P) Ltd

© 2013, Jaypee Brothers Medical Publishers

Inquiries for bulk sales may be solicited at: [email protected]

First Edition: 2013

Part 1: General Pathology

2. Acute and Chronic Inflammation 11

3. Tissue Repair, Regeneration, Healing and Fibrosis 18

5. Diseases of the Immune System 32

7. Genetic and Pediatric Diseases 64

8. Environmental and Nutritional Diseases 74

•• Packed cell volume 88

Part 2: Systemic Pathology

10. Blood Vessels 93

11. Heart 103

12. Hematopoietic and Lymphoid Systems 114

•• Portal hypertension 184

21. Musculoskeletal System 226

22. Skin 238

23. Nervous System 241

AA Amino acid B Basophils

CO Cardiac output FFP Fresh frozen plasma

IC Immune complex LVH Left ventricular hypertrophy

OCP Oral contraceptive pills RNP Ribonucleoproteins

CELLULAR RESPONSE Hypertrophy

4. Pathological: b. Stratified squamous epithelium of

Classification Fat Necrosis

a. Antioxidant mechanisms: APOPTOSIS

Fig. 1.2: ATP depletion Fig. 1.3: Mitochondrial damage

2. Involution of hormone-dependant 4. Atrophy due to duct obstruction.

Fig. 1.6: Accumulation of reactive O2 species

Fig. 1.8: Intrinsic/mitochondrial pathway

Fig. 1.7: Damage to DNA proteins

2. Accumulation of misfolded proteins

•• Decreased fatty acid oxidation,

Glycogen 3. Normal levels of serum calcium. For

4. Usually in vasculature of kidneys, e. Lifestyle.

ACUTE INFLAMMATION b. The mechanisms leading to in-

– Via newly formed channels •• Selectins.

•• Cells: b. These opsonins are produced in

4. Actions are vasodilatation, ↑ vascular Reactive Oxygen Species

3. Actions: Opsonization, vasodilata- 3. Prolonged toxic exposure in silicosis

Conditions 2. TNF, IL-1 are the most important me-

CELL CYCLE Paracrine Signaling

Fig. 3.1: Cell cycle

2. Without intrinsic enzyme activity

Vascular Endothelial Growth Factors

3. Small scar and minimum wound con- a. Inflammatory reaction is much

ii. Takes place by procallus forma-

shaped or fusiform ap- Remodeling

EDEMA a. Increased salt intake with renal in-

Fig. 4.1: Mechanism of formation of edema

•• Polycythemia and sickle cell

– Hyperestrogenic state— 3. Dissolution—by fibrinolytic system.

•• Occur usually after fracture of – Lanugo hair

2. Histologically: b. Caused by hemorrhage and fluid

c. This acidic pH blunts the vasomo- b. Activation of endothelial cell.

Fig. 4.6: Production of mediators in septic shock