Neoplasia-Carcinogenesis

Krisna Murti
Department of Anatomic Pathology, Faculty of Medicine,
University of Sriwijaya
 Nomenclature

• Neo + Plasia: New + Growth

• Tumour: Swelling or any swelling

• Clinically tumour = neoplasm (technically incorrect..!)

• Willis definition:
“A neoplasm is an abnormal mass of tissue, the growth of which exceeds
and is uncoordinated with that of the normal tissue and persists in the
same manner after cessation of the stimuli which evoked the change”

• “Cell division without control”

• Irreversible DNA damage, resulting in autonomous growth of abnormal

cells
 Neoplasms Nomenclature:
Oma - Tumour
Carcin-oma – Hard Tumour
Sarc-oma - Soft Tumour

Cell of Origin Benign Malignant

• Gland. Epithelium • Adenoma - Adenocarcinoma
• Lining. Epithelium • Papilloma - Squamous cell
carcinoma
• Fibroblast
• Osteoblast • Fibroma - Fibrosarcoma
• Chondrocyte • Osteoma - Osteosarcoma
• Lipocyte • Chondroma Chondrosarcoma
• Smooth muscle • Lipoma Liposarcoma
• Skeletal muscle • Leiomyoma Leiomyosarcoma
• Rhabdomyoma Rhabdomyosarcoma
 Nomenclature: exceptions

• Teratoma – Tumour of Germ cell – multiple tissues. Benign (mature)

or malignant (immature)
• Melanoma (Melano-carcinoma) – Malignancy of melanocytes
• Seminoma (Seminal carcinoma) –carcinoma of Testes
• Leukemia – white blood – Malignancy of Haemopoietic stem cells
• Lymphoma (Lymphosarcoma)– Malignancy of lymphocytes
• Mixed Tumours: Both epithelial & connective tissue components
Pleomorphic adenoma (Salivary gland) & Carcinosarcoma
(breast/uterus)

What is a Granuloma, Hamartoma & Choristoma?

 Differentiation and anaplasia

Differentiation
The extent to which neoplastic parenchymal cells resemble the corresponding normal
parenchymal cells, both morphologically and functionally

Anaplasia
• Lack of differentiation. Malignant neoplasms that are composed of poorly
differentiated cells are said to be anaplastic.
• Considered a hallmark of malignancy
• Form backward, implying a reversal of differentiation to a more primitive level
• Cancer arise from reverse differentiation of mature normal cells or from
incomplete differentiation of less mature cells
 Anaplasia
Anaplasia is often associated with many other morphologic changes:
• Pleomorphism: variation in size and shape (no uniform), range from small cells
with undifferentiated appearance to tumor giant cells
• Abnormal nuclear morphology: a nuclear to cytoplasm ratio; 1:1 (N 1:4 or 1:6)
• Nuclear shape is variable and often irregular, chromatin is often coarsely
clumped and distributed along the nuclear membrane (vesicular) or more darkly
stained than normal (hyperchromatic), also abnormally large nucleoli
• Mitoses: in undiff tumors many cells are in mitosis, reflecting the high activity of
the replicating cells
• In normal cells: indicative of rapid cell growth or rapid turnover of cells
• In malignancy: are atypical, bizarre, sometimes with tripolar, quadripolar or
multipolar spindles.
• Loss of polarity: the orientation of anaplastic cells is markedly disturbed, sheets
or large tumor cells grow in an anarchic disorganized fashion.
• Other changes: ischemic necrosis, developed by imbalance of availability and
the need of blood suply
 Metaplasia

• Replacement of one type of cell with another

type (better suited in the local environment
• Always found in association with tissue
damage, repair and regeneration or close to
carcinoma

Barret’s esophagus
 Dysplasia
• Disordered growth in epithelia: loss in
uniformity of the individual cells and their
architectural orientation
• Precursor to malignant transformation
• Does not always progres to cancer when
the causes are removed-reversible
• Carcinoma in situ when full thickness
involved
 Characteristics of a cancer
Growth of cancer is accompanied by
• Progressive infiltration-invasiveness-metastasize to distant sites
• Destruction of surrounding tissue
Benign lesion is the opposite

• Uncontrolled growth
• beyond normal hyperplasia in vivo
• loss of cell-cell inhibition in vitro
• anaplasia (highly variable)
• apoptosis (normal cell death) defective
• Tendency to invade surrounding tissue
• Tendency to travel beyond site of origin
• metastasis may occur late
 Metastasis
Spread of a tumor to sites that are physically discontinuous with the primary tumor
and unequivocally marks a tumor as malignant
-benign neoplasms do not metastasize-

Pathways of spread
• Direct seeding of body cavities or surfaces-peritoneal, pleural,
subarachnoid, joint spaces

• Lymphatic-common for initial dissemination of carcinoma, sarcoma also

• Sentinel lymphnode: the first node in a regional lymphatic basin that receives
lymph flow from the primary tumor

• Hematogenous-typical for sarcoma but carcinoma may do so

• Iatrogenic-surgical instruments???
 Metastasis
Metastasis: Lymphatic, Hematogenous, Direct
Metastasis
Pathogenesis:
1. Cell loosening
2. BM degradation
3. Invasion
4. Locomotion
5. BV adhesion
6. Intra-vasation
7. Tumour embolus
8. Adhesion
9. Extra-vasation
10. Angiogenesis • E-Cadherin, β-catenin
11. Growth. • Matrix Metalloproteinases (MMP)
• Collagenase (not in benign)
• Actin Cytoskeleton, chemokine
What chemical mediators are involved?
 BENIGN MALIGNANT
• Well differentiated • Poorly differentiated
• Slow growth • Rapid growth
• Cohesive, • Non Cohesive,
• Expansile • No capsule
• Capsule • Invasion/infiltration
• No invasion/infiltration • Metastases.

Necrosis

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Epidemiology of cancer
Leading sites of new cancer cases and death

American Cancer Society. 2016. Surveillance Research

Cancer statistic
Cancer statistic
 Environment of cancer

Development of cancer influenced by genetic and

environmental factors

Environmental factors is dominant risk factor for most cancer

• Infectious agents: 15%
• Smoking: cigarettes (90% cause lung ca. death)
• Alcohol consumption: Ca. oropharynx, larynx, esophagus, hepar
• Diet
• Obesity: 14% of men/20% of women
• Reproductive history: cumulative exposure to estrogen
• Environmental carcinogens: food (meat, high-fat diet, alcohol), UV, arsenic in drink
water, medications, work (asbestos)
 Molecular basis of cancer

• The only hope for cancer control lies in learning more about its pathogenesis and
molecular basis of cancer

• Cancer is a genetic disorder caused by DNA mutations that are acquired

spontaneously or induced by environmental insults

• These genetic alteration is heritable, being passed to daughter cells upon cell
division, hence cells harboring these alterations are subject to Darwinian selection

• Accumulation of mutations gives rise to a set of properties that have been called
hallmarks of cancer
 Molecular basis of cancer:
Role of genetic and epigenetic alteration

• Nonlethal genetic damage lies at the heart of

carcinogenesis

• A tumor is formed by the clonal expansion of a single

precursor cell that has incurred genetic damage
 Genetic roles in carcinogenesis

• The influence of hereditary factors is subtle and sometimes indirect.

• The genotype may influence the likelihood of developing environmentally induced cancers.

• For example, polymorphisms in drug ­metabolizing enzymes confer genetic predisposition to lung
cancer in people who smoke cigarettes.

• More strikingly, genome wide association studies (GWAS) in lung cancer:

identified variants in a nicotinic acid receptor as being associated with development of lung cancer.

• Of interest, these variants were strongly associated with the number of cigarettes smoked,
suggesting that they indirectly increase lung cancer risk by enhancing the addictiveness of cigarettes
 Genetic lesions in cancer

• Tumor cells may acquire mutations through several means:

• Point mutations, and
• nonrandom chromosomal abnormalities that contribute to malignancy; include
balanced translocations, deletions, and cytogenetic manifestations of gene
amplification.
• Balanced translocations contribute to carcinogenesis by overexpression of oncogenes or
generation of novel fusion proteins with altered signaling capacity.
• Deletions frequently affect tumor suppressor genes,
• Gene amplification increases the expression of oncogenes.
• Overexpression of miRNAs can contribute to carcinogenesis by reducing the expression of tumor

suppressors,
• Deletion or loss of expression of miRNAs can lead to overexpression of proto-oncogenes.
• Tumor suppressor genes and DNA repair genes also may be silenced by epigenetic changes,
which involve reversible, heritable changes in gene expression that occur not by mutation but by
methylation of the promoter.
Development of cancer

Stepwise acquisition of complementary mutations

 Development of cancer

• Carcinogenesis results from the accumulation of complementary mutations in stepwise

fashion over time
• Malignant neoplasm have several phenotypes (cancer hallmark)
• Excessive growth
• Local invasiveness
• Able to form distant metastases
• Driver mutations-initiating mutation
• Loss of function mutations in gene that maintain genomic integrity–early step to
malignancy-solid tumor
• Once established, tumors evolve genetically during their outgrowth and progression
under the pressure of Darwinian selection
 Predisposing conditions

• Chronic inflammations

• Precursor lesions:
• Metaplasia, dysplasia
• Benign tumor-transform to malignant tumour-villous adenoma-
50%-adenocarcinoma

• Immunodeficiency states: low level of T lymphocytes-

risk to develop lymphoma, certain carcinomas and
sarcomas due to oncogenic virus
 Fundamental changes in cancer

• Self-sufficiency in growth signals-tumor have the capacity to proliferate without external stimuli (as
a consequence of oncogene activation)
• Insensitivity to growth-inhibitory signals (inactivation of tumor suppressor genes that encode
components of these growth inhibitory)
• Altered cellular metabolism. Tumor cells undergo a metabolic switch to aerobic glycolysis
(Warburg effect)
• Evasion of apoptosis
• Limitless replicative potential (immortality)
• Sustained angiogenesis
• Ability to invade and metastasize
• Ability to evade the host immune response

 Warburg effect: Most cancer cells predominantly produce energy by a high rate of glycolysis
followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of
glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.
Hallmark of cancer

Clinically each
patient’s cancer has a
different mix of
features depending
on quality & quantity
of mutations
& changes with
time...!

Hanahan and Weinberg, 2011

 Proto-oncogenes

Proto-oncogenes
• Normal genes that code for proteins that help to regulate cell growth and differentiation
• Could become an oncogene due to mutations or increased expression.
• Often involved in signal transduction and execution of mitogenic signals, usually
through their protein products.
• Examples: RAS, WNT, MYC, ERK, and TRK

Oncogene / tumor-inducing agent

• Genes promote autonomous cell growth
• Due to an activating mutation in proto-oncogenes
• Encode oncoproteins: able to promote cell growth in the absence of normal growth
promoting signals-free from the normal check points and controls that limit growth –
proliferate excessively
 Oncogenes - 1

• Oncogenes are activated, unregulated versions of

protooncogenes
• Protooncogenes normal genes encoding for protein
kinase and other growth signals
• Their gene products stimulate cell growth
• Viral oncogenes are altered copies of
protooncogenes
• 20% of human tumours show oncogenes
 Oncogenes - 2

• Single copies of oncogenes are sufficient to

result in malignant transformation

• Oncogene products are convenient

biomarkers of effect

• Thought by some to be underlying

mechanisms (distinct from cause) of all
cancers
 Tumour suppressor genes

• Genes that block neoplastic growth, e.g. p53

• Functional opposites of oncogenes, hence originally
named anti-oncogenes
• Very difficult to identify and characterize
• Characteristic double allelic activity:
• both alleles must be damaged for malignant activity
 Cancer biology
• Structure:
• Parenchyma – Neoplastic cells.
• Stroma: Non neoplastic - normal DNA
• Features:
• Differentiation – Maturation of cells.
• Rate of Growth – Mitotic rate / Ki 67
• Local invasion – Hemorrhage, necrosis, destruction
• Metastasis – Distant Spread.
 Clonality
Normal
cell

• Tumors are clonal (one parent)

First
mutation • But have different mutations  different
shapes & features.
Second • Each new mutation adds a new feature.
mutation

Third
mutation
Malignant cells
Fourth or
later mutation

More new mutations with time.

Retrograde evolution of malignant cells
Embryo Neoplasia: Cancer

Self growth
Auto regulation
Limitless potential
Angiogenesis
Evade apoptosis
Invasion & infiltration
 Pathogenesis of Lung cancer

Irritation  Carcinogens  Initiation  Promotion  Ca.

Anaplasia

Smoke
C-myc K-Ras

p53
 Transformation
Colon: Normal  Adenoma  Carcinoma

Carcinogenesis)

Colon Cancer: Common type - 80%

 Stage and grade of cancer
Staging: Progression or spread in the body.
Grading: Cell differentiation and rate of growth – Microscopy.

Well differentiated (low grade) Adenocarcinoma Grade Undiff. (high grade)

Prostate Ca: Gleason grading

Low Grade
High Grade
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 Staging of tumor
Stage - Features
TNM: Staging of tumor: Lung Ca
T0 In-situ
T1 Primary site
TUMOR
T2 Sec. Anat. site
T3 Tertiary site
T4 Adjacent region
N0 No LN mets.
T4
NODE N1 Primary LN
N2 Seondary LN
N3 Tertiary LN T1
M0 No metastases
METASTASES

M1 Metastases +

Based on - ANATOMY & LYMPHATICS

 Staging of colon cancer

Pre-Cancer
 Cancer

Prostate Cancer Staging

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 Cancer diagnosis
Cancer diagnosis: e.g. Lung cancer.

• Cell of origin • Bronchial Epith.

• Rate of growth • Mitotic rate – grade.

Grade
• Low, Intermediate, high
• Differentiation
• Maturation of cells
• Well – Mod – Poor – Un diff.
• Local Invasion
• Tumour Stage.. 1,2,3,4.
• Metastasis
• Distant Spread..

Stage
DIAGNOSIS: (Lung cancer)
Bronchogenic Squamous cell Carcinoma, high grade,
Stage T2, N1, M1, Liver+ LN++ (in.. patient details..).
Thank you

Anger may be frozen

but the sun of forgiving
can make it melted

By Gede prama