Neoplasia

NEOPLASIA (TUMORS)

Definitions
Nomenclature
Biology of Tumor Growth
Epidemiology
Molecular Basis of Cancer
Molecular Basis of Carcinogenesis
Agents (The Usual Suspects)
Host Defense (Tumor Immunity)
Clinical Features of Tumors

Defnition of Neoplasia
A neoplasm is an abnormal mass of tissue, the
growth of which exceeds and is
uncoordinated with that of the normal tissues
and persists in the same excessive manner
after cessation of the stimuli which evoked
the change - Willis
Genetic changes
Autonomous
Clonal

Nomenclature Benign Tumors

-oma = benign neoplasm (NOT carcin-, sarc-, lymph-,

or melan-)
Mesenchymal tumors (mesodermal derived)

chrondroma: cartilaginous tumor

fibroma: fibrous tumor
osteoma: bone tumor

Epithelial tumor (ecto- or endo- derived)

adenoma: tumor forming glands

papilloma: tumor with finger like projections
papillary cystadenoma: papillary and cystic tumor forming
glands
polyp: a tumor that projects above a mucosal surface

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2005 Elsevier

Tumor

Stalk

Colonic Polyp: Tubular

Nomenclature Malignant Tumors

Sarcomas: mesenchymal tumor

chrondrosarcoma: cartilaginous tumor
fibrosarcoma: fibrous tumor
osteosarcoma: bone tumor

Carcinomas: epithelial tumors

adenocarcinoma: gland forming tumor
squamous cell carcinoma: squamous differentiation
undifferentiated carcinoma: no differentiation
note: carcinomas can arise from ectoderm,
endoderm, or less likely, mesoderm

Tumors with mixed differentiation

Teratoma

tumor comprised of cells from more than one germ layer

arise from totipotent cells (usually gonads)
benign cystic teratoma of ovary is the most common teratoma

Aberrant differentiation (not true neoplasms)

mixed tumors: e.g. pleomorphic adenoma of salivary gland

carcinosarcoma

Hamartoma: disorganized mass of tissue whose cell types are

indiginous to the site of the lesion, e.g., lung
Choriostoma: ectopic focus of normal tissue (heterotopia),
e.g., pancreas, perhaps endometriosis too

Misnomers

hepatoma: malignant liver tumor

melanoma: malignant skin tumor
seminoma: malignant testicular tumor
lymphoma: malignant tumor of lymphocytes

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2005 Elsevier

Natural History Of Malignant Tumors

1.

2.

Malignant change in the target

cell, referred to as transformation
Growth of the transformed cells

3. Local invasion
4.

Distant metastases.

Differentiation

Well differentiated neoplasm

Poorly differentiated neoplasm

Resembles mature cells of tissue of origin

Composed of primitive cells with little
differentiation

Undifferentiated or anaplastic tumor

Correlation with biologic behavior
Benign tumors are well differentiated
Poorly differentiated malignant tumors usually
have worse prognosis than well differentiated
malignant tumors.

If cells LOOK

BAD, they are probably going to BEHAVE BAD

Looking bad means NOT looking like the cells

they supposedly arose from!

If cells

LOOK GOOD, they are probably going to BEHAVE

GOOD

ANAPLASIA = CANCER
***Pleomorphism

Size
shape

Abnormal nuclear morphology

***Hyperchromasia
High nuclear cytoplasmic ratio
Chromatin clumping
Prominent nucleoli
Mitoses

Mitotic rate
Location of mitoses

Loss of polarity

Dysplasia

Literally means abnormal growth

Malignant transformation is a multistep process
In dysplasia some but not all of the features of
malignancy are present, microscopically
Dysplasia may develop into malignancy

Uterine cervix
Colon polyps

Graded as low-grade or high-grade, often prompting

different clinical decisions
Dysplasia may NOT develop into malignancy
HIGH grade dysplasia often classified with CIS

Tumor Growth Rate

Doubling time of tumor cells

Lengthens as tumor grows
30 doublings (109 cells) = 1 g
(months to years)
10 more doublings (1 kg) = lethal burden
()

Fraction of tumor cells in replicative pool

May be only 20% even in rapidly growing tumors
Tumor stem cells

Rate at which tumor cells are shed or lost

Apoptosis
Maturation

Implications for therapy

clonal

Schematic Representation Of Tumor

Growth

Features of Malignant Tumors

Cellular features

Local

invasion

Capsule
Basement membrane

Metastasis
Unequivocal sign of malignancy
Seeding of body cavities
Lymphatic
Hematogenous

Significance of Nodal Mets

Example of breast cancer

Halsted radical mastectomy
Sentinel node biopsy

Prognostic

Number of involved nodes is an important

component of TNM staging system

Therapeutic

Overall risk of recurrence

Extent of nodal involvement
Histologic grade and other considerations

Adjuvant chemotherapy

Benign vs Malignant Features

Feature

Benign

Malignant

Rate of growth

Progressive but
slow. Mitoses few
and normal

Variable. Mitoses
more frequent and
may be abnormal

Differentiation

Well differentiated Some degree of

anaplasia

LOCAL
INVASION

Cohesive growth. Poorly cohesive

Capsule & BM
and
not breached
infiltrative!

Metastasis

Absent

infiltrative!

May occur

Geographic & Environmental

Sun exposure

Smoking and alcohol abuse

Body mass

Overweight = 50% increase in cancer

Environmental vs. racial factors

Melanomas 6x incidence New Zealand vs. Iceland

Blacks have low incidence of melanoma, so do normally
pigmented areas like areolae on white people

Japanese immigrants to USA

Viral exposure

Human papilloma virus (HPV) and cervical cancer

Hepatitis B virus (HBV) and liver cancer (Africa, Asia)
Epstein-Barr Virus (EBV) and lymphoma

Change In Incidence Of Various Cancers With

Migration From Japan To The United States

Predisposing Factors for Cancer

Age

Most cancers occur in persons 55 years

Childhood cancers

Genetic predispostion

Familial cancer syndromes

Leukemias & CNS neoplasms

Bone tumors

Early age at onset

Two or more primary relatives with the cancer (soil theory)
Multiple or bilateral tumors

Polymorphisms that metabolize procarcinogens, e.g., nitrites

Nonhereditary predisposing conditions

Chronic inflammation?
Precancerous conditions

Chronic ulcerative colitis

Atrophic gastritis of pernicious anemia
Leukoplakia of mucous membranes
Immune collapse?

Defnition of Neoplasia
A neoplasm is an abnormal mass of tissue, the growth
of which exceeds and is uncoordinated with that of
the normal tissues and persists in the same excessive
manner after cessation of the stimuli which evoked
the change - Willis

Genetic changes
Autonomous
Clonal

MOLECULAR BASIS
of CANCER
NON-lethal genetic damage
A tumor is formed by the clonal expansion
of a single precursor cell (monoclonal)
Four classes of normal regulatory genes

PROTO-oncogenes
Oncogenes Oncoproteins
DNA repair genes
Apoptosis genes

Carcinogenesis is a multistep process

TRANSFORMATION &
PROGRESSION
Self-sufficiency in growth signals
Insensitivity to growth-inhibiting signals
Evasion of apoptosis
Defects in DNA repair: Spell checker
Limitless replicative potential: Telomerase
Angiogenesis
Invasive ability
Metastatic ability

Normal CELL CYCLE Phases

INHIBITORS: Cip/Kip, INK4/ARF

Tumor (really growth) suppressor

ONCOGENES

Are MUTATIONS of NORMAL genes

(PROTO-oncogenes)
Growth Factors
Growth Factor Receptors
Signal Transduction

Proteins (RAS)
Nuclear Regulatory Proteins
Cell Cycle Regulators

Oncogenes code for Oncoproteins

Category

PROTOOncogene

Mode of
Activation

Associated Human
Tumor

GFs
PDGF- chain SIS
Fibroblast
HST-1
growth factors
INT-2

TGF

HGF

Overexpression Astrocytoma
Osteosarcoma
Overexpression Stomach cancer
Amplification

Bladder cancer

TGF

Breast cancer
Melanoma
Overexpression Astrocytomas

HGF

Hepatocellular
carcinomas
Overexpression Thyroid cancer

Category

PROTOOncogene

Mode of
Activation

Associated Human
Tumor

GF
Receptors
EGF-receptor
family

ERB-B1
(ECFR)

Overexpression

Squamous cell carcinomas of

lung, gliomas

ERB-B2

Amplification

Breast and ovarian cancers

CSF-1 receptor

FMS

Point mutation

Leukemia

Receptor for
neurotrophic
factors

RET

Point mutation

Multiple endocrine neoplasia 2A

and B, familial medullary thyroid
carcinomas

PDGF receptor

PDGF-R

Overexpression

Gliomas

Receptor for stem

cell (steel) factor

KIT

Point mutation

Gastrointestinal stromal tumors

and other soft tissue tumors

Category

PROTOOncogene

Mode of
Activation

Associated Human
Tumor

Signal
Transduction
Proteins
GTP-binding

Nonreceptor
tyrosine kinase

K-RAS

Point mutation

Colon, lung, and pancreatic

tumors

H-RAS

Point mutation

Bladder and kidney tumors

N-RAS

Point mutation

Melanomas, hematologic
malignancies

ABL

Translocation

Chronic myeloid leukemia

Acute lymphoblastic leukemia

RAS signal
transduction

BRAF

Point mutation

Melanomas

WNT signal
transduction

-catenin

Point mutation

Hepatoblastomas,
hepatocellular carcinoma

Category
Nuclear
Regulatory
Proteins

PROTOOncogene

Mode of
Activation

Associated Human
Tumor

Transcrip. C-MYC
activators

Translocation Burkitt lymphoma

N-MYC

Amplification Neuroblastoma,
small cell
carcinoma of lung

L-MYC

Amplification Small cell

carcinoma of lung

MYC
Encodes for transcription factors
Also involved with apoptosis

P53 and RAS

p53

Activates DNA repair

proteins
Sentinel of G1/S
transition
Initiates apoptosis
Mutated in more than
50% of all human
cancers

RAS

H, N, K, etc., varieties
Single most common
abnormality of
dominant oncogenes in
human tumors
Present in about 1/3 of
all human cancers

Tumor (really GROWTH)

suppressor genes

TGF- COLON
E-cadherin STOMACH
NF-1,2 NEURAL TUMORS
APC/-cadherin GI, MELANOMA
SMADs GI
RB RETINOBLASTOMA
P53 EVERYTHING!!
WT-1 WILMS TUMOR
p16 (INK4a) GI, BREAST (MM if inherited)
BRCA-1,2 BREAST
KLF6 PROSTATE

Evasion of APOPTOSIS

BCL-2
p53
MYC

DNA REPAIR GENE DEFECTS

DNA repair is like a spell checker

HNPCC (Hereditary Non-Polyposis Colon

Cancer [Lynch]): TGF-, -catenin, BAX

Xeroderma Pigmentosum: UV fixing gene
Ataxia Telangiectasia: ATM gene
Bloom Syndrome: defective helicase
Fanconi anemia

LIMITLESS REPLICATIVE
POTENTIAL
TELOMERES determine the limited

number of duplications a cell will

have, like a cat with nine lives.
TELOMERASE, present in >90% of
human cancers, changes telomeres so
they will have UNLIMITED
replicative potential

TUMOR ANGIOGENESIS

Q: How close to a blood vessel must a cell be?

A: 1-2 mm

Activation of VEGF and FGF-b

Tumor size is regulated (allowed) by

angiogenesis/anti-angiogenesis balance

TRANSFORMATION
GROWTH
BM INVASION
ANGIOGENESIS
INTRAVASATION
EMBOLIZATION
ADHESION
EXTRAVASATION
METASTATIC GROWTH
etc.

Invasion Factors
Detachment ("loosening up") of

the tumor cells from each other

Attachment to matrix components
Degradation of ECM, e.g.,
collagenase, etc.
Migration of tumor cells

METASTATIC GENES?
NM23
KAI-1
KiSS

CHROMOSOME CHANGES
in CANCER

TRANSLOCATIONS and INVERSIONS

Occur in MOST Lymphomas/Leukemias

Occur in MANY (and growing numbers) of NONhematologic malignancies also

Malignancy

Translocation

Affected Genes

Chronic myeloid leukemia

(9;22)(q34;q11)

Ab1 9q34

bcr 22q11

Acute leukemias (AML and ALL)

(4;11)(q21;q23)

AF4 4q21

MLL 11q23

(6;11)(q27;q23)

AF6 6q27

MLL 11q23

Burkitt lymphoma

(8;14)(q24;q32)

c-myc 8q24

IgH 14q32

Mantle cell lymphoma

(11;14)(q13;q32)

Cyclin D 11q13

IgH 14q32

Follicular lymphoma

(14;18)(q32;q21)

IgH 14q32

bcl-2 18q21

T-cell acute lymphoblastic leukemia

(8;14)(q24;q11)

c-myc 8q24

TCR- 14q11

(10;14)(q24;q11)

Hox 11 10q24

TCR- 14q11

Ewing sarcoma

(11;22)(q24;q12)

Fl-1 11q24

Carcinogenesis is MULTISTEP

NO single oncogene causes cancer

BOTH several oncogenes AND several

tumor suppressor genes must be involved
Gatekeeper/Caretaker concept

Gatekeepers: ONCOGENES and TUMOR

SUPPRESSOR GENES
Caretakers: DNA REPAIR GENES

Tumor PROGRESSION
ANGIOGENESIS
HETEROGENEITY from original single cell

Carcinogenesis:
The USUAL (3) Suspects
Initiation/Promotion concept:
BOTH initiators AND promotors are needed
NEITHER can cause cancer by itself

INITIATORS (carcinogens) cause

MUTATIONS
PROMOTORS are NOT carcinogenic by
themselves, and MUST take effect AFTER
initiation, NOT before
PROMOTORS enhance the proliferation of

initiated cells

Q: WHO are the usual suspects?

Inflammation?
Teratogenesis?
Immune
Suppression?
Neoplasia?
Mutations?

A: The SAME 3 that are

ALWAYS blamed!
1)

Chemicals
2) Radiation
3) Infectious Pathogens

CHEMICAL CARCINOGENS:
INITIATORS
PROCARCINOGENS

DIRECT

-Propiolactone
Dimeth. sulfate

Diepoxybutane
Anticancer drugs

(cyclophosphamide,
chlorambucil,
nitrosoureas, and others)
Acylating Agents

1-Acetyl-imidazole
Dimethylcarbamyl chloride

Polycyclic and Heterocyclic

Aromatic Hydrocarbons
Aromatic Amines, Amides,
Azo Dyes
Natural Plant and Microbial
Products

Aflatoxin B1 Hepatomas
Griseofulvin Antifungal
Cycasin from cycads
Safrole from sassafras
Betel nuts Oral SCC

CHEMICAL CARCINOGENS:
INITIATORS

OTHERS

Nitrosamine and amides (tar, nitrites)

Vinyl chloride angiosarcoma in Kentucky
Nickel
Chromium
Insecticides
Fungicides
PolyChlorinated Biphenyls (PCBs)

CHEMICAL CARCINOGENS:
PROMOTORS

HORMONES
PHORBOL ESTERS (TPA), activate kinase C
PHENOLS
DRUGS, many

Initiated cells respond and

proliferate FASTER to
promotors than normal cells

RADIATION CARCINOGENS
UV: BCC, SCC, MM (i.e., all 3)
IONIZING: photons and particulate
Hematopoetic and Thyroid (90%/15yrs) tumors
in fallout victims
Solid tumors either less susceptible or require a
longer latency period than LEUK/LYMPH
BCCs in Therapeutic Radiation

VIRAL CARCINOGENESIS

HPV SCC
EBV Burkitt Lymphoma
HBV HepatoCellular Carcinoma (Hepatoma)
HTLV1 T-Cell Malignancies
KSHV Kaposi Sarcoma

H. pylori CARCINOGENESIS

100% of gastric lymphomas (i.e., M.A.L.T.-omas)

Gastric CARCINOMAS also!

HOST DEFENSES

IMMUNE SURVEILLENCE CONCEPT

CD8+ T-Cells
NK cells
MACROPHAGES
ANTIBODIES

CYTOTOXIC CD8+ T-CELLS are the main eliminators

How do tumor cells

escape immune surveillance?

Mutation, like microbes

MHC molecules on tumor cell surface

Lack of CO-stimulation molecules, e.g.,
(CD28, ICOS), not just Ag-Ab recognition
Immunosuppressive agents
Antigen masking
Apoptosis of cytotoxic T-Cells (CD8), i.e.,
the damn tumor cell KILLS the T-cell!

Effects of TUMOR on the HOST

Location anatomic ENCROACHMENT

HORMONE production
Bleeding, Infection
ACUTE symptoms, e.g., rupture, infarction
METASTASES

CACHEXIA
Reduced diet: Fat loss>Muscle loss
Cachexia: Fat loss AND Muscle loss
TNF ( by default)
IL-(6)
PIF (Proteolysis Inducing Factor)

PARA-Neoplastic Syndromes

Endocrine (next)
Nerve/Muscle, e.g., myasthenia w. lung ca.
Skin: e.g., acanthosis nigricans,
dermatomyositis
Bone/Joint/Soft tissue: HPOA (Hypertrophic
Pulmonary OsteoArthropathy)
Vascular: Trousseau, Endocarditis
Hematologic: Anemias
Renal: e.g., Nephrotic Syndrome

ENDOCRINE
Cushing syndrome

Small cell carcinoma of lung

ACTH or ACTH-like substance

Pancreatic carcinoma

Neural tumors

Syndrome of inappropriate
antidiuretic hormone
secretion

Small cell carcinoma of lung;

intracranial neoplasms

Antidiuretic hormone or atrial

natriuretic hormones

Hypercalcemia

Squamous cell carcinoma of lung

Parathyroid hormone-related protein

(PTHRP), TGF-, TNF, IL-1

Breast carcinoma

Renal carcinoma

Adult T-cell leukemia/lymphoma

Ovarian carcinoma

Hypoglycemia

Fibrosarcoma

Insulin or insulin-like substance

Other mesenchymal sarcomas

Hepatocellular carcinoma

Carcinoid syndrome

Bronchial adenoma (carcinoid)

Serotonin, bradykinin

Pancreatic carcinoma

Gastric carcinoma

Polycythemia

Renal carcinoma

Erythropoietin

Cerebellar hemangioma

Hepatocellular carcinoma

GRADING/STAGING
GRADING:

HOW
DIFFERENTIATED ARE THE
CELLS?
STAGING: HOW MUCH
ANATOMIC EXTENSION? TNM
Which one of the above do you
think is more important?

WELL?
(pearls)

MODERATE?
(intercellular bridges)

POOR?
(WTF!?!)

GRADING for Squamous Cell

ADENOCARCINOMA GRADING
Lets have some FUN!

LAB DIAGNOSIS
BIOPSY
CYTOLOGY: (exfoliative)
CYTOLOGY: (FNA,

Needle Aspirate)

Fine

IMMUNOHISTOCHEMISTRY
Categorization

of
undifferentiated tumors
Leukemias/Lymphomas
Site of origin
Receptors, e.g., ERA, PRA

TUMOR MARKERS

HORMONES: (Paraneoplastic Syndromes)

ONCOFETAL: AFP, CEA
ISOENZYMES: PAP, NSE
PROTEINS: PSA, PSMA (M = membrane)
GLYCOPROTEINS: CA-125, CA-195, CA-153
MOLECULAR: p53, RAS
NOTE: These SAME substances
which can be measured in the
blood, also can be stained by

MICRO-ARRAYS
THOUSANDS of genes
identified from tumors give
the cells their own identity
and FINGERPRINT and may
give important prognostic
information as well as
guidelines for therapy. Some
say this may replace standard
histopathologic identifications
of tumors.

What do you think?

THANK YOU