7/27/2013

NEOPLASIA (TUMORS)

Topic
neoplasia
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

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

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

Do wn l o a d e d from: Rob bi ns &Co tra n Path ol og ic Ba si s of Dis ea se (o n 2 8 Ju ly 20 05 0 3:4 1 PM)

2 0 0 5 El se vi er

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Tumor

Nomenclature Malignant Tumors

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

Stalk

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

Colonic Polyp: Tubular Adenoma

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Tumors with mixed differentiation

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

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)

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

Do wn l o a d e d from: Rob bi ns &Co tra n Path ol og ic Ba si s of Dis ea se (o n 2 8 Ju ly 20 05 0 3:4 1 PM)

2 0 0 5 El se vi er

Natural History Of Malignant Tumors

1. Malignant change in the

target cell, referred to as
transformation
2. Growth of the transformed
cells

3.Local invasion
4. Distant metastases.

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Differentiation
Well differentiated neoplasm
Resembles mature cells of tissue of origin

Poorly differentiated neoplasm

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

Looking good means looking like the cells they supposedly arose from!

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

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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

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Features of Malignant Tumors

Cellular f eatures
Local

invasion

Capsule
Basement membrane

Metastasis
Unequivocal sign of malignancy
Seeding of body cavities
Lymphatic
Hematogenous

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Benign vs Malignant Features

Significance of Nodal Mets

Example of breast cancer
Halsted radical mastectomy
Sentinel node biopsy

Feature

Benign

Rate of growth

Progressive but
slow. Mitoses few
and normal
Well differentiated

LOCAL
INVASION

Variable. Mitoses
more frequent and
may be abnormal
Some degree of
anaplasia
Cohesive growth. Poorly cohesive
Capsule & BM
and
not breached

Metastasis

Absent

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

Malignant

Differentiation

infiltrative!
May occur

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Geographic & Environmental

Sun exposure
Melanomas 6x incidence New Zealand vs. Iceland

Blacks have low incidence of melanoma, so do

normally pigmented areas like areolae on white
people

Smoking and alcohol abuse

Body mass
Overweight = 50% increase in cancer

Environmental vs. racial factors

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

Age

Predisposing Factors for Cancer

Most cancers occur in persons 55 years

Childhood cancers
Leukemias & CNS neoplasms
Bone tumors

Genetic predispostion
Familial cancer syndromes

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?

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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

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

ONCOGENES
Are MUTATIONS of NORMAL genes
(PROTO-oncogenes)
Growth Factors
Growth Factor Receptors
Signal Transduction Proteins (RAS)
Nuclear Regulatory Proteins
Cell Cycle Regulators

INHIBITORS: Cip/Kip, INK4/ARF

Tumor (really growth) suppressor genes:

p53

Oncogenes code for

Oncoproteins

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Category

PROTOMode of
Oncogene Activation

Associated Human
Tumor

GFs
PDGF- chain SIS

Fibroblast
HST-1
growth factors
INT-2

Overexpression Astrocytoma
Osteosarcoma
Overexpression Stomach cancer
Amplification

Bladder cancer

TGF

Breast cancer
Melanoma
Overexpression Astrocytomas

HGF

HGF

Hepatocellular
carcinomas
Overexpression Thyroid cancer

Category

PROTOMode of
Oncogene Activation

TGF

Associated Human
Tumor

Signal
Transduction
Proteins
GTP-binding

K-RAS

Point mutation

Colon, lung, and pancreatic

tumors

H-RAS

Point mutation

Bladder and kidney tumors

N-RAS

Point mutation

Melanomas, hematologic
malignancies

Nonreceptor
ABL
tyrosine kinase

Translocation

Chronic myeloid leukemia

RAS signal
transduction

BRAF

Point mutation

Melanomas

WNT signal
transduction

-catenin

Point mutation

Hepatoblastomas,
hepatocellular carcinoma

Acute lymphoblastic leukemia

MYC
Encodes for transcription
factors
Also involved with apoptosis

PROTOMode of
Oncogene Activation

Category

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
PDGF receptor

RET

Point mutation

PDGF-R

Overexpression

Multiple endocrine neoplasia 2A

and B, familial medullary thyroid
carcinomas
Gliomas

Receptor for stem KIT

cell (steel) factor

Point mutation

Gastrointestinal stromal tumors

and other soft tissue tumors

Mode of
PROTOActivation Associated Human
Tumor
Category Oncogene
Nuclear
Regulatory
Proteins
Transcrip. C-MYC
Translocation Burkitt lymphoma
activators
N-MYC
Amplification Neuroblastoma,
small cell
carcinoma of lung
L-MYC
Amplification Small cell
carcinoma of lung

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

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Evasion of APOPTOSIS

BCL-2
p53
MYC

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

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

DNA REPAIR GENE DEFECTS

DNA repair is like a spell checker

HNPCC (Hereditary Non-Polyposis

LIMITLESS REPLICATIVE
POTENTIAL

Tumor (really GROWTH)

suppressor genes

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

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

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

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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

Malignancy

CHROMOSOME CHANGES
in CANCER

Translocation

Chronic myeloid leukemia

(9;22)(q34;q11)

Acute leukemias (AML and ALL)

(4;11)(q21;q23)

Affected Genes
Ab1 9q34
bcr 22q11

AF4 4q21
MLL 11q23

TRANSLOCATIONS and INVERSIONS

(6;11)(q27;q23)

AF6 6q27
MLL 11q23

Burkitt lymphoma

(8;14)(q24;q32)

Mantle cell lymphoma

(11;14)(q13;q32)

Follicular lymphoma

(14;18)(q32;q21)

T-cell acute lymphoblastic leukemia

(8;14)(q24;q11)

c-myc 8q24
IgH 14q32
Cyclin D 11q13
IgH 14q32

Occur in MOST Lymphomas/Leukemias

Occur in MANY (and growing numbers) of
NON-hematologic malignancies also

IgH 14q32
bcl-2 18q21
c-myc 8q24
TCR- 14q11

(10;14)(q24;q11)

Hox 11 10q24

TCR- 14q11
Ewing sarcoma

(11;22)(q24;q12)

Fl-1 11q24
EWS 22q12

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Carcinogenesis:
The USUAL (3) Suspects

Carcinogenesis is MULTISTEP
NO single oncogene causes cancer

Initiation/Promotion concept:

BOTH several oncogenes AND

several tumor suppressor genes must
be involved
Gatekeeper/Caretaker concept

BOTH initiators AND promotors are needed

NEITHER can cause cancer by itself

INITIATORS (carcinogens) cause

Gatekeepers: ONCOGENES and TUMOR

MUTATIONS
PROMOTORS are NOT carcinogenic by
themselves, and MUST take effect AFTER
initiation, NOT before

SUPPRESSOR GENES

Caretakers: DNA REPAIR GENES

Tumor PROGRESSION

PROMOTORS enhance the proliferation

ANGIOGENESIS
HETEROGENEITY from original single cell

of initiated cells

Q: WHO are the usual suspects?

Inflammation
?
Teratogenesi
s?
Immune
Suppression
?
Neoplasia?
Mutations?

A: The SAME 3 that are

ALWAYS blamed!

1) Chemicals
2) Radiation
3) Infectious
Pathogens

CHEMICAL CARCINOGENS:
DIRECT

INITIATORS
PROCARCINOGENS

Polycyclic and
-Propiolactone
Heterocyclic Aromatic
Dimeth. sulfate
Hydrocarbons
Diepoxybutane
Aromatic Amines,
Anticancer drugs
Amides, Azo Dyes
(cyclophosphamide,
Natural Plant and
chlorambucil,
Microbial Products
nitrosoureas, and
Aflatoxin B1 Hepatomas
others)
Griseofulvin Antifungal
Acylating Agents

1-Acetyl-imidazole
Dimethylcarbamyl
chloride

Cycasin from cycads

Safrole from sassafras

Betel nuts Oral SCC

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CHEMICAL CARCINOGENS:

CHEMICAL CARCINOGENS:

INITIATORS

PROMOTORS

OTHERS
Nitrosamine and amides (tar, nitrites)
Vinyl chloride angiosarcoma in
Kentucky
Nickel
Chromium
Insecticides
Fungicides
PolyChlorinated Biphenyls (PCBs)

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

Initiated cells respond and proliferate

FASTER to promotors than normal cells

VIRAL CARCINOGENESIS

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

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

H. pylori CARCINOGENESIS

HOST DEFENSES
IMMUNE SURVEILLENCE CONCEPT

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

Gastric CARCINOMAS also!

CD8+ T-Cells
NK cells
MACROPHAGES
ANTIBODIES

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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

CYTOTOXIC CD8+ T-CELLS are the main eliminators of tumor cells

Immunosuppressive agents
Antigen masking
Apoptosis of cytotoxic T-Cells (CD8),

CACHEXIA

Effects of TUMOR on the HOST

Location anatomic ENCROACHMENT

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

Reduced diet: Fat loss>Muscle

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

ENDOCRINE

PARA-Neoplastic Syndromes

Endocrine

Cushing syndrome

(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

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/lymph o ma
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

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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 Carcinoma

ADENOCARCINOMA GRADING
Lets have some FUN!

LAB DIAGNOSIS
BIOPSY
CYTOLOGY: (exfoliative)
CYTOLOGY: (FNA, Fine
Needle Aspirate)

TUMOR MARKERS

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

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 immunochemical methods in tissue

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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?

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