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Page 1 of 9

1.5 NEOPLASIA
PATHOLOGY


NEOPLASIA
New growth
It is def ined as abnormal mass of tissue, the growth of which
exceeds and is uncoordinated with that of the normal tissue
and persists in the same manner af ter cessation of stimuli
which evoked the change
Cancer- common term to all malignancies
All neoplasms ultimately depends on the host f or their nutrition
and vascular supply.
Two basic components of Neoplasia:
1. Prolif erating neoplastic cell-parenchyma
2. Supportive stroma- connective tissue and blood vessels.
INCIDENCE & MORTALITY DATA
10.1 Million new cases
6.2 Million deaths
22.4 Million living with Cancer year 2005
Increase of 19% in incidence
Increase of 18% in mortality since 1990

MOST COMMON CANCER CAUSING DEATH
Lung 17.8 %
Stomach 10.4 %
Liver 8.8 %

MOST COMMON CANCER WORLDWIDE
Lung Cancer 12.3 %
Breast Cancer
Prostate Cancer
10.4 %
Colorectum 9.4 %

NOMENCLATURE
Parenchyma Prolif erating neoplastic cells
Stroma Connective tissue and blood vessels

Benign Tumors
suf f ix oma
Malignant Tumors
2 broad categories:
Carcinomas - epithelial cells
sarcomas - mesenchymal tissues
Some tumors with more than one parenchymal cell type: mixed
tumors & teratomas
Two non-neoplastic lesions bear the names that are
deceptively similar to tumors: choristomas & hamartomas
CLASSIFICATION OF NEOPLASMS
A. Site
B. Biologic Behavior benign, borderline, malignant
C. Cell ( tissue of origin )
D. Embryologic derivation
E. Dif f erentiation potential of cell of origin totipotent cell
F. Etiology
Tumors are classif ied to 2 broad categories: benign and
malignant.
BENIGN MALIGNANT
Slow growing Rapidly growing
Encapsulated Not encapsulated
No inf iltration/Expansile growth Inf iltrative growth
No metastasis Metastasis
Well dif f erentiated Well-poorly dif f erentiated
High patient survival af ter
successf ul surgical removal
Poor patient survival rate;
tendency f or local and distant
recurrence

BENIGN MALIGNANT
GROSS FEATURES
Smooth surf ace with a f ibrotic
capsule; compress surrounding
tissue
Irregular surf ace without
encapsulation; destruction to
surrounding tissue
Slow rate of growth Rapid rate of growth
Rarely f atal Usually f atal
Small to large Small to large
MICROSCOPIC
Growth by compression Growth by invasion
Highly dif f erentiated Well or poorly dif f erentiated
Cell similar to normal and
resembling to one another
-Cytologic abnormalities
(Pleiomorphism)
- Anaplasia (Morphologic
HALLMARK of malignancy)
No mitosis With mitosis
Well f ormed blood vessel Poorly f ormed and numerous
blood vessel
(-) Necrosis/Hemorrhage
(-) Metastasis
(+) Necrosis & Hemorrhage
(+) Metastasis
INVESTIGATIVE TECHNIQUE
DNA content usually normal DNA content of cells usually
increased
Karyotype normal Aneuploidy
Polyploidy
Clonal Genetic
Abnormality


Fig1. Comparison of Leiomyoma & Leiomyosarcoma

Fig 2. Choristoma: Ectopic rest of normal tissue









Fig 3 & 4. Hamartoma: mass of disorganized but mature
specialized cells or tissue native to the particular site
BENIGN TUMORS

Cell of origin + OMA
Adenoma Benign tumor arising f rom glandular cells
Leiomyoma Benign tumor arising f rom smooth muscle cells
Chrondroma Benign tumor arising f rom chondrocytes
Papilloma Has f inger-like projections
Polyp Projects upward, f orming a lump
Cystadenoma Has hollow spaces (cysts) inside










Fig 5 & 6. Tubular adenoma, colon








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1.5 NEOPLASIA

Pathology










Fig 7. Papillomas: architecture f inger like projections














Fig 8 & 9. Polyp: macroscopic projection of mucosal surf ace
MALIGNANT NEOPLASMS
Malignant tumors:
Dif f erentiation and anaplasia
Dysplasia
Rapid rate of growth
Widespread invasion
Metastases
Carcinomas arise in epithelial tissue
Adenocarcinoma malignant tumor of glandular cells
Squamous cell carcinoma malignant tumor of
squamous cells
Sarcomas arise in mesenchymal tissue
Chrondrosarcoma Malignant tumor of
chondrocytes
Angiosarcoma Malignant tumor of blood vessels
Rhabdomyosarcoma Malignant tumor of skeletal
muscle cells
ANAPLASIA
Lack of dif f erentiation
Hallmark of malignant transf ormation
Numerous morphologic changes












Fig 10. Pleomorphism: variation in size and shape











Fig 11. Abnormal nuclear morphology: hyperchormatic
(abundant DNA), increased N:C ratio (normal 1:4- 1:6)











Fig 12. Mitoses: Increased, bizarre











Fig 13. Loss of polarity










Fig 14. Tumor giant cells
















Fig 15 & 16. Dysplasia : Disordered growth
CELL (TISSUE OF ORIGIN)
I. Composed of One Parenchymal Cell type:
A. Epithelial
B. Mesenchymal
II. More than one Neoplastic Cell Type derived f rom one germ layer:
A. Salivary Gland
B. Breast
C. Renal Anlage
III. More than one Neoplastic Cell Type derived f rom more than one germ
layer: Teratoma

TISSUE OF ORIGIN BENIGN MALIGNANT
Mesenchymal/
connective tissue
Fibroma
Lipoma
Chondroma
Osteoma
Fibrosarcoma
Liposarcoma
Chondrosarcoma
Osteogenic sarcoma
Endothelial & relaxed
tissue
Hemangioma
Lymphangioma
Meningioma
Angiosarcoma
Lymphangiosarcoma
Synovial sarcoma
Mesothelioma
Invasive meningioma
Hematopoietic Leukemias
Lymphoma
Muscle Leiomyoma
Rhabdomyoma
Leiomyosarcoma
Rhabdomyosarcoma
Epithelial Squamous papilloma
Adenoma
Papilloma
Cystadenoma
Bronchial adenoma
Renal tubular
adenoma
Liver cell adenoma
Transititonal cell
papilloma
Hydatif orm mole
SCC or epidermoid
CA
BCC
Adenocarcinoma
Papillary carcinoma
Cystadenocarcinoma
Bronchogenic
carcinoma
Renal cell carcinoma
Transitional cell
carcinoma
Choriocarcinoma
Seminoma
Embryonal CA
Melanocytes

Nevus

Malignant Melanoma


MIXED TUMOR
Mixed tumors show divergent dif ferentiation
Examples
o Pleiomorphic adenoma glands + f ibromyoid stroma
Teratomas



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1.5 NEOPLASIA

Pathology
MORE THAN ONE NEOPLASTIC CELL MIXED
Salivary gland Pleomorphic
Adenoma
Malignant mixed
tumor of salivary
gland origin
Renal Wilms tumor
TERATOGENOUS (FROM MORE THAN ONE GERM CELL LAYER)
Totipotential cells Mature
teratoma/dermoid cyst
Immature tertoma,
teratocarcinoma

CONFUSING TERMS
Malignant tumors that sound benign
o Lymphoma
o Mesothelioma
o Melanoma
o Seminoma
Non tumors that sound like tumors
o Hamartoma mass of disorganized indigenous
tissue
o Choristoma Heterotopic rest of cells
Names that seem to come out of nowhere
o Nevus
o Leukemia
o Hyatidif orm mole
BORDERLINE TUMORS
Variable growth rate
Locally inf iltrative
Low or no metastatic potential
Intermediate patient survival rate; tendency f or local recurrence
af ter successful surgical removal
INTACT BASEMENT MEMBRANE
PRE-MALIGNANT (PRE CANCEROUS) LESIONS
A. Hyperplasia
-Endometrial Hyperplasia
-Lobular and Ductal Hyperplasia
-Cirrhosis of the liver
B. Dysplasia
C. Metaplasia
-Barrets Esophagus
D. Inf lammatory Lesions
-Ulcerative Colitis, Atrophic Gastritis
-Autoimmune (Hashimotos) Thyroiditis
E. Benign neoplasms
- Colonic Adenoma
MECHANISMS & CAUSES OF NEOPLASIA
At MOLECULAR LEVEL , neoplasia is def ined as disorder of growth
regulatory genes ( proto-oncogenes and tumor suppressor genes ).
Origin of Neoplasia:
Monoclonal Origin
Field Origin
MONOCLONAL THEORY
- The initial neoplastic change af f ects a single cell, which then
multiplies and give rise to neoplasm.
FIELD THEORY
- A carcinogenic agent acting on a large number of similar cells may
produce a f iled potentially neoplastic cells. Then neoplasms may then
arise f rom one or more cells within this f ield.
MOLECULAR BASIS OF CANCER
Inherited cancer syndrome, usually involving germ-line mutation in
tumor suppressor or DNA repair genes, accounts f or 4 % of all
Cancer
Genetic susceptibility signif icantly alter the risk f rom environmental
exposures
Fundamental Principles:
Non-lethal genetic damage lies at the heart of carcinogenesis.
A tumor is f ormed by the clonal expansion of a single precursor
cell that has incurred genetic damage.
Carcinogenesis is a multistep process hence multiple
mutations.
The 7 key changes are the f f : (Essentials f or malignant
transf ormation)
Self -suf ficiency in growth signals
Insensitivity to growth inhibitory signals
Evasion of apoptosis
Limitless replicative potential
Sustained angiogenesis
Ability to invade and metastasize
Def ects in DNA repair






















Fig 17. Events in neoplastic transf ormation
Oncogenes and Cancer
Oncogenes
Proto-oncogenes
Protein products of Oncogenes
Activation of Oncogenes
Point mutations
Chromosomal rearrangements
Gene amplifications
Oncogenes are genes capable of causing cancer.
The genes are activated by mutation, amplif ication, or
translocation. Activation can lead to the loss of normal
regulation and dif f erentiation, increased prolif eration.
Activation is the f unctional concept whereby the normal
action of growth regulation is diverted into oncogenesis.
Mechanisms of Occurrence:
1. Mutation
2. Translocation
3. Insertion
MOLECULAR BASIS OF NEOPLASIA
Basic underlying cause of cancer:
DISORDER IN THE GROWTH REGULATORY GENE
Four kinds of normal genes are damaged:
1. Genes that promote growth (protooncogenes)
2. Genes that inhibit growth (tumor-suppressor genes)
3. Genes that regulate apoptosis
4. Genes involved in DNA repair
Cancers develop in multiple steps


















Fig.18 Transf ormation of Neoplasia
HALLMARKS OF CANCER






















Fig. 19. Hallmarks of Cancer



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1.5 NEOPLASIA

Pathology
GROWTH FACTOR SIGNALING PATHWAYS IN CANCER


























Fig 20. Growth Factor Signaling pathways in Cancer
















Fig 21. Escape f rom senescence and mitotic catastrophe
SELF RENEWING CAPACITY IN CANCER CELLS

PATHOGENESIS IN RETINOBLASTOMA





















Fig 22.Retinoblastoma Pathogenesis
EVASION OF IMMUNE SURVEILLANCE
Dif f erent classes of tumor antigens are products of :
1. Mutated proto-oncogenes
2. Tumor suppressor genes
3. Overexpressed or aberrantly expressed proteins
4. Tumor antigens produced by oncogenic viruses
5. Oncof etal antigens
6. Altered glycolipids and glycoproteins
7. Cell types specif ic dif f erentiation antigens
Tumors may avoid the immune system by:
1. Selective outgrowth of antigen negative variants
2. Loss or reduced expression of histocompatibility antigens
3. Immunosuppression mediated by expression of certain f actors
(ex. TGF-B, PD-1 ligand, galectins) by the tumor cells.



HOST DEFENSE AGAINST TUMOR IMMUNITY

Fig 23. Tumor antigens recognized by CD8+ T cells


Fig.24. Mechanisms by which tumors evade the immune system.
GENETIC LESIONS IN CANCER
Oncogenic mutations, including point mutations and other
nonrandom chromosomal abnormalities, such as
translocations, deletions, and gene amplif ications.
Balanced translocations.
Deletions
Gene amplif ication
Numerous cryptic (subcytogenetic) rearrangements.
TUMOR EVOLUTION

Fig 25.















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1.5 NEOPLASIA

Pathology
MOLECULAR MODEL FOR CANCER EVOLUTION

Fig 26. Molecular model f or the evolution of colorectal cancers
through the adenoma-carcinoma sequence.

Each cancer must result f rom the accumulation of multiple
mutations.
CARCINOGENIC AGENTS AND THEIR CELLULAR INTERACTIONS
Steps involved in Chemical Carcinogenesis
1. Initiation results f rom exposure of cells to a suf f icient dose of a
carcinogenic agent. (initiator)
2. Initiation causes permanent DNA damage. (mutations)
3. Promoters can induce tumors in initiated cells, but they are non
tumorigenic by themselves.
CHEMICAL CARCINOGENESIS
Chemical carcinogens have highly reactive electrophile groups
that directly damage DNA, leading to mutations and eventually
cancer.
Direct acting agents do not require metabolic conversion to
become carcinogenic.
Indirect-acting agents arent active until converted to an
ultimate carcinogen by endogenous metabolic pathways.
DEVELOPMENT OF A CANCER

Fig 27. Tumor progression and generation of heterogeneity.
CARCINOGENIC AGENTS AND THEIR CELLULAR INTERACTIONS
Radiation Carcinogenesis
o UV rays
o Ionizing radiation
Microbial Carcinogenesis
o Onconegenic RNA viruses
Human T cell Leukemia Virus Type I
o Onconegenic DNA viruses
Human papilloma virus
Epstein Barr virus
Hepatitis B & C virus
Bacterial Carcinogenesis
o Helicobacter pylori
RADIATION CARCINOGENESIS
Ionizing radiation causes chromosome breakage,
translocations, band, less f requently, point mutations, leading
tobgenetic damage and carcinogenesis. (X-rays, gamma rays,
alpha, beta, positrons, protons, neutrons and primary cosmic
radiation)
UV rays induce f ormation of pyrimidine dimers within DNA,
leading to mutations.
GENES CANCER GENES
Autonomous growth
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
Invasion and metastasis
PROTO-ONCOGENES (CELLULAR ONCOGENES)
Code f or a variety of growth f actors, receptors, and signal-relay
or transcription f actors which act in concert to control entry into
the cell cycle.
PROTO-ONCOGENES code f or a number of protein products
(growth f actors, kinases, etc). The expression is well controlled,
playing a role in normal growth and development.
o Normal cellular genes whose products promote cell
prolif eration.
Ras- proto-oncogene: a G protein def ect.
SRC proto-oncogene: tyrosine kinase def iciency.
Sis proto-oncogene: platelet derived growth f actor receptor
def ect.
Erb B proto-oncogene- epidermal growth f actor receptor defect.
Myc (c-myc, n-myc, l-myc) proto-oncogenes- nuclear f actors.
HER-2/neu over expression in 15-30% of pts with breast
cancer.
LiFraumeni syndrome: def ect in p53 gene. Patients get
childhood sarcomas, breast cancer, brain tumors, leukemia,
adrenal cancer.
Medullary thyroid cancer: associated with Ret proto-oncogene
on chr 10. Patients with Ret oncogene def ect plus f amily
history- 90% get medullary cancer of thyroid, need total
thyroidectomy.
MENIN a product of MEN1 gene also associated with
medullary cancer of thyroid.
ONCOPROTEIN: A protein encoded by an oncogene that
drives increased cell prolif eration through one of several
mechanisms.
ONCOGENES: Mutated or overexpressed versions of proto-
oncogenes that f unction autonomously.
ONCOGENES, THEIR MOA & ASSOCIATED HUMAN TUMORS

CATEGORY PROTOCONCOGENES MECHANISM A.TUMOR
Growth f actors
PDGF- chain

sis

Ov erexpression Astrocy toma
Growth Factor Receptors

EGF-receptor
f amily

erb-B1

Ov erexpression
Squamous
cell CA of
the lungs
Proteins involved in Signal Transduction pathway

GTP-binding

ras

Pt mutations CA of
Lung,
colon,
pancreas;
many
leukemias
Nuclear Regulatory proteins

Transcriptional
activators

myc

Translocation Burkitt
lymphoma
Cell Cycle Regulators

Cyclins cyclin D

Translocation Mantle cell
lymphoma

TUMOR SUPPRESOR GENES (ANTI ONCOGENES)
Which serve to down-regulate the cell cycle.

Note: a net increase in the production of stimulatory (promoter) f actors, a
decrease in inhibitory (suppressor) growth f actors may lead to
uncontrolled cell growth.

Cancer-Suppressor Genes
Protein Products of Tumor Suppressor Genes
Gene amplifications
p53
BRCA-1 and BRCA-2
APC gene
NF-1 gene
cell surface receptors
WT-1
Genes That Regulate Apoptosis
bcl-2
Genes That Regulate DNA Repair
hMSH2 and hMLH1
Molecular Basis of Multistep Carcinogenesis
gatekeeper genes - APC, NF-1, and Rb
caretaker genes - DNA repair genes

Retinoblastoma (RB1)- chr 13: involved in cell cycle.
P53- chr 17: involved in cell cycle (normal gene induces cell
cycle arrest and apoptosis, abnormal gene allows unrestrained
cell growth.
APC- chr 5; involved with cell adhesion and cytoskeleton
f unction.


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1.5 NEOPLASIA

Pathology
BRCA I and II
RB
Governor the cell cycle
When hypophosphorylated, RB exerts antiprolif erative
Normal growth f actor signaling leads to RB
hyperphosphorylation and inactivation.
1. Loss of f unction mutations af f ecting RB
2. Gene amplif ications of CDK4 and cyclin 0 genes
3. Loss of cyclin-dependent kinase inhibitors (p16/INK4a)
4. Viral oncoproteins that bind and inhibit RB (E7 protein of
HPV)
P53
Guardian of the genome
The p53 protein is the central monitor of stress in the cell.
Involved in cell cycle arrest, DNA repair, cellular senescence
and apoptosis.
Kinases phosphorylate p53, liberating it f rom inhibitors causing
cell-cycle arrest at the G1-S checkpoint.
This pause allows cells to repair DNA damage.
The majority of human cancers demonstrates biallelic loss of
f unction mutations in TP53.



















Fig 28. Role of p53 in maintaining the integrity of the genome.
KARYOTYPIC CHANGES IN TUMOR CELLS
Three types of nonrandom chromosomal abnormalities have been
described:
(1) translocation
(2) deletions
(3) amplif ication

CYTOGENETIC ABNORMALITIES IN HUMAN NEOPLASMS
TUMOR CYTOGENETIC
ABNORMALITY
EFFECTS
Chronic myeloid
leukemia
Translocation
between chromosome
9 & 22 (Philadelphia
chromosome)
Forms a protein with
tyrosine kinase
activity (bcr-abi
protein)
Follicular lymphoma Translocation
between
choromosome 14 &
18
Production of protein
that prevents cell
death (bcl 2 product)
Neuroblastoma Homogenous regions
and double minute
chromosomes
Amplif ication of n-myc
in poor prognosis type
Ewings tumor Translocation
between chromosome
11 & 22
Uncertain

CHARACTERIZED HERITABLE NEOPLASIA SYNDROME
SYNDROME TUMOR CAUSED DEFECT
MEN syndrome Multiple tumor in
endocrine organs
Mutations on
chromosomes 10 &
11
Polyposis coli Adenomata and
carcinomas of the
colon
Absnt tumor
suppressor gene
Li-Fraumeni Breast cancer and
sarcomas
Mutated tumor
suppressor gene
Xeroderma
Pigmentosum
Skin cancer Abnormal DNA repair
Familial
retinoblastoma
Malignant tumor of the
retina
Absent tumor
suppressor gene
Neurof ibromatosis
Type I
Benign and malignant
tumors of peripheral
nerves
Abnormal tumor
suppressor gene



Neoplasia Associated with Constant Genetic Abnormality:
a. Philadelphia Chromosome- CML
b. Retinoblastoma-Rb gene
c. Wilms Tumor-WT-1
d. Familial Polyposis Coli-APC

There is increasing recognition of the causative role of lifestyle
factors, including diet, physical activity and alcohol
consumption.
The most important human carcinogens include tobacco,
asbestos, aflatoxins and ultraviolet light.
TOBACCO SMOKING
Accounts f or 30 % of all malignant tumors
25 % of all Cancers in Men
4 % of all Cancers in Women
16 % both, in well developed countries
10 % in less developed countries
ALCOHOL
Accounts f or 3 % of all cancers
4% of Cancer in Men
2% of Cancer in Women
Analytical epidemiological studies of cohort and case-control
type conducted, the causal association of drinking alcohol has
been established in oral, esophageal and liver cancer
Risk for cancer is a linear function of the level of consumpti on,
up to an intake of about 80 g/day.
OCCUPATIONAL EXPOSURE
20 % - proportion of cancer attributable to occupational
carcinogen exposure
4.5% - estimated proportion of Cancer in developed countries
Lung Cancer is the most f requent
ENVIRONMENTAL EXPOSURE
1-4% of all Cancer are attributed to pollution of air, soil and
water
Asbestos is one of the best characterized cause
Less than 5 %, a small proportion of Lung Cancer is attributed
to air pollution
CHRONIC INFECTION
Inf ections agents are one of the main causes of cancer
accounting f or 18 %
(1.6 million) of cases worldwide
Approximately 9 million new cases of Cancer attributed to
inf ectious agents
23 % in developing countries
9 % in developed countries
EBV
- 65% f or Burkitts Lymphoma and Nasopharyngeal CA
Hepatitis B virus
-60% of cases of Primary Liver CA worldwide
-67 % in developing countries
Hepatitis C virus
-25 % of cases of Liver CA
HPV
- 80 % of Cervical CA
- 35 % of Cancers of the Vulva, Vagina, Penis & Anus
BIOLOGY OF TUMOR GROWTH
Kinetics of Tumor Cell Growth
variables inf luence tumor cell growth:
doubling time of tumor cells
growth f raction
cell production and loss
Tumor Angiogenesis
2 most important tumor angiogenic f actors are:
vascul ar endothelial growth factor
(VEGF)
basi c fi broblast growth factor (bFGF).
Tumor Progression and Heterogeneity
Mechanisms of Invasion and Metastasis
Invasion of Extracellular Matrix
Detachment of tumor cells
attachment to matrix components
degradation of extracellular matrix
Migration of tumor cells
Vascular Dissemination and Homing of Tumor Cells
METASTASIS
Establishment of a second neoplastic mass thru transf er of
neoplastic cells f rom the f irst neoplasm to a secondary location
separate f rom the original tumor
Tumor not contiguous to its primary site.
Def initive proof of malignancy
1. Lymphatic Spread:
Occurs early in carcinomas and melanomas but is an unusual
occurrence in most sarcomas.
Malignant cells are carried by the lymphatics to the regional
lymph nodes where their advance may be temporarily
arrested by immune response.


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1.5 NEOPLASIA

Pathology
2. Hematogenous Spread:
Believed to occur during the early clinical course.
Malignant cells are destroyed by the immune system, but some
become ocated with f ibrin and entrapped in the capillaries.
Metastasis occur only if enough cancer cells survive in the
tissue and prolif erate.
TAF ( tumor angiogenesis f actor )
3. Direct Seeding or Metastasis via body cavities (pleura,
peritoneum, preicardium):
Entry of malignant cells into the body cavities may be f ollowed
by dissemination of the cells elsewhere.
METASTATIC PROCESS
Inef f icient, multistep process called the metastatic cascade.
Detachment and invasion: pass in to lymphatic or venous
system.
Transport: to a distant site of growth. Has to survive a bunch of
host def enses on the way.
Arrest and extravasation: Stuck up in target organ. Digestion of
BM to invade.
Establishment of new growth.
METASTATIC CASCADE
1. Primary tumor will undergo donal expansion , growth,
diversif ication
2. Metastatic subclone
3. Adhesion to and invasion of basement membrane
4. Intravasation
5. Interaction with host lymphoid cells
6. Tumor cell rmbolus
7. Adhesion to basement membrane
8. Extravasation
9. Metastatic deposit





















Fig 29. Cellular events needed f or metastasis
HOST DEFENSE AGAINST TUMORS





















Fig 30. Main routes f or tumor spread


































Fig 31. Main sites of blood borne metastasis
CANCER SPREAD
Supraclavicular: breast, lung, stomach (Virchows), pancreas.
Axillary: lymphoma (#1), breast, melanoma.
Periumbilical: pancreas (SMJ node).
Ovarian: stomach (Krukenberg tumor), colon.
Bone mets: Breast (#1), prostate.
Skin mets: breast, melanoma.
CARCINOGENIC SITES
Chemical Carcinogenesis
Initiation
Promotion
Molecular Targets of Chemical Carcinogens
DNA
Carcinogenic Chemicals
alkylating agents, aromatic hydrocarbons, azo dyes
etc
Radiation Carcinogenesis
UV rays and ionizing radiations
Viral and Microbiological Carcinogenesis
DNA Viruses
(1) HPV, Epstein-Barr virus (EBV) and
Hepatitis B virus (HBV)
RNA Oncogenic Viruses
(HTLV-1)

VIRUSES IMPLICATED IN HUMAN NEOPLASIA
VIRUS NEOPLASM
Epsetin-barr virus Burketts lymphoma
Nasopharyngeal carcinoma
Other B cell lymphomas and some
cases of Hodgkins disease
Hepatitis B virus Hepatocellular carcinoma
Human papilloma virus Cervical carcinoma
Some f orms f carcinoma of the
skin
HTLV-I T-cell leukemia / lymphoma
Immunosurveillance
Increased f requency of cancers in patients
with congenital or acquired
immunodef iciency
increased susceptibility to EBV inf ections
and EBV-associated lymphoma in boys
with X-linked immunodef iciency
Tumors may escape immunosurveillance
selective outgrowths of antigen-negative
variants
loss or reduced expression of
histocompatibility antigens
tumor-induced immunosuppression
f ailure of sensitization
apoptosis of cytotoxic T cells
CLINICAL FEATURES OF TUMORS
Local and Hormonal Ef f ects
related to location
hormone production
Cancer Cachexia
Paraneoplastic Syndromes
endocrinopathies
Hypercalcemia
Acanthosis nigricans
clubbing of fingers and hypertrophic osteoarthopy
thromboembolic diatheses


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Pathology
APPROACH TO CANCER DIAGNOSIS
I. Clinical Suspicion
II. Screening Tests
III. Tumor Markers
IV .Def initive Diagnosis
- tissue biopsy ( most accurate )
1.Ordinary H and E stain
2. Immunohistochemistry
3. Electron Microscopy
LABORATORY DIAGNOSIS OF CANCER
Histologic and Cytologic Methods
Immunohistochemistry and f low cytometry
Molecular diagnosis
Molecular prof ile of tumors
Proteomics
Fine-Needle Aspiration
Cytologic (Papinacolaou Smears)
DNA Probe Analysis
Tumor Markers
Assays of circulating tumor cells and of DNA
GRADING & STAGING OF TUMORS
Grading Determined by cytologic appearance; based on the
idea that behavior and dif f erentiation are related, with poorly
dif f erentiated tumors having more aggressive behavior.
Grades I to IV with increasing anaplasia
Imperf ect because
(1) the dif f erentiated parts of the same
tumor may display dif f erent degrees of
dif f erentiation
(2) the grade of tumor may change as the
tumor grows
Staging Determined by surgical exploration or imaging, is
based on size, local and regional lymph node spread, and
distant metastases; of greater clinical value than grading.
anatomic extent of the tumor
TNM
Inf ormation Provided by Pathologic Diagnosis:
1. Type of Neoplasm - name of the neoplasm
2. Biologic Behavior- benign or malignant
3. Histologic Grade degree of dif f erentiation
4. Degree of Invasion- depth
5. Staging - size of the mass/depth of involvement
- involvement of nodes
- +/- metastasis
OTHER CLINICAL ASPECTS OF TUMORS
Cachexia Progressive loss of body f at and lean body mass,
accompanied by prof ound weakness, anorexia and anemia.
Paraneoplastic syndromes Symptom complexes in
individuals with cancer that cannot be explained by tumor
spread or release of hormones that are indigenous to the tumor
cell of origin.
PARANEOPLASTIC SYNDROMES
Endocrinopathies (Cushing syndrome, hypercalcemia)
Neuropathic syndromes (polymyopathy, peripheral
neuropathies, neural degeneration, myasthenic syndrome)
Skin disorders (acanthosis nigricans)
Skeletal and joint abnormalities (hypertrophic
osteoarthritis)Hypercoagulability (migratory thrombophlebitis,
disseminated intravascular coagulation, nonbacterial
thrombotic endocarditis)
TREATMENT OF NEOPLASMS
A. Benign
Surgical removal
B. Malignant
- Surgery ( radical, wide excision, palliative surgery )
- Lymph node removal
- Palliative:
a. Chemotherapy
b. Radiotherapy
c. Immunotherapy

The goal of primary prevention is to avoid the development of
Cancer by reducing or eliminating exposure to cancer-causing
factors and by frequent medical check-ups and population
based-screening programs

World Cancer Report
World Health Organization
2003
IMPORTANT DEFINITION RELATED TO CANCER SCREENING
SCREENING
Testing people who have no symptoms and have not noticed any
problems suggestive of disease.
A particular screening test may be suggested f or everyone or only
f or people with certain risk f actors.
Ideally, a screening test would stage or be able to detect cancer
at an early bef ore cancer has developed.
PREVENTION
Removing the cause or risk f or a certain type of cancer.
Prevention of ten consists of lif e-style changes like quitting
smoking or using sunscreen properly
Screening is not considered prevention.
Screening involves checking f or cancer or cancerous
conditions in persons without symptoms
Screening f or some cancers is ef f ective in detecting
precancerous cells or f inding cancer at an early stage when
treatment is more ef f ective.
Screening procedures include visual exams, laboratory tests,
or procedures such as mammography or colonoscopy that test
f or internal cancers.
TUMOR MARKERS
Secreted into the blood in measurable concentration only af ter
the cells produce it had undergone malignant transf ormation.
Adjunct towards correct diagnosis.
Marker f or prognostic and risk f actors
QUALITY INDEX
SENSITIVITY percentage of test results which are correctly
positive in the presence of a tumor
SPECIFICITY percentage of healthy persons or persons with
benign conditions in whom the test correctly gives a negative
result

* The significance of the data on the diagnostic specificity and sensitivity
of a tumor marker is critically dependent upon tumor stage and selection
of control groups
POINTERS IN USING TUMOR MARKERS
1. Never rely on the result of a single test.
2. When ordering serial testing, be certain to order every test f rom
laboratory using same assay kit.
3. Be certain that the tumor marker selected f or monitoring recurrence
was elevated in patient prior to surgery
4. Consider the half -lif e of the tumor marker when interpreting the result.
5. Consider how the tumor marker was removed or metabolized f rom the
blood circulation.
6. Consider ordering multiple tumor markers to improve both the
sensitivity and specif icity of the diagnosis.
7. Be aware of the presence of ectopic tumor marker. (AFP, Calcitonin,
Chromogranin A HCG, Thyroglobulin).
8. Be aware of the possibility of hook ef f ect.
- Takes place when the assay tends to give a f alsely low value when
the tumor marker concentration in the specimen rises above a certain
highly elevated concentration.
CARCINOEMBRYONIEC ANTIGEN (CEA)
Glycoprotein
Oncof etal antigen produced during embryonic and f etal lif e
Scarcely detectable in normal adults (2.5-5 ng/ml)
Found mostly in the gastrointestinal tract and serum of f etus
Small quantities in the intestinal, pancreatic, and liver tissues of
healthy adults
ALPHA-FETOPROTEIN (AFP)
Glycoprotein
Formed physiologically in the yolk sac, f etal liver and f etal GI
tract.
Hepatocellular carcinoma, germ cell tumors
Maybe elevated in breast, bronchial and colorectal carcinomas
CANCER ANTIGEN 19-9 (CA 19-9)
Glycolipid
Fetal stomach, intestine and pancreas
Ref erence range 37 U/ml
Marker of choice f or pancreatic carcinoma
CANCER ANTIGEN 125 (CA 125)
Dif f erentiation antigen that arises in f etal tissue f rom coelomic
epithelial derivatives.
Applicable f or ovarian neoplasms.
Maybe elevated in benign gynecologic tumors and
inf lammation of adnexa.
NEURON SPECIFIC ENOLASE (NSE)
Glucose splitting enzyme identif ied in neurons of the brain and
peripheral nervous system.
Also f ound in neuroendocrine tissue and APUD cells.
False positive: hemolysis and delayed centrif ugation of blood.
Neuroblastoma, Carcinoid
HUMAN CHORIONIC GONADOTROPIN (HCG)
Glycoprotein
Formed physiologically in syncytiotrophoblast
Diagnosing and monitoring GTD.
Monitoring germ cell tumor of the testis and ovaries
ESTROGEN RECEPTOR & PROGESTERONE ASSAY
Used to identif y patients who are to benef it f rom endocrine
therapy.
Indicate good prognosis, longer disease-f ree survival


Page 9 of 9

1.5 NEOPLASIA

Pathology
55-60% patients are positive to eER or PR only
85% positive to both.
WHAT ARE THE FINAL COMPLICATIONS OF MALIGNANCY
(CAUSES OF DEATH)
Pneumonia
Cachexia
Renal Failure
Bleeding
Severe anemia, Thrombocytopenia
Inf ections
Hypercoagulability
DIC
Pain more of devastating symptom than a complication. It has
to be controlled
Multiple Organ Failure

END OF TRANS