NEOPLASIA

BETHY S HERNOWO
 Introduction
 A tumor is an abnormal mass of tissue, the
growth of which virtually autonomous and
exceeds that of normal tissues.
 The growth of tumors persists after cessation of
the stimuli that initiated the change.
 Tumors are classified into two broad categories :
Benign and malignant
 The type of neoplasm is based on the
characteristics of its parenchyma
 Nomenclature
 All tumors have two basic components
1. the transformed neoplastic cells
2. the supporting stroma composed of non
trasformed elements, such as connective tissues
and blood vessels

Benign tumors :
 Typically end with suffix - oma
 Example: benign mesenchymal tumor : lipoma,
fibroma, angioma, osteoma, and leiomyoma
 Nomenclature
 The nomenclature of benign epithelial tumors is
somewhat complex and is based on both histogenesis
and architecture
 Example :
- Adenomas : benign epithelial tumors arising in glands or
forming glandular pattern
- Cystadenomas : adenomas producing large cystic
masses, seen typically in the ovary
- Papillomas : epithelial tumors forming microscopic or
macroscopic finger like projection
- Polyp : a tumor projecting from the mucosa into the
lumen of a hollow viscus
 Nomenclature
Malignant tumors
 Malignant tumors are called cancer and are divided into
two general categories
1. Carcinomas : arising from epithelial cells
2. Sarcomas : arising from mesenchymal tissues

 The nomenclature of specific types of carcinomas or

sarcomas is based on their appearance and presumed
histogenetic origin
 Adenocarcinoma : malignant epithelial tumors with
glandular growth pattern
 Leiomyosarcoma : sarcomas arising from or resembling
smooth muscle cells
 Nomenclature
 Some tumors appear to have more than one
parenchymal cell type :
Mixed tumors are derived from one germ cell layer
that differentiate into more than one
parenchymal cell type. E.c benign mixed tumor
parotis
Teratomas are made up of a variety of
parenchymal cell type representative of more
than one germ cell layer, usually all three. They
arise from totipotential cells  endoderm,
ectodermal and mesenchymal
 Nomenclature
 There are two non-neoplastic lesion that
grossly resemble tumors; moreover, their
names are deceptively similar to tumors
and sound omnious:
- Choristomas : ectopic rests of
nontransformed tissues
- Hamartomas : masses of disorganized
tissue indigenous to a particular site
 Biology of tumor growth
 The distinction between benign and malignant
tumor is based on appearance (morphology)
and ultimately on behaviour (clinical course)
using four criteria
1. Malignant change (transformation) of the target
cells (differentiation vs anaplasia)
2. Rate of growth
3. Local invasion
4. Metastases
 Biology of tumor growth
I. DIFFERENTIATION AND ANAPLASIA
 Differentiation is the extent to which tumor
cells resemble comparable normal cells
 Cells within most benign tumors closely
mimic corresponding normal cells. Thus
lipoma look like those in normal adipose
tissue
 Lack of differentiation is called anaplasia,
and is a hallmark of malignant cells
 Biology of tumor growth
The following cytologic features are used to
characterize anaplasia:
 Nuclear and cellular pleomorphism : variation in
the shape and size of cells and nuclei
 Hyperchromasia : darkly stained nuclei that
frequently contain prominent nucleoli
 Nuclear – cytoplasmic ratio : approaches 1:1
istead of 1 : 4 or 1 : 6, reflecting nuclear
enlargement
 Biology of tumor growth
 Abundant mitoses : reflect proliferative
activity. Mitotic figures may be abnormal
 Loss of polarity : anaplastic cells show
disturbed orientation and tend to form
anarchic, diaorganized masses
 Tumor giant cells : containing a single
large polypoid nucleus or multiple nuclei
 Biology of tumor growth
Poorly differentiated, anaplastic tumors
demonstrate a total disarray of tissue architecture
Well differentiated tumors, whether benign or
malignant tend to retain the functional
characteristics of their normal counterparts
Dysplasia refers to disorderly but non-neoplastic
growth, it usually encountered in epithelia.
Pleomorphisms, hyperchromasia and loss of
normal orientation may occur.
when involve the entire thickness  carcinoma
in situ
 Biology of tumor growth
2. RATES OF GROWTH
 Most malignant tumor grow more rapidly than
benign tumor
 Growth of cancer arising from hormone sensitive
tissue (e.g breast) may affected by hormonal
variation associated with pregnancy and
menopause
 The progression of tumors and their growth rates
are determined by an excess of cell production
over cell loss
 Biology of tumor growth
 A clinically detectable tumor (typically
containing 109 cells is a heterogenous
population of cells originating from the
clonal growth of the progeny of a single
cell
 Tumor stem cells have the capacity to
initiate and ultimately sustain tumor growth
 Biology of tumor growth
3. LOCAL INVASION
 Benign tumors
- most benign tumors grow as cohesive
expansile masses that develop a rim of
condensed connective tissues or capsule.
- these tumors do not penetrate the capsule
or surrounding tissues
- therapy  enucleation
 Biology of tumor growth
 Malignant neoplasms
- invasive and infiltrative
- destroy normal tissue surrounding them
- lack of well defined capsule
- therapy  wide excision
 Biology of tumor growth
4. METASTASIS
 Is the single most important feature
distinguishing benign from malignant tumors
 With exception of brain tumor and basal cell
carcinoma, almost all malignant tumors have the
capacity to metastasize
 The process involved : invasion of blood
vessels, lumphatics or body cavities  transport
and growth of secondary tumor
 Biology of tumor growth
Pathways of spread
 Body cavity : seeding surface of peritoneal, pleural,
pericardial or subarachnoid spaces, e.g carcinoma
of the ovary  perinoteum  liver & bowel
 Lymphatics : transport tumor cells to regional
nodes
 Hematogenous: typical sarcomas but also certain
carcinoma (kidney). Vein are more frequent. Lung
and liver is the most common sites of metastasis.
Other location : brain and bone
 Epidemiology
 A variety of factors predispose an
individual or a population to the
development of cancer
 Sex, geographic & environmental factors,
age, genetic predisposition  influence
the epidemiology of cancer
 Sex : female ca  breast, ovary, cervix
male ca  prostate, testis
 Epidemiology
Geographic and Environmental factors
 Significantly influence the specific forms of
cancer in different part of the world
 For example : Japan death for gastric
cancer 7x > USA, but ca colon less
common
 Environmental factor:
- asbestos, vinyl chloride, 2-naphthylamine
- cigarette smoling, alcohol
 Epidemiology
Age
 Cancer is most common in those older than 55
years
 Is the main cause of death in woman aged 40-79
and men aged 60-79
 Certain cancer common in children <15years:
- tumors of hematopoietic system
- neuroblastoma, wilm’s tumors, retinoblastoma,
sarcomas of bone and skeletal muscle
 Epidemiology
Genetic predisposition
 Heredity plays role in the development of
cancer (0.1% - 10%)
 Genetic predisposition can be divided into three
categories
1. Autosomal dominant (retinoblastoma and FAP)
2. Defective DNA repair syndrome (HNPCC)
3. Familial cancers (breast,colon, brain, ovary)
Selected Tumor Suppressor Genes Responsible for Familial Cancer Syndromes
Syndrome Gene Chromosome Tumors
Location
Basal cell nevus PTC 9q22.3 Basal cell cancer, jaw cysts, medulloblastoma
Familial breast/ovarian BRCA1 17q21 Breast, ovarian, colon, prostate cancer
cancer
Familial breast cancer BRCA2 13q12-13 Breast cancer, male breast cancer
Familial melanoma p16 9p21 Melanoma, pancreatic cancer
Familial polyposis coli APC 5q21 Intestinal polyposis, colorectal cancer
Familial retinoblastoma RB 13q24 Retinoblastoma, osteosarcoma
Familial Wilms' tumor WT1 11p13 Wilms' tumor, WAGRa
Hereditary multiple EXT1 11p11-13 Exostoses, chondrosarcoma
exostoses
Li-Fraumeni p53 17q13 Sarcomas, breast cancer
Neurofibromatosis type 1 NF1 17q11.2 Neurofibroma, neurofibrosarcoma, brain tumor
Neurofibromatosis type 2 NF2 22q12 Acoustic neuroma, meningioma
Tuberous sclerosis TSC2 16p13.3 Angiofibroma, renal angiomyolipoma
Von Hippel-Lindau VHL 3p25-26 Renal cell cancer, pheochromocytoma, retinal
angioma, hemangioblastoma
a WAGR, Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation.
 Epidemiology
Non hereditary predisposing condition
1. Chronic inflammation
 cytokines  growth of transformed cell
& genomic instability.
 increase local pool of stem cells
2. Precancerous condition
e.g leukoplakia  oral cancer
villous adenoma  colon cancer
 Success repair
DNA damaging agent:
Chemical
Radiation NORMAL CELLS DNA DAMAGE
Viruses
Failure repair

Mutation in the
Genome of Somatic Cells

Activatiion of Alteration of Inactivation of

Growth Promoting Genes that Cancer Suppressor
Oncogenes Regulated Apoptosis Genes

Inheritaged Mutations in:

Genes Affecting DNA repair
Expresion of Altered Gene Product Genes Affecting Cell Growth
& Lost of Regulatory Gene Product or Apoptosis

Clonal expansion
Additional Mutation
Heterogenecity

Malignant Neoplasm
 Molecular basis of cancer
 The genes that contribute to malignant transformation
act on one or more of these pathways
1. self sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Defects in DNA repair
5. Limitless replicative potential
6. Sustained angiogenesis
7. Ability to invade and metastasize
8. Ability to escape immune recognition and regulation
 Molecular basis of cancer
1. Self sufficiency in growth signal
 Tumor growth autonomy occurs when the
normal step of cell proliferation occur in
the absence of growth-promoting signals
 Oncogene are gene that promote
autonomous cell growth in cancer cells
 Protooncogenes are normal cellular genes
that affect growth and differentiation
 Molecular basis of cancer
 Oncoproteins are the protein products of
oncogenes, resemble the normal products
of protooncogene except that they are
devoid of normal regulatory elements
 Protooncogene can be converted to
oncogenes by one of these mechanisms:
- Point mutation
- Chromosomal rearrangements
- gene amplification
 Molecular basis of cancer
2. Insensitivity to growth inhibitory signal
 Cancer may arise not only by activation of
growth promoting oncogenes but also by
inactivation of gene that normally suppress
cell proliferation (tumor suppressor gene)
 Tumor suppressor gene :
RB genes, p53, APC gene/beta catenin,
TGF-beta, NF-1, WT-1
 Signal Transducing Proteins
GF GF + reseptor

i_RAS (GDP) a_RAS (GTP)

GAP MAP kinase

PROLIFERATION
 RB gene & Cell Cycle
CDKI_r21 G0 CDKI_p15
CDKI_p16
CDKI_r27
CDKI_r52 CDKI_p18
CDKI_p19
M G1

CYCLIN

CYCLIN
a_RB CDK 2
CDK 1 CDK 4
i_RB CDK 6

G2 S
GROWTH

CYCLIN
GROWTH
FACTOR
FACTOR
CDK 1
CDK 2
 Cyclin & Cyclin Dependent Kinase
CDKI_r21 G0 CDKI_p15
CDKI_p16
CDKI_r27
CDKI_r52 CDKI_p18
CDKI_p19
M G1

CYCLIN

CYCLIN
a_RB CDK 2
CDK 1 CDK 4
i_RB CDK 6

G2 S
GROWTH

CYCLIN
GROWTH
FACTOR
FACTOR
CDK 1
CDK 2
Normal Cell TP 53 gene AbNormal Cell
[TP 53 normal] [TP 53 AbNormal

DNA damage M G DNA damage

TP 53 activated G S TP 53 not activated

Transcriptional UpRegulation
G No Cell No DNA
Of Target Genes
Cycle Arrest Repair

DNA repair Mutant Cell

Expansion &
P21[CDK Inhib] BAX [Apoptosis gene] Additional
Mutation

Normal Cell Apoptosis Malignant Tumor

 Molecular basis of cancer
3. Evasion of apoptosis
 The accumulation of neoplastic cells
requires not only the activation of
oncogenes or inactivation of tumor
suppressor gene but also mutation in the
genes that regulate apoptosis
 BCL2
 Molecular basis of cancer
4. Defects in DNA repair
 DNA repair genes do not contribute directly to
cell growth or proliferation, they act indirectly by
correcting errors in DNA that occur
spontaneously during cell division or follow
exposure to mutagenic chemical or irradiation
 DNA repair gene are not directly oncogenic
 Defect can occur in 3 types of DNA repair
system : mismatch repair, nucleotide excision
repair, recombination repair
 Molecular basis of cancer
5. Limitless replicative potential :
telomerase
 Enzyme telomerase is not active in most
somatic cells
 Cellular telomeres shorten with each cycle
 arrest in terminally non dividing state.
 Cancer cells reactivating telomerase
 Molecular basis of cancer
6. Sustained angiogenesis
 Tumor cannot enlarge beyond 1 to 2 mm
in diameter without inducing host blood
vessel growth (angiogenesis) to provide
nutrients and removed wastes
 VEGF, bFGF  angiogenesis
 New tumor vessels are tortuous, irregular,
highly leaky
 Angiogenic Factors
Hypoxia
FGF-1,2
Angiogenin
TGF β,α
VEGF TNF α
bFGF PDEGF
IL-8
Proliferin
Leptin

MalignantCells
Malignant Cells
TP53

Plasminogen Angiostatin
Thrombospondin-1 Collagen Vasculostatin
Transthyretin Endostatin
Other Cells

Platelet F 4
Interferon Alpha
IL-12
Troponin
Maspin
Antiangiogenic Factors
 Molecular basis of cancer
7. Invasion and metastasis
 Invasion of extracellular matrix
- detachment of tumor cells from each other
- attachment to matrix components
- degradation of extracellular matrix
- migration of tumor cells
 Vascular dissemination and homing of
tumor cells
 Molecular basis of multistep
carcinogenesis
 No single genetic alteration is sufficient to
induce cancer invivo
 Multiple control exerted by multiple
categories of genes; oncogenes, tumor
suppressor genes and apoptosis
regulating genes must be lost for the
emergence of cancer cells
 The tumors are initially
 Molecular basis multistep
carcinogenesis
 No single genetic alteration is sufficient to
induce cancer in vivo
 Multiple controls exerted by multiple
categories of genes ; oncogenes, tumor
suppressor gene and apoptosis regulating
gene must be lost
 Example : colon adenoma- carcinoma
sequences
Carcinogenetic agents and their
cellular interaction
Agents that can cause genetic damage and
induce neoplastic transformation include :
 Chemical carcinogen
 Radiant energy
 Oncogenic viruses and other microbes
Carcinogens and Associated Cancers or Neoplasms
Carcinogensa Associated Cancer or Neoplasm
Immunosuppressive agents Non-Hodgkin's lymphoma
(azathioprine, cyclosporine,
glucocorticoids)

Nitrogen mustard gas Cancer of the lung, head and neck, nasal sinuses
Nickel dust Cancer of the lung, nasal sinuses
Phenacetin Cancer of the renal pelvis and bladder
Polycyclic hydrocarbons Cancer of the lung, skin (especially squamous cell
carcinoma of scrotal skin)
Schistosomiasis Bladder cancer (squamous cell)
Sunlight (ultraviolet) Skin cancer (squamous cell and melanoma)
Tobacco (including smokeless) Cancer of the upper aerodigestive tract, bladder
Vinyl chloride Liver cancer (angiosarcoma)
Carcinogenetic agents and their
cellular interaction
Chemical carcinogenesis
 Neoplastic transformation by chemical broadly
divided into 2 stages
1. Initiation
2. Promotion

Initiation
 Irreversible change in genome of cells
 Give rise to tumors when stimulated by
promoting agents
Carcinogenetic agents and their
cellular interaction
Promotion
 induction in previously initiated cells
 The effect is relatively short lived and
reversible
 Do not effect DNA and non tumorigenic by
themselves
Carcinogenetic agents and their
cellular interaction
Carcinogenic chemical :
 Alkylating agent
 Polycyclic aromatic hydrocarbon
 Aromatic amines and azo dyes
 Naturally carcinogens : aflatoxin B1
 Nitrosamines and amides
 Miscellaneous : asbestos, vinyl chloride,
nickel
Carcinogenetic agents and their
cellular interaction
Radiation carcinogenesis
 Two mechanisms in UV induction of
cancer :
1. damage to DNA by formation of
pyrimidine dimers
2. Immunosuppresiion
Carcinogenetic agents and their
cellular interaction
Viral and microbial carcinogenesis
 Variety of DNA and RNA viruses are
known to cause cancer in animals :
1. Human papilloma virus (HPV)
2. Epstein barr virus (EBV)
3. Hepatitis B virus (HBV)
4. Kaposi sarcoma herpesvirus (KSHV)
Carcinogenetic agents and their
cellular interaction
Human papilloma virus (HPV)
 Approximately 70 types
 Some (e.g, 1,2,4 and 7)  warts
 Types 16-18  90% of squamous cell
carcinoma cervix
 Low malignant potential : 6 and 11 
condyloma
 HPV produced E6 and E7  inhibit RB
and p53
Carcinogenetic agents and their
cellular interaction
Epstein Barr Virus (EBV)
 Associated with four human cancer:
1. Burkitt lymphoma
2. Nasopharyngeal carcinoma
3. B-cell lymphoma in immunosuppressed
person
4. Hodgkin lymphoma
 Dysregulate growth controlling pathway
Carcinogenetic agents and their
cellular interaction
Hepatitis B virus
 Casuing hepatocellular injury 
regenerative hyperplasia  mutation
 HBx  activation protooncogenes
 HBx  Bind to p53
 Clinical feature of tumor

 Effect tumor on host

- local and hormonal effect : expand and destroy
remaining tisuue  obstruction, hemorrhage,
endocrine disorder
 Cancer cachexia
loss of body fat, wasting, weakness
due to : loss of appetite, metabolic change,
production of tumor necroting factor, catabolism
of muscle and adipose tisuue
 Clinical feature of tumor
 Paraneoplastic syndrome
- symptoms that are not directly related to
the spread of the tumor
- may be the earliest clinical manifestation
- the most common syndrome :
endocrinopathies, hypercalcemia,
acanthosis nigrans, clubbing of finger and
hyperthropic osteoarthropathy, thrombotic
diatheses
 Clinical feature of tumor
Grading and staging of tumors
 Grading
- based on the degree of differentiation and
the number of mitoses
- Grades I to IV
- imperfect because : different type of tumor may
display different degrees of differentiation and may
change as tumor grows
 Staging
- based on anatomic extent of tumor
- TNM system and AJC system
 Laboratory diagnosis of cancer
 Histologic and cytologic method
- usual parraffin embedded section or frozen
section
- Fine needle aspiration for cytologic evaluation
- Papanicolaou smears
 Immunohistochemistry  origin and prognostic
 Molecular diagnosis : FISH, N-MYC, BRCA,
DNA microarray
 Flow cytometry
 Tumor marker : CEA, AFP
TERIMAKASIH