RESPON

NEOPLASTIK
PROGRAM MAGISTER ILMU BIOMEDIK
FAKULTAS KEDOKTERAN UNIVERSITAS ANDALAS

NAMA : MIRNAWATI
BP : 2020312003
Mata kuliah : Patologi Dasar
Dosen : dr. Tofrizal, Sp. PA, P. hD, M. Biomed
Nomenclature

■ “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
■ Neoplasia means “new growth,” and a new growth is called a neoplasm.
■ Tumor originally applied to the swelling caused by inflammation, but the nonneoplastic
usage of tumor has almost vanished; thus, the term is now equated with neoplasm.
■ Oncology (Greek oncos = tumor) is the study of tumors or neoplasms
Nomenclature - Benign Tumors

 -oma= benign neoplasm

 Mesenchymaltumorschrondroma: cartilaginous tumor
• fibroma: fibrous tumor
• osteoma: bone tumor

 Epithelial tumoradenoma: 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
Nomenclature - Malignant Tumors

Sarcomas: mesenchymaltumorchrondrosarcoma: cartilaginous tumor

 fibrosarcoma: fibrous tumor
 osteosarcoma: bone tumor

Carcinomas: epithelial tumorsadenocarcinoma: gland forming tumor

 squamouscell carcinoma: squamousdifferentiation
 undifferentiated carcinoma: no differentiation
note: carcinomas can arise from ectoderm, mesoderm, or endoderm
 Nomenclature - Malignant Tumors

 Tumors with mixed differentiationmixed tumors: e.g. pleomorphicadenoma of salivary gland carcinosarcoma

 Teratomatumor comprised of cells from more than one germ layer arise from totipotentcells (usually gonads)
benign cystic teratomaof ovary is the most common teratoma

 Aberrant differentiation (not true neoplasms)

 Hamartoma: disorganized mass of tissue whose cell types are indiginousto the site of the lesion
 Choriostoma: ectopic focus of normal tissue (heterotopia)

 Misnomershepatoma: malignant liver tumor

• melanoma: malignant skin tumor
• seminoma: malignant testicular tumor
• lymphoma: malignant tumor of lymphocytes
Differentiation, Anaplasia, Dysplasia,
Carcinoma in Situ
Differentiation

■ Well differentiated neoplasm

 Resembles mature cells of tissue of origin
■ Poorly diffentiated neoplasm
 Composed of primitive cells with little diffrerentiation
■ Undifferentiated or “anaplastic” tumor
■ Correlation with biologic behavior
• Benign tumors are well differentiated
• Poorly differentiated malignant tumors usually have worse prognosis

■ Grading of malignant tumor is done based on differentiation, like:

■ 1. Well differentiated tumor is Grade I.

■ 2. Moderately differentiated is Grade II.
■ 3. Poorly differentiated is Grade III.
 Anaplasia
• Anaplasia: Lack or loss of differentiation is
called anaplasia.

• Lack of differentiation or anaplasia is

considered as hallmark of malignancy.

• Anaplastic features are found in malignant

tumor.
Characteristics of a malignant cells/
Features of Anaplasia
Anaplasia is associated with cellular feature like:

1. Pleomorphism
2. Increased nuclear cytoplasmic ratio
3. Hyperchromasia
4. Increased mitosis and abnormal
mitosis
5. Loss of polarity
 Pleomorphism

• Pleomorphism is the variation in size and

shape of the cells.

• Cancer cells show pleomorphism. Cells

ranges from small cell to a large atypical
tumor giant cell.

• Some tumor cells possess a huge nucleus

with two or more large, hyperchromatic
nuclei.
 Abnormal nuclear morphology
• A normal nucleus is large in relation to
cytoplasm. Normalnuclear-to-cytoplasm
ratio is 1:4 to 1:6. In malignancy NC ratio
may become 1:1.

• Nucleus is darkly stained (hyperchromatic)

with coarsely clumped chromatin.

• Abnormally large nucleoli are also

commonly seen.
Mitosis:
• In tumours many cells are in mitosis because
of high proliferative activity of the tumor cells.

• There may be atypical, bizarre mitotic figures,

sometimes tripolar, quadripolar mitoses.

Loss of polarity:
• The orientation of anaplastic cells is markedly
disturbed. Tumor cells grow in disorganized
fashion.
Fig: Pleomorphism
Fig: Atypical Mitosis
 Dysplasia
• Dysplasia means “disordered growth.”

• Dysplasia is the loss of uniformity of the

individual cells and loss of their
architectural orientation.

• Dysplasia may be a precursor to malignant

transformation. but it does not always
progress to cancer.
 Dysplasia
• Dysplastic cells may exhibit pleomorphism
and large hyperchromatic nuclei with a high
nuclear-to-cytoplasmic ratio.

• Mitotic figures are more abundant than in

the normal tissue and may be seen at all
levels including surface epithelial cells.
Fig: Dysplasia
 Uterine Cervix dysplasia
(CIN/ Cervical intraepithelial neoplsia)

■ • CIN –I: When the dysplastic cells involves lower one third of the epithelium
(Mild dysplasia).
■ • CIN –II: When the dysplastic cells involves lower two thirds of the epithelium
(Moderate dysplasia).
■ • CIN –III: When the dysplastic cells involves almost full thickness of the epithelium
(severe dysplasia).
Cervical dysplasia classification
 Carcinoma in Situ (CIS)
• When dysplastic changes are marked and
these atypical dysplastic cells involve
the full thickness of the epithelium it is
called carcinoma in situ.

• Carcinoma in situ is limited to the basement

membrane and do not cross the basement
membrane.
 Carcinoma in Situ (CIS)
• Carcinoma in Situ (CIS) is a malignant
condition but the malignant cells does not
cross the basement membrane.

• Once the tumor cells cross the basement

membrane, it is called invasive carcinoma.

• Management of CIS is same like invasive

carcinoma.
Fig: Carcinoma in Situ
Tumor Growth Rate
■ Doubling time of tumor cells
Lengthens as tumor grows
30 doublings (109cells) = 1 g
 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
Normal Cell Cycle Phases

INHIBITORS: Cip/Kip, INK4/ARF

Tumor (really growth) suppressor genes: p53
Schematic Representation Of Tumor Growth
Characteristics of Benign and Malignant Neoplasms
Feature Benign Malignant

Rate of Growth Progressive but slow. Mitosis Variable. Mitoses more frequent
few and normal. and may be abnormal.

Differentiation Well differentiated. Some degree of anaplasia.

Local invasion Cohessive growth. Capsule and Poorly cohesive and infiltrative.
BM not breached infiltrative.

Metastasis Absent May occur

Epidemiology of Cancer
 Geographic & Environmental
■ Sun exposure
Melanomas 6x incidence New Zealand vs Iceland
Blacks have low incidence of melanoma
■ Smoking and alcohol abuse
■ Body mass
Overweight = 50% increase in cancer
■ Viral exposure
 Human papilloma virus (HPV) and cervical cancer
 Hepatitis B virus (HBV) and liver cancer (Africa)
 Epstein-Barr Virus (EBV) and lymphoma
 Predisposing Factors for Cancer

■ Age
Most cancers occur in persons ≥ 55 years
Childhood cancers
• Leukemias& CNS neoplasms
• Bone tumors
■ Genetic predisposition
Familial cancer syndromes
• Early age at onset
• Two or more primary relatives with the cancer
• Multiple or bilateral tumors
Polymorphisms that metabolize procarcinogens, e.g., nitrites
 Predisposing Factors for Cancer
■ Nonhereditary predisposing conditions
 Chronic inflammation
 Precancerous conditions
 Chronic ulcerative colitis
 Atrophic gastritis of pernicious anemia
 Leukoplakia of mucous membranes
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
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

MYC

■ Encodes for transcription factors

■ Also involved with apoptosis
P53 and RAS

p53 RAS
Activates DNA repair proteins H, N, K, etc., varieties
Sentinel of G1/S transition Single most common abnormality of dominant
oncogenesin human tumors
Initiates apoptosis Present in about 1/3 of all human cancers

Mutated in more than 50% of all human

cancers
The hallmark of cancer
Hallmark of cancer

Self-sufficiency in growth signals.

Tumors have the capacity to proliferate without external stimuli,
usually as a consequence of oncogene activation.

• Insensitivity to growth-inhibitory signals.

Tumors may not respond to molecules that inhibit the proliferation
of normal cells, usually because of inactivation of tumor suppressor
genes that encode components of these growth inhibitory pathways.
Hallmark of cancer

Altered cellular metabolism.

Tumor cells undergo a metabolic switch to aerobic glycolysis (called the
Warburg effect), which enables the synthesis of the macromolecules and
organelles that are needed for rapid cell growth.
Evasion of apoptosis.
Tumors are resistant to programmed cell death.
Limitless replicative potential (immortality).
Tumors have unrestricted proliferative capacity, a stem cell–like property that
permits tumor cells to avoid cellular senescence and mitotic catastrophe.
Hallmark of cancer
• Sustained angiogenesis.
Tumor cells, like normal cells, are not able to grow without a vascular supply to bring
nutrients and oxygen and remove waste products. Hence, tumors must induce
angiogenesis.

•Ability to invade and metastasize.

Tumor metastases are the cause of the vast majority of cancer deaths and arise from the
interplay of processes that are intrinsic to tumor cells and signals that are initiated by the
tissue environment.
• Ability to evade the host immune response.
You will recall that the cells of the innate and adaptive immune system can recognize and
eliminate cells displaying abnormal antigens (e.g., a mutated oncoprotein). Cancer cells
exhibit a number of alterations that allow them to evade the host immune response.
Model for action of RAS genes

CSBRP-July-2012
Schematic illustration of the role of cyclins, CDKs, and CDK
inhibitors (CDKIs) in regulating the cell cycle.

CSBRP-July-2012
Main Cell Cycle Components and Their Inhibitors
Cell Cycle
Component Main Function
CYCLIN-DEPENDENT KINASES
CDK4 Forms a complex with cyclin D that phosphorylates RB, allowing the cell to progress
through the G1 restriction point.
CDK2 Forms a complex with cyclin E in late G1, which is involved in G1/S transition. Forms a
complex with cyclin A at the S phase that facilitates G2/M transition.
CDK1 Forms a complex with cyclin B that facilitates G2/M transition.
INHIBITORS
CIP/KIP family: p21, p27 Block the cell cycle by binding to cyclin-CDK complexes; p21 is induced by the tumor
(CDKN2A-C) suppressor p53; p27 responds to growth suppressors such as TGF-β.
INK4/ARF family p16/INK4a binds to cyclin D–CDK4 and promotes the inhibitory effects of RB; p14/ARF
(CDKN1A-D) increases p53 levels by inhibiting MDM2 activity.
CHECKPOINT COMPONENTS
p53 Tumor suppressor gene altered in the majority of cancers; causes cell cycle arrest and
apoptosis. Acts mainly through p21 to cause cell cycle arrest. Causes apoptosis by inducing
the transcription of pro-apoptotic genes such as BAX. Levels of p53 are negatively
regulated by MDM2 through a feedback loop. p53 is required for the G1/S checkpoint and
is a main component of the G2/M checkpoint.
Ataxia-telangiectasia Activated by mechanisms that sense double-stranded DNA breaks. Transmits signals to
mutated arrest the cell cycle after DNA damage. Acts through p53 in the G1/S checkpoint. At the
G2/M checkpoint, it acts both through p53-dependent mechanisms and through the
inactivation of CDC25 phosphatase, which disrupts the cyclin B–CDK1 complex.
Component of a network of genes that include BRCA1 and BRCA2, which link DNA damage
with cell cycle arrest and apoptosis
CSBRP-July-2012
 Selected Tumor Suppressor Genes Involved in Human Neoplasms

Tumors Associated with Tumors Assocated with

Subcellular Locations Gene Function Somatic Mutations Inherited Mutations
Cell surface TGF-β receptor Growth inhibition Carcinomas of colon Unknown
E-cadherin Cell adhesion Carcinoma of stomach Familial gastric cancer
Inner aspect of plasma NF1 Inhibition of RAS signal Neuroblastomas Neurofibromatosis type 1
membrane transduction and of p21 and sarcomas
cell cycle inhibitor
Cytoskeleton NF2 Cytoskeletal stability Schwannomas and Neurofibromastosis type
meningiomas 2, acoustic schwannomas,
and meningiomas
Cytosol APC/β-catenin Inhibition of signal Carcinomas of stomach, Familial adenomatous
transduction colon, pancreas; polyposis coli/colon
melanoma cancer
PTEN PI3 kinase signal Endometrial and prostate Cowden syndrome
transduction cancers
SMAD2 and SMAD4 TGF-β signal transduction Colon, pancreas tumors Unknown
Nucleus RB1 Regulation of cell cycle Retinoblastoma; Retinoblastomas,
osteosarcoma carcinomas osteosarcoma
of breast, colon, lung
p53 Cell cycle arrest and Most human cancers Li-Fraumeni syndrome;
apoptosis in response to multiple carcinomas and
DNA damage sarcomas
WT1 Nuclear transcription Wilms' tumor Wilms' tumor
P16/INK4a Regulation of cell cycle by Pancreatic, breast, and Malignant melanoma
inhibition of esophageal cancers
cyclindependent kinases
BRCA1 and BRCA2 DNA repair Unknown Carcinomas of female
breast and ovary;
CSBRP-July-2012 carcinomas of male breast
The role of RB in regulating the G1-S
checkpoint of the cell cycle

CSBRP-July-2012
The role of p53 in maintaining the
integrity of the genome

CSBRP-July-2012
 The role of APC in regulating the stability
and function of β-catenin

CSBRP-July-2012
Sequence of events in the development of limitless
replicative potential

CSBRP-July-2012
 The metastatic cascade.
Sequential steps involved
in the hematogenous
spread of a tumor

CSBRP-July-2012
 Sequence of events in the
invasion of epithelial
basement membranes by
tumor cells

CSBRP-July-2012
 Mechanisms of
metastasis
development
within a
primary tumor

CSBRP-July-2012
 Molecular model for the evolution of colorectal cancers
through the adenoma-carcinoma sequence

CSBRP-July-2012
DIRECT-ACTING CARCINOGENS
Alkylating Agents

β-Propiolactone
Dimethyl sulfate
Diepoxybutane
Anticancer drugs (cyclophosphamide, chlorambucil, nitrosoureas, and others)
Acylating Agents

1-Acetyl-imidazole

Major
Dimethylcarbamyl chloride
PROCARCINOGENS THAT REQUIRE METABOLIC ACTIVATION
Polycyclic and Heterocyclic
Aromatic Hydrocarbons

Benz[a]anthracene
Benzo[a]pyrene
Dibenz[a,h]anthracene
3-Methylcholanthrene
Chemical
Carcinogens
7,12-Dimethylbenz[a]anthracene
Aromatic Amines, Amides,
Azo Dyes

2-Naphthylamine (β-naphthylamine)
Benzidine
2-Acetylaminofluorene
Dimethylaminoazobenzene (butter yellow)
Natural Plant and
Microbial Products
Aflatoxin B1

Griseofulvin
Cycasin
Safrole
Betel nuts
Others

Nitrosamine and amides

Vinyl chloride, nickel, chromium
Insecticides, fungicides
Polychlorinated biphenyls

CSBRP-July-2012
 General
schema of
events in
chemical
carcinogenesi
s
CSBRP-July-2012
 Possible
evolution of
EBV-induced
Burkitt
lymphoma.

CSBRP-July-2012
Tumor antigens recognized by CD8+ T cells

CSBRP-July-2012
Mechanisms by which tumors evade
the immune system

CSBRP-July-2012
Paraneoplastic Syndromes
Major Forms of Underlying
Clinical Syndromes Cancer Causal Mechanism
ENDOCRINOPATHIES
Cushing syndrome Small-cell carcinoma of lung ACTH or ACTH-like substance
Pancreatic carcinoma
Neural tumors
Syndrome of inappropriate Small-cell carcinoma of lung; Antidiuretic hormone or atrial
antidiuretic hormone secretion intracranial neoplasms natriuretic hormones
Hypercalcemia Squamous cell carcinoma of lung Parathyroid hormone–related
Breast carcinoma protein (PTHRP), TGF-α, TNF, IL-1
Renal carcinoma
Adult T-cell leukemia/lymphoma
Hypoglycemia Ovarian carcinoma
Fibrosarcoma Insulin or insulin-like substance
Other mesenchymal sarcomas
Carcinoid syndrome Hepatocellular carcinoma
Bronchial adenoma (carcinoid) Serotonin, bradykinin
Pancreatic carcinoma
Polycythemia Gastric carcinoma
Renal carcinoma Erythropoietin
Cerebellar hemangioma
Hepatocellular carcinoma
CSBRP-July-2012
Paraneoplastic Syndromescont….
NERVE AND MUSCLE SYNDROMES
Myasthenia Bronchogenic carcinoma Immunological
Disorders of the central and Breast carcinoma
peripheral nervous system
DERMATOLOGIC DISORDERS
Acanthosis nigricans Gastric carcinoma Immunological; secretion of
Lung carcinoma epidermal growth factor
Uterine carcinoma
Dermatomyositis Bronchogenic, breast carcinoma Immunological
OSSEOUS, ARTICULAR, AND SOFT-TISSUE CHANGES
Hypertrophic osteoarthropathy Bronchogenic carcinoma Unknown
and clubbing of the fingers
VASCULAR AND HEMATOLOGIC CHANGES
Venous thrombosis (Trousseau Pancreatic carcinoma Tumor products (mucins that
phenomenon) Bronchogenic carcinoma activate clotting)
Other cancers
Nonbacterial thrombotic Advanced cancers Hypercoagulability
endocarditis
Red cell aplasia Thymic neoplasms Unknown
OTHERS
Nephrotic syndrome Various cancers Tumor antigens, immune
CSBRP-July-2012 complexes
 Selected Tumor Markers
HORMONES
Human chorionic gonadotropin Trophoblastic tumors, nonseminomatous testicular tumors

Calcitonin Medullary carcinoma of thyroid

Catecholamine and metabolites Pheochromocytoma and related tumors
Ectopic hormones See “Paraneoplastic Syndromes” ( Table 7-11 )
ONCOFETAL ANTIGENS
α-Fetoprotein Liver cell cancer, nonseminomatous germ cell tumors of testis

Carcinoembryonic antigen Carcinomas of the colon, pancreas, lung, stomach, and heart

ISOENZYMES
Prostatic acid phosphatase Prostate cancer
Neuron-specific enolase Small-cell cancer of lung, neuroblastoma
SPECIFIC PROTEINS
Immunoglobulins Multiple myeloma and other gammopathies
Prostate-specific antigen and prostate-specific membrane antigen Prostate cancer

MUCINS AND OTHER GLYCOPROTEINS

CA-125 Ovarian cancer
CA-19-9 Colon cancer, pancreatic cancer
CA-15-3 Breast cancer
NEW MOLECULAR MARKERS
p53, APC, RAS mutants in stool and serum Colon cancer
p53 and RAS mutants in stool and serum Pancreatic cancer
p53 and RAS mutants in sputum and serum Lung cancer
p53 mutants in urine Bladder cancer
CSBRP-July-2012
 Referensi
■ Robbin and cotran. (2015). Phatologic basis of disease professional edition ninth
edition. Elsevier saunders.
■ Harrison’s principle of internal medicine, 17th edition.
■ Nadia Gamoudi and Renald Blundell. 2008. Atielogy and Pathophysiology of Neoplastic Growth.
Research Journal of Medical Sciences 2 (2): 77-84, 2008
Terima Kasih