Carcinogenesis

Dr Evlina Suzanna SpPA

Kelompok Staf Medik Fungsional
RSK Dharmais-Pusat Kanker Nasional
 DISTRIBUTION OF MORPHOLOGY

Morfologi Male Female

Small cell carcinoma, NOS 2.1 0.8
Non-small cell carcinoma 2.8 3.4
Adenocarcinoma 27.7 32.4
Squamous cell carcinoma 9.3 4.7
Large cell carcinoma 1.4 0.6
 Curriculum Vitae
• Nama : Evlina Suzanna Sinuraya
• Tempat tanggal Lahir : Sidikalang 12 April
• Pendidikan : FK USU 1982-1988.
FK UI 1995-2000. Patologi Anatomi.
Fellowship Breast Lession ( Premalignant –DCIS)
Univ Medisch Centrum Groningen Netherlands
Jabatan : SMF Paatologi Anatomi RSKD
Ka Subag Registrasi Kanker Bagian LitBang RSKD
Ka Divisi Data dan Informasi KPKN
Organisasi : Sekretaris Jenderal Perhimpunan Onkologi Indonesia (POI)
Ketua Ikatan Ahli Patologi Indonesia Cabang Jakarta (IAPI)
Steering Committee Indonesia Asia Cancer Registry Network
Steering Committee Indonesia Asia Pacific Organization for Cancer Prevention
(APOCP)
Counselor Indonesia for Asia Pacific Society Molecular Immunohistochemistry
(APSMI)
 NCCPs : Programs
Adopted from WHO Guideline on Cancer Control
1. Prevention (Cancer Awareness)..cancer is preventable

2. Early detection-screening-Early treatment ..curable

3. Diagnostic and Treatment..Routine-Molecular

4. Surveillance &Cancer Registry..HBCR-PBCR 1,2,6,7

5. Research ..Epidemiology-translational-clinical trial

6. Palliative Care..quality of life

7. Support and Rehabilitation..quality of life

 The Role of Cancer Registries in NCCPs
Pre-Clinical Phase Clinical Phase

Onset of Early Onset of Symptoms

Exposure and/or Signs
Disease Detection
D1
Cure

A B C D2 Disability

D3 Death

Primary Secondary Tertiary

Prevention Prevention Prevention
 Carcinogenesis

• CYTOGENETIC
• EMBRYOGENESIS
• HISTOGENESIS-ORGANOGENESIS
• MOLECULAR BIOLOGY
• MOLECULAR PATHOLOGY
Cancer Definition - Causes
Cancer is an acquired genetic disease.
It is initiated by an irreversible
genome damage (mutation)

Cancer:
*abnormal tissue proliferation in the
cell with genetic modification
*Proliferation>dimension and speed of
regeneration, recovery and inflamation
 Sel
Suatu struktur dan fungsi pada hewan, tumbuhan
dan manusia yang merupakan satuan hidup yang
paling kecil yang sanggup hidup mandiri.

Sejarah
Robert Hooke 1665 – Jaringan gabus , rongga-rongga
kosong.

Virchow 1885 – Semua sel berkembang dari sel

yang telah ada.
sequence of sense strands of exon 1 (codons 11-13) of the K-ras gene
from the six pancreatic cancer cell lines. K-ras has the GGT→GTT
mutation at codon 12, but has wild-type GGC at codon 13. The
negative control BXPC-3 is shown to be wild-type at codons 12 and 13.
Bottom: sequence of antisense strands of exon 1 of the K-ras gene
from the six pancreatic cancer cell lines. K-ras codon 12 has the
ACC→AAC mutation at codon 12, but has wild-type GCC at codon 13.
BXPC-3 is shown to be wild-type at codons 12 and 13.

➢Gene – segment of DNA that codes for a

polypeptide chain
➢Includes Exons and Introns
➢Transcriptome – the complete set of genes
expressed under particular conditions
 Genome
➢ Genome – complete set of hereditary information for
any organism (Its genome is first duplicated and then
distributed to each daughter cell)

➢ Chromosome – a discrete unit of genome carrying

many genes

➢Consists of long duplex DNA molecule and

proteins
EMBRIOGENESIS-ORGANOGENESIS
1 fertilized egg
50x1012

1016 cell divisions/lifetime

Proliferation Differentiation Death

SITOGENETIK
 Tissue-
proliferative
Activity
• The tissues of the body are
divided into three groups on the
basis of their proliferative activity.
1. continuously dividing
tissues (also called labile
tissues)
2. Quiescent (or stable)
tissues
3. Non dividing
(permanent) tissues

Cell-cycle landmarks. The figure shows the cell-cycle phases (G0, G1, G2, S, and M), the location of the
G1 restriction point, and the G1/S and G2/M cell-cycle checkpoints. Cells from labile tissues such as the
epidermis and the gastrointestinal tract may cycle continuously; stable cells such as hepatocytes are
quiescent but can enter the cell cycle; permanent cells such as neurons and cardiac myocytes have lost
the capacity to proliferate.
(Modified from Pollard TD and Earnshaw WC: Cell Biology. Philadelphia, Saunders, 2002.)
 1. continuously dividing (labile) tissues
• In continuously dividing tissues (also called labile tissues) cells proliferate
throughout life, replacing those that are destroyed.
• These tissues include surface epithelia, such as
– stratified squamous surfaces of the skin, oral cavity, vagina, and
cervix;
– the lining mucosa of all the excretory ducts of the glands of the body
(e.g., salivary glands, pancreas, biliary tract);
– the columnar epithelium of the gastrointestinal tract and uterus;
– the transitional epithelium of the urinary tract, and cells of the bone
marrow and hematopoietic tissues.
• In most of these tissues, mature cells are derived from stem cells, which
have an unlimited capacity to proliferate and whose progeny may undergo
various streams of differentiation
 2. Quiescent (or stable) tissues
• Quiescent (or stable) tissues normally have a low level of replication;
however, cells from these tissues can undergo rapid division in response to
stimuli and are thus capable of reconstituting the tissue of origin.
• They are considered to be in the G0 stage of the cell cycle but can be
stimulated to enter G1.
• In this category are
– the parenchymal cells of liver, kidneys, and pancreas;
– mesenchymal cells, such as fibroblasts and smooth muscle;
– vascular endothelial cells;
– and resting lymphocytes and other leukocytes.
• The regenerative capacity of stable cells is best exemplified by the ability
of the liver to regenerate after partial hepatectomy and after acute
chemical injury.
• Fibroblasts, endothelial cells, smooth muscle cells, chondrocytes, and
osteocytes are quiescent in adult mammals but proliferate in response to
injury.
 3. Non dividing (permanent) tissues
• Nondividing (permanent) tissues contain cells that have left the cell cycle
and cannot undergo mitotic division in postnatal life.
• To this group belong neurons and skeletal and cardiac muscle cells. If
neurons in the central nervous system are destroyed, the tissue is
generally replaced by the proliferation of the central nervous system
supportive elements, the glial cells.
– However, recent results demonstrate that neurogenesis from stem cells may
occur in adult brains.
– Although mature skeletal muscle cells do not divide, skeletal muscle does have
some regenerative capacity, through the differentiation of the satellite cells
that are attached to the endomysial sheaths. If the ends of severed muscle
fibers are closely juxtaposed, muscle regeneration in mammals can be
excellent, but this is a condition that can rarely be attained under practical
conditions.
– Cardiac muscle has very limited, if any, regenerative capacity, and a large
injury to the heart muscle, as may occur in myocardial infarction, is followed
by scar formation.
CELL
 Cell proliferation
the process that results in an increase of the number of cells, and is
defined by the balance between cell divisions and cell loss through
cell death or differentiation.

Cell proliferation can be stimulated by physiologic and pathologic conditions.

1. Physiologic condition
– The proliferation of endometrial cells under estrogen stimulation during the
menstrual cycle and the thyroid-stimulating hormone-mediated replication of
cells of the thyroid that enlarges the gland during pregnancy are examples of
physiologic proliferation.
– Physiologic stimuli may become excessive, creating pathologic conditions
such as nodular prostatic hyperplasia resulting from dihydrotestosterone
stimulation and the development of nodular goiters in the thyroid as a
consequence of increased serum levels of thyroid-stimulating hormone.
2. Pathologic condition
– Many pathologic conditions such as injury, cell death, and mechanical
alterations of tissues also stimulate cell proliferation.
Proliferative – Growth Factor

Cell proliferation is typically initiated by

the action of growth factors
Growth Factors:
1. Epidermal Growth Factor (EGF) and
Transforming Growth Factor-α (TGF-α).
2. Hepatocyte Growth Factor (HGF)
3. Vascular Endothelial Growth Factor (VEGF)
4. Platelet-Derived Growth Factor (PDGF)
5. Fibroblast Growth Factor (FGF)
6. TGF-β and Related Growth Factors
7. Cytokines
NORMAL CELL PROLIFERATION is
necessary for
1. growth and development
Recall:
a. A totipotent cell has the capacity to
develop into any type of cell,
whether embryonic, extra-
embryonic, or adult.
b. A pluripotent cell can develop into
any type of adult cell, but cannot
give rise to extraembryonic
membranes (amnion, chorion,
allantois).
c. A multipotent cell can develop into
multiple types of cells, but not as
many types as a pluripotent cell.
These stem cells usually give rise to
a particular type of cells.
2. replacement of destroyed cells
 Apoptosis: Programmed Cell Death
Apoptosis also known as as "programmed cell death" and can be triggered
by a variety of signals. It involves...
• sequential destruction of the doomed cell via
• fragmentation of chromosomes
• organelle disruption
• fragmentation of cell
• removal of apoptotic body (cell corpse) by scavenger cells
• In multicellular organisms, programmed cell death occurs primarily in
somatic cells.
• Cell proliferation replaces somatic cells lost to cell death.
CELL DEATH is necessary for
• removal of cells not needed after a certain point in development
• removal of potentially dangerous damaged cells
Proliferation vs. Apoptosis Controls
These are interrelated, and may induce apoptosis in cells that fail to successfully complete
some phase of cell cycle.

Intracellular signals
• cell cycle negative controls: inhibition of CDK-cyclin (see illustration below)
• cell cycle positive controls: activation of CDK-cyclin
• mitogens are polypeptide ligands (signals released from a nearby (paracrine) source
and received by plasma membrane receptors). Some of these are growth factors that
activatereceptor tyrosine kinases (RTK proteins). This initiates a signal cascade that
affects the configuration of many different transcription factors, affecting the gene
activity in the cell
• apoptosis positive controls: leakage of cytochrome c from defective mitochondria acts
as a trigger for apoptosis
• apoptosis negative controls: proteins such as Bcl-2 and Bcl-x block the release of
cytochrome c from mitochondria, possibly stabilizing the mitochondrial membrane and
preventing its rupture). This maintains the apoptosis system in "off" mode

Extracellular signals
• based on cell-cell communication
• secreted molecules (paracrine signals act locally, are not sent via circulatory system)
• direct cell-cell contact
 Cell Differentiation
• Cellular differentiation is the process of a cell changing from one cell
type to another.
• Most commonly this is a less specialized type becoming a more specialized
type, such as during cell growth.
• Differentiation occurs numerous times during the development of
a multicellular organism as it changes from a simple zygote to a complex
system of tissues and cell types.
• Differentiation continues in adulthood as adult stem cells divide and create
fully differentiated daughter cells during tissue repair and during normal
cell turnover.
• A cell that can differentiate into all cell types of the adult organism is known
as pluripotent. A cell that can differentiate into all cell types, including the
placental tissue, is known as totipotent.
• Some differentiation occurs in response to antigen exposure.
• Differentiation dramatically changes a cell's size, shape, membrane
potential, metabolic activity, and responsiveness to signals.
– These changes are largely due to highly controlled modifications
in gene expression and are the study of epigenetics.
– With a few exceptions, cellular differentiation almost never involves a
change in the DNA sequence itself. Thus, different cells can have very
different physical characteristics despite having the same genome.
• In cytopathology, the level of cellular differentiation is used as a measure
of cancer progression. "Grade" is a marker of how differentiated a cell in a
tumor is.
ORGANISASI KEHIDUPAN
 Cellular equilibrium
Proliferation Differentiation Death

Transit
Renewing
Proliferating

Exiting
Cancer: disruption of cellular equilibrium

Proliferation Differentiation Death


Molecular Basis
Of Diseases
Environment
And genes
Growth regulation
e.g.Rb causing
Retinoblastoma etc
Changes in structural
Proteins
1.e.g. collagen, Deletions
Or point mutation that
Produce reduced amount
Of normal collagen or
Normal amounts of mutant
Collagen. Causing
Osteogenesis imperfecta
2.e.g cell membrane Fibrillin
Missense mutations causing
Marfan syndrome
Or deletion of dystrophin gene
Causing Duchene muscular
Dystrophy
Changes an Enzyme
e.g. Phenylalanine hydroxylase
Splice site mutation leading to reduced amount
Causing phenylketonuria
Changes an Enzyme inhibitor
e.g. 1-Antitrypsin
Missense mutation that impair secretion from liver
To serum causing Emphysema and Liver disease
Changes a receptor
e.g. Low density lipoprotein receptor
Deletion or point mutation that reduce synthesis,
Or transport to the cell surface or binding to low
density lipoprotein
Causing Familial hypercholesterolemia
Change a transport or carrier protein
1.e.g. Haemoglobin
Mutations in splice sites (commonest) leading to
Reduced -globin.causing -Thalassemia in
-Thalassemia the -globin gene is usually deleted
2.e.g. Cystic fibrosis transmembrane conductance
Regulator. Deletions or point mutation causing
Cystic fibrosis.
Changes in Hemostasis
e.g. Factor VIII deletions, insertions, nonsense
Mutation reduce synthesis or abnormal factor VIII
Causing Hemophilia A.
 ACTIVATION INACTIVATION
of of Tumor
Growth Promoting Suppressor Genes
Oncogenes ( Anti Oncogenes )

CANCER
MUTASI BERULANG SEBAGAI PENYEBAB KANKER

Sel normal
Mutasi
pertama
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kedua
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ketiga

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keempat
MUTASI BERULANG SEBAGAI PENYEBAB KANKER

Sel normal
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kedua
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MUTASI BERULANG SEBAGAI PENYEBAB KANKER

Sel normal
Mutasi
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MUTASI BERULANG SEBAGAI PENYEBAB KANKER

Sel normal
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MUTASI BERULANG SEBAGAI PENYEBAB KANKER

Sel normal
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kedua
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MUTASI BERULANG SEBAGAI PENYEBAB KANKER

Sel normal
Mutasi
pertama
Mutasi
kedua
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ketiga

Mutasi
keempat
Sel-sel ganas
 ◼ Sel Kanker membelah setiap 2-6
minggu
2-6 minggu
 Ukuran sel kanker:
 Satu juta sel
2-6 minggu kanker = ujung
jarum

 Satu milyar sel

kanker = sebesar
buah anggur

 230 = 1,073,741,824
2-6 minggu = 1 milyar sel
Karsinogenesis- Waktu terjadinya kanker
 MOLECULAR
MOLECULAR BIOLOGY
BIOLOGY OF CARCINOGENESIS
OF CARCINOGENESIS

◆ Tumours develop through the clonal expansion of a

single genetically damaged progenitor cell
(monoclonal theory of carcinogenesis).
◆ Tumour evolution multistep process which may
last for years and decades and results from
progressive accumulation of genetic defects and
altered gene products.
◆ Genes involved in carcinogenesis are normal
constituents of the human genome and their products
play a central role in the physiological regulation of
cell growth, division and differentiation.
◆ Tumour development is caused by regulation errors
or structural changes in this network.
 Carcinogenesis
• Where are the targets of the genetic
damage??
• Four regulatory genes are the main targets:
– Growth promoting protooncogenes
• Protooncogene > mutation > oncogene
– Growth inhibiting (supressors) genes
– Genes regulating apoptosis
– DNA repair genes
Barret JC. Environmental Health Perpectives.1993:100;9-20
 Molecular Basis of Cancer
◼ Targeted genes:
◼ 1. Proto-oncogenes (oncogenes)
◼ 2. Tumor suppressor genes
◼ 3. Genes controlling apoptosis
◼ 4. Genes regulating DNA repair
◼ Other genes involved:
◼ Genes regulating angiogenesis
◼ Genes enhancing invasion and metastasis
◼ Carcinogenesis is a multistep process
◼ At both genetic and phenotypic levels
◼ Progression results from accumulation of genetic
defects
 ONCOGENE PRODUCTS
•Growth factors: PDGF (platelet-derived growth
factor) CSF-1 (colony stimulating factor-1) EGF (epidermal
growth factor) TGF-α and β (transforming growth factors),
etc.
•Growth factor receptors: EGFR (human epidermal growth factor
receptor 1/HER1) HER2 (c-erbB-2/neu), etc.
•GTP-binding proteins (intracellular signal transmission) : RAS
family
•Nuclear transcription factors: MYC family, FOS, MYB
TUMOR SUPRESSOR GENES
Estimated age-standardized incidence and mortality rates
Men Women
 TOP 10 MALIGNANCY IN DHARMAIS NCC 1993-2010

Men

Courtesy:
Hospital-Based Cancer Registry Women
Dharmais NCC
 LUNG CANCER IN
DHARMAIS NCC
1993-2010

Courtesy:
Hospital-Based Cancer Registry
Dharmais NCC
total all cases Lung ca in men Lung ca in women
Estimated age-standardized incidence and mortality rates
Men Women
2013 :Registration activity 2018 : National data
INDONESIAN CANCER INCIDENCE DATA BY AGE, 2018

Incidence by Crude Rate

 Risk factor for breast cancer
Direct factor
Radiation especially during puberty
Inherited mutation

Contributing factor Vulnerability

Lack of exercise Early menses
Excess of alcohol Late menopause
Deficiencies of vitamin D, fiber, No pregnancy
melatonin ?? Breast
Harmful xenohormones (some cancer
plastic, fuels, pesticides)
Increased Insulin-like Growth Factor
 Breast profile

A. Ducts
B. Lobules
C. Dilated section of
duct to hold milk
D. Nipple
E. Fat
F. Pectoralis major
muscle
G. Chest wall/rib cage

Enlargement
A. Normal duct cells
B. Basement membrane
C. Lumen (center of duct
 Well-Established (Traditional) Prognostic Factors
A. Clinical factors : TNM staging, Age, Menstrual status.
Grade 1 Grade 2 Grade 3
B. Pathological factors
1. Anatomic Size
2. Histologic Type
3. Histologic Grade
4. Node Involvement – SLND
5. Molecular Classification
6. Other Histologic Features ER/PR
7. Hormonal Receptor (Estrogen and Progresteron)
8. HER-2 / Cerb-B2

Prognostic Factors in Non-Operable (Inflammatory and Non

Inflammatory Carcinoma)

Prognostic Factors in Operable Breast Carcinoma

New Prognostic Factors
1. Circulating tumor cells : Micro array, Proliferation Ki67, PCNA
2. Oncogen and Antioncogen
3. Angiogenesis (VEGF)
 Pathology and Genetics:
Tumors of the Lung, Pleura, Thymus, and Heart (IARC 2014)
Lung Pleura Thymus Heart
• Epithelial tumors • Mesothelial tumours • Epithelial tumours • Benign tumours and
• Mesenchymal • Mesenchymal tumours • Germ cell tumours tumour-like lesions
tumours • Lymphoproliferative of the mediastinum • Tumours of
• Lymphoproliferative tumours • Lymphomas of the uncertain behavior
tumours mediastinum • Germ cell tumours
• Tumours of ectopic • Histiocytic and • Malignant tumours
origin dendritic cell • Tumours of the
• Metastatic Tumours neoplasms of the pericardium
mediastinum
• Myeloid sarcoma
and extramedullary
acute myeloid
leukemia
• Soft tissue tumours
of the mediastinum
• Ectopic tumours of
the thymus
• Bronchoscopy
• Pleural Puncture
• FNAB
• CT guided TTNA
• Biopsy
• Pleuroscopy
• Mediastinoscopy with
VATS
• Exploration
Thoracotomy
Tumor Progression

Cellular

Multiple mutations lead to colon cancer

Genetic changes --> tumor changes
 What causes Cancer?
• Cancer is caused by
alterations or mutations
in the genetic code
• Can be induced in
somatic cells by:
– Carcinogenic
chemicals
– Radiation
– Some viruses
• Heredity - 5%
 CHEMICAL CARCINOGENESIS
INITIATION
Rapid onset
Ireversible, DNA Damage
Modification of the morphological potenciy of the affected Cell

PROMOTION
Slow development ( latency periode 5-30 yrs), Reversible, non-additive
Expression of altered gene product (No direct DNA damage), Dose treshold
Increase proliferation (Clonal Expansion), Atypical differentiation
Development of a pre-cancerous lesion

MALIGNANT TRANSFORMATION
Conversion of pre-neoplastic cell into a cell with malignant phenotype
(uncontrolled growth, genetic instability)
Inheritance of damaged genetic material to daughter cells

TUMOR PROGRESSION
• Tumor growth ( clonal growth, tumor angiogenesis, tumor heterogenetic, cell
production and loss
• Invasion and metaztasise
Karsinogen
 Klasifikasi
Karsinogen
Group 1 : Carcinogenic
Group 2a : Probably carcinogenic
Group 2b : Possibly carcinogenic
Group 3 : Carcinogenecity not
classifiable
Group 4 : Probably not carcinogenic
DNA
 DNA Synthesis
• DNA synthesis is the natural or artificial creation
of deoxyribonucleic acid (DNA) molecules.
• The term DNA synthesis can refer to any of the following in
various contexts:
• DNA replication - DNA biosynthesis (in vivo DNA
amplification)
• Polymerase chain reaction - enzymatic DNA synthesis
(in vitro DNA amplification)
• Gene synthesis - physically creating artificial gene
sequences
 DNA Replication
• DNA replication is the biological process of producing two identical replicas
of DNA from one original DNA molecule.
• This process occurs in all living organisms and is the basis for biological
inheritance.
DNA Damage
Endogenous Factors
Spontaneous
DNA Damage a. Errors in proofreading
b. Deamination of bases
c. Depurination / Depyrimidination

Induced
a. Byproducts of normal cellular
processes (reactive oxygen
species etc)
Exogenous factors
a. UV irradiation (sunlight)
b. High energy irradiation (x-rays)
c. Mutagenic chemicals (Mustard
gas, ciggarette smoke, food
additives)
 DNA Repair

REPAIR PATHWAY

1. Direct reversal

2a. Base excision repair

2b. Nucleotide excision repair

DNA Repair 3. Mismatch repair

4a. Double strand break repair:

Homologous recombination
4b. Double strand break repair:
Non-homologous end joining
The Hallmarks of Cancer
 Emerging Hallmarks and Enabling
Characteristics
An increasing body of research suggests
that two additional hallmarks of cancer
are involved in the pathogenesis of
some and perhaps all cancers:
• One involves the capability to
modify, or reprogram, cellular
metabolism in order to most
effectively support neoplastic
proliferation.
• The second allows cancer cells
to evade immunological
destruction, in particular by T
and B lymphocytes,
macrophages, and natural killer
cells.
Because neither capability is yet generalized and fully validated, they are labeled as emerging hallmarks.
Additionally, two consequential characteristics of neoplasia facilitate acquisition of both core and emerging
hallmarks.
Genomic instability and thus mutability endow cancer cells with genetic alterations that drive tumor
progression.
Inflammation by innate immune cells designed to fight infections and heal wounds can instead result in their
inadvertent support of multiple hallmark capabilities, thereby manifesting the now widely appreciated
tumor-promoting consequences of inflammatory responses.
 The Hallmarks of Cancer
1. Sustaining proliferative signaling
2. Evading growth suppressors
3. Avoiding immune destruction
4. Enabling replicative immortality
5. Tumor-promoting inflammation
6. Activating invasion and metastasis
7. Inducing angiogenesis
8. Genome instability and mutation
9. Resisting cell death
10.Deregulating cellular energetics
Unrepaired DNA Damage

Cancerous cell
The rate of DNA repair depends on
many factors:
1. cell type
2. the age of the cell
3. the extracellular environment.

A cell that has accumulated a lot

of DNA damage, or one that no
longer effectively repairs damage,
can enter one of three states:
1. an irreversible state of
dormancy, known as
senescence
2. cell suicide, also known as
apoptosis (programmed cell
death)
3. unregulated cell division,
which can lead to the
formation of a tumor that is
cancerous
 DNA Damage → Unpaired DNA Damage → Cancerous Cell
• Cancer is a renegade system of growth that originates within a patient's body. There are
many different types of cancers, but all share one characteristic, unchecked cell growth that
may progress toward limitless expansion.
• The most important thing to remember is that cancer cells do not stop growing; soon the
numbers become huge and a tumor can be seen, felt or detected. All of these cells have
changes in their DNA or their surrounding tissue that cause them to behave in ways that are
harmful. Normal cells know when to stop growing/dividing.
• DNA damage or epigenetic changes have to occur before anyone gets cancer.

DNA damage can be caused by the following

factors:
1. Mutations make a person more
susceptible to cancer
2. Aging, chemicals, lifestyle, environment
and radiation act by: damaging genes
3. Viruses introduce their own genes into
cells, sometimes causing cancer.
4. Other Infectious Agents cause
inflammation and DNA changes that can
potentially lead to cancer.
 DNA Mutation
• Mutations are errors in DNA structure that alter genetic information.
• To function correctly, each cell depends on thousands of proteins to do their jobs in
the right places at the right times. Sometimes, gene mutations prevent one or more
of these proteins from working properly. By changing a gene's instructions for making
a protein, a mutation can cause the protein to malfunction or to be missing entirely.
When a mutation alters a protein that plays a critical role in the body, it can disrupt
normal development or cause a medical condition.
• Mutations may be caused spontaneously by mistakes that occur during cell division,
or they may be caused by exposure to DNA-damaging agents in the environment.
Mutations can be harmful, beneficial, or have no effect. If they occur in cells that
make eggs or sperm, they can be inherited; if mutations occur in other types of
cells, they are not inherited. Certain mutations may lead to cancer or other diseases.
DNA Mutation
• All mutations are changes in the normal base sequence of DNA. Many mutations are
silent and have no effect. This is because:
• We have a great deal of duplication in our genetic code
• We have repair mechanisms to fix errors
• Mutated cells are often unable to reproduce

• However, when more and more mutations build up in a single cell, these mechanisms
may not be sufficient to protect us from the uncontrolled reproduction that is
characteristic of cancer.
• One of the biggest problems with all of this genetic instability in cancer cells is that a
tumor is likely to have several different genotypes amongst its many cells, which
makes treatment difficult.

• There are two types of mutations

1. Hereditary mutations: mutations passed on to us by our parents and present in
all of our cells from birth. These are referred to as germ line mutations since
they were present in the egg and/or sperm cells (called germ cells). Only about
10% of cancer is hereditary.
2. Somatic mutations: are caused randomly during a lifetime of regenerating cells
by: Cell cycle errors, Copy errors during DNA replication, Environmental agents
such as chemicals, smoking or pesticides, Radiation, Certain viruses, and Other
life style exposures
 DNA Damage
Damages are physical
abnormalities in the DNA
DNA damages can be recognized
by enzymes, and thus, they can
be correctly repaired
If a cell retains DNA damage,
transcription of a gene can be
prevented, and thus, translation
into a protein will also be blocked
DNA Mutation
A Mutation is a change in the
base sequence of the DNA
A Mutation cannot be recognized
by enzymes once the base
change is present in both DNA
strands, and thus, a mutation
cannot be repaired
Mutations can cause alterations
in protein functions and
regulation.
Mutations are replicated when
the cell replicates
 Cellular Adaptation
Decrease in the size of cells
Atrophy
Results in reduced tissue mass
Increased in cell size
Hypertrophy
Results in enlarged tissue mass
Increased number of cells
Hyperplasia
Results in enlarged tissue mass
Mature cell type is replaced by a different
Metaplasia
mature cell type
Dysplasia Cells vary in size and shape within a tissue
Undifferentiated cells, with variable nuclear and
Anaplasia
cell structures
Neoplasia “New growth” – commonly called tumor
 Abnormal cell growth patterns
Normal
cells

Hypertrophy
Artrophy
Different
Normal cells
Replacement cells

Hyperplasia
Metaplasia

Neoplasia
Dysplasia (malignant)
Karsinogenesis
 Types of tissue growth
Hypertrophy Hyperplasia Metaplasia Dysplasia Anaplasia Neoplasia
Definition Increase in size Increase in the Reversible Altered cell “To form “New growth”
of the cells number of replacement of maturation, backward” Unregulated
without an cells; can be one cell type orientation, Lack of cell cell
increase in physiologic or with another; and tissue differentiation; proliferation as
number. pathologic adaptation to architecture; a hallmark of a result of
external may progress malignancy genetic
environment to cancer or changes
regress to
normal cells.
Mechanism Increase in Growth factors External stimuli Dysregulation New theories Carcinogenesis
protein stimulate cell triggers altered of cell suggest that
production in proliferation gene maturation and anaplasia
response to from existing transcription, growth as a results from
mechanical mature cells or leading to result of lack of
stress and stem cells. differentiation altered gene differentiation
growth factors of stem cells to expression or of cancer stem
a different cell genetic cells instead of
type; nota mutations. dedifferentiati
conversion on of mature
from one cells.
differentiated
cell type to
another.
Cancer risk – + ++ +++ ++++ Cancer formed
 Neoplasia / Neoplasm
Definitions

• Neoplasia – new growth

• Abnormal mass of tissue with growth that exceeds
and is uncoordinated with that of the surrounding
normal tissues; autonomous
• Tumor – synonymous with neoplasm
• Cancer – common term for malignant neoplasm
• Neoplasm have parenchyma and stroma
• Benign and malignant tumors each have their own
nomenclature
 Tumors and cell origin

Benign Neoplasm Cell origin Cell type

Biliary tree Cholangioma
Tumor

Colon Colonic polyp

A benign tumor : Adenoma
a mass of cells (tumor) that lacks Glandular Papilloma
Cystadenoma
the ability to invade Endodermal Liver Liver cell adenoma
neighboring tissue or metastasize Placental Hydatiform mole
Renal Renal tubular adenoma
Squamous cell
Squamous
papilloma
Stomach Gastric polyp
Blood vessel Hemangioma
Bone Osteoma
Cartilage Chondroma
Fat tissue Lipoma
Mesenchymal
Fibrous tissue Fibroma
Lymphatic vessel Lymphangioma
Smooth muscle Leiomyoma
Striated muscle Rhabdomyoma
Glia Astrocytoma
Melanocytes Nevus
Ectodermal
Meninges Meningioma
Nerve cells Ganglioneuroma
Wujcik, Debra; Yarbro, Connie Henke; Barbara H. Gobel (2011). Cancer
nursing: principles and practice. Boston: Jones and Bartlett Publishers
• Benign tumors generally have a slower growth rate than malignant tumors and the
tumor cells are usually more differentiated (cells have normal features).
• Benign tumors are typically surrounded by an outer surface (fibrous sheath
of connective tissue) or remain with the epithelium.
• Although benign tumors will not metastasize or locally invade tissues, some types may
still produce negative health effects.
• The growth of benign tumors produces a "mass effect" that can compress tissues and
may cause nerve damage, reduction of blood to an area of the body (ischaemia), tissue
death (necrosis) and organ damage.
• The mass effect of tumors are more prominent if the tumor is within an enclosed space
such as the cranium, respiratory tract, sinus or inside bones. Tumors
of endocrine tissues may overproduce certain hormones, especially when the cells are
well differentiated. Examples include thyroid adenomas and adrenocortical adenomas.
• Although most benign tumors are not life-threatening, many types of benign tumors
have the potential to become cancerous (malignant) through a process known as tumor
progression
Borderline Neoplasm

• Tumors of borderline malignancy are epithelial

tumors that don’t clearly appear to be
cancerous.
• Although the cells of the tumor appear
malignant (cancerous), they have not invaded
the underlying or nearby tissue
In situ Neoplasm
• Carcinoma in situ (CIS), also known as in situ neoplasm
• Carcinoma in situ is, by definition, a localized phenomenon, with no
potential for metastasis unless it progresses into cancer. Therefore, its
removal eliminates the risk of subsequent progression into a life-
threatening condition. Many forms of CIS have a high probability of
progression into cancer, and therefore removal may be recommended;
however, progression of CIS is known to be highly variable and not all CIS
becomes invasive cancer.
• These terms are related since they represent the steps of the progression
toward cancer:
• Dysplasia is the earliest form of precancerous lesion recognizable in
a biopsy. Dysplasia can be low-grade or high-grade. High-grade
dysplasia may also be referred to as carcinoma in situ.
• Invasive carcinoma, usually simply called cancer, has the potential to
invade and spread to surrounding tissues and structures, and may
eventually be lethal.
Malignant Neoplasm
A malignant neoplasm is composed of cells that look less like the normal cell of
origin. It has a higher rate of proliferation. It can potentially invade and
metastasize.

Characteristics of malignant neoplasms include:

• More rapid increase in size
• Less differentiation (or lack of differentiation, called anaplasia)
• Tendency to invade surrounding tissues
• Ability to metastasize to distant tissues

Cytologic features of malignant neoplasms include:

• Increased nuclear size (with increased nuclear/cytoplasmic ratio--N/C ratio).
• Variation in nuclear or cell size (pleomorphism).
• Lack of differentiation (anaplasia).
• Increased nuclear DNA content with subsequent dark staining on H and E
slides (hyperchromatism).
• Prominent nucleoli or irregular chomatin distribution within nuclei.
• Mitoses (especially irregular or bizarre mitoses).
 Spread of Malignant Neoplasms
• By direct extension (invasion) into surrounding tissues.
• Through lymph channels to lymph nodes (lymphatic spread)--typical of
carcinomas.
• Via the bloodstream (hematogenous spread)--typical of carcinomas or
sarcomas.
• Within body cavities (seeding)--typical of neoplasms impinging upon body
cavities, such as the peritoneal cavity.

Source:
http://www.nature.com/nrc/journal/v3/n1/fig_tab/nrc967_F1.html
 Characteristics of tumors
• Majority of neoplasm can be categorized clinically and
morphological into benign and malignant on the basis of
certain characteristics listed below:
1. Rate of growth
2. Cancer phenotype and stem cells
3. Clinical and gross features
4. Microscopic features
5. Local invasion (direct spread)
6. Metastasis (distant spread)
 1. Rate of Growth
• The tumor cell proliferate more rapidly than the normal cells
• The tumor enlarge rate is depends upon
Rate of growth of a tumor
1. Doubling time (mitotic rate) of tumor cells
2. Number of cells remaining in pre-operative pool
(growth fraction)
3. Rate of loss of tumor cells by cell shedding
Cancer cell do not follow the normal cell control in
cells, and are immortal. The cell dvision rate is
high and center of tumor do not receive
adequate nourishment and undergo ischemic
necrosis, loss shedding
Death tumor cells appear as apoptotic figures and
dividing tumors are seen as normal/abnormal
mitotic figure → ultimately tumor grow in size
Degree of differentiation of a
tumor
• Rate of growth of malignant
tumor is directly proportionate to
the degree of differentiation
• Poorly differentiated tumors show
aggresive growth pattern compare
to better differentiated tumors
• Rarely, a malignant tumor may
disappear spontaneously from the
primary site, due to good host
immune attack
 2. Cancer phenotype and stem cells
Cancer cells
1. Disobey the growth control – proliferate rapidly
2. Escape from death signals – immortality
3. Imbalance between cell proliferation and cell death – excessive growth
4. Loss differentiation properties – no function
5. Are unstable – newer mutations
6. Overrun their neighbouring tissue – invade locally
7. Have run the ability to travel from the site of origin to other part of body –
distant metastasis

Cancer stem cells / tumor-initiating cells have the properties of self-renewal,

asymmetric replication and transdifferentiation
 3. Clinical and gross features
- Benign tumor are generally slow growing and depending upon locations
remains asymptomatic or may cause serous symptoms. Benign tumors are
generally spherical or ovoid shape
- Malignant tumor grow rapidly, invade locally into deeper tissue and spread
to distant sites (metastasis). Malignant tumours are usually irregular in
shape, poor-circumscribed and extent into adjacent tissues

4. Microscopic features
- Microscopic pattern
- Cytomorphology of neoplastics cells
- Tumor angiogenesis and stroma
- Inflammatory reaction
5-6. Direct and Distant Spread
- Local invasion (direct spread)
- Benign: Expand and push aside without invading, infiltrating, or
metastasising
- Malignant: expand, inasion, infiltration, and destruction of the
surrounding tissue
- Metastasis (distant spread)
- Metastasis: spread of tumor by invasion
- Routes of metastasis
- Lymphatic spread
- Haematogenous spread
- Spread along body cavities and natural passages
Diagnosis Tumor ganas
 Pendekatan Diagnosis Tumor Ganas
• Diagnosis tumor ganas adalah usaha untuk mengidentifikasi jenis
tumor ganas yang diderita.
• Menegakkan diagnosis suatu tumor ganas adalah sangat penting
walaupun tidak selalu mudah dan harus dilakukan sebelum
memberikan terapi atau penatalaksanaan tumor ganas itu sendiri.

• Pendekatan diagnostik tumor ganas difokuskan pada:

1. Pemeriksaan Klinis
2. Pemeriksaan Laboratorium
3. Pemeriksaan Imaging / Radiologi
4. Pemeriksaan Tumor marker / Penanda tumor
5. Pemeriksaan Patologi Anatomi → baku emas / gold standard
6. Pemeriksaan Diagnosis molekuler
1. Pemeriksaan Klinis
ANAMNESA
A. Riwayat kesehatan personal:
1. Penyakit terdahulu
2. Kondisi medis
3. Riwayat operasi
4. Imunisasi
5. Riwayat penggunaan obat
6. Faktor gaya hidup : misalnya diet,
olahraga, merokok, alkohol, riwayat
seksual dan reproduksi
7. Detail tentang tanda dan gejala atau
masalah kesehatan potensial
B. Riwayat kesehatan keluarga
1. Tipe dan letak tumor
C. Riwayat pekerjaan untuk mengidentifikasi
paparan zat atau bahaya yang terkait dengan
kanker
Untuk anak, ditambahkan dengan
- Riwayat tumbuh kembang saat prenatal dan
neonatal termasuk riwayat penyakit ibu saat
hamil dan paparan terhadap obat dan
alkohol
- Tumbuh kembang
PEMERIKSAAN FISIK
Pemeriksaan Fisik Lengkap
1. Mengukur berat dan tinggi badan
2. Memeriksa kulit dan mata
3. Memeriksa hidung, mulut, dan tenggorokan
4. Meraba nadi pada leher, inguinal, dan kaki
5. Menguji refleks
6. Mendengarkan jantung, paru, dan abdomen
7. Meraba KGB pada leher, axilla, dan inguinal
8. Memeriksa tekanan darah dan denyut nadi
9. Meraba abdomen untuk memeriksa adanya
abnormalitas pada organ (terutama hepar,
limpa, dan ginjal)
Tergantung pada usia dan jenis kelamin, dapat
ditambah:
1. Clinical breast examination (CBE) untuk
memeriksa benjolan pada payudara
2. Digital rectal examination (DRE) untuk
memeriksa abnormalitas rektum dam prostat
3. Pemerisaan pelvik pada wanita untuk
memeriksa uterus dan ovarium, serta secara
langsung melihat vagina dan serviks untuk
pap smear
4. Memeriksa testis pada pria
2. Pemeriksaan Laboratorium
• Darah lengkap, faal hemostatik, urin lengkap, protein serum, tes fungsi hati,
alkali fosfatase, tes fungsi ginjal, elektrolit serum, gula darah, LDH, asam urat,
serum Igm
• Untuk menunjang diagnosis tumor ganas tidak banyak artinya, tetapi penting
dilakukan dengan tujuan untuk mengetahui keadaan pasien apakah ada
penyulit kanker atau penyakit sekunder, dan juga untuk persiapan terapi yang
akan dilakukan baik itu tindakan bedah maupun tindakan medik
3. Pemeriksaan Radiologi
• Ultrasound, Scanning radioaktif, CT Scan, Position Emission Tomography (PET
Scan), Magnetic Resonance Imaging (MRI), X-ray
• Dalam diagnosis tumor ganas, pemeriksaan radiologi berperan dalam 4 hal,
yaitu:
• Untuk membantu menegakkan diagnosis tumor ganas (radiodiagnosis)
• sebagai guiding untuk biopsi tumor ganas yang letaknya profunda dari
bagian tubuh atau organ
• berperan dalam menentukan staging
• Follow up
4. Pemeriksaan Penanda
Tumor
• Peran penanda tumor:
• Skrining atau deteksi dini
terhadap kanker
• Alat diagnostik terhadap
kanker dan jenis kanker
• Memperkirakan prognosis
dari penderita kanker
• Monitor tingkat
keberhasilan terapi
kanker (seperti operasi,
radiasi atau kemoterapi)
• Deteksi kekambuhan
kanker
5. Patologi Anatomi
Pemeriksaan Patologi Anatomi (PA) ialah pemeriksaan morfologi tumor, meliputi
pemeriksaan makroskopi dan mikroskopi.

Bahan untuk pemeriksaan PA dapat diperoleh dari biopsi tumor ganas atau dari
spesimen operasi.

1. Identitas Immuno- Flow Cytometry Sitogenetik

Pasien histokimia (IHK)
2. Gambaran
Makroskopik
• Menentukan tumor • Dapat digunakan Teknik:
3. Gambaran primer untuk diagnosis, - FISH
Mikroskopik • Membedakan antara klasifikasi, dan - PCR
4. Diagnosis (Tipe jenis kanker yang manajemen kanker
- Real Time PCR
berbeda, seperti seperti leukemia akut,
histologi dan penyakit - Reverse
karsinoma, melanoma,
grade) dan limfoma limfoproliferatif kronis, Transcriptase PCR
5. Ukuran tumor • Membantu dan Limfoma Non
mendiagnosa dan Hodgkin • Informasi tentang
6. Batas Sayatan
mengklasifikasikan prognosis yang dapat
Tumor leukemia dan limfoma memberikan
rekomendasi terapi
 Jenis pemeriksaan patologi anatomi
1. Sitopatologi 2. Histopatologi
perubahan inti sel dan sitoplasma sel bentuk dan struktur jaringan
Jarum halus dengan ukuran kecil lebih disukai sehingga kurang Evaluasi umumnya dimulai dengan biopsi jaringan
invasif dan traumatis sehingga lebih invasif dan traumatik
Pewarnaan dasar : pewarnaan Pap dan H&E Pewarnaan dasar : H&E
Diagnosis didapatkan dalam beberapa menit Diagnosis didapatkan setelah beberapa hari
Metode : Metode :
1. Exfoliative Specimens : Pap’s smear , Sputum , Swab, Bronchial 1. Core Biopsy specimen
brushing 2. Open Biopsy specimen
2. Fine Needle Aspiration Biopsy With/Without guiding : 3. Resection Specimen
Superficial lump)
3. Touch Imprint preparation : Discharge
4. Fluid Specimen : Ascites, Pleural effusion, Pericardial effusion,
Urine, Cerebrospinal, Bronchial washing)
Fungsi : Fungsi :
1. Diagnosa : pada pasien dengan keluhan, gejala atau kecurigaan 1. Diagnosa penyakit (Standar baku emas)
besar (mempunyai factor resiko) terhadap adanya kanker. 2. Untuk membedakan tipe sel (kanker) dan
2. Skrining : pada seseorang yang dicurigai mempunyai penyakit, memonitor respon sel terhadap pengobatan
meskipun belum muncul keluhan. Dengan kata lain, 3. Untuk menentukan metastasis kanker dan
pemeriksaan diagnosa dilakukan pada seseorang yang pengukuran derajat kanker (grading dan
mempunyai hasil skrining yang positif. staging)

3. Intra operative Vries Coupe (VC) / Potong Beku / Frozen Section

• Pemeriksaan ini dilakukan selama operasi.
• Tumor atau kanker dibedah dan langsung diperiksakan saat operasi dan hasilnya langsung diperoleh saat
itu juga. Hasil yang diperoleh menentukan jenis tindakan operasi apa yang akan dikerjakan.
http://www.campbellmedicalillustration.com/pathology-lab-process-infographic/
1. Booking in and labeling 2. Specimen container 3. Gross examination, 4. Cut specimens are placed 5. Cassettes are placed
specimen by laboratory with barcode for recording and cutting of in small, labeled containers into a processor overnight
personnel identification specimen carried out by called cassettes.
pathologist

6. Processor gradually 7. Processed tissue fragments are taken out 8. Specimen segments are then 9. Wax blocks are then
removes water from the of the processor and cassettes and embedded in paraffin wax blocks transferred to a
specimen transferred to a tissue embedding station. that harden at room temperature. microtome station.

10. The microtome cuts 11. Thin specimen slices are placed 12. The specimen slides 13. Once stained the slides are then ready for
the wax blocks into on a slide and put through an are stained with eosin review by the pathologist through a
extremely thin slices. automatic slide cover slipper before (red) and haematoxylin microscope. They will then be able to make a
being put through a stainer (blue). diagnosis or undertake further techniques to
http://www.campbellmedicalillustration.com/pathology-lab-process-infographic/
aid in diagnosis.
 Immunohistokimia
• metode untuk mendeteksi protein di dalam sel suatu jaringan dengan menggunakan
prinsip pengikatan antara antibodi dan antigen pada jaringan hidup.
• Pengecatan imunohistokimia banyak digunakan pada pemeriksaan sel abnormal seperti
sel kanker.
• Molekul spesifik akan mewarnai sel-sel tertentu seperti sel yang membelah atau sel
yang mati sehingga dapat dibedakan dari sel normal.
A. Epithelial markers 3. Neural antigens D. Biochemical markers
1. Cytokeratins (CK) a. S 100 1. Enzymes and isoenzymes
2. Epithelial membrane antigen b. Neuron specific enolase a. Prostatic acid
(EMA) (NSE) phosphatase (PAP)
3. Oncofetal antigens c. Glial fibrillary acidic b. Prostate Specific
a. Alpha-fetoprotein (AFP) protein (GFAP) Antigen (PSA)
b. Carcinoembryonic d. Synaptophysin c. Placental Alkaline
antigen (CEA) e. Nerve growth factor Phosphatase (PALP)
4. Desmoplakin receptor d. Lysozyme
B. Mesenchymal markers C. Prognostic markers 2. Protein
1. Muscle antigens 1. Cell adhesion molecules a. Ferritin
a. Desmin a. Cadherins b. Glycoprotein
b. Actin b. Integrins c. Beta protein
c. Myoglobin c. Selectins d. Immuno globulins
d. Myosin 2. Proliferation markers E. Hormone receptors
2. Vascular antigen a. PCNA 1. Estrogen receptor (ER)
a. CD 34 b. Ki67 2. Progesterone receptor (PR)
b. CD 31 c. AgNORs
6. Pemeriksaan Diagnosis Molekuler
Teknik:
- FISH
- PCR
- Real Time PCR
- Reverse Transcriptase PCR