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Department of Pathology
Gadjah Mada University School of Medicine
Blok Biomedis, 4 Maret 2009 [11]
Neoplasia
Neoplasia new growth
Neoplasm: abnormal tissue mass growing
excessively and indefinitely without
coordination with normal tissue
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coordination with normal tissue
Behaviour: progressive, useless,
independent from surrounding tissue,
unrelated to host needs, parasitic,
autonomic.
NEOPLASIA
(BASIC SCIENCES OF ONCOLOGY)
GENERAL DIAGNOSIS
COMPREHENSION
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EPIDEMIOLOGY THERAPY
PATHOBIOLOGY MANAGEMENT
NEOPLASIA
General Comprehension of Cancer
Definition, Perspective, Nomenclature, Epidemio-
logy, Hereditary Pre-neoplastic Disease
The Pathobiology of cancer
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Molecular Basis of Cancer, Oncogenes, Apoptotic
Genes, Suppressor Genes, Telomerase, Epige-
netic Theory
The Clinical Relevancies of Cancer
Biology of Tumor Growth, The Kinetic of Tumor,
Immunology of Tumor, Clinical Features of Tumor
Related terms
Hypertrophy
Hyperplasia
Metaplasia
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Metaplasia
Displasia
Anaplasia
HAMARTOMA
Hiperplasia: an increase in the number of cells in
an organ/ tissue
Hipertrofi: an increase in the size of the cells
Metaplasia : a reversible change in which one adult
cell type is replaced by another adult cell type
ISTILAH YANG BERUBUNGAN DENGAN NEOPLASIA
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cell type is replaced by another adult cell type
Displasia: a loss in the uniformity of the individual
cells + a loss of their architectural orientation
Anaplasia: lack of differentiation
Hamartoma: tumor like lesion, consist of two/ more
mature cell type normally found in an organ in which
the lesion arises
Metaplasia
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Apocrine metaplasia of the breast
Squamous metaplasia
Diferensiasi
Suatu proses/keadaan/perkembangan sel
tumor sampai tingkat tertentu di mana ada
kemiripan sel-sel neoplastik dengan sel
asalnya (baik, sedang, buruk tanpa
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asalnya (baik, sedang, buruk tanpa
diferensiasi / anaplasi)
Anaplasia:
- pleomorfisma selular dan nuklear
- peningkatan rasio inti/sitoplasma
- meningkatnya kromatin inti clumping /
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- meningkatnya kromatin inti clumping /
irregular
- mitosis patologik bizarre
- hilangnya orientasi (polarisasi sel)
- hilangnya kapasitas fungsional sel
Dysplasia
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History 1
Cancer has become increasingly prominent
in modern time
Cancer is not a modern disease
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Cancer is not a modern disease
recorded in ancient civilization: mummies from Egypt,
Ramayana history (2500 BC)
early cultures attributed the cause of cancer
to various gods
History 2
ancient civilization
middle ages
Hippocrates: ~400BC 1
st
theory
of natural causes of cancer: imbalance between
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of natural causes of cancer: imbalance between
black humor and the three bodily humors: blood,
phlegm, bile
Cancer house, cancer family, cancer village
History 3
Sir Percival Pott (1775)
(the 1
st
recorded epidemiological study of cancer)
Young boy as a chimney sweeps In their twentieth had a
high rate of death due to cancer of the scrotum then
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high rate of death due to cancer of the scrotum then
he suggested frequent washing and changing of clothing
that trapped the soot reduce exposure to carcinogen
Other epidemiological study identified major
environmental factors: tobacco smoke, various
occupational exposure
History 4
Invention of microscope
Virchow every cell is born from another cell cancer is
a cellular disease
Cell biology molecular genetics the advancement of
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Cell biology molecular genetics the advancement of
knowledge about cancer biology cancer is
a genetic disease
Diagnostic, prognostic factors, therapy depend on the
study of populations of patients
History 5
Population study of cancer patients
Recognize the presence of heterogeneity
among patients with certain tumors
Predict the probability of certain outcome (e.g. survival as function of
time), based on the properties of tumors and host
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time), based on the properties of tumors and host
Challenge in therapeutic studies: application of knowledge about:
produce overall improvements in treatment outcome
with acceptable level of toxicity
The biology of tumor
Normal cells
Malignant cells
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Changes:
Genotypic
Phenotypic
Nomenklatur (tatanama)
Awalan yang menunjukkan asal jaringan
Skuamosa (epitel gepeng berlapis), adeno-(epitel kelenjar),
transisional, fibro- (jaringan ikat fibrosa, leiomio-(otot polos),
rabdomio-(otot lurik), lipo-(lemK), kondro (tulang rawan), osteo-
(tulang), hemangio-(pembuluh darah), limfangio-(pembuluh limfe)
Awalan yang menunjukkan pola pertumbuhan
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Awalan yang menunjukkan pola pertumbuhan
Folikular, sistik, papilar, vilosa, kribriformis, dll.
Kata tambahan menunjukkan gambaran makroskopik
Scirrhous (keras), medular (lunak, menyerupai sumsum tulang),
koloid)
Teratoma
Berasal dari lebih dari satu germ layer (jinak & ganas)
Benign epithelial tumors
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Adenomatous polyp
Benign germ cell tumors
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Benign cystic teratoma (dermoid cyst)
Benign epithelial tumor
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Squamous cell Papilloma
Benign epithelial tumor
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Fibroadenoma of the breast
Benign epithelial tumor
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Pleomorphic Adenoma of the salivary gland
Benign vs malignant epithelial tumor
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Adenoma Adenocarcinoma
Malignant epithelial tumor
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Carcinoma of the breast
Malignant tumor
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Cystadenocarcinoma of the ovari
Malignant epithelial tumor
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Squamous cell carcinoma
Malignant Epithelial Tumors
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Carcinoma in situ of the uterine cervix
Malignant epithelial tumor
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Colon carcinoma
Malignant Epithelial Tumors
Well differentiated
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Well differentiated
adeno-carcinoma
of the colon
Benign germ cell tumors
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Benign cystic teratoma (dermoid cyst)
Malignant mesenchymal tumor
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Rhabdomyosarcoma
Principal characteristics
of benign and malignant tumors
Features Benign Malignant
Growth rate Slow Relatively rapid
Mitotic activity Low High
Histologic resemblance to
normal tissue
Good Variable, often poor
Nuclear morphology Mostly normal Hyperchromatic,multiple
nucleoli, pleomorphic
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Invasion No Yes
Metastasis never Frequent
Border Circumscribed/
encapsulated
Poorly defined/ irregular
Necrosis Rare Common
Ulceration Rare Common
Growth Often exophytic Often endophytic
Malignant Mesenchymal Tumors
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Rhabdomyosarcoma
Benign vs malignant
Benign malignant
Circumscribed/ encapsulated
Intact surface
Exophytic growth
Ulcerated surface
Endophytic growth
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Circumscribed/ encapsulated
Homogenous cut surface
Heterogenous cut surface due to necrosis
Vascular permeation
Irregular infiltrative edge
Benign vs Malignant Tumors
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Benign vs malignant
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Benign vs malignant mesenchymal tumor
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Leiomyoma of the uteri
Spread of Malignant Tumors
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Metastatic cancer in the liver (pancreatic
adenocarcinoma)
Cystic lesion of the breast
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Metastasis
1. Limfogen
2. Hematogen
- Sistem venas porta hati
- Sistem venosa sistemik paru
- Sistem vena paru jantung kiri sirkulasi umum
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- Sistem vena paru jantung kiri sirkulasi umum
- Ca uteri & abdomen limfonodi cisterna chyli
ductus thoracicus sistemik
3. Trans-coelomic
4. Intra-epitelial
The Pathobiology of Cancer
Molecular basis of cancer: Oncogenes and regulator genes
Carcinogenic agents and their cellular interaction: chemical,
radiation, viral, bacterial carcinogenesis
Biology of tumor growth: kinetic, angiogenesis, progression
and heterogeneity, invasion and metastasis
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and heterogeneity, invasion and metastasis
Host defense against tumors: tumor antigens and
immunosurveillance
Clinical features of tumors: efect of tumors on host
grading and staging of tumors
Epidemiologi : Faktor risiko
1. Umur
Makin tua pengaruh karsinogen makin kuat
2. Diet
Perbedaan geografis insiden kanker mencerminkan
perbedaan diet
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perbedaan diet
Minuman alkohol berpengaruh terhadap karsinogenesis
3. Lingkungan
Polusi (rokok, pekerjaan, kendaraan, pabrik)
Ativitas seksual
4. Perubahan genetik
Cancer
epidemiology
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Comparison between native Japanese,
Japanese immigrants and Calif.white
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HEREDITY & CANCER
Question:
Is cancer inherited?
Evidence:
Lung cancer in most instances clearly related to
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Lung cancer in most instances clearly related to
cigarette smoking, yet,
mortality to lung cancer has been shown to be four
times greater among non-smoking relatives
(parents & siblings) of lung cancer patients than
non-smoking relatives of controls
Hereditary forms of cancers can
be divided into 3 categories:
1. Inherited Cancer Syndromes
(autosomal dominant)
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2. Familial Cancers
3. Autosomal Recessive Syndromes of
Defective DNA Repair
1. Inherited Cancer Syndromes
(autosomal dominant)
Inheritance of a single mutant gene greatly
increases the risk of developing a tumor
The predisposition of these tumors shows an
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The predisposition of these tumors shows an
autosomal dominant pattern of inheritance
Inherited predisposition is indicated by strong
family history of uncommon cancer and/or
associated marker phenotype
1. Inherited Cancer Syndromes
(autosomal dominant)
Contoh tumor
Familial retinoblastoma
Familial adenomatous polyposis
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Familial adenomatous polyposis
of the colon
Multiple endocrine neoplasia
syndromes (MEN)
Neurofibromatosis type 1 and 2
Von HippelLindau Syndromes
Inherited Cancer
Syndromes
RETINOBLASTOMA
Carriers of mutant Rb
gene have a 10,000 fold
increased risk of
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increased risk of
developing
retinoblastoma (familial
type)
greatly increased of
developing second
cancer (ostreosarcoma)
Inherited Cancer Syndromes
Multiple endocrine neoplasia (MEN)
- The familial occurrence of the combination of:
medullary thyroid Ca, bilateral pheochromocy-
tomas, hyperparathyroidism (due to tumor)
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tomas, hyperparathyroidism (due to tumor)
- Mutation of ret proto-oncogene that is transmitted
in the germline
Inherited Cancer Syndromes
Von Recklinghausen neurofibromatosis
type 1 and 2
- multiple benign neurofibromas, cafe au lait
spot, iris hamartoma, increased risk of
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spot, iris hamartoma, increased risk of
developing fibrosarcomas
- mutation of NF-1 and NF-2 (tumor suppressor
genes which functions as a GAP protein that
inactivates ras)
Familial Adenomatous Polyposis Coli
Another hereditary disorder marked by
an extraordunarily high risk of cancer
Inherited Cancer Syndromes
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an extraordunarily high risk of cancer
Autosomal dominant mutation from
birth innumerable polypoid
adenomas mostly develop colon Ca
by age of 50
Adenoma-Carcinoma Sequence
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Inherited Cancer Syndromes
Von Hippel-Lindau Syndrome
Germ line mutation of VHN gene on
chromosome 3p hereditary renal cell
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chromosome 3p hereditary renal cell
cancer, phaeochromocytoma,
hemangioblastoma of the CNS, retinal
angioma, renal cyst
2. Familial Cancers
Evident familial clustering of cancer but role of
inherited predisposition may not be clear in an
individual case
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Breast Cancer
Ovarian cancer
Colon cancer other than familial
adenomatous polyps
3. Autosomal Recessive Syndromes of
Defective DNA Repair
Xeroderma pigmentosum
Ataxia telangiectasia
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Ataxia telangiectasia
Bloom syndrome
Fancony anemia
- autosomal recessive disorder hypersensitive
to UV
Xeroderma pigmentosum
Autosomal Recessive Syndromes of Defective DNA Repair
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- increased incidence of skin cancers
- defect in genes that function in nucleotide
excision repair, which is required for repair of
UV-induced pyrimidine dimers
Autosomal Recessive Syndromes of Defective
DNA Repair
Ataxia Telangiectasia AT gene (mutation in
single gene)
Gradual loss of Purkinje cells
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Immunodeficiency
Acute sensitivity to ionizing radiation
Profound susceptibility to lymphoid
malignancies
Autosomal Recessive Syndromes of Defective
DNA Repair
Bloom Syndrome
Hypersensitivity to ionizing
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Hypersensitivity to ionizing
radiation
Developmental defects
Predisposition to cancer
Autosomal Recessive Syndromes of Defective
DNA Repair
Fanconi anemia
Hypersensitivity to DNA cross-
linking agents (nitrogen mustard)
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linking agents (nitrogen mustard)
Anemia
Predisposition to cancer
Acquired Preneoplastic Disorders
Cell replication is involved in cancerous
transformation
Fertile soil for the origin of malignant neoplasm:
- regenerative proliferation: hepatoma
- hyperplasia: endometrium
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- hyperplasia: endometrium
- dysplasia: cervical
- metaplasia: bronchogenic Ca
the risk to develop neoplasm is
greater than average
Certain non-neoplastic disorder pre-neoplastic
- chronic atrophic gastritis
- solar keratosis
Acquired Preneoplastic Disorders
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- solar keratosis
- leukoplakia
The great majority of instances no malignant
neoplasm emerges the term persists because
it calls attention to the increased risk
The question then .
Is there any risk with all benign neoplasms?
although some risk may be inherent, most benign
neoplasm neoplasms do not become cancerous.
Some malignant tumors were developed from benign
tumors: leiomyoma leiomyosarcoma, pleomorphic
adenoma Ca
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Was the tumor an indolent form of cancer from the outset,
or was there a malignant focus in the benign tumor?
Generalization is impossible because each type of
benign neoplasm is associated with a particular level of
risk ranging from almost zero to frequently present
PATOGENESIS KANKER
Faktor geografik dan lingkungan
Umur
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Umur
Predisposisi genetik
Predisposisi non-herediter
Bacteria?
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CARCINOGENESIS
The Molecular basis of Cancer
Jantung permasalahan karsinogenesis:
kerusakan genetik non-letal
Tumor terbentuk dengan eksansi klonal sel
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Tumor terbentuk dengan eksansi klonal sel
prekursor tunggal akibat dari kerusakan
genetik
Karsinogenesis adalah suatu proses
multistep pada tingkat genetik dan fenotipik
sekaligus
CARCINOGENESIS
The Molecular basis of Cancer
4 kelas gena regulator normal (target utama
kerusakan genetik): (1) growth promoting
protooncogenes, (2) antioncogenes (growth
inhibiting suppressor genes), (3) apoptotic
genes (mengatur programmed cell death), dan
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genes (mengatur programmed cell death), dan
(4) gena reparasi DNA
Gena reparasi DNA mempengaruhi proliferasi
sel dan survival secara tidak langsung dengan
kemampuan reparasi kerusakan non letal
gena lain, termasuk gena-gena replikasi sel.
Perubahan fenotipik
Sifat pertumbuhan
- lepas dari kontrol
- kegagalan maturasi
- transplantable
- immortal
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- immortal
Perubahan morfologik
Kariotipik
Antigenik
Deviasi metabolik
Membran sel
AKTIVASI ONOGENA
Mekanisma perubahan protoonkogena menjadi
onkogena
Perubahan struktur gena prodk gena abnormal
(onkoprotein)
- Mutasi titik
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- Insersi dan delesi
Perubahan regulasi: expresi gena meningkatkan
produksi berlebihan protein perangsang pertumbuhan
(growth-promoting protein)
- translokasi kromosom
- amplifikasi gena
Mutasi titik
ras oncogene the best example
A very large number of human tumors carry ras point-
mutations
Mutation affect a domain critical to the GAP-induced
hydrolysis of GTP mutant ras proteins have a reduced
ability to hydrolyze GTP
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ability to hydrolyze GTP
Frequency:
- 90%: pancreatic adenocarcinoma
- 50%: colon and thyroid cancer
- 30%: lung adenocarcinoma & myeloid leukemia
- 0%: most ovarian and breast tumors
Chromosomal
translocations
Burkitts lymphoma
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Chronic Myelogenous
Leukemia
Gene
Amplification
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Amplification of N-myc gene in neuroblastoma: double minutes /
HSR (Homogenous-staining region)
CANCER SUPPRESSOR GENES
Misnomer
Physiologic function: regulate cell growth
apply brakes to cell proliferation
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apply brakes to cell proliferation
Discovered by studying rare disease such as
retinoblastoma
Knudson two-hit hypothysis of oncogenesis
Sub-cellular location of protein product of
tumor suppressor genes
2 broad categories regarding the functions:
Molecules that regulate nuclear transcription and cell
cycle
Cell surface: TGF-receptor, E-cadherin
Under plasma mebrane: NF-1
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Under plasma mebrane: NF-1
Cytoskeleton: NF-2
Cytosol: APC
Molecules that regulate signal tranduction
Nucleus: Rb, p53, WT-1, p16(INK4a), BRCA-1,
BRCA-2
CANCER SUPPRESSOR GENES
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The central role of the pRB in
regulating the cell cycle
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Selected tumor-suppressor gene involved in human neoplasm
TGF- receptor
Function: Growth inhibition
Tumors associated with somatic mutation:
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Tumors associated with somatic mutation:
Carcinoma of colon
Tumors associated with inherited mutation:
Unknown
Selected tumor-suppressor gene involved in human neoplasm
E-cadherin
Function:
Cell adhesion
Tumors associated with somatic mutation:
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Tumors associated with somatic mutation:
Ca. gaster & breast
Tumors associated with inherited mutation:
Familial gastric cancer
Selected tumor-suppressor gene involved in human neoplasm
NF-1
Function:
Inhibition of ras signal transduction
Tumors associated with somatic mutation:
Schwannoma
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Schwannoma
Tumors associated with inherited mutation:
Neurofibromatosis type 1 and
sarcomas
Selected tumor-suppressor gene involved in human neoplasm
NF-2
Function:
Unknown
Tumors associated with somatic mutation:
Schwannoma and meningioma
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Schwannoma and meningioma
Tumors associated with inherited mutation:
Neurofibromatosis type 2,
acoustic schwannoma &
meningioma
Selected tumor-suppressor gene involved in human neoplasm
APC
Function:
Inhibition of signal transduction
Tumors associated with somatic mutation:
Ca. of stomach, colon, pancreas;
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Ca. of stomach, colon, pancreas;
melanoma
Tumors associated with inherited mutation:
Familial Adenomatous Polyposis coli;
colon cancer
Selected tumor-suppressor gene involved in human neoplasm
Rb
Function:
Regulation of cell cycle
Tumors associated with somatic mutation:
Retinoblastoma, osteosarcoma,
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Retinoblastoma, osteosarcoma,
Ca breast, colon, lung
Tumors associated with inherited mutation:
Retinoblastoma, osteosarcoma
Selected tumor-suppressor gene involved in human neoplasm
p53
Function:
Regulation of cell cycle & apoptosis
in response
to DNA damage
Tumors associated with somatic mutation:
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Tumors associated with somatic mutation:
Ca. gaster & breast
Tumors associated with inherited mutation:
Li-Fraumeni syndrome
Multiple carcinoma and sarcoma
Selected tumor-suppressor gene involved in human neoplasm
WT-1
Function:
Nuclear transcription
Tumors associated with somatic mutation:
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Tumors associated with somatic mutation:
Wilms tumor
Tumors associated with inherited mutation:
Wilms tumor
Selected tumor-suppressor gene involved in human neoplasm
p16(INK-4a)
Function:
Regulation of cell cycle by inhibiting
CDK
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CDK
Tumors associated with somatic mutation:
Pancreatic, esophageal cancer
Tumors associated with inherited mutation:
Melanoma
Selected tumor-suppressor gene involved in human neoplasm
BRCA-1
Function:
DNA repair
Tumors associated with somatic mutation:
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Tumors associated with somatic mutation:
Unknown
Tumors associated with inherited mutation:
Ca of female breast and ovary
Selected tumor-suppressor gene involved in human neoplasm
BRCA-2
Function:
DNA repair
Tumors associated with somatic mutation:
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Tumors associated with somatic mutation:
Unknown
Tumors associated with inherited mutation:
Ca of male and female breast
The role of p53 in maintaining the
integrity of the genome
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Apoptosis
(programmed cell death)
Internally programmed and coordinated death / loss of
single cells spread among healthy cells,
in a form of cell death designed to eliminate unwanted
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in a form of cell death designed to eliminate unwanted
cells,
through the serial event activities,
by a set of responsible gene product.
Genes that Regulate Apoptosis
bcl-2 family:
Antagonists
bcl-2 and bcl-xL
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bcl-2 and bcl-xL
Agonists
bax, bcl-xS,
bad, bid
Regulation of cell death
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Biological Mechanism
1. Signaling pathways apoptosis initiation
2. Control and integration balance
between negative regulatory molecule
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(inhibit) and positive (stimulate)
3. Common-execution phase actual
death program accomplished largely by
caspase family protease
4. Removal of death cells by phagocytosis
APOPTOSIS
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Promotion of Carcinogenesis
Promoters: phorbol esters, hormone, phenols, drugs
Not mutagenic how do they contribute to
tumorigenesis study of TPA
TPA: - phorbol esters
- powerful activator for protein kinase C, an
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- powerful activator for protein kinase C, an
enzyme that phophrylates several substrates
involved in signal transduction pathways
Initiation
&
Promotion
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Initiation & promotion
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Radiation Carcinogenesis
Transform all kind of cells in vitro and induce neoplasms
in vivo, in human & experimental animal
UV light skin cancer
Ionizing radiation of medical, occupational, and bomb of
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Ionizing radiation of medical, occupational, and bomb of
origins produce a variety of malignant neoplasms
The effect of UV light is somewhat differ from those of
ionizing radiation
Hierarchy of Vulnerability
1. Leukemia
2. Thyroid
3. Breast, lung, salivary gland
(intermediate)
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(intermediate)
4. Skin, bone, gastrointestinal tract
(relatively resistant)
Sifat dasar transformasi sel
1. Pemenuhan kebutuhan sendiri signal
pertumbuhan
2. Insensitif terhadap signal inhibisi
3. Kemampuan mengelak dari aapoptosis
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3. Kemampuan mengelak dari aapoptosis
4. Kehilangan kemampuan reparasi DNA
5. Potensi replikasi tak terbatas
6. Kemampuan angiogenesis terus menerus
7. Kemampuan invasi dan metastasis
8. Melepaskan diri dari imunitas dan rejeksi