PLENARY 2

“Yang Tersembunyi”
 LEARNING OBJECTIVE
1. M3 mengidentifikasi agen endogen dan eksogen kimia, fisika,
biologi yang mengakibatkan jejas sel serta mekanisme perubahan
2. M3 dapat membedakan mekanisme dan proses dalam sel akibat jejas
sel
3. M3 adaptasi sel terhadap jejas dan kematian sel
4. M3 perubahan dalam siklus sel neoplasma, repair dan regenerasi
5. M3 proses dan mekanisme karsinogenesis
6. M3 jenis dan peran gen dalam karsinogenesis dalam progresifitas
kanker
7. M3 proses invasi dan metastasis dalam tumor
8. M3 histopatologi neoplasma
9. M3 imunologi tumor
 LO 1
AGEN ENDOGEN & EKSOGEN SERTA MEKANISME
JEJAS SEL
 JEJAS SEL
• Cells are active participants in their environment, which
constantly adjust their structure & function to
accommodate extracellular change & stress demands.
• Cells tend to maintain their immediate & intracellular
environment in a relatively narrow range of physiological
parameters - cells maintain normal homeostasis

4
5
• 2 basic patterns of cell death:
• - necrosis (especially coagulative nerve) occurs after the
blood supply is lost / after being exposed to toxins &
marked with cell swelling, denaturation protein
and damage to organelles → severe tissue
dysfunction.
• - apoptosis (physiology:
embryogenesis; pathological: mutation damage that
is not repaired)

6
 CAUSES OF JEJAS SEL
•
Oxygen Deprivation
• Chemical material
• Infectious agent
• Immunological reaction
• Genetic defect Nutritional imbalance
• Physical agent Aging

7
Mekanisme jejas sel
 LO 2
M3 dapat membedakan mekanisme dan proses dalam sel akibat
jejas sel
 Possible Biochemical Mechanisms of Cell Injury

1) ATP depletion.

2) Generation of reactive oxygen free radicals.

3) Loss of ca++ homeostasis.

4) Defect in plasma membrane permeability.

5) Mitochondrial damage.
 Mechanisms of Cell Injury

1) ISCHEMIC & HYPOXIC INJURY

 Reversible injury
 Irreversible injury
 Ischemic and Hypoxic Injury

Reversible Injury

Mechanism:

1) Decreased oxidative phosphorylation

2) Increased anaerobic glycolysis
1) Detachment of ribosomes/reduced protein synthesis
3) Worsening mitochondrial function
4) Increasing membrane permeability
5) Cytoskeleton dispersion
6) Swelling of mitochondria, endoplasmic reticulum, and entire cells
 Irreversible injury

• After the initiation of irreversible

death, the cell and its organelles start
to disintegrate, leading to rupture of
the cells.
• Gradually, the cytotoxic edema starts
to resolve and interstitial edema
develops as the cell membranes
disintegrate and the intracellular
components become extracellular.
 LO 3
Adaptasi sel terhadap jejas dan kematian sel
 Cell Adaptation
Cells can regulate themselves by changing their structure and function in response
to various physiological and pathological conditions. This ability is called cellular
adaptation.

1. Hypertrophy
Hypertrophy is a large increase in organs due to the increase in the size of cells in
the organ.
Example: skeletal muscle in bodybuilders and heart cut across, so the capacity becomes
smaller and the heart's work becomes heavier.

2. Metaplasia
Metaplasia is a change in cells from one type to another. Occurs in response to
continuous injury or irritation that results in chronic inflammation of the tissue.
Example: changes in respiratory tract cells from ciliated columnar epithelial cells to
multilevel squamous epithelial cells in response to long-term smoking
3. Dysplasia

Dysplasia is a change in the size, shape and orientation of

cells. The cause of dysplasia is related to chronic irritation or
inflammation. In diplasia changes in cells become irregular which
shows disruption of normal development of the cell layers and
with variations in the size, shape and appearance of each cell.
These increased cells can increase the amount and the
thickening of the epithelium.

4. Atrophy
Atrophy is the shrinking of cell mass due to the loss of cell
organelles.
Causes of atrophy:
a) The reduced need for these cell organelles. Usually
occurs in older bedrests.
b) Reduced energy supply which results in the inability of
cells to replace their organelles. This can happen to
people who starvate protein.
c) Cannibalistic digestion of several cells against their
organelles.
d) Specific machine inhibitions that synthesize the needs
of organelles. Example: inhibition of the ribosomal RNA
system by actinomycin which inhibits new ribosomal
production.
5. Hypertrophy
• Increase in number of cells
• In cells that have the ability to divide
• Chronic hormones & irritation
• Reversible
• Non-neoplastic but is a "fertile soil" for neoplastic
development.
• The arrangement of the jar is still regular
Jejas Reversible
• Vascular degeneration
• fatty change
 Jejas Irreversible
Necrosis shows a sequence of morphological changes
that follow the death of living cells which are generally
caused by enzymes degradative in cells that experience
lethal injury
Page  23
Types of necrosis:

1. Coagulativa necrosis
2. Liquefactive / kolikuativa necrosis
3. Caseous necrosis
4. Fat necrosis
5. Gangrenous necrosis
6. Fibrinoid necrosis
 Repair
Repair: physiological adaptation of organs after injury
to restore organ / tissue continuity regardless of whether the
replacement of the damaged / lost tissue has occurred
 Regeneration
Regeneration: replacement of damaged / lost tissue
with exactly the same "copy" so that the organ / tissue
morphology and function can be restored
 Scar Formation

Angiogenesis : VEGF
granulation tissue formation: fibroblasts, neovascular,
loose extracellular matrix, cell inflammation t.u
macrophages
remodeling: maturation and reorganization of connective
tissue: stable fibrous scar
Angiogenesis
Macrophages
 LO 4

Perubahan dalam Siklus Neoplasma

A. Definisi

• New growth”
• Willis: massa jaringan yang abnormal, tumbuh
berlebihan, tidak terkoordinasi dengan jaringan normal
dan tumbuh terus meskipun stimulus yang
menimbulkannya telah hilang.
• Dasar pertumbuhan neoplasma: hilangnya kontrol
pertumbuhan normal.
B. Karakteristik Neoplasma Jinak & Ganas

Neoplasma dapat dibedakan menjadi jinak / ganas,

berdasarkan:
– Differensiasi & anaplasia
– Kecepatan pertumbuhan (rate of growth)
– Invasi lokal (local invasion)
– Metastasis (anak sebar)
1. Differensiasi & anaplasia

• Differensiasi: derajat kemiripan sel neoplastik (sel parenkim

tumor) dengan sel normal. Makin mirip – makin baik
differensiasinya.
– Well differentiated
– Moderately differentiated
– Poorly differentiated
– undifferentiated
• Semua tumor jinak --- tersusun dari sel neoplastik yang mirip
dengan sel normal (well differentiated)
• Tumor ganas bisa: well differentiated s.d undifferentiated.
Anaplasia

• Menunjukkan pertumbuhan ke arah tingkatan lebih

rendah atau hilangnya differensiasi struktural &
fungsional suatu sel normal.
• Anaplasia --- hallmark of malignant transformation
(petanda tumor ganas).
• Ciri-ciri morfologik sel anaplastik
– Pleomorfik: ukuran & bentuk bervariasi (variation in size &
shape). Sel bisa berukuran >> besar atau << kecil.
– Morfologi inti sel tidak normal
• Inti sel hiperkromatik (karena DNA >>)
• Rasio inti : sitoplasma (N/C ratio) (hampr 1:1)
(normalnya N/C ratio 1:4 atau 1:6)
• Butiran kromatin kasar
• Nukleoli (anak inti) nyata / prominent
– Mitosis: jumlah > & didapatkan mitosis atipik.
– Hilangnya polaritas: gangguan orientasi susunan sel dalam
jaringan.
Sel anaplastik:
• Displasia
– Artinya: disordered growth.
– Terutama pada sel epitelial, ditandai oleh hilangnya
uniformitas individual sel & hilangnya orientasi arsitektur
normal sel dalam jaringan.
– Morfologi:
• Pleomorfisme (+) ( ukuran + bentuk bervariasi )
• Inti hiperkromatik (+) ( DNA >>> )
• Mitosis meningkat ( jumlah > + didapatkan mitosis atipik )
– Derajat dysplasia
• Displasia ringan (mild dysplasia)
• Displasia sedang (moderate dysplasia)
• Displasia berat (severe dysplasia) = Carsinoma insitu.
• Dysplasia cervix
2. Kecepatan pertumbuhan (rate of growth)

• Secara umum:
– Kebanyakan tumor jinak: tumbuh lambat.
tergantung hormon & supply darah
contoh: leiomyoma uterus akan tumbuh cepat jika estrogen
>> (kehamilan)
– Kebanyakan tumor ganas: tumbuh cepat.
• Secara umum, kecepatan pertumbuhan tumor berhubungan
dengan derajat differensiasinya – kebanyakan tumor ganas
tumbuh lebih cepat daripada tumor jinak.
3. Invasi lokal (local invasion)

• Tumor jinak
– Tumbuh lokal & tidak mempunyai kemampuan untuk
menginfiltrasi, menginvasi jaringan sekitarnya.
– Berbatas jelas dengan jaringan sekitar, mempunyai kapsul
(simpai) ataupun pseudocapsul (simpai semu).
– Tidak metastasis (tidak beranak sebar)
– Pengecualian: hemangioma (tumor jinak pembuluh darah) –
tidak berkapsul & tumbuh seperti infiltratif dalam jaringan.
• Leiomyoma uteri
• Tumor ganas:
– Tumbuh progresif, invasi & infiltrasi ke jaringan
sekitarnya.
– Batas tidak jelas & tidak berkapsul
– pengecualian: tumor ganas yang tumbuhnya lambat
bisa terlihat berbatas jelas pada makroskopis, namun
secara mikroskopis akan terlihat pertumbuhan yang
infiltratif ke jaringan sekitar.
4. Metastasis

• Adalah anak sebar ke jaringan yang jauh dari tumor asal.

• Merupakan petanda keganasan yang paling kuat diantara
tanda lain:
– Tumor jinak --- tidak metastasis
– Tumor ganas --- metasatasis
• Metastasis:
– Percontinuatum – lewat rongga
– Limfogen
– Hematogen
• Metastasis per continuatum:
– Lewat rongga tubuh (body cavity)
– Contoh: Ca ovarium --- ke peritoneum
Ca colon --- ke cavum peritoneum
Ca paru --- ke cavum pleura
• Metastasis secara limfogen:
– Terutama pada carcinoma
– Pola penyebaran metastasis kelenjar limfe mengikuti rute
normal dari lymphatic drainage.
contoh: Ca mamma - metastasis KGB axilla
Ca paru – metastasis ke KGB hilus
Ca nasofaring – metastasis KGB colli
• Metastases secara hematogen
– Terutama pada sarcoma
– Dapat juga terjadi pada carcinoma
• Renal cell ca --- vena renalis
• Penetrasi ke vena > arteri, karena arteri memiliki
dinding > tebal – lebih tahan.
• Invasi pada vena --- sel tumor mengikuti aliran vena ---
metastasis sering terjadi pada paru & hepar.
Hepar yang mengandung metastasis kanker
 LO 5

The process and mechanism of

carcinogenesis
 Factors that Influence the Degree of
Occurrence of Cancer
• 1.diet
• 2.ages
• 3.gender
• 4.race
• 5.genetic
• 6.hormone
• 7.environment
• 8.persistent
 Mechanism of Carcinogenesis
• 1. initiation
• 2. promotion
• 3. Progression
 LO 6

Types and Roles of Genes in Carcinogenesis in

Cancer Progression
• 1.Proto-oncogenes
• 2.Genes that encode and regulate protein formation for
growth.
• 3.Genes responsible for repairing damaged DNA or DNA
repair genes.
• 4.Genes that regulate programmed cell death / Apoptosis
 LO 7

The Process of Invasion an Metastatic

 Invasion
• spread of tumor cells to the surrounding area causing
damage to the surrounding tissue.
• Human networks are arranged into a series of
compartments separated from each other by two types of
extracellular matrices (ECM)
• ECM consists of collagen, glycoproteins, and
proteoglycans
 The stages of invasion
1. Stretch of tumor cell
2. The attachment of tumor cells to various ECM proteins
3. Local degradation of the basal membrane and interstitial
connective tissue
4. Local degradation of the basal membrane and interstitial
connective tissue
 Metastatic
Invasion of tumor cells over longer distances allowing
the growth of the same tumor cells in the new place / organ
Metastatic
process
 Type of Metastatic Spread
1. Hematogenous spread
2. Lymphogen spread
3. Direct transplant
4. Transluminal spread
Histopatologi Tumor
 Klasifikasi
1. Tumor Jinak (Benigna)
2. Tumor Ganas ( Maligna)
 Tumor Jinak
1. Tumbuhnya lambat dan biasanya mempunyai kapsul
2. Tidak tumbuh infiltratif
3. Tidak merusak jaringan sekitarnya
4. Tidak menimbulkan anak sebar pada tempat yang jauh

Umumnya disembuhkan dengan sempurna kecuali yang

mensekresi hormone atau yang terletak pada tempat yang
sangat penting, misalnya disumsum tulang belakang yang
dapat menimbulkan paraplesia atau pada saraf otak yang
menekan jaringan otak.
 Tumor ganas ( maligna )
1. Tumor ganas pada umumnya tumbuh cepat
2. Infiltratif
3. Merusak jaringan sekitarnya
4. Dapat menyebar keseluruh tubuh melalui aliran limpe
atau aliran darah
5. Sering menimbulkan kematian.
 Intermediate
Diantara 2 kelompok tumor jinak dan tumor ganas terdapat
segolongan kecil tumor yang mempunyai sifat :
Invasive local tetapi kemampuan metastasisnya kecil.

Tumor demikian disebut tumor agresif local tumor ganas

berderajat rendah. Sebagai contoh ialah karsinoma sel
basal kulit.
 LO 9
Imunologi tumor
 TUMOR IMMUNOLOGY
Objectives
 Know the evidence for immune reactivity to tumor
 Know the changes in cellular characteristics due to malignancy
 Know the host components which affect tumor progression
 Know the tumor cell components which protect it from the immune
system
 Understand the rationale & approaches of tumor immunotherapy
Evidence for immune reactivity to tumors
Tumors that have severe lympho -reticular infiltration have
a better prognosis than those that do not.
Certain tumors regress spontaneously
There is an increased incidence of primary and secondary
malignancies
(particularly lympho-reticular tumors) in immunodeficient patients
Antibodies and immune T lymphocytes have been
detected in patients with tumors.
The young and the very old have an increased
occurrence of tumors.
Finally, animals can be specifically immunized against
various types of tumors
Tumor associated antigens
• In order for the immune system to react against a tumor, the latter
must have antigens that are recognized as foreign.
(enzymes, receptors, membrane antigens, etc.).

• Most relevant are surface membrane molecules which might be

antigenic or suppression of membrane proteins that are essential
for immune recognition and activation
Antigenic changes:
Antigenic changes observed in malignant cells include
reappearance of fetal antigens (onco-fetal antigens)
 Some of these antigens may be secreted while others are
membrane-associated molecules.
Neo-antigens that contribute toward tumor rejection are referred
to as tumor associated transplantation antigens (TATA).
Onco-fetal antigens
• Onco-fetal antigens may appear due to de-repression of genes that were
only expressed early in life.
• Two major onco-fetal antigens are
1- alpha-fetoprotein (AFP)
AFP is produced only as a secreted protein
2- carcino-embryonic antigen (CEA )
CEA is found both on cell membranes and in secreted fluids.
• Since secreted antigens contribute little toward immunity against tumors, the
role of these neo-antigens in immuno-surveillance is questionable
Alpha-fetoprotein
The normal range of AFP concentrations in humans is 0-20
ng/ml.
This level rises considerably in patients with hepatomas and
non-seminal testicular carcinoma.
A 5-fold or higher rise in this protein is used for monitoring
hepatomas and testicular cancers.
AFP level may also be raised in some non-malignant
conditions, such as cirrhosis, in hepatitis and other forms of
liver damage.
Carcinoembryonic antigens
CEA levels in normal people range up to 2.5 ng/ml,
They increase significantly in certain malignancies, particularly
colo-rectal cancers.
They may also rise in some non-malignant conditions (such as
chronic cirrhosis, pulmonary emphysema and heavy
smoking).
Levels that are 4-5 times normal have been used to predict
recurrence of colo-rectal tumors.
 Tumor associated transplantation antigens
(TATA) on viral tumors
• A number of viruses cause different types of tumors in
animals
EXAMPLES: adenovirus, Rous sarcoma virus, erythroleukemic
virus,
Viruses are involved or suspected to be involved in some
human malignancies (HTLV-1 in leukemia, hepatitis-B
virus in hepatic carcinoma, papilloma virus in cervical
cancer).
• Virus-induced tumors express cell surface antigens
• These are shared by all tumors induced by the same
virus.
• These antigens are characteristic of the
tumor-inducing virus, regardless of tissue origin of the tumor
or animal species in which the tumor exists
Tumor associated transplantation antigens on
chemically-induced tumors
• Chemically-induced tumors are different from virally-induced
tumors in that they are extremely heterogeneous in their
antigenic characteristics.
• Thus, any two tumors induced by the same chemical, even in the
same animal, rarely share common tumor specific antigens
• These unique antigens on chemically-induced tumors are referred
to as tumor specific transplantation antigens
(TSTA).
 Immunity against tumors
• Evidence for immunity against malignancy comes mostly from experimental
tumors, although there is ample evidence for anti-tumor immune reactivity in
humans. In experimental studies,
• Animals can be immunized by administering inactivated tumor cells or by
removal of a primary tumor.
• Also, immunity can be transferred from an animal, in which a tumor has
regressed, to a naive animal by injection of lymphocytes (T cells).
• All components of the immune system (non-specific and specific; humoral
and cellular) can affect the growth and progression of a tumor
 Escape from immuno-surveillance
• Number of mechanisms have been suggested for the
escape of malignant cells from host immuno-surveillance:
1-Tumors may not express neo-antigens that are
immunogenic
2- Tumors may fail to express co-stimulatory molecules for
the activation of T-cells.
3- Certain tumors are known to lack or be poor expressers
of MHC antigen
• Another reason for failure of immunosurveillance may be the fact that in
the early development of a tumor, the amount of antigen may be too
small to stimulate the immune system and, due to the rapid proliferation
of malignant cells, the immune system is quickly overwhelmed.
• In addition, some tumors may evade the immune system by secreting
immunosuppressive molecules and others may induce suppressor
cells.
• Also, some tumors may shed their unique antigens which block
antibodies and T cells from reacting with malignant cells.
 Immuno-Diagnosis
Monoclonal antibodies labeled with radioisotope have
been used for in vivo detection of relatively small tumor
foci.
Antibodies have also been used in vitro to identify the
cell origin of undifferentiated tumors, particularly of
lymphocytic origin.
Immuno-histological staining is used to confirm
suspected metastatic foci, especially in bone marrow.
 Immunotherapy
• Immunotherapy has been used as adjunct to traditional
treatments.
• Both active and passive means of stimulating the non-
specific and specific immune systems have been
employed, in some cases with significant success
 A variety of immunopotentiating agents (biological response modifiers) are
used to enhance anti-tumor immunity. They include:
 bacterial products
 synthetic chemicals
 cytokines

 Most of these agents exert their effects by activating macrophages and

natural killer (NK) cells, eliciting cytokines or enhancing T-cell functions.
.
A number of cytokines have been used to potentiate the immune function
of the host
Cytokine Tumor types Anti-tumor
mechanism(s)
IFN-alpha, beta Remission of hairy cell Increased expression
leukemia, of class I MHC,
possible cytostatic
anti-tumor effect
IFN-gamma Carcinoma of ovary Increased MHC
antigens; macrophage,
Tc and NK cell
activation
IL-2 Renal carcinoma and T cell proliferation and
melanoma activation of NK cells

TNF-alpha Reduce malignant Macrophages and

ascites lymphocyte activation