CASE 10

CARCINOMA CERVIX

GENERAL PATHOLOGY:
NEOPLASIA

TIM AKADEMIK
DIVISI SOOCA
NOSTRA
 CASE REVIEW

Mrs. M 54 Y.O, P5A1

Postmenopausal vaginal bleeding

History taking Physical Examination Lab Examination

• frequent vaginal dis-
charge
• didn’t undergo pap
smear examination
• had cervical polyp once
but it wasn’t treated well
• low economic back-
ground
• married 5 times, first at
15 y.o.
• anemic conjuctiva
• no palpable mass in abdomen
and lymph node
• inspeculo, found a hemorrhagic
ulcerative fungating lesion in the
cervix (2cm)
• Hb level = 7 mg/dl
• chest x-ray shows no
metastatic lesion
• biopsy shows lesion is a
malignant neoplasm
• cells showed koilocyto-
sis
• nuclei were polymorph
and hyperchromatic
• non-keratinizing squa-
mos cell carcinoma of the
cervix and positive for
HPV

Diagnosis : carcinoma cervix

Management and Treatment:

• Radical hysterectomy
• Salphingoophorectomy
• Radiotherapy
 FBS
Sign & symptoms
CONCEPT MAPPING
Mrs. M,54 y.o. predisposing factors,
RF: changing partner, underage
marriage carcinogenic agents,
“immature cervix”
control of communable
disease
presence of transformation zone
infection by HPV HPV infection & vac-
DNA alteration cination
mutation of genomes in cervix
cells
molecular basis of cancer, clini-
cal features of cancer
viral E6 binds to p53
viral E7 binds to Rb
inactivation of tumor suppres- apoptosis inactivation inactivation of Rb
sor gene
cell proliferation ↑
dysplasia
anaplasia hyperchromatic nuclei, poly-
chromatic nuclei, koilocytosis
carcinoma in situ
production of mucous from cervical polyp angiogenesis
cervix Hb ↓
squamous cell carcinoma leaky vessel bleeding
anemic conjunc-
vaginal discharge tiva
nonkeratinizing no metastatic lesion hemorrhaging ulcerative
laboratory diagnosis, grading and fungating lesion
staging of cancer, tumor growth, malignant neoplasm no palpable mass
mechanism of tumor
BHP & PHOP CARCINOMA CERVIX
metastasis
 1. Describe the biology of tumor growth (characterize
the diff between benign & malignant)
2. Understand the mechanism of tumor metastasis
3. Predisposition factors of the cancer
4. Carcinogenic agents
5. Molecular basis of cancer
6. Clinical features of tumors
7. Grading & staging of tumors
8. Laboratory diagnosis of cancer
9. Philosophy of science related to the case (HPV infec-
tion, vaccination)
10. PHOP: concept of prevention & control
11. BHP

CLINICAL SCIENCE
CARCINOMA CERVIX
Signs and symptoms
The most common finding in patients with cervical cancer is an abnormal Papanicolaou (Pap) test
result. Physical symptoms of cervical cancer may include the following:
• Abnormal vaginal bleeding
• Vaginal discomfort
• Malodorous discharge
• Dysuria
Diagnosis
Human papillomavirus (HPV) infection must be present for cervical cancer to occur. Complete evalu-
ation starts with Papanicolaou (Pap) testing.
Screening recommendations
The American College of Obstetricians and Gynecologists issued new cervical cancer screening
guidelines in November 2012 . According to the new guidelines, most women do not need cervical
cancer screening more often than every 3-5 years.
Immunization
Evidence suggests that HPV vaccines prevent HPV infection. The Advisory Committee on Immuniza-
tion Practices (ACIP) recommendations for vaccination are as follows:
• Routine vaccination of females aged 11-12 years of age with 3 doses of either HPV2 or
HPV4
• Routine vaccination with HPV4 for boys aged 11-12 years of age, as well as males aged 13-
21 years of age who have not been vaccinated previously
• Vaccination with HPV4 in males aged 9-26 years of age for prevention of genital warts;
routine use not recommended
Stage-based treatment
The treatment of cervical cancer varies with the stage of the disease, as follows:
• Stage 0: Carcinoma in situ (stage 0) is treated with local ablative or excisional measures
such as cryosurgery, laser ablation, and loop excision; surgical removal is preferred
• Stage IA1: The treatment of choice for stage IA1 disease is surgery; total hysterectomy,
radical hysterectomy, and conization are accepted procedures
 • Stage IA2, IB, or IIA: Combined external beam radiation with brachytherapy and radical
hysterectomy with bilateral pelvic lymphadenectomy for patients with stage IB or IIA disease;
radical vaginal trachelectomy with pelvic lymph node dissection is appropriate for fertility pres-
ervation in women with stage IA2 disease and those with stage IB1 disease whose lesions are 2
cm or smaller
• Stage IIB, III, or IVA: Cisplatin-based chemotherapy with radiation is the standard of care
• Stage IVB and recurrent cancer: Individualized therapy is used on a palliative basis; radia-
tion therapy is used alone for control of bleeding and pain; systemic chemotherapy is used for
disseminated disease
Etiology
With rare exceptions, cervical cancer results from genital infection with HPV, which is a known
human carcinogen. Although HPV infections can be transmitted via nonsexual routes, the majority
result from sexual contact. Consequently, major risk factors identified in epidemiologic studies are
as follows:
• Sex at a young age
• Multiple sexual partners
• Promiscuous male partners
• History of sexually transmitted diseases
HIV infection is associated with a 5-fold increase in the risk of cervical cancer, presumably because
of an impaired immune response to HPV infection.Exposure to diethylstilbestrol in utero has been
associated with an increased risk of CIN grade 2 or higher.
Epidemiology
Cervical cancer is the third most common malignancy in women worldwide. The frequency varies
considerably between developed and developing countries, however: Cervical cancer is the sec-
ond most common cancer in developing countries, but only the tenth most common in developed
countries. Similarly, cervical cancer is the second most common cause of cancer-related deaths in
women in developing countries but is not even among the top 10 causes in developed countries.
 BASIC SCIENCE
biology of tumor growth
Neoplasia means "new growth" and the growth is associated with tumor. Neoplasia is defined as an
abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the
normal tissue and persists in the same excessive manner after cessation of the stimuli which
evoked the change.
genetic alteration

passed down to progeny of tumor cells

autonomous excessive & unregulated proliferation

persistent tumors

All tumor, benign and malignant, have two basic components:

Parenchyma
Constructed of clonal neoplastic cells that determine a tumor's behavior and pathological conse-
quences. In some cases the parenchymal cells strimulate the formation of desmoplasia (an abun-
dant collagenous stroma). Some demoplastic tumors, e.g. breast cancer, and stony hard (scirrhous).
The nomenclature & biologic behavior are based primarily on the parenchymal component.
Reactive stroma
Made up of conncetive tissue, blood vessels, and variable numbers of macrophages and lympho-
cytes. A tumor's growth and evolution is critically dependent on their stroma.
• Stromal blood supply → requisite for the tumor cells to live and divide
• Stromal connective tissue → provide structural framework essential for the growing cells
Tumors are divided into benign and malignant tumors.

nomenclature
Benign tumors
General designation: cell of origin + suffix -oma
• Tumors of mesenchymal cells generally follow the rule above, e.g. fibroma and chondroma
• Tumors of epithelial follows a more complex rule:
ƒƒ Adenoma: benign epithelial neoplasm derived from glands
ƒƒ Papilloma: neoplasm producing micro/macroscopically visible finger-like projections
from epithelial surface
ƒƒ Cystadenoma: form large cystic masses, as in the ovary
ƒƒ Papillary cystadenoma: produce papillary pattern protruding into cystic spaces
ƒƒ Polyp: neoplasm producing a macroscopically visible projection above mucosal surface
Malignant tumors
• Mesenchymal tissue tumors: origin + sarcoma
• Epithelial tissue tumors: origin/microscopic architecture/macroscopic pattern + carcinoma
ƒƒ Squamous cell carcinoma: tumor resemble stratified squamous epithelium
ƒƒ Adenocarcinoma: lesion in which neoplastic epithelial cells grow in glandular pattern
• Undifferentiated malignant tumor: composed of undifferentiated cells of unknown tissue
origin
In both benign & malignant tumors
• Mixed tumors: divergent differentiation of a single neoplastic clone along two lineages,
composed of cells representative of a single germ layer
• Teratoma: mature/immature cells/tissue representative of more than one germ cell layer
characteristics of benign & malignant tumor
Characteristics Benign
Differentiation/ Well differentiated; structure may be
anaplasia typical of tissue of origin
Rate of growth Usually progressive and slow; may
come to a standstill or regress; mi-
totic figures are rare and normal
Local invasion Usually cohesive and expansile well-
demarcated masses that do not in-
vade or infiltrate surrounding normal
tissues
Metastasis Absent
Malignant
Some lack of differentiation with anapla-
sia; structure is often atypical
Erratic and may be slow to rapid; mitotic
figures may be numerous and abnormal
Locally invasive, infiltrating the sur-
rounding normal tissues; sometimes may
be seemingly cohesive and expansile
Frequently present; the larger and more
undifferentiated the primary, the more
likely are metastases

Differentiation & anaplasia

Differentiation: extent to which neoplastic parenchymal cells resemble the corresponding normal
parenchymal cells, both moprhologically and functionally
• Benign tumors are well differentiated → mitoses normal and scant in number
• Malignant neoplasms are characterized by a wide range of parenchymal cell differentiation,
from well differentiated to moderately well differentiated to completely undifferentiated
Anaplasia: lack of differentiation, considered hallmark of malignancy; means differentiation to a
more primitive level; often associated with these morphologic changes:
• Pleomophism: variation in size and shape
• Abnormal nuclear morphology: hyperchromatic (contain abundant chromatin and are dark
stained, and the nuclear-to-cytoplasm ratio approach 1:1
• Mitoses: atypical, bizarre mitotic figures, sometimes producing tripolar, quadripolar, or
multipolar spindles
• Loss of polarity: anaplactic cell lose normal polarity, grow in anarchic, disorganized fashion
• Other changes: formation of tumor giant cells with huge polymorphic nucleus or multiple
hyperchromatic nuclei
Metaplasia: replacement of one type of cell with another type.
Dysplasia: disordered growth in epithelia, characterized by a constellation of change that include a
loss in uniformity of cells and architectural orientation; doesn't necessarily progress to cancer.
Rates of growth
• In general, the growth rate of tumors correlates with their level of differentiation, and
thus most malignant tumors grow more rapidly than benign lesions do.
Local invasion
Next to the development of metastases, invasiveness is the most reliable feature that differentiates
malignant from benign tumors.
• Benign tumors grow as cohesive expansile masses that remain localized to their site of
origin, do not have the capacity to infiltrate, invade, or metastasize to distant sites, develop
fibrous capsule, have a well-demarcated cleavage plane
• Malignant tumors' growth is accompanied by progressive infiltration, invasion, and destruc-
tion of surrounding tissue, poorly demarcated from the surrounding normal tissue
Metastasis
• Defined as tumor implants discontinuous with the primary tumor
• Unequivocally marks a tumor as malignant because all malignant tumors can metastasize
• With exceptions: malignant neoplasms of glical cells in CNS, called gliomas, and basal cell
carcinomas of the skin
 mechanism of tumor metastasis
pathways of spread
Dissemination of cancers may occur through one of three pathways:
Seeding of body cavities and surfaces
• Occurs whenever a malignant neoplasm penetrates into a natural "open field"/cavity, most
often the peritoneal cavity but also pleural, pericardial, subarachnoid, and joint space
• E.g. carcinoma arising from ovaries can spread to peritoneal surfaces
Lymphatic spread
• Most common pathway for the initial dissemination of carcinomas, sarcomas may also use
this route
• The pattern of lymph node involvement follows the natural routes of lymphatic drainage
• However some local lymph nodes may be bypassed (skip metastasis) because of anastomo-
ses or obliterated lymphatic channels
• The fist node in a regional lymphatic basin receiving lymph flow from primary tumor is a
sentinel lymph
• E.g. carcinomas of breast usually dissiminate first to the axillary lymph nodes
Hematogenous spread
• Typical of sarcomas but also seen with carcinomas
• Arterial spread (which are less readily penetrated) may occur when tumor cells pass
through the pulmonary capillary bed or pulmonary metastases give rise to additional emboli
• In venous invasion, the tumor cells often come to rest in the first capillary bed → liver
and lungs are most frequently involved because all portal area drainage flows to liver and all
caval blood flows to the lungs
• Cancers with propensity for invasion of veins: renal cell and hepatocellular carcinoma
Invasion and metastasis are biologic hallmarks of malignant tumors. They are the major cause of
cancer-related morbidity and mortality but have been revealed as inefficient. Each step in the
process is subject to a multitude of controls, so at any point the breakaway cell may not survive.
The metastatic cascade will be divided into two: invasion of the ECM and vascular dissemination,
homing of tumor cells, and colonization.

invasion of extracellular matrix

 Dissociation of tumor cells from each other
• Result of alterations in intercellular adhesion
molecules
• In tumors there is a down-regulation of E-cad-
herins (mediator of homotypic adhesions in epithelial
tissue) → reduces ability of cells to adhere to each
other and facilitates detachment
• E-cadherin is linked to cytoskeleton by catenin
→ in some tumors E-cadherin is normal but has
reduced expression because of mutation in the gene
of cathenin
Degradation of basement membrane and interstitial
connective tissue
• Tumor cells secrete proteolytic enzymes them-
selves of induce stromal cells to elaborate proteases,
e.g. matrix metalloproteinases (MMPs), cathepsin D,
to cut through the ECM
• MMPs: remodel insoluble component of base-
ment membrane & relase ECM-sequestered GFs
• E.g. MMP9 cleaves type IV collagen of epithelial
and vascular basement membrane; stimulates release
of VEGF from ECM-sequestered pool
• Second mode of interchangeable invasion: ame-
boid migration, where tumor cells squeeze through
spaces in matrix and use collagen fibers in their travel
Changes in attachment of tumor cells to ECM proteins
• Increase of laminin and fibronectin receptor in
tumor cells and distributed all around cell membrane;
modification of the matrix itself to promote invasion
& metastasis
• E.g. cleavage of the basement membrane pro-
The metastatic cascade. Sequential steps in-
volved in the hematogenous spread of tumor
teins collagen IV and laminin by MMP2 or MMP9 gener-
ates novel sites that bind to receptors on tumor cell
and stimulate migration
Locomotion or migration
• Cells attach to the matrix at the leading edge, detach from the matrix at the trailig edge,
and contract the actin cytoskeleton to ratchet forward
• Potentiated & directed by tumor cell-derived cytokines, e.g. autocrine motility factors

vascular dissemination and homing of tumor cells

• Intravasation → Interaction with host lymphoid cells → Tumor cell embolus → Adhesion
to basement membrane → Extravasation → Metastatic deposit → Angiogenesis → Growth
• Tumor cell embolus: formation of platelet-tumor aggregates may enhance tumor cell sur-
vival and implantability
• Adhesion of tumor cells to basement membrane is involved in arrest and extravasation of
tumor emboli at distant sites, follwed by egress through basement membrane (with adhesion
molecules and proteolytic enzymes)
• At the new site, tumor cells proliferate, develop a vascular supply, and evade the host
defenses
• Organ tropism may occur (preference of tumor to metastasize to a certain tissue, e.g. pros-
tatic carcinoma preferentially spreads to bone
 Predisposition factors of the cancer
geographic and environmental factors
• Environmental factors are thought to be the more significant contributors in most common
sporadic cancers; risk from environmental factors was found to be 65%, as suggested by differ-
ences in incidence and death rate of specific forms of cancer around the world
• E.g. death rate for stomach carcinoma in Japan = 7-8 times than in USA
• Carcinogenic environmental factors include UV light when going outside, in medications
(methotrextae), at work (asbestos, vinyl chloride), at home (high-fat diet), obesity, alcoholism,
smoking

age
Age has an important influence on the likelihood of being afflicted with cancer
• Most carcinomas occur in the later years of life (>55 years)
• Cancer is the main cause of death on women aged 40-79 and men aged 60-79
ƒƒ Might be explained by the accumulation of somatic mutations and decline in immune
competence that accompanies aging
• Also affect children under 15 with predominating cancers:
ƒƒ Hematopoietic tumors (leukemia and lymphoma)
ƒƒ Neuroblastoma: sarcoma originating from the nervous system, mainly neutroblasts;
most often found in babies and toddlers
ƒƒ Wilms tumor: acute malignant mixed tumor, composed of embryonal tissues, found in
children under 5
ƒƒ Retinoblastoma: malignant congenital blastoma, may be hereditary or sporadic
ƒƒ Rhabdomyosarcomas

genetic predisposition to cancer

Genetic predisposition of cancer can be divided into three categories:
Autosomal dominant inherited cancer syndromes
• Include well-defined cancers in which inheritance of a single autosomal dominant mutant
gene greatly increases the risk of developing a tumor
• The inherited mutation is usually a point mutation occuring in a single allele of a tumor
supressor gene; the silencing of the second allele occurs in somatic cells by deletion/recomb.
• The most frequent example: retinoblastoma (40% of them are inherited)
• Features that characterize inherited cancer sydromes:
ƒƒ Tumors tend to arise in specific (or sometimes severeal specific) sites and tissues
ƒƒ Tumors within this group are often associated with a specific marker phenotype
Defective DNA-Repair syndromes
• Characterized by defects in DNA repair and resultant DNA instability, generally have an
autosomal recessive pattern of inheritance
• E.g. xeroderma pigmentosum, ataxiatelangiectasia, Bloom syndrome, and HNPCC
Familial cancers
• Cancers that occur at higher frequency in certain families without a clearly defined pattern
of transmission
• Characterized by early age of onset,tumors arising in two or more close relatives of the
index case, and sometimes multiple or bilateral tumors
• Not associated with specific marker phenotypes, unclear transmission pattern

nonhereditary predisposing conditions

Chronic inflammation and cancer
• In the setting of unresolved chronic inflammation, as occurs in viral hepatitis of chronic
gastritis, the immune response may become maladaptive, promoting tumorigenesis
 • In tissue injuries there is a compensatory proliferation of cells to repair the damage → in
chronic inflammation such behavior is maladaptive for allowing creation and fixation mutations
• The growth factors, cytokines, chemokines promote cell survival, tissue remodelling, and
angiogenesis; also cause genomic stress and mutations; activate immune cells to produce reac-
tive oxygen species that are directly genotoxic
• Chronic inflammation may also increase the pool of tissue stem cells, which become the
subject to the effect of mutagens
Precancerous conditions
• Certain non-neoplastic disorders have such well-define association with cancer that they
have been termed precancerous conditions
• E.g. villous adenoma of the colon becoming malignant 50% of the time, leiomyosarcoma
beginning in a leiomyoma, carcinoma appearing in long-standing pleomorphic adenomas

Carcinogenic agents
Terms we need to know:
• Carcinogen: any substance which causes cancer, adjective carcinogenic
• Carcinogenesis: the production of carcinoma
• Carcinoma: a malignant new growth made up of epithelial cells tending to infiltrate sur-
rounding tissues and to give rise to metastasis
• Carcinogenicity: the ability or tendency to produce cancer
• Initiator: carcinogen-altered cells must undergo proliferation (reproduction/multiplication)
so the change in DNA become fixed
• Promoter: proliferation of preneoplastic cells, malignant conversion and tumor progression
The classic experiments that allowed the distinction between initiation and promotion were per-
formed on mouse skin. Concepts arising from
these experiments:
• Initiation results from exposure of cells
to a sufficient dose of a carcinogenic agent
(initiator); initiation alone is not sufficient
for tumor formation
• Initiation causes permanent DNA dam-
age (mutations): it is therefore rapid and
irreversible and has memory
• Promoters can induce tumors in initi-
ated cells, but they are nontumorigenic by
themselves; and causes cellular changes
that do not affect DNA directly and are
reversible

chemical carcinogenesis
• All initiating chemical carcinogens are highly reactive electrophiles that can react with
nucleophilic sites in cell
• Targets DNA, RNA, and proteins → initiation inflict nonlethal irrepairable damage on the
DNA that's passed down to daughter cells
• Classified into two categories:
Direct-aging agents
• Require no metabolic conversion to become carcinogenic
• Most are weak carcinogens → important because some are cancer chemotherapeutic drugs
that has cured certain types of cancer while evoking a second form of cancer
 Alkylating agents: Acylating agents:
• β-propiolactone • 1-Acetyl-imidazole
• Dimethyl sulfate • Dimethylcarbamyl
• Diepoxybutane chloride
• Anticancer drugs (cyclophosphamide, chlorambucil,
nitrosoureas, and others)

Indirect-acting agents
• Require metabolic conver-
sion to an ultimate carcinogen
before they become active
• Polycyclic hydrocarbons (in
fossil fuels)
• Polycyclic and heterocyclic
aromatic hydrocarbons (benzaan-
thracene)
• Aromatic amines, amides,
azo dyes (benzidine)
• Natural plant and microbial
products (aflatoxin, griseofulvin)
• Others (Nitrosamine and
amides)

Most chemical carcinogens require

metabolic activation for conversion
into carcinogens. Other metabolic
pathways may lead to the inactiva-
tion (detoxification) of the procar-
cinogens. Thus the carcinogenic
potency of a chemical is determined
not only by the inherent reactivity of
its electrophilic derivative but also
the balance between metabolic acti-
vation and inactivation activities.

Molecular targets of chemical carcinogens

• DNA is the primary target for chemical carcinogens
• The commonly mutated oncogenes and tumor suppressors, such as RAS and p53, are par-
ticularly important targets
• Oncogenic: giving rise to tumors or cause tumor formations, said especially of tumor-
inducing viruses
Initiation and promotion of chemical carcinogens
• Unrepaired alterations in the DNA = first steps in the process of initiation
• For the change to be heritable, the damage DNA template must be replicated
• For initiation to occur, carcinogen-altered cells must undergo at least one cycle of prolif-
eration so that the change in DNA becomes fix
• Proliferation: the reproduction or multiplication of similar forms, especially of cells
• Promotion
ƒƒ Proliferation of preneuplastic cells
ƒƒ Malignant conversion
ƒƒ Eventually tumor progression
radiation carcinogenesis
• Radiant energy is a well-established carcinogen, whether UV rays or ionizing electromag-
netic and particulate radiation
• Latency of damage and cumulative effect require extremely long periods of observation
UV Rays
• UV rays derived from the sun cause an increased incidence of squamous cell carcinoma,
basal cell carcinoma, and possibly melanoma of the skin
• The degree of risk depends on the type of UV rays, the intensity of exposure, and the quan-
tity of the light-absorbing melanin in the skin
• Nonmelanoma skin cancers are associated with total cumulative exposure to UV radiation
whereas melanomas are associated with intense intermittent exposure
• Divided into three wavelength ranges: UVA (320-400 nm), UVB (280-320 nm), UVC (200-
280 nm); from these UVB is believed responsible for induction of cutaneous cancers
Ionizing radiation
• Electromagnetic (x-rays, γ rays) and particulate (α particles, β particles, protons, neutrons)
radiations are all carcinogenic
• Most frequent are the acute and chronic myeloid leukemia - cancer of the thyroid follows
closely but only in the young
• In the intermediate category are cancers of the breast, lungs, and salivary glands; in con-
trast, skin, bone, and the GI tract are relatively resistant to radiation-induced neoplasia

microbial carcinogenesis
Oncogenic RNA viruses
• Human T-cell leukemia virus type 1 (HTLV-1) → only one human retrovious firmly impli-
cated the causation of cancer in human
• Transmission of infected T-cells by sexual intercourse, blood products, breast feeding
Oncogenic DNA viruses
• Implicated in the causation of human cancer: papillomaviruses [HPV], Epstein-Barr virus
[EBV], hepatitis B virus [HBV], and Kaposi sarcoma herpesvirus [KSHV]
• Human Papilloma Virus: at least 70 genetically distinct type of HPV → Type 1,2,4,7 : be-
nign squamous papillomas (warts); type 16, 18, 31 (high-risk HPV): squamous cell carcinoma of
the cervix and anogenital region
• Conclusion: cervical cancers are sexually transmitted disease caused by HPV transmission
Bacterium
• Helicobacter pylori: the first bacterium classified as a carcinogen
• Implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas
• Involves increased epithelial cell proliferation in a background of chronic inflammation
• There is an initial development of chronic gastritis, followed by gastric atrophy, intestinal
metaplasia of the lining cells, dysplasia, and cancer
 Molecular basis of cancer
fundamental principles
• Nonlethal genetic damage lies at the heart of carcinogenesis
• A tumor is formed by the clonal expansion of a single percusor cell that has incurred ge-
netic damage (i.e., tumors are monoclonal)
• Four classes of normal regulatory genes are the principal targets of genetic damage
ƒƒ Growth promoting proto-oncogenes
ƒƒ Growth-inhibiting tumor supressor genes
ƒƒ Genes that regulate programmed cell death (apoptosis)
ƒƒ Genes involved in DNA repair
• Carcinogenesis is a multistep process at both the phenotypic and the genetic levels, result-
ing from accumulation of multiple mutations; even though most malignant tumors are mono-
clonal in origin, by the time they become clinically evident their constituent cells are extremely
homogenous

scheme of molecular basis of cancer

physiologic changes in cancer
Self-sufficiency in growth signals
Tumors have capacity to proliferate without external stimuli, usually as consequence of oncogene
activation.
• Proto-oncogenes: a normal gene that w/ slight alteration by mutation or other mechanism
becomes an oncogene; most are believed to normally function in cell growth and differentiation
• Oncogenes: genes that promote autonomous cell growth in cancer cells
• Oncoproteins are the protein products of oncogenes, resemble the normal products of pro-
tooncogene except that they are devoid of normal regulatory elements; function as:
ƒƒ Growth factors: for proliferation (TGF-α, HGF, PDGF-β)
ƒƒ Growth factor receptors: may be activated without binding to GF, send mitotic signals
ƒƒ Signal-transducting proteins: located on inner plasma membrane, receive growth fac-
tor signals and transmit them to the cell's nucleus
• Protooncogene can be converted to oncogenes by one of these mechanisms:
ƒƒ Point mutation
ƒƒ Chromosomal rearrangements
ƒƒ Gene amplification
Insensitivity to growth-inhibitory signals
• Cancer may arise not only by activation of growth promoting oncogenes but also by inacti-
vation of gene that normally suppress cell proliferation (tumor suppressor gene)
• Tumor suppressor gene : -RB genes, p53, APC gene/beta catenin, TGF-beta, NF-1, WT-1
• p53: important pro-apoptotic gene that induces apoptosis in cells that are unable to repair
DNA damage
Evasion of apoptosis
• The accumulation of neoplastic cells requires not only the activation of oncogenes or inac-
tivation of tumor suppressor gene but also mutation in the genes that regulate apoptosis
• Tumors are resistant to programmed cell death (apoptosis) because of mutations affecting
the component proteins directly, as well as by loss of sensors of genomic integrity such as p53
Defects in DNA repair
• Indirectly by correcting errors in DNA that occur spontaneously during cell division or fol-
low exposure to mutagenic chemical or irradiation
• DNA repair gene are not directly oncogenic
• Defect can occur in 3 types of DNA repair system: mismatch repair, nucleotide excision
repair, recombination repair
Limitless replicative potential
• In cellular aging, we know that, it was pointed out that after a fixed numbers of division,
normal cells become arrested in a terminally nondividing state known as replicative senescene
• It has been noted that with each cell division, there are some shortening of specialized
structures, called telomeres
• Once the telomeres are shortened beyond a certain point, the loss of telomere function
leads to activation of p53 dependent cell cycle checkpoint, causing proliferative arrest of apop-
tosis
• Cellular telomeres shorten with each cycle → arrest in terminally non dividing state
• Cancer cells are activating telomerase → prevent telomere shortening
• Thus, telomerase activity and maintenance of telomere length are essential for the mainte-
nance of replicative potential in cancer cells
Sustained angiogenesis
• Tumor cannot enlarge beyond 1 to 2 mm in diameter without inducing host blood vessel
growth (angiogenesis) to provide nutrients and removed wastes
• VEGF, bFGF → angiogenesis
• New tumor vessels are tortuous, irregular, highly leaky
Ability to invade and metastasize
• Invasion of extracellular matrix
ƒƒ Detachment of tumor cells from each other
ƒƒ Attachment to matrix components
ƒƒ Degradation of extracellular matrix
ƒƒ Migration of tumor cells
• Vascular dissemination and homing of tumor cells
Ability to escape immune recognition and regulation
• Failure of immune system to recognize the tumor cell, so they can’t be destroyed. The
mechanisms:
ƒƒ Selective outgrowth of antigen
ƒƒ Loss or reduced expression of MHC molecules (major histocompability complex) →
responsible for lymphocyte recognition and antigen presentation
ƒƒ Lack of constimulation
ƒƒ Immunosuppression
ƒƒ Antigen masking
ƒƒ Apoptosis of cytotoxic T cell

Clinical features of tumors

Any tumor, both malignant and banign, may cause morbidity and mortality because of
• Location and impingement on adjacent structures
• Functional activity such as hormone synthesis or the development paraneoplastic syn-
dromes
• Bleeding and infections when the tumor ulcerates through adjacent surfaces
• Symptoms that result from rupture or infarction
• Cachexia or wasting

local and hormonal effects

Location
• Location is crucial in both benign and malignant tumors
• E.g. a small pituary adenoma can compress and destroy the surrounding normal gland →
hypopituarism
• Cancers arising in/metastatic in endocrine gland → endocrine insufficiency
Hormone production
• Seen in (more typically) benign and malignant neoplasms arising in endocrine glands
• A benign beta-cell adenoma of pancreatic islets may produce sufficient insulin to cause
fatal hypoglycemia
• Growth of cancers on ay natural surface (skin, mucosa of gut) may cause ulecrations, sec-
ondary infections, and bleeding

cancer cachexia
• Cachexia is progressive loss of body fat and lean body mass accompanied by profound
weakness, anorexia, and anemia → weight loss in cachexia is loss of fat and lean muscle
• Not caused by nutritional demands of the tumor but from the action of soluble factors such
as cytokines produced by the tumor and the host rather than reduced food intake
• Responsible cytokines: TNF, IL-1, interferon-γ; additional soluble factors e.g. proteolysis
inducing factor and lipid-mobilizing factor
• Hampers effective chemotherapy and estimated to cause 1/3 of deaths of cancer
paraneoplastic syndromes
• Defined as symptom complexes in cancer-bearing individuals that cannot be readily ex-
plained, either by local or distant spread of the tumor or by the elaboration of hormones indig-
enous to the tissue from which the tumor arose
• May represent the earliest manifestation of an occult neoplasm, represent significant clini-
cal problems and may be lethal
• Mimic metastatic disease and confound treatment
Common paraneoplastic syndromes
• Endocrinopathies: ectopic hormone production, most commonly Cushing syndrome
• Hypercalcemia: most common paraneoplastic syndrome which includes osteolysis induced
by cancer and the production of calcemic humoral substances by extraosseous neoplasms; ex-
ception is hypercalcemia due to skeletal muscles
• Neuromyopathic paraneoplastic syndromes: takes diverse forms such as peripheral neuropa-
thies, cortical cerbellar degeneration, a polymyopathy resembling polymyotis, myasthenic synd.
• Acanthosis nigricans: characterized by gray-black pathces of verrucous hyperkeratosis on
the skin, occurs as genetically determined disease
• Hypertrophic osteoarthopathy: periosteal new bone formation, arthritis on the adjacent
joints, clubbing of the digits

Grading & staging of tumors

CANCER GRADING
Grade is an extent of spread of a cancer within the patient. Grading of a cancer is based on the
degree of differentiation of the tumor cells and, in some cancers, the number of mitoses or archi-
tectural features.
The most commonly used system of grading is as per the guidelines of the American Joint
Commission on Cancer. As per their standards, the following are the grading categories.
• GX Grade cannot be assessed
• G1 Well differentiated (Low grade)
• G2 Moderately differentiated (Intermediate grade)
• G3 Poorly differentiated (High grade)
• G4 Undifferentiated (High grade)

CANCER STAGING
.Stage as parameters of the clinical gravity of the disease. The staging of cancers is based on the
size of the primary lesion, its extent of spread to regional lymph nodes, and the presence or ab-
sence of blood-borne metastases.
TNM system
TNM Staging System is the most common to measure the extent of the spread of cancer.
• "T" refers to the size of the tumor
• "N" refers to the number and location of lymph nodes involved
• "M" refers to metastasis
When a cancer is staged, a number is given for each of these three characteristics. For example, in
stomach cancer:
• T-1 means the primary tumour is still in the stomach wall. T-3 means the primary tumour
has grown right through the stomach wall and T-4 means it is invading nearby structures such as
the pancreas.
• N-0 means there is no spread to lymph nodes. N-1 means that some local lymph nodes are
affected. N-2 means more extensive spread to local lymph nodes.
• M-0 means there are no metastases. M-1 means that there are metastases to some other
area of the body such as the liver or brain.
So, for a certain case of stomach cancer, a doctor may say something like "the stage is T-3, N-1,
M-0" which means "the cancer has spread through the stomach wall, there is some spread to local
lymph nodes, but no metastases in other parts of the body".
Number System
Generally, the lower the cancer stage, the better the treatment prognosis (prediction of the result).
• Stage 1 —small cancer found only in the organ where it started. cancers are localized to
one part of the body
• Stage 2 —larger cancer that may or may not have spread to the lymph nodes. cancers are
locally advanced
• Stage 3 —larger cancer that is also in the lymph nodes. Stage II indicates affected lymph
nodes on only one side of the diaphragm, whereas Stage III indicates affected lymph nodes
above and below the diaphragm
• Stage 4 —cancer in a different organ from where it started. cancers have often metasta-
sized, or spread to other organs or throughout the body

laboratory diagnosis of cancer

Histologic and cytologic methods
Histologic examination
• Most important method of diagnosis
• Formalin-fixed section, paraffin-embedded section, quick-frozen section → provide rapid
diagnoses during procedures
• Requires complete clinical data (i.e., age, gender, site, previous therapy, etc.), good tissue
preservation, and adequate specimen sampling
Cytologic interpretation
• Based chiefly on changes in the appearance of individual cells
• False-positive → uncommon; false-negative do occur because of sampling errors
• Must be confirmed by biopsy before therapeutic intervention
Examples
• Fine-needle aspiration involves aspiration of cells and fluids from tumors or masses; im-
proved imaging techniques allow the sampling of deep as well as more readily palpated lesions.
• Cytologic (Pap) smears involve examination of shed cells; exfoliative cytologic examina-
tion is used most commonly in the diagnosis of cancer of the uterine cervix and tumors of the
stomach, bronchus, endometrium, and urinary bladder.

Immunohistochemistry
• Detects cell products or surface markers using specific antibodies
• Antibody binding is visualized by fluorescent labels, or chemical reaction that generate a
coloured product
• Settings:
ƒƒ Diagnosis of undifferentiated tumors by the detection of tissue-specific intermediate
filaments or other markers. For example, the presence of cytokeratins, detected by immu-
nohistochemistry, points to an epithelial origin (carcinoma), whereas desmin is specific for
neoplasms of muscle cells origin.
ƒƒ Determination of the site of origin of metastases by using reagents that identify spe-
cific cell types (e.g., prostate-specific antigen for prostate cancer)
ƒƒ Detection of molecules that have prognostic or therapeutic significance (e.g., im-
munochemical detection of hormone receptors in breast cancer, or products of proto-onco-
genes, e.g., ERB-B2 on breast cancer).
Flow cytometry
• Can be used to rapidly and quantitatively measure the presence of membrane antigens or
DNA content of tumor cells.
• Routinely used in the diagnosis and classification of leukemias and lymphomas.

Molecular diagnosis
Used for diagnosis and, in some cases, for predicting behavior of tumors.
Diagnosis of malignant neoplasms
• Although molecular methods are not the primary modality of cancer diagnosis, they are of
considerable value in selected cases
Prognosis of malignant neoplasms
• Certain genetic alterations are associated with poor prognosis; identification of these can
stratify treatment
• Thus N-MYC amplifications bode ill for neuroblastomas and HER-2/NEU over-expression in
breast cancer is an indication for monoclonal antibody therapy against the ERBB2 receptor
Detection of minimal residual disease
• After treatment of patients with leukemia or lymphoma, the presence of minimal disease
or the onset of relapse can be monitored by PCR-based amplification of nucleic acid sequences
unique to the malignant clone
Diagnosis of hereditary predisposition to cancer
• As was discussed earlier, germ-line mutations in several tumor suppressor genes, includ-
ing BRCA1, BRCA2, and the RET proto-oncogene, are associated with a high risk of developing
specific cancers

Molecular profiles of tumors

• Microarray analysis of mRNA levels provides gene expression signatures/molecular profiles
for tumors → identifying tumor subtypes and also have prognostic and therapeutic significance
• The heterogeneity of tumors and the contribution of associated stromal and inflammatory
elements can confound such analyses; this can be overcome by laser capture microdissection
techniques that allow the specific analysis of selected cells as identified from histologic sec-
tions

tumor markers
Biochemical assays for tumor-associated enzymes, hormones, and other tumor markers in the blood
cannot be used for definitive diagnosis of cancer; however, they contribute to the detection of can-
cer and in some instances are useful in determining the effectiveness of therapy or the appearance
of a recurrence. Examples:
Human chorionic gonadotropin Trophoblastic tumors, nonseminomatous tes-
ticular tumors
Calcitonin Medullary carcinoma of thyroid
Carcinoembryonic antigen Carcinomas of the colon, pancreas, lung, stom-
ach, and heart
Prostatic acid phosphatase Prostate cancer
Immunoglobulins Multiple myeloma and other gammopathies
CA-125 Ovarian cancer
CA-15-3 Breast 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
 Philosophy of science related to the
case (HPV infection, vaccination)
human papilloma virus
Speciality
• Stimulate DNA synthesis
• Restricted host range
• Significant cause in human cancer (especially cervical cancer)
• Viral oncoproteins interact with cellular tumor supressor protein
Classification: divided into 16 genera, 5 of which infect human
Replication
• Highly tropic for epithelial cells of skin and mucous membrane
• Viral nucleic acid can be found on basal stem cells, capsid protein is restricted to upper-
most layer of differentiated keratinocyte
• Strong dependence of viral replication in differentiated state of epithelial cells
Pathogenesis & Pathology
• Transmission occurs by close contact
• Viral particles → released from surface of papillomatous lesions
• Microlesions → allow infection of proliferating basal cells
• Sometimes lead to development of warts
ƒƒ Skin warts
ƒƒ Plantar warts
ƒƒ Anogenital warts
• Sometimes cause cancers
ƒƒ Cervix, vulva, penis, anus subset of head and neck cancers
Risk factor
• Multiple sex partner
• Young age at first intercourse
• Persistent infection
• Immunosupression
• Nicotine usage
Divided into 2
• Low- risk HPV: usually HPV type 6 & 11 → cause skin warts/ around genitals/ anus
• High-risk HPV: cancerous, usually type 16 & 18
ƒƒ Cancer caused by HPV:
ŠŠ Cervical cancer: most commonly caused (60% by type 16, 10% by type 18)
ŠŠ Vulvar cancer: 50% caused by HPV
ŠŠ Vaginal cancer: 65% caused by HPV
ŠŠ Penile cancer: 35% caused by HPV
ŠŠ Anal cancer: 95% caused by HPV
• Most HPV infection are transient and eliminated in few months (low risk: 8 months, high-
risk: 13 months)

vaccination
• Two vaccines to prevent HPV infection:
ƒƒ Gardasil, marketed by merck → for HPV 6,11, 16, 18 to prevent cervical cancer in
females and anal cancer in males
ƒƒ Cervarix, marketed by glaxosmithkline → for HPV 16 and 18
• Both protect against initial infection with HPV types 16 and 18
• Both vaccines are delivered in three shots over six months
• May be started as early as from 9 years old
 PHOP
concept of prevention & control
• Primary prevention is the effort to prevent HPV virus exposure by vaccination and promo-
tion/education of cervical cancer prevention
• Secondary prevention is the screening/early detection effort to identify cervical cancers as
early as possible through a pap smear
• Tertiary prevention is medical treatment for a person that has contracted cervical cancer
aiming to prevent complications and premature death. The method of treatment is surgical exci-
sion, such as hysterectomy and salphingooophorectomy, radiation therapy, chemotherapy or a
combination of above methods
• Although cervical cancer occurs only in women, men play a big role in its spread. Men who
have sex with women with cervical cancer can spread HPV virus to other women through sexual
intercourse. It is important to take precautions with not taking multiple partners
Prevention Promotive Curative
• Vaccination • Public education • Surgery
• Condom • HPV vaccination among • Radiation therapy
• No Smoking teenagers and female • Chemotherapy
• Nutrition • Rehabilitative
• Cervical Screening

bhp
• Kodeki Pasal 7C: Seorang dokter harus menghormati hak-hak pasien, hak-hak rekan se-
jawatnya, dan hak tenaga medik lainnya, dan harus menjaga kepercayaan pasien.
• WMA International Code of Medical Ethics: A physician shall respect the rights and pref-
erences of patients, colleagues, and other health professionals
• Principle of medical ethics → autonomy: patients' right to know about their disease and
to take a decision regarding their treatment
• Breaking the bad news: being diagnosed having cancer is one of the most traumatic and
revolutionary events that will ever happened to the patient. The doctor have to tell about pa-
tient’s diagnosis in right manner and the right procedure.
• General consent: Consent that arises automatically when the patient is about to be given
the health care, entering hospital for routine test and procedure needed for diagnosis and treat-
ment
• Informed consent: Written consent given by patients for diagnostic tests or treatment
that will involve danger or pain after being told about the procedure and the risk.