cancer of uterine cervix

2. Cervical Cancer

3. • In 1930s, it was the number one cause of cancer-related deaths among women
in the US.
• By the advent of cytologic screening, there has been 70% reduction in deaths.
• The average age of diagnosis:52
• Distribution of cases is biomodal (with 2 picks):
1. 35-39
2. 60-64
• worldwide it continues to be a leading cause of death due to cancers among
women.

4. Risk factors
1. Screening
2. Race
3. Sexual & reproductive factors
4. Smoking
5. Contraceptive use
6. Immunosuppression
7. Human papillomavirus infection

5. 1- Screening
• Cerviacl cytology has proved to be the most efficacious & cost-effective method for cancer
screening by detection of preinvasive & early invasive disease.
• Cytologic evaluation of cells obtained from cervix and vagina was first proposed by
Papanicolaou & Traut in 1940s as a method of detecting cervical cancer & its precursors.
• Has decreased both incidence & mortality in communities with active screening program.
• A single negative pap smear decrease the risk by 45%.
• Nine negative smears during a lifetime decrease the risk as much as 99%.
• The liquid based cytology can better triage women with earlu cytologic changes, because:
1. Improved sensitivity without loss of specificity.
2. HPV testing can be performed on the remaining sample.
• Women over age of 65 should continue to be screened, as 25% of all cases of cervical cancer
and 41% deaths from this disease occur in women in this age group.

6. 2-Race
• Racial differences are apparent in survival & incidence.
• Socioeconomic factors should be controlled in studies.
• Rate among blacks remain about twice as high as those among whites & for Hispanic
Americans is higher than for native Americans.

7. 3-Sexual and reproductive factors
Cervical cancer risk is proportional to:
1. Age at the first coitus (before 16 with a twofold increased risk compared with after 20)
2. Number of lifetime sexual partners
3. Parity

8. 4-Smoking
• The increased risk is about twofold.
• The highest risk observed for:
1. Long term smoking
2. High-intensity smoking
• Mechanism: genotoxic or immunosuppressive effects of smoke-derived nicotine & cotinine,
present in high level in the cervical mucus of smokers.

9. 5-Contraceptive use
• Long-term OCP users at about twofold increased risk.
• Barrier methods, especially those that combine both mechanical & chemical protection, lower
the risk by reducing exposure to infectious agents.

10. 6-Immunosuppression
• Cell-mediated immunity is a factor in the development of cervical cancer.
• Immynosuppression causes:
1. Higher risk for disease
2. Rapid progression from preinvasive to invasive form
• HIV-positive women with cervical cancer may have:
1. Higher recurrence risk
2. Highere cancer-related death rate

11. 7-HPV infection
• A necessary but insufficient factor in development of invasive cancer.
• 75-80% of sexually active women will test positive for HPV DNA.
• The majority of infections are transient( incidence of dysplasia is about 10 times lower than
incidence of HPV infection)
• Persistent infection occurs in minority of women and these individuals are at highest risk
precancerous and invasive lesions.

12. Human Papilloma Virus

13. Human Papilloma Virus
• A member of Papovaviridae
• Noneneloped virion with a dsDNA(circular) in an icosahedral capsid
• Infects epithelial cells of the skin & mucosal membranes.
• genome contains 3 regions:
1. The upstream regulatory region (URR) controls production of viral proteins.
2. The early region encodes for proteins E1, E2, E3, E4, E5, E6, and E7, which influence viral
infection and replication.
3. The late region encodes proteins L1 and L2, which are the major and minor capsid proteins.
• Differences in E6, E7, and L1 gene sequences constitute more than 100 distinct HPV types.

14. Mechanism of causing cancer
• The E6 and E7 open reading frames of the HPV genome are important in the immortalization
and transformation of infected cells. The protein products synthesized from the E6 and E7 open
reading frames can bind to the gene products of the p53 and retinoblastoma (Rb) tumor
suppressor genes.
1. In condylomas and low grade dysplasias, HPV DNA remains in an episomal(closed circular)
form in which E6 and E7 transcription remains well regulated.
2. Viral integration results in the overexpression of the E6 and E7 viral protein products with
increased binding and inactivation of their respective tumor suppressor proteins.

15. HPV oncogenic risk-types
The oncogenic risk of the HPV types appears to be related to the binding affinity of their E6 and
E7 proteins to p53 and Rb respectively:
1. Low oncogenic risk-type viruses: 6, 11,42, 43, and 44 which are associated with condyloma
acuminatum and some cases of low-grade squamous intraepithelial lesions but rarely with
invasive cancer.
2. Intermediate oncogenic risk-type :33, 35, 39, 51, and 52 which are occasionally associated
with high-grade squamous intraepithelial lesion (HGSIL) and invasive carcinomas.
3. High oncogenic risk-type :16, 18, 31, 45, and 56 and are commonly detected in women with
HGSIL and invasive cancer.

16. Presenting symptoms
1. AUB(most common finding):postcoital spotting, intermenstrual bleeding, menorrhagia, or
postmenopausal spotting( Chronic bleeding can be associated with fatigue or other
symptoms related to anemia)
2. Serosanguineous or yellowish vaginal discharge(most common finding)frequently associated
with a foul odor, may accompany an advanced or necrotic carcinoma
3. Pelvic pain may result from locally advanced disease or tumor necrosis
4. Sciatic pain or back pain associated with urinary tract obstruction and hydronephrosis due
to extension of tumor to the pelvic side walls.
5. Lumbosacral back pain because metastatic tumor to the iliac and paraaortic lymph nodes
can extend into the lumbosacral nerve roots.
6. Urinary or rectal symptoms (e.g., hematuria, hematochezia, fistulas) can be associated with
bladder or rectal invasion by advanced-stage cervical carcinoma.

17. Physical findings
• Early lesions may be focally indurated or ulcerated or present as a slightly elevated and
granular area that bleeds readily on contact.
• More advanced tumors have several types of gross appearance:
1. Exophytic: have a friable polypoid or papillary appearance.
2. Endophytic: usually ulcerated or nodular but may be clinically inapparent if located high
within the endocervical canal. Such tumors frequently invade deep into the cervical stroma
to produce an enlarged, hard, barrel-shaped cervix that may only be appreciated on
rectovaginal pelvic examination
3. Infiltrative: may produce surrounding tissue necrosis and erosion of normal anatomic
landmarks.

18. Spread of disease
1. Parametrial extension
2. Lymph node involvement
3. Vaginal extension
4. Bladder & rectal involvement
5. Endometrial involvement
6. Ovarian metastasis
7. Hematogenous spread

19. 1-Parametrial extension
1. spread through parametrial lymphatic vessels, expanding and replacing parametrial lymph
nodes. These individual tumor masses enlarge and become confluent, eventually replacing
the normal parametrial tissue.
2. Less commonly, the central tumor mass reaches the pelvic sidewall by direct
contiguous extension through the cardinal (Mackenrodt) ligament. Significant
involvement of the medial portion of this ligament may result in ureteral
obstruction and hydronephrosis.

20. 2-Lymph node involvement
• obturator, external iliac, and hypogastric & isolated common iliac nodes.

21. 2-Lymph node involvement
• The inferior gluteal and sacral lymph nodes are less frequently involved.
• Secondary nodal involvement (i.e., paraaortic) seldom occurs in the absence of pelvic nodal
disease.
• Rarely, retrograde lymphatic embolization may occur to the inguinal lymph nodes. Patients
with locally advanced pelvic disease may have detectable metastatic spread to the scalene
nodes. Consequently, careful clinical assessment of the groin and supraclavicular fossa areas
should be included as part of the physical examination.

22. 3-Vaginal extension
• When the primary tumor has extended beyond the confines of the cervix, the upper vagina is
frequently involved (50% of cases).
1. Anterior extension through the vesicovaginal septum is most common, often obliterating
the dissection plane between the bladder and underlying cervical tumor, making surgical
therapy difficult or impossible.
2. Posteriorly, a deep peritoneal cul-de-sac (pouch of Douglas) can represent an anatomic
barrier to direct tumor spread from the cervix and vagina to the rectum.

23. 4-Bladder & rectal involvement
In the absence of lateral parametrial disease, anterior and posterior spread of cervical cancer to
the bladder and rectum is uncommon.

24. 5-Endometrial involvement
• The endometrium is involved in 2% to 10% of cervical cancer cases treated with surgery,
although the overall incidence (including nonsurgical cases) is unknown.
• Although endometrial extension does not alter a patient's stage of disease, it has been
associated with decreased survival and a higher incidence of distant metastases.

25. 6-Ovarian metastasis
Rarely, ovarian involvement with cervical cancer occurs through the lymphatic connections
between the uterus and adnexal structures.

26. 7-Hematogenous spread
• Hematogenous spread of cervical cancer is uncommon, particularly at the time of
initial diagnosis.
• However, when blood-borne metastases do occur, the
1. lung
2. liver
3. bone
are the sites most frequently involved.

27. Staging
• Examination under anesthesia is recommended for accurate staging.
• It is important to palpate the entire vagina to determine whether disease is limited to the
cervix, or also extends to other areas.
• It is impossible at clinical examination to decide whether a smooth and indurated
parametrium is truly cancerous or only inflammatory, and the case should be considered
stage III only if the parametrium is nodular on the pelvic wall or if the growth itself extends to
the pelvic wall.
• Biopsy- proven invasion of bladder or rectal mucosa by cystoscopy or proctoscopy is required
for a diagnosis of stage IVA disease.
• When there is doubt concerning which stage a tumor should be assigned, the earlier stage is
mandatory.
• Once a clinical stage has been determined and treatment initiated, subsequent findings on
either extended clinical staging (CT, MRI, etc.) or surgical exploration should not alter the
assigned stage. Assignment of a more advanced stage during treatment will result in an
apparent but deceptive improvement in the results of treatment for earlier stage disease.

28. Staging
Cervical cancer & vaginal cancer still use a clinically based staging system:
1. clinical evaluation (visual inspection,palpation, colposcopy)
2. radiographic examination of the chest, kidneys, and Skeleton
3. endocervical curettage and biopsies (conization or incisional
biopsies)
Lymphangiograms, arteriograms, CT scans, MRI, and laparoscopy or laparotomy should not
be used for clinical staging.

29. Staging
• 0 Carcinoma in situ, intraepithelial carcinoma
• I Carcinoma is strictly confined to the cervix
• IA Invasive cancer identified only microscopically. All gross lesions even with superficial
invasion are stage IB cancers. Invasion is limited to measured stromal invasion = 5 mm deep
and <7 mm wide.
• IA1 Measured invasion of stroma = 3 mm deep and <7 mm wide
• IA2 Measured invasion of stroma >3 mm deep but = 5 mm deep and <7 mm wide
• IB Clinical lesions confined to the cervix or preclinical lesions greater than stage IA
• IB1 Clinical lesions = 4 cm in size
• IB2 Clinical lesions >4 cm in size

30. Staging
• II Carcinoma extends beyond the cervix but has not extended to the pelvic wall. Carcinoma
involves the vagina but not as far as the lower third.
• IIA No obvious parametrial involvement
• IIB Obvious parametrial involvement
• III Carcinoma has extended to the pelvic wall. On rectal examination, there is no cancerfree
space between the tumor and the pelvic wall. The tumor involves the lower third of the
vagina.
All cases of hydronephrosis or nonfunctioning kidney are included(stageIII) unless known to
be due to another cause.
• IIIA No extension to the pelvic wall
• IIIB Extension to the pelvic wall, hydronephrosis, or nonfunctioning kidney

31. Staging
• IV Carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the
bladder or rectum. Bullous edema does permit a case to be allocated to stage IV.
• IVA Spread of growth to adjacent organs
• IVB Spread to distant organs

32. Prognosis
• Clinical stage of disease at the time of presentation is the most important determinant of
subsequent survival, regardless of treatment modality. Five-year survival declines as FIGO
stage at diagnosis increases.
• tumor histology, histologic grade, lymph node status, depth of invasion, overall tumor size
and host factors are also prognostic variables relating to survival.
• Among surgically treated patients, survival is directly related to the number and location of
lymph node metastasis. The frequency of positive lymph nodes increases with the stage of
disease.
For all stages of disease:
1. when both pelvic and paraaortic lymph nodes are negative, the 5-year survival rate is 75.2%.
2. Survival decreases to 45.6% with positive pelvic nodes, and the risk of recurrence is related
to the number of nodes involved. (The recurrence rate is 35% with one positive pelvic lymph node, 59%
with two or three positive nodes, and 69% with metastases to more than three pelvic lymph nodes)
3. When paraaortic nodes are involved, the 5-year survival rate ranges from 15% to 45%.

33. Tumor histology
Cervical cancer includes:
• SCCs(74.9% of cases) can be categorized according to the degree of histologic tumor
differentiation:
1. Well-differentiated: about 5% of cervical SCCs, composed of sheets and cords of cells with
abundant acidophilic cytoplasm, clearly visible intercellular bridges, and production of
variable amounts of keratin. 5 year survival:74.5%
2. Moderately differentiated: 85% of SCCs, characterized by masses and cords of Spindle-
shaped squamous cells with elongated nuclei and scant cytoplasm and more frequent
mitoses. 5 year survival:63.7%
3. Poorly differentiated: 10% of cervical SCCs, with numerous mitoses and cells with closely
crowded nuclei and scant cytoplasm. 5 year survival:51.4%
• Adenocarcinomas: 15% to 20% of cases
• Adenosquamous
No difference in overall survival between patients with cervical SCC and adenocarcinoma.
However, adenosquamous histology was associated with decreased survival.

34. Host factors
1. pretreatment anemia (hemoglobin of 12 g/dL or less) is associated with a higher incidence
of pelvic recurrences and decreased survival, primarily due to more frequent radiation
therapy failures(due to tumor hypoxia).
2. thrombocytosis (>400,000/mm3), associated with decreased survival.
3. patient age at diagnosis of cervical cancer is a significant and independent predictor of
clinical outcome remains controversial.
4. Coexistent medical conditions may affect the success of treatment. Diabetes and HTN:
frequently associated with significant vascular disease and potentially contribute to both
tumor hypoxia and decreased blood supply to normal pelvic tissues. These conditions result
in a higher incidence of treatment complications and pelvic tumor recurrence as well as
decreased survival.