1. Cervical cancer

2. Incidence and mortality Worldwide, cervical cancer accounted for an estimated 530,000 new cancer cases and for 275,000 deaths In developed countries in 2008, cervical cancer was the tenth most common type of cancer in women (9.0 per 100,000 women) and ranked below the top ten causes of cancer mortality (3.2 per 100,000). In contrast, in developing countries it was the second most common type of cancer (17.8 per 100,000) and cause of cancer deaths (9.8 per 100,000) among women

3. Histopathology: Squamous cell carcinoma – 69% Adenocarcinoma (including adenosquamous) – 25% Other histology (e.g. small cell carcinoma, lymphoma, sarcoma,…etc.) – 6%

4. Age distribution - The lifetime risk of developing cervical cancer for United States women is 0.76%. The mean age at diagnosis is 48 years Age (year) Incidence of cervical cancer <200.1/100,000 20-241.5/100,000 30-8511-15.8/100.000

5. Pathogenesis Human papillomavirus (HPV) is central to the development of cervical neoplasia and can be detected in 99.7% of cervical cancers. There are four major steps in cervical cancer development: 1)Oncogenic HPV infection of the metaplastic epithelium at the cervical transformation zone 2)Persistence of the HPV infection 3)Progression of a clone of epithelial cells from persistent viral infection to precancer 4)Development of carcinoma and invasion through the basement membrane

6. Pathogenesis Most HPV infections are transient. When HPV infection persists, the time from initial infection to development of high grade cervical intraepithelial neoplasia and, finally, invasive cancer takes an average of 15 years, although more rapid courses have been reported Among the more than 40 genital mucosal HPV types identified, approximately 15 are known to be oncogenic. Subtypes. HPV 16 and 18 are found in over 70 percent of all cervical cancers.

7. Risk factors Most of these factors are associated with an increased risk of acquiring or having compromised immune response to infection with human papillomavirus (HPV), the etiologic agent of most cervical cancers. These include: Early onset of sexual activity Multiple sexual partners A high-risk sexual partner (e.g., a partner with multiple sexual partners or known human papillomavirus infection) History of sexually transmitted infections (e.g., Chlamydia trachomatis, genital herpes) History of vulvar or vaginal squamous intraepithelial neoplasia or cancer

8. Risk factors Immunosuppression (e.g. AIDS) Low socioeconomic status Others: Non-white women Early age at first birth ( 3 or more) Smoking (SCC of the cervix only) Oral contraceptive use Cervical cancer is less common in sexual partners of circumcised males

9. Routes of Spread: Cervical cancer can spread by: Direct extension: may involve uterine corpus, vagina, parametria, peritoneal cavity, bladder, or rectum. Ovarian involvement by direct extension of cervical cancer is rare; (0.5% in SCC and 1.7% of adenocarcinomas) Lymphatic spread Hematogenous dissemination: the most common sites are the lungs, liver, and bone

11. Clinical manifestation: Asymptomatic – abnormal cervical smear Vaginal bleeding Postcoital bleeding Abnormal vaginal discharge In advanced disease Pelvic or lower back pain, which may radiate along the posterior side of the lower extremities Bowel or urinary symptoms, such as pressure-related complaints, hematuria, hematochezia, or vaginal passage of urine or stool

12. FIGO staging of carcinoma of the cervix uteri Stage 0: preinvasive carcinoma, CIS Stage I: carcinoma strictly confined to the cervix (extension to the corpus should be disregarded) stage Ia - Preclinical carcinoma of the cervix, i.e. those diagnosed only by microscopy o Stage Ia1: lesion < 3 mm invasion & < 7 mm in width o Stage Ia2: lesion 3-5 mm invasion & < 7 mm in width. Stage Ib - lesion invasion > 5mm & / or diameter > 7 mm o Stage Ib1: lesion < 4 cm o Stage Ib2: lesion > 4 cm Stage II: the carcinoma extend beyond the cervix but has not extend onto the pelvic wall. The carcinoma involve the vagina, but not the lower one-third Stage IIa - No obvious parametrial involvement (extension to the upper two third of the vagina) Stage IIb - Obvious parametrial involvement

14. Stage III: the carcinoma has extended to the pelvic wall. On rectal exam, there is no cancer-free space between the tumor & the pelvic wall. The tumor involved the lower third of the vagina. All cases of hydronephrosis or nonfunctioning kidney Stage IIIa - Tumor extend to the lower third of the vagina (no extension to the pelvic wall) Stage IIIb - Extension onto the pelvic wall &/or hydronephrosis or non-functioning kidney Stage IV: the carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum. Stage Iva - Spread to adjacent organs Stage IVb - Spread to distant organs

15. Diagnosis: Examination Pelvic examination – speculum, bimanual, and rectovaginal examination for palpation and inspection of the primary tumor, uterus, vagina, and parametria Examination for distant metastases – palpation of groin and supraclavicular lymph nodes Cervical biopsy: the diagnosis of cervical cancer is made based upon histologic evaluation of a cervical biopsy Colposcopy with directed cervical biopsy Endocervical curettage Conization

16. Diagnosis Imaging studies - X rays, CT,MRI, PET…etc Lab: CBC,KFT, LFT, UA…etc.

17. Treatment Surgical Management of Early Invasive Cancer of the Cervix StageCommentRx Stage Ia1 < 3 mm invasion No lymph vascular space invasion Conization (or) Simple hysterectomy (abdominal or vaginal) Stage Ia1 < 3 mm invasion With lymph vascular space invasion Trachelectomy + pelvic LNDs (or) Simple hysterectomy or modified radical hysterectomy + pelvic LNDs

18. Treatment Stage Ia2 >3-5 mm invasion & <7 mm in diameter Radical trachelectomy + pelvic LNDs (or) Modified radical hysterectomy + pelvic LNDs Stage Ib1 Lesion <2 cm Modified radical hysterectomy with pelvic lymphadenectomy Stage Ib1 Lesion > 2 cmRadical hysterectomy with pelvic lymphadenectomy

19. Complication of radical hysterectomy: Acute / subacute Complications Ureterovaginal / vesicovaginal fistula (2-3%) Pulmonary embolus (1-2%) Blood loss Febrile morbidity (25-50%): atelectasis, pelvic cellulitis, urinary tract infection, wound infection, pelvic abscess, and phlebitis Postoperative bladder dysfunction Lymphocyst formation Chronic Complications Bladder hypotonic Ureteral strictures Compromised sexual activity, decreased lubrication, & shortened vagina

20. Treatment For more advanced disease (> stage 1B1): Chemoradiation Compared with surgery, chemoradiation resulted in: Higher incidence of sexual dysfunction Higher incidence of bowel dysfunction A higher incidence of urinary incontinence Ovarian failure — women treated with surgery may be at risk for premature ovarian failure possibly due to impairment of ovarian perfusion. Pelvic RT (with or without concomitant chemotherapy) uniformly results in ovarian failure due to the doses required for curative intent therapy.

21. Comparison of surgery versus radiations for stage Ib / IIa cancer of the cervix SurgeryRadiation Serious complicat ions - Urologic fistula 3% - Intestinal & urologic fistula & stricture in 1.4-5.3% Vagina - Initially shortened, but may lengthen with regular intercourse - Fibrosis & possible stenosis particularly in postmenopausal women Ovaries- may be conserved- Destroyed Chronic effects - Bladder atony in 3%- Radiation fibrosis of bladder & bowel in 6- 8%

22. Anatomic structure Simple hysterectomy Modified radicalRadical UterusRemoved OvariesOptional removal CervixRemoved Vaginal marginNone1-2 cm margin> 2-3 cm margin UretersNot mobilized Dissected through broad ligament Cardinal ligaments Divided at uterine border Divided where ureter transit the broad ligament Divided at pelvic sidewall Uterosacral ligaments Divided at cervical border Partially resected Divided near sacral origin Bladder Mobilized to base of cervix Mobilized to upper vagina Mobilized to middle vagina RectumNot mobilizedMobilized below cervix Mobilized below middle vagina

23. Treatment Women who are not surgical candidates due to poor functional status – chemoradiation Women who wish to preserve fertility – For women of reproductive age who wish to preserve their fertility and have a lesion size ≤2 cm and no lymph node metastases Trachelectomy +/- PLNs may be offered

24. Prognosis The major prognostic factors affecting survival among women with cervical cancer are stage, nodal status, tumor volume, depth of cervical stromal invasion, and lymphovascular space invasion (LVSI). Disease stage is the most important prognostic factor Stage5-years Survival rate Ia95% Ib80% II64% III38% IV14%

25. Recurrent Disease Following treatment of early stage cervical cancer, distant metastases or multiple recurrence sites develop in 15 to 61 percent of cases, usually within the first two years of completing treatment. Recurrent cervical cancer presents as disease isolated to the pelvis (locoregional recurrence) or with disease involving other organs or outside the pelvis Treatment depends on the mode of primary therapy & the site of the recurrence, e.g.: Patient who have initial treatment by surgery should be considered for radiotherapy Patient who had radiotherapy should be considered for surgery provided the recurrence is central & there is no evidence of distal recurrence

26. Screening and Prevention Cervical smear: the rate of cervical cancer has declined significantly in settings in which cervical cancer screening is employed HPV vaccine