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Cervical Carcinoma Cervical Carcinoma Chris DeSimone, M.D. Assistant Professor Division of Gynecologic Oncology Outline Cervical Carcinoma Epidemiology Clinical symptoms Risk factors Staging Cell types Prognostic factors Treatment Cervical Cancer 2nd most common cancer among women world wide Estimated 493,000 new cases 293,000 deaths annually worldwide 7th most common cancer among women in the United States Estimated 10,000 new cases each year 3700 deaths annually from cervical cancer Parkin et al. Int J Cancer, 2005. Who Develops Cervical Cancer? 50% of women diagnosed with cervical cancer have not had a Pap test in 5 years 25% of all cervical cancers are diagnosed in women older than 65 In women older than 65, it is estimated that over 50% have not had a Pap test in the past 10 years Bottom Line – the majority of women with cervical cancer fail to get annual Pap tests Symptoms Early stages Vaginal bleeding Post coital spotting Foul smelling, yellowish discharge Late stages Back pain Lethargy Nausea/vomiting Most symptoms attributable to renal failure from ureteral obstruction Classic Risk Factors for Cervical Cancer Early first age of sexual contact Multiple sexual partners Smoking Multiple sexually transmitted diseases Immunocompromised Lower socio-economic class Family history is not a risk factor Main Risk Factors for Cervical Cancer Human papillomavirus (HPV) is the cause of cervical cancer Estimated that 80% of men and women will have been exposed to the virus by the age of 50 Smoking is an important cofactor for malignant transformation Staging of Cervical Cancer Clinically staged (at least partially) Stage I is confined to the cervix Ia1 Stromal invasion < 3 mm and lateral spread < 7 mm Ia2 Stromal invasion 3-5 mm and lateral spread < 7 mm lateral spread Ib1 Clinically visible lesion ≤ 4 cm Ib2 Clinically visible lesion > 4cm in greatest dimension Staging of Cervical Cancer Stage IIa Upper 2/3 of vagina Stage IIb Parametrial involvement Stage IIIa Lower 1/3 of vagina Stage IIIb Pelvic sidewall or hydronephrosis Stage IVa Rectal or bladder mucosa Stage IVb Distant disease Cervical Anatomy Cell Types Squamous (80%) Squamous cell Large cell keratinizing Large cell non-keratinizing Grade 2 most common grade Adenocarcinoma (20%) Incidence is increasing ~30% (70’s to 90’s) Adenocarcinoma Mucinous (rare) Endometrioid Clear Cell (DES exposure) Adenosquamous malignant glandular and squamous cell types Poor prognosis Cell Types Glassy Cell Carcinoma Poorly differentiated adenosquamous carcinoma with eosinophilic cytoplasm Poor prognosis Adenoid Cystic Carcinoma Cribriform gland pattern Aggressive and poor prognosis S100 immunohistochemistry Adenoid Basal Carcinoma Indolent and excellent prognosis Neuroendocrine tumors Carcinoid Small-cell carcinoma Strong association with HPV 18 Chemosensitive but recurrences likely Surgical treatment best therapy Chromogranin and neuronspecific enolase immunohistochemistry Survival Rates Ia 95% Ib 80% II 63% III 36% IV 15% Benedet J. Annual report on the treatment of GYN CA. J Epidemiol Biostat, 2001. Prognostic Factors Age Women < 35 have a poorer prognosis? No conclusive data to support this concept Race African –American women are more likely to have numerous risk factors, advanced stage and less likely to undergo therapy Anemia Grogan et al. Cancer; 1999. 475 patients evaluated Presenting hemoglobin ≥ 12 g/L had a better prognosis Significant on univariate analysis ONLY Prognostic Factors Tumor Invasion/Size Delgado et al. Gynecol Oncol; 1990. GOG 49. Patients with minimal stromal invasion had better 3 year survival rates following radical hysterectomy < 10 mm: 86-94% 11 to 20 mm: 71 to 75% > 21 mm: 60% van Nagell et al. Cancer; 1979. Recurrence rate for Ib cervical cancers: RAH vs. XRT Tumor <2 cm: 5% recurrence for RAH or XRT Tumor 2-5 cm: 24% recurrence with RAH, 11% with XRT Prognostic Factors Stage Stehman et al. Cancer; 1991. Confirmed that tumor burden is a poor prognostic factor Clinical staging limits thorough evaluation of tumor burden such as tumor volume, nodal status etc; therefore stage not the best indicator of a patient’s prognosis Lymph Vascular Space Invasion Delgado et al. Gynecol Oncol; 1990. GOG 49. Disease free survival 77% with LVSI vs. 89% without LVSI Prognostic Factors Nodal Status The MOST significant negative prognostic factor Tinga et al. Gynecol Oncol; 1990 and Delgado et al. Gynecol Oncol; 1990. GOG 49. Higher 5 year survival rates among surgically treated patients with negative LN’s (90%), positive pelvic LN’s (50-60%) and positive para-aortic LN’s (20-45%) Reported 87% survival rate for 1 involved LN vs. 53% for 2 or more involved LN’s (p<0.02) Parametrial, Pelvic and Para- aortic Lymph Node Involvement per Stage Stage Parametrial Pelvic Para-aortic Ia2 - 5% 1% Ib 11% 15% 5% IIa - 22% 15% IIb 22% 35% 20% III - 45% 35% Hoskin's. 4th ED. 745. Treatment for Stage I Surgery is reserved for early staged cervical cancer Stage Ia1 Cervical cone Hysterectomy Stage Ia2, Ib1 and some Ib2 or IIa Radical hysterectomy (abdominal, vaginal or laparoscopic) Fertility-sparing: radical trachelectomy Radical Hair Radical Hysterectomy Objective is to remove the cervical cancer, uterus and tissue adjacent to the uterus: Parametrial tissue Complete pelvic lymphadenectomy (internal, external, common iliac nodes and obturator nodes) Upper 2 cm of the vagina Higher morbidity than a simple hysterectomy Types of Radical Hysterectomies Extrafascial Type I Modified Radical Type II Radical Type III Cervical Fascia Completely removed Completely removed Completely removed Vaginal Cuff Small rim removed Proximal 1-2 cm Upper ⅓ to ½ removed Bladder Partially mobilized Partially mobilized Mobilized Rectum Partially mobilized Partially mobilized Mobilized Ureters Not mobilized Unrooted in ureteral tunnel Complete dissection to bladder entry Cardinal Ligament Resected medial to ureters Resected at level of ureter Resected at pelvic sidewall Uterosacral Resected at level of cervix Partially resected Resection at post-pelvic Ligaments insertion Uterus Removed Removed Removed Cervix Completely removed Completely removed Completely removed Extended Radical - - Above plus, resection of Hysterectomy Type superior vesical artery and IV more vagina Type V - - Above plus, resection of ureter and bladder Radical Hysterectomy Anatomy Radical Hysterectomy Anatomy Radical Hysterectomy Anatomy Complications of Radical Hysterectomy Estimated that 10% of patients will have some form of bladder dysfunction or injury Ueland et al. Gynecol Oncol, 2005. Evaluated 290 RAH’s from 1965-2002 Since 1985, incidence of ureteral injury <2%, bladder injury <1% and fistulas <1% These injuries were more common when EBL >1000 ml (p<0.01) Pulmonary embolis Transfusion Survival Rate from Radical Hysterectomy Related to size of the tumor Generally 90% 5-year survival rate Ueland et al. Gynecol Oncol, 2005. All size Ib1 tumors 98% 2-year, 96% 5-year, 94% 10-year Gadduci et al. Anticancer Res, 1995. ≤4 cm, 92% 5-year >4 cm, 56% 5-year (p=0.001) Hopkins et al. Am J Obstet Gynecol, 1991. ≤3 cm, 91% 5-year >3 cm, 76% 5-year (p=0.007) Positive Lymph Nodes Following RAH Positive lymph nodes equate to poor prognosis Ib1 survival with RAH and (-) LN’s 80-90% Ib1 survival with RAH and (+) LN’s 50-60% Several studies document decreased local recurrence with XRT; BUT no improvement in overall survival What about Chemo/XRT? Delgado et al. Gynecol Oncol. 1990. Positive Lymph Nodes Following RAH Peters WA et al. J Clin Oncol, 2000. GOG 109. Randomized study for Ia2-IIa cervical carcinomas treated by RAH with positive lymph nodes Treatment group consisted of XRT versus Chemo/XRT XRT: 4900 cGy. No brachytherapy Chemo: q 21 days Cisplatin 70 mg/m2 D1 5-FU 1000mg/m2 D2-5 Positive Lymph Nodes Following RAH Majority of women stage Ib cervical carcinomas and majority had positive pelvic lymph nodes Median follow up 42 months 4 year survival: Chemo/XRT 81% XRT 71% HR 1.96 (p=0.007) Toxicity: Chemo/XRT grade 4 toxicity (n=27) [Neutropenia 11] XRT grade 4 toxicity (n=4) Radical Fashion High Risk Groups s/p RAH with (-) LN’s Risk factors significant for recurrence Depth of invasion Size of tumor LVSI Estimated 25% of Ib tumors with negative pelvic lymph nodes have these factors GOG 49- Delgado et al. Gynecol Oncol, 1990. High Risk Groups s/p RAH with (-) LN’s Sedlis et al. Gynecol Oncol, 1998. GOG 92 Randomized study for Ia2-Ib2 cervical carcinomas treated by RAH with negative lymph nodes AND: > ⅓ stromal invasion (>15 mm) LVSI (positive) Large clinical tumor (>4 cm) Treatment group consisted of XRT versus no further therapy (NFT) XRT: 4600 to 5040 cGy. No brachytherapy High Risk Groups s/p RAH with (-) LN’s 21 patients (15%) recurred with XRT versus 39 patients (28%) with no further therapy Majority of recurrences local 18/21 XRT vs. 27/39 NFT 47% reduction in risk of recurrence: RR 0.53, p=0.008 Recurrence free rate at 2 years 88% XRT vs. 79% NFT 11 patients with Grade 3-4 toxicity with XRT vs. 3 with NFT (majority GI and/or GU complications) High Risk Groups s/p RAH with (-) LN’s Summary Deep stromal invasion > 15 mm LVSI Tumor > 4 cm Negative LN’s Tailor therapy per patient for XRT ± Cisplatin Radical Hippies Arrow points to the hippy Neoadjuvant Chemotherapy and RAH for Bulky Cervical Disease Reference FIGO Stage Chemo regimen NACT+S Control Median Overall follow
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