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Faustino R. Pérez-López University of Zaragoza Faculty of Medicine and Lozano-Blesa University Hostpital, Zaragoza 50009, Spain ENDOMETRIAL AND OTHER CANCERS IN THE MENOPAUSE Learning Objectives Recognize the current evidence-based recommendations for women in their second half of life regarding genital cancer risk and diagnosis Describe current general approaches for the management of genital cancer Cancer and menopause Menopause is not associated with increased cancer risk However, cancer rates increase with age and cancer is the second leading cause of death in women Special attention should be provided about oncologic issues during the second half of life Genetic factors and cancer Genetics may contribute to the risk of various cancers Mass screening for specific mutations cannot be used in the general population There are no clear screening tests for some cancers (endometrial, ovarian, vulvar, lung) Preventive measures are based upon early organ extirpation in genetic mutation carriers Lifestyle and cancer: modifiable risk factors Smoking Alcohol High body mass index Dietary factors Physical activity Use of hormones Infertility treatments Hormone contraception Menopause hormone therapy Outline 1. Endometrial cancer 2. Uterine sarcoma 3. Ovarian cancer 4. Cervix cancer 5. Vulvar cancer 6. Other cancers Endometrial cancer It is the most common gynecological cancer It occurs most often in postmenopausal women, with less than 5% diagnosed under 40 years of age There is no effective screening program, but occasionally cervical smears contain endometrial cells or double ultrasound endometrial thickness of 4 mm or more indicating the need for endometrial sampling Risk factors for endometrial cancer Age Family history of endocrinerelated cancers (breast, ovary) Previous breast or ovarian cancer Endometrial hyperplasia in the past Radiation therapy to the pelvis High number of menstrual cycles (early menarche, late menopause) Polycystic ovarian syndrome Nulliparity Infertility or failure of ovulation Unopposed estrogen therapy Tamoxifen treatment Diabetes Obesity Sedentarism Metabolic syndrome Diet high in animal fat Protective factors for endometrial cancer Pregnancies Physical activity Use of oral contraceptives Use of IUD Smoking Symptoms of endometrial cancer Non-menstrual bleeding or discharge Dysuria Pain: Especially post-menopausal bleeding Heavy bleeding During intercourse (dyspareunia) Pain and/or mass in pelvic area Back pain Weight loss Endometrial cancer diagnosis Pelvic examination Pap smear (may detect cancer spread to cervix) Transvaginal ultrasound Endometrial sampling (hysteroscopy) or curettage is mandatory Who needs a biopsy? Postmenopausal bleeding Perimenopausal intermenstrual bleeding Abnormal bleeding with history of anovulation Postmenopausal women with endometrial cells on PAP Thickened endometrial stripe via sonography Histopathology Endometrioid adenocarcinoma (70-80%) Clear cell and serous tumor are more aggressive and probably present at a more advances age (8-12%) Adenosquamous (4%) Mucinous (2%) and others Endometrial cancer: Type I and II Type I Estrogen-related Younger and heavier patients Low grade Background of hyperplasia Perimenopausal Exogenous estrogen Type II (~10% of total cases) Aggressive High grade Unfavourable histology Unrelated to estrogen stimulation Occurs in older and thinner women Familial/genetic (~15% of total cases) Lynch II syndrome/HNPCC Familial trend HNPCC = Hereditary Non-Polyposis Colon Cancer Genetic syndromes: HNPCC (Lynch síndrome) Autosomal dominant inheritance Early age of colon cancer: mean 45 years Endometrial cancer: second most common malignancy MMR (mismatch repair) mutations hMSH2 (chromosome 2) hMLH1 (chromosome 3) 20% cumulative incidence by age 70 Earlier age of onset than sporadic cancer Other: ovary (3.5-8 fold), stomach, pancreas, etc Endometrial cancer treatment Surgery Hysterectomy Salpingo-oophorectomy Pelvic lymph node dissection Radiation therapy Hormone therapy: antiestrogens Chemotherapy progestogens, Overall results The overall results are better than for cervix carcinoma, not because it is less malignant, yet because treatment is received earlier Postmenopausal bleeding is much more difficult to ignore than the irregular bleeding of younger woman Cancer dissemination seems to be more rapid for cervix carcinoma than for endometrial spread Recurrence of endometrial cancer The incidence of recurrence within 5 years is in the range of 20 to 30%, depending on the stage at diagnosis, treatment and individual characteristics The majority recurrences appear within 3 years of treatment. Early recurrence has a poor prognosis Progestogens Many endometrial cancers are hormone dependent and progestogens have been used as part of a combined primary treatment as well as for recurrent or metastatic growths Between 15% and 50% recurrences respond to medroxyprogesterone, with or without tamoxifen Outline 1. Endometrial cancer 2. Uterine sarcoma 3. Ovarian cancer 4. Cervix cancer 5. Vulvar cancer 6. Other cancers Uterine sarcoma Accounts for fewer than 10% of all corpus cancers Abnormal vaginal bleeding the most frequent presenting symptoms for all histologic types Types: carcinosarcoma (60%), leiomyosarcoma (30%), endometrial sarcoma (10%), and adenosarcoma (<1%) Uterine sarcomas: general characteristics Exposure to radiation may enhance the development of uterine sarcomas (seen mainly in mixed sarcomas) Mean age 65-75 for carcinosarcoma but earlier for leiomyosarcoma and endometrial stroma sarcoma Early hematogenous spread to liver and lung is common In patients without extrauterine disease, 40% chance of distant recurrence Uterine sarcomas: management Surgery is the hallmark of treatment with hysterectomy and bilateral salpingo-oophorectomy being the standard For patients with advanced or recurrent disease, aggressive surgical intervention is unlikely to influence outcome Adjuvant radiotherapy has been shown to improve local control, effect on overall survival unknown Outline 1. Endometrial cancer 2. Uterine sarcoma 3. Ovarian cancer 4. Cervix cancer 5. Vulvar cancer 6. Other cancers Ovarian tumors Nearly 25% of all ovarian neoplasms are malignant Approximately 80% are primary malignancies of the ovary 80% of all cases of primary carcinomas of the ovary arise in serous or mucinous cysts The remainder are secondary tumors, usually carcinomas Epidemiology of ovarian cancer 9th most common cancer among women 5th most common cause of cancer death 1st most common genital cancer death Epithelial ovarian cancer (EOC) Most common type of ovarian cancer Epithelial (75%) Germ cell (15-20%) Sex-cord stromal (5%) Median age of presentation 65 Overall lifetime risk 1 in 70 75-80% of patients are diagnosed with stage III or IV disease Ovarian cancer risk factors Age is the most important risk factor Family history (2 or more first degree relatives) Nulliparity Early menarche, late menopause Late childbirth Environmental factors Ovarian cancer protective factors Multiparity First pregnancy before age 30 Oral contraceptives Breast feeding Tubal ligation Salpingectomy Hysterectomy Risk reduction oophorectomy Hereditary ovarian cancer BRCA1 and BRCA2 mutations Account for 10% of EOC Hereditary non polyposis colorrectal cancer (HNPCC), Lynch II Colorectal cancer before age 50 Endometrial cancer before age 50 Other cancer localizations: ovarian, pancreas, gastric, small bowel, etc Epithelial carcinogenesis: ovarian vs the fallopian tubes Ref. Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol. 2008 Nov 10;26:5284-93. Malignant tumor symptoms Lack of any specific symptom, tumors are often large by the time the professional is consulted Menstrual function is seldom upset, and any irregularity is attributed to the patient’s “time of life” Weight gain, abdominal swelling or pressure symptoms Very large tumors may cause respiratory embarrassment and edema or leg varicosities Cachexia due to interference with alimentary function General clinical rule An experienced examiner will recognize an ovarian tumor mainly because ovarian tumor is the most likely diagnosis A fluid thrill may be elicited from an ovarian cyst, and ascites and tumor may coexist, but as a rule the distinction should be easily made All abdominal swelling should be subjected to ultrasound and X-ray examination Other clinical complications Rupture of a cyst Pseudomyxoma peritonei is a rare condition that follows the rupture of a mucionous tumor. The epithelial cells implant on the peritoneum which is not absorbed, producing abdominal visceral spreading Hydrothorax may accompany ascites due to any cause or as an accompaniment of a lung tumor. Sometimes this conditions is associated with ascites (the so-called Meigs’ syndrome) Features suggestive of malignancy Age: if the patient is > 50 the chance of malignancy is over 50% as opposed to less than 15% in premenopausal. Tumors in childhood are usually malignant Rapid growth Ascites Solid tumors, especially when bilateral Multilocular cysts with solid areas Pain, especially when referred pain suggests malignant involvement of nerve roots Tumor markers, such as CA125, may be measured in the blood, but a normal level does not exclude malignancy Principles and purpose of ovarian cancer surgery Staging of disease Prognosis and treatment depend upon surgical findings and subsequent stage Debulking (cytoreduction) Overall reduction of tumor burden to less than 1 cm (preferably no gross residual disease) improves survival Palliation of symptoms Goldie-Coldman Hypothesis: resistance to chemotherapy will develop in fraction of remaining viable cells Ovarian cancer surgical management Biopsies (Staging) Exploration TAH/BSO Washings/Ascites (Staging) TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy Goals (Debulking) •Assessment of extent of disease •Optimal tumor reduction First-line therapy: Standard treatment options Surgery with maximum cytoreduction effort <1 cm residual disease Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Goals of treatment: relapsed ovarian cancer Prolong survival Delay time to progression Control disease-related symptoms Maintain or improve quality of life Outline 1. Endometrial cancer 2. Uterine sarcoma 3. Ovarian cancer 4. Cervix cancer 5. Vulvar cancer 6. Other cancers Cervix cancer and menopause PAP test every 3 years (or every 5 years if combined with HPV test) after a normal report 3 years in a row for women Screening not necessary ≥ age 65 with 3 or more normal PAP tests in a row, no abnormal PAP in past 10 years, or 2 or more negative HPV tests in past 10 years Cervical cancer Incidence in Europe 8-12% Associated with Young age at first intercourse Number of sexual partners HPV 16,18, 33 and others Smoking Immunosupression Pathology of cervix cancer Peaks 35-44 and 75-85 years Squamous (70%) Adenocarcinoma (12%) Adenosquamous (12%) Direct spread - anatomical Clinical features at presentation Abnormal bleeding Postcoital, intermenstrual, postmenopausal bleeding Abnormal smears Advanced disease related with Offensive vaginal discharge Neuropathic pain Renal failure Deep venous thrombosis Cervical cancer Microinvasive Cone biopsy, trachelectomy, hysterectomy Invasive Radical hysterectomy, node dissection Radical vaginal hysterectomy, laparoscopic node dissection Chemoradiotherapy Outline 1. Endometrial cancer 2. Uterine sarcoma 3. Ovarian cancer 4. Cervix cancer 5. Vulvar cancer 6. Other cancers Vulvar cancer 3-4% of all gynecologic malignancies The incidence increases with age Longevity Increased prevalence of HPV infections Increased smoking habit Vulvar cancer: risk factors Human papillomavirus infection Genital condilomas are detected in 5% of vulvar cancer Vulvar intraepitelial neoplasia (VIN) Medical history Previous squamous cell carcinoma of the cervix or vagina Chronic immunosuppression Smoking Vulvar cancer diagnosis Patients do not ask for early consultation Patients consider symptoms as trivial skin conditions Physicians may neglect small skin lesions Clinical symptoms Chronic pruritus vulvae Palpable vulvar lesion Asymptomatic: in 20% of patients the lesion is detected during examination for unrelated condition Later the lesion becomes necrotic cauliflower or hard ulcerated Bleeding, watery discharge, superinfection and pain Melanomas frequently appear as bluish black, pigmented, or papillary lesions Prevention of vulvar cancer Detection and management of Lichen and VIN Proper management of all cases with pruritus vulvae All vulval lesions should be diagnosed accurately especially those arising during the second half of life All pigmented vulvar lesions should be assessed for biopsy Vulvar surgery options Skinning vulvectomy: this is an option for treating extensive VIN Simple vulvectomy Radical vulvectomy Vulvar radiotherapy Malignant disease of the vulva is not commonly managed by radiotherapy Postoperative radiotherapy can reduce regional recurrences and inguinal lymph node metastases Chemotherapy as radiation sensitizer improve response of the malignant tissue can Vulvar melanoma Rare: incidence 0.1/100,000 women Second most common vulvar malignancy No symptoms (most) Itching, bleeding, groin mass Labia minora, clitoris Vulvar nevi are junctional, precursor lesion to melanomas Outline 1. Endometrial cancer 2. Uterine sarcoma 3. Ovarian cancer 4. Cervix cancer 5. Vulvar cancer 6. Other cancers Vaginal cancer < 1% of gynecological malignancies Average age at diagnosis is 65 High risk factors HPV infection of the cervix or the vulva Exposure to diethylstilbestrol in utero It might progress to clear cell adenocarcinoma of the vagina and cervix The mean age at diagnosis is 19 years Colorectal cancer risk factors Age More than 90% of colorrectal cancer is found in people ages 50 and over Familial history (in a mother, father, brother, sister, or child): Colorectal cancer, adenomatous polyps or “adenomas” Ovarian or endometrial cancer before age 50 Inflammatory colitis and Crohn´s scolitis Smoking, high fat diet, obesity in premenopausal women Lung cancer risk and protective factors Incidence and mortality rates begin to increase between the ages 45 and 54 and rise progressively until 75 In the US African-Americans have the highest incidence and mortality Median age at diagnosis 70 In developing countries female cigarette use is low Beneficial micronutrients in fruits and vegetables Prevention of lung cancer Cigarette smoking causes 90% of lung cancer deaths Avoid second hand smoking Get you home tested for radon Avoid carcinogens at work