Epithelial Ovarian Cancer 8/2/2013. Tu-be or Not Tu-be: Is the Fallopian Tube the Source of Ovarian Cancer?

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1 Tu-be or Not Tu-be: Is the Fallopian Tube the Source of Ovarian Cancer? Ann E. Smith Sehdev, MD Director, Center for Gynecologic Pathology Cascade Pathology, Portland, Oregon Ann E. Smith Sehdev has no financial relationship with a commercial or proprietary entity that produces healthcare related products and/or services relevant to the content planned, developed or presented for this activity. Epithelial Ovarian Cancer Leading cause of death from gynecologic cancer in the US 5 th most common cause of cancer mortality in women ,990 new diagnoses 15,460 deaths OSCAR (2004-8) Annual average 297 1

2 Epithelial Ovarian Cancer Fewer than 40% of women with ovarian cancer cured 70% of patients present with advanced stage disease Research focused on detection of early stage disease Ref: J Natl Compr Canc Netw Jan;9(1): Epithelial Ovarian Cancer Consensus guidelines for symptoms Bloating, pelvic/abdominal pain, difficulty eating, feeling full quickly, urinary symptoms Screening with CA-125, transvaginal ultrasound, no reduction in ovarian cancer mortality (JAMA 2011;305: ) Epithelial Ovarian Cancer Despite efforts, overall survival for women with ovarian cancer has not changed Suggests that concepts of histogenesis are flawed 2

3 Dualistic Model KRAS/BRAF/ERBB2 mutations Loss of 1p36 Loss of CDKN2A/B serous borderline APST MPSC low grade CA serous cystadenoma Type I pathway inclusion cyst unlikely high grade CA Type II pathway fallopian tube TP53 mutations + CIN Difficulties with surface epithelial theory of ovarian cancer Mullerian-type epithelium on ovarian surface is rare Metaplastic origin not been demonstrated OSE rarely shows neoplastic changes Lesions usually found in cortical inclusion cysts Theory based on unverified assumptions Dubeau, Gynecol Oncol 1999, 72: Does HGSC arise from secondary mullerian system? Histologically similar to tubal epithelium Explains why HGSC can arise outside ovary (peritoneum) 3

4 New evidence to support tubal origin of ovarian cancer STIC a precursor of HGSC or a metastasis? Linking serous tubal intraepithelial carcinoma (STIC) with sporadic HGSC. (Am J Surg Pathol 2007; 31:161) Sporadic reports of tubal carcinoma and dysplasia (Hum Reprod 1998; 13:1425) Tubal lesions closely resemble high grade ovarian serous carcinoma (HGSC), in women with a genetic predisposition (BRCA1/2 mutation carriers). (J Pathol 2001; 195:451) HGSC might develop as a result of implantation of malignant cells from the tubal carcinoma on to the ovary (Lancet 2001; 358:844) fallopian tubes were not carefully examined Serous Tubal Intraepithelial Carcinoma (STIC) 4

5 p53 STICs precursor or metastasis? Gene expression profiling shows that HGSC from FT and ovary indistinguishable STICs express several potential oncogenes frequently found in HGSC linking both lesions (Rsf-1, cyclin E, FASN, p16) AS Sehdev et al, Mod Pathol, 2010, 23: 844 STICs precursor or metastasis? Highly significant difference in overall telomere length between STICs and normal tubal epithelium Consistent with other reports showing telomere shortening in preneoplastic cells in prostate, pancreatic, breast, lung, colorectal cancers Majority of HGSC-longer telomeres compared to STICs; stabilization of telomeres essential in supporting tumor progression Kuhn et al. Am J Surg Pathol, 2010; 34:

6 Hypothesis *Kuhn et al. AJSP, 2010; 34: **AS Sehdev et al. Mod Pathol, 2010; 23: Why is Fallopian Tube Cancer Rare? Criteria for Assigning Primary Site of Origin Criteria for FT cancer diagnosis Grossly, the main tumor arises from the tube Size of the fallopian tube tumor larger than ovarian tumor Transition from benign to malignant epithelium 6

7 Variation in Sampling the Fallopian Tubes Traditionally 1-3 sections grossly normal tube Examining the distal tube/fimbriae SEE-FIM protocol Sectioning and extensively sampling the fimbriated end Submitting cross sections of mid and proximal tube SEE-FIM Protocol Arch Pathol Lab Med Vol 133, July 2009 Case Presentations 7

8 JF 62 y/o g0 patient with 2-3 month history of increasing abdominal distension and difficulty with bowel movement, increasing lower abdominal pain. CA-125 >400, CEA and CA-19-9 negative. CT scan showed ascites with tumor nodules in pericolic gutters, liver surface and an omental cake Left ovary 8

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11 EC 59 y/o g5 p4 with complicated medical history including type 2 diabetes, CAD and COPD. Prior history of vaginal hysterectomy. y Developed abdominal pain and early satiety. Colonscopy negative. Symptoms worsened, CT studies revealed 20 cm complex solid-cystic mass in pelvis. CA- 125 elevated to 276. Right ovary 11

12 Left ovary Right fallopian tube 12

13 Left fallopian tube TT 41 y/o who developed LLQ pain over several weeks, treated as diverticular disease with no improvement. She then developed bloating and early satiety. Ultrasound and CT demonstrated left pelvic complex mass, ascites and omental thickening. 13

14 Omentum Right ovary Left ovary 14

15 Left fallopian tube Right fallopian tube 15

16 GA 58 y/o g2 p2, developed post menopausal bleeding after motorcycle accident. EMB showed at least complex hyperplasia with atypia. Patient underwent hysterectomy with salpingectomy. MIS revealed normal appearing uterus, tubes and ovaries. 16

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20 TB 77 y/o with 3 month history of RLQ pain. Ultrasound evaluation revealed 9 cm right adnexal mass, predominantly a simple cyst but with area of multiple l septations. No free fluid, CA Laparoscopy revealed smooth-walled right adnexal mass adherent to vaginal cuff and right pelvic sidewall. Underwent lysis of adhesions and BSO. 20

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24 JS 59 y/o with history of dysfunctional uterine bleeding. Endometrial biopsy showed complex atypical hyperplasia. p Hysterectomy with BSO performed. Representative sections of ovary and entire fallopian tubes submitted. 24

25 Hysterectomy Right fallopian tube 25

26 Left fallopian tube 26

27 NB 75 year old female with worsening pelvic organ prolapse despite pessary therapy, ultimately with 3 rd degree cystocele, who underwent robotic supracervical hysterectomy, BSO and sacro-colpopexy. Family history of ovarian cancer in mother and breast cancer in grandmother. 27

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29 LBD 50 y/o chief complaint pelvic pain, postmenopausal bleeding. Clinical history of endometriosis. Status post endometrial ablation. Underwent BSO. 29

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31 Ovarian Carcinogenesis: Clinical Implications Screening/early detection Primary prevention/prophylaxis 31

32 Screening/Early Detection Type I tumors Grow to large size while confined to ovary Detected by pelvic exam, transvaginal ultrasound Represent only 25% of ovarian cancers Account for 10% of deaths Screening/Early Detection Type II tumors Rarely confined to ovary Represent 75% of ovarian cancers Account for 90% of deaths Biomarkers? Johns Hopkins Scientists Use Pap Test Fluid To Detect Ovarian, Endometrial Cancers Release Date: 01/09/2013 Using cervical fluid obtained during routine Pap tests, scientists at the Johns Hopkins Kimmel Cancer Center have developed a test to detect ovarian and endometrial cancers. In a pilot study, the PapGene test, which relies on genomic sequencing of cancer-specific mutations, accurately detected all 24 (100 percent) endometrial cancers and nine of 22 (41 percent) ovarian cancers. Results of the experiments are published in the Jan. 9 issue of the journal Science Translational Medicine Learn more. 32

33 Primary Prevention/Prophylaxis Birth control pills BRCA testing Prophylactic surgery for high risk Obstetrics & Gynecology: Sep 2010: 116 (3), Prophylactic and Risk-Reducing BSO Women at high risk (BRCA1 or BRCA2 mutation, strong family history) should undergo a risk-reducing BSO Women at average risk who are undergoing a hysterectomy for benign conditions, decision to also perform a BSO should be individualized Obstetrics & Gynecology: Sep 2010: 116 (3), Fallopian tube: Primary site of most pelvic HGSC Most occult cancers in women with BRCA occur in fallopian tube Most cases of non-hereditary HGSC start in fallopian tube 2010: Remove tubes! BCCA launched efforts to educate doctors to remove tubes during gyn surgeries Int J Gynecol Cancer, 2009;19:

34 Routine salpingectomy 30% American women have hysterectomy, ½ keep fallopian tubes. If women have tubes removed 10% reduction in HGSC Distal fimbriectomy instead of routine partial tubal ligation 20% reduction If women with BRCA had tubes removed 20% reduction Int J Gynecol Cancer, 2009;19:58-64 Oregon Registry? U.B.C. currently established tumor registry to track surgical outcomes in women with and without removal of fallopian tubes In order to prove hypothesis that removal of tubes can reduce deaths from pelvic HGSC registry needs to be done internationally Summary Concept that majority of epithelial ovarian carcinomas originate outside of ovary has emerged only recently New insights into ovarian cancer carcinogenesis--time to rethink ovarian cancer screening Salpingectomy for primary prevention 34

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