Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms

Background: Mucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be “RAS-pathway alteration negative”, using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations. Methods: Using the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously. Results: We detected mutations in KRAS, TP53, CDKN2A, PIK3CA, PTEN, BRAF, FGFR2, STK11, CTNNB1, SRC, SMAD4, GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell populations, while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event. Conclusions: Overall, the prevalence of RAS-alteration and striking co-occurrence of pathway “double-hits” supports a critical role for tumor progression in this ovarian malignancy. Given the spectrum of RAS-activating mutations, it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma, however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS-activating alterations

Lymphatic Mapping and Sentinel Lymph Node Biopsy in Women With Squamous Cell Carcinoma of the Vulva: A Gynecologic Oncology Group Study

To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer

Is bilateral lymphadenectomy for midline squamous carcinoma of the vulva always necessary? An analysis from Gynecologic Oncology Group (GOG) 173

To determine which patients with near midline lesions may safely undergo unilateral groin dissection based on clinical exam and lymphoscintigraphy (LSG) results

Pattern of retroperitoneal dissemination of primary peritoneum cancer: Basis for rational use of lymphadenectomy

Introduction: The rationale for lymphadenectomy in primary peritoneal cancer (PPC) is unclear. We sought to define the pattern of lymphatic metastasis in PPC and propose evidence-based rationale for lymphadenectomy in relevant cases. Methods: Patients with PPC undergoing primary surgery at Mayo Clinic were identified. Demographics, tumor characteristics, procedures performed and follow up were analyzed. Results: Forty eight patients with PPC were identified; 39 had stage IIIC (81.2%) and 9 (18.8%) had stage IV. Residual disease (RD) after primary surgery was microscopic in 6 cases (12.5%), less than 1\ua0cm in 33 (68.8%), more than 1\ua0cm in 9 patient (18.7%) with median survivals of 5.8, 3.2 and 1.3\ua0years, respectively. Overall, 24 patients had lymphadenectomy performed (pelvic (PND) or paraortic (PAND) or both). Pelvic nodes were involved in 12/23 (52.7%) cases, while para-aortic nodes were involved in 5/21 (23.8%) of cases. The rate of simultaneously positive pelvic and para-aortic nodes was 20% (4/20). Nodal involvement was a poor prognostic factor with 5\ua0year overall survival 63% vs. 25% (p = 0.014) in node positive vs. negative cases. Compared to patients with primary ovarian cancer (OC), OC cases had a higher rate of positive para-aortic nodes (57.6%: 77/132; p = 0.004). Conclusions: Retroperitoneal lymph nodes are a common site of metastases in PPC, therefore it is logically consistent to perform PND and PAND if a patient can be cytoreduced to microscopic RD in other sites or remove grossly positive nodes in patients with RD < 1\ua0cm

Association of endometrial cancer risk with postmenopausal bleeding in women a systematic review and meta-analysis

© 2018 American Medical Association. All rights reserved. IMPORTANCE As the worldwide burden of endometrial cancer continues to rise, interest is growing in the evaluation of early detection and prevention strategies among women at increased risk. Focusing efforts on women with postmenopausal bleeding (PMB), a common symptom of endometrial cancer, may be a useful strategy; however, PMB is not specific for endometrial cancer and is often caused by benign conditions. OBJECTIVE To provide a reference of the prevalence of PMB in endometrial cancers and the risk of endometrial cancer in women with PMB. DATA SOURCES For this systematic review and meta-analysis, PubMed and Embase were searched for English-language studies published January 1, 1977, through January 31, 2017. STUDY SELECTION Observational studies reporting the prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB in unselected populations were selected. DATA EXTRACTION AND SYNTHESIS Two independent reviewers evaluated study quality and risk of bias using items from the Newcastle-Ottawa Quality Assessment Scale and the Quality Assessment of Diagnostic Accuracy Studies tool. Studies that included highly selected populations, lacked detailed inclusion criteria, and/or included 25 or fewer women were excluded. MAIN OUTCOMES AND MEASURES The pooled prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB. RESULTS A total of 129 unique studies, including 34 432 unique patients with PMB and 6358 with endometrial cancer (40 790 women), were analyzed. The pooled prevalence of PMB among women with endometrial cancer was 91% (95% CI, 87%-93%), irrespective of tumor stage. The pooled risk of endometrial cancer among women with PMB was 9% (95% CI, 8%-11%), with estimates varying by use of hormone therapy (range, 7% [95% CI, 6%-9%] to 12% [95% CI, 9%-15%]; P \u3c .001 for heterogeneity) and geographic region (range, 5% [95% CI, 3%-11%] in North America to 13% [95% CI, 9%-19%] in Western Europe; P = .09 for heterogeneity). CONCLUSIONS AND RELEVANCE Early detection strategies focused on women with PMB have the potential to capture as many as 90% of endometrial cancers; however, most women with PMB will not be diagnosed with endometrial cancer. These results can aid in the assessment of the potential clinical value of new early detection markers and clinical management strategies for endometrial cancer and will help to inform clinical and epidemiologic risk prediction models to support decision making