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Bartholin Gland Carcinomas 3/27/2017 Disclosure of Relevant Financial Relationships Bartholin Gland Carcinomas USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial Hugo Horlings MD PhD relationship WITH COMMERCIAL INTERESTS which they or their The Netherlands Cancer Institute spouse/partner have, or have had, within the past 12 months, which relates to Amsterdam, The Netherlands the content of this educational activity and creates a conflict of interest. GYN PATH evening specialty - case 4 OBJECTIVES (1) OVERVIEW OF BARTHOLIN GLAND CARCINOMA 1. Overview of Bartholin Gland Carcinomas • Caspari Bartholini 1677 2. Case presentation • 1864 first Bartholin Gland Carcinoma 3. Difficulties in diagnosing: • Located posterior to Labium Majus • Mammary-like adenocarcinoma of the vulva • 1% of all female genital malignancies • Invasive Paget disease of the vulva • Bartholin gland adenocarcinoma • 2~7% of all vulvar carcinomas • Mean age 60 years (33-93 years) GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 SIGNS & SYMPTOMS • Vulvar mass, slow growing, painless, bleeding • Diagnosed at advanced stage due to late presentation • Not to be mistaken for benign cyst / abcess Histology for Pathologist 3rd edition; p 1048 GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 1 3/27/2017 HISTOPATHOLOGICAL CRITERIA HISTOLOGICAL TYPES • Squamous cell and adenocarcinoma (80%) 1. The tumor involving the area of the Bartholin gland is histologically compatible with origin from the Bartholin gland • Adenoid cystic carcinoma (~15%) 2. Transition from normal Bartholin gland elements to cancer • Others (~5%) 3. Intact overlying surface epithelium • Transitional cell carc. / Adenosquamous / Undiff. carc. 4. There is no evidence of primary tumor elsewhere • Merkel Cell carc. / Epithelial-Myoepithelial carc. GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 PROGNOSIS & TREATMENT 2. Case presentation (# 4) Poor Prognostic indicators: • Size & stage at time of diagnosis • Larger size of nodal metastasis & extracapsular invasion 54 year old woman with right vulvar mass of Treatment Recommendations: 4.5 cm who underwent a partial vulvectomy • Early stage: local excision and sentinel lymphadenectomy • Advanced stage: radical (hemi-)vulvectomy, lymphadenectomy & adjuvant postoperative chemoradiation treatment GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 2 3/27/2017 Diagnosis Adenoid Cystic Carcinoma (ACC) of the vulva with perineurial invasion GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 Oncogenic mechanisms in ACC Adenoid cystic carcinoma • Vulvar ACC: complex chromosomal changes involving chromosomes 1, • Rare tumor, arises from salivary & lachrymal glands 4, 6, 11, 14, and 22* • Also arises in tissue containing secretory glands: • Translocation in salivary gland ACC t(6;9) (q22-23;p23-24) leading to Skin, Breast, Upper Respiratory Tract, Cervix, Vulva oncogenic fusion protein MYB- NFIB** • Cervical carcinomas with mixed differentiation including ACC are high- • 1% of all lower genital tract are ACC and arise from: risk HPV related, whereas pure ACC are unrelated to high-risk HPV*** • Bartholin gland or reserve cells of uterine cervix * Kiechle-Schwarz M et al. 1992;61:26–30.**Persson M, et al. 2009;106:18740–4. *** Xing D, et al. 2016;40: 529–36; GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 Frequent NFIB-associated Gene Rearrangement in MYB – NFIB Fusion t(6;9) Vulva Adenoid Cystic Carcinoma D. Xing, et. al. Int. J. of Gyn. Path, pp. 1–5, Sep. 2016. D. Xing, et. al. Int. J. of Gyn. Path, pp. 1–5, Sep. 2016. GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 3 3/27/2017 Other structural aberrations in ACC 3. Difficulties in diagnosing • MYBL1-NFIB fusion (11%)* • NFIB with other partners (RIMS1, MYO6, RPS6KA2, MAP3K5)** How to distinguish • Super enhancer translocations in NFIB, TGFBR3, RAD51B loci • Mammary Like adenocarcinoma from the vulva act as drivers for MYB activation*** • Invasive Paget disease of the vulva or **Y. Drier, et al. * P. T. Wysocki et al., Oncotarget, vol. 7, no. 40, pp. 66239–66254, Oct. 2016. ** Rettig EM,et al. • Bartholin gland adenocarcinoma (Philadelphia, Pa). 2016. ***Y. Drier, et al. NG, vol. 48, no. 3, pp. 265–272, Feb. 2016. GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 Mammary-like adenocarcinoma of the vulva (MLAV) • Aggressive tumors with poor prognosis, 30-40 cases reported • Initially thought to originate from supernumerary breast tissue remnants • Currently believed mammary-like glands arise from vulvar eccrine glands • Gene expression profiling was performed recently on two cases • Treated similarly to breast carcinoma: • Two case reports successfully using hormonal therapy and trastuzumab Mammary-like adenocarcinoma of the vulva GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 Molecular subtyping of MLAV and Paget Disease Molecular subtyping of MLAV Invasive In situ Molecular MLAV Paget Disease Paget Disease Subtype / IHC n = 7 n = 7 n = 10 Luminal A Luminal A 12 7 3 with Luminal B Luminal B 33 HER2+ HER2 HER2 21 0 Basal-Like Basal-like 11 0 C. M. Perou, et al.Nature, vol. 406, no. 6797, pp. 747–752, Aug. 2000. GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 4 3/27/2017 Mammary like adenocarcinoma versus MLAV and Paget disease adenocarcinoma of Bartholin gland • Part of a continuum of disease arising form the mammary like glands of the vulva • Diagnostic criteria for MLAV: No real clue!! • Invasive breast carcinoma morphology • The absence of extramammary Paget disease • Distinction would be based on non-mammary like morphology • Less sensitive criteria would include • Immunophenotype required for diagnosis of Bartholin gland carcinoma • Breast carcinoma-like immunophenotype and • In theory, adenocarcinoma of Bartholin gland could be HPV related • The presence of mammary-like glands adjacent to the invasive carcinoma GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 Bartholin Gland Carcinomas & Take Home Message High risk HPV infection • 1984-2015: 15 cases, 3 ACC were exclude, stained 11 cases Understanding oncogenic mechanisms that • p16 ~ surrogate biomarker for High Risk HPV underly Bartholin Gland (vulva) Carcinomas are • 10 poorly to well differentiated SCC and 1 adenocarcinoma emerging and highlight that genetic alterations • 10 SCC: expressed p16 diffusely & 1 adeno: patchy staining can affect malignant transformation, disease • We observed early stage and overall favorable outcome in this small study progression and therapeutic susceptibility Tayyebeh M Nazeran, et al. Manuscript in preparation GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 Acknowledgments University of British Columbia Johns Hopkins University Basile Tessier-Cloutier Tayyebeh Nazeran Deyin Xing Salwa Bakhsh Christina Isacson Nataliya Melnyk Brigitte Ronnett Karama Asleh-Aburaya Julie Ho Singleton Hospital, Swansea, UK Angela CHeng Anna Tinker Varsha Shah Anthony Karnezis Torsten Nielsen Belfast Health and Social Care Trust David Huntsman Glenn McCluggage Blake Gilks GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 5 3/27/2017 Important Information Regarding CME/SAMs The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, 2017. No claims can be processed after that date! After September 30, 2017 you will NOT be able to obtain any CME or SAMs credits for attending this meeting. GYN PATH evening specialty - case 4 GYN PATH evening specialty - case 4 6.
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