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)

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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

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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.

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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

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Diagnosis

Adenoid Cystic Carcinoma (ACC) of the vulva

with perineurial invasion

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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;

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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.

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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.

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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

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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.

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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

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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

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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

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Important Information Regarding CME/SAMs

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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.

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