Combined squamous cell carcinoma and Merkel cell carcinoma of the vulva: Role of human papillomavirus and Merkel cell polyomavirus
Journal
JAAD Case Reports
Journal Volume
1
Journal Issue
4
Pages
196-199
Date Issued
2015
Author(s)
Abstract
Merkel cell carcinoma (MCC), an uncommon and highly aggressive cutaneous malignancy, usually occurs on the sun-damaged skin of the elderly and is characterized by coexpression of neuroendocrine markers and CK20, a discriminant from other types of visceral neuroendocrine neoplasias. Since the discovery of Merkel cell polyomavirus (MCV), many researchers have confirmed its presence in about 80% of cutaneous MCCs.1Busam K.J. Jungbluth A.A. Rekthman N. et al.Merkel cell polyomavirus expression in Merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas.Am J Surg Pathol. 2009; 33: 1378-1385Crossref PubMed Scopus (204) Google Scholar Although some cutaneous MCCs were reported to be associated with squamous cell carcinomas (SCCs), such combined cases accounted for only a minor portion and the viral status appeared to be different from pure MCC.1Busam K.J. Jungbluth A.A. Rekthman N. et al.Merkel cell polyomavirus expression in Merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas.Am J Surg Pathol. 2009; 33: 1378-1385Crossref PubMed Scopus (204) Google Scholar, 2Kuwamoto S. Higaki H. Kanai K. et al.Association of Merkel cell polyomavirus infection with morphologic differences in Merkel cell carcinoma.Hum Pathol. 2011; 42: 632-640Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 3Paik J.Y. Hall G. Clarkson A. et al.Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population.Hum Pathol. 2011; 42: 1385-1390Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 4Mitteldorf C. Mertz K.D. Fernandez-Figueras M.T. Schmid M. Tronnier M. Kempf W. Detection of Merkel cell polyomavirus and human papillomaviruses in Merkel cell carcinoma combined with squamous cell carcinoma in immunocompetent European patients.Am J Dermatopathol. 2012; 34: 506-510Crossref PubMed Scopus (27) Google Scholar Rarely, primary MCCs occur on the female vulva,5Aron M. Zhou M. Merkel cell carcinoma of the genitourinary tract.Arch Pathol Lab Med. 2011; 135: 1067-1071Crossref PubMed Scopus (5) Google Scholar with or without combined SCCs,6Sheikh Z.A. Nair I. Vijaykumar D.K. Jojo A. Nandeesh M. Neuroendocrine tumor of vulva: a case report and review of literature.J Cancer Res Ther. 2010; 6: 365-366Crossref PubMed Scopus (11) Google Scholar, 7Iavazzo C. Terzi M. Arapantoni-Dadioti P. Dertimas V. Vorgias G. Vulvar Merkel carcinoma: a case report.Case Rep Med. 2011; 2011: 546972Crossref PubMed Scopus (12) Google Scholar the latter is often human papillomavirus (HPV) related. A 63-year-old woman had a vulvar tumor over the right labium majus for 5 years, with recent enlargement and pain. The erosive exophytic tumor measured 5 cm in its greatest dimension. No other cutaneous lesions were found. The excision specimen consisted of a nodular dermal tumor measuring 3.6 × 2.5 × 1.3 cm in size with an eroded surface and irregular tumor borders. Microscopically, the tumor was biphasic and composed of: (1) a moderately differentiated malignant squamous cell component with keratin pearl formation; and (2) a poorly differentiated basophilic malignancy consisting of cells in sheetlike pattern with high nucleocytoplasmic ratio, vesicular nuclei, and small to occasionally prominent nucleoli. Comedo necrosis was common, without peripheral palisading. There was an abrupt transition from the squamous component to the blue cell component (Fig 1). Immunohistochemically, the basophilic tumor cells expressed an immunoprofile of synaptophysin+/chromogranin+/CK+ (dotlike)/CK20+/CD56+/CK5−/p63−/p16+ (Fig 2), whereas the squamous part was synaptophysin−/chromogranin−/CK+ (diffuse)/CK20−/CD56−/CK5+/p63+/p16+, consistent with a primary tumor of combined SCC and MCC. Both parts were negative to MCV large T-antigen (CM2B4) antibody (sc-136172, Santa Cruz Biotechnology, Dallas, TX) (dilution 1:50). P53 was overexpressed in both components.Fig 2CK20 and synaptophysin immunostains. Right upper area with CK20+ immunostaining is Merkel cell carcinoma (MCC) and left lower area is squamous cell carcinoma. (Hematoxylin-eosin stain; original magnification: ×400.) Inset, Synaptophysin+ immunostaining in MCC area.View Large Image Figure ViewerDownload (PPT) Genomic DNA from both components was collected from paraffin blocks via manual microdissection for HPV and MCV detection by polymerase chain reaction (PCR) and TP53 gene mutation by direct sequencing. To increase the chance for MCV detection, 5 primer sets were used8Rodig S.J. Cheng J.W. Wardzala J. et al.Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus.J Clin Invest. 2012; 122: 4645-4653Crossref PubMed Scopus (167) Google Scholar and 2 ascertained MCV+ MCCs were included as the biologic positive controls. No MCV DNA (Fig 3) or inactivating mutation in the TP53 was detected. By contrast, an identical clone of type-16 HPV in both components was identified (Fig 3). To eliminate possible cross-contamination, we validated the result by RNAscope in situ hybridization to detect HPV E6/E7 messenger RNA expression on slides and identified cytoplasmic punctate dots in both components (Fig 1). MCC, known as a primary neuroendocrine carcinoma of the skin, tends to affect the elderly and is associated with chronic sun damage, immunosuppression, or both. Feng et al9Feng H. Shuda M. Chang Y. Moore P.S. Clonal integration of a polyomavirus in human Merkel cell carcinoma.Science. 2008; 319: 1096-1100Crossref PubMed Scopus (2378) Google Scholar first demonstrated the clonal integration of MCV DNA in the cutaneous MCC tumor cells. Later, several studies indicated that no MCV DNA was detected in other visceral high-grade neuroendocrine carcinomas. These discoveries stressed the oncogenic role of MCV in cutaneous MCCs. However, there are insufficient data regarding the role of MCV in MCCs arising from unusual sun-protected regions of the body. In the current case, a combined SCC component raises the suspicion of HPV DNA integration, rather than MCV DNA, as the pathogenesis of vulvar MCC development. We have determined this by PCR demonstrating the 2 malignant components (squamous and neuroendocrine) incorporating the same high-risk HPV DNA in their genome, but no MCV DNA. Moreover, combined squamous and neuroendocrine carcinomas of skin in sun-damaged regions share ultraviolet light–related TP53 mutations in both components,10Popp S. Waltering S. Herbst C. Moll I. Boukamp P. UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas.Int J Cancer. 2002; 99: 352-360Crossref PubMed Scopus (165) Google Scholar whereas in the current case the TP53 mutation is lacking, further supporting the concept of MCV-independent and HPV-related tumorigenesis in vulvar MCCs. Busam et al1Busam K.J. Jungbluth A.A. Rekthman N. et al.Merkel cell polyomavirus expression in Merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas.Am J Surg Pathol. 2009; 33: 1378-1385Crossref PubMed Scopus (204) Google Scholar reported 7 cutaneous SCC-MCC combined lesions, immunonegative to CM2B4 antibody, which was against an antigenic epitope on the MCV T antigen. Paik et al3Paik J.Y. Hall G. Clarkson A. et al.Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population.Hum Pathol. 2011; 42: 1385-1390Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar reported another 15 SCC-MCC combined lesions, which were all immunonegative to CM2B4 antibody. Kuwamoto et al2Kuwamoto S. Higaki H. Kanai K. et al.Association of Merkel cell polyomavirus infection with morphologic differences in Merkel cell carcinoma.Hum Pathol. 2011; 42: 632-640Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar reported 4 MCV− cutaneous SCC-MCC combined lesions, investigated by CM2B4 antibody and real-time PCR. Later, Mitteldorf et al4Mitteldorf C. Mertz K.D. Fernandez-Figueras M.T. Schmid M. Tronnier M. Kempf W. Detection of Merkel cell polyomavirus and human papillomaviruses in Merkel cell carcinoma combined with squamous cell carcinoma in immunocompetent European patients.Am J Dermatopathol. 2012; 34: 506-510Crossref PubMed Scopus (27) Google Scholar reported 2 patients with cutaneous SCC-MCC combined lesions, and detected MCV DNA in both cases and HPV type-6 DNA in one of them by PCR. It seems that by current definition, MCCs are a heterogeneous group of diseases that share similar morphological and immunohistochemical features and are related to miscellaneous conditions including MCV infection, ultraviolet light damage, arsenic intoxication, immunosuppression, and on the vulva, HPV infection. Vulvar MCC is extremely rare with fewer than 20 cases reported in the English-language medical literature.6Sheikh Z.A. Nair I. Vijaykumar D.K. Jojo A. Nandeesh M. Neuroendocrine tumor of vulva: a case report and review of literature.J Cancer Res Ther. 2010; 6: 365-366Crossref PubMed Scopus (11) Google Scholar, 7Iavazzo C. Terzi M. Arapantoni-Dadioti P. Dertimas V. Vorgias G. Vulvar Merkel carcinoma: a case report.Case Rep Med. 2011; 2011: 546972Crossref PubMed Scopus (12) Google Scholar However, neuroendocrine carcinoma of the uterine cervix is a well-established entity that is highly correlated with HPV type-18 infection.11Ambros R.A. Park J.S. Shah K.V. Kurman R.J. Evaluation of histologic, morphometric, and immunohistochemical criteria in the differential diagnosis of small cell carcinomas of the cervix with particular reference to human papillomavirus types 16 and 18.Modern Pathol. 1991; 4: 586-593PubMed Google Scholar Generally, 2 major pathogenetic routes are linked to the development of vulvar carcinoma, ie, HPV infection and inflammatory dermatoses. The result from this study suggests that a portion of vulvar MCC is HPV related (cervical type), whereas the other portion is more akin to usual cutaneous MCV-related MCC (cutaneous type). An association with basaloid-type (or moderately to poorly differentiated) SCC may argue for the former, whereas an association with well-differentiated SCC or dermatoses may suggest the latter. Unfortunately, the reported vulvar MCC cases in English-language literature seldom included this information, and tests for HPV and MCV were rarely done (Table I). The current case suggests that a subset of vulvar MCC is HPV related. This also suggests that the phenotype of MCC might represent a distinctive pathway of HPV-related tumorigenesis in certain body regions. Interestingly, Schrama et al12Schrama D. Groesser L. Ugurel S. et al.Presence of human polyomavirus 6 in mutation-specific BRAF inhibitor-induced epithelial proliferations.JAMA Dermatol. 2014; 150: 1180-1186Crossref PubMed Scopus (49) Google Scholar recently found the coexistence of MCV and HPV DNA in mutation-specific BRAF inhibitor-induced epithelial proliferations. This raises the suspicion that an epigenetic scenario of MCV "hit-and-run tumorigenesis" might also be considered in the current case.Table IMerkel cell carcinoma of the vulvaReferencesAge, yLocationSize, cmCombined SCCMCV testHPV testTP53 testTang et al,13Tang C.K. Toker C. Nedwich A. Zaman A.N. Unusual cutaneous carcinoma with features of small cell (oat cell-like) and squamous cell carcinomas. A variant of malignant Merkel cell neoplasm.Am J Dermatopathol. 1982; 4: 537-548Crossref PubMed Scopus (96) Google Scholar 198267Labium minus1.5SCC in situNDNDNDBottles et al,14Bottles K. Lacey C.G. Goldberg J. Lanner-Cusin K. Hom J. Miller T.R. Merkel cell carcinoma of the vulva.Obstet Gynecol. 1984; 63: 61S-65SPubMed Google Scholar 198473Labium majus3 × 2SCC in situNDNDNDCopeland et al,15Copeland L.J. Cleary K. Sneige N. Edwards C.L. Neuroendocrine (Merkel cell) carcinoma of the vulva: a case report and review of the literature.Gynecol Oncol. 1985; 22: 367-378Abstract Full Text PDF PubMed Scopus (33) Google Scholar 198559Labium majus8 × 6AbsentNDNDNDHusseinzadeh et al,16Husseinzadeh N. Wesseler T. Newman N. Shbaro I. Ho P. Neuroendocrine (Merkel cell) carcinoma of the vulva.Gynecol Oncol. Jan 1988; 29: 105-112Abstract Full Text PDF PubMed Scopus (19) Google Scholar 198847Labium minus4.2 × 3AbsentNDNDNDChandeying et al,17Chandeying V. Sutthijumroon S. Tungphaisal S. Merkel cell carcinoma of the vulva: a case report.Asia Oceania J Obstet Gynaecol. 1989; 15: 261-265Crossref PubMed Scopus (12) Google Scholar 198928Labium majus4AbsentNDNDNDCliby et al,18Cliby W. Soisson A.P. Berchuck A. Clarke-Pearson D.L. Stage I small cell carcinoma of the vulva treated with vulvectomy, lymphadenectomy, and adjuvant chemotherapy.Cancer. 1991; 67: 2415-2417Crossref PubMed Scopus (17) Google Scholar 199135Vulva<1AbsentNDNDNDLoret de Mola et al,19Loret de Mola J.R. Hudock P.A. Steinetz C. Jacobs G. Macfee M. Abdul-Karim F.W. Merkel cell carcinoma of the vulva.Gynecol Oncol. 1993; 51: 272-276Abstract Full Text PDF PubMed Scopus (20) Google Scholar 199349Fourchette2AbsentNDNDNDChen,20Chen K.T. Merkel's cell (neuroendocrine) carcinoma of the vulva.Cancer. 1994; 73: 2186-2191Crossref PubMed Scopus (44) Google Scholar 199468Vulva3 × 2.5AbsentNDNDNDScurry et al,21Scurry J. Brand A. Planner R. Dowling J. Rode J. Vulvar Merkel cell tumor with glandular and squamous differentiation.Gynecol Oncol. 1996; 62: 292-297Abstract Full Text PDF PubMed Scopus (27) Google Scholar 199668Labium minus4 × 3Squamous differentiationNDNDNDFawzi et al,22Fawzi H.W. Cross P.A. Buckley C.H. Monaghan J.M. Neuroendocrine (Merkel cell) carcinoma of the vulva.J Obstet Gynaecol. 1997; 17: 100-101Crossref PubMed Scopus (6) Google Scholar 199778Vulva5.5AbsentNDNDNDGil-Moreno et al,23Gil-Moreno A. Garcia-Jimenez A. Gonzalez-Bosquet J. et al.Merkel cell carcinoma of the vulva.Gynecol Oncol. 1997; 64: 526-532Abstract Full Text PDF PubMed Scopus (26) Google Scholar 199774Labium majus9AbsentNDNDPolymorphism p53PIN3 without loss of heterozygosityHierro et al,24Hierro I. Blanes A. Matilla A. Munoz S. Vicioso L. Nogales F.F. Merkel cell (neuroendocrine) carcinoma of the vulva. A case report with immunohistochemical and ultrastructural findings and review of the literature.Pathol Res Pract. 2000; 196: 503-509Crossref PubMed Scopus (33) Google Scholar 200079Labium minus2.5AbsentNDNDNDKhoury-Collado et al,25Khoury-Collado F. Elliott K.S. Lee Y.C. Chen P.C. Abulafia O. Merkel cell carcinoma of the Bartholin's gland.Gynecol Oncol. 2005; 97: 928-931Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar 200549Bartholin gland2AbsentNDNDNDPawar et al,26Pawar R. Vijayalakshmy A.R. Khan S. al Lawati F.A. Primary neuroendocrine carcinoma (Merkel's cell carcinoma) of the vulva mimicking as a Bartholin's gland abscess.Ann Saudi Med. 2005; 25: 161-164PubMed Google Scholar 200535Labium majus6 × 4AbsentNDNDNDMohit et al,27Mohit M. Mosallai A. Monabbati A. Mortazavi H. Merkel cell carcinoma of the vulva.Saudi Med J. 2009; 30: 717-718PubMed Google Scholar 200950Labium majus12 × 10AbsentNDNDNDSheikh et al,6Sheikh Z.A. Nair I. Vijaykumar D.K. Jojo A. Nandeesh M. Neuroendocrine tumor of vulva: a case report and review of literature.J Cancer Res Ther. 2010; 6: 365-366Crossref PubMed Scopus (11) Google Scholar 201063Labium majus7 × 5AbsentNDNDNDIavazzo et al,7Iavazzo C. Terzi M. Arapantoni-Dadioti P. Dertimas V. Vorgias G. Vulvar Merkel carcinoma: a case report.Case Rep Med. 2011; 2011: 546972Crossref PubMed Scopus (12) Google Scholar 201163Vulva9AbsentNDNDNDCurrent case63Labium majus3.6 × 2.5PresentNegativePositiveNegativeHPV, Human papillomavirus; MCV, Merkel cell polyomavirus; ND, not done; SCC, squamous cell carcinoma. Open table in a new tab HPV, Human papillomavirus; MCV, Merkel cell polyomavirus; ND, not done; SCC, squamous cell carcinoma. Based on the experiences from cutaneous MCCs, patients with combined SCC and MCC matched pure MCC in clinical aggressiveness. They tended to progress rapidly and have metastatic foci with pure neuroendocrine features. As for the patients with vulvar MCC, most of the patients died within the first 2 years after diagnosis. Our patient died of cancer-related cachexia and infection 6 months after initial diagnosis. Chemotherapy and radiotherapy provided only limited benefits. However, our case implicates that prophylactic vaccination against oncogenic HPV could prevent not only anogenital SCC, but also certain cases of HPV-associated vulvar/genital MCC. With efforts to elucidate the pathogenesis of vulvar MCCs (eg, HPV, MCV, ultraviolet related), further individualized therapy could be expected.
Other Subjects
CD56 antigen; chromogranin; cytokeratin 20; cytokeratin 5; genomic DNA; keratin; protein E6; protein E7; protein p16; protein p63; synaptophysin; virus large T antigen; adult; Article; basophil; case report; comedo; disease duration; female; gene mutation; human; immunohistochemistry; in situ hybridization; Merkel cell polyomavirus; Merkel cell tumor; microdissection; middle aged; priority journal; skin defect; skin nodule; squamous cell carcinoma; tumor cell; tumor differentiation; tumor volume; virus detection; vulva carcinoma; Wart virus
Publisher
Elsevier Inc
Type
journal article