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Small cell cancers of the female genital tract: Molecular and clinical aspects

Published:February 17, 2018DOI:https://doi.org/10.1016/j.ygyno.2018.02.004

      Highlights

      • Small cell carcinomas of the gynecologic tract are rare, aggressive malignancies.
      • Small cell carcinoma of the ovary, hypercalcemic type has a germline genetic component.
      • Understanding the molecular features will improve diagnosis and expand treatments.

      Abstract

      Objective

      Extra-pulmonary small cell carcinomas of the gynecologic tract (EPSCC-GTs) are a rare group of aggressive malignancies associated with poor prognoses and limited treatment options. Here, we review the clinical and molecular aspects of EPSCC-GTs and discuss how understanding their molecular features can assist in their diagnosis and the identification of novel effective treatments.

      Methods

      We searched PubMed and Scopus for articles using the following keywords: “small cell carcinoma” in combination with “neuroendocrine”, “ovary”, “vagina”, “fallopian tube”, “vulva”, “endometrium”, “uterus”, “cervix”, or “gynecologic”. Articles were limited to those published in English from January 1984 to October 2017.

      Results

      EPSCC-GTs account for 2% of all gynecologic malignancies. The molecular features of EPSCC-GTs are largely understudied and unknown, with the exception of small cell carcinoma (SCC) of the ovary, hypercalcemic type (SCCOHT) and SCC of the cervix (SCCC). In nearly all cases, SCCOHT displays mutation in a single gene, SMARCA4, a member of the SWI/SNF chromatin remodeling complex. The loss of expression of the SWI/SNF protein SMARCA2 is another feature of SCCOHT. Dual negative staining for SMARCA2 and SMARCA4 is specific for SCCOHT and is generally used by gynecologic pathologists for the accurate diagnosis of this malignancy. Mutational analysis of SCCC has shown alterations in PIK3CA, KRAS and TP53, of which the last is the most common, although other actionable mutations have been identified. The molecular features of other EPSCC-GTs are largely unknown.

      Conclusions

      Due to their rarity, the majority of EPSCC-GTs are understudied and poorly understood. As demonstrated in the case of SCCOHT, unraveling the mutational profiles of these tumors can lead to improved diagnosis and the identification of novel therapeutic targets.

      Keywords

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      References

        • van Meerbeeck J.P.
        • Fennell D.A.
        • De Ruysscher D.K.
        Small-cell lung cancer.
        Lancet. 2011; 378: 1741-1755
        • Remick S.C.
        • Ruckdeschel J.C.
        Extrapulmonary and pulmonary small-cell carcinoma: tumor biology, therapy, and outcome.
        Med. Pediatr. Oncol. 1992; 20: 89-99
        • Haider K.
        • Shahid R.K.
        • Finch D.
        • et al.
        Extrapulmonary small cell cancer: a Canadian province's experience.
        Cancer. 2006; 107: 2262-2269
        • Wong Y.N.
        • Jack R.H.
        • Mak V.
        • et al.
        The epidemiology and survival of extrapulmonary small cell carcinoma in South East England, 1970–2004.
        BMC Cancer. 2009; 9: 209
        • Crowder S.
        • Tuller E.
        Small cell carcinoma of the female genital tract.
        Semin. Oncol. 2007; 34: 57-63
        • Atienza-Amores M.
        • Guerini-Rocco E.
        • Soslow R.A.
        • et al.
        Small cell carcinoma of the gynecologic tract: a multifaceted spectrum of lesions.
        Gynecol. Oncol. 2014; 134: 410-418
        • Brennan S.M.
        • Gregory D.L.
        • Stillie A.
        • et al.
        Should extrapulmonary small cell cancer be managed like small cell lung cancer?.
        Cancer. 2010; 116: 888-895
        • Eichhorn J.H.
        • Young R.H.
        • Scully R.E.
        Primary ovarian small cell carcinoma of pulmonary type. A clinicopathologic, immunohistologic, and flow cytometric analysis of 11 cases.
        Am. J. Surg. Pathol. 1992; 16: 926-938
        • Young R.H.
        • Oliva E.
        • Scully R.E.
        Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases.
        Am. J. Surg. Pathol. 1994; 18: 1102-1116
        • Munstedt K.
        • Estel R.
        • Dreyer T.
        • et al.
        Small cell ovarian carcinomas - characterisation of two rare tumor entities.
        Geburtshilfe Frauenheilkd. 2013; 73: 698-704
        • Estel R.
        • Hackethal A.
        • Kalder M.
        • et al.
        Small cell carcinoma of the ovary of the hypercalcaemic type: an analysis of clinical and prognostic aspects of a rare disease on the basis of cases published in the literature.
        Arch. Gynecol. Obstet. 2011; 284: 1277-1282
        • Longy M.
        • Toulouse C.
        • Mage P.
        • et al.
        Familial cluster of ovarian small cell carcinoma: a new mendelian entity?.
        J. Med. Genet. 1996; 33: 333-335
        • Conlon N.
        • Silva A.
        • Guerra E.
        • et al.
        Loss of SMARCA4 expression is both sensitive and specific for the diagnosis of small cell carcinoma of ovary, hypercalcemic type.
        Am. J. Surg. Pathol. 2016; 40: 395-403
        • Jelinic P.
        • Mueller J.J.
        • Olvera N.
        • et al.
        Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.
        Nat. Genet. 2014; 46: 424-426
        • Jelinic P.
        • Schlappe B.A.
        • Conlon N.
        • et al.
        Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type.
        Mod. Pathol. 2016; 29: 60-66
        • McCluggage W.G.
        • Witkowski L.
        • Clarke B.A.
        • et al.
        Clinical, morphological and immunohistochemical evidence that small-cell carcinoma of the ovary of hypercalcaemic type (SCCOHT) may be a primitive germ-cell neoplasm.
        Histopathology. 2017; 70: 1147-1154
        • Witkowski L.
        • Carrot-Zhang J.
        • Albrecht S.
        • et al.
        Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.
        Nat. Genet. 2014; 46: 438-443
        • Ramos P.
        • Karnezis A.N.
        • Craig D.W.
        • et al.
        Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4.
        Nat. Genet. 2014; 46: 427-429
        • Ramos P.
        • Karnezis A.N.
        • Hendricks W.P.
        • et al.
        Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).
        Rare Dis. 2014; 2e967148
        • Eichhorn J.H.
        • Young R.H.
        • Scully R.E.
        Nonpulmonary small cell carcinomas of extragenital origin metastatic to the ovary.
        Cancer. 1993; 71: 177-186
        • Eichhorn J.H.
        • Young R.H.
        Neuroendocrine tumors of the genital tract.
        Am. J. Clin. Pathol. 2001; 115: S94-112
        • Yaghmour G.
        • Prouet P.
        • Wiedower E.
        • et al.
        Genomic alterations in neuroendocrine cancers of the ovary.
        J. Ovarian Res. 2016; 9: 52
        • Witkowski L.
        • Goudie C.
        • Ramos P.
        • et al.
        The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type.
        Gynecol. Oncol. 2016; 141: 454-460
        • Karnezis A.N.
        • Wang Y.
        • Ramos P.
        • et al.
        Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type.
        J. Pathol. 2016; 238: 389-400
        • Kadoch C.
        • Hargreaves D.C.
        • Hodges C.
        • et al.
        Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy.
        Nat. Genet. 2013; 45: 592-601
        • Jelinic P.
        • Ricca J.
        • Van Oudenhove E.
        • et al.
        Immune-active microenvironment in small cell carcinoma of the ovary, hypercalcemic type: rationale for immune checkpoint blockade.
        J. Natl. Cancer Inst. 2018; https://doi.org/10.1093/jnci/djx277
        • Harrison M.L.
        • Hoskins P.
        • du Bois A.
        • et al.
        Small cell of the ovary, hypercalcemic type—analysis of combined experience and recommendation for management. A GCIG study.
        Gynecol. Oncol. 2006; 100: 233-238
        • Callegaro-Filho D.
        • Gershenson D.M.
        • Nick A.M.
        • et al.
        Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT): a review of 47 cases.
        Gynecol. Oncol. 2016; 140: 53-57
        • Chan-Penebre E.
        • Armstrong K.
        • Drew A.
        • et al.
        Selective killing of SMARCA2- and SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type cells by inhibition of EZH2: in vitro and in vivo preclinical models.
        Mol. Cancer Ther. 2017; 16: 850-860
        • Fahiminiya S.
        • Witkowski L.
        • Nadaf J.
        • et al.
        Molecular analyses reveal close similarities between small cell carcinoma of the ovary, hypercalcemic type and atypical teratoid/rhabdoid tumor.
        Oncotarget. 2016; 7: 1732-1740
        • Witkowski L.
        • Goudie C.
        • Foulkes W.D.
        • et al.
        Small-cell carcinoma of the ovary of hypercalcemic type (malignant rhabdoid tumor of the ovary): a review with recent developments on pathogenesis.
        Surg. Pathol. Clin. 2016; 9: 215-226
        • Huntsman D.G.
        • Clement P.B.
        • Gilks C.B.
        • et al.
        Small-cell carcinoma of the endometrium. A clinicopathological study of sixteen cases.
        Am. J. Surg. Pathol. 1994; 18: 364-375
        • van Hoeven K.H.
        • Hudock J.A.
        • Woodruff J.M.
        • et al.
        Small cell neuroendocrine carcinoma of the endometrium.
        Int. J. Gynecol. Pathol. 1995; 14: 21-29
        • Pocrnich C.E.
        • Ramalingam P.
        • Euscher E.D.
        • et al.
        Neuroendocrine carcinoma of the endometrium: a clinicopathologic study of 25 cases.
        Am. J. Surg. Pathol. 2016; 40: 577-586
        • Terada T.
        KIT-positive primary small cell carcinoma of the endometrium: a case report with immunohistochemical and molecular genetic analysis of KIT and PDGFRA genes.
        Arch. Gynecol. Obstet. 2010; 282: 413-416
        • Rouzbahman M.
        • Clarke B.
        Neuroendocrine tumors of the gynecologic tract: select topics.
        Semin. Diagn. Pathol. 2013; 30: 224-233
        • Sato H.
        • Kanai G.
        • Kajiwara H.
        • et al.
        Small-cell carcinoma of the endometrium presenting as Cushing's syndrome.
        Endocr. J. 2010; 57: 31-38
        • Korcum A.F.
        • Aksu G.
        • Ozdogan M.
        • et al.
        Stage I small cell carcinoma of the endometrium: survival and management options.
        Acta Obstet. Gynecol. Scand. 2008; 87: 122-126
        • Ureyen I.
        • Karalok A.
        • Turan T.
        • et al.
        Small cell carcinoma of the endometrium: a report of three cases.
        J. Turk. Ger. Gynecol. Assoc. 2013; 14: 113-115
        • Scully R.E.
        • Aguirre P.
        • DeLellis R.A.
        Argyrophilia, serotonin, and peptide hormones in the female genital tract and its tumors.
        Int. J. Gynecol. Pathol. 1984; 3: 51-70
        • Chafe W.
        Neuroepithelial small cell carcinoma of the vagina.
        Cancer. 1989; 64: 1948-1951
        • Bhalodia J.N.
        • Kapapura D.V.
        • Parekh M.N.
        Primary small cell neuroendocrine carcinoma of vagina: a rare case report.
        Pathol. Res. Int. 2011; 2011306921
        • Petru E.
        • Pasterk C.
        • Reich O.
        • et al.
        Small-cell carcinoma of the uterus and the vagina: experience with ten patients.
        Arch. Gynecol. Obstet. 2005; 271: 316-319
        • Prasad C.J.
        • Ray J.A.
        • Kessler S.
        Primary small cell carcinoma of the vagina arising in a background of atypical adenosis.
        Cancer. 1992; 70: 2484-2487
        • Hopkins M.P.
        • Kumar N.B.
        • Lichter A.S.
        • et al.
        Small cell carcinoma of the vagina with neuroendocrine features. A report of three cases.
        J. Reprod. Med. 1989; 34: 486-491
        • Weberpals J.
        • Djordjevic B.
        • Khalifa M.
        • et al.
        A rare case of ectopic adrenocorticotropic hormone syndrome in small cell carcinoma of the vagina: a case report.
        J. Low. Genit. Tract Dis. 2008; 12: 140-145
        • Colleran K.M.
        • Burge M.R.
        • Crooks L.A.
        • et al.
        Small cell carcinoma of the vagina causing Cushing's syndrome by ectopic production and secretion of ACTH: a case report.
        Gynecol. Oncol. 1997; 65: 526-529
        • Oliveira R.
        • Bocoli M.C.
        • Saldanha J.C.
        • et al.
        Primary small cell carcinoma of the vagina.
        Case Rep. Obstet. Gynecol. 2013; 2013827037
        • Mirhashemi R.
        • Kratz A.
        • Weir M.M.
        • et al.
        Vaginal small cell carcinoma mimicking a Bartholin's gland abscess: a case report.
        Gynecol. Oncol. 1998; 68: 297-300
        • Yan W.X.
        • Jia X.J.
        • Chen Y.B.
        • et al.
        Primary small cell carcinoma of the vagina with pulmonary metastasis: a case report.
        Eur. J. Gynaecol. Oncol. 2016; 37: 129-132
        • Brzezniak C.
        • Oronsky B.
        • Trepel J.
        • et al.
        RRx-001 priming of PD-1 inhibition in the treatment of small cell carcinoma of the vagina: a rare gynecological tumor.
        Case Rep. Oncol. 2017; 10: 276-280
        • Bobos M.
        • et al.
        Immunohistochemical distinction between merkel cell carcinoma and small cell carcinoma of the lung.
        Am. J. Dermatopathol. 2006; 28: 99-104
        • Matsumoto R.
        • Bito T.
        • Washio K.
        • et al.
        Primary cutaneous small cell carcinoma of the vulva arising from squamous cell carcinoma.
        Br. J. Dermatol. 2011; 165: 1147-1148
        • Eckert F.
        • Fehm T.
        • Bamberg M.
        • et al.
        Small cell carcinoma of vulva: curative multimodal treatment in face of resistance to initial standard chemotherapy.
        Strahlenther. Onkol. 2010; 186: 521-524
        • Alvarado-Cabrero I.
        • Young R.H.
        • Vamvakas E.C.
        • et al.
        Carcinoma of the fallopian tube: a clinicopathological study of 105 cases with observations on staging and prognostic factors.
        Gynecol. Oncol. 1999; 72: 367-379
        • Chen J.
        • Macdonald O.K.
        • Gaffney D.K.
        Incidence, mortality, and prognostic factors of small cell carcinoma of the cervix.
        Obstet. Gynecol. 2008; 111: 1394-1402
        • Bermudez A.
        • Vighi S.
        • Garcia A.
        • et al.
        Neuroendocrine cervical carcinoma: a diagnostic and therapeutic challenge.
        Gynecol. Oncol. 2001; 82: 32-39
        • Wistuba I.I.
        • Thomas B.
        • Behrens C.
        • et al.
        Molecular abnormalities associated with endocrine tumors of the uterine cervix.
        Gynecol. Oncol. 1999; 72: 3-9
        • McCluggage W.G.
        • Kennedy K.
        • Busam K.J.
        An immunohistochemical study of cervical neuroendocrine carcinomas: neoplasms that are commonly TTF1 positive and which may express CK20 and P63.
        Am. J. Surg. Pathol. 2010; 34: 525-532
        • Rekhi B.
        • Patil B.
        • Deodhar K.K.
        • et al.
        Spectrum of neuroendocrine carcinomas of the uterine cervix, including histopathologic features, terminology, immunohistochemical profile, and clinical outcomes in a series of 50 cases from a single institution in India.
        Ann. Diagn. Pathol. 2013; 17: 1-9
        • Stoler M.H.
        • Mills S.E.
        • Gersell D.J.
        • et al.
        Small-cell neuroendocrine carcinoma of the cervix. A human papillomavirus type 18-associated cancer.
        Am. J. Surg. Pathol. 1991; 15: 28-32
        • Zivanovic O.
        • Leitao Jr., M.M.
        • Park K.J.
        • et al.
        Small cell neuroendocrine carcinoma of the cervix: analysis of outcome, recurrence pattern and the impact of platinum-based combination chemotherapy.
        Gynecol. Oncol. 2009; 112: 590-593
        • Dongol S.
        • Tai Y.
        • Shao Y.
        • et al.
        A retrospective clinicopathological analysis of small-cell carcinoma of the uterine cervix.
        Mol. Clin. Oncol. 2014; 2: 71-75
        • Hirahatake K.
        • Hareyama H.
        • Kure R.
        • et al.
        Cytologic and hormonal findings in a carcinoid tumor of the uterine cervix.
        Acta Cytol. 1990; 34: 119-124
        • Cohen J.G.
        • Kapp D.S.
        • Shin J.Y.
        • et al.
        Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients.
        Am. J. Obstet. Gynecol. 2010; 203: 347.e1-347.e6
        • Ishida G.M.
        • Kato N.
        • Hayasaka T.
        • et al.
        Small cell neuroendocrine carcinomas of the uterine cervix: a histological, immunohistochemical, and molecular genetic study.
        Int. J. Gynecol. Pathol. 2004; 23: 366-372
        • Mannion C.
        • Park W.S.
        • Man Y.G.
        • et al.
        Endocrine tumors of the cervix: morphologic assessment, expression of human papillomavirus, and evaluation for loss of heterozygosity on 1p, 3p, 11q, and 17p.
        Cancer. 1998; 83: 1391-1400
        • Frumovitz M.
        • Burzawa J.K.
        • Byers L.A.
        • et al.
        Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer.
        Gynecol. Oncol. 2016; 141: 588-591
        • Wang K.L.
        • Chang T.C.
        • Jung S.M.
        • et al.
        Primary treatment and prognostic factors of small cell neuroendocrine carcinoma of the uterine cervix: a Taiwanese gynecologic oncology group study.
        Eur. J. Cancer. 2012; 48: 1484-1494
        • Paraghamian S.E.
        • Longoria T.C.
        • Eskander R.N.
        Metastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report.
        Gynecol. Oncol. Res. Pract. 2017; 4: 3