Annals of Diagnostic Pathology xxx (2015) xxx–xxx

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Annals of Diagnostic Pathology

Original Contribution

SMARCA4-deficient undifferentiated carcinoma of the ovary (small cell carcinoma, hypercalcemic type): clinicopathologic and immunohistochemical study of 3 cases☆,☆☆ Abbas Agaimy, MD a,⁎,1, Falk Thiel, MD b,1,2, Arndt Hartmann, MD a, Masaharu Fukunaga, MD c a b c

Institute of Pathology, Friedrich‐Alexander University Erlangen‐Nürnberg, Erlangen, Germany Department of Obstetrics & Gynecology, Friedrich‐Alexander University Erlangen‐Nürnberg, Erlangen, Germany Department of Pathology, Jikei University School of Medicine, Tokyo, Japan

a r t i c l e

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Available online xxxx Keywords: small cell carcinoma ovary hypercalcemia SMARCA4 BRG1 rhabdoid

a b s t r a c t Small cell carcinoma of the ovary, hypercalcemic type is a very rare aggressive neoplasm of unknown histogenesis, affecting mainly girls and young women. Recently, inactivating mutations in SMARCA4 (BRG1), a member of the switch/sucrose nonfermenting chromatin remodeling complex, has been identified as driver events in most cases. We herein describe 3 cases in 34, 34, and 37-year-old women. Symptoms were mainly abdominal pain and mass. One patient was normocalcemic, and the other 2 had no preoperative serum calcium values available. All patients received radical hysterectomy with salpingo-oophorectomy, lymphadenectomy, and variable multimodality therapy. Two developed abdominal recurrences/metastases and died of disease at 4 and 12 months. One patient was alive without disease 17 months after surgery and radiochemotherapy. Histologic examination showed undifferentiated neoplasms composed of diffuse sheets, nests and cords of noncohesive monomorphic small blue/basaloid cells (classic variant, 1 case), and large undifferentiated/rhabdoid cells with abundant cytoplasm (large cell/rhabdoid variant, 2 case) admixed with minor small cell areas. One case contained rare isolated goblet cells, but true glandular component was absent. All tumors expressed vimentin and variably pancytokeratin and WT1. Nuclear SMARCB1 was intact in all cases (1 case showed small foci with mosaic loss). All tumors showed complete loss of SMARCA4. In conclusion, SMARCA4 immunohistochemistry represents a highly valuable emerging tool in identifying small cell carcinoma of the ovary, hypercalcemic type in routine practice. Distinguishing this aggressive neoplasm from juvenile granulosa cell tumor and other undifferentiated ovarian cancers is mandatory in selecting appropriate chemotherapeutic regimens and would allow better characterization of this entity, for which targeted molecular therapy still remains to be established. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but histologically and clinically distinctive highly aggressive primary ovarian neoplasm that mainly affects adolescent girls and young women at a mean age of 24 years (range, 9-43 years) but can rarely affect children and older women as well [1,2]. Histologically, SCCOHT features either undifferentiated monotonous small cells arranged into nests, cords, and single cell pattern (small cell, prototypical variant) or displays large anaplastic cells with abundant eosinophilic cytoplasm ☆ Grant support to this study: none. ☆☆ Disclosure/conflict of interest: The authors have no conflicts of interest or National Institutes of Health finding to disclose. ⁎ Corresponding author at: Pathologisches Institut, Universitätsklinikum Erlangen, Krankenhausstrasse 8-10, 91054 Erlangen, Germany. Tel.: +49 9131 85 22288; fax: +49 9131 85 24745. E-mail address: [email protected] (A. Agaimy). 1 Equally contributed. 2 Current affiliation: ALB FILS KLINIKEN GmbH, 3 73035 Göppingen, Germany. http://dx.doi.org/10.1016/j.anndiagpath.2015.06.001 1092-9134/© 2015 Elsevier Inc. All rights reserved.

and large vesicular nuclei containing central macronucleoli and variable rhabdoid cytoplasmic inclusions (large cell or rhabdoid variant) [3]. Although their epithelial nature has been confirmed by earlier immunohistochemical and electron microscopic studies [3,4], the histogenetic line of differentiation of SCCOHT still remains unclear. Until very recently, their molecular pathogenesis remained obscured as well. The switch/sucrose nonfermenting (SWI/SNF) is a highly conserved protein complex involved in chromatin remodeling as well as in regulation of cell differentiation and growth processes [5,6]. The constituent genes of the SWI/SNF complex encode several proteins that represent integral core subunits of the complex. These include in particular SMARCB1 (hSNF5/INI1 or BAF47), SMARCA4 (BRG1), SMARCA2 (BRM), SMARCC1 (BAF155), and SMARCC2 (BAF170) [5,6]. As a core subunit of the SWI/SNF complex, SMARCB1 (on chromosome 22q11.2) has been extensively studied in human neoplasms, and it was shown to be involved in the initiation (driver event) and/or progression (dedifferentiation) of a variety of pediatric and adult human neoplasms [7-9]. Based on recent observations, the family of SMARCB1-deficient neoplasia has been ever increasing to include pediatric central atypical

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Table Clinicopathologic features of SMARCA4-deficient ovarian carcinomas (small cell carcinoma, hypercalcemic type). No

Age

Site

Size (cm)

TNM

treatment

Histology

Outcome/follow-up (mo)

Preoperative serum calcium

1

34

Left ovary

N10

Stage IC

34

Right ovary

17

Stage III

Predominantly (N90%) large cell type Predominantly (N90%) large cell type

3

37

Right ovary

15

Stage III

Radical surgery

Conventional (small cell)

Extensive peritoneal recurrence (4 mo), DOD (12 mo) Inguinal & retroperitoneal nodal metastases (6 mo), ANED 17 mo from diagnosis DOD (4 mo)

NA (normal postoperative values)

2

Radical surgery + platin-based CT Radical surgery + CT

NA

Normal

Abbreviations: CT, chemotherapy; DOD, died of disease; ANED, alive with no evidence of disease; NA, not available; mo, months.

teratoid/rhabdoid tumors (AT/RTs), malignant rhabdoid tumors of kidney and extrarenal sites, both types of epithelioid sarcoma, subsets of epithelioid malignant peripheral nerve sheath tumors, myoepithelial carcinoma, and extraskeletal myxoid chondrosarcoma in addition to subsets of SMARCB1-deficient carcinomas of gastroenteropancreatic and upper aerodigestive system, among others [8,9]. Although wholegenome studies on different tumor entities uncovered a surprisingly high frequency of mutations in several components of the SWI/SNF complex (~20% of all malignancies) [5,6], the role of SWI/SNF subunits other than SMARCB1 stills remains largely unknown and poorly understood. SMARCA4 (BRG1), another member of the SWI/SNF complex, has been recently shown to represent an alternative molecular mechanism in the pathogenesis of a rare subset of pediatric AT/RTs having intact SMARCB1 expression and normal SMARCB1 gene locus [10]. Occasional occurrence of familial SCCOHT cases and rare co-clustering in families with rhabdoid tumors suggested a link between SCCOHT and the SWI/ SNF pathway [11,12]. More recently, biallelic inactivation of SMARCA4 was characterized as a molecular driver event in most cases of SCCOHT [13-15]. We herein describe the clinicopathologic and immunohistochemical features of 3 cases originally diagnosed as SCCOHT based on histologic features at our department but not tested for SMARCA4 expression before. We also discuss the molecular pathogenesis of this rare entity in the light of recent developments.

2. Material and methods The 3 cases were retrieved from our institutions. One case has been reported previously but without SMARCA4 immunohistochemistry at that time [16]. All cases have been sampled excessively for histologic assessment. Immunohistochemical studies were performed on 3-μm conventional tissue sections cut from paraffin blocks using a fully automated system (“Benchmark XT System,” Ventana Medical Systems Inc, Tucson, AZ) and the following antibodies: pancytokeratin (clone AE1/AE3, 1:40; Zytomed, Berlin, Germany), vimentin (V9, 1:100; Dako), desmin (clone D33, 1:250; Dako), protein S-100 (polyclonal, 1:2500; Dako), CD34 (clone BI-3C5, 1:200; Zytomed), SMARCB1/INI1 (MRQ-27, 1:50; Zytomed), CK7 (OV-TL, 1:1000; Biogenex), synaptophysin (clone SY38, 1:50; Dako), EMA (clone E29, 1:20; Dako), CD99 (clone 12E7, 1:100; Dako), α inhibin (clone HP6025, 1:50; Serotec), calretinin (polyclonal, 1:100; Zytomed), and N-terminus WT1 (clone 6F-H2, 1:50; Dako). SMARCA4 immunohistochemistry was performed on all cases using conventional tissue slides and a monoclonal antibody (sc-17796, 1:500; Santa Cruz). After pretreatment in EDTA cooking buffer, the antibody was incubated overnight. Visualization of the antibody was achieved by using a Polymer/Ap detection system (Zytomed). Assessment of SMARCB1 and SMARCA4 was done the same way, that is, only unequivocal clean absent staining in the tumor cell nuclei was considered “deficient.” As a control, the presence of homogeneous strong nuclear staining of stromal fibroblasts, inflammatory cells, and vascular endothelial cells in the background was a prerequisite for assessable staining in the tumor as described recently [17].

3. Patients and results 3.1. Clinical features The patients were 34, 34, and 37 years old at the time of first diagnosis (Table). Abdominal pain and mass were main presenting symptoms. Preoperative calcium serum values were not available in 2 cases, as diagnosis was not suspected preoperatively. One patient had normocalcemic value preoperatively, and 2 patients were normocalcemic at the time of disease recurrence. All patients received radical surgery (total hysterectomy, salpingo-oophorectomy, omentectomy, and lymph node dissection). Two patients developed repeated abdominal recurrences/metastases and died of disease 4 and 12 months later. The third patient was alive with no evidence of disease at last follow-up 17 months after surgery and radiochemotherapy. Extra-abdominal disease was not recorded in any of the patients. 3.2. Pathologic findings Grossly, primary and recurrent tumors were described as tan yellow to grayish with soft friable and focally hemorrhagic cut surface (Fig. 1). Histologic examination showed undifferentiated highly malignant neoplasms. Two cases represented the so-called large (rhabdoid) cell variant and were closely similar to proximal-type epithelioid sarcoma and malignant rhabdoid tumors with variable rhabdoid features and highgrade anaplastic nuclei with vesicular chromatin, prominent centrally located macronucleoli, and extensive areas of necrosis (Fig. 2A and B). The cytoplasm frequently was occupied by a large filamentous hyaline inclusion displacing the nucleus to the cell periphery and imparting a “rhabdoid cell appearance (Fig. 2C).” Rhabdoid cells frequently showed binucleation and occasionally multinucleation (Fig. 2C). Focally, small pseudofollicular spaces were seen that contained pale secretion or erythrocytes. No serous or glandular component was seen in any of

Fig. 1. Recurrent small cell carcinoma, hypercalcemic type (large cell rhabdoid variant) showed tan cut surface with extensive areas of hemorrhagic necrosis with infiltration of adjacent intestine.

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these 2 cases. Case 1 showed a 1.5-cm focus with features identical to the small cell variant. This focus was well circumscribed but showed minor focal blending with the bulk of the tumor (Fig. 2D-F). Immunohistochemistry showed strong co-expression of vimentin and variably pancytokeratin (Fig. 2G) with limited expression of CK7 in a few tumor cells. WT1 was focally expressed in 10% to 40% of tumor cells in all 3 cases. All 3 cases lacked CD34 expression and showed intact SMARCB1 expression in the nuclei (Fig. 2H). Case 1 however showed variable loss of SMARCB1 in the larger pleomorphic rhabdoid tumor cells resulting in a hybrid pattern (Fig. 2I). However, SMARCA4 was completely lost in the entire tumor cells, being retained only in stromal cells and vascular endothelia (Fig. 2J). Case 3 displayed diffuse sheets and nests of monotonous small-to-medium–sized rounded-to-ovoid and occasionally slightly elongated undifferentiated basaloid cells with homogeneous chromatin, distinctive nuclear membranes, and inconspicuous nucleoli (Fig. 3A and B). Minor foci of larger cells were seen, but these were essentially devoid of rhabdoid features. The cytoplasm was mainly scanty with focal moderate rim of pale-to-clear cytoplasm

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(Fig. 3B). In the background, fine reticular fibrosis encased nested aggregates of tumor cells with residual ovarian stroma in some areas. A few pseudoalveolar and gland-like spaces were seen in all cases occasionally containing eosinophilic secretion or erythrocytes (Fig. 3C). This case showed features of the prototypical (classic) variant of SCCOHT. The immunophenotype of the classic variant did not differ from that of the large cell variant (Fig. 3D-G).

4. Discussion The descriptive term small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) was coined by Dickersin et al [1] in 1982 for a rare undifferentiated ovarian neoplasm, based on uniform and reproducible tumor morphology, distinctness from pulmonary-type small cell carcinoma, and frequent association with paraneoplastic hypercalcemia. SCCOHT predominantly affects girls and young women with an age range of 0 to 43 years (mean, 24 years). Only 24% of patients were

Fig. 2. Large (rhabdoid) cell variant SCCOHT showed sheets of tumor cells punctuated by areas of necrosis (A), high-grade nuclear features (B), prominent rhabdoid cell morphology with binucleation and multinucleation (C), and focal small cell areas (D) with pseudofollicle formation (E) and microtrabecular sex-cord like pattern (F). Immunohistochemistry showed expression for pancytokeratin (G), intact SMARCB1 in most of tumor cells (H), focal mosaic loss of SMARCB1 (I), and complete loss of SMARCA4 (J).

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aged 30 years or older at the time of diagnosis. Hypercalcemia was detected in 62% of patients with available preoperative calcium levels [3]. Although extra-ovarian spread was noticed in 50% of cases, the tumor was unilateral in 99% of patients at the time of initial laparotomy with a mean size of 15 cm [3]. Small cell carcinoma of the ovary, hypercalcemic type persues a highly aggressive course with all patients with a disease stage II or higher dying of their disease, usually during a 2-yearperiod [1,3]. Only 33% of those with stage IA disease remained disease free at a mean follow-up of 5.7 years (1-13 years) [3]. In the largest series published to date (n = 150), features noted to be associated with a less favorable outcome are age younger than 30 years, size greater than 10 cm, preoperative hypercalcemia, and presence of large cell component [3]. The large cell pattern was observed in 50%, was the predominant cell type in 12%, and the only cell type in 1% of the cases [3]. Rhabdoid cell features were observed in 60% of the large cell type cases. It is notable that the presence of large cell component was among the features associated with a worse outcome [3]. In line with this, the presence of large cell “rhabdoid” features has been also linked to adverse outcome in medullary carcinoma of the kidney yet another neoplasm with SWI/SNF-related pathogenesis caused by SMARCB1 inactivation [18]. Altogether, these observations suggest that the large “rhabdoid” cell phenotype in SWI/SNF-linked neoplasms likely represents a less differentiated and hence more aggressive phenotype. The histogenetic derivation and the line of differentiation of SCCOHT are still unknown. Although follicle-like spaces were noted in 80% of cases, true epithelial glands were seen only in 12% of the cases [3]. These glands were lined by epithelium with variable mucinous cell component. Notably, in 78% of cases with detectable glands, the glandular cells showed atypical (malignant) nuclei that seem to merge with the surrounding neoplastic small cells [3]. Even a focus of unequivocal signet ring cells within mucinous pools was illustrated in the series of Young et al (their Fig. 9 [3]) indicating a minor component of mucinous carcinoma, at least in that case. Several recent studies convincingly illustrated the origin of SMARCB1-deficient undifferentiated neoplasm from

SMARCB1-intact differentiated parent neoplasm in different organs in adults [19-21]. The extent of the differentiated component was highly variable ranging from extensive to minor, being just represented by a mere minute focus of intraepithelial neoplasia. Very recently, a case of SMARCA4-deficient undifferentiated carcinoma with rhabdoid features was reported to originate from differentiated SMARCA4-intact endometrioid adenocarcinoma of the endometrium [17]. In light of these recent observations, it is conceivable that at least a subset of SCCOHT might have originated from a very early epithelial neoplasm (intraepithelial lesion) by a specific pathway of dedifferentiation, in which inactivation of SMARCA4 is the central or even the only molecular alteration. This view is supported by the above quoted studies and in particular by the observation of Young et al [3], that histologically, malignant glands were observed in a small subset of SCCOHT. Thus, a process of dedifferentiation (analogous to mucinous neoplasm with anaplastic sarcomatous nodule/component but occurring at a very early stage) might be a possibility [22]. It is unclear yet, whether the expression of the N-terminus WT1 in a subset of the neoplastic cells in our cases is indicative of abortive serous origin or representing an aberrant phenotype. Admittedly, the exact pathogenesis of this enigmatic entity remains currently merely speculative. Parallel to its uncertain histogenesis, the appropriate nomenclature of SCCOHT remains a controversial issue. As the authors of the original and the subsequent review series discussed, the original name was suggested just to underline the histologic and clinical uniformity of the entity and to separate it from the pulmonary-type small cell carcinoma [23]. Already in their seminal original papers, Dickersin et al [1] and Young et al [3] discussed a potentially wider range of histologic appearance and clinicopathologic spectrum of SCCOHT, as more cases are recognized and that the name might then need to be adjusted accordingly. In this context, it is worth mentioning that the defining hypercalcemia is noticed in no more than 62% of the cases with available preoperative serum calcium measurements [3]. Likewise, the presence of large cells represents another confusing feature seen in at least 50% of the cases,

Fig. 3. Classic (small cell) variant showed diffuse sheets of basaloid small cells (A) with occasional pseudoalveolar acantholytic pattern (B) and pseudofollicular cystic spaces (C). Immunohistochemistry showed strong expression of pancytokeratin (D) with focal EMA positivity in pseudofollicular structures (D, inset), nuclear expression of WT1 (E), intact nuclear SMARCB1/INI1 (F), and loss of SMARCA4 (G).

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and this pattern was even dominating in 13% of cases [3]. Although sharing the same molecular pathogenesis with SMARCA4-related AT/ RT [24], to call SCCOHT “malignant rhabdoid tumor” seems a “inappropriate simplification” in the light of different histogenesis and clinicopathologic characteristics of this unique neoplasm compared with central nervous system and soft tissue counterparts. In line with the increasingly used terminology for SWI/SNF-related neoplasms of other organs, the histogenetically uncommitted term SMARCA4-deficient undifferentiated ovarian carcinoma might prove to be more appropriate if used in conjunction with the widely used old descriptive name SCCOHT. From a differential diagnostic point of view, SCCOHT emphasizes the emerging role of immunohistochemistry using specific antibodies developed against the different components of the SWI/SNF chromatin remodeling complex, which currently proved to be highly useful adjunct diagnostic tools in surgical pathology. In this setting, SMARCB1 (INI1) has already been characterized as a defining marker for a plethora of neoplasms; most of them are unified by the presence of either “large rhabdoid cells,” undifferentiated medium-sized to small monotonous blue (basaloid) cells, or variable combination thereof [7,8]. Currently, SMARCA4 immunohistochemistry is emerging as a potentially useful diagnostic marker for identifying/confirming SCCOHT. Our observation of focal mosaic loss of SMARCB1 in 1 case of SCCOHT is in line with recent studies showing variable combined (secondary) loss of other components of the SWI/SNF complex in AT/RT [25] and in rare types of rhabdoid carcinomas [26]. SCCOHT can be confused with granulosa cell tumor of the juvenile type [27-29]. Adult granulosa cell tumor is rare in the young. SCCOHT has spread beyond the ovary at presentation, which would be unusual for either variant of granulosa cell tumor. Granulosa cell tumor is usually positive for α inhibin and calretinin but negative for EMA. These profiles are opposed to those of SCCOHT. Distinction of these entities is possible based on currently established conventional histologic and immunophenotypical diagnostic criteria. In summary, we described detailed histologic and immunohistochemical features of 3 cases of SCCOHT, thereby highlighting the consistent loss of SMARCA4 expression in the neoplastic cells. Distinguishing this rare neoplasm from other poorly differentiated/undifferentiated ovarian cancers and its proper classification is mandatory for selection of appropriate multimodality therapy and might allow for establishment of targeted molecular therapy in the future.

References [1] Dickersin GR, Kline IW, Scully RE. Small cell carcinoma of the ovary with hypercalcemia. A report of 11 cases. Cancer 1982;49:188–97. [2] Florell SC, Bruggers CS, Matlak M, Young RH, Lowichik A. Ovarian small cell carcinoma of the hypercalcemic type in a 14-month-old: the youngest reported case. Med Pediatr Oncol 1999;32:304–7. [3] Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type: a clinicopathologic analysis of 150 cases. Am J Surg Pathol 1994;18:1102–16. [4] McCluggage WG, Oliva E, Connolly LE, McBride HA, Young RH. An immunohistochemical analysis of ovarian small cell carcinoma of hypercalcemic type. Int J Gynecol Pathol 2004;23:330–6.

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[5] Shain AH, Pollack JR. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS One 2013;8:e55119. [6] Wang X, Haswell JR, Roberts CW. Molecular pathways: SWI/SNF (BAF) complexes are frequently mutated in cancer—mechanisms and potential therapeutic insights. Clin Cancer Res 2014;20:21–7. [7] Judkins AR. Immunohistochemistry of INI1 expression: a new tool for old challenges in CNS and soft tissue pathology. Adv Anat Pathol 2007;14:335–9. [8] Hollmann TJ, Hornick JL. INI1-deficient tumors: diagnostic features and molecular genetics. Am J Surg Pathol 2011;35:e47–63. [9] Agaimy A. The expanding family of SMARCB1(INI1)-deficient neoplasia: implications of phenotypic, biological, and molecular heterogeneity. Adv Anat Pathol 2014;21:394–410. [10] Hasselblatt M, Gesk S, Oyen F, Rossi S, Viscardi E, Giangaspero F, et al. Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol 2011;35:933–5. [11] Lamovec J, Bracko M, Cerar O. Familial occurrence of small-cell carcinoma of the ovary. Arch Pathol Lab Med 1995;119:523–7. [12] Kupryjańczyk J, Dansonka-Mieszkowska A, Moes-Sosnowska J, Plisiecka-Hałasa J, Szafron L, Podgórska A, et al. Ovarian small cell carcinoma of hypercalcemic type—evidence of germline origin and SMARCA4 gene inactivation. A pilot study. Pol J Pathol 2013;64:238–46. [13] Jelinic P, Mueller JJ, Olvera N, Dao F, Scott SN, Shah R, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet 2014;46:424–6. [14] Ramos P, Karnezis AN, Craig DW, Sekulic A, Russell ML, Hendricks WP, et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet 2014;46:427–9. [15] Witkowski L, Carrot-Zhang J, Albrecht S, Fahiminiya S, Hamel N, Tomiak E, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet 2014;46:438–43. [16] Fukunaga M, Endo Y, Nomura K, Ushigome S. Small cell carcinoma of the ovary: a case report of large cell variant. Pathol Int 1997;47:250–5. [17] Strehl JD, Wachter DL, Fiedler J, Heimerl E, Beckmann MW, Hartmann A, et al. Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant. Ann Diagn Pathol 2015. http://dx.doi.org/10.1016/j.anndiagpath.2015.04.001 [Epub ahead of print]. [18] Cheng JX, Tretiakova M, Gong C, Mandal S, Krausz T, Taxy JB. Renal medullary carcinoma: rhabdoid features and the absence of INI1 expression as markers of aggressive behavior. Mod Pathol 2008;21:647–52. [19] Cho YM, Choi J, Lee OJ, Lee HI, Han DJ, Ro JY. SMARCB1/INI1 missense mutation in mucinous carcinoma with rhabdoid features. Pathol Int 2006;56:702–6. [20] Agaimy A, Rau TT, Hartmann A, Stoehr R. SMARCB1 (INI1)-negative rhabdoid carcinomas of the gastrointestinal tract: clinicopathologic and molecular study of a highly aggressive variant with literature review. Am J Surg Pathol 2014;38:910–20. [21] Agaimy A, Haller F, Frohnauer J, Schaefer IM, Ströbel P, Hartmann A, et al. Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes. Mod Pathol 2015;28:248–60. [22] Prat J, Young RH, Scully RE. Ovarian mucinous tumors with foci of anaplastic carcinoma. Cancer 1982;50:300–4. [23] Eichhorn JH, Young RH, Scully RE. Primary ovarian small cell carcinoma of pulmonary type. A clinicopathologic, immunohistologic, and flow cytometric analysis of 11 cases. Am J Surg Pathol 1992;16:926–38. [24] Foulkes WD, Clarke BA, Hasselblatt M, Majewski J, Albrecht S, McCluggage WG. No small surprise—small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. J Pathol 2014;233:209–14. [25] Rao Q, Xia QY, Wang ZY, Li L, Shen Q, Shi SS, et al. Frequent co-inactivation of the SWI/SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhabdoid tumours. Histopathology 2014. http://dx.doi.org/10.1111/his.12632 [Epub ahead of print]. [26] Rao Q, Xia QY, Shen Q, Shi SS, Tu P, Shi QL, et al. Coexistent loss of INI1 and BRG1 expression in a rhabdoid renal cell carcinoma (RCC): implications for a possible role of SWI/SNF complex in the pathogenesis of RCC. Int J Clin Exp Pathol 2014;7: 1782–7. [27] Zaloudek C, Norris HJ. Granulosa tumors of the ovary in children. A clinical and pathologic study of 32 cases. Am J Surg Pathol 1982;6:503–12. [28] Young RH, Dickersin GR, Scully RE. Juvenile granulosa cell tumor. A clinicopathological analysis of 125 cases. Am J Surg Pathol 1984;8:575–96. [29] Young RH. Ovarian tumors and tumor-like lesions in the first three decades. Semin Diagn Pathol 2014;31:382–426.

SMARCA4-deficient undifferentiated carcinoma of the ovary (small cell carcinoma, hypercalcemic type): clinicopathologic and immunohistochemical study of 3 cases.

Small cell carcinoma of the ovary, hypercalcemic type is a very rare aggressive neoplasm of unknown histogenesis, affecting mainly girls and young wom...
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