Ovarian Sertoli-Leydig Cell Tumor with Predominant Heterologous

Home , Germ cell tumor

Available online at www.annclinlabsci.org 348 Annals of Clinical & Laboratory Science, vol. 45, no. 3, 2015 Ovarian Sertoli-Leydig Cell Tumor with Predominant Heterologous Mucinous Differentiation and Foci of Hepatocytic Differentiation: Case Report and Review of The Literature

Li Liang1,3, Andrew Menzin2, John Louis Lovecchio2, and Maria D. Navarro1

1Department of Pathology and Laboratory Medicine, NSLIJHS/ Hofstra North Shore-LIJ School of Medicine Program, New Hyde Park, NY, 2Department of OBS-GYN-Oncology, NSLIJHS/ Hofstra North Shore-LIJ School of Medicine Program, New Hyde Park, NY, and 3Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Abstract. Sertoli-Leydig cell tumor is a rare ovarian neoplasm and belongs to the group of sex cord stromal tumors. We present a case of a 15-year old girl diagnosed with Sertoli-Leydig cell tumor with heterologous elements consisting predominantly of mucinous epithelium and a sparse Sertoli-Leydig cell component, mimicking mucinous neoplasm. Furthermore, foci of hepatocytic differentiation were also identified. Im- munohistochemical stains showed the component of Sertoli cell differentiation was positive for cytokeratin 18 and inhibin. The component of Leydig cell differentiation was strongly positive for inhibin. The component of hepatocytic differentiation was positive for low molecular weight keratin, HepPar1, alpha- fetoprotein and weakly positive for inhibin. Thus, this was a very rare case which created a challenge for pathologists, especially on frozen sections.

Key words: Sertoli-Leydig cell tumor, sex cord stromal tumor, heterologous elements.

Introduction challenging case of SLCT with predominant mucinous differentiation but also with foci of hepato- Ovarian Sertoli-Leydig cell tumors (SLCTs) are cytic differentiation, while Sertoli and Leydig cells rare sex cord stromal neoplasms and account for were only a small component of the tumor. less than 1% of ovarian neoplasms [1-6]. The average age of presentation is 25-years-old. The well- Case Report differentiated SLCTs usually present at an older age, while the retiform variant usually presents at a A 15-year-old girl presented with constipation for 8 younger age [2]. Sertoli-Leydig cell tumors can be months. Physical examination revealed a distended ab- classified into well-differentiated, intermediate-dif- domen. Lab test showed elevated alpha-fetoprotein (AFP). Computerized Tomography (CT scan) showed a ferentiated, poorly-differentiated, retiform variant 26x24x14 cm abdominal/pelvic mass displacing the and SLCTs with heterologous elements. Sertoli stomach, pancreas, splenic vessels, and small intestine. cells, Leydig cells, and gonadal stroma are cell types Clinically, the differential diagnosis of complex cystic native to the ovary. Other cell types not native to ovarian epithelial neoplasm and/or germ cell neoplasm, the ovary are called heterologous elements, which such as yolk sac tumor, had been considered. have been reported in approximately 20% of SLCTs [1]. Mucinous epithelium is the most common het- The patient underwent exploratory laparotomy, left sal- erologous elements, but carcinoid, rarely hepato- pingo-oophorectomy, and omentectomy. According to cyte-like cells, and mesenchymal heterologous ele- the operation report, a smooth-walled mass replacing the ments such as immature cartilage and skeletal left ovary was removed intact. Grossly, the tumor was mostly cystic with focal solid areas. The cysts were filled muscles have also been reported. We report a very with straw-colored mucinous material. The solid areas were gray-white to yellow-tan and partially translucent. Address correspondence to Maria D. Navarro, MD, Department of Pathology and Laboratory Medicine, NSLIJHS/Hofstra North Shore- Intraoperative consultation was performed, and the di- LIJ School of Medicine Program, 6 Ohio Drive, New Hyde Park, agnosis was benign seromucinous cystadenoma, defer- NY 11042, USA; phone: 516 304 7235; fax: 516 224 8586; e mail: [email protected] ring the final diagnosis until permanent sections could

0091-7370/15/0300-348. © 2015 by the Association of Clinical Scientists, Inc. Ovarian Sertoli-Leydig Cell Tumor 349 be examined. Final pathology findings showed a varied histologic appearance (Figure 1). Bland mucinous epithelial cells lined the numerous small and large cysts. The underlying stroma was fi- brotic with scat- tered small foci of cells forming ir- regular, slightly lobulated clusters and cords, and in some places forming nests, trabec- ulae, and open tubules compati- ble with Sertoli cell differentiation (positive for cytokeratin 18 and inhibin). Intermixed with these cells were small aggregates of Leydig cells (strongly positive for inhibin) and non-differentiated hyperchromat- ic stromal cells. A Figure 1. A Sertoli-Leydig cell tumor composed of mucinous epithelium (asterisk), Sertoli cell dif- particularly inter- ferentiation (arrowhead), Leydig cell differentiation (blue arrow), and hepatocytic differentiation esting feature of (red arrow). A and B. H&E stain (original magnification ×200). C and D. Immunohistochemical this tumor was stains for inhibin (original magnification ×200). E. Immunohistochemical stain for alpha-fetopro- the presence of tein (original magnification ×200). F. Immunohistochemical stain for HepPar1 (original magnification ×200). heterologous hepatocyte-like cells within these aggregates, which were epithelium, foci of hepatocytic differentiation, and large polygonal cells with abundant eosinophilic cyto- a sparse Sertoli-Leydig cell component, is extremely plasm (positive for low molecular weight keratin, rare and diagnostically challenging. The differential HepPar1, and alpha-fetoprotein and weakly positive for diagnoses of SLCTs include epithelial tumors of the inhibin). This findingov pr ided an explanation for the ovary (e.g., mucinous neoplasm and endometrioid patient’s elevated alpha-fetoprotein. carcinoma with sex cord-like differentiation), germ cell tumors (e.g., yolk sac tumor), other sex cord Discussion stromal tumors, and metastatic carcinoma [1,2]. The abundant heterologous mucinous cystic com- SLCTs account for less than 1% of ovarian neo- ponent in our case mimicked a mucinous neoplasm plasm [1,2]. Our case, with heterologous elements of the ovary, especially on frozen section. It may be consisting of a predominance of mucinous helpful to take multiple sections for intraoperative 350 Annals of Clinical & Laboratory Science, vol. 45, no. 3, 2015 consultation, especially in tumors with . us hs hs hs hs in at s atypical features. Careful examination of nt nt nt nt nt ar St the stroma underneath the epithelium is t mo mo p mo mo me 9 6 en 6 6 ye 8 -u vi essential for making the correct rr r D, D, ow D, D, D, fo diagnosis. ll ve Recu Fo DO NE NA NE NE DO NA

gati In addition, the patient had elevated al- ne ,

, pha-fetoprotein. Thus, germ cell tumor, s n) t um um li li especially yolk sac tumor, was clinically er ou ma en r . tt he he rr og co

re suspected. However, a yolk sac compo- it it mo pa ol ar he ep ep tu os ar nent was not identified in our case. ter s s Recu ++ d e ed ul a a ts my oi

He Elevated alpha-fetoprotein has been pre- st ic ag nou nou r en li in il al do om om ci ci viously reported in SLCTs. In the SCLTs rt rc he rc rc ab em an (c No El Ot Mu rh Mu No Sa Ca Sa Ca No were with elevated alpha-fetoprotein, AFP had n ts been detected in Sertoli cells, Leydig cells, ge en 1 ti p

rt or heterologous gastrointestinal epitheli- on an . NA He NA Pa NA NA

ic um [7-14]. Tr ue hepatocytic differentia- mp le on on co tion is rarer and may need to be confirmed ti lab r ry P ia ai by immunohistochemistry since in some nt av . mb - AF - - othe t re in

oe cases the hepatocytes are in close proxim- + - - + - n no ffe nt e. in : bi ng ng ity to Leydig cells, and intracytoplasmic rc . The Di me hi ro ro ca NA vi on bile or bile plugs within canaliculi are not ratur In St St NA d r ti te e; Cell ia fo always present. To our knowledge, there n an as Li ig ti nt se ve in were only approximately ten cases of ra re yd the di ps ffe gati of Ke Le - - SLCTs with hepatocytic differentiation, of ry di w ne e -t and detailed clinical history and/or im- ie ti te d nc 1 p an . cy an rt

de munohistochemistry has been reported in Rev in to n : n, NA NA NA He NA NA NA Pa NA NA evi si

ti the English language literature (Table 1). ps pa on on i yp ry rri ti he

No Mooney et al. (1999) studied the immu- -t tr fe ia d P ti ntiat nt D:

n, nohistochemical profile of Sertoli cell and an mo re an AF + + + + re ll r mi hy ffe NE hepatocytic differentiation and found ffe ce fo -c bu e; Di e ti

Di that hepatocytes were positive for keratin ig al c as iv c r an ti yd it se ti

r (AE1/AE3 and CAM5.2), AFP, ferritin, fo cy di Le cy fo to pos ate+ , to ve n albumin, anti-trypsin and carcinoembry- e + + + - of to ll ti pa ly bi iv si ak ak der pa ce onic antigen (canalicular pattern), weak it ed hi ak He i di In He mo We We NA ol to moderately positive for inhibin, and we pos rt be po D: n with be be negative for vimentin. The Leydig cells Se ti r to to ra to of DO were strongly positive for inhibin, posi- mo ed ts NA NA Ke NA NA + + + ed ed n; rt

Tu tive for vimentin, and negative for keratin rt rt ei en po ll th ot po po re on [8]. Our case showed similar immunohis- r) Ce pr re re e on g ea so mp to tochemical features. Additionally, immu- so so al di -m 11 (y 13 Ag 15 44 74 18 23 15 17 fe co al al ey

a- nohistochemical stain of HepPar1 was s s ve ph were li-L wa wa also performed and was positive in tumor * ha e Al e e 14 cl . ve cl cl 7# 7# 7# 7# 7# cells with hepatocyte differentiation. + 12 . . . . . ti P: . al Serto ti ti 11 al al al al al . al ar e abo ar of ar se AF al s s et et et et et is et nc is is s: ca se ad et se et The clinical significance of heterologous th re t ey ey ey ey ey th th ha on g ca fe Ca en ti in on on on on on mucinous and hepatocytic differentiation in in e mm un s es ia Re 1. th T

e is still unclear. The development of hepa- Ha Chad Yo Mo Mo Pr Mo Mo Mo l rev CT CT se bl LC Al tocellular carcinoma has been reported in SL SL 3 *S Ta + # ++ 2 Ca 1 6 7 9 Abb 5 8 4 Ovarian Sertoli-Leydig Cell Tumor 351

SLCTs with hepatocytic differentiation [8]. References Furthermore, Mooney et al. also reported a case of 1. Devilee P and Tavassoli FA. World Health Organization: SLCT that showed hepatocytic differentiation ad- Tumors of the Breast and Female Genital Organs, 2003, mixed with sarcomatous elements present in the Oxford University Press, Oxford. metastatic site [8]. However, further study needs to 2. Nucci MR and Oliva E. Gynecologic Pathology:A Volume in the Series: Foundations in Diagnostic Pathology, 2009, be done to determine whether such differentiation Churchill Livingstone/Elservier, Edinburgh. affects prognosis. Approximately 30% of SLCTs are 3. Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors.A hormonally active, most commonly producing an- clinicopathological analysis of 207 cases. Am J Surg Pathol 1985;9:543-569. drogens [1,2]. However, our case was 4. Young RH, Prat J, Scully RE. Ovarian Sertoli-Leydig cell tu- hormonally-inactive. mor with heterologous elements. Gastrointestinal epithelium and carcinoid: a clinicopathological analysis of thirty-six cases. Cancer 1982;50:2448-2456. Retiform variant of SLCT is composed of anasto- 5. Gui T, Cao D, Shen K, Yang J, Zhang Y, Yu Q, Wan X, Xiang mosing slit-like spaces resembling rete testis and Y, Xiao Y, Guo L. A clinicopathological analysis of 40 cases of ovarian Sertoli-Leydig cell tumors. Gynecol Oncol shows the highest incidence of heterologous ele- 2012;127:384-389. ments [1,13]. The retiform variant usually presents 6. Chen L, Tunnell CD, De Petris G. Sertoli-Leydig cell tumor at a younger age (average 15-years-old). However, with heterologous element: a case report and a review of the literature. Int J Clin Exp Pathol 2014;7:1176-1181. retiform elements were not identified in our case. 7. Mooney EE, Nogales FF, Bergeron C, Tavassoli FA. Retiform Sertoli-Leydig cell tumors: clinical, morphological and immunohistochemical findings. Histopathology 2002;41:110-117. Of interest, other ovarian tumor that can show he- 8. Mooney EE, Nogales FF, Tavassoli FA. Hepatocytic differen- patocytic or hepatoid differentiation include yolk tiation in retiform Sertoli-Leydig cell tumors: distinguishing a sac tumor (up to 40%), teratoma, and hepatoid heterologous element from Leydig cells. Hum Pathol 1999;30:611-617. carcinoma [1,2]. The identification of Sertoli and 9. Watanabe T, Yamada H, Morimura Y, Abe M, Motoyama T, Leydig cells in our case ruled out these Sato A. Ovarian Sertoli-Leydig cell tumor with heterologous possibilities. gastrointestinal epithelium as a source of alpha-fetoprotein: a case report.J Obstet Gynaecol Res 2008;34:418-421. 10. Amato G, Izzo G, Izzo A. A paradoxical inhibition of andro- In summary, this is a very rare case of SLCT, with genic hyperproduction by a Sertoli-Leydig cell tumor ovary. Hum Reprod 1995;10:2967-2969. predominant heterologous mucinous and foci of 11. Young RH, Perez-Atayde AR, Scully RE. Ovarian Sertoli- hepatocytic differentiation, which can cause a diag- Leydig cell tumor with retiform and heterologous components. nostic challenge on both frozen and permanent sec- Report of a case with hepatocytic differentiation and elevated serum alpha-fetoprotein. Am J Surg Pathol 1984;8:709-718. tions. It is important to extensively sample the tu- 12. Chadha S, Honnebier WJ, Schaberg A. Raised serum alpha- mor and carefully examine the stromal cells fetoprotein in Sertoli-Leydig cell tumor (androblastoma) of underneath the epithelium to make the correct di- ovary: report of two cases. Int J Gynecol Pathol 1987;6:82-88. 13. Talerman A. Ovarian Sertoli-Leydig cell tumor with retiform agnosis. Even though elevated alpha-fetoprotein is pattern. A clinicopathologic study. Cancer an important clue, true hepatocytic differentiation 1987;60:3056-3064. 14. Hammad A, Jasnosz KM, Olson PR. Expression of alpha-feto- may need to be confirmed by protein by ovarian Sertoli-Leydig cell tumors. Case report and immunohistochemistry. review of the literature. Arch Pathol Lab Med 1995;119:1075-1079.