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대한병리학회지: 제 36 권제2 호 2002 The Korean Journal of Pathology. 2002; 36: 128-31

Alpha-Fetoprotein Producing Sertoli-Leydig Cell Tumor of the - A Case Report -

Kee-Taek Jang, Hye-Rim Park A 26-year-old woman had an ovarian Sertoli-Leydig cell tumor (SLCT) associated with an ele- Duck-Hwan Kim, Chang-Mo Kim1 vated level of serum alpha-fetoprotein (AFP). The tumor had a heterologous element of intesti- Woo-Seok Sohn1 and nal-type mucinous epithelium, retiform and intermediately differentiated tubules of the Sertoli Hyung-Sik Shin cells, and AFP-producing Leydig cells. AFP was demonstrated within the Leydig cells by an immunohistochemical technique. After surgery, the serum AFP level of the patient fell to the Departments of Pathology and normal range. The present case is the first documented case of AFP producing a SLCT of 1Obstetrics and Gynecology, the ovary reported in Korea. College of Medicine, Hallym University, Seoul, Korea

Received : September 20, 2001 Accepted : January 7, 2002

Corresponding Author Kee-Taek Jang, M.D. Department of Pathology, Hallym University, Sacred Heart Hospital, 896 Pyungchon-dong, Dongan-gu, Anyang 431-070, Korea Tel: 031-380-3938 Fax: 031-381-9646 E-mail: [email protected] Key Words : Sertoli-Leydig Cell Tumor-alpha-Fetoproteins-Ovarian

Sertoli-Leydig cell tumors (SLCTs), which comprise less than CASE REPORT 0.2% of all ovarian neoplasms, are sex cord-stromal tumors that exhibit a testicular differentiation. Endocrine manifesta- A 26-year-old, gravida 0, para 0 woman was admitted with a tions are absent in about 60% of patients, but some patients 3-month history of amenorrhea. There was no clinical evidence develop defeminization or virilization.1,2 However, they usually of endocrine disturbance except a mild masculine voice. The do not produce alpha-fetoprotein (AFP). Over the last 20 years, level of serum testosterone was 0.9 ng/mL (normal, 0.1-1.0 approximately 25 cases of SLCTs with an elevated serum AFP ng/mL). The levels of serum estrone, estradiol, estriol, cortisol, level have been reported. In general, the elevation of serum human chorionic gonadotropin, and AFP, a fetal oncoprotein, is a feature observed in patients with were normal. Her serum AFP level was elevated to 56.6 ng/mL yolk sac tumors, or less commonly, with other (normal, 0-8.1 ng/mL). The physical examination findings tumors (including , and in rare cases ).3-5 were unremarkable except for a pelvic mass. Pelvic sonograghy This glycoprotein is a major component of the fetal mam- showed a normal-sized uterus with a large left ovarian mass. A malian plasma, produced by the yolk sac and the liver, with a laparotomy disclosed an enlarged left . The trace synthesis by the gastrointestinal tract. We are reporting a serum AFP level returned to the normal range and the mascu- case of ovarian SLCT associated with a slight elevation of serum line voice improved after surgery. Administration of three AFP levels, with an immunohistochemical demonstration of courses of , , and began one AFP in the Leydig cells. month after surgery. During the six month follow-up period, she was free of the disease.

128 Alpha-Fetoprotein Producing Sertoli-Leydig Cell Tumor 129

The ovarian tumor measured 11×9×9 cm and weighed cystic areas were stained with periodic acid-Schiff (PAS) reac- 980 g. The tumor was completely encapsulated and no rupture tion with or without diastase digestion and alcian blue (pH was noted. The cut surface was predominantly solid with many 2.5). Deparaffinized sections from the selected paraffin blocks papillae and small measuring up to 4 cm in diameter, were stained with primary antibodies for AFP (1:100, DAKO, filled with mucoid material (Fig. 1). Paraffin blocks from the Carpenteria, CA, U.S.A.), broad-spectrum cytokeratin (1:100,

A B

Fig. 1. The ovarian tumor measures 11×9×9 cm and weighs Fig. 3. Clusters of Leydig cells are scattered in edematous stro- 980 g. The cut surface shows encapsulated solid mass with a ma. Leydig cells show eosinophilic cytoplasm (A). Immunohisto- few small cysts, filled with mucoid material. chemical expression of AFP is seen in Leydig cells (B).

A B

Fig. 2. Immature Sertoli cells are arranged in nested group pat- Fig. 4. Heterologous element of intestinal-type mucinous glands. tern (A). Some tumor cells show hollow branching tubule struc- These glands are lined by tall columnar cells with basally located ture, so-called a retiform pattern (B). nuclei. 130 Kee-Taek Jang∙Hye-Rim Park∙Duck-Hwan Kim, et al.

Ventana, Arizona, U.S.A.), chromogranin (1:100, Zymed, San and sex cord stromal tumors such as SLCT).4-6 Twenty five Francisco, U.S.A.), (1:100, Zymed, San Francisco, cases of SLCTs of the ovary with an elevated AFP level have U.S.A.) and inhibin and (1:40, Serotec, Oxford, U.K.) been reported in the English literature since the early 1980s.6-13 using the avidin-biotin staining method. Microscopically, the AFP was detected by immunohistochemistry in most of those tumor was composed predominantly of immature Sertoli cells cases.7-10 Immunohistochemical staining has shown that the mainly arranged in solid tubules and a nested group pattern positive cells of AFP were Leydig cells in six cases; both Sertoli (Fig. 2A), and less frequently, in hollow branching tubules. and Leydig cells in four cases; Sertoli cells only in two cases; These tubules were lined by columnar epithelial cells contain- and hepatoid cells in eight cases.11-13 In one case, the nature of ing scanty cytoplasms and moderately pleomorphic nuclei with the AFP-positive cells could not be determined with certain- prominent nucleoli, a so-called retiform pattern (Fig. 2B). ty.14 The remaining four cases had no available immunohisto- These retiform components occupied about 40% of the total chemical results for AFP. The present case showed the AFP tumor cells. Leydig cells with dense eosinophilic cytoplasm immunostaining only in the Leydig cells. Recently, a hepato- were scattered at peripheral portion of the tumor (Fig. 3A). In cytic differentiation was identified in five cases of SLCTs a few Leydig cells, immunohistochemical staining showed a through an immunohistochemical profile.13 The cells showing weak cytoplasmic staining for AFP (Fig. 3B). These cells were a hepatocytic differentiation were morphologically similar to negative for cytokeratin but positive for vimentin and inhibin. the Leydig cells. It was difficult to make a distinction between The intervening spindle cell stroma was edematous and con- these two cells based on histologic findings. The identification tained dilated blood vessels and scattered lymphocytes. The of hepatocytic differentiation required an immunohistochemi- heterologous element was cystically dilated intestinal-type cal profile. The cells with hepatocytic differentiation showed a mucinous glands (Fig. 4). No mesenchymal component was positive immunoreactivity with keratin cocktail and CAM 5.2, found. These mucinous glands are lined either by tall columnar but were negative for vimentin and inhibin.13 In our case, no cells with granular eosinophilic cytoplasms and round-to-oval hepatocytic differentiation was found and the AFP-producing basally located nuclei or by short cuboidal cells. Periodic acid- Leydig cells were positive for inhibin and vimentin, but nega- Schiff and alcian blue stain showed a focal weakly positive reac- tive for keratin immunistaining. tion only in the lining epithelium. Chromogranin immunos- Although it was somewhat easy to reach a diagnosis in the taining showed negativity in mucinous epithelium. These fea- present case, it is not always easy to differentiate SLCTs from tures were consistent with a diagnosis of intermediate grade other germ cell tumors based on histopathological features SLCT, with a retiform pattern and heterologous element of alone, especially in poorly differentiated SLCTs or SLCTs with intestinal-type mucinous epithelium. The clinical stage was IA an extensive retiform pattern.2,6 The retiform pattern leads to a (T1a, N0, M0). frequent initial misinterpretation of this tumor as a of another type, including endodermal sinus tumor and serous .6 Awareness of the retiform pattern with other DISCUSSION heterologous elements is important in differential diagnosis of an ovarian with elevated serum AFP, especially in a frozen We report a case of intermediate grade (moderately differen- histologic examination. Heterologous element occur in approx- tiated) ovarian SLCT with a heterologous element of intestinal- imately 20% of SLCTs.14 Most commonly, glands and cysts type mucinous epithelium. The elevated level of serum AFP in lined by gastric type or intestinal type mucinous epithelium this case led to a suspicion of a diagnosis of yolk sac tumor of are seen.14 The embryologic continuum between the yolk sac, the ovary. AFP is produced by the early embryonal endoderm primitive gut, and liver is reflected in the finding of mucinous and preferentially in the secondary yolk sac, and has been a use- epithelium as one of the most common endodermal derivatives ful serum marker for the diagnosis of primary or recurrent yolk in , and also one of the most frequent heterologous sac tumor.3 The finding of an elevated level of serum AFP in a elements in SLCT.14 Among all the reported cases, six showed young woman with an ovarian tumor is, therefore, most sug- the presence of heterologous elements, eight showed a retiform gestive of a yolk sac tumor. However, elevation of AFP is pre- pattern, and six showed both heterologous elements and a reti- sent in a wide range of other than form pattern.6-10,12,15 Seven patients experienced a tumor recur- yolk sac tumors (such as dysgerminoma, , rence or died of the disease. These patients showed relatively Alpha-Fetoprotein Producing Sertoli-Leydig Cell Tumor 131

high AFP levels and the retiform pattern was present in six out Gynecol Scand 1987; 66: 75-8. of the seven patients. In one report, SLCT with retiform com- 6. Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors with a ponent showed a high rate (20%) compared to retiform pattern: a problem in histopathologic diagnosis. A report SLCT without retiform component (12%) in stage I.6 Thus it is of 25 cases. Am J Surg Pathol 1983; 7: 755-71. suggested that a SLCT with high AFP level and retiform pat- 7. Chadha S, Honnebier WJ, Schaberg A. Raised serum alpha-feto- tern harbors a poor prognosis. In this case, the patient recieved protein in Sertoli-Leydig cell tumors (androblastoma) of ovary: despite being in clinical stage IA due to retiform report of two cases. Int J Gynecol Pathol 1987; 6: 82-8. component. But it is still controversial to use chemotherapy in 8. Chumas JC, Rosenwaks Z, Mann WJ, Finkel G, Pastore J. Sertoli- stage I SLCT with retiform component. Leydig cell tumor of ovary producing alpha-fetoprotein. Int J In all of the reported cases, the serum AFP levels showed a Gynecol Pathol 1984; 3: 213-9. rapid decrease after tumor resection. When the patient experi- 9. Mann WJ, Chumas J, Rosenwaks Z, Merrill JA, Davenport D. Ele- enced tumor recurrence or distant metastases, the AFP level vated serum-fetoprotein associated with Sertoli-Leydig cell tumors rose. The use of serum AFP levels is well established for diag- of the ovary. Obstet Gynecol 1986; 67: 141-4. nostic purposes, monitoring of the treatment, and for the 10. Motoyama I, Watanabe H, Gotoh A, Takeuchi S, Tanabe N, detection of recurrences and metastases in germ cell tumors16-18 Nashimoto I. Ovarian Sertoli-Leydig cell tumor with elevated and also may be useful in the monitoring of tumor recurrences serum alpha-fetoprotein. Cancer 1989; 63: 2047-53. and metastases in SLCTs.16,17 11. Gagnon S, Tebu B, Silva EG, McCaughey WT. Frequency of AFP In conclusion, the ovarian SLCT is a neoplasm occurring in production by Sertoli-Leydig cell tumors of the ovary: an immuno- young females that may be associated with an elevated level of histochemical study of eight cases. Mod Pathol 1989; 2: 63-7. serum AFP, and thus must be clinically and histologically dis- 12. Hammad A, Jasnoz KM, Olson PR. Expression of alpha-fetoprotein tinguished from a germ cell tumor with a yolk sac tumor com- by ovarian Sertoli-Leydig cell tumors: case report and review of the ponent. literature. Arch Pathol Lab Med 1995; 119: 1075-9. 13. Mooney EE, Nogaless FF, Tavassoli FA. Hepatocytic differentia- tion in retiform Sertoli-Leydig cell tumors: distinguishing a heterol- REFERENCES ogous element from Leydig cells. Hum Pathol 1999; 30: 611-7. 14. Young RH, Prat J, Scully RE: Ovarian Sertoli-Leydig cell tumors 1. Zaloudek C, Norris HJ. Sertoli-Leydig cell tumors of the ovary: a with heterologous elements. 1. Gastrointestinal epithelium and car- clinicopathological study of 64 intermediate and poorly differenti- cinoid: a clinicopathological analysis of thirty-six cases. Cancer ated neoplasm. Am J Surg Pathol 1984; 8: 405-18. 1982; 50: 2448-56. 2. Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors: a clinico- 15. Sekiya S, Inaba N, Iwasawa H, et al. AFP-producing Sertoli-Leydig pathological analysis of 207 cases. Am J Surg Pathol 1985; 9: 543-69. cell tumor of the ovary. Arch Gynecol 1985; 236: 187-96. 3. Talerman A, Haije WG, Baggerman L. Serum alpha-fetoprotein 16. Young RH, Perez-Atayde AR, Scully RE. Ovarian Sertoli-Leydig (AFP) in patients with germ cell tumors of the and extrago- cell tumors with a retiform pattern and heterologous component: nadal sites: correlation between endodermal sinus (yolk sac) tumor report of a case with hepatocytic differentiation and elevated and raised serum AFP. Cancer 1980; 46: 380-5. serum alpha-fetoprotein. Am J Surg Pathol 1984; 8: 709-18. 4. Nogales FF, Ruiz AI, Concha A, del Moral E. Immature teratoma of 17. Singh ZN, Singh MK, Chopra P. Sertoli-Leydig cell tumor with the ovary: embryologic correlations and immunohistochemistry. malignant heterologous element and raised serum alpha-fetopro- Hum Pathol 1993; 24: 364-70. tein. J Obstet Gynaecol Res 1996; 22: 595-8. 5. Sekiya S, Inaba N, Takamizawa H, Nagao K. Human chorionic 18. Galbang P, Khan A, Scurry J, MacIsaac I, Planner R. Cervical sarco- gonadotrophin and alpha-fetoprotein in sera and tumor cells of a ma botryoides and ovarian Sertoli-Leydig cell tumor. Gynecol patient with pure dysgerminoma of the ovary. Acta Obstet Oncol 1997; 67: 102-6.