Moderate to poorly differentiated Sertoli-Leydig cell tumor.
Sertoli-Leydig cell tumors (SLCT) belong to the group of sex-cord stromal tumors of the ovary. They account for less than 0.5% of all ovarian tumors and are almost always unilateral. The clinical characteristics are related to the degree of histological differentiation. Up to 50% of SLCTs have endocrine functions (androgenic or estrogenic), and the prognosis is correlated most meaningfully with the degree of differentiation and stage of the tumor. The age at diagnosis averages 25 years (range 2 to 75 years) with 70-75% of these tumors presenting during the second and third decade of life, and less than 10% occurring either prior to menarche or after the menopause.
Our case represented a diagnostic challenge, giving the unusual clinical presentation (lack of hormonal symptoms) and the late age of presentation. The gross appearance and unilaterality favored the diagnose of SLCT. Over 97% of SLCTs are unilateral and they present most often as solid to solid-cystic mass with a yellow to brown appearance on sectioned surface. The size ranges from not detectible to 35 cm (mean 12-14 cm). Additionally, the case presented with poorly differentiated features including: predominantly spindle cell growth pattern, high nuclear grade and almost absence of recognizable Sertoli tubule formation and Leydig cells. Our case showed some tubule representing intermediately differentiated component, thus suggesting the diagnosis of SLCT.
In older patients, the differential diagnosis with other sex cord/stromal tumors, endometrioid adenocarcinoma and carcinoid tumors is aided by the use of immunohistochemistry to discern the final diagnosis. Zhao et al. very elegantly determined the best immunohistochemical panel to differentiate SLCT from other sex cord/stromal and epithelial ovarian tumors. The authors concluded that inhibin is the most discriminatory sex cord marker (2% positivity in carcinoid and 4% positivity in well-differentiated endometrioid carcinoma) followed by calretinin with CD10 being much less useful and CD99 not being discriminatory (up to 40% positivity in carcinoid and 33% positivity in well-differentiated endometrioid carcinoma). EMA is the best epithelial marker with no sex cord tumors showing positivity, followed closely by CK7, ER and PR. It is important to mention that up to 65% of the analyzed sex cord tumors were positive for pan-keratin antibody rendering it of no use for ruling out sex cord ovarian tumors. Chromogranin and synaptophysin are excellent discriminatory markers for carcinoid tumor with CD56 being neither sensitive nor specific for this differential diagnosis. In a more recent paper, the same authors concluded that in addition to inhibin and calretinin, SF-1 and WT1 are also excellent options for ruling in sex cord tumors.
In our case, positivity for inhibin and calretinin and negativity for EMA and ER, together with the H&E appearance ruled out the main differential diagnoes, i.e. endometrioid/clear cell adenocarcinoma, carcinoid tumor and the less likely adult granulosa cell tumor.
The prognosis of SLCTs is good, although poorly differentiated tumors may recur. Conservative surgery is acceptable for young patients wishing to preserve fertility, and postoperative adjuvant chemotherapy and long-term follow up are recommended in those with high-risk factors. Our patient presents with several risk factors including: older age, no androgenic symptoms, poor differentiation and stage pT2a at the time of diagnosis; giving her a poorer prognosis.
In summary, the left adnexal mass presented in our 65-year-old patient was highly concerning for malignancy. The main differential diagnosis was between poorly differentiated adenocarcinoma (endometrioid or clear cell), carcinoid tumor and sex-cord/stromal tumors. Even though age favored an epithelial neoplasia, the gross appearance (yellow-to-brown cut surface) and unilaterality favored a sex cord tumor. Ultimately, the combined use of inhibin, calretinin and EMA antibodies helped in ruling out an epithelial ovarian cancer and carcinoid tumor. Another important differential diagnosis to consider would have been adult granulosa cell tumor, giving the age and the gross appearance of the tumor; however, the lack of histological features of granulosa cell tumor, including the absence of Call-Exner bodies ruled out that diagnosis. For more detailed information and other differential diagnosis please refer to Zhao et. al 2009.
Travassoli F.A, Devilee P. (Eds.): World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Breast and Female Genital Organs. IARC Press: Lyon 2003.
Christopher P. Crum, Marisa R. Nucci, Kenneth R. Lee (Eds.): Diagnostic gynecologic and obstetric pathology. Elsevier Saunders: 2nd Edition, 2011.
Zhao C, Vinh TN, McManus K, Dabbs D, Barner R, Vang R. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol. 2009 Mar;33(3):354-66.
Zhao C, Bratthauer GL, Barner R, Vang R. Comparative analysis of alternative and traditional immunohistochemical markers for the distinction of ovarian sertoli cell tumor from endometrioid tumors and carcinoid tumor: A study of 160 cases. Am J Surg Pathol. 2007 Feb;31(2):255-66.
Durdík Š, Danihel L, Galbavý Š. Sertoli-Leydig cell tumor of the ovary--morphological and immunohistochemical analysis. Neuro Endocrinol Lett. 2012;33(3):257-9.
Gui T, Cao D, Shen K, Yang J, Zhang Y, Yu Q, Wan X, Xiang Y, Xiao Y, Guo L. A clinicopathological analysis of 40 cases of ovarian Sertoli-Leydig cell tumors. Gynecol Oncol. 2012 Nov;127(2):384-9. doi: 10.1016/j.ygyno.2012.07.114. Epub 2012 Jul 28.
Bhat RA, Lim YK, Chia YN, Yam KL. Sertoli-Leydig cell tumor of the ovary: Analysis of a single institution database. J Obstet Gynaecol Res. 2012 Jun 13. doi: 10.1111/j.1447-0756.2012.01928.x. [Epub ahead of print]
QUESTIONS FOR CASE REVIEW:
Which percentage of patients with SLCT present with androgenic symptoms?
Correct answer: C, as many as 50% of SLCTs are associated with androgenic symptoms including: virilism, amenorrhea, deepening of voice and clitoromegaly. Patients with poorly differentiated neoplasm are slightly more likely to present with androgenic manifestations. (2003 WHO Book, Tumors of the Breast and Female Genital Organs and Diagnostic Gynecologic and Obstetric Pathology, Crum, Nucci and Lee, 2nd Edition)
Regarding laterality of SLCT, which of the following is correct?
Correct answer: B, over 97% of SLCTs are unilateral (2003 WHO Book, Tumors of the Breast and Female Genital Organs and Diagnostic Gynecologic and Obstetric Pathology, Crum, Nucci and Lee, 2nd Edition).
For the identification of a sex cord component, which immunostain best aids on the diagnosis of sex cord versus epithelial tumors?
Correct answer: D, Inhibin is the most discriminatory sex cord marker, CD10 and calretinin are markedly less useful. CD99 is not discriminatory. Even though pan-keratin will be most likely positive in endometrioid tumors, up to 65% of sex cord tumors have been reported to be pan-keratin positive. In that regard, EMA antibody is much more specific (Zhao et al. 2007 and 2009).
What is the most frequent stage in which SLCT presents at the time of diagnosis?
Correct answered: C, the vast majority of SLCTs present on stage Ia and are limited to one ovary at the time of diagnosis (2003 WHO Book, Tumors of the Breast and Female Genital Organs and Diagnostic Gynecologic and Obstetric Pathology, Crum, Nucci and Lee, 2nd Edition).
Which of the following is TRUE regarding the difference between SLCT and Endometrioid ovarian ADC?
Correct answer: D, as mentioned above, inhibin is the best marker of sex stromal ovarian tumors. EMA is almost always positive in endometrioid ADC. SLCT are almost always unilateral. The mean age of presentation of SLCT is 25 with well-differentiated SLCT presents in patients 10 years older. Endometrioid ADC occurs most commonly in women in the 5th and 6th decades of life. Signet ring cells occur more often in the Krukenberg tumor (2003 WHO Book, Tumors of the Breast and Female Genital Organs and Diagnostic Gynecologic and Obstetric Pathology, Crum, Nucci and Lee, 2nd Edition).
Contributed by Humberto Trejo Bittar, MD; R. Marshall Austin, MD, PhD and Chengquan Zhao, MD.