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Ovarian sex cord-stromal tumors comprise a heterogeneous group of neoplasms with wide morphological diversity, and they can be mistaken for a variety of other tumors. Some types, including granulosa and Sertoli cell tumor, may be confused with a neuroendocrine neoplasm. CD56 is a widely used neuroendocrine marker with a high sensitivity for neuroendocrine tumors and is commonly used as part of a panel to distinguish between a neuroendocrine neoplasm and other tumors in the differential diagnosis. In this study, we investigate CD56 staining in ovarian sex cord-stromal tumors. CD56 staining has not previously been studied in this group of neoplasms. We stained a large series of ovarian sex cord-stromal neoplasms (n = 85) with CD56. Neoplasms studied were adult granulosa cell tumor (n = 40), juvenile granulosa cell tumor (n = 8), Sertoli cell tumor (n = 1), Sertoli-Leydig cell tumor (n = 14), Leydig cell tumor (n = 2), steroid cell tumor, not otherwise specified (n = 2), sclerosing stromal tumor (n = 1), sex cord tumor with annular tubules (n = 2), and fibroma (n = 15). Three uterine tumors resembling ovarian sex cord tumor were also studied. Nonneoplastic ovaries, including 3 cases of pregnancy-related granulosa or Sertoli cell proliferation, were also included. In nontumorous ovaries, granulosa cells of follicular and corpus luteum cysts were consistently negative. The normal ovarian stroma was diffusely positive, as were the 3 pregnancy-related proliferations. All sex cord-stromal tumors except one were positive with CD56; staining ranged from focal to diffuse but was usually diffuse involving more than 50% of tumor cells. Staining was usually membranous with weaker cytoplasmic positivity. CD56 immunoreactivity is almost universal in ovarian sex cord-stromal tumors of all the major morphological types and is of no value in distinguishing a sex cord-stromal and a neuroendocrine neoplasm. Since CD56 is an extremely sensitive marker of ovarian sex cord-stromal tumors, it may be useful in the diagnosis of this group of neoplasms, especially in cases which are α inhibin or calretinin negative, and in distinguishing these from mimics which are CD56 negative.