Section 4 -

Sex Cord / Gonadal Stromal Tumors of the Testis Isabell A. Sesterhenn

Sex-cord/ gonadal stromal tumors account for 3-6% of testicular tumors in adults and 20-30% in prepubertal children [1, 2, 3, 4]. Unlike germ cell tumors they are equally common in patients of different race. The histology of these tumors recapitulates the appearance of Leydig, Sertoli and granulosa cells, and nonspecific stromal cells of the immature and mature testis. The classification is listed in Table 1: [5]. Table 1: Classification of Stromal tumors Sex Cord/Gonadal Stromal Tumours Leydig cell tumor Malignant Leydig cell tumor Sertoli cell tumour Sertoli cell tumor lipid rich variant Sclerosing Sertoli cell tumor Large cell calcifying Sertoli cell tumou Others Malignant Sertoli cell tumour Granulosa cell tumour Adult type granulosa cell tumour Juvenile type granulosa cell tumour Tumours of the thecoma/fibroma group Thecoma Fibroma Sex cord/gonadal stromal tumors, incompletely differentiated Sex cord/gonadal stromal tumors, mixed forms Malignant sex cord/gonadal stromal tumors Tumors containing both germ cell and sex cord/gonadal stromal elements Gonadoblastoma Germ cell-sex cord/gonadal stromal tumor, unclassified The most helpful immunohistochemical markers are inhibin and calretinin although the absence of these markers does not exclude the diagnosis of a stromal tumor [6, 7, 8, 9, 10]. A whole host of markers e.g. keratins, desmin has been observed. Prognostic Factors. The behavior of sex cord/ stromal tumors may be unpredictable since tumors with bland histological features can metastasize. However, tumors exhibiting necrosis, nuclear anaplasia, frequent and abnormal mitoses, irregular borders and large size (greater than 5 cm), extension into paratesticular tissue and vascular invasion are more likely to progress [1, 2, 3, 4, 11]. Pure Forms Included in this category are Leydig cell tumors, Sertoli cell tumors, granulosa cell tumors and tumors of the thecoma/fibroma group. A. Leydig Cell Tumor Macroscopically, the tumor appears circumscribed, even encapsulated, homogeneous, bulging and yellowish or mahogany brown. Histologically, it is composed of elements recapitulating normal development and evolution of Leydig cells [11, 12]. The most common appearance is that of medium-sized cells with distinct cell borders, eosinophilic cytoplasm and a round or oval vesicular and rarely grooved nucleus, frequently containing a prominent nucleolus. The cells may be larger with finely or coarsely vacuolated cytoplasm containing lipids, while others consist of elongated, spindle-shaped cells with granular eosinophilic cytoplasm. The nuclei may vary from small to large, round to oval, or vesicular to pyknotic. Occasional cells may be binucleated. The Reinke crystals are helpful in the identification of Leydig cell tumor, but they are detectable in only about 40% of cases. Lipofuscin pigment is often present. The cells occur in sheets, columns, cords and trabeculae. Rare tumors are microcystic [13]. About 10% of Leydig cell tumors are malignant. Criteria for the diagnosis of malignancy are anaplasia of the cells, individual cell necrosis, large areas of tumor necrosis, extension to the tunica or epididymis, frequent mitoses, vascular invasion and tumor size of 5 or more cm [11, 14]. However, rarely the tumor may show none of these features but metastasize. In such cases, the metastases are usually delayed five or more years. Leydig cell tumors have to be distinguished from nodules of Leydig cell hyperplasia found in the testes of persons with atrophy, cryptorchid, the Klinefelter syndrome and Klinefelter-like syndrome. In such cases, the testes are small and the seminiferous tubules are small and often sclerotic. Hyperplasia differs from neoplasia in that the tubules are entrapped in the former but not in the latter; although a few entrapped tubules may be seen in the periphery of a tumor. Leydig cell tumors and hyperplasia can be distinguished from similar changes in the androgen insensitivity and the adreno-genital syndromes by the absence of clinical symptoms or laboratory evidence of those syndromes. B. Sertoli Cell Tumors Macroscopically, the tumors are rather firm, grayish-white or yellow and appear encapsulated. The cells range in shape from oval to columnar. They have a small or medium-sized, round or oval vesicular nucleus containing a fine chromatin network and a solitary, small basophilic nucleolus. The cytoplasm may be scanty or abundant with a single large or multiple small lipid vacuoles. The cells form tubules with a more or less distinct lumen which may contain basement membrane-like material, or the tubules appear solid as in the prepubertal testis [15, 16]. The tumor may occur in sheets with only occasional tubule formation. The stroma can be scanty or composed of abundant, sometimes hyalinized, fibrous tissue. The tumors with extensive hyalinization are known as the "sclerosing Sertoli cell tumor". [17]. Sertoli cell tumors constitute about 3% of testicular tumors - occur in all ages, but mostly in infants and children [18]. In adults, 40% show gynecomastia. In a few instances estrogens and pregnanediol are elevated. The tumors are usually benign, but 10% are malignant, and those patients who are going to die usually do within one year [19, 20]. Sertoli cell tumors must be distinguished from the small nodules of coiled tubules lined by immature Sertoli cells found in over 20% of cryptorchids and occasionally in descended testes. Such nodules are sometimes mislabeled Sertoli cell or tubular adenoma, but represent residual nodules of immature tubules. Occasionally, scattered spermatogonia are found within the tubules of the Sertoli cell nodules. a. Large Cell Calcifying Sertoli Cell Tumor On gross examination the tumors are tan to yellow, often multifocal and firm. 20% are bilateral and most of these are associated with Carney syndrome. The cells are large with cuboidal, hexagonal, columnar, or spindle shapes. The cytoplasm is abundant, finely granular, and eosinophilic, but may be amphophilic and slightly vacuolated, and contain abundant lipid in fine droplets or large vacuoles. The nuclei are round, oval, or elongated with one or two small nucleoli. Mitoses are generally absent or rare. The neoplastic cells often form tubules or cords, clusters, trabeculae, or solid sheets. The stroma may be loose, myxoid or densely collagenous with varying degrees of calcification. Calcification appears as large, wavy, laminated nodules or massive deposits; sometimes it is sparse. In the absence of prominent tubule formation and minimal calcification, the tumor may simulate a Leydig cell tumor, especially in a child with precocious puberty [21, 22]. The large cell calcifying Sertoli cell tumor is most common in children and is often associated with Carney syndrome: hyperplasia and neoplasia of other endocrine organs, bilateral primary adrenocortical hyperplasia and pituitary adenomas, spotty mucocutaneous pigmentation, and cardiac myxomas [23]. Clinical associations have included sexual precocity, acromegaly, pituitary gigantism, hypercortisolemia, and sudden death. b. Testicular Tumors in Peutz-Jeghers Syndrome Stromal tumors in the Peutz-Jeghers syndrome resemble the sex-cord stromal tumors with annular tubules or the large cell calcifying Sertoli cell tumor. They have a prominent intratubular component and lack the calcifications [24, 25]. C. Granulosa Cell Tumors Two types are recognized: the adult and the juvenile. Both display the same histologic patterns as their ovarian counterparts. a. Granulosa Cell Tumor, Adult Type The gross appearance is grayish-white or yellow, homogeneous lobulated. The nuclei are vesicular and grooved, but they may be large, round, and hyperchromatic. The cells are small, round, or hexagonal; the cytoplasm is generally scant. The tumor may have a diffuse or microfollicular pattern with Call-Exner bodies. About half of the patients have gynecomastia [12, 26, 27]. b. Granulosa Cell Tumor, Juvenile Type Macroscopically, they are lobulated often with a cystic component. The cells are polyhedral or round and contain abundant pale to eosinophilic cytoplasm. The nuclei are round or oval and hyperchromatic with occasional nucleoli. There may be many mitoses. Histologically, the tumor is usually cystic but may be follicular or have solid areas. The follicles are usually large and round. The tumor is almost always encountered before the age of two years. It is the most common testicular tumor of the newborn. A few have been reported in cryptorchid testes with intersex disorders [28, 29, 30, 31]. D. Tumors of the Thecoma/Fibroma Group These tumors are known under a number of synonyms and today are considered to be fibromas with the histologic features of their ovarian counter parts [32, 33]. Tumors showing both germ cell and gonadal stromal elements A. Gonadoblastoma Macroscopically, the tumor is multinodular with yellowish gritty cut surface. The nodules are composed of two principal cell types: large germ cells and small cells resembling immature Sertoli and granulosa cells; elements resembling Leydig and lutein cells may also be present. The two cells (germ cell and sex cord/gonadal stromal elements) are usually in irregular or rounded discrete nests presenting one or more of three patterns. Most often the sex cord cells surround rounded hyaline nodules of basement membrane substance which merges with the surrounding basement membrane. The second pattern consists of nests composed of large germ cells surrounded by many smaller Sertoli cells. In the third growth pattern, the Sertoli cells form a ring of single cells at the periphery of a central nest of germ cells. Focal calcification may begin in hyaline bodies, sometimes forming large, wavy, laminated masses separated by dense fibrous tissue. Large polyhedral cells resembling Leydig cells but without Reinke crystals may be present after puberty [34]. By immunohistochemistry, the germ cells are positive for VASA, p53 and other germ cell markers. They also can be positive for PLAP and c-kit. The stromal cells are positive for inhibin and WT-1 [35]. Sometimes the germ cells of a gonadoblastoma transgress the margins of the nests and grow as a seminoma or embryonal carcinoma with only small foci of gonadoblastoma within them or at their margins. The type of germ cell tumor should be specified. Gonadoblastomas arise almost exclusively in patients with rudimentary or streak gonads, most of whom are phenotypic females and almost all of whom are X-chromatin-negative and have a Y-chromosome. B. Mixed Germ Cell – Sex Cord/Gonadal Stromal Tumors, Unclassified A tumor consisting of closely admixed germ cells and sex/cord gonadal stromal cells. The germ cells resemble spermatogonia with ample cytoplasm and varying amounts of glycogen. The nuclei are round and may have nucleoli. 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