A 40-year-old man, married and a father of two children, presented at the department of urology with sudden onset of low- to intermediate-grade, left testicular pain. There was no history of trauma, urethral discharge, or dysuria. There was no clinical history of infertility, gynecomastia, or any endocrine changes. There was no significant familial history.

On clinical examination, there was tenderness of the left testis. There was no testicular swelling or mass palpated. Ultrasonography of the testis showed a normal size testis with a solitary 9 × 8-mm hypervascular hypoechoic mass (Figure 1, arrow). The patient underwent a radical orchiectomy.

Gross examination of the specimen showed 2 separate well-circumscribed, pale-yellow nodules measuring 0.9 × 0.7 × 0.7 cm and 0.6 × 0.6 × 0.6 cm (Figure 2, large and small arrows), respectively. The 2 nodules were deeply embedded in the testicular parenchyma, and were 2 cm apart from each other. The histology of the tumor with hematoxylin-eosin stain revealed well-circumscribed, nonencapsulated nodules. The nodules consisted of diffuse cellular stroma with numerous large round, polygonal, and spindle-shaped cells with less than 5 mitotic figures per high-power field (Figure 3, hematoxylin-eosin, original magnification ×20). The neoplastic cells contain abundant, finely granular, eosinophilic cytoplasm and central round nuclei with prominent nucleoli and rare eccentrically located binucleoli. Several neoplastic cells are distended by fine, fat vacuoles. Giant lobulated nuclei and rare nuclear grooves are present (Figure 4, a, hematoxylin-eosin, original magnification ×60). There were no infiltrative margins or lymphatic or blood vessel invasion. Intracytoplasmic crystalloids are identified (Figure 4, a, arrow). Immunohistochemical studies show positive vimentin stain, positive inhibin stain (Figure 4, b, inhibin immunoperoxidase, original magnification ×20), and negative cytokeratin, synatophysin, chromogranin, and S100 protein immunostain.

What is your diagnosis?

The incidence of Leydig cell tumors (LCTs) of the testis currently account for 3.0% of testicular tumors.1 It is the most common sex cord–stromal tumor and approximately 10% of tumors that present in adults are malignant.2,3 Clinical presentation is usually a palpable testicular mass and about 15% present with gynecomastia. Some cases of LCT are discovered on work-up for infertility.2,3 Leydig cell tumor can develop in both children and adults. Most tumors occur between the ages of 5 and 9 years and 20 and 50 years. Children usually present with isosexual pseudoprecosity and cryptorchidism. Leydig cell tumors may also be silent, unassociated with endocrine changes. Rarely, LCT will produce estrogen, leading to feminization.4 

Leydig cell tumor has been described by Kim et al3 to consist of 3 types of cells. Type 1 cells have a polygonal shape and are medium to large. They have granular eosinophilic cytoplasm, indistinct cell borders, and round regular to oval nuclei with sharply defined nuclear membranes. Type 2 cells are large, with abundant finely or coarsely granular cytoplasm, distinct cell borders, and small nuclei. Type 3 cells are small, with scant cytoplasm and round hyperchromatic nuclei. These cells may have densely eosinophilic cytoplasm and eccentric nuclei. However, our case consists of focal areas of spindle cells in addition to the 3 types of cells described above (Figure 3). Spindle cell morphology in LCT has been previously described.5 The presence of spindle cells seems to suggest that the LCT is of mesenchymal origin and positive staining to vimentin and negative staining to cytokeratin support the possibility that it arises from fibroblasts. The diagnostic Reinke crystalloids, large intracytoplasmic inclusions, were identified as light-pink rectangular inclusions by light microscopy (Figure 4, a). The presence of Reinke crystalloids has also been reported in perivascular fibroblasts of normal human adrenal gland, virus-infected or chemically treated cells, and sexual antebranchial organ of the prosimian primate (Lemur latta).6 Leydig cell tumors show variable staining with epithelial membrane antigen and desmin and are usually positive with antibodies to chromogranin and synaphytosin.7,8 Leydig cells produce inhibin and immunostain for inhibin has proven to become sensitive and specific for LCT as well as other sex cord–stromal tumors.9,10 

This lesion typically evokes a broad clinical differential diagnosis that includes testicular tumor of the adrenal genital syndrome. Grossly, adrenal genital syndrome presents with a single or multiple nodules, usually is bilateral with dark-brown cut surface, and histologically exhibits diffuse proliferation of large cells with abundant eosinophilic cytoplasm. Crystals of Reinke have not been identified within the cells of the testicular tumors of the adrenal genital syndrome but are found in 35% to 40% of LCTs. Another mimic of LCT is adrenal cortical rest; it is usually an incidental finding, found in the spermatic cord, epididymis, or mediastinum testis or in hydrocele sac. It usually presents in infants younger than 1 year old. The nodule ranges from 0.5 to 7 mm in diameter. Microscopically, they contain zones of vacuolated cells mimicking the histologic appearance of adrenal cortical cells but no medullary component is present.

The distinction between benign LCT and Leydig cell hyperplasia is difficult. Clinical history of the use of pharmacologic doses of gonadotrophic hormones and diseases with enhanced gonadotrophic hormone secretion, such as the various forms of gonadal dysgenesis (ie, Klinefelter syndrome, cryptorchism, gonadotrophic hormone–producing extrapituitary neoplasm), favor Leydig cell hyperplasia. It is also associated with functional impairment of the pituitary-testicular axis, liver cirrhosis, renal insufficiency, and malnutrition. Histologic findings have not provided specific distinguishing features between LCT and Leydig cell hyperplasia.

Gross findings of tumor size greater than 5 cm, necrosis and capsular involvement, and histologic findings of mitoses (more than 5 mitoses per 10 high-power fields), pleomorphism, cytologic atypia, coagulative tumor necrosis, lymphovascular invasion, and extension beyond the testis suggest malignant LCT.

In conclusion, LCT should be considered in the differential diagnosis of multinodular testicular lesion. The presence of spindle cell morphology may be observed. Although crystalloids of Reinke are a helpful diagnostic feature, they are not always present.

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Author notes

Corresponding author: Bamidele A. Adeagbo, MD, Department of Pathology, Monmouth Medical Center, 300 Second Ave, Long Branch, NJ 07740 ([email protected])