A 56-year-old man without symptomatology presented for routine annual physical examination and was found to have a 1.5 cm. left testicular mass. The mass was confirmed by ultrasonography and an orchiectomy was performed. Images from the resultant specimen are shown below.
Within the testis parenchyma is a sharply demarcated mass composed of sheets of cells with abundant eosinophilic cytoplasm. There is no evidence of glandular differentiation, although some entrapped seminiferous tubules are noted within the lesion. The neoplastic cells have relatively unifrom nuclei with medium-sized nucleolil. Mitotic figures are rare and there is no evidence of necrosis.
What is your diagnosis?
This is a straightforward example of the most common sex-cord tumor in the testis, a Leydig cell tumor. When Leydig cell tumors present in pre-pubertal males they are typically associated with clinically obvious isosexual pseudoprecocity. It adults, however, signs of androgen excess are not typically obvious, with the exception that about 1/3rd of patients will develop gynecomastia.
The sheet-like growth pattern of polygonal cells seen in the current case is the most typical pattern, although the cells also may form ribbon, cords, and small nests in a more prominent fibrous stroma, or exhibit a clearly spindled morphology. Although Reinke crystals are often obvious in hyperplastic Leydig cells, in my experience they can be quite difficult or impossible to find in Leydig cell tumors. I could not find any convincing examples in the current case.
Although seldom required, immunohistochemical markers may be of value in recognizing Leydig cells. The tumors (and their normal conterparts) are strongly positive for inhibin-alpha, melan-A, calretinin, and vimentin. There may be patchy positivity for low molecular weight cytokeratins.
Leydig cell tumors may be confused with the eosinophilic histiocytes of malakoplakia, but the latter process is invariably associated with other forms of inflammation and has characteristic Michaelis-Gutmann bodies. If necessary, as for example in small biopsy specimens, immunohistochemistry will allow ready distinction. The neoplasm most likely to be confused with Leydig cell tumor is the large cell calcifying variant of the Sertoli cell tumor. The latter are more commonly mulifocal, may exhibit intratubular growth, have more prominent stroma and, as the name indicates, frequent calcifications. Immunohistochemical studies show considerable overlap with Leydig cell tumors. About a third of patients with large cell calcifying Sertoli cell tumors have Carney syndrome or Peutz-Jeghers syndrome.
Less than 10% of Leydig cell tumors have been said to behave in a malignant and in all likelihood that number is inflated due to over reporting of aggressive cases. As with all endocrine tumors predicting malignant behavior is notoriously difficult. Factors associated with malignancy have included increasing age, larger tumor size, infiltrating margins, necrosis, significant nuclear atypia, increased mitotic rate, atypical mitotic figures, aneuploidy, vascular invasion, and increased expression of p53. Gynecomastia has been associated with a decreased risk of malignant behavior and no malignant cases have been documented in prepubertal boys.