Answer: Malignant Leydig cell tumor

Histology: The tumor consists of nodules of cells with varying degrees of eosinophilic cytoplasm and relatively bland nuclei. There are areas of necrosis, vascular invasion, and up to 12 mitoses per 10 HPF. The tumor appears invasive with extension into paratesticular adipose tissue. The tumor stained on the outside institution was positive for synaptophysin and Melan-A and was negative for chromogranin and calretinin.

Discussion: The tumor lacks the vascular pattern of a carcinoid tumor. Another subtle clue is that there are clusters of cells with clear vacuolated cytoplasm indicating lipid. As Leydig cell tumors are steroid secreting tumors, the finding of lipidized cells helps to support the diagnosis of a sex cord stromal tumor. If that was a consideration, then the best IHC stain would be keratin as carcinoid would be diffusely positive and Leydig cell tumors typically negative. A pitfall in this differential diagnosis is that Leydig cell tumors can be synaptophysin positive.

The distinction between benign and malignant Leydig cell tumors is based on a constellation of features. Cytologically, benign Leydig cell tumors have nuclei that are usually round with conspicuous nucleoli. Scattered larger cells may be seen, but lacks nuclear hyperchromasia seen in malignant tumors. Benign Leydig cell tumors lack necrosis or lymphovascular invasion and have no or low (<3 per 10 HPF) mitotic activity. They are usually less than 5 cm. If no worrisome histologic features, these tumor can be diagnosed as “benign Leydig cell tumor.” If only a few atypical features are present (i.e., larger size but otherwise benign), then diagnose “Leydig cell tumor of uncertain malignant potential.” If only one atypical feature present, add that a favorable prognosis is likely. Approximately 10% are malignant. Most malignant Leydig cell tumors have at least 4 of the following characteristics:
1) >5 cm;
2) nuclear hyperchromasia and pleomorphism,
3) increased mitoses,
4) vascular invasion,
5) widespread invasion into surrounding the testis, and
6) necrosis.

Leydig cell tumors occur in two incidence peaks in the first and third decades but may occur in older adults with a mean age of 40. Tumors are almost always unilateral They may be associated with isosexual precocity in children and gynecomastia in one-third of adult patients. In up to 10% of cases, they are associated with cryptorchidism.