Leydig Cell Tumor

LCTs are responsible for 10% of all cases of early pseudopuberty in children. The presentation of the precocious pseudopuberty symptoms occurs in the first 5 years of life (isosexual pseudoprecocity) (Kim et al. 1985). LCTs may be seen at any age in the adult life with asymptomatic testicular mass, but they may present with gynaecomastia and with the Cushing syndrome. Increased serum levels of testosterone and androstenedione are commonly seen. Bilaterality is an unusual presentation, found in 3% of cases. A minority of tumors occur with metastases in the setting of rare cases of malignant LCT (Suardi et al. 2009). In a few cases, LCT was found to be associated with Klinefelter syndrome (Sogge et al. 1979).


Clinical Features
LCTs are responsible for 10% of all cases of early pseudopuberty in children. The presentation of the precocious pseudopuberty symptoms occurs in the first 5 years of life (isosexual pseudoprecocity) (Kim et al. 1985). LCTs may be seen at any age in the adult life with asymptomatic testicular mass, but they may present with gynaecomastia and with the Cushing syndrome. Increased serum levels of testosterone and androstenedione are commonly seen. Bilaterality is an unusual presentation, found in 3% of cases. A minority of tumors occur with metastases in the setting of rare cases of malignant LCT (Suardi et al. 2009). In a few cases, LCT was found to be associated with Klinefelter syndrome (Sogge et al. 1979).

Macroscopy
LCTs are usually small, solid, well-circumscribed masses with maximum diameter ranging from 0.5 to 5 cm. They are yellow, homogeneous, and soft and may present grossly hemorrage, necrosis (in about 25% of them), hyalinization, and calcification ( Fig. 1). Extratesticular spread occurs in 10% of cases.

Microscopy
The tumor presents medium to large polygonal cells with abundant eosinophylic cytoplasm and a single round nucleolus (Fig. 2). The cytoplasm may present lipid vacuoles and LCT with adipose metaplasia is a variant. Brownish pigmentation and Reinke crystals are characteristic but found in only one third of cases. A variety of unusual appearances are reported, including microcystic changes, myxoid degeneration, ossification, ribbon-like, spindle cell differentiation, insular and trabecular pattern, lipid-rich and adrenocortical-like cells, and sarcomatoid change (Ulbright et al. 2002). Rarely the occurrence of a microcystic appearance of LCT has been reported. Adipose cells can occur as individual, scattered cells that are associated with vacuolated, neoplastic cells, retaining the nuclear features of Leydig cells. The most important feature of malignant LCT is its size, which on average is about 7 cm versus <3 cm in benign LCT. Mitoses are obviously also more frequent in malignant than benign tumors (13.9/HPF vs. 1.9/HPF). Further microscopic indicators of malignancy are a spindle cell shape, nuclear atypia, and polymorphism, necrosis (Fig. 3), vascular invasion, and invasion of surrounding tissue (Fig. 4). Number of proliferating cells is also greater in malignant LCT (Cheville et al. 1998). To predict a malignant course at least two of these features should be present.

Immunohistochemistry
Over 90% of LCTs are positive for calretinin, a-inhibin, melan-A, and steroidogenic factor 1 (SF1). But they stain with b-catenin, CD 99, FOXL2, and synaptophysin and in 20% of cases with CK and S100. It has been reported negativity with WT1.

Large Cell Calcifying Sertoli Cell Tumor (LCCSCT)
The presence of psammomatous calcifications are common features of both LCT and LCCSCT: in the series of Ulbright (Ulbright et al. 2002) 2 LCTs with calcifications had ossification with typical areas of LCT in other areas. The differences among the two entities are highlightened by immunohistochemical positivity for melan A and negativity for WT1 in LCT.

Yolk Sac Tumor
Complex collections of Leydig cells with prominent vacuoles could resemble a yolk sac tumor (YST), and sometimes the coalescence of these vacuoles produces large cystic spaces. This reticular pattern could be misinterpreted, but the absence of other types of germ cell components, such as the absence of GCNIS and the rarity of pure YST in adults together with immunohistochemical findings (positivity for Glypican 3 and alfafetoprotein in YST) support the diagnosis of YST.
Congenital Adrenal Hyperplasia (CAH) Testicular tumors of the adrenogenital syndrome resemble histologically LCTs, which poses a difficulty to differential diagnoses. CAH is an autosomal recessive disorder of the adrenal steroid Leydig Cell Tumor, Fig. 1 Leydig cell tumor. A yellowish, homogeneous nodule with regular contour Leydig Cell Tumor, Fig. 2 Leydig cell tumor showing medium to large polygonal cells with abundant eosinophylic cytoplasm and round centrally located nucleolus synthesis caused by defects in the enzymes involved in the production of cortisol, aldosterone, and sex hormones. CAH occurs with almost always bilateral tumors and typically shows bands of fibrosis, more voluminous cytoplasm, prominent lipofuscin, and greater tendency for adipose metaplasia. Generally testicular adrenal rest tumors lack nuclear reactivity for androgen receptor (Wang et al. 2011).