Leydig Cell Tumors

Testicular tumors occur at a rate of 2 cases per 100,000 men and constitute 1% of all tumors in men. Leydig cell tumors (LCTs) account for 1 to 3% of testicular tumors (119). LCTs were first identified by Sacchi in 1895 (120). Although they are rare gonadal stromal tumors, LCTs may occur at any age and represent approx 40% of all non-germ cell testicular tumors (121). Most LCTs are unilateral; only 3% are bilateral (121).

LCTs are found at all ages from 2 to 90 yr, with a peak occurrence in the fifth decade of life. In boys, these tumors typically occur between the ages of 4 and 10 yr and account for approx 10% of cases of precocious puberty (122). They are uniformly benign hormonally active tumors that present with macrogenitosomia (a syndrome that is characterized by precocious enlargement of the genitals), including an enlarged phallus and/or prostate, and premature growth of pubic hair (120). Adult men with LCTs often present with a painless testicular mass, usually associated with gynecomastia, infertility, decreased libido, and other feminizing features. Gynecomastia is bilateral in 90% of the cases (123,124).

LCTs secrete both androgenically and estrogenically active steroids. Unlike normal Leydig cells, androgen secretion by the tumor is in independent of pituitary control. LCTs have an abnormally high aromatase activity and secrete E2 (125). The resulting elevated E2 and decreased, or low-normal T values cause gynecomastia and infertility (126). This alteration in the T/E2 ratio, together with suppressed LH secretion, may be useful for clinical diagnosis.

Macroscopically, the lesions are generally small, yellow to brown, well circumscribed, and rarely hemorrhagic or necrotic. Microscopically, they consist of uniformly polyhedral packed cells with round and slightly eccentric nuclei, and eosinophilic granular cytoplasm with lipoid vacuoles, lipofuscin granules, and occasionally, Reinke's crystals (127).

Most LCTs are benign, but approx 10% are malignant (128). Large size, extensive necrosis, gross or microscopic evidence of infiltration, invasion of blood vessels, and excessive mitotic activity are all features that suggest malignancy. However, the presence of metastases, most often to pelvic lymph nodes and bone, is the only reliable criterion of malignancy. The appearance of metastases may be delayed for as many as 9 yr (129).

Inguinal orchidectomy is the treatment of choice for benign tumors. Recent reports have cited testis-sparing enucleation as an alternative treatment for benign lesions in children, especially those with bilateral tumors (130,131). Testis-sparing surgery is also an option for children with the clinical and biochemical findings typical of LCTs and an ultrasonographically defined encapsulated intratesticular mass. In cases managed by enucleation, local relapse remains a possibility, even when specimen margins are free of tumor cells and uniformly benign (120). Malignant LCTs are radioresistant and chemoresistant and have a poor prognosis. The mean survival time after surgery for patients with malignant LCTs is approx 3 yr (127).

Leydig cell hyperplasia (LCH) shares the same clinical presentation as LCTs, including painful gynecomastia and decreased libido in adults, precocious puberty in children,

Leydig Cell Testosterone

Fig. 6. Benign and malignant Leydig cell tumors (LCTs). The upper left panel, (A) an example of Leydig cell hyperplasia (LCH), is seen with an increased number of Leydig cells and an intertubular growth pattern (original image magnification X 200). The lower left panel, (C) is a benign LCT with a loss of normal tubules and peripheral compression of adjacent seminiferous tubules (original image magnification X 100). In the right panel, (B) a malignant LCT is shown with significant nuclear atypia and an invasive border (original image magnification X 300). (Photos supplied by Drs. Cathy Naughton and Peter Humphrey of Washington University School of Medicine.)

Fig. 6. Benign and malignant Leydig cell tumors (LCTs). The upper left panel, (A) an example of Leydig cell hyperplasia (LCH), is seen with an increased number of Leydig cells and an intertubular growth pattern (original image magnification X 200). The lower left panel, (C) is a benign LCT with a loss of normal tubules and peripheral compression of adjacent seminiferous tubules (original image magnification X 100). In the right panel, (B) a malignant LCT is shown with significant nuclear atypia and an invasive border (original image magnification X 300). (Photos supplied by Drs. Cathy Naughton and Peter Humphrey of Washington University School of Medicine.)

and complaints of infertility or even palpable testicular masses. However, histological features help to distinguish LCH from normal Leydig cells and benign LCTs. Hyperplastic Leydig cells are arranged in diffuse, multifocal, small nodules and lack cytological atypia, frequent mitoses, necrosis, and vascular invasion. Hyperplastic Leydig cells usually infiltrate between seminiferous tubules, whereas benign LCTs form nodules that compress surrounding tubules. LCTs grow as nodules, efface normal testicular architecture, with loss of seminiferous tubules, and compress the adjacent tissue. Most LCH cases are multifocal and bilateral (132). Figure 6 shows the histological appearance of benign and malignant LCTs, as well as LCH.

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