Leydig cell tumors are rare testicular tumors of the male gonadal interstitium that may be hormonally active and lead to feminizing or virilizing syndromes.
Clinical manifestations include the following:
Adults with androgen-secreting tumors are generally asymptomatic. Manifestations in adults with estrogen-secreting tumors include the following:
Leydig cell tumors may be an incidental finding of a testicular mass on scrotal ultrasonography performed for other conditions.
See Clinical Presentation for more detail.
Serum testosterone levels are usually elevated; however, serum estradiol levels may also be increased, especially when feminization is evident. Results of the following laboratory studies are normal in patients with pure Leydig cell tumors:
See Workup for more detail.
Radical orchiectomy was once the primary treatment for Leydig cell tumors, and it remains in use for malignant cases. However, testis-sparing surgery with enucleation of the mass is increasingly being reported for benign cases.
When diagnosed and treated early, testicle-sparing surgery has proved to be a feasible and safe choice and could be regarded as first-line therapy. In a study of 20 patients with Leydig cell tumors who were treated with conservative surgery, follow-up for a mean of 15 years found 100% disease-free survival, with no local recurrences or metastases. Patients ranged in age from 5 to 61 years. 
See Treatment for more detail.
Leydig cell tumors.
Leydig cell tumors are rare testicular tumors of the male gonadal interstitium. They are frequently hormonally active, leading to feminizing or virilizing syndromes.
Although uncommon, Leydig cell tumors comprise 1-3% of all testicular neoplasms. These tumors can be pure or can be mixed with other sex cord-stromal or germ cell tumors. Leydig cell tumors are usually benign, but malignant variants also occur.
Leydig cell tumors were once managed primarily with radical orchiectomy. However, the experience with conservative approaches has been growing, and enucleation has been used increasingly in both the adult and pediatric populations.
A German anatomist, Franz Leydig, first described Leydig cells in 1870. Leydig cells are located within the interstitium of the testis, between the seminiferous tubules, and produce testosterone in response to luteinizing hormone. Through their hormonal balance, these cells play an important role in the development of secondary male characteristics and spermatogenesis.
The etiology of Leydig cell tumors remains unknown. Unlike germ cell testicular tumors, Leydig cell neoplasms are not associated with cryptorchidism. It is thought that an endocrine role may contribute to the development of these tumors. For example, an excessive stimulation of Leydig cells with luteinizing hormone due to a disorder of the hypothalamic-pituitary axis may induce their oncogenesis. Animal models have also demonstrated Leydig cell tumorigenesis following long-term estrogen administration.
Although these tumors usually secrete testosterone, the production of estrogen, progesterone, and corticosteroids has also been described. Estrogen excess and feminizing syndromes may occur from the peripheral aromatization of testosterone or from the direct production of estradiol by the tumor itself.
Leydig cell testicular neoplasms are the most common sex cord-stromal tumors and comprise 1-3% of all testicular neoplasms. The tumors are most common in prepubertal boys aged 5-10 years and in adults aged 30-60 years. Approximately 10% of Leydig cell tumors are bilateral and 10% are malignant. However, Leydig cell tumors are always benign in children, as malignant variants have been reported only after puberty.
Leydig cell tumors are usually benign, but approximately 10% are malignant. The malignant variants occur only in adults.
Leydig cell tumors are most commonly found in males. Nonetheless, these tumors have been well-described in the ovarian stroma of females, who may present with signs and symptoms of virilization. Ovarian Leydig cell tumors are usually malignant, unlike Leydig cell tumors found in males.
Leydig cell tumors may occur in prepubertal boys but are most common in men aged 30-60 years.
Macroscopically, Leydig cell tumors present as well-circumscribed, yellow to brown masses within the testicle.
Microscopically, these tumors are composed of large, closely packed cells with eosinophilic cytoplasm, bland nuclei, and small nucleoli (see image below). Reinke crystals are pale-staining, cylindrical, rectangular, or rhomboid inclusions that are pathognomonic for Leydig cell tumors and are found in up to 30% of patients with such tumors. Microscopic features such as necrosis, marked pleomorphism, lymphovascular invasion, increased mitotic activity, and DNA aneuploidy are more consistent with a malignant variant.
Leydig cell tumors.
Immunohistochemical markers such as alpha-inhibin, calretinin, and melan-A have also been shown to be valuable in the identification of Leydig cell and other sex cord-stromal testicular tumors.