Leydig Cell Tumors

Practice Essentials

Leydig cell tumors (see the image below) are rare testicular tumors of the male gonadal interstitium that may be hormonally active and lead to feminizing or virilizing syndromes. Leydig cell tumors comprise 1-3% of adult testicular neoplasms and 3% of testicular tumors in infants and children. 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 appproximately 10% are malignant.^[1]

As with germ cell tumors, the route of spread is hematogenous and lymphatic to the retroperitoneal lymph nodes. Unlike germ cell tumors, however, Leydig cell tumors show relative lack of sensitivity to radiotherapy and chemotherapy agents.^[2]

View Image

Leydig cell tumor.

Signs and symptoms

Clinical manifestations include the following:

• A nontender palpable testicular mass or nodule
• Precocious puberty in prepubertal boys with androgen-secreting tumors
• Feminizing symptoms in boys with estrogen-secreting tumors

Adults with androgen-secreting tumors are generally asymptomatic. Manifestations in adults with estrogen-secreting tumors include the following:

• Loss of libido
• Erectile dysfunction
• Infertility
• Gynecomastia
• Feminine hair distribution
• Gonadogenital atrophy

Leydig cell tumors may be an incidental finding of a testicular mass on scrotal ultrasonography performed for other conditions.

See Presentation for more detail.

Diagnosis

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:

• Serum alpha-fetoprotein
• Beta human chorionic gonadotropin
• Lactate dehydrogenase
• Urine ketosteroids
• Plasma cortisol
• Adrenocorticotropic hormone stimulation test
• Dexamethasone suppression test

Imaging studies

• Scrotal ultrasonography: Confirms the diagnosis, especially when physical examination findings are equivocal^{[3, 4]}
• Magnetic resonance imaging: Can reveal small nonpalpable Leydig cell tumors that are not visible on ultrasound.
• CT scanning of the abdomen and chest radiography: Indicated if malignancy is suspected

See Workup for more detail.

Management

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, in both the adult and pediatric populations.^{[5, 6, 7]}

When Leydig cell tumors are 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.^[8] Frozen section examination during surgery is key.

See Treatment for more detail.

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Pathophysiology

A German anatomist, Franz Leydig, first described Leydig cells in 1870.^[9] 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.^[10]

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.

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Epidemiology

Frequency

In the United States, Leydig cell testicular neoplasms are the most common sex cord–stromal tumors and comprise 1-3% of all testicular neoplasms.^[10] However, a study in Austria demonstrated of all patients that are undergoing surgery for testicular tumor between 1999 and 2008, Leydig cell tumors accounted for 14.7% of all testicular tumors removed.^[11] The tumors are most common in prepubertal boys aged 5-10 years and in adults aged 30-60 years. Approximately 3% of Leydig cell tumors are bilateral and 10% are malignant.^[1] However, Leydig cell tumors are always benign in children, as malignant variants have been reported only after puberty.

Sex-, race-, and age-related demographics

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.

African-American race is more common in Sertoli and Leydig cell tumors (23 and 24% respectively), than germ cell tumors (3%).^[10]

The incidence of Leydig cell tumors peaks in children 3 to 9 years and in adults 30 to 60 years.^[12]

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Prognosis

Patients with benign Leydig cell tumors have an excellent prognosis. In contrast, the mean survival in patients with a malignant variant is 2-3 years. Advanced patient age is associated with a poorer prognosis. Pathologic risk factors for occult metastatic disease include the following^[13] :

• Tumor diameter >5 cm
• Positive margins or rete testis invasion
• Lymphovascular invasion
• Cellular atypia
• Necrosis
• Increased mitotic rate (≥5 mitoses per high-power field [HPF])

A systematic review of pathologic risk factors found that the risk of occult metastatic disease (OMD) increased with each additional risk factor. Five-year OMD-free survival was 98.1% for patients with fewer than two risk factors vs 44.9% for those with two or more risk factors (P < 0.001).^[14]

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Patient Education

Patients should be taught to examine their remaining testicle monthly.

For patient education information, see Testicular Cancer and Testicle Self-Exam.

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History

In most cases, patients present with an incidental finding of a testicular mass on scrotal ultrasonography during evaluation of hydroceles or varicoceles or during workup of other conditions (eg, infertility). A nontender palpable testicular mass or nodule may be noted.

Prepubertal boys with androgen-secreting tumors may present with precocious puberty; features may include prominent external genitalia, pubic hair growth, accelerated skeletal and muscle development, and mature masculine voice. Boys with estrogen-secreting tumors may present with feminizing symptoms such as gynecomastia, breast tenderness, and gonadogenital underdevelopment.

Adults with androgen-secreting tumors are generally asymptomatic. In adults with estrogen-secreting tumors, symptoms such as loss of libido, erectile dysfunction, and infertility have been reported.

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Physical Examination

An intratesticular mass may be palpated in patients with Leydig cell tumors. In children, early pubertal and musculoskeletal development may be appreciated. In adults, gynecomastia, feminine hair distribution, and/or gonadogenital atrophy may be observed.

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Laboratory Studies

Laboratory study results in patients with Leydig cell tumors are usually nonspecific. Levels of testicular tumor markers such as serum alpha-fetoprotein (AFP), beta human chorionic gonadotropin (beta-HCG), and lactate dehydrogenase (LDH) should be within the reference range in pure Leydig cell tumors.

The steroid secretion of Leydig cell tumors varies. Serum testosterone levels are usually elevated; however, serum estradiol levels may also be increased, especially when feminization is evident.

Urine and serum endocrinological tests such as urine ketosteroids, plasma cortisol, or the dexamethasone suppression test may help differentiate Leydig cell tumors from other adrenocortical disorders. Leydig cell tumor endocrine function is independent of the hypothalamus-pituitary-gonadal hormonal axis and should not demonstrate a response to adrenocorticotropic hormone stimulation or dexamethasone suppression.

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Imaging Studies

Scrotal ultrasonography is typically performed to confirm the diagnosis, especially in patients in whom the physical examination findings are equivocal.^{[3, 4]} On color Doppler ultrasonography (CDUS), a typical Leydig cell tumor appears as a round, infracentimeter hyperechoic mass with a clear delineation from the surroundings; lobulated margins are seen in up to 50% of cases.^[15]

MRI can reveal small nonpalpable Leydig cell tumors not otherwise visible on sonograms. On T1-weighed imaging, the tumors are not visible before administration of contrast agents, since they have similar signal intensity as normal testicular parenchyma. They appear with marked enhancement after intravenous injection of contrast material. Other testicular tumors do not show a similar pattern of enhancement.^[16]

CT scanning of the abdomen and chest radiography are indicated if malignancy is suspected.

Contrast-enhanced ultrasound (CEUS) is a possible future imaging technique for Leydig cell tumors. CEUS demonstrates hypervascularization in these cases. In CEUS, Leydig cell tumor is suggested by findings of a short filling time or by a circumferential vessel with rapid centripetal filling.^[17]

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Histologic Findings

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.^[18]

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Leydig cell tumor.

Immunohistochemical markers such as alpha-inhibin,^[19] calretinin,^[11] and melan-A have also been shown to be valuable in the identification of Leydig cell and other sex cord–stromal testicular tumors.

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Medical Care

Medical therapy plays little role in the management of Leydig cell tumor, as follows:

• Chemotherapy with the bleomycin-etoposide-platinum regimen used for germ cell malignancies has limited efficacy in managing malignant Leydig cell tumors^[20]
• The tyrosine kinase inhibitor imatinib has shown some chemotherapeutic activity in animal models,^{[10, 21]}
• No known role exists for radiation therapy in malignant Leydig cell tumors^[22]

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Surgical Care

Leydig cell tumors have been primarily managed with surgical extirpation using radical inguinal orchiectomy. Inguinal orchiectomy should be performed with early control of the spermatic cord and without violation of the scrotal skin.

However, testis-sparing surgery with enucleation of the mass, to maintain fertility, has been increasingly reported in children and younger adults.^{[23, 24]}  Typically, this testis-sparing approach is performed through an inguinal or scrotal incision, and intraoperative ultrasound guidance has been used to locate nonpalpable tumors. 

The rationale for testis-sparing surgery is that testicular sex cord stromal tumors differ from germ cell tumors as they are not multifocal, are not associated with precancerous lesions (ie, testicular intratubular neoplasia) that could progress to invasive cancer, and have shown a low rate of local recurrence. These aspects seem to be appropriate premises to justify testis-sparing surgery in the case of testicular sex cord stromal tumors.^{[8, 25]}

In testisi-sparing surgery, the mass is enucleated with a small surrounding edge of testicular parenchyma and immediately sent for frozen section analysis. Frozen section examination successfully discriminated between benign and malignant neoplastic lesions in a study of 86 patients with testicular nodules, including five patients with Leydig cell tumors and six patients with Leydig cell hyperplasia.^[26]

Additional frozen sections of the tumor bed can be assessed and/or a radical inguinal orchiectomy can be performed if malignancy is subsequently suspected. If the tumor appears malignant, retroperitoneal lymph node dissection (RPLND) is also recommended.

In a retrospective study of 25 patients with testicular tumors who underwent testis-sparing surgery, including four patients with Leydig tumors, overall survival was 100% at a mean follow-up of 42.7 months. Three patients experienced local recurrence. Frozen-section examinations were performed in tumors from 14 patients; results matched the final pathological analysis in 11. None of the patient with a preserved testicle needed androgen therapy.^[27]

Retroperitoneal lymph node dissection

Limited data are available regarding the role of RPLND for Leydig cell tumors. Moshara et al reported on 4 patients with clinical stage II who underwent RPLND; all of them had documented disease, but 1 patient remained alive and disease free.^[28]   Silberstein et al reported on 2 patients with clinical stage IIa who underwent RPLND; disease was confirmed in one and both remained alive and disease free.^[29]

Nicolai et al described successful treatment with RPLND alone in four of five patients with retroperitoneal metastasis, which had been identified at presentation in three patients and at follow-up in one patient who had a delayed intervention for a small retroperitoneal recurrence.  Three of the five patients undergoing immediate RPLND had nodal metastasis; all three, and another node-negative patient remained alive and disease free, whereas one patient with negative nodes developed distant metastasis and ultimately died of disease.  All three patients with at least three risk factors actually had metastasis.^[27]

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Long-Term Monitoring

Observation is sufficient in patients with a benign Leydig cell tumortreated with radical inguinal orchiectomy.

Patients with malignant tumors require regular follow-up imaging, including CT scanning of the chest and abdomen. Metastases most frequently involve the retroperitoneal lymph nodes. Other reported metastatic sites include the liver (45%), lungs (40%), and bone (25%).

The ideal frequency of subsequent abdominal CT scanning and chest imaging is poorly defined. However, a reasonable follow-up protocol includes a chest imaging study and abdominal CT scanning every 4 months during the first year, followed by similar imaging at 6-month intervals during the second year and yearly examinations thereafter.^[8]

Late onset of metastasis have been reported as long as 8 and 17 years after orchiectomy.^[12] This supports the recommendation of long-term tumor surveillance, continuing for 10-15 years after surgery.

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