Leydig Cell Cancer

Etiology

Leydig cell tumors derive from Leydig cells, which are histologically packed between the seminiferous tubules of the testis and are physiologically responsible for testosterone secretion in response to luteinizing hormone.

Epidemiology

As a rare subtype of a rare tumor, Leydig cell tumors had traditionally been considered a very infrequent diagnosis, comprising only 1% to 3% of total testicular tumors removed each year.[6][7][8]

Interestingly, more contemporary data sets have questioned the rarity of Leydig cell tumors and have found them to be a potentially more common entity with estimates of the tumor incidence being anywhere from 14% to 22% of all surgically removed testicular cancer.[9] Potential reasons for this include the increasing use of improved ultrasound technology, leading to increased detection of small nodules that have not previously detected historical series.[9]

Histopathology

The mass usually reveals a well-circumscribed lesion in the testis. The cut surface of the mass shows a distinct golden brown or homogeneous yellow to light brown appearance. Microscopically, the tumor cells are large to polygonal with a round to oval nucleus and deeply acidophilic with granular cytoplasm. The cytoplasm also shows rod-shaped crystals referred to as "crystalloids of Reinke," which appear in 35% of tumors, and lipofuscin pigment in a smaller percent (10% to 15%).

History and Physical

Like other tumors of the testicle, painless swelling of a testicle is the single most common presentation of Leydig cell tumors.[10] Painless testicular swelling is the clinical presentation in about 50% of patients eventually diagnosed with testicular cancer.[11] A complete physical exam should include palpation of both the affected and contralateral testicle, making an important note of relative size and firmness as well as any distinct intrinsic or extrinsic testicular masses. Hydroceles also present as painless testicular swelling, but it is critical to keep in mind that this benign pathology may accompany a testicular tumor and could reduce the ability to identify a mass on physical exam.

Unique to Leydig cell tumors, however, are patients presenting with conspicuous clinical manifestations owing to the tumor’s propensity to secrete androgens or (less commonly) estrogen, directly or by peripheral conversion of testosterone.[5]

In prepubertal patients, this can present as precocious puberty, including early development of pubic hair as well as penile and musculoskeletal growth beyond that expected for the child’s age.

Interestingly, the physiologic effects of the elevated levels of circulating androgens in postpubertal men are usually clinically unnoticeable. Therefore, the most common hormone-related presentation of a man with a Leydig cell tumor is gynecomastia.[4] Other literature reported presentations to include breast tenderness, reduced libido, erectile dysfunction, azoospermia, primary infertility, or even Cushing syndrome.[12][13][14][15][16][17]

Evaluation

Due to the ubiquity and relative inexpensiveness of ultrasonography, any patient presenting with testicular swelling, hydrocele, or scrotal signs or symptoms of unclear etiology should receive a scrotal ultrasound. Unexplained infertility, precocious puberty, or gynecomastia should also prompt scrotal ultrasonography as well as elevated serum androgens or estrogens on labwork without an identifiable source.

If a Leydig cell tumor is present, it will be identified on scrotal ultrasound as an intratesticular mass and sonographically indistinguishable from a more commonly malignant germ cell tumor. An intratesticular mass should be considered cancer unless proven otherwise. When malignancy is likely, tumor markers should be drawn, including alpha-fetoprotein (AFP), quantitative beta-human chorionic gonadotropin (beta-HCG), and lactate dehydrogenase (LDH). At this point, staging and further work-up may be necessary after a radical inguinal orchiectomy.

Treatment / Management

After drawing tumor markers, the treatment of an intratesticular mass is a radical inguinal orchiectomy. Rarely is there a role for biopsy before orchiectomy unless exceptional circumstances exist, such as a solitary testis with mass. Prior to orchiectomy, patients should receive counsel on sperm banking. Radical orchiectomy should take place through an inguinal incision to avoid leaving the inguinal portion of the spermatic cord or altering the lymphatic drainage in the setting of a potentially malignant tumor. The clinician should consider an inguinal biopsy of the contralateral testicle if scrotal ultrasound demonstrates a suspicious mass or marked atrophy or if there exists a clinical history of cryptorchidism on that side.

Some authors have proposed Leydig cell tumors to be an ideal testicular tumor for testis-sparing surgery.[10] In these cases, preoperative tumor markers should all be within the normal range, a suspicion of a Leydig cell tumor should be clinically evident (gynecomastia, elevated testosterone or estrogen, infertility, etc.), the tumor should be less than 2.5 cm in size and frozen section should be obtained after spermatic cord clamping confirming a Leydig cell tumor. With these parameters, the authors have reported no relapse in 29 patients who underwent testis-sparing surgery and received a pathologic diagnosis of Leydig cell tumor.[10] Nevertheless, the rarity of Leydig cell tumors and the similar clinical presentation and ultrasound appearance to germ cell tumors mean that most patients eventually diagnosed with Leydig cell tumors undergo initial inguinal radical orchiectomy.

While the majority of Leydig cell tumors are benign and orchiectomy curative, post-orchiectomy surveillance is still a recommendation. However, primarily because of the limited number of cases, there exist no widely accepted protocols for follow-up.[18] Patients require monitoring at regular intervals for at least the first two years after diagnosis; most patients with Leydig cell tumors that do metastasize, do so within the first two years.[19] These appointments should include a physical exam, hormonal profile (luteinizing hormone [LH], follicle-stimulating hormone [FSH], testosterone, estrogen, and estradiol), germ cell tumor markers (beta-HCG, AFP, LDH) and cross-sectional imaging of the chest, abdomen and pelvis every 6 months for the first 2 years.[19](B3)

Malignant behavior of Leydig cell tumors is exhibited by metastasis to the retroperitoneal lymph nodes, liver, lungs, and bone.[4] If metastatic disease does occur, it responds poorly to chemotherapy or radiation, leaving surgical resection (retroperitoneal lymph node dissection or RPLND) as the only treatment capable of rendering patients disease-free.[18](B3)

Differential Diagnosis

Several differential diagnoses may be compiled depending on where in the clinical presentation or work-up a provider finds themself.

If a patient is presenting with gynecomastia:

• Drug side effect (ACE inhibitor, marijuana, spironolactone, etc…)
• Obesity
• Hyperthyroidism
• Liver disease
• Klinefelter syndrome
• Adrenal tumor

If a patient is presenting with hypogonadism:

• Primary hypogonadism (Klinefelter syndrome, testicular trauma/radiation/infection)
• Secondary hypogonadism (prolactin-secreting pituitary tumor, Kallman syndrome, hypogonadotropic hypogonadism)

Upon identifying an intratesticular mass via scrotal ultrasound, the differential diagnosis includes:

• Germ cell tumor (seminoma, teratoma, yolk sac tumor, embryonal carcinoma, choriocarcinoma)
• Non-germ cell tumor (Sertoli cell tumor, granulosa cell tumor, gonadoblastoma)
• Intratesticular hematoma

Prognosis

Orchiectomy alone is curative in patients with benign Leydig cell tumors.[20] The cancer-specific mortality for Leydig cell tumors is 2%, with an overall 5-year survival of greater than 90% after orchiectomy.[21][22] Malignant Leydig cell tumors are variable with the survival of patients with metastases ranging from 2 months to 17 years with a median of 2 years.[5] Interestingly, in those who present initially with hypogonadism, Leydig cell dysfunction may continue even after the removal of the tumor and 40% of men may require testosterone replacement therapy postoperatively.[23]

Complications

Complications from the disease itself arise mostly from delays in diagnosis and treatment; this may manifest itself as any or all of the symptoms described in detail above, including gynecomastia, infertility, hypogonadism, or erectile dysfunction. Delayed treatment of malignant Leydig cell tumors may result in metastasis and death.

Unfortunately, delay in the diagnosis of testicular cancer is a well-known entity with a mean delay to diagnosis cited as 26 weeks.[11] Patient-mediated delays are mainly due to ignorance, embarrassment, fear of cancer, or fear of emasculation.[24] Physician-mediated delay is most commonly due to the misdiagnosis of a testis tumor as an infection.[11]