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.

View Image

Leydig cell tumors.

Signs and symptoms

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:

Imaging studies

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 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.[3]

See Treatment for more detail.


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.[4]


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.



In the United States, 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.


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.


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.

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.

Imaging Studies

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.[5]

View Image

Leydig cell tumors.

Immunohistochemical markers such as alpha-inhibin,[6] calretinin,[7] and melan-A have also been shown to be valuable in the identification of Leydig cell and other sex cord-stromal testicular tumors.

Medical Care

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

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 .[4] 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 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.[10]

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, a retroperitoneal lymph node dissection 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.[11]

Further Outpatient Care

Observation is sufficient in patients in whom a benign Leydig cell tumor is treated 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.

Late onset of metastasis, up to 8 years after orchiectomy, has been reported. This supports the recommendation of long-term tumor surveillance, continuing for 10-15 years after surgery.


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.


Edmund S Sabanegh Jr, MD, Chairman, Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation

Disclosure: Nothing to disclose.


Anil A Thomas, MD, Urologist, Department of Urology, Sunnybrook Medical Office,Kaiser Permanente

Disclosure: Nothing to disclose.

Specialty Editors

Erik T Goluboff, MD, Professor, Department of Urology, College of Physicians and Surgeons, Columbia University College of Physicians and Surgeons; Director of Urology, Allen Pavilion, New York Presbyterian Hospital

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Associate Chair for Urologic Surgical Services, Director, Division of Endourology and Stone Disease, Department of Urology, University of Michigan Medical School

Disclosure: Nothing to disclose.

Chief Editor

Edward David Kim, MD, FACS, Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center

Disclosure: Lilly Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Actavis Honoraria Speaking and teaching; Auxilium Honoraria Speaking and teaching

Additional Contributors

Scott Rutchik, MD Assistant Professor, Department of Surgery, Division of Urology, University of Connecticut School of Medicine

Scott Rutchik, MD is a member of the following medical societies: American Urological Association

Disclosure: Nothing to disclose.

Dan Theodorescu, MD, PhD Paul A Bunn Professor of Cancer Research, Professor of Surgery and Pharmacology, Director, University of Colorado Comprehensive Cancer Center

Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology

Disclosure: Key Genomics Ownership interest Co-Founder-50% Stock Ownership; KromaTiD, Inc Stock Options Board membership


  1. Leonhartsberger N, Ramoner R, Aigner F, Stoehr B, Pichler R, Zangerl F, et al. Increased incidence of Leydig cell tumours of the testis in the era of improved imaging techniques. BJU Int. Nov 2011;108(10):1603-7. [View Abstract]
  2. Lock G, Schmidt C, Helmich F, Stolle E, Dieckmann KP. Early experience with contrast-enhanced ultrasound in the diagnosis of testicular masses: a feasibility study. Urology. May 2011;77(5):1049-53. [View Abstract]
  3. Bozzini G, Picozzi S, Gadda F, Colombo R, Decobelli O, Palou J, et al. Long-Term Follow-Up Using Testicle-Sparing Surgery for Leydig Cell Tumor. Clin Genitourin Cancer. Jan 10 2013;[View Abstract]
  4. Henderson CG, Ahmed AA, Sesterhenn I, Belman AB, Rushton HG. Enucleation for prepubertal leydig cell tumor. J Urol. Aug 2006;176(2):703-5. [View Abstract]
  5. Stoop H, Kirkels W, Dohle GR, Gillis AJ, den Bakker MA, Biermann K, et al. Diagnosis of testicular carcinoma in situ '(intratubular and microinvasive)' seminoma and embryonal carcinoma using direct enzymatic alkaline phosphatase reactivity on frozen histological sections. Histopathology. Feb 2011;58(3):440-6. [View Abstract]
  6. Iczkowski KA, Bostwick DG, Roche PC, Cheville JC. Inhibin A is a sensitive and specific marker for testicular sex cord-stromal tumors. Mod Pathol. Aug 1998;11(8):774-9. [View Abstract]
  7. Augusto D, Leteurtre E, De La Taille A, Gosselin B, Leroy X. Calretinin: a valuable marker of normal and neoplastic Leydig cells of the testis. Appl Immunohistochem Mol Morphol. Jun 2002;10(2):159-62. [View Abstract]
  8. Basciani S, Brama M, Mariani S, De Luca G, Arizzi M, Vesci L, et al. Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity. Cancer Res. Mar 1 2005;65(5):1897-903. [View Abstract]
  9. Froehner M, Beuthien-Baumann B, Dittert DD, Schuler U, Wirth MP. Lack of efficacy of imatinib in a patient with metastatic Leydig cell tumor. Cancer Chemother Pharmacol. Nov 2006;58(5):716-8. [View Abstract]
  10. Bozzini G, Rubino B, Maruccia S, Marenghi C, Casellato S, Picozzi S, et al. Role of frozen section examination in the management of testicular nodules: a useful procedure to identify benign lesions. Urol J. Jul 8 2014;11(3):1687-91. [View Abstract]
  11. Ferretti L, Sargos P, Gross-Goupil M, Izard V, Wallerand H, Huyghe E, et al. Testicular-sparing surgery for bilateral or monorchide testicular tumours: a multicenter study of long-term oncological and functional results. BJU Int. Dec 2014;114(6):860-4. [View Abstract]
  12. Al-Agha OM, Axiotis CA. An in-depth look at Leydig cell tumor of the testis. Arch Pathol Lab Med. Feb 2007;131(2):311-7. [View Abstract]
  13. Bertram KA, Bratloff B, Hodges GF, Davidson H. Treatment of malignant Leydig cell tumor. Cancer. Nov 15 1991;68(10):2324-9. [View Abstract]
  14. Brunner HG, Otten BJ. Precocious puberty in boys. N Engl J Med. Dec 2 1999;341(23):1763-5. [View Abstract]
  15. Carmignani L, Colombo R, Gadda F, Galasso G, Lania A, Palou J, et al. Conservative surgical therapy for leydig cell tumor. J Urol. Aug 2007;178(2):507-11; discussion 511. [View Abstract]
  16. Cheville JC. Classification and pathology of testicular germ cell and sex cord-stromal tumors. Urol Clin North Am. Aug 1999;26(3):595-609. [View Abstract]
  17. Dilworth JP, Farrow GM, Oesterling JE. Non-germ cell tumors of testis. Urology. May 1991;37(5):399-417. [View Abstract]
  18. Grem JL, Robins HI, Wilson KS, Gilchrist K, Trump DL. Metastatic Leydig cell tumor of the testis. Report of three cases and review of the literature. Cancer. Nov 1 1986;58(9):2116-9. [View Abstract]
  19. Holm M, Rajpert-De Meyts E, Andersson AM, Skakkebaek NE. Leydig cell micronodules are a common finding in testicular biopsies from men with impaired spermatogenesis and are associated with decreased testosterone/LH ratio. J Pathol. Mar 2003;199(3):378-86. [View Abstract]
  20. Kaufman E, Akiya F, Foucar E, Grambort F, Cartwright KC. Viralization due to Leydig cell tumor diagnosis by magnetic resonance imaging. Case management report. Clin Pediatr (Phila). Jul 1990;29(7):414-7. [View Abstract]
  21. Kim I, Young RH, Scully RE. Leydig cell tumors of the testis. A clinicopathological analysis of 40 cases and review of the literature. Am J Surg Pathol. Mar 1985;9(3):177-92. [View Abstract]
  22. Konrad D, Schoenle EJ. Ten-year follow-up in a boy with Leydig cell tumor after selective surgery. Horm Res. 1999;51(2):96-100. [View Abstract]
  23. Maeda T, Itoh N, Kobayashi K, et al. Elevated serum estradiol suggesting recurrence of Leydig cell tumor nine years after radical orchiectomy. Int J Urol. Nov 2002;9(11):659-61. [View Abstract]
  24. Mineur P, De Cooman S, Hustin J, Verhoeven G, De Hertogh R. Feminizing testicular Leydig cell tumor: hormonal profile before and after unilateral orchidectomy. J Clin Endocrinol Metab. Apr 1987;64(4):686-91. [View Abstract]
  25. Ober WB, Sciagura C. Leydig, Sertoli, and Reinke: three anatomists who were on the ball. Pathol Annu. 1981;16 Pt 1:1-13. [View Abstract]
  26. Testis-sparing surgery for benign testicular tumors in children. J Urol. Jun 2001;165(6 Pt 2):2280-3. [View Abstract]

Leydig cell tumors.

Leydig cell tumors.

Leydig cell tumors.