Leydig Cell Tumors

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Practice Essentials

Leydig cell tumors are rare testicular tumors of the male gonadal interstitium that may be hormonally active and lead to feminizing or virilizing syndromes.

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.

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:

Imaging studies

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.

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. [3]

See Treatment for more detail.

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Leydig cell tumors.

Background

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]

Pathophysiology

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.

Epidemiology

Frequency

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.

Mortality/Morbidity

Leydig cell tumors are usually benign, but approximately 10% are malignant. The malignant variants occur only in adults.

Sex

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.

Age

Leydig cell tumors may occur in prepubertal boys but are most common in men aged 30-60 years.

History

Physical

Laboratory Studies

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]


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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

Surgical Care

Further Outpatient Care

Prognosis

Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

Anil A Thomas, MD, Urology Resident, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation

Disclosure: Nothing to disclose.

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

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 Clinical Operations, 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 Consulting fee Advisor; Astellas Consulting fee Speaking and teaching; Watson Consulting fee Speaking and teaching

Additional Contributors

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

References

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  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. 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]
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  16. 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]
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. 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]
  24. 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.