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Leydig Cell Tumors Last Updated: April 7, 2006 |
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| Synonyms and related keywords: Leydig cell tumor, stromal testis tumor, interstitial testis tumor, interstitial testicular tumor, precocious puberty, androgenizing tumors, feminizing syndrome, virilizing syndrome, testicular neoplasms
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AUTHOR INFORMATION
| Section 1 of 10   |
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| Author: 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 |
| Editor(s): Erik T Goluboff, MD, Program Director, Assistant Professor, Department of Urology, Columbia-Presbyterian Medical Center, Columbia University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine;
Dan Theodorescu, MD, PhD, Paul Mellon Professor of Urologic Oncology, Department of Urology, University of Virginia Health Sciences Center;
J Stuart Wolf, Jr, MD, FACS, David A Bloom Professor of Urology, Director, Division of Minimally Invasive Urology, Department of Urology, University of Michigan Medical Center;
and Stephen W Leslie, MD, FACS, Founder and Medical Director, Lorain Kidney Stone Research Center; Clinical Assistant Professor, Department of Urology, Medical College of Ohio; Chief Editor - eMedicine Urology |
Disclosure
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INTRODUCTION
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Background: Leydig cell tumors are rare tumors of the male gonadal interstitium, although they are the most common type of interstitial testis tumor. Leydig cell tumors are frequently hormonally active, leading to feminizing or virilizing syndromes (see Image 1). The tumors are usually benign, but malignant variants are described. Pathophysiology: The etiology of Leydig cell tumors in humans remains unknown; however, they have been produced in animal models following prolonged estrogen treatments. Although these tumors most frequently produce testosterone, a feminizing syndrome is common. This syndrome is probably secondary to aromatization of the testosterone moiety, leading to increases in estrogenic steroids, although the tumors can produce estradiol. Therefore, gynecomastia and breast tenderness are the common presenting symptoms in adults, who may also present with infertility. Because of its androgenizing effects, a Leydig cell tumor must always be considered in the differential diagnosis of precocious puberty in boys. Frequency:
- In the US: Leydig cell testicular tumors comprise approximately 3% of testicular neoplasms. Likewise, bilateral tumors are also observed in 3% of patients.
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. Unlike their male counterparts, ovarian Leydig cell tumors are usually malignant.
Age: Leydig cell tumors may occur in prepubertal boys but are most commonly observed in men aged 30-60 years.
History: - Patients may report breast enlargement or nipple soreness.
- Erectile dysfunction with decreased libido may be present.
- In a child, the patient's parents report symptoms of precocious puberty, such as genital enlargement and pubic or axillary hair development.
Physical: - An intratesticular mass may be palpated.
- In children, early pubertal and musculoskeletal development can be appreciated.
- In adults, feminine hair distribution and gonadogenital atrophy or underdevelopment are observed.
Causes: The cause of Leydig cell tumors is unknown, although animal models suggest a link between chronic estrogen exposure and the development of cell tumors.
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DIFFERENTIALS
| Section 4 of 10 |
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Adrenal Adenoma
Other Problems to be Considered:
Leydig cell tumors are diagnosed based on histopathology. On physical examination, they present as a testis mass. The differential diagnoses of a testis mass is critical to understand and includes seminomas and nonseminomatous germ cell tumors. The diagnosis is made only after excision.
Sertoli cell tumors (exceedingly rare)
Congenital adrenal hyperplasia |
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Lab Studies:
- The steroid secretion pattern of Leydig cell tumors is variable, and no specific diagnostic test exists.
- Testosterone levels are usually elevated, although urinary 17-hydroxy ketosteroid levels may not be elevated.
- Serum estradiol measurements may also be increased, particularly in men with feminization stigmata.
- The differential diagnosis of Leydig cell tumors includes adrenal hyperplasia or tumor.
- In some situations, laboratory test results can distinguish the tumors.
- Leydig cell tumor endocrine function is independent of the hypothalamus-pituitary-gonadal hormonal axis and should demonstrate no response to either adrenocorticotropic hormone stimulation or dexamethasone suppression testing.
- Obtain serum tumor-marker testing for alpha-fetoprotein and beta-human chorionic gonadotropin. These markers are often elevated in germ cell tumors but not in pure Leydig cell neoplasms.
- Liver function tests are appropriate for patients with malignant Leydig cell tumors.
- Augusto et al showed that, on occasion, immunohistochemical staining for calretinin is useful when histologic distinction between Leydig and other sex cord/stromal tumors is difficult.
Imaging Studies:
- Perform ultrasonography on the scrotum if the physical examination is ambiguous for a testicular mass.
- Abdominal and chest CT scanning or radiography is reserved for patients who have a malignant Leydig cell tumor, although procession to CT imaging upon diagnosis of a testis mass prior to orchiectomy is not uncommon.
Histologic Findings: Macroscopically, Leydig cell tumors are well circumscribed and are yellow to light brown. Microscopically, the tumors are composed of large cells with eosinophilic cytoplasm, bland nuclei, and small nucleoli. Reinke crystals are present in as many as 30% of patients (see Image 1). The malignant variants, which comprise approximately 10% of Leydig cell tumors, exhibit irregular margins, increased mitotic figures, nuclear pleomorphism, and vascular invasion. Inhibin immunohistochemical staining is a useful diagnostic tool for stromal testis tumors.
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TREATMENT
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Medical Care: - Some degree of regression of precocious pubertal manifestations in pediatric patients may be anticipated following successful treatment of Leydig cell tumors. However, phallic enlargement or clitoromegaly, as well as gynecomastia, may persist in adults.
- No known role exists for radiation therapy in malignant Leydig cell tumors.
- Chemotherapy with the bleomycin-etoposide-platinum regimen used for germ cell malignancy has limited efficacy for malignant Leydig cell tumors.
- The tyrosine kinase inhibitor imatinib has shown some chemotherapeutic activity in animal models.
Surgical Care: - Perform an inguinal orchiectomy for all solid testicular masses, with early control of the spermatic cord and nonviolation of the scrotal skin as guiding principles.
- If the tumor is malignant, a retroperitoneal lymph node dissection is recommended because this may be curative in some instances of limited metastases.
Consultations: Consultation with an endocrinologist may be useful.
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FOLLOW-UP
| Section 7 of 10 |
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Further Inpatient Care:
- For patients whose tumor is benign, follow-up office visits focus primarily on regression and possible treatment of tumor sequelae.
- Only a few articles in the literature describe the optimum treatment of malignant Leydig cell tumors. The general consensus is to treat patients by primary retroperitoneal lymph node dissection.
- The frequency of subsequent abdominal CT scanning and chest imaging is also 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.
Further Outpatient Care:
- Observation is sufficient for patients who have a benign Leydig cell tumor treated with radical orchiectomy.
- Patients with malignant tumors require a metastatic workup, including abdominal CT scanning, chest radiography, and serum blood chemistries.
Prognosis:
- The prognosis for benign Leydig cell tumors is excellent.
- The mean survival for patients with a malignant variant is 2 years.
Patient Education:
- Teach patients to examine the remaining testicle every month.
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MISCELLANEOUS
| Section 8 of 10 |
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Medical/Legal Pitfalls:
- Failure to identify elements of a germ cell tumor within a specimen is a pitfall.
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BIBLIOGRAPHY
| Section 10 of 10 |
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Augusto D, Leteurtre E, De La Taille A, et al: Calretinin: a valuable marker of normal and neoplastic Leydig cells of the testis. Appl Immunohistochem Mol Morphol 2002 Jun; 10(2): 159-62[Medline].
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Basciani S, Brama M, Mariani S, et al: Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity. Cancer Res 2005 Mar 1; 65(5): 1897-903[Medline].
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Brunner HG, Otten BJ: Precocious puberty in boys. N Engl J Med 1999 Dec 2; 341(23): 1763-5[Medline].
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Cheville JC: Classification and pathology of testicular germ cell and sex cord-stromal tumors. Urol Clin North Am 1999 Aug; 26(3): 595-609[Medline].
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Cheville JC, Sebo TJ, Lager DJ, et al: Leydig cell tumor of the testis: a clinicopathologic, DNA content, and MIB-1 comparison of nonmetastasizing and metastasizing tumors. Am J Surg Pathol 1998 Nov; 22(11): 1361-7[Medline].
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Cuevas P, Ying SY, Ling N, et al: Immunohistochemical detection of inhibin in the gonad. Biochem Biophys Res Commun 1987 Jan 15; 142(1): 23-30[Medline].
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Gana BM, Windsor PM, Lang S, et al: Leydig cell tumour. Br J Urol 1995 May; 75(5): 676-8[Medline].
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Grem JL, Robins HI, Wilson KS, et al: Metastatic Leydig cell tumor of the testis. Report of three cases and review of the literature. Cancer 1986 Nov 1; 58(9): 2116-9[Medline].
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Iczkowski KA, Bostwick DG, Roche PC, Cheville JC: Inhibin A is a sensitive and specific marker for testicular sex cord-stromal tumors. Mod Pathol 1998 Aug; 11(8): 774-9[Medline].
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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 1985 Mar; 9(3): 177-92[Medline].
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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 2002 Nov; 9(11): 659-61[Medline].
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Mellor SG, McCutchan JD: Gynaecomastia and occult Leydig cell tumour of the testis. Br J Urol 1989 Apr; 63(4): 420-2[Medline].
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Mineur P, De Cooman S, Hustin J, et al: Feminizing testicular Leydig cell tumor: hormonal profile before and after unilateral orchidectomy. J Clin Endocrinol Metab 1987 Apr; 64(4): 686-91[Medline].
Leydig Cell Tumors excerpt |
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