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Leydig Cell Tumors
Article Last Updated: Jun 11, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 9  
Author: Edmund S Sabanegh, MD, Director, Center for Male Fertility, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation
Edmund S Sabanegh is a member of the following medical societies: American College of Surgeons, American Medical Association, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, Society for the Study of Male Reproduction, Society of Reproductive Surgeons, and Southwestern Oncology Group
Coauthor(s):
Anil A Thomas, MD, Urology Resident, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation;
Scott Rutchik, MD, Assistant Professor, Department of Surgery, Division of Urology, University of Connecticut School of Medicine
Editors: Erik T Goluboff, MD, Assistant Professor, Program Director, 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; 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
Author and Editor Disclosure
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
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.1
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.
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
- 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 be reported.
Physical
- An intratesticular mass may be palpated.
- In children, early pubertal and musculoskeletal development may be appreciated.
- In adults, gynecomastia, feminine hair distribution, and/or gonadogenital atrophy may be observed.
Other Problems to be Considered
Leydig cell hyperplasia
Large cell Sertoli cell tumors
Hyperplastic testicular nodules in persons with congenital adrenal hyperplasia
Feminizing testicular disorders
Feminizing adrenocortical disorders
Pituitary lesions
Klinefelter syndrome
Lab Studies
- Laboratory studies in 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
- Scrotal ultrasonography is typically performed to confirm the diagnosis, especially in patients in whom the physical examination findings are equivocal.
- MRI can reveal small nonpalpable Leydig cell tumors not otherwise visible on sonograms.
- CT scanning of the abdomen and chest radiography are indicated if malignancy is suspected.
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 1). 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.
Immunohistochemical markers such as alpha-inhibin,2 calretinin,3 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
- Chemotherapy with the bleomycin-etoposide-platinum regimen used for germ cell malignancies has limited efficacy in managing malignant Leydig cell tumors.
- The tyrosine kinase inhibitor imatinib has shown some chemotherapeutic activity in animal models,4 although this was not demonstrated in human trials.5
- No known role exists for radiation therapy in malignant Leydig cell tumors.
Surgical Care
- Leydig cell tumors have been primarily managed with surgical extirpation using radical inguinal orchiectomy. However, increasing reports have described conservative management with testis-sparing surgery in younger adults and children.
- Inguinal orchiectomy should be performed with early control of the spermatic cord and without violation of the scrotal skin.
- Testis-sparing surgery with enucleation of the mass has been reported in children and younger adults in order to maintain fertility.1 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. 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.
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, which supports the recommendation of long-term tumor surveillance for 10-15 years after surgery.
Prognosis
- The prognosis for benign Leydig cell tumors is excellent.
- The mean survival in patients with a malignant variant is 2-3 years.
Patient Education
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Leydig Cell Tumors excerpt Article Last Updated: Jun 11, 2008
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