Austin R. Younger, MD
James S. Rosoff, MD
BASICS
DESCRIPTION
• Leydig cell tumors (LCTs) are hormonally active steroid secreting tumors that may produce feminizing/virilizing syndromes
• Most common sex cord/stromal tumors
– (Neoplasms containing Leydig, Sertoli, granulosa, or thecal cells) commonly referred to as nongerm cell tumors
• Usually benign, 10% malignant variants reported in adults only (1)
• TNM staging follows current NCCN Guidelines for Testis Cancer
EPIDEMIOLOGY (1)
Incidence
• An estimated 8,820 new cases of testicular cancer were diagnosed in 2014
• LCTs represent 1–3% of all testicular neoplasms (90% of nongerm cell tumors)
• Bimodal distribution with peak incidences occurring between ages 4–5 and 30–60
• Equal incidence between right and left testis with 4–10% occurring bilaterally
Prevalence
Roughly 25% of cases of LCT occur in the pediatric population
RISK FACTORS
• No association with cryptorchidism
• Increased prevalence in Caucasians
Genetics
• No documented familial inheritance pattern or associated syndromes
• Association with specific activating mutation of luteinizing hormone receptor (LHR) gene (2)
– LHR is a stimulatory G-protein–coupled receptor present on surface of Leydig cell
• Hypothesized that oncogenesis is increased by (1) hyperstimulation of LHR and (2) Long-term estrogen exposure from aromatase conversion (seen in animal studies only)
PATHOPHYSIOLOGY
• Leydig cells are located in the interstitium of testicle between seminiferous tubules; produce testosterone in response to stimulation by luteinizing hormone
– Hypothalamic–pituitary axis is directly involved in Leydig cell stimulation and testosterone production
Vital role in development of male secondary sex characteristics and spermatogenesis
In neoplasia, feedback regulation is disrupted resulting in uncontrolled hormone production.
• LCTs usually secrete testosterone, may also secrete other androgens, corticosteroid, estrogen, and progesterone.
• Feminization may result directly from estradiol producing tumors or from peripheral conversion of testosterone to estrogens by aromatase
• Virilization occurs due to unopposed testosterone/androgen production independent of LH stimulation.
ALERT
• Virilizing signs are often not observed in adults.
• More frequently present with feminizing signs due to peripheral conversion of testosterone to estrogens.
ASSOCIATED CONDITIONS
• Adrenogenital syndromes—adrenal rest tumors are often misdiagnosed as LCTs.
– 80% of these are bilateral whereas only 4–10% of LCT are bilateral (1)
– Hyperplastic nodules will resolve with appropriate steroid replacement
• LCTs are not associated with cryptorchidism
GENERAL PREVENTION
• Routine self-exam in adult population
• Regular pediatric office visit during childhood development to identify any deviation in normal growth and maturation
DIAGNOSIS
• Low estradiol, increased testosterone, gynecomastia, and hypoechoic lesion on ultrasound are highly suspicious for LCT
• Histopathology confirms diagnosis
HISTORY
• Children commonly present with:
– Precocious puberty due to androgen secreting tumors; irreversible and profound physical changes—early diagnosis is critical
– Feminization from estrogen-secreting tumors
• Adults commonly present with:
– Nontender testicular mass/nodule
– Incidental finding on imaging for other conditions
– Feminization symptoms—low energy, anhedonia, gynecomastia, infertility
PHYSICAL EXAM
• A unilateral mass is palpable in 90% of cases with careful exam
• Hormonal imbalance responsible for physical changes
– Virilizing changes
Children: Precocious puberty, early growth, early change in penile length, deepened voice, increased muscle mass
Adults: Usually asymptomatic
– Feminizing change
Children: Delayed maturation, testicular atrophy, gynecomastia
Adults: Female hair distribution, gynecomastia, testicular atrophy
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Increased testosterone (with normal LH and FSH) is most common positive lab finding. With feminization syndrome, serum estradiol may be elevated
– All other tests should be within normal limits if leaning toward diagnosis of pure LCT
• Testicular mass work-up (AFP, β-hCG, LDH, testosterone, basic chemistry panel)
• Precocious puberty work-up (LH, FSH, testosterone, serum cortisol, urinary ketosteroids, 17-OH progesterone, ACTH stimulation test, dexamethasone suppression)
– Rule out:
Pituitary lesions—increased LH and FSH
Leydig cell hyperplasia—normal urinary ketosteroids, histopathology
Congenital adrenal hyperplasia (CAH): Elevated 17-OH progesterone, elevated urinary ketosteroids
Imaging
• CXR
• Testicular ultrasound—preferred imaging if mass is palpable (3)
– Solid hypoechoic mass
• MRI: May detect smaller nonpalpable lesions (4)
• CT chest/abdomen/pelvis: If concern for malignancy, lungs and retroperitoneal nodes are common metastatic sites
Diagnostic Procedures/Surgery
• Historically, radical inguinal orchiectomy was gold standard treatment
• Testis-sparing surgery (TSS): Enucleation of tumor and frozen-section analysis is acceptable option in some cases; no evidence of local recurrence or metastases on long-term follow-up (3,5)
Pathologic Findings
• Gross pathology
– Benign LCT: 3–5 cm, sharply delineated, solid mass, embedded within testicle, displaces normal stromal/tubular architecture (1)
Brown to yellow-white depending on total lipid content
– Malignant LCT: Larger, >5 cm, infiltrative margins, hemorrhage/necrosis present, replace or spread beyond testicular parenchyma
• Microscopic pathology (1)
– Tumor cells in nests/sheets, large polygonal cells with eosinophilic/granular cytoplasm, round regular nuclei, rare mitotic figures, prominent nucleoli
– Reinke crystals: Pathognomonic for LCT, rhomboid/cylindrical crystals, pale staining within cytoplasm and nucleus.
Confirms diagnosis but are only present in 40% of tumors
• Findings that correlate with malignancy
– Cytologic/nuclear atypia, increased mitotic activity 3–5 per 10 hpf, DNA aneuploidy
– Coagulative tumor necrosis, lymphovascular invasion
– Extension of the tumor to the spermatic cord, invasion of the capsule
– Abscence of Reinke’s crystals
• Immunohistochemistry (IHC)—beneficial if challenging diagnosis. May stain for inhibin A, calretinin, melan-A (1)
DIFFERENTIAL DIAGNOSIS
• Testicular masses (see Section I: “Testis Cancer, Adult General Considerations” and “Testis Cancer, Pediatric, General Considerations”)
• Precocious puberty
– Adrenocortical syndromes: CAH
– Large-cell Sertoli cell tumors
– Leydig cell hyperplasia
– Pituitary lesions
• Gynecomastia/feminization
– Pituitary lesions
– Paraneoplastic syndromes
– Marijuana use
TREATMENT
GENERAL MEASURES
• Management is primarily surgical
• Radical orchiectomy is the gold standard
• TSS is being performed more frequently with good results (5)
– Especially applies to cases of bilateral testicular tumors, subfertility, monorchidism, and in children where preservation of testicular function is of high importance
– There is no evidence for increased risk of local recurrence on long-term follow-up (3)
– TSS is a safe procedure in patients with LCT <25 mm (5)
• Malignant disease
– 3–10% of cases
– RPLND is indicated if concerned for malignancy based on histopathologic findings or presentation
– Malignant LCT responds poorly to radiation and chemotherapy
– Elevated serum estrogen after resection may indicate micrometastatic disease and requires monitoring
– Median survival: 2–4 yr
MEDICATION
First Line
Chemotherapy regimens using standard bleomycin-etoposide-platinum regimens for germ cell tumors have limited efficacy for malignant Leydig cell tumors
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Radical inguinal orchiectomy:
– Definitive method of diagnosis and treatment for stages I, II neoplasm
• Enucleation of mass with TSS:
– Inguinal exploration as for radical orchiectomy with use of intraoperative US and frozen-section confirmation of benign Leydig cell tumor
– May have a role in children and younger adults to preserve fertility.
• RPLND if suspicion of malignancy by CT criteria
ADDITIONAL TREATMENT
Radiation Therapy
Responds poorly to radiation
Additional Therapies
N/A
Complementary & Alternative Therapies
Patients should consider sperm banking prior to treatment to aid in avoiding risk of infertility.
ONGOING CARE
PROGNOSIS
Benign/local disease in the majority of patients portends a good prognosis
COMPLICATIONS
• Residual gynecomastia
• Physical changes of precocious puberty are permanent
FOLLOW-UP
Patient Monitoring
• Focused physical exam: Remaining testis, regional lymph nodes, abdomen
• Tumor markers, serum testosterone, estradiol
• CBC, electrolytes, and endocrine markers
• CT imaging of the chest and abdomen may be indicated
• RPLND patients should be evaluated every 3 mo for 2 yr, then every 6 mo for 3 yr, then yearly.
Patient Resources
Testicular Cancer Society. www.testicularcancersociety.org
REFERENCES
1. Al-Agha OM, Axiotis CA. An in-depth look at Leydig cell tumor of the testis. Arch Pathol Lab Med. 2007;131(2):311–317.
2. Fowler KA, Gill K, Kirma N, et al. Overexpression of aromatase leads to development of testicular Leydig cell tumors: An in vivo model for hormone-mediated testicular cancer. Am J Pathol. 2000;156(1):347–353.
3. Bozzini G, Picozzi S, Gadda F, et al. Long-term follow-up using testicle-sparing surgery for Leydig cell tumor. Clin Genitourin Cancer. 2013;11:321–324.
4. Leonhartsberger N, Ramoner R, Aigner F, et al. Increased incidence of Leydig cell tumours of the testis in the era of improved imaging techniques. BJU Int. 2011;108(10):1603–1607.
5. Loeser A, Vergho DC, Katzenberger T, et al. Testis-sparing surgery versus radical orchiectomy in patients with Leydig cell tumors. Urology. 2009;74:370–372.
ADDITIONAL READING
Olivier P, Simoneau-Roy J, Francoeur D, et al. Leydig cell tumors in children: contrasting clinical, hormonal, anatomical, and molecular characteristics in boys and girls. J Pediatr. 2012;161:1147–1152.
See Also (Topic, Algorithm, Media)
• Precocious Puberty
• Reference Tables: TNM: Testis Cancer
• Testis Cancer, Adult General Considerations Images 
• Testis Cancer, Pediatric, General Considerations
• Testis Cancer, Seminoma
• Testis Cancer, Nonseminomatous Germ Cell Tumors, General
• Testis, Leydig Cell Tumor Images
• Testis, Sertoli Cell Tumor
• Testis, Teratoma, Mature and Immature
• Testis, Tumor and Mass, Pediatric, General Considerations
CODES
ICD9
• 186.9 Malignant neoplasm of other and unspecified testis
• 222.0 Benign neoplasm of testis
• 259.51 Androgen insensitivity syndrome
ICD10
• C62.90 Malig neoplasm of unsp testis, unsp descended or undescended
• D29.20 Benign neoplasm of unspecified testis
• E34.50 Androgen insensitivity syndrome, unspecified
CLINICAL/SURGICAL PEARLS
• Leydig cell tumors (LCT’s) are hormonally active steroid-secreting tumors that may produce feminizing/virilizing syndromes.
• LCTs are usually benign, 10% malignant variants reported in adults only.
• Low estradiol, increased testosterone, gynecomastia, and hypoechoic lesion on ultrasound are highly suspicious for LCT.
• Scrotal exploration with frozen section is reliable in diagnosing LCT.
• Testicular sparing surgery (TSS) is a reasonable option in certain cases and has no reported increased risk of local recurrence or metastasis compared with radical orchiectomy.