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Leydig Cell Cancer of the Testis

Author: Jose I. Nolazco Editor: Stephen W. Leslie Updated: 9/14/2025 1:11:11 PM

Introduction

Although generally considered a testicular neoplasm, with the vast majority occurring in men, Leydig cell tumors may occur in both sexes.[1] In men, Leydig cell tumors initially appear as testicular neoplasms. While accounting for a relatively small proportion of all cancer diagnoses in men, testicular neoplasms are the most common malignancy in men aged 15 to 44.[2] Testicular neoplasms are broadly categorized into germ cell tumors, which comprise approximately 95% of all testis cancers, and sex cord–stromal tumors, accounting for 2% to 5% in adults but 25% in children due to the lower incidence of germ cell tumors in the pediatric population.[3] Among sex cord–stromal tumors, Leydig cell tumors are the most common subtype (75%), originating from the specialized Leydig cells within the testicular interstitium between the seminiferous tubules. These tumors were first described by German zoologist and anatomist Franz von Leydig in 1870.[4][5][6][7] Leydig cell tumors are relatively rare, but they represent the most common type of nongerm cell testicular tumors.[8]

Leydig cells are essential for testosterone production, which is stimulated by luteinizing hormone, and are critical to the development of the male reproductive organs, such as the prostate and testes. Testosterone is responsible for the secondary male sexual characteristics, as well as increased muscle and bone mass, maintenance of libido, stimulation of erythropoiesis, and promotion of spermatogenesis.[4][9][10][11][12] Furthermore, Leydig cell tumors are typically benign, and malignancy is rare in children.[13][14][15][16] In adults, older estimates reported malignancy rates of 5% to 10%; recent large-scale study results report a considerably lower rate of approximately 2.5%.[3][17][18][19][20][21][22] However, other results indicate a malignancy rate of around 10% during follow-up.[23] 

These tumors exhibit a bimodal age distribution, with incidence peaks in prepubertal boys (5 to 10 years) and adults (30 to 60 years).[3] Their inherent hormonal activity can lead to diverse clinical manifestations, including precocious puberty (62%), gynecomastia in adults (20%), or infertility (17% to 18%).[3][8][24] However, many Leydig cell tumors are discovered incidentally, such as during an infertility evaluation in men, in otherwise asymptomatic individuals.[4][25]

In women, Leydig cell tumors constitute less than 0.5% of all ovarian neoplasms.[1] Most occur around the time of menopause (70% to 85%), accompanied by increased androgen levels, causing hirsutism and virilization.[1] High serum testosterone levels (more than 3 times the reference range for age) cause an increase in masculinization symptoms.[1][26][27] Other sources of hyperandrogenism should be excluded, such as endocrinopathies, other hormonally active ovarian tumors, iatrogenic factors, and idiopathic causes.[1][27]

Diagnostic imaging in women may include transvaginal ultrasonography of the ovaries, pelvic MRI, and abdominal CT scans to evaluate the adrenal glands.[1][28] Fluorodeoxyglucose positron emission tomography can identify smaller foci of Leydig cell tumors.[1][29][30] Negative imaging results indicate that diagnostic laparoscopy is necessary.[1] In the absence of any apparent ovarian lesions, if no clear etiology is determined and adrenal causes of hyperandrogenism have been excluded, bilateral oophorectomy should be considered.[28][30][31][32][33] Treatment is surgical resection of the affected ovaries and fallopian tubes, and possible hysterectomy. Leydig cell malignancies in women are rare, with a poor prognosis due to the aggressive nature of these neoplasms.

Etiology

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Etiology

Leydig cell tumors originate from Leydig cells, which are located between the seminiferous tubules of the testis and are responsible for testosterone secretion in response to luteinizing hormone.[34] The mechanism of Leydig cell oncogenesis remains poorly understood, although disruption of the hypothalamic-pituitary-testicular axis, resulting in excessive luteinizing hormone stimulation, is thought to be a cause.[4]

Genetic mutations, both somatic and inherited, are involved:

  • A heritable mutation in the fumarate hydratase gene has been identified in adults. This mutation activates the hypoxia-angiogenesis pathway, thereby promoting the growth of Leydig cell tumors.[35]
  • A somatic activating mutation in the guanine nucleotide–binding protein α gene has been identified in several cases.[36] 
  • Fumarate hydratase inactivation, multiple copy number variations (including repeated, rearranged, or deleted sequences) without recurrent mutations, activation of the Wnt signaling pathway, and nuclear translocation of β-catenin all promote the malignant progression of Leydig cell tumors.[37][38]

Leydig cell tumors are strongly associated with male infertility, cryptorchidism, and gynecomastia, suggesting a role for testicular dysgenesis syndrome in their development.[39] Other factors that influence the development of Leydig cell tumors include inhibin, various growth factors, temperature changes, and Müllerian duct inhibitory factor.[40]

Epidemiology

Leydig cell tumors are considered rare, comprising 1% to 3% of all testicular neoplasms.[41][42][43] However, recent data have questioned this rarity, suggesting Leydig cell tumors may be more common. Some study results report an incidence as high as 22% of all small testicular nodules, with a mean prevalence of 26.6% among nonpalpable testicular masses.[17] This shift may be attributed to the routine use of ultrasonography, which enables the detection of small, nonpalpable, incidental testicular nodules that were previously undetectable.[17][39][44]

  • Approximately 5% of patients with malignant Leydig cell tumors have a history of Klinefelter syndrome.[45][46]
  • Leydig cell tumors are detected in 10% of young individuals with precocious puberty.[47] Unfortunately, physical changes associated with early puberty are irreversible.[14][15][24]
  • The median age of presentation of all Leydig cell tumors is approximately 60 years.[37][48]
  • The median age of presentation for benign Leydig cell tumors is 37.5 years.[7][37]
  • The median age of presentation for malignant Leydig cell neoplasms is 68.5 years (27 to 80 years).[37][49][50]

Histopathology

Benign Leydig cell tumors typically present as small (<5 cm), well-circumscribed, solid masses within the testis. The cut surface is characteristically golden brown, a color imparted by abundant lipofuscin pigment. The color can range from yellow to gray-white depending on the lipid content.[7] While usually unilateral, bilateral cases are observed in approximately 3%.[51][52] Malignant Leydig cell tumors tend to be large (>5 cm) and demonstrate neoplastic infiltration outside the parenchyma of the testis into the adjacent epididymis, rete testis, or tunica.[53]

Microscopically, benign Leydig cell tumors commonly display nests or sheets of cells separated by delicate fibrovascular septa. Other, less common growth patterns include small clusters, trabeculae, pseudotubular, ribbon-like, spindled, or microcystic formations. The tumor cells are typically large and polygonal with abundant, eosinophilic, finely granular cytoplasm that may appear pale or clear due to lipid accumulation. Abundant lipofuscin pigment, appearing as golden yellow to brown cytoplasmic granules, is also characteristic.[7]

A distinctive feature of Leydig cell tumors, identified in approximately 30% to 35% of cases, is the presence of characteristic rod-shaped Reinke crystals within the cytoplasm. Reinke crystals are proteinaceous crystalline structures found exclusively in Leydig cells. They are composed of 5-nm filaments in a hexagonal pattern and fluoresce red when stained with eosin. Reinke crystals are refractile, come in various shapes (cylindrical, rectangular, or rhomboidal), and are typically arranged in a linear pattern.[54] See Image. Leydig Cell Tumor.

Immunohistochemistry can help differentiate Leydig cell masses from germ cell neoplasms and other testicular sex-cord stromal tumors. Leydig cell tumors stain strongly and diffusely positive for cytoplasmic inhibin.[4] This staining pattern makes inhibin a practical, sensitive, and distinctive marker to differentiate Leydig and Sertoli cell neoplasms (testicular sex-cord stromal tumors) from germ cell malignancies.[4][7][55] Leydig cell tumors, like Sertoli cell neoplasms, do not demonstrate positive immunostaining for alpha-fetoprotein, lactate dehydrogenase, and beta-human chorionic gonadotropin.[4][55][56][57]

In addition to characteristic Reinke crystals, Leydig cell tumors typically stain strongly and diffusely positive for inhibin, calretinin, Melan-A, and steroidogenic factor 1 (SF-1), but negatively for a Wilm tumor 1 (WT1) and cytokeratin.[4][55][58] Some Leydig cell tumors may exhibit focal, weak, or cytoplasmic staining for β-catenin, in contrast to the strongly positive nuclear staining observed in Sertoli cell neoplasms. Kiel-67 (Ki-67) is a nuclear protein antigen stained by the mindbomb homolog-1 (MIB-1) monoclonal antibody, produced by actively reproducing cells.[59][60][61] The higher the percentage of cells actively reproducing, the greater the risk of malignancy.[62][63][64] Various names refer to this percentage, including the Ki-67 or MIB-1 index, growth index, labeling index, or the proliferation index. An MIB-1 index of greater than 30% strongly favors malignancy, while an MIB-1 index of approximately 1.2% indicates a benign neoplasm.[53][57][58][62][58][65][66][67][68][69][70][71][72][73][74]

In malignant Leydig cell tumors, inhibin staining is intense, while calretinin, Melan-A, CD99, and SF-1 stain positive. In contrast, WT1 and cytokeratin stains are negative. The MIB-1 index is high, and test results for oncogenic markers, including B-cell lymphoma 2 (bcl-2), Ki-67, and tumor protein 53 (p53), tend to be positive.[53][58][65][66][67][68][69][62] Positive test results for MDM2 oncogene amplification and increased copy number variations (without recurrent mutations) are more likely present in malignant Leydig cell neoplasms.[37][75][76]

Differentiating Leydig Cell Tumors From Leydig Cell Hyperplasia and Sertoli Cell Neoplasms

Leydig cell hyperplasia presents as bilateral, well-circumscribed, brown-yellowish nodules, ultimately leading to atrophy of the testis. There is an increased number of Leydig cells and nucleoli, accompanied by a decrease in lipofuscin.[77] The hyperplastic Leydig cells infiltrate the seminiferous tubules (containing only Sertoli cells) without obliterating or displacing them.[77] Hyperplasia lacks necrosis or hemorrhage and is considered a benign neoplasm. Microscopically, Leydig cell hyperplasia is characterized by large, eosinophilic, polygonal or round cells, decreased lipofuscin, and Reinke crystals in 25% to 40% of lesions. Urinary 17-ketosteroid levels are typically within the reference range.[77] Furthermore, Leydig cell hyperplasia should be considered in patients with Klinefelter syndrome who have negative tumor markers and multiple small bilateral testicular lesions.[78]

Leydig cell tumors may contain Reinke crystals, which is a definitive finding.[54] Leydig cell tumors will stain strongly positive for inhibin, calretinin, Melan-A, and SF-1, but weakly positive or negative for β-catenin, and will be negative for WT1 and cytokeratin.[4][23][55][58][79] Positive findings for bcl2, Ki-67, and p53 suggest malignancy, and a higher MIB-1 proliferation index suggests greater tumor aggressiveness.[53][65][66][68][80][81][82][83][84][85]

Sertoli cell tumors exhibit a distinct histological appearance compared to Leydig cell neoplasms.[54][86] Histologically, Sertoli cell tumors comprise proliferating cellular tubules with elongated nuclei arranged in a cord-like pattern. In contrast, Leydig cell tumors have a microscopic appearance of large, polygonal cells arranged in sheets.[7][54][86] 

Sertoli cell neoplasms tend to exhibit positive, diffuse β-catenin nuclear staining and do not typically demonstrate Reinke crystals.[54][68][87] While some Leydig cell tumors may show weakly positive β-catenin staining, it's typically focal or cytoplasmic rather than the strongly positive, diffuse nuclear staining seen in Sertoli cell neoplasms.[23][68][86][88] In addition to β-catenin, Sertoli cell tumors will stain positively for WT1 and SF-1, but only weakly for inhibin, cytokeratin, and calretinin, while staining negatively for Melan-A.[4][68][79][89][90][91]

Microscopic features suggestive of Leydig cell tumor malignancy, particularly when 2 or more are found, include the following: 

  • Coagulative necrosis
  • DNA aneuploidy
  • Increased mitotic activity (>3–5 per 10 high-power fields) with atypical mitotic figures
  • MIB-1
  • Percentage of cells that stain positive for MIB-1
  • High MIB-1 proliferation index
    • While it cannot differentiate between Leydig and Sertoli cell tumors, a high MIB-1 proliferation index suggests malignancy and increased aggressiveness.[53][65][80][81][82][83][84][85]
  • Cells that stain positive for MIB-1
    • The greater the percentage of cells that stain positive for MIB-1, the faster the tumor cells grow and divide, the more aggressive the neoplasm.[53][65][80][81][82][83][84][85]
  • Increased MIB-1 activity (mean activity of 18.6% compared to the benign Leydig cell tumors' mean activity of 1.2%) [53]
  • Infiltrative surgical margins
  • Lymphovascular invasion
  • Marked cytologic and nuclear atypia
  • Marked pleomorphism
  • Necrotic foci [4][25][53][69][75][92]

The risk of metastases increases with the number of positive histopathologic risk factors.[93][94] No specific histopathological findings can definitively distinguish between malignant and benign Leydig cell neoplasms.[7][20][25][43][48][53][95] The most conclusive finding would be confirmation of a metastatic Leydig cell cancer on a surgical biopsy specimen.[49][69][96][97] In such cases, Reinke crystals, as detected by fine-needle aspiration or biopsy of the metastatic deposit, would be considered conclusive, as they are exclusively found in Leydig cell tumors.[49][54][69] Because the only definitive evidence of malignancy is the presence of metastasis, surveillance of patients with Leydig cell tumors is warranted, even when the initial histology is benign.[20]

History and Physical

Common Clinical Presentation

Like other testicular tumors, a painless intrascrotal mass or swelling is the most common clinical finding in patients with Leydig cell tumors.[98] However, the prevalence of palpable masses varies, with reports ranging from approximately 14% to 26% of patients.[8][44] Many Leydig cell tumors, particularly smaller ones, may be nonpalpable. Painless testicular swelling, precocious puberty, infertility, and gynecomastia (20%) are the most common presenting symptoms.[8][99] Other symptoms include breast tenderness, loss of libido, and erectile dysfunction.[8] Scrotal pain is a relatively uncommon symptom, reported in approximately 7% of patients.[44] Tumors are usually unilateral, and only 3% are bilateral.[25][51][100]

With the increased use of ultrasonography, especially in men with infertility, incidental testicular nodules are discovered more frequently.[17][22][101] Up to 22% of testicular masses smaller than 1.5 cm detected incidentally during an infertility evaluation were identified as Leydig cell tumors in recent studies.[17][102] Up to 49% of all incidentally discovered solid testicular nodules identified during ultrasonography, and as many as 48% of incidental masses found during an infertility evaluation, were Leydig cell tumors.[39][42][101][103]

Physical Examination

A complete physical examination should include palpating the affected and contralateral testicles, noting relative size, consistency, and any distinct intrinsic or extrinsic masses. Findings suggestive of a possible testicular Leydig cell cancer include large scrotal masses (>5 cm), older age, and the presence of metastatic lesions.[53] Moreover, hydroceles may also present as painless testicular swelling, but they are typically transilluminable and appear hypoechoic on ultrasonography.[104] Hydroceles may accompany a testicular tumor, so it is critical to obtain scrotal ultrasonography to detect underlying malignancy.[105]

Unique Hormonal Manifestations

A defining characteristic of Leydig cell tumors is their hormonal activity. These steroid-secreting tumors produce androgens (mainly testosterone) and estrogen, either directly or through the peripheral conversion of testosterone. This hormonal activity leads to clinical manifestations in many patients.

Prepubertal boys

  • Androgen-secreting tumors typically present with precocious puberty, including early development of the penis and pubic hair, accelerated skeletal and muscle growth, advanced bone age, and skin changes.[24]
  • Estrogen-secreting tumors in boys may lead to gynecomastia and breast tenderness, accompanied by a feminized hair distribution and underdeveloped genitalia.[106]
  • Leydig cell tumors are consistently benign in prepubertal children.[13][14][15][16]
  • Physical changes associated with precocious puberty are irreversible.[14][15][24]

Postpubertal adolescents and men

Hormonal imbalances are common, often characterized by elevated serum levels of testosterone or estradiol. Notably, testicular dysfunction and infertility can be a serious long-term consequence, particularly in estrogen-secreting Leydig cell tumors, due to impaired spermatogenesis.[4] Other clinical manifestations include:

  • Cushing syndrome is a rare clinical manifestation of Leydig cell neoplasms.[95][107][108]
  • Gynecomastia is the most common hormone-related presentation in men, occurring in about 20% (15% to 23%) of cases.[3][8]
  • Other reported hormone-related presentations include breast tenderness, loss of libido, erectile dysfunction, impotence, and infertility.[51][109]

Associated Conditions

  • Cryptorchidism (undescended testis) is more common in patients with Leydig cell tumors (15.6%) than in the general population, supporting the hypothesis that testicular dysgenesis syndrome may play a role in the development of testicular neoplasms.[39]
  • Klinefelter syndrome (47, XXY karyotype) is a recognized risk factor for Leydig cell tumors.[3][78][110] 
    • Approximately 5% of patients with malignant Leydig cell tumors have a history of Klinefelter syndrome.[45][46]
    • Characteristic ultrasound findings in patients with Klinefelter syndrome include severe testicular hypotrophy (average volume 2 mL) with a coarse or micronodular echotexture and increased bilateral symmetrical microlithiasis.[110]
    • Histology often confirms these nodules as benign Leydig cell tumors or hyperplasia. For these patients, radical orchiectomy should be avoided in favor of testis-sparing surgery to preserve testosterone levels.[78]
    • Patients with Klinefelter syndrome have an increased risk of extragonadal germ cell tumors, especially in the mediastinum.[110]
  • Leydig cell tumors are strongly associated with male infertility, present in a substantial proportion of patients (48.2%) referred for infertility evaluation.[39][111]

Evaluation

Imaging

Scrotal ultrasound

This is the preferred initial imaging modality for evaluating patients with testicular disorders, such as unexplained pain, nodules, lumps, swellings, hydroceles, masses, or other nonspecific scrotal symptoms, due to its speed, broad availability, noninvasiveness, lack of ionizing radiation, painlessness, and cost-effectiveness.[17][112][113] Leydig cell tumors appear on ultrasound as well-defined, solid, homogeneous, hypoechoic intratesticular masses.[17][112][114] Benign ultrasonographic characteristics include a small size (≤7 mm) and a distinct margin from the adjacent parenchyma.[114] A hyperechoic peripheral rim may be observed, and intrinsic or peripheral rim hypervascularization may be present.[114][115] Microlithiasis is uncommon, but if present, it tends to be nongrouped (in contrast with seminoma, which may contain grouped microliths).

Color Doppler imaging reveals increased peripheral vascularity, often accompanied by a prominent feeding artery. Contrast-enhanced ultrasonography demonstrates homogeneous enhancement from a centralized source; elastography shows increased stiffness.[17][116] However, Leydig cell tumors are often sonographically indistinguishable from more common malignant germ cell tumors. Any intratesticular mass should be presumed malignant until proven otherwise.[17][117]

Magnetic resonance imaging

This is not part of the routine; initial evaluation is recommended by the American Urological Association and the European Association of Urology guidelines for evaluating solid testicular masses, lumps, or nodules.[118][119][120] However, selective contrast-enhanced MRI may aid diagnosis in equivocal cases, particularly when considering testis-sparing surgery.[17][67][118][119][120][121][122][123][124][125][126] Typical findings for benign Leydig cell tumors include a markedly hypointense signal on T1- and T2-weighted imaging, rapid and significant wash-in, and a prolonged washout.[67][121][122][123][124][127][128] Sustained enhancement of vascularized tissue suggests the presence of a tumor.[77] A fibrous capsule may appear hyperintense on T2-weighted imaging, while intralesional hyperintense signals may indicate scarring.[122]

MRI characteristics of malignant Leydig cell tumors compared to benign tumors include larger size, indistinct margins, weakly hypointense signals on T2-weighted imaging, lower apparent diffusion coefficient, inhomogeneous enhancement, and progressive but muted wash-in on contrast-enhanced T1-weighted imaging.[116][121][129][130] The overall diagnostic accuracy of scrotal MRI is 93%.[121] The sensitivity of contrast-enhanced scrotal MRI to diagnose Leydig cell tumors is 89.47% with 95.65% specificity.[121] For malignant Leydig cell tumors, the sensitivity is 95.65% with a specificity of 80.95%.[121] 

Laboratory Studies 

Serum germ-cell tumor markers 

These markers, including alpha-fetoprotein, quantitative beta-human chorionic gonadotropin, and lactate dehydrogenase, should be obtained whenever a testicular malignancy is suggested based on clinical or imaging findings.[117][131][132] Pure, isolated Leydig cell tumors present with serum tumor markers within the reference range.[7] This finding helps distinguish Leydig cell tumors and other testicular sex-cord stromal neoplasms from germ cell tumors, which present with elevated tumor marker levels.[7][19][117][131][132] Ultimately, histologic tissue examination and immunohistochemistry are required to definitively distinguish Leydig cell tumors from other testicular neoplasms. Notably, biopsy and fine needle aspiration are contraindicated for primary testicular tumors.

Hormone levels 

These levels may be abnormal in patients with Leydig cell tumors who present with symptoms like unexplained infertility, precocious puberty, or gynecomastia.[24][99][111][133][134][135][136][137] In such cases, a complete serum hormonal profile, including follicle-stimulating hormone, luteinizing hormone, estradiol, estrogen, and testosterone, is essential.[24][111][134] Typical findings in Leydig cell tumors include elevated serum testosterone or elevated estradiol, which can suppress luteinizing and follicle-stimulating hormone levels, particularly in patients with precocious puberty.[7][24] Moreover, urinary ketosteroids, serum cortisol, dexamethasone suppression, or adrenocorticotropic hormone stimulation testing may exclude other endocrinopathies, such as adrenocortical dysfunction.[138][139] However, endocrine dysfunction due to Leydig cell tumors is independent of the hypothalamus-pituitary-gonadal hormonal axis and is therefore unresponsive to dexamethasone suppression or adrenocorticotropic hormone stimulation.[140][141][142]

Metastatic Evaluation

When a Leydig cell tumor is discovered, a metastatic evaluation is necessary, especially if microscopic findings suggest a malignancy.[43] This evaluation includes a CT scan of the abdomen, pelvis, and chest. The most common sites of metastases from malignant Leydig cell tumors are the inguinal, regional, and retroperitoneal lymph nodes (70%), the liver (45%), the lungs (40%), and bones (25%).[14][20][95] Long-term surveillance is recommended even for benign Leydig cell tumors, because metastatic lesions may appear years after surgical procedures.

Treatment / Management

The standard of care for an intratesticular mass is radical inguinal orchiectomy, particularly when malignancy is a consideration, because the sonographic appearance is indistinguishable from that of germ cell tumors.[119] Increasingly, testis-sparing surgery with intraoperative frozen sections is performed for small (<2 cm), benign-appearing testicular masses, including most benign Leydig cell tumors.[8][143][144] Testis-sparing surgery is considered a safe and effective alternative to radical inguinal orchiectomy, particularly when preserving testicular function and fertility are priorities, such as in patients with Klinefelter syndrome, younger patients with infertility, and men with a solitary testis.[14][15][43][46][143][145][146][147][148][149][150] A conservative testis-sparing approach is recommended only when serum germ cell tumor markers (alpha-fetoprotein and beta-human chorionic gonadotropin) are within the reference range. This approach is appropriate if a benign Leydig cell or similar benign neoplasm is suggested based on clinical findings (gynecomastia, elevated testosterone or estrogen, or infertility), the mass lesion is small (<2 cm), imaging studies do no demonstrate malignant characteristics, the contralateral testicle is normal, the intraoperative frozen section confirms benign histological features, and the patient agrees to long-term surveillance.[18][46][119][120](A1)

According to results from several studies, benign Leydig cell tumors treated with testis-sparing surgical procedures have not demonstrated local recurrence.[43][46][143][145][146][147][148][149][150][151][152] Active surveillance via clinical and radiological evaluation can be an option for small Leydig cell tumors without malignant characteristics, particularly in individuals with Klinefelter syndrome, a solitary testicle, and infertility. Notably, surgical intervention may not significantly improve fertility. Preoperative counseling about sperm banking is crucial, as patients with Leydig cell tumors have an increased risk for endocrine and spermatogenesis dysfunction even after tumor resection, necessitating prompt fertility preservation.[119][120] Preoperative decisions should also address the possibility of a radical orchiectomy depending on the frozen section results, even if testis-sparing surgery were originally intended, and the possible use of a testicular prosthesis.[119](A1)

Initial surgical procedures for solid testicular masses are often performed through an inguinal incision, even when testis-sparing surgery is planned, because conversion to a radical orchiectomy intraoperatively may be required. An inguinal incision prevents the spread of malignant testicular cells to the scrotum and its lymphatic drainage. This incision allows direct access to the testis and spermatic cord to the internal ring.[119][120][153] Scrotal incisions are not recommended when exploring solid scrotal masses.[118][119][120][154](A1)

While primary tumor biopsy before orchiectomy is contraindicated, an intraoperative frozen section can guide management. Frozen section evaluation may be considered when there are no signs of malignancy on imaging, the neoplasm is solitary, bilateral testicular tumors are present, the mass is small (<2 cm), and serum tumor marker results are negative. This approach avoids unnecessary orchiectomies in selected patients willing to undergo continued surveillance.[119][120][145][155][156] The intraoperative decision regarding testis-sparing surgery is based on mandatory frozen section examination of the tumor; evidence of malignancy requires radical orchiectomy.[119][120][157] (A1)

Ultimately, the final diagnosis is based primarily on immunohistochemical analysis of the resected tissue because the frozen section is accurate and reliable in diagnosing malignancy.[3][4][118][158][159][160][161][162][163][164][165] In the unlikely event that testis-sparing surgery is performed and the final diagnosis indicates a malignant Leydig cell tumor, an inguinal salvage radical orchiectomy is indicated. Unfortunately, due to the rarity of Leydig cell tumors and their similar presentation to germ cell neoplasms, many patients ultimately found to have Leydig cell tumors undergo initial radical inguinal orchiectomy. (A1)

Post-Orchiectomy Surveillance and Management

Leydig cell tumors are overwhelmingly benign, representing the most common nongerminomatous testicular tumor.[7] While the majority of Leydig cell tumors are cured after initial local excision, such as radical orchiectomy or testis-sparing surgery for smaller lesions, post-treatment surveillance is recommended.[118] When metastasis occurs, it is most often found in the retroperitoneal lymph nodes (70%), followed by the liver (45%), lungs (40%), and bones (25%).[44][48][166][167][168](B2)

Due to the very low incidence of malignant Leydig cell tumors, the optimal postoperative monitoring protocol has not been standardized. However, reasonable consensus suggests examination every 4 to 6 months during the first year after surgery, every 6 months for the second year, and annually for at least 5 years thereafter.[18][43] Long-term follow-up is warranted even in benign appearing Leydig cell tumors due to the potential for delayed metastases and metachronous contralateral neoplasms, observed in approximately 3% of cases.[8][20][39][106] These follow-up visits include physical examination, hormonal levels (including estradiol, estrogen, follicle-stimulating hormone, luteinizing hormone, and testosterone), and periodic chest, abdominal, and pelvic CT imaging.[55][169] Unfortunately, histopathologic evidence of malignancy may not be present at the time of orchiectomy, and some patients develop metastases years later.[45][95][170] Metastases have been reported up to 17 years after the original radical orchiectomy; however, approximately 82% of metastases occur within the first 5 years following the procedure.[8][171] (B2)

A retroperitoneal lymph node dissection and a longer surveillance interval are recommended for patients at higher risk for metastatic disease, such as older age at presentation, larger tumor size (>5 cm), multiple (>2) adverse histopathologic features, shorter duration of symptoms, positive surgical margins, evidence of tumor spread outside the testis, and the absence of endocrine manifestations.[8][45][172] With some metastases developing several years after surgery, and because histological and immunohistochemical testing is not definitive, surveillance for 10-15 years postoperatively should be considered, especially for Leydig cell tumors with malignant characteristics.[7][20][25][43][45][48][53][95][170][173](B2)

Retroperitoneal lymph node dissection remains the standard of care for Leydig cell tumors that present with 2 or more histopathologic risk factors for malignancy. The procedure should be performed immediately after the radical orchiectomy.[7][21][45][119][174] A retroperitoneal lymph node dissection is not justified unless significant histopathologic or other risk factors are identified after orchiectomy.[175] Patients with Leydig cell tumors who were initially observed but later developed retroperitoneal metastases and underwent delayed retroperitoneal lymph node dissection often had worse outcomes than those who had an immediate lymph node dissection.[21][45] However, a few patients with low-volume retroperitoneal disease at presentation have had durable responses after retroperitoneal lymph node dissection.[45][176](B2)

Despite retroperitoneal lymph node dissection being the recommended treatment immediately following a diagnosis of Leydig cell tumor with malignant characteristics, only limited data are available on its effectiveness.[21][176] There is a general lack of effective treatment options because radiation and chemotherapy are relatively ineffective. Retroperitoneal lymph node dissection is recognized for its efficacy and prognostic value, and can eradicate retroperitoneal micrometastases. Because this procedure may be life-saving, it remains the standard of care when 2 or more histopathological risk factors are identified, regardless of whether obvious metastasis is detected.[21][45][94][174][176][177][178](B2)

There are 3 different surgical approaches to retroperitoneal lymph node dissection: open, laparoscopic, and robotic, with equivalent efficacy.[179][180] Laparoscopic and robotic surgeries offer significantly reduced hospitalizations, improved cosmesis, and fewer complications than traditional open surgery.[181][182][183][184][185] However, laparoscopic and particularly robotic retroperitoneal lymph node dissection procedures are technically demanding and require extensive experience.[179][184][185][186][187][188] The American Urological Association and the National Comprehensive Cancer Network guidelines recommend that surgeons with extensive experience perform the procedures in high-volume centers.[179][184][185][189][190](A1)

Metastatic disease involving Leydig cell tumors generally demonstrates poor responsiveness to systemic chemotherapy or radiation therapy, and overall patient survival is poor. No standardized treatment guidelines exist for advanced disease.[4][21][169][191] While these modalities may offer palliative benefits or, rarely, achieve partial or complete remissions, surgical resection of metastases, particularly retroperitoneal lymph node dissection, is considered the primary and potentially curative treatment option, especially for micrometastatic disease.(B3)

Despite surgical interventions, patients with metastatic Leydig cell tumors have a poor prognosis, and no definitive standard treatment guidelines exist for advanced disease.[4][191] While these tumors are generally unresponsive to chemotherapy and radiation, there are anecdotal reports of complete remission with surgical resection of metastatic deposits as well as the use of bleomycin, cisplatin, and etoposide, and with local radiotherapy in low-volume, unresectable, metastatic disease.[8][168][169][192] The potential role of immunotherapy (immune checkpoint inhibitors, such as programmed cell death protein 1 inhibitors and inhibin vaccinations) and targeted treatments (like imatinib, a tyrosine kinase inhibitor) is under investigation.[193][194](B2)

Differential Diagnosis

The differential diagnosis for Leydig cell tumors varies based on the clinical presentation and diagnostic workup performed.[110][134] For patients presenting with hormonal manifestations such as gynecomastia or feminizing symptoms, consider the following conditions:

  • Adrenal tumor/adrenal hyperplasia (functioning) [139]
  • Drug adverse effects, such as angiotensin-converting enzyme inhibitors, marijuana, or spironolactone [195][196]
  • Germ cell tumors [132]
  • Hyperthyroidism [197]
  • Klinefelter syndrome [110]
  • Liver disease [198]
  • Obesity [199]

For patients presenting with hypogonadism or infertility, consider the following conditions:

When a scrotal ultrasound identifies an intratesticular solid mass, the differential diagnosis should include the following:

  • Germ cell tumors [131][132][208]  
  • Other sex cord-stromal tumors [7]
    • Adult granulosa cell tumor 
    • Benign Leydig cell tumor 
    • Fibrothecoma 
    • Gonadoblastoma 
    • Large cell calcifying Sertoli cell tumor 
    • Mixed and unclassified sex cord–stromal tumors 
    • Myoid gonadal stromal tumor 
    • Sertoli cell tumor 
    • Sertoli-Leydig cell tumor [7]
  • Other intratesticular masses
    • Adrenal rest tumor [204] 
    • Granular cell tumor [205]
    • Intratesticular hematoma
    • Leydig cell hyperplasia 
    • Lymphoma [206]
    • Malakoplakia 
    • Metastatic carcinoma
    • Plasmacytoma [207]

Prognosis

Endocrine dysfunction and infertility may persist even after the tumor resection.[209] For those presenting with hypogonadism, hormonal insufficiency may continue postorchiectomy, with a significant proportion of patients (40%), requiring ongoing testosterone replacement therapy.[133][210] Local recurrence after testis-sparing surgery occurs in 7% of patients.[8] Radical orchiectomy is curative in the vast majority of patients with benign Leydig cell tumors, with 5-year survival rates exceeding 90% and cancer-specific mortality rates of approximately 2%.[211][212][213] However, patients with Leydig cell malignancy have a markedly worse prognosis.

Patients diagnosed with malignant Leydig cell tumors without evidence of metastases have reported 1-year and 5-year survival rates of 98% and 91%, respectively.[45][212] Patients with malignant Leydig cell-proven metastatic disease have highly variable outcomes, with a reported median survival of approximately 2 years. However, this ranges from several months to over a decade in rare cases.[3][45][214] 

Complications

Complications from Leydig cell tumors arise mainly from delays in diagnosis and treatment; these delays may result in gynecomastia, infertility, hypogonadism, or erectile dysfunction.[39] Delayed or inadequate treatment of malignant Leydig cell tumors may result in metastases and death.[215] Unfortunately, diagnostic delay in testicular cancer is common, with a mean delay of 26 weeks.[216] Patient-mediated delays are mainly due to lack of awareness, embarrassment, denial, fear of cancer, or emasculation.[217] Physician-mediated delay is most commonly due to initial misdiagnosis of the testicular tumor as an infection.[216]

Retroperitoneal lymph node dissections have a significant complication rate (up to 96% in one study) and a 30-day hospital readmission rate of 7%.[184][186][187][188] Smoking and concomitant vascular repair/reconstruction are risk factors.[184] For these complex and demanding surgeries, the American Urological Association advocates for the procedure, and the National Comprehensive Cancer Network guidelines recommend that patients requiring retroperitoneal lymph node dissections be managed at a high-volume center of excellence.[189][190] 

Deterrence and Patient Education

Patients diagnosed with Leydig cell tumors should be informed that a large majority of these tumors are benign, and orchiectomy is curative in almost all cases. Early detection and treatment can be vital for fertility preservation in men due to the detrimental effects of long-term estrogen exposure on spermatogenesis.[133] Patients considered for testis-sparing surgery must understand the risks and accept the requirement for prolonged surveillance. They must also be educated on the pros and cons of sperm banking, accept the possibility of a radical orchiectomy, and decide if they desire a testicular prosthesis. Informing patients that even after tumor excision, 40% of men presenting with hypogonadism may still require testosterone replacement therapy is essential.

Pearls and Other Issues

Pearls and other important information regarding Leydig cell cancer of the testis include the following:

  • Approximately 1% (0.5% to 2%) of all adult neoplasms and 5% of all urological tumors are testicular in origin.[218]
    • Of testicular tumors, 95% are germ cell tumors, and the rest, about 5%, are sex–cord stromal neoplasms, with benign Leydig cell tumors by far the most common (95%).[7] 
    • Of Leydig cell tumors, only about 2.5% in adults are malignant. (Historically, it was estimated at 10%, but recent large studies indicate an incidence of 2.5%.)[3][17][18][19][20][21][22]
  • An intraoperative frozen section should be obtained during testis-sparing surgery, and a radical orchiectomy should be done if malignancy is suspected.[143][147][151]
  • Immunohistochemistry markers for Leydig cell malignancy include the following:
    • Negative immunostaining for β-catenin, cytokeratin, WT1, alpha-fetoprotein, lactate dehydrogenase, and beta-human chorionic gonadotropin [4][55][56][57][58]
    • Positive immunostaining for inhibin, calretinin, Melan-A, CD99, and SF-1, with a high MIB-1 index, and will tend to have positive oncogenic markers (bcl-2, Ki-67, and p53) [53][58][65][66][67][68][69][62]
  • Leydig cell tumors (benign) exhibit a bimodal distribution, with an initial peak in the prepubertal age group, ranging from 4 to 10 years, and a second peak between 30 and 60 years.[3]
  • Leydig cell tumors, like other testicular tumors, most commonly present as a painless testicular mass or swelling.[98]
  • Leydig cell tumors definitively demonstrate malignancy by metastasizing.[170]
  • Prolonged surveillance is necessary because late metastases from Leydig cell tumors have been reported even many years after orchiectomy.[7][43][48]
  • Radical orchiectomy alone is generally curative for clinically benign Leydig cell tumors, but surveillance is recommended.[7][43][48][55]
  • Retroperitoneal lymphadenectomy should be considered if pathology suggests a Leydig cell malignancy or if enlarged retroperitoneal lymph nodes are present.[48]
  • Testis-sparing surgery is considered if the clinical findings suggest a Leydig cell tumor, preoperative testicular tumor marker levels are within normal limits, and the tumor is less than 2.5 cm.[143][147]
  • The only effective treatment for malignant Leydig cell tumors besides radical orchiectomy is retroperitoneal lymph node dissection because they are resistant to chemotherapy and radiation.[21][169]
  • There are no reported cases of malignant Leydig cell tumors in the prepubertal pediatric population.[13][14][15][16]
  • Due to the hormonal production of Leydig cell tumors, patients may present with symptoms of gynecomastia, breast tenderness, precocious puberty, infertility, hypogonadism, or erectile dysfunction.[3][8][99]
    • The most common symptom in adult patients is gynecomastia, due to the conversion of excess (unregulated) testosterone to estradiol by aromatase enzymes.[3][8]

Enhancing Healthcare Team Outcomes

The diagnosis and management of Leydig cell malignancies can be particularly challenging, especially given the tumor's relative rarity and highly variable presentation. Generally, the longer the delay in diagnosis, the worse the outcomes; therefore, an educated interprofessional healthcare team is beneficial in diagnosing and managing small testicular masses and suspected Leydig cell tumors.[118][119][219] Primary care and emergency department clinicians should consider ultrasonography as a routine extension of the physical examination for any patient with unilateral scrotal swelling, a solid intrascrotal lump, or unexplained testicular pain.[113] They should refer patients with equivocal ultrasound results to a urologist for further evaluation and treatment.

Primary care physicians and endocrinologists should consider Leydig cell tumors in the differential diagnosis of male infertility, hypogonadism, and particularly gynecomastia.[7][134] Specialty-trained nursing staff in urology and oncology can be invaluable throughout the diagnosis and management of these tumors, providing counseling and patient education, assisting during procedures, and facilitating surveillance examinations. The entire interprofessional team, comprising primary care clinicians, endocrinologists, urologists, radiologists, oncologists, radiation therapists, sonographers, and nurses, should communicate and collaborate to enhance patient care, facilitate early diagnosis, and optimize outcomes.

Media


(Click Image to Enlarge)
<p>Leydig Cell Tumor

Leydig Cell Tumor. This histological image reveals sheets and cords of polygonal cells with abundant eosinophilic cytoplasm, round nuclei with prominent nucleoli, and pathognomonic eosinophilic Reinke crystals—all set within a delicate, vascular stroma.

Contributed by S Bhimji, MD

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