Testicular sex cord stromal tumors

INTRODUCTION — Sex cord stromal tumors (SCSTs) comprise approximately 5 percent of all testicular tumors, while the remainder are of germ cell origin [1-3]. SCSTs, which arise from the supporting tissues of the testis, include Leydig, Sertoli, and granulosa cell tumors, as well as tumors in the fibroma-thecoma family of tumors, and mixed and other SCST subtypes (table 1) [4-8].

The clinical presentation and management of SCSTs are discussed here. The following topics are discussed separately:

●Anatomy and pathology of SCSTs (see "Anatomy and pathology of testicular tumors", section on 'Sex cord-stromal tumors')

●Clinical manifestations, diagnosis, and staging of testicular germ cell tumors (see "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors")

●Treatment approach to testicular germ cell tumors (see "Initial risk-stratified treatment for advanced testicular germ cell tumors")

●Treatment approach to ovarian SCSTs (see "Sex cord-stromal tumors of the ovary: Management in adults")

CLASSIFICATION AND EPIDEMIOLOGY — According to the World Health Organization (WHO), testicular non-germ cell tumors are classified as follows (table 1) [8]:

Leydig cell tumors — Leydig cell tumors are the most common testicular SCSTs and account for 1 to 2 percent of all testicular tumors [2]. In a series of approximately 79,000 cases of testicular cancer in the National Cancer Database, 250 were malignant Leydig tumors (0.3 percent) [9]. The pathology of these tumors is discussed separately. (See "Anatomy and pathology of testicular tumors", section on 'Leydig cell tumors'.)

Leydig cell tumors can present at any age, with peak presentations in children between the ages of 5 and 10 years and in adults between the ages of 30 and 35 years [2]. These tumors are most commonly diagnosed in adults [4,10].

Sertoli cell tumors — Sertoli cell tumors (SCT) are classified as malignant Sertoli cell tumor (not otherwise specified [NOS]) and large cell calcifying Sertoli cell tumor (LCCSCT). Sclerosing SCT is part of the spectrum of SCT NOS [11]. Sertoli cell tumors are the second most common type of testicular SCST, after Leydig cell tumors, and account for 0.1 percent of testicular tumors in an analysis from the National Cancer Database [2,9]. (See "Anatomy and pathology of testicular tumors", section on 'Sertoli cell tumors'.)

Sertoli cell tumors can present at any age, with a reported mean of 45 years [5]. However, patients with the large cell calcifying variant tend to be younger, with an average age at diagnosis of 21 years [12].

Granulosa cell tumors — Granulosa cell tumors are rare neoplasms that are similar to their ovarian counterparts. They are divided into adult and juvenile types. (See "Anatomy and pathology of testicular tumors", section on 'Granulosa cell tumors'.)

●Adult type – The adult type of granulosa cell tumor is very rare in the testis [13]. The average age at presentation is 44 years [2,14,15].

●Juvenile type – The juvenile type of granulosa cell tumor is the most common testicular tumor of infancy and is only rarely seen in adults [16]. These tumors are most commonly seen in infants less than six months old [3]. These tumors appear to be uniformly benign.

Other tumor types — Other stromal tumors arising in the testis include:

●The fibroma-thecoma family of tumors – Testicular fibromas are very rare with approximately 50 total reported cases [17]. Testicular fibromas are derived from either the gonadal stroma or tunica albuginea. While they resemble ovarian fibromas, these tumors are much rarer. (See "Anatomy and pathology of testicular tumors", section on 'Fibroma thecoma family of tumors'.)

●Mixed and other sex cord stromal tumors – These tumors contain either a mixture of sex cord stromal elements or cells with no specific differentiation. These tumors comprise about five percent of SCSTs. Approximately 50 percent of these tumors occur in children, although they can present at any age. (See "Anatomy and pathology of testicular tumors", section on 'Mixed and other sex cord-stromal tumors'.)

●Gonadoblastoma – Gonadoblastoma is composed of neoplastic germ cells and sex cord stromal cells. It is a precursor of invasive tumors such as dysgerminoma/seminoma. Gonadoblastomas usually occur with disorders of sex development before age 20 and involve the bilateral testes [11]. (See "Anatomy and pathology of testicular tumors", section on 'Gonadoblastoma' and 'Additional diagnostic evaluations' below.)

RISK FACTORS — There are no known risk factors for testicular SCSTs, although some may be associated with certain genetic conditions. (See 'Additional diagnostic evaluations' below.)

Is cryptorchidism a risk factor? — Unlike testicular germ cell tumors, there has been no definitive association with cryptorchidism or testicular dysgenesis (with the exception of gonadoblastoma), although such associations cannot be excluded [10,18]. Cryptorchidism and testicular germ cell tumors are discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Cryptorchidism' and "Epidemiology and risk factors for testicular cancer", section on 'Cryptorchidism' and "Treatment-related toxicity in testicular germ cell tumors", section on 'Gonadal effects'.)

CLINICAL PRESENTATION

Symptoms — The diagnosis of testicular SCST should be suspected in young adults and prepubescent males presenting with testicular abnormalities and/or other specific endocrinologic manifestations, such as gynecomastia [3,4,19].

Testicular mass — The most common clinical presentation in patients with testicular SCST is an asymmetric testicular mass. While a majority of masses are painless, some may present with dull discomfort, scrotal heaviness, or swelling [3,20]. Acute testicular pain is rare and may indicate bleeding within the tumor or concomitant epididymitis [3].

Endocrine manifestations

●Adults – In adults, endocrine manifestations are found in 20 to 30 percent of patients with SCST and may precede development of a testicular mass [3,21]. Patients with Leydig cells tumors may present with either virilizing or feminizing symptoms, as Leydig cells are capable of producing both androgens and estrogen [10]. By contrast, patients with Sertoli cell tumors may present with signs of feminization (due to hyperestrogenism) in 20 to 30 percent of cases, but virilization is rarely seen. Further details on the histologic subtypes of testicular SCSTs are found above. (See 'Classification and epidemiology' above.)

The most common endocrinologic symptom is gynecomastia, which occurs in 20 to 30 percent of patients with Leydig cell tumors [22]; 26 to 33 percent of those with Sertoli cell tumors [23]; and 20 to 50 percent of those with adult type granulosa cell tumors [2,14,15]. Gynecomastia is typically caused by excess estrogen production from the SCST but may also result from excess testosterone from the tumor that is converted to estrogen via aromatization in peripheral tissues [24]. (See "Clinical features, diagnosis, and evaluation of gynecomastia in adults".)

Other common endocrinologic symptoms in adults include impotence, loss of libido, erectile dysfunction, and infertility [1,10,20,22].

●Children – Children with testicular SCSTs commonly present with precocious puberty [25]. In those with Leydig cell tumors, precocious puberty is typically noted between the ages of 6 and 10 years [1]. In boys with precocious puberty, Leydig cell tumor should be considered if asymmetric testicular enlargement is also present. Signs and symptoms of precocious puberty are discussed in detail separately. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Classification'.)

In contrast to older children, infants with juvenile granulosa cell tumors lack hormonal symptoms. These patients more typically present with sex chromosome abnormalities, ambiguous genitalia, and ipsilateral cryptorchidism [26].

Systemic symptoms — Systemic symptoms are less common as approximately 10 to 20 percent of patients present with metastatic disease at initial diagnosis [3]. The most common sites of metastatic disease are the retroperitoneal lymph nodes (70 percent). Less common sites of disease include the liver (45 percent), lungs (40 percent), and bones (25 percent) [3,4,27,28].

Patients with symptomatic involvement of these sites may present with constitutional symptoms (eg, weight loss), pulmonary symptoms (eg, cough, shortness of breath, chest pain), abdominal pain, or bony discomfort. Patients with retroperitoneal involvement are typically asymptomatic. Unlike testicular germ cell tumors, neurologic symptoms due to brain metastases are extremely rare [29].

The clinical presentation for testicular germ cell tumors is discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Clinical manifestations'.)

Age of presentation — SCSTs most commonly present in young adults and prepubescent males. In general, there is a wide age range for adults with SCSTs, ranging between 14 and 87 years [30,31]. The age of presentation is associated with each particular histologic subtype and is discussed separately. (See 'Classification and epidemiology' above.)

Physical exam — In patients with suspected testicular SCST, physical exam should include a testicular exam, and the approach is similar to that of patients with suspected testicular germ cell tumors. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Testicular examination'.)

The most common physical exam finding in young adults and prepubescent males is a palpable, asymmetric testicular mass. Testicular masses may also be discovered incidentally on routine physical examination or during scrotal ultrasound evaluation for endocrine symptoms and/or excess sex hormone production [4,19].

Prepubescent males should also be evaluated for signs of precocious puberty, which may include testicular and penile enlargement, pubic and/or axillary hair, and apocrine odor. Other signs include increased linear growth for age and advanced bone age. In particular, Leydig cell tumors should be suspected in patients with precocious puberty if asymmetric testicular enlargement is also present and continues to increase on clinical follow-up. (See 'Additional diagnostic evaluations' below.)

By contrast, exam findings on infants with juvenile granulosa cell tumors include ambiguous genitalia and ipsilateral cryptorchidism [26].

The chest should be examined for gynecomastia, another common physical exam finding. It is important to obtain a baseline assessment of gynecomastia at diagnosis, which can be clinically monitored to indirectly assess treatment response and possible disease recurrence. (See 'Surveillance' below.)

Gynecomastia may be the initial presenting symptom of a testicular SCST and, in some cases, even precede the development of a testicular mass or other endocrinologic abnormalities [21]. Therefore, diagnostic evaluation for a testicular mass should still be obtained in patients with gynecomastia and a normal manual testicular exam. (See 'Diagnostic evaluation' below.)

The lungs should be auscultated for potential lung/thoracic involvement and the abdomen palpated for potential liver involvement. Although most bony involvement may be asymptomatic, any areas of bony discomfort should be carefully examined for discrete tenderness to palpation or fractures. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults".)

DIAGNOSTIC EVALUATION — An SCST should be suspected in patients with a testicular mass and endocrinologic abnormalities (ie, gynecomastia). (See 'Clinical presentation' above.)

The initial diagnostic evaluation of a patient with a suspected SCST is discussed below.

Scrotal ultrasound — Scrotal ultrasound is the diagnostic imaging tool of preference, as it has a high sensitivity for diagnosing testicular tumors (98 to 100 percent) [3]. Scrotal ultrasound can also be used to distinguish testicular SCST from other non-malignant diagnoses such as epididymitis or hydrocele. However, ultrasound findings for certain testicular SCST and germ cell tumors may be similar, and pathology is needed to distinguish between the two possible diagnoses. (See 'Diagnosis' below.)

For example, Leydig cell tumors typically appear as hypoechoic and hypervascular lesions on ultrasound [3]. Large cell calcifying Sertoli cell tumors have a classic presentation on ultrasound, including dense areas of calcification within the involved testis [32]. By contrast, Sertoli cell tumors and testicular germ cell tumors (such as seminomas) may both be hypoechoic with peripheral vascularity and thus difficult to distinguish from each other on ultrasound alone without surgical pathology [33]. The specific ultrasound findings for patients with testicular germ cell tumors are discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Scrotal ultrasound'.)

Tumor markers and hormonal markers — In patients with a suspected testicular SCST, we evaluate for both tumor markers and hormonal markers [3]. For tumor markers, we check lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and beta-human chorionic gonadotropin (B-hCG). For hormonal markers, we check testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). If tumor markers are not detected, or if patients have signs of feminization, we also check estrogen, estradiol, progesterone, and cortisol.

Normal levels of LDH, AFP, and hCG may indicate the diagnosis of a testicular SCST, which does not produce these particular tumor markers [3] but cannot distinguish between testicular SCSTs and other germ cell tumors (which can also lack these tumor markers). By contrast, elevated levels of these tumor markers could indicate the presence of a testicular germ cell tumor as an alternative diagnosis. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Serum tumor markers'.)

Similarly, hormonal markers are more commonly elevated in patients with testicular SCST compared with patients with germ cell tumors, who typically have normal serum levels of LH, FSH, testosterone, and estradiol [3].

Additional diagnostic evaluations — In patients with a suspected diagnosis of testicular SCST, additional diagnostic evaluations are suggested for the following specific findings:

●Precocious puberty – The diagnosis of testicular SCSTs should be suspected in prepubescent boys with precocious puberty and testicular asymmetry. Even if a distinct mass cannot be palpated and is not detectable by ultrasonography, the larger testis should be assessed surgically if it enlarges during follow-up. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Males' and 'Diagnosis' below.)

These patients should also be assessed for congenital adrenal hyperplasia, which can also present in children with symptoms of virilizing precocious puberty or ambiguous genitalia and can be associated with hyperplastic testicular nodules. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

●Genetic conditions – Testicular SCSTs can, in rare circumstances, be associated with certain genetic conditions. For example, Leydig cell tumors can be associated with certain genetics conditions such as Klinefelter syndrome, hereditary leiomyomatosis, and hereditary renal cell cancer syndromes [2,34,35]. Sertoli cell testicular tumors have been associated with two inherited disorders, Peutz-Jeghers syndrome and Carney complex [36,37]. Gonadoblastomas can be associated with male pseudohermaphroditism with presenting features of cryptorchidism, hypospadias, and gynecomastia.

Males with signs or symptoms of such conditions should seek clinical evaluation and appropriate genetic counseling. As examples:

•Unexplained infertility should prompt an evaluation for Klinefelter syndrome, which is associated with Leydig cell tumors. The diagnosis of Klinefelter syndrome is often made in adulthood due to the variability of phenotype severity and the failure of many clinicians to recognize its clinical features. (See "Clinical features, diagnosis, and management of Klinefelter syndrome".)

•Multiple skin leiomyomata and/or renal masses should prompt an evaluation for hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC), which has also been associated with Leydig cell tumors [34]. (See "Hereditary kidney cancer syndromes", section on 'Hereditary leiomyomatosis and renal cell cancer syndrome'.)

•Multiple hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation, and a history of certain gastrointestinal malignancies should prompt an evaluation for Peutz-Jeghers syndrome, which is associated with Sertoli cell tumors. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)

•Distinctive pigmented lesions of the skin and mucosal surfaces, cardiac and noncardiac myxomatous tumors, and multiple endocrine tumors should prompt an evaluation for Carney complex, which is also associated with Sertoli cell tumors. (See "Carney complex", section on 'Diagnosis'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for patients with similar signs and symptoms to those with SCSTs includes both malignant and benign etiologies.

Malignant etiologies include testicular germ cell tumors and tumors of other cell types presenting in the testes such as lymphoma, carcinoid tumors, and metastatic carcinoma. (See "Anatomy and pathology of testicular tumors".)

Benign etiologies include epididymitis, epididymo-orchitis, and testicular torsion [3]. Less commonly, this presentation can be associated with hernias, hematomas, hydrocele, spermatocele, varicocele, or hematocele. (See "Acute scrotal pain in adults" and "Causes of scrotal pain in children and adolescents".)

DIAGNOSIS — The diagnosis and histologic classification of an SCST is made on pathologic evaluation upon surgical resection of the testicular tumor.

Radical orchiectomy — All patients undergo initial surgical treatment with inguinal orchiectomy [38,39]. Surgical resection establishes the histopathologic diagnosis, treats the primary tumor, and predicts risk for metastatic disease (based on the pathologic findings at orchiectomy). (See 'Stage IIA or high-risk features on orchiectomy' below.)

Radical resection remains the procedure of choice over partial orchiectomy [38]. Although retrospective observational data suggest that partial orchiectomy results in similar disease-free survival (DFS) compared with radical orchiectomy [39], there are limited prospective data to inform the decision between the two procedures. As an example, in one observational study of 56 patients with Leydig cell tumors, the local recurrence rate for partial orchiectomy was 10 versus 0 percent for radical orchiectomy. DFS was similar between the two treatment arms [39].

EVALUATION OF CONFIRMED DISEASE

Staging imaging — For patients with histologically confirmed Leydig, Sertoli, or granulosa cell tumors on orchiectomy specimens, we suggest staging for evidence of metastatic disease using computed tomography (CT) of the chest, abdomen, and pelvis. (See 'Radical orchiectomy' above.)

The role of positron emission tomography-CT (PET-CT) scans for staging of these tumors has not been defined. The presence of symptoms should determine whether other tests (eg, bone scan, neuroimaging) are indicated to evaluate for distant metastatic disease.

Patients with testicular SCST are staged using pathology from orchiectomy specimens and from systemic imaging, using the American Joint Committee on Cancer (AJCC) eighth edition staging system for testicular germ cell tumors (table 2A-B) [40]. Children are staged using the Children's Oncology Group staging system (table 3), which is also applicable to those with both germ cell and SCST histologies.

Assessment of pituitary/gonadal axis — In patients with histologically confirmed Leydig, Sertoli, or granulosa cell tumors, assessment of the pituitary/gonadal axis is recommended regardless of whether patients have localized or metastatic disease. This evaluation includes measurement of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, progesterone, estrogen, estradiol, and cortisol [5]. These labs may have been assessed prior to histologic confirmation, based on clinical suspicion for the diagnosis of testicular SCST. If any of these hormones were elevated, they may be serially evaluated as a marker of response to therapy, such as orchiectomy. (See 'Tumor markers and hormonal markers' above.)

The incidence of hypogonadism after orchiectomy appears to be higher in males with SCSTs than in those with germ cell tumors (42 versus 5 to 13 percent) [4,41]. Thus, males with SCSTs are more likely to need testosterone replacement following surgery [4]. (See "Testosterone treatment of male hypogonadism".)

MANAGEMENT AFTER ORCHIECTOMY

Localized disease — For patients with localized (stage I or II) disease, we suggest the approach outlined in the sections below.

Stage I disease — For patients with stage I disease (table 2A-B) treated curatively with orchiectomy and without high-risk pathologic features, we suggest observation rather than further interventions, as these patients have a favorable prognosis. The approach to patients with high-risk pathologic features on orchiectomy is discussed below. (See 'Stage IIA or high-risk features on orchiectomy' below.)

The good prognosis for patients with clinical stage I disease is also supported by two single-institution retrospective series. In one report, 38 males were successfully managed with excision of the primary tumor alone [42]. At a median follow-up of seven years, none had developed metastatic disease. In another series of 48 males with short-term follow-up, the conclusion was that patients with one or no high-risk features can be safely observed without retroperitoneal lymph node dissection (RPLND) [43,44].

Stage IIA or high-risk features on orchiectomy — For patients with clinical stage IIA disease (table 2A-B) or those with two or more high-risk features on orchiectomy, we suggest early RPLND rather than observation. These risk factors can predict the risk for occult metastatic disease at the time of orchiectomy [45]:

●Tumor >5 cm

●>3 mitoses per high-powered field

●Positive margins

●Rete testis invasion

●Lymphovascular invasion (LVI)

●Cellular atypia

●Necrosis

Patients with a tumor demonstrating two or more risk factors had a five-year occult metastatic disease-free survival (DFS) of 48 percent. Patients with tumors demonstrating fewer than two risk factors have a five-year occult metastatic DFS of 98 percent [45]. In another observational study of 17 patients with testicular SCST treated with RPLND, there were no recurrences in five patients with stage I disease and at least two risk factors [46]. These risk projections provide a guide to features of metastatic potential, although they may be limited due to the retrospective nature and small size of the published series as well as the absence of central pathology review.

Patients at high risk for metastases based on this risk stratification who decline RPLND may be offered more frequent surveillance imaging. There are no specific guidelines for such surveillance imaging in patients with testicular SCST. One reasonable approach is to follow a surveillance schedule similar to those with nonseminoma germ cell tumors of comparable stage, who have undergone a similar treatment approach. If advanced disease is detected, RPLND and/or metastasectomy could be offered at that time. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'NSGCT' and 'Advanced or metastatic disease' below.)

Advanced or metastatic disease — Patients with advanced or metastatic disease are typically treated with surgical resection of all sites of disease, as systemic chemotherapy and radiation have limited efficacy.

Surgical resection of all metastatic sites — All patients with suspected metastatic disease should undergo radical orchiectomy, similar to those with localized disease. Upon confirmation of metastatic disease on postsurgical imaging, we suggest surgical resection of all known sites of disease whenever possible. The most common procedures include RPLND and surgical metastasectomy of the lungs and liver. Such procedures typically occur separately from orchiectomy, which is required for initial histologic diagnosis [3]. (See 'Radical orchiectomy' above.)

RPLND has been used both as treatment in patients with established nodal disease on clinical imaging and as a staging procedure to resect microscopic disease [5,43,45,47]. In a large single-institution series, 17 patients with SCSTs underwent RPLND [47]. Among the nine with clinical stage I disease, retroperitoneal disease was not identified in any case, and all remained free of disease from 9 to 135 months after surgery. In the eight patients with clinical stage II or III disease, six died at 9 to 69 months after surgery, one was alive with disease at 13 months, and one was disease free at eight months.

In patients with limited metastatic disease to sites other than the retroperitoneal lymph nodes, metastasectomy is offered because the response to chemotherapy and radiotherapy is generally poor [18,47-49]. In one observational study of eight patients with metastatic disease treated with aggressive surgery including RPLND and metastasectomy, median overall survival was 1.2 years [46,47]. For those who do not pursue or delay surgery, survival is typically less than one year.

Is there a role for chemotherapy or radiation? — Systemic chemotherapy or radiation therapy (RT) have a limited role in patients with unresectable metastatic disease, as these treatments have low response rates [50]. We typically reserve these therapies for palliation in those with widespread unresectable disease. Patients should be referred for clinical trials where available.

●Cisplatin-based regimens for testicular cancer – Active testicular germ cell regimens such as BEP (bleomycin, etoposide, cisplatin) or VIP (vinblastine, ifosfamide, cisplatin) have been relatively ineffective, with only transient responses [4,47,51].

●Mitotane – Leydig cell tumors and adrenocortical cancers have common histologic and biochemical features. Case reports of mitotane, an agent used in adrenocortical cancer, suggest low palliative response rates [4,52,53]. (See "Treatment of adrenocortical carcinoma", section on 'Mitotane monotherapy'.)

●Other systemic agents – Data are limited for the utility of other systemic agents, such as other chemotherapy regimens (eg, taxanes, gemcitabine), antiangiogenic agents, tyrosine kinase inhibitors, and checkpoint inhibitor immunotherapy [54].

●Radiation therapy (RT) – RT has generally been unsuccessful in the treatment of metastatic testicular SCSTs with limited response rates [55,56]. In select patients with spinal cord compression from bony metastases treated with initial surgery, postoperative radiation may be offered to palliate symptoms and/or attenuate the potential for recurrent tumor growth at the site of surgical decompression [57].

●Clinical trials – Given the rarity of these tumors and lack of effective therapies for metastatic SCSTs, we suggest referral to a tertiary care center and evaluation for clinical trials where available. Tumor gene profiling to assess for actionable targets is also appropriate, in the context of detecting actionable mutations for such trials, although data are limited for the identification of therapeutic targets. As an example, in one report of tumor sequencing of primary and metastatic sites of testicular SCSTs, targetable genomic alterations were uncommon [58]. However, several potential molecular alterations could be targeted on clinical trials:

•Cell cycle inhibitors (cyclin-dependent kinase 4 [CDK4])

•Mechanistic target of rapamycin (mTOR)

•Moesin-ezrin-radixin like (MERLIN) tumor suppressor (NF2)

•Phosphatase and tensin homolog (PTEN)

•Hedgehog inhibitors (protein patched homolog 1 (PTCH1)

•Poly(ADP-ribose)-polymerase (PARP) inhibitors (breast cancer type 1 [BRCA1]-associated protein 1 [BAP1])

Of note, there were no microsatellite instability (MSI)-high tumors, suggesting that these tumors may not be responsive to checkpoint inhibitor immunotherapy and that such therapy should be evaluated in the context of a clinical trial. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

PROGNOSIS

Localized disease — Patients with localized disease (table 2A-B) have an overall favorable prognosis, and treatment intent is typically curative. Five-year overall survival rates range between 91 percent for those with Leydig cell tumors and 77 percent for those with Sertoli cell tumors [9,42].

Advanced or metastatic disease — Although most testicular SCSTs are benign, the prognosis is poor for patients with advanced or metastatic SCSTs (ie, those with disease that has metastasized to the retroperitoneal lymph nodes or distant organs). Approximately 10 to 20 percent of patients with SCSTs develop distant metastases and ultimately die from their disease. Although prolonged survival has been reported, the median survival is between one and two years, and two-thirds of patients die within two years of developing metastases [4,10,59].

SURVEILLANCE — In patients treated curatively for testicular SCSTs, we suggest obtaining any tumor or hormonal markers elevated at diagnosis and computed tomography (CT) of the chest, abdomen, and pelvis every three to six months for the first two years after treatment completion, as metastatic disease occurs most commonly during this time [3,20]. Alternatively, for adults, clinicians may offer a surveillance schedule similar to those with nonseminomatous germ cell tumors of comparable stage and treatment approach. Children with an age-related elevation in alpha-fetoprotein (AFP) at diagnosis should have this marker monitored regularly to ensure a clinically appropriate decline [20]. Patients with juvenile granulosa cell tumor do not require any surveillance imaging or labs [20]. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'NSGCT'.)

The duration and frequency of further follow-up is dependent upon the clinician and the patient's histologic diagnosis and clinical disease status. For example, lifelong surveillance is suggested in patients with certain subtypes of SCSTs such as adult type granulosa cell tumors, as these patients can develop metastatic disease many years after diagnosis [2]. (See "Approach to the care of long-term testicular cancer survivors".)

Patients with gynecomastia at diagnosis may be clinically monitored for regression of symptoms, which occurs in approximately 80 percent of patients treated with radical orchiectomy [3]. Persistent or progressive gynecomastia may indicate the presence of a contralateral tumor or recurrent or progressive disease.

The approach to surveillance of patients with testicular germ cell tumors is discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testicular cancer".)

SUMMARY AND RECOMMENDATIONS

●Common histologies – Testicular sex cord stromal tumors (SCSTs) are rare tumors that arise from the supporting tissues of the testis. Common histologies include Leydig cell tumors, Sertoli cell tumors, and granulosa cell tumors (table 1). (See 'Classification and epidemiology' above.)

●Clinical presentation – The diagnosis of testicular SCST should be suspected in males presenting with testicular abnormalities and/or specific endocrinologic manifestations (eg, gynecomastia). (See 'Clinical presentation' above.)

●Diagnostic evaluation – The initial diagnostic evaluation of a patient with a suspected testicular SCST includes a scrotal ultrasound, tumor markers, and hormonal markers. (See 'Diagnostic evaluation' above.)

●Diagnosis – For all patients presenting with a testicular mass thought to be an SCST, we suggest a radical inguinal orchiectomy rather than a partial orchiectomy (Grade 2C), in order to establish the histopathologic diagnosis and treat the primary tumor. (See 'Diagnosis' above.)

●Staging imaging – For patients with histologically confirmed testicular SCST, we suggest staging for evidence of metastatic disease using computed tomography (CT) of the chest, abdomen, and pelvis (table 2A and table 2B and table 3). (See 'Staging imaging' above.)

●Management

•Stage I – For patients with stage I disease treated curatively with orchiectomy and without high-risk pathologic features, we suggest observation rather than further interventions (Grade 2C), as these patients have a favorable prognosis. (See 'Stage I disease' above.)

•Stage IIA or high-risk features on orchiectomy – For patients with clinical stage IIA disease or those with two or more high-risk pathologic features on orchiectomy, we suggest early retroperitoneal lymph node dissection (RPLND) rather than observation (Grade 2C). (See 'Stage IIA or high-risk features on orchiectomy' above.)

•Resectable advanced or metastatic disease – For patients with advanced or metastatic disease who are surgical candidates, we suggest surgical resection of all known sites of disease (including RPLND) rather than other treatment modalities (eg, chemotherapy, radiation) (Grade 2C). Surgery to metastatic sites typically occurs after radical orchiectomy has taken place. (See 'Advanced or metastatic disease' above.)

•Unresectable metastatic disease – For patients with unresectable metastatic disease, systemic chemotherapy or radiation therapy (RT) have a limited role due to low response rates. Patients should be evaluated for clinical trials where available. (See 'Is there a role for chemotherapy or radiation?' above.)

●Surveillance – For patients treated curatively for testicular SCST, we recommend surveillance with tumor and hormonal markers elevated at diagnosis and CT of the chest, abdomen, and pelvis every three to six months for the first two years after treatment completion. The duration and frequency of further follow-up is dependent upon the clinician and the patient's histologic diagnosis and clinical disease status. Alternatively, clinicians may offer a surveillance schedule similar to those with nonseminomatous germ cell tumors of comparable stage and treatment approach. (See 'Surveillance' above.)