Testicular Sex Cord–Stromal Tumors

Mayank Kapoor; Stephen Leslie

Testicular Sex Cord–Stromal Tumors

Author: Mayank Kapoor Editor: Stephen W. Leslie Updated: 6/5/2024 3:14:08 AM

Introduction

Most solid testicular neoplasms (comprising 95%) are germ-cell tumors, categorized as either seminomatous or nonseminomatous tumors.[1][2][3] This leaves 5% of testicular neoplasms, which encompass the very rare testicular sex cord–stromal tumors (SCSTs). These tumors are usually benign, heterogeneous groups of neoplasms that arise from the supportive and hormone-producing tissues of the testes. Please see StatPearls' companion resources, "Nonseminomatous Testicular Tumors" and "Testicular Seminoma," for further information.[1][2]

SCSTs include Leydig and Sertoli cell tumors, adult- and juvenile-type granulosa cell neoplasms, gonadoblastomas, fibroma-thecomas, and mixed-type stromal tumors.[4] Of these, the most common type of SCST is the Leydig cell tumor, accounting for over 90% of these cases.[4][5] Although SCSTs constitute a small percentage of all testicular cancers, their unique characteristics and the complexities involved in their diagnosis and treatment make them a significant area of interest for medical professionals. A comprehensive understanding of the pathophysiology, clinical presentation, diagnostic techniques, and treatment options for SCSTs is essential for enhancing patient outcomes.

Etiology

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Etiology

SCSTs are believed to develop from neoplastic changes in normal sex-cord or stromal testis tissue elements.[6] Few known risk factors are associated with the development of SCSTs. Unlike germ cell tumors, which strongly correlate with undescended testes, SCSTs have not demonstrated such associations, although further studies are needed.[7][8] Genetic inheritance has a much less important role in SCSTs than in testicular cancer. Although genetic factors typically account for less than 20% risk in most other cancers, inheritance of germ cell tumors of the testes falls in the range of 37% to 49%.[9]

SCSTs have sometimes been associated with various underlying genetic conditions, such as:[10]

Leydig cell tumors: These have been associated with Klinefelter syndrome, hereditary leiomyomatosis, and renal cell cancers.[11][12][13][14] Please see StatPearls' companion resources, "Klinefelter Syndrome" and "Renal Cell Cancer," for further information.[15][16]

Sertoli cell testicular neoplasms: These are associated with the Carney complex and Peutz-Jeghers syndrome.[17][18][19][20] Please see StatPearls' companion resources, "Carney Complex" and "Peutz-Jeghers Syndrome," for further information.[17][18]

Gonadoblastomas: These may present with cryptorchidism, gynecomastia, hypospadias, and male pseudohermaphroditism.[10]

Sertoli-Leydig cell tumors and paratesticular sarcomas: These may be linked to DICER1 syndrome.[10][21]

In addition, SCSTs have also been associated with adenomatous polyposis coli (APC) germline mutations and familial adenomatous polyposis syndrome.[10][22][23] Please see StatPearls' companion resource, "Familial Adenomatous Polyposis," for further information.[23]

Epidemiology

Testicular cancer is rare and accounts for only 1% of all male tumors.[3] SCSTs comprise about 5% of adult testicular neoplasms, increasing to 8% of all testicular tumors in the pediatric age group.[4][24] The most common type of SCST is the Leydig cell neoplasm, which makes up over 90% of SCSTs and about 1% to 2% of all testicular neoplasms. Overall, 80% of Leydig cell tumors occur in adults aged between 30 and 35, while in children, the peak age is between 5 and 10.[25]

As mentioned below, SCSTs demonstrate varying prevalence and risk factors based on age, race, ethnicity, and geography.

Age: The most prevalent age group for SCSTs is 20 to 34, which includes half of the total cases. Prepubertal males have a slightly higher risk for these neoplasms.

Race and ethnicity: In White men, the incidence is 4 to 5 times greater than in Black and Asian Americans. The risk among American Indians falls between the Asian and White ethnic groups. Black Americans tend to have higher-grade disease and a worse prognosis than White populations.[26]

Geography: The highest risk is in the United States and Europe, whereas it is lowest in Africa and Asia.

Recent studies suggest that the true incidence of Leydig cell tumors may have been significantly underestimated, indicating that these tumors might actually be present in 14% to 22% of all orchiectomy specimens removed for malignancy.[25][27]

Pathophysiology

Poor gonadal development may lead to testicular neoplasms. Various histological studies show that diverse dysgenetic features are seen in these patients. These features include tubules that are undifferentiated and immature Sertoli cells.[28][29][30][31] Mutations and polymorphisms, along with environmental and lifestyle factors, may alter the Leydig and Sertoli cells during early development, ultimately resulting in SCSTs. The spectrum of outcomes ranges from the most severe but least common form of dysgenesis syndrome (a disorder of sexual development with gonadoblastoma or germ cell neoplasia in situ) to the mildest but most common form of abnormal spermatogenesis.[32]

SCSTs are usually not aggressive neoplasms, and the majority of them are benign.[33] Only about 2.5% of Leydig cell tumors are malignant, and this is only the case in adults; in children, these tumors are benign.[5][25][33] The National Cancer Database, which contains over 79,000 cases of testicular malignancies, has only 250 recorded cases of cancerous Leydig cell tumors.[34] In general, about 10% of all SCST cases are cancerous, with 20% being metastatic at the time of diagnosis, usually to the retroperitoneal lymph nodes (70%).[35] Gonadoblastomas are exclusively found in the dysgenetic gonads of individuals with a disorder of sexual development, and they are considered benign.[36]

Histopathology

SCSTs originate in the supporting tissue of the testes, including Leydig, Sertoli, and granulosa cell tumors. Other non-germ cell tumors not considered SCSTs include tunica vaginalis malignant mesotheliomas, adenocarcinomas of the rete testes, testicular lymphoma, and paratesticular rhabdomyosarcoma. SALL4 is a stem cell marker that is positive in germ cell tumors but negative in SCSTs, whereas inhibin alpha is negative in germ cell tumors but positive in SCSTs.[37][38][39] These two markers are very useful for quickly distinguishing between these types of testicular tumors.[37][38][39]

Major Types of Testicular Sex Cord–Stromal Tumors

Leydig cell, Sertoli cell, and granulosa cell tumors constitute the majority of SCSTs, with Leydig cell tumors being the most common. The following classification is based on the World Health Organization (WHO) guidelines.[4][24][40]

Leydig cell tumors: These are generally benign testicular neoplasms that develop from the Leydig cells located in the interstitium of the testes between the seminiferous tubules.[41][42][43] The normal function of Leydig cells is to produce testosterone when stimulated by luteinizing hormone (LH) from the pituitary. Grossly, Leydig cell tumors are well-circumscribed and typically measure 3 to 5 cm in diameter at diagnosis. Their cut surface ranges from golden brown to yellow. They are bilateral in 3% of cases, and about 2.5% are malignant (previously thought to be 10%), usually occurring in adults.

Microscopically, tumor cells tend to be large and polygonal, displaying either a predominantly diffuse or nodular pattern.[25] In the nodular pattern, stroma with extensive hyalinization and wide bands may be observed. Hemorrhage and/or necrosis are present in about 30% of cases. The cytoplasm of these cells is typically mildly granular and can be clear or eosinophilic, often with a high lipid content. The nuclei are generally round with a single prominent nucleolus.[25]

Eosinophilic Reinke crystals are present in the cytoplasm in about 33% of cases.[44] They are pathognomonic for Leydig cells but do not necessarily indicate malignancy.[44] Lipochrome pigment may be present in 10% to 15% of cases.[45][46][47]

Malignancy is suggested by larger tumor size (>5 cm), evidence of lymphovascular invasion, necrosis, significant pleomorphism, DNA aneuploidy, greater MIB-1 expression, and increased mitotic activity.[8][45][48][49] Conversely, gynecomastia, lipofuscin pigmentation, and Reinke crystals tend to make Leydig cell malignancy less likely.[50]

Cytogenetically, Leydig cell tumors commonly exhibit a gain of chromosome X, 19, and 19p, along with the loss of chromosomes 8 and 16. In a few childhood cases, Ledig cell tumors will have acquired missense mutations in codon 578 of the gene for LH/choriogonadotropin receptor (LHCGR). In addition, an FH gene mutation, which can occur sporadically or as part of the spectrum of hereditary leiomyomatosis and renal cell carcinoma syndrome, may rarely be detected.[51]

Immunohistochemistry staining of Leydig cell tumors typically shows diffusely positive cytoplasm for inhibin alpha, SF1 (positive in >95% of cases), calretinin (positive in approximately 80% of cases), Melan-A, and vimentin. However, immunostaining with cytokeratin is negative.[52][53][54]

Sertoli cell tumors: These tumors are derived from Sertoli cells found in the seminiferous tubules. The normal cellular function of Sertoli cells is to support spermatogenesis when stimulated by follicle-stimulating hormone (FSH) from the pituitary.[55][56] The classification of Sertoli cell tumors can be into large-cell calcifying, malignant, or not otherwise specified types. The previous subtype of sclerosing Sertoli cell tumor of the testis is no longer used, and these neoplasms are now classified as not otherwise specified types.[4]

A subtype of Sertoli cell tumors is associated with Peutz-Jeghers syndrome and is characterized by intratubular large-cell hyalinizing Sertoli cells with prominent basement membranes. These neoplasms secrete aromatase, leading to gynecomastia due to the conversion of androgens and estrogens in the periphery.

Most Sertoli cell tumors are benign, with only about 10% malignant. Most of these tumors are classified as not otherwise specified.[57][58][59][60] Grossly, these tumors are usually unilateral, except when associated with Peutz-Jegher syndrome or large-cell calcifying type. They are well-circumscribed and lobulated, and they present a white, yellow, or tan surface upon sectioning. Their mean diameter is relatively small, approximately 3.5 cm, with tumors associated with Peutz-Jeghers syndrome tending to be smaller.

Histologically, Sertoli cell tumors often exhibit abundant tubular and/or cystic structures lined by elongated, cuboidal, or polyhedral-shaped cells. The eosinophilic cells typically contain abundant cytoplasmic lipids, which may form vacuoles. Additionally, their stroma may demonstrate edema, hyalinization, or sclerosis. Cytogenetically, the most common chromosomal abnormality involves a gain of chromosome X and the loss of part or all of chromosomes 2 and 19. The not otherwise specified type commonly shows a CTNNB1 mutation (70%).[61]

Immunohistochemistry staining of Sertoli cell tumors typically shows positivity for inhibin, calretinin, CD99, vimentin, and neuron-specific enolase but negativity for chromogranin in these tumors.[62]

Granulosa cell tumors: These tumors are not native to the testes and are notably rare compared to their female variant. The juvenile type occurs in males during the early months of life.[63] Adult granulosa cell tumors tend to be sizable, reaching up to 15 cm, and are characterized by their homogenous, firm, lobulated appearance, often presenting in shades of white to yellowish-gray. Cysts may also be present. These neoplasms are exceptionally rare, with fewer than 100 reported cases.

The histological appearance of granulosa cell tumors is similar to adult ovarian granulosa cell tumors. They may show a diffuse microfollicular pattern with Call-Exner bodies. The cells have scant cytoplasm with elongated nuclei and multiple grooves. Mitoses are present but not common. A prominent fibroma-thecomas background may be present.

Call–Exner bodies are small, eosinophilic, follicle-like fluid-filled spaces that typically appear scattered among the sheets of tumor cells. Although characteristic of granulosa cell tumors, they are found in no more than 60% of cases. FOXL2 stains are usually positive, with the FOXL2 marker being 80% sensitive and 99% specific for SCSTs, as it will be positive in almost all such neoplasms (98%). Histologically, the tumors may present as solid, nodular, or follicular masses. The follicles may contain basophilic or eosinophilic secretions (mucicarmine positive). Mitoses are far more common than in the adult type, but Call–Exner bodies and nuclear grooves, seen in the adult type, are absent. Additionally, extensive hyalinization and a myxoid background may be present.[64][65][66]

Only Leydig, Sertoli, and granulosa cell tumors are considered clinically significant, as they constitute the vast majority of SCSTs. For completeness, the following are also classified as SCSTs by the WHO.[24][40]

Mixed and Unclassified Testicular Sex Cord–Stromal Tumors

These tumors contain multiple components with individual characteristics. Neoplasms with components of various types of SCSTs without adequate features to be classified as an individual entity are termed unclassified types. This category includes the following:

Signet ring stromal tumors: These tumors exhibit features similar to real signet ring tumors, such as fibrous septations and thick, fibrous capsules. However, unlike true signet ring cells, they lack intracellular mucin.[67] These tumors are exceedingly rare.

Myoid gonadal stromal tumors: These tumors demonstrate both sex cord–stromal and smooth muscle cellular differentiation.[68] They are usually found in adults aged approximately 40, and they present with a typical diameter of 3 cm. Microscopically, they are mostly comprised of spindle cells, with about half of the cases demonstrating epithelial differentiation.[68] Mitoses are typically observed but are not common, generally averaging 2 mitotic figures per 10 high-powered fields (HPF).[68]

Sertoli-Leydig cell tumors: These tumors feature a cellular, neoplastic stroma with intermediate Leydig cell components. They are relatively rare and are more commonly found in the ovaries. Formerly referred to as neuroblastomas, these tumors may induce precocious puberty or virilization in males.

Gonadoblastomas: These tumors consist of seminoma-like cells scattered among sex cord–stromal cells that resemble immature Sertoli cells arranged in a palisading pattern. Gonadoblastomas uniquely have cellular elements of both germ cells and sex cord–stromal cells. Focal calcification is characteristic. Gonadoblastomas may be considered premalignant as they can develop into dysgerminomas and seminomas. They are typically found in dysgenetic gonads.

Fibroma-thecomas: These tumors are exceptionally rare, with no more than 50 reported cases in the medical literature.[69] Grossly, they are well-demarcated and appear white, yellowish, or tan. Microscopically, they exhibit low or moderate cellularity with uniform spindle-shaped fibroblasts arranged in a storiform pattern. There is an absence of inflammatory infiltrate or evidence of mitoses, nuclear atypia, or cellular necrosis.[70]

In most clinical settings, anatomic pathologists are unlikely to have substantial experience with these exceedingly rare tumors, particularly those lacking distinguishing morphological or histological characteristics.[6][32][60] Therefore, arriving at the correct diagnosis may necessitate the use of immunohistochemistry staining and other advanced techniques, which may not be readily available in every pathology laboratory.[71][72][73]

History and Physical

SCSTs present similarly to germ cell neoplasms of the testes. They usually appear as a solid testicular mass, which may be accompanied by localized swelling or discomfort but are usually nontender.[74] On physical examination, a testicular lump or swelling is commonly detected, and gynecomastia may additionally be observed. Among adults, hormone-related symptoms are present in approximately 25% of cases. Typical markers of testicular germ cell cancers, such as lactate dehydrogenase (LDH), β-human chorionic gonadotropin (β-hCG), and α-fetoprotein (AFP), are generally not elevated in SCSTs.

The most common and clinically significant SCSTs include Leydig, Sertoli, and granulosa cell tumors. Individually, specific sex cord–stromal neoplasms will show certain characteristic features as mentioned below.

Leydig cell tumors: These tumors are the most common form of SCST and account for over 90% of cases. While they are most frequently observed in men aged 30 to 35, 25% of cases are diagnosed in men aged 50 or older. Gynecomastia is present in 20% to 30% of men with these tumors.[75]

These tumors can produce androgens or, less commonly, estrogens, leading to signs of male virilization or feminization in patients.[7] Endocrinological symptomatology is observed in about 25% of cases, with gynecomastia being the most common finding in adults. Additional symptoms may include loss of libido, erectile dysfunction, and infertility.[7][46][75] Malignancy has traditionally been reported in about 10% of adult patients with Leydig cell tumors, particularly in older men, but not in children.[6][50] However, recent studies suggest that the actual percentage of malignant Leydig cell tumors is only 2.5%.[49][76]

Children with Leydig cell tumors typically present with signs of androgen excess, such as early virilization and gynecomastia, due to excessive secretion of sex hormones. In adults, a testicular mass is the most common presenting symptom.[5][77] Between 10% and 30% of adult men with Leydig cell tumors also have gynecomastia. In children, precocious puberty is a common presenting symptom, particularly if there is asymmetrical testicular enlargement. Children with this neoplasm nearly always exhibit isosexual pseudo-precocity, and about 10% may also have cryptorchidism, Klinefelter syndrome, or Turner syndrome.

Studies suggest that a biopsy of the larger testis should be performed if its size continues to increase during follow-ups, even if a mass cannot be palpated or specifically detected by ultrasound.[46]

Sertoli cell tumors: These tumors are the second most common type of SCST but account for only 0.1% of all testicular neoplasms.[11][34] They typically present as a testicular mass without endocrine-related features or symptoms. However, various endocrine manifestations of increased estrogen production can occur, such as gynecomastia, erectile dysfunction, and impotence. Risk factors include cryptorchidism and familial adenomatous polyposis.

Gynecomastia is found in about 30% of patients. Although Sertoli cell tumors can occur at any age, from infancy to older age, they are extremely rare in children and uncommon before the age of 20. The mean age at diagnosis is 45. While these tumors generally occur in prepubertal patients, approximately 10% will exhibit malignant characteristics, such as areas of necrosis, cellular atypia, increased mitotic activity, evidence of vascular invasion, and large size.[6][78]

High estrogen levels produced by Sertoli cells may result in a phenotypically female appearance, although male virilization is rare. Hyperestrogenism can have toxic effects on the bone marrow, leading to anemia, granulocytopenia, and thrombocytopenia. Some Sertoli cell tumors may produce inhibin, which inhibits gonadotropin-releasing hormone (GnRH) production and reduces serum LH and FSH levels.

Sertoli cell tumors may occasionally be found in patients with Peutz-Jegher syndrome (intratubular large cell hyalinizing type), Carney complex (usually associated with large cell calcifying tumor type), and androgen insensitivity syndrome, with the neoplasm being generally benign and multifocal.[17][18][79] Large-cell calcifying-type tumors tend to present at a younger age—between 16 and 37—with an average age of 21. Please see StatPearls' companion resources, "Peutz-Jegher Syndrome," "Carney Complex," and "Androgen Insensitivity Syndrome," for further information.[17][18][79]

Granulosa cell tumors: These tumors are rare neoplasms in men, with an average patient age of 42. About one-fifth of patients will also have gynecomastia. Granulosa cell neoplasms are divided into 2 types, as mentioned below.

Adult granulosa cell tumors: They present as exceedingly rare neoplasms in mature men, with a very limited number of cases (<100) reported.[79][80] They typically manifest at an average age of 44, often with a prolonged history of a testicular mass due to the tumor's slow growth. Up to about half of patients may also exhibit gynecomastia.[81][82] Metastases have been reported in about 10% of these rare cases.[65][80][83]

Juvenile granulosa cell tumors: These tumors are the most prevalent testicular neoplasm in infancy, with 90% occurring within the first 6 months after birth.[66][84][85] Notably, 40% of cases are found to be associated with undescended testes, and one-fifth will exhibit an anomaly affecting the Y chromosome, resulting in ambiguous genitalia (known as Denny-Drash syndrome). Infants with this disorder typically do not show hormone-related symptoms. Juvenile granulosa cell tumors are invariably benign, with no reported malignant cases.[66]

Signet ring and myoid gonadal stromal tumors: These tumors are very rare testicular neoplasms that the WHO now classifies as separate subcategories of benign SCSTs.

Signet ring stromal tumors: These tumors are exceedingly rare, and exhibit features akin to actual signet ring tumors, including fibrous septations and thick, fibrous capsules. However, unlike true signet ring cells, they lack intracellular mucin.[67]

Myoid gonadal stromal tumors: These tumors demonstrate both sex cord–stromal and smooth muscle cellular differentiation.[68] They are usually found in adults aged around 40, with a typical diameter of 3 cm. Microscopically, they are predominantly composed of spindle cells, with approximately half of the cases showing epithelial differentiation.[68] While mitoses are typically observed, they are not common, generally averaging around 2 mitotic figures per 10 HPF.[68]

Mixed and Unclassified Testicular Sex Cord–Stromal Tumors

Gonadoblastomas: These tumors are considered to be secondary to a disorder of sexual development and typically occur before the age of 20.[86] Gonadoblastomas comprise sex cord–stromal cells and immature neoplastic germ cells, which involve both testes in about one-third of cases.[86] Gonadoblastomas are often associated with ambiguous genitalia, hypospadias, gynecomastia, undescended testes, male pseudohermaphroditism, and gonadal dysgenesis.[86]

About 80% of cases may be observed in phenotypic females with gonadal dysgenesis and either a 46,XY or 45,X/46,XY karyotype. The remainder are found in phenotypic males with cryptorchidism, hypospadias, and internal female secondary sex organs.

Testicular fibromas and fibroma-thecomas: They are derived from the gonadal stroma or tunica albuginea tissue. While they resemble ovarian fibromas, they are considerably rarer, with fewer than 50 reported cases.[69] While benign, they may exhibit rapid growth.[87]

Evaluation

The evaluation begins with a complete history and physical examination of patients. A careful, focused testicular examination should be performed, along with the assessment for any signs of gynecomastia and abnormal secondary sexual characteristics. Subsequently, routine investigations may be conducted. This includes drawing serum tumor markers and assessing sex hormone levels such as FSH, LH, testosterone, and estradiol. While serum sex hormone levels may be elevated, germ cell tumor markers, including AFP, β-hCG, and LDH, will not be elevated in SCSTs.

Imaging Modalities for Evaluation

Testicular ultrasound: Testicular ultrasound has been the primary imaging modality for evaluating and diagnosing testicular masses and neoplasms. This procedure is safe, cost-efficient, and repeatable, with no potentially harmful radiation exposure, and its sensitivity for diagnosing testicular tumors approaches 100%.[35] Additionally, it can differentiate solid masses from hydroceles, spermatoceles, and inflammatory conditions of the testicles. However, this procedure cannot differentiate sex cord–stromal neoplasms from germ cell testicular tumors, which necessitates histological examination for accurate diagnosis. Indications for testicular ultrasound include unexplained infertility, precocious puberty, gynecomastia, and unilateral testicular swelling or firmness.

Leydig cell tumors show an isolated hypoechoic central mass, clearly demarcated from the adjacent stroma. They often exhibit intrinsic hypervascularization with a characteristic peripheral rim pattern. Large cell calcifying Sertoli cell tumors present with dense internal calcified areas within the testis.[88] Hypoechoic Sertoli cell tumors may appear sonographically similar to testicular seminomas as both will demonstrate peripheral hypervascularity. However, histological examination is frequently necessary to differentiate between these 2 neoplasms.[89] When diagnosed, granulosa cell tumors appear as hypoechoic, solid masses on ultrasound with well-demarcated margins and an average size of slightly over 2 cm.[90]

Scrotal multiparametric magnetic resonance imaging: Scrotal multiparametric magnetic resonance imaging (MRI) has shown potential in discriminating between malignant testicular neoplasms and benign SCSTs.[91][92][93] Malignant germ cell tumors tend to present as larger and more heterogeneous masses on T2-weighted imaging, exhibit a greater degree of diffusion restriction, display less enhancement in the corrected venous phase, and demonstrate lower apparent diffusion coefficient values.[91] MRI is suggested as a useful tool in cases of indeterminate testicular masses when ultrasound alone is inconclusive.[92][93][94]

Other imaging modalities include contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis, which is utilized to detect metastatic lesions. In cases where brain metastases are suspected, an MRI of the brain is recommended.

Treatment / Management

A radical inguinal orchiectomy is the primary standard treatment for all solid testicular masses. This procedure provides a definitive histologic diagnosis, is curative and therapeutic in many cases, and decreases the local tumor load (grade 1C). Preliminary biopsies are generally contraindicated and not recommended due to the risk of local and regional disease spread and the high likelihood of performing an orchiectomy in any case, even if the lesion ultimately turns out to be benign.

The overwhelming majority of SCSTs (about 90%) are benign and clinically indolent, meaning they can be safely managed with a simple radical inguinal orchiectomy.[95] For SCSTs determined or likely to be malignant (Leydig cell, Sertoli cell, and adult granulosa cell tumors), further evaluation and treatment with a retroperitoneal lymph node dissection (RPLND) is suggested. This is particularly important for patients with resectable retroperitoneal node involvement, stage II lesions, and stage I neoplasms with malignant characteristics or significant high-risk factors (>1) due to their poorer prognosis.[34][96][97](B2)

High-risk factors typically include the following:[84][98][99](A1)

Cellular atypia (moderate or severe)
Evidence of lymph node involvement
Frequent mitoses (>5 mitotic cells per 10 HPF or 3 mitotic figures in 1 HPF)
Larger tumor size (>5 cm)
Lymphovascular invasion
Necrosis
Tumor invasion or infiltrating margins

Additional high-risk factors have been suggested, such as angiolymphatic invasion and gynecomastia or other tumor-related hormonal symptoms, particularly for granulosa cell tumors. Furthermore, it is unclear if elevated AFP or β-hCG levels should be considered an additional high-risk factor.

RPLNDs are the gold standard in identifying nodal micrometastasis and providing accurate pathologic staging of retroperitoneal disease. The number, size, and pathology of lymph nodes have prognostic implications. Poor response rates of metastatic SCST lesions to radiation and chemotherapy have led to a recommendation for surgical resection of such lesions whenever possible, along with adjuvant chemotherapy.[100](B3)

Leydig cell tumors: These tumors are generally cured by radical inguinal orchiectomy surgery alone.[101] The European Association of Urology (EAU) guidelines recommend testis-sparing surgery for selected small, sonographically-detected, impalpable intraparenchymal testis lesions.[74] Overall survival appears to be similar between testis-sparing surgery and radical inguinal orchiectomy.[95](B2)

To be considered for testis-sparing surgery, the suggested parameters are as follows:[25][102]

All preoperative tumor markers and sex hormone levels should be within the normal range.

There should be a reasonable suspicion of a Leydig cell tumor based on clinical findings (elevated estrogen or testosterone levels, gynecomastia, and unexplained infertility).

The tumor should measure less than 2.5 cm in diameter.

A frozen section of the tumor performed after clamping the spermatic cord during surgery should confirm a benign Leydig cell tumor.

For malignant Leydig cell tumors, no standard algorithms exist, but RPLNDs are recommended, as neither chemotherapy nor radiation appears to be effective if metastases develop. Immunotherapy has shown a somewhat better response, but further studies are needed.[103]

Metastatic spread typically occurs within 2 years following primary surgery, affecting sites such as retroperitoneal, mediastinal, and cervical lymph nodes, as well as the lungs, liver, and bones. In cases of disseminated disease, RPLND and metastasectomy provide limited benefits, while advanced disease shows resistance to radiotherapy and cisplatin-based chemotherapy.

In a retrospective study of 8 cases with stages II and III metastatic tumors, RPLND was performed, with a survival rate of approximately 1.2 years despite aggressive surgical interventions (abdomen and pelvic mass excision, bowel resection, hepatic lobectomy, and splenectomy) and postoperative chemoradiotherapy. In one case, a steroidogenesis inhibitor (mitotane) was administered due to elevated estradiol and testosterone levels, resulting in a partial response, but the patient succumbed within 9 months.[96][104][105](B3)

Assessing the malignant potential of SCSTs in men is challenging. Patients with fewer than 2 high-risk factors demonstrated a 5-year occult metastasis disease-free survival rate of 98%, contrasting with 45% for those with more than 2 such factors. Risk factors include tumor size greater than 5 cm, more than 3 mitoses per HPF, positive margins, rete testes involvement, lymphovascular invasion, cellular atypia, and necrosis.[98][106] (A1)

If a patient has a higher likelihood of occult disease, comprehensive imaging should be conducted to detect early metastases, with early consideration given to RPLND or metastasectomy. Metastasectomy may be feasible in cases of limited spread, considering the typically poor response to chemotherapy and radiotherapy.[50](B2)

Chemotherapy and/or radiotherapy are reserved for palliative purposes in patients with widespread unresectable disease. Traditional regimens such as bleomycin, etoposide, and cisplatin (BEP) or vinblastine, ifosfamide, and cisplatin (VIP), typically used in germ cell tumors, are ineffective. The clinical effectiveness of new drugs and therapies such as taxane, gemcitabine, anti-angiogenic agents, tyrosine kinase inhibitors, and immunotherapy, such as programmed cell death 1 (PD-1) pathway inhibitors, is unknown.

Tumor genetic profiling may lead to the discovery of novel experimental drugs. Leydig cell tumors and adrenocortical cancers show common histological and biochemical features. Case reports of palliation with mitotane, used in adrenocortical cancer, have been reported.[100][107][108] (B3)

Leydig cell tumors and adrenocortical cancers share histological and biochemical similarities. Palliative effects have been reported with mitotane, typically used in adrenocortical cancer, suggesting potential therapeutic avenues for Leydig cell tumors. Estrogen-producing Leydig cell tumors can cause long-lasting impaired male fertility even after their resection. The infertility is due to long-term inhibition of the hypothalamic-pituitary axis and direct effects on the testes.[109] Early detection and treatment can help maintain spermatogenesis and protect future fertility.[109](B3)

Sertoli cell tumors: These tumors are conventionally managed with inguinal radical orchiectomy as the primary treatment. A metastatic assessment should follow, with resection of any detected metastases, complemented by adjuvant chemotherapy as recommended.[110][111]

Large cell calcifying Sertoli cell tumors usually follow a benign course. In Carney syndrome, tumor metastasis is improbable, with orchiectomy often serving as a curative measure, although ongoing research explores the potential of testis-sparing surgery.[112][113] Reported 5-year survival rates for stage I Sertoli cell tumors stand at 77%, notably lower than those for stage I Leydig cell tumors (91%) and stage I seminomas (98%).(B3)

Primary RPLND has been recommended as the mainstay of management, even for stage I Sertoli cell tumor disease. This recommendation is based on the potential for metastases, lower survival rates compared to other testicular tumors, and the tumor's limited response to chemotherapy and radiation.[34][97](B2)

Granulosa cell tumors: These tumors are predominantly benign neoplasms. While testis-sparing surgery is deemed feasible in cases with normal AFP levels and considerable residual normal testicular tissue, orchiectomy remains a common recommendation. For stage I tumors, adjuvant therapy is not typically advised. Regional lymph node metastases exhibit a complete response to initial cisplatin-based chemotherapy induction, a characteristic distinct from others.[114][115] (B3)

Summary of Treatment Recommendations [99](B2)

A testicular mass that appears to be a solid tumor should undergo a radical inguinal orchiectomy without a preliminary biopsy.

CT-guided evaluation of the abdomen, pelvis, and chest is essential for staging SCSTs and detecting metastases.

Serial assessments of the pituitary or gonadal axis via serum testosterone, estrogen, and progesterone levels should be done (grade 2C).

In the case of metastases, surgical resection of all possible sites of metastatic disease should be done (grade 2C).

Systemic therapy has not shown any promising effects, and nonresectable metastatic disease necessitates inclusion into clinical trials whenever possible.

Patients with 0 or 1 high-risk factor may be observed without RPLND, but long follow-ups are recommended.

Early RPLND may be beneficial for those with multiple high-risk factors, stage II disease, or stage I malignant SCSTs, particularly Sertoli cell neoplasms.

Furthermore, it has been suggested that all not otherwise specified Sertoli cell tumors, including stage I, undergo RPLND due to their lower 5-year survival rates compared to other testicular tumors and their limited response to chemotherapy and radiation.

Differential Diagnosis

Due to their diverse histological features and clinical presentations, differential diagnosis of SCSTs is crucial. Clinicians need to differentiate these tumors from other testicular masses, such as germ cell tumors and secondary neoplasms, to ensure precise diagnosis and treatment.

Leydig Cell Tumors

This differential diagnosis encompasses Leydig cell hyperplasia, lymphoma, plasmacytoma, adrenal or testicular rest tumors (in males with congenital adrenal hyperplasia), and Sertoli cell or germ cell tumors.[116] Immunohistochemistry stain with inhibin alpha helps to differentiate Leydig cell neoplasms from germ cell tumors but not Sertoli cell neoplasms. Calretinin is a positive marker for Leydig cell tumors. NKX3.1 is expressed routinely in Sertoli cells and P501S in Leydig cells, as well as in the rete testis epithelium.[117][118][119]

Most SCSTs exhibit immunoreactivity with anti-inhibin, aiding in their differentiation from other testicular neoplasms.[117] Calretinin A tends to be strongly positive in the nucleus and cytoplasm of Leydig cell tumors but only mildly positive in the cytoplasm of Sertoli cell neoplasms.[49]

SALL4, a newer stem cell marker, is negative in Leydig and Sertoli cell tumors but positive in granulosa cell neoplasms.[37][119]

Sertoli Cell Tumors

The differential diagnoses include juvenile granulosa cell tumors, Leydig cell tumors, seminomas, and mixed Sertoli-Leydig cell neoplasms. Many tumors classified as Sertoli cell neoplasms that are not otherwise specified could be reclassified as juvenile granulosa cell tumors. Sertoli cell tumors typically exhibit positive staining for cytokeratin, WT-1, and inhibin but negative staining for placental alkaline phosphatase (PLAP) and SALL4.[119]

Sertoli cell tumors may appear similar to juvenile granulosa cell neoplasms. Sertoli cell tumors typically exhibit uniform tubules, whereas juvenile granulosa cell neoplasms display prominent follicular differentiation characterized by irregular contours and varying sizes.

Epithelial, mesothelial, and other soft tissue testicular tumors may be seen in the rete testis and paratesticular areas. Mesothelial lesions include cysts, reactive hyperplasia, adenomatoid tumors, and benign cystic, papillary, and malignant mesotheliomas. Among these, adenomatoid tumors are prevalent, occasionally exhibiting infiltration, potentially leading to misdiagnosis as malignancy. Additionally, leiomyomas and lipomas are common benign paratesticular neoplasms.[120]

Testicular lymphoma, an aggressive extranodal non-Hodgkin lymphoma, typically presents bilaterally and extends beyond the nodes. Notably, it is the leading cause of testicular masses in men aged 60 or older, primarily large-cell diffuse B-cell type. Doxorubicin-based chemotherapy often induces remissions. Differentials include hydrocele, varicocele, epididymal and scrotal malignancies, and epididymo-orchitis.

Staging

Staging of SCSTs is essential for determining the extent of disease and guiding treatment decisions. Accurate staging involves assessing tumor size, local invasion, and potential metastasis to provide a comprehensive understanding of the patient's condition.

Tumor Stage

Following radical orchiectomy, the extent of the primary tumor (T) is classified as:

TX: Primary tumor cannot be assessed (if radical orchiectomy has not been performed, Tx is used).
T0: No evidence of primary tumor (eg, a histological scar in the testis).
Tis: Intratubular germ cell neoplasia (carcinoma in situ).
T1: Tumor is limited to the testis and epididymis without vascular/lymphatic invasion or tumor invasion into the tunica albuginea but not the tunica vaginalis.
T2: Tumor is confined to the testis and epididymis with vascular/lymphatic invasion or tumor extending through the tunica albuginea with the involvement of the tunica vaginalis.
T3: Tumor invades the spermatic cord with or without vascular/lymphatic invasion
T4: Tumor invades the scrotum with or without vascular/lymphatic invasion

Node

Regional lymph node involvement is used for clinical (N) or pathological (pN) staging, as follows:

NX: Regional lymph nodes cannot be assessed.
N0: No regional lymph node metastases.
N1: Metastases with a lymph node mass less than or equal to 2 cm in its greatest dimension, or multiple lymph nodes, none greater than 2 cm in size.
N2: Metastases with a lymph node mass greater than 2 cm but less than 5 cm in its greatest dimension or multiple lymph nodes; any one may be greater than 2 cm but less than 5 cm in size.
N3: Metastases with a lymph node mass greater than 5 cm in its greatest dimension.

Metastasis

Distant metastasis (M) is classified as follows:

MX: Distant metastasis cannot be assessed.
M0: No distant metastasis.
M1: Distant metastasis
M1a: Nonregional nodal or pulmonary metastasis
M1b: Distant metastasis other than to nonregional lymph nodes and lungs

Prognosis

Stage I disease generally carries a favorable prognosis. For stage I Leydig cell tumors, survival rates were 98% and 91% at 1 and 5 years, respectively.[34] However, Sertoli cell tumors exhibit a somewhat less favorable prognosis, with reported survival rates at 1 and 5 years of 93% and 77%, respectively.[34]

In a report, 38 men were successfully treated solely through excision of the primary tumor. After a 7-year follow-up, none had developed metastatic disease. The conclusion drawn was that patients with 0 or 1 high-risk features can be safely observed without RPLND. However, early RPLND may be beneficial for selected patients with 2 or more high-risk features or stage IIa disease, as well as for all not otherwise specified Sertoli cell tumors.

Patients with gonadoblastoma generally enjoy an excellent prognosis, particularly if the neoplasm is surgically removed before any malignant transformation occurs. Even in cases where the disease has progressed from an advanced to a metastatic stage, platinum-based chemotherapy offers a cure rate exceeding 90%.[121][122] The prognosis for patients with metastatic SCSTs, excluding gonadoblastoma, is poor. Although prolonged survival has been reported, the median overall survival is only 1 to 2 years, with approximately 66% of patients succumbing within 2 years after the diagnosis of metastases.[123]

Complications

Complications of SCSTs can arise from both the disease itself and its treatment. While these tumors are typically less aggressive than germ cell tumors, there is still a risk of metastasis, which can lead to complications in distant organs such as the lungs, liver, or bones.

Surgical treatment, a common approach for these tumors, carries risks such as infection, bleeding, and potential damage to surrounding structures, which can impact fertility and endocrine function. Research indicates that the incidence of male hypogonadism following orchiectomy is greater in patients with SCSTs compared to those with germ cell cancers (42% versus 10%).[100][124] Hence, patients with SCSTs will likely require testosterone replacement therapy after surgery and should undergo regular monitoring of their androgen levels.

Moreover, patients undergoing chemotherapy or radiation therapy may experience systemic adverse effects, including nausea, fatigue, and an elevated risk of secondary malignancies. The adverse effects of chemotherapy and radiotherapy are typically consistent with those commonly associated with these treatments, but they can often be effectively managed using state-of-the-art medications. Long-term follow-up is crucial for monitoring recurrence and effectively managing these complications.

Postoperative and Rehabilitation Care

Postoperative and rehabilitative care for patients with SCSTs is crucial to ensure optimal recovery and long-term health. Individuals diagnosed with SCSTs typically necessitate regular monitoring and follow-up examinations, with particular emphasis on surveillance during the first 2 years after diagnosis and treatment. This heightened vigilance is essential as most patients with Leydig cells and other potentially malignant SCSTs, capable of metastasizing, tend to do so within this initial 2-year period.[19][25]

Follow-up evaluations should include a comprehensive physical examination, a complete hormonal profile (LH, FSH, testosterone, and estradiol), and testicular germ cell tumor markers (β-hCG, AFP, and LDH). Additionally, CT imaging of the chest, abdomen, and pelvis should be conducted every 6 months for the initial 2 years.[19][25]

After surgery, patients require close monitoring for potential complications such as infection, bleeding, and proper wound healing. Effective pain management and supportive care are imperative during the immediate postoperative phase. Furthermore, addressing potential impacts on fertility and endocrine function is crucial, often necessitating consultations with specialists in reproductive health and endocrinology.

Rehabilitation following treatment for SCSTs may encompass physical therapy aimed at regaining strength and mobility. Additionally, psychological support is essential to assist patients in coping with the emotional impact of their diagnosis and treatment. Comprehensive care plans that integrate these elements can significantly enhance the quality of life and outcomes for patients recovering from SCSTs.

Deterrence and Patient Education

Deterrence and education are crucial in addressing SCSTs, serving both preventive and educational purposes. Public education about the signs and symptoms of testicular tumors, including SCSTs, can facilitate earlier detection and intervention. This initiative can be achieved through targeted campaigns in schools, workplaces, and healthcare settings, emphasizing the importance of self-examination and prompt medical consultation for any concerning changes.

Patients should be informed that advancements in oncology are occurring constantly. SCSTs typically carry an excellent prognosis, as malignancy and metastases are rare occurrences. Emphasis should be placed on the significance of early diagnosis, prompt treatment, and regular follow-up examinations.

Furthermore, ongoing education for healthcare providers regarding the latest diagnostic and treatment guidelines for these rare tumors is crucial to ensure accurate diagnosis and appropriate management. By promoting awareness and knowledge, clinicians can proactively screen patients and alleviate the burden of SCSTs on both patients and healthcare systems.

Pearls and Other Issues

Numerous critical pearls enhance the understanding of SCSTs as follows:

Patients with precocious puberty should raise suspicion of possible SCSTs, particularly Leydig-cell type, especially if unilateral testicular enlargement is detected.

Regular self-examinations and awareness of testicular changes can facilitate the early detection of SCSTs.

Ultrasound serves as the primary imaging modality for evaluating testicular masses, while MRI can offer additional detailed information.

An MRI of the scrotum should be considered in select cases where ultrasound findings are equivocal or inconclusive.

Unlike germ cell tumors, SCSTs typically do not result in elevated serum tumor markers (such as AFP and hCG), underscoring the importance of histological examination.

Accurate diagnosis relies on detailed histopathological analysis, as these tumors can mimic other neoplasms.

Genetic testing should be considered for patients with a family history of similar tumors or syndromic features to identify potential hereditary syndromes.

Patients should be counseled on fertility preservation options before surgical intervention, as treatments may affect reproductive capabilities.

Orchiectomy serves as the primary treatment for localized tumors, with testis-sparing surgery being an option in select cases.

RPLNDs should be considered for Sertoli cell and malignant stage I SCSTs and stage II lesions, as well as for patients with resectable retroperitoneal involvement.

Although typically indolent, some SCSTs can metastasize; therefore, staging and surveillance protocols are essential.

Enhancing Healthcare Team Outcomes

For optimal outcomes, a management plan is essential after consultation with an interprofessional team comprising primary care physicians, pediatricians, pathologists, urologists, medical oncologists, surgical oncologists, radiation oncologists, radiologists, advanced care practitioners, nurses, pharmacists, and other healthcare professionals.

Each healthcare team member has distinct responsibilities in caring for patients with SCSTs. Physicians and advanced practitioners require specialized skills in accurately diagnosing and staging SCSTs, utilizing advanced imaging modalities, and conducting histopathological assessments. Nurses are pivotal in educating patients, managing symptoms, and providing supportive care throughout treatment. Pharmacists contribute by ensuring appropriate medication management, including chemotherapy agents and supportive medications, while monitoring for potential drug interactions and adverse effects.

A collaborative strategy involves establishing multidisciplinary tumor boards, where experts from various specialties collaborate to discuss each patient's case, formulate individualized treatment plans, and navigate complex clinical scenarios. This approach fosters shared decision-making and ensures patients receive the most appropriate and evidence-based care.

Effective communication among healthcare team members is paramount for coordinating care and optimizing outcomes. Regular interprofessional meetings facilitate information sharing, collaborative decision-making, and alignment of treatment goals. Clear and concise communication with patients and their families is also essential, ensuring they understand their condition, treatment options, and the importance of adherence to the care plan.

Care coordination involves seamlessly integrating services across different healthcare settings and disciplines to ensure continuity of care. This collaborative effort includes scheduling appointments, coordinating diagnostic tests and procedures, and facilitating transitions between inpatient and outpatient care settings. By streamlining the care process, care coordination minimizes delays, reduces healthcare disparities, and enhances the overall patient experience. Leveraging their collective skills, healthcare professionals working as an interprofessional team can optimize patient-centered care, improve outcomes, enhance patient safety, and elevate team performance in treating patients with SCSTs.

The field of molecular genetics holds significant promise in the realm of SCSTs. This area has the potential to enhance and expedite diagnosis, determine tumor malignant potential, and optimize treatment strategies. Furthermore, it enables individualized, programmable cancer treatment tailored to the unique genomic profile of each tumor. Molecular genetics represents the next frontier in oncology, offering unprecedented opportunities for advancing patient care and outcomes in managing SCSTs.

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