Extremely rare case of large cell calcifying Sertoli cell tumor in a young male

INTRODUCTION

Large cell calcifying Sertoli cell tumor (LCCSCT) is an exceedingly rare subtype of sex cord-stromal tumors of the testis, accounting for <1% of all testicular neoplasms. LCCSCT is distinguished by its unique histopathological and immunohistochemical features, including large Sertoli cells, calcifications (often psammomatous), and a myxoid to hyalinized stroma with varying degrees of inflammation.^[1] Sertoli cell tumors arise from the sex cord-stromal component of the testis and are classified into classic, large cell calcifying, sclerosing, and not otherwise specified categories.^[2] Among these, LCCSCTs are notable for their propensity to present in the pediatric and young adult population, with a mean age of onset around 15 years. Although the majority are benign, a minority of cases may exhibit malignant behavior, making accurate diagnosis and risk stratification essential.^[3] Clinically, LCCSCT typically presents as a painless testicular mass, often discovered incidentally or due to sensations of heaviness or discomfort, as seen in the present case. Endocrinological manifestations such as gynecomastia or precocious puberty may occur, especially in younger patients, due to hormone secretion by the tumor. However, these features are not universally present.^[4] In the current case, no hormonal symptoms were observed, and the serum tumor markers, including alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (b-hCG), and lactate dehydrogenase (LDH), were within normal limits, consistent with the typical biomarker profile of sex cord-stromal tumors. Histopathologically, LCCSCTs are characterized by large polygonal Sertoli cells with abundant eosinophilic cytoplasm, vesicular nuclei, and central nucleoli. The cells are arranged in nests, cords, or trabeculae within a variably calcified and often myxoid or hyalinized stroma.^[5] Psammoma bodies, although not universally present, are a hallmark finding and aid in diagnosis. The presence of inflammatory infiltrates, predominantly neutrophils, may also be observed. Mitotic activity is usually low, and features such as necrosis, high-grade atypia, and vascular invasion, suggestive of malignancy which are typically absent in benign cases.^[6]

Immunohistochemistry plays a crucial role in confirming the diagnosis. LCCSCTs usually express markers such as inhibin-A, calretinin, melan-A, and b-catenin, reflecting their sex cord-stromal origin.^[7] The present case displayed positivity for all these markers, further supporting the diagnosis. These immunohistochemical features also help distinguish LCCSCTs from other testicular neoplasms, including germ cell tumors and metastatic lesions, which exhibit different profiles. Genetically, LCCSCTs are frequently associated with Carney complex, an autosomal dominant syndrome characterized by spotty skin pigmentation, myxomas, endocrine tumors, and schwannomas. Approximately 40% of LCCSCTs in this context harbor inactivating mutations in the Protein Kinase cAMP-Dependent Regulatory Subunit Type-I Alpha (PRKAR1A) gene, which encodes the regulatory subunit type 1a of protein kinase A (PKA). This mutation results in dysregulation of PKA signaling, promoting tumorigenesis.^[8] Interestingly, LCCSCTs associated with Carney complex are often bilateral and multifocal, in contrast to the typically unilateral, solitary tumors seen in sporadic cases. Genetic testing for PRKAR1A mutations may therefore aid in distinguishing syndromic from non-syndromic cases, though such testing was not available in our case due to institutional limitations.^[8] While LCCSCT is rare worldwide, it is even more infrequently reported in the Middle East. Only two cases have previously been documented in Saudi Arabia before this report.^[9,10] This lack of regional data underscores the importance of reporting and characterizing such cases to build a more comprehensive understanding of the tumor’s epidemiology, clinical course, and prognostic factors within different populations. Cultural, genetic, or environmental factors may influence the prevalence and presentation of rare tumors like LCCSCT, making regional documentation essential for effective diagnosis and management. In the present case, none of these adverse prognostic indicators were observed. The tumor was small (1.2 cm), well-circumscribed, without necrosis, atypia, or vascular invasion. The mitotic rate was low (1/10 high-power fields [HPF]), and the patient was 15 years old, all favoring a benign course. Post-operative recovery was uneventful, and the patient was discharged in stable condition. Given the rarity of this neoplasm and its potential association with syndromic conditions, a multidisciplinary approach involving pathologists, urologists, endocrinologists, and geneticists is recommended. In cases where Carney complex is suspected, referral for genetic counseling and screening for associated conditions is prudent. LCCSCT is a rare, mostly benign testicular neoplasm with distinct clinical, histologic, and immunohistochemical characteristics. Accurate recognition and diagnosis are crucial, particularly in regions where the tumor is underreported. This case adds to the limited data from Saudi Arabia and highlights the need for increased awareness and documentation of such rare entities. Continued reporting of similar cases will enhance our understanding of their biological behavior, diagnostic criteria, and optimal management strategies.

CASE REPORT

A 15-year-old male patient presented to the urology clinic complaining of heaviness in his left testis. Physical examinations revealed a left testicular mass, otherwise unremarkable. By the ultrasound, there was a well-defined hypoechoic mass in the upper pole of the left testis. It was located within the testis parenchyma, but near the epididymis. It measured 1.2 × 1.1 cm with marginal calcification and normal internal vascularity [Figure 1].

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Figure 1:

Ultrasound image showed a well-defined hypoechoic mass in the testis.

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Serological investigations showed that the patient had normal levels of AFP, b-HCG, and LDH. Radical orchiectomy was done for him, and the specimen was sent to the histopathology department for further examination and evaluation. In the laboratory, the specimen was received in formalin in one container labeled with the patient’s name, Medical Record Number, and as “Left Testis.” It consisted of a left orchiectomy specimen composed of the testis and spermatic cord. The unremarkable spermatic cord measured 7.2 cm in length and 0.8 cm in maximum diameter. The testis measured 5.4 × 3.2 × 3 cm. The outer surface of the testis was smooth and gray brown in color. The outer surface was inked in black. Slicing the testis showed a single well-demarcated oval gray brown firm mass with areas of calcification. This mass measured 1.2 × 0.8 × 0.8 cm. It was located 0.4 cm away from the tunica vaginalis and 0.2 cm from the epididymis. The remainder of the testicular parenchyma is brown and unremarkable. Sections were taken for microscopic examinations. Microscopically, there was an encapsulated tumor inside the testicular parenchyma [Figure 2]. This tumor was composed of neoplastic cells arranged in nests and cords in a myxoid, inflamed, calcified background [Figure 3]. The cells had ill-defined cell borders, abundant eosinophilic cytoplasm, round vesicular nuclei, and central visible nucleoli [Figure 4]. The number of mitoses in the high spot area was 1/10 HPF. No atypia or necrosis was seen. The background was myxoid and contained many inflammatory cells, predominantly neutrophils. Psammoma bodies calcifications were also present [Figure 5]. Immunohistochemically, the tumor cells were positive for inhibin-A, melan-A, calretinin, and b-catenin. They were negative for AFP [Figure 6].

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Figure 2:

Tumor with fibrous capsule (black arrow) with calcifications (red arrow) and myxoid matrix inside it, while the adjacent testicular parenchyma showed inflammation (yellow arrow) (hematoxylin and eosin ×40).

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Figure 3:

Neoplastic cells (black arrow) embedded in myxoid matrix that contains many neutrophils (red arrow) (hematoxylin and eosin ×200).

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Figure 4:

The neoplastic cells (black arrow) had abundant eosinophilic cytoplasm with round nuclei. Between them, there are many neutrophils (red arrow) (hematoxylin and eosin ×400).

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Figure 5:

Psammoma bodies were present (black arrow). They showed concentric lamellar calcifications (hematoxylin and eosin ×400).

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Figure 6:

Immunohistochemical stains for (A) inhibin-A, (B) melan-A, (C) calretinin, and (D) beta-catenin are positive in the neoplastic cells (immunohistochemically stains ×400).

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Based on all of the above, the diagnosis of “Large Cell Calcifying Sertoli Cell Tumor” was made. After the operation, the patient was doing well and was discharged home within a few days.

DISCUSSION

LCCSCT is an exceptionally rare testicular neoplasm. It represents a unique subtype of Sertoli cell tumors within the broader category of sex cord-stromal tumors. These tumors, while generally benign, can exhibit malignant potential in certain cases, necessitating a comprehensive diagnostic and prognostic evaluation.^[11] Our case contributes to the scarce literature on LCCSCT in Saudi Arabia and highlights several important clinical, pathological, and diagnostic features relevant to the current practice. LCCSCT accounts for <1% of all testicular tumors and roughly 5% of Sertoli cell tumors. To date, approximately 130 cases have been reported worldwide, with only two previously documented in Saudi Arabia.^[9,10] The tumor predominantly affects children and young adults, with a median age of 15–16 years, though the age range extends from 2 to 51 years.^[1] Males are disproportionately affected compared to females, although rare ovarian counterparts have been described.^[1] Clinically, patients most commonly present with a painless testicular mass, often discovered incidentally or due to mild discomfort or heaviness in the scrotum, as was seen in our case. Hormonal manifestations such as gynecomastia or precocious puberty may occur in a subset of patients due to hormone production by the tumor.^[4] These endocrine symptoms are particularly frequent in tumors associated with Carney complex, a genetic syndrome often linked to LCCSCT. Other rare symptoms may include testicular pain, which can mimic infectious or inflammatory conditions of the testis and delay diagnosis.^[4]

In the present case, the patient, a 15-year-old male, presented with left testicular heaviness and no signs of endocrine disturbances. Tumor markers, including AFP, b-HCG, and LDH, were within normal limits, consistent with the non-germ cell origin of LCCSCT. These findings align with the established profile of sex cord-stromal tumors, which typically do not elevate conventional serum tumor markers. Scrotal ultrasonography remains the first-line imaging modality for evaluating testicular masses. LCCSCTs typically appear as well-circumscribed, hypoechoic lesions with coarse or psammomatous calcifications. They may occasionally exhibit posterior acoustic shadowing due to calcification and demonstrate variable vascularity on Doppler imaging. Grossly, the tumor is typically small, firm, well-demarcated, and confined to the testicular parenchyma. In our case, the lesion measured 1.2 × 0.8 × 0.8 cm and displayed calcifications. The lesion’s proximity to the epididymis and tunica vaginalis underscores the importance of detailed anatomical mapping to rule out extratesticular extension. The definitive diagnosis of LCCSCT is made through histological examination. Classic features include large polygonal Sertoli cells arranged in nests, cords, or trabeculae within a myxoid to hyalinized stroma. Psammoma bodies, which are concentric lamellate calcifications, are considered hallmark for this tumor, however they are not universally present. Mitotic activity is generally low, and nuclear atypia and necrosis are rare in benign cases.^[4] Our case demonstrated all key histological features: Large Sertoli cells with eosinophilic cytoplasm and vesicular nuclei, embedded in a myxoid and inflamed background with psammoma bodies. No significant atypia, necrosis, or mitotic activity beyond 1/10 HPF was noted, suggesting a benign phenotype. Immunohistochemistry is indispensable in differentiating LCCSCT from other neoplasms, especially germ cell tumors and metastatic carcinomas. The typical immunoprofile includes positivity for inhibin-A, calretinin, melan-A, and b-catenin and markers that confirm the tumor’s origin from the sex cord-stromal lineage.^[1] Our findings were consistent with this profile. Negative staining for AFP, a germ cell tumor marker, further supported the diagnosis. A comprehensive differential diagnosis should also be considered. The classical Sertoli cell tumors group and Leydig cell tumors group have variable cellular architectural patterns and do NOT show calcifications. Teratomas and Yolk Sac Tumors are usually arising in younger age group patients and show positive staining pattern for alpha-fetoprotein (AFP), placental alkaline phosphatase (PLAP), and cytokines.^[12] Metastatic carcinomas, rare in pediatric testis, may mimic LCCSCT but show a different immunophenotype.^[12] Although most LCCSCTs are benign, malignant transformation can occur.^[12] Our patient was 15 years old, with a small tumor confined to the testis and no histologic evidence of mitotic activity, necrosis, or vascular invasion. These findings strongly favor a benign clinical course.

Up to 40% of LCCSCTs are associated with Carney complex, an autosomal dominant condition linked to PRKAR1A gene mutations. This gene encodes the regulatory subunit type 1a of PKA, and its inactivation results in increased cyclic adenosine monophosphate (cAMP) signaling and tumorigenesis. Carney complex is characterized by multiple endocrine and non-endocrine tumors, lentigines, and myxomas. In the testis, it typically presents as bilateral, multifocal LCCSCTs during adolescence.^[13] In our case, no clinical signs of Carney complex were observed, and the tumor was unilateral and solitary. Unfortunately, genetic testing was unavailable at our institution, a common limitation in resource-limited settings. However, the absence of systemic or dermatological features makes syndromic association unlikely. Recent studies examined both metastatic and non-metastatic LCCSCTs, emphasizing the importance of integrating molecular profiling into diagnosis and prognosis. They found PRKAR1A mutations and b-catenin pathway alterations were common, suggesting a broader molecular pathway involvement than previously recognized.^[14] Radical inguinal orchiectomy remains the gold standard for managing intratesticular masses, especially when malignancy cannot be ruled out preoperatively. Intraoperative frozen section analysis, though not always definitive, may assist in certain cases where testis-sparing surgery is considered, typically in bilateral or multifocal disease. In benign cases, surgery is curative, and surveillance without adjuvant therapy is appropriate. Long-term follow-up with physical examinations and imaging may be warranted, especially in younger patients or those with incomplete surgical margins.^[15] In malignant cases, management strategies are less defined due to the rarity of the condition. Some authors advocate for retroperitoneal lymph node dissection or chemotherapy in the setting of confirmed metastasis, though the efficacy of these interventions remains uncertain.^[15] Our patient underwent radical orchiectomy and was discharged in stable condition, with no signs of recurrence to date. Continued clinical surveillance has been advised.

To the best of our knowledge, this report represents only the third case of LCCSCT documented in Saudi Arabia, underscoring its extreme rarity in the region. Al-Maghrabi et al. (2005) reported the first Saudi case in a young adult with macrocalcification and benign histologic features.^[9] A second case was later published by Bardisi et al. (2020), again confirming benign morphology.^[10] These regional data suggest that the clinical and pathological features of LCCSCT in Saudi Arabia mirror those seen globally. However, the lack of genetic testing and advanced imaging in many institutions highlights the need to enhance diagnostic capacity and raise awareness of rare tumors among general pathologists, urologists, and radiologists. These regional data suggest that the clinical and pathological features of LCCSCT in Saudi Arabia mirror those seen globally. However, the lack of genetic testing and advanced imaging in many institutions highlights the need to enhance diagnostic capacity and raise awareness of rare tumors among general pathologists, urologists, and radiologists. In short, LCCSCT is a rare type of testicular sex cord-stromal tumor, accounting for <1% of testicular neoplasms. First described in the 1960s, it typically affects young males and presents as a painless testicular mass. While most LCCSCTs are benign, a few may exhibit malignant behavior. Diagnosis relies heavily on histopathological evaluation and immunohistochemical staining, with markers such as inhibin-A, calretinin, melan-A, and b-catenin supporting its identification. Psammoma body calcifications and a myxoid or inflamed stroma are characteristic microscopic features. This tumor can occur sporadically or in association with Carney complex, a genetic syndrome involving PRKAR1A mutations. LCCSCTs linked to Carney complex are often bilateral and multifocal, unlike the usual unilateral presentation of sporadic cases. While genetic testing is useful for confirmation, it was unavailable in this case due to facility limitations. Only two previous LCCSCT cases have been reported in Saudi Arabia, underscoring the rarity and importance of documentation in this region. Radical orchiectomy is the treatment of choice, and prognosis is generally favorable in the absence of malignant features. This case adds to the limited regional literature and highlights the need for awareness and further study of this rare tumor.

CONCLUSION

LCCSCT is a rare but distinct testicular tumor, typically presenting in adolescents and young adults as a painless mass. Histologically defined by large eosinophilic Sertoli cells, psammomatous calcifications, and a myxoid stroma, and it is immunoreactive for inhibin-A, calretinin, melan-A, and b-catenin. While most cases are benign, malignancy risk should be assessed using established histologic criteria. Association with Carney complex, although not seen in our case, warrants consideration, particularly in bilateral or multifocal presentations. Our case reinforces the importance of thorough histopathological examination and immunoprofiling in diagnosing rare testicular tumors. It also emphasizes the need for greater awareness and reporting within underrepresented regions like Saudi Arabia. Future efforts should focus on integrating molecular diagnostics, promoting multidisciplinary collaboration, and improving access to genetic screening in resource-limited settings.