Primary testicular neuroendocrine tumor: Diagnostic challenges and WHO 2022 classification insights

Introduction

Neuroendocrine tumors (NETs) are a diverse group of neoplasms arising from neuroendocrine cells dispersed throughout the body. ¹ Although these tumors most commonly originate in the gastrointestinal tract (55%–70%) and bronchopulmonary system (20%–30%), primary testicular NETs (TNETs) are exceptionally rare, accounting for <1% of all testicular neoplasms.^2,3 TNETs primarily affect males in their 30s and 40s. The most commonly reported symptoms include a painless scrotal mass or swelling, scrotal discomfort or a painful testicular mass, and isolated carcinoid syndrome. ⁴ The prognosis of NETs is largely dependent on the tumor grade, proliferative activity, and disease extent. ⁵ Well-differentiated NETs (Grade 1) generally exhibit an indolent course and excellent prognosis, while poorly differentiated forms carry a higher risk of metastasis and mortality. ⁶ However, poorly differentiated variants or those with metastatic spread can exhibit aggressive behavior, necessitating a multidisciplinary approach to management. ⁵

TNETs pose distinct diagnostic challenges owing to their histological similarity to other testicular tumors, warranting meticulous histopathological and immunohistochemical evaluation. The diagnosis is based on the microscopic characteristics of tumor cells and immunohistochemical (IHC) staining.^7,8 Comprehensive imaging and clinical assessment are essential to exclude metastatic disease, given that approximately 10% of NETs may be metastatic. ⁷ Imaging limitations encompass initial ultrasound findings that may lack definitiveness, alongside the need for advanced imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/DOTATATE scans, which can be constrained by factors such as availability and cost. ⁸ Traditional testicular tumor markers, including alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH), are typically present within normal ranges in NETs, resulting in diagnostic ambiguity.^4,9 To the best of our knowledge, primary TNETs remain exceedingly rare, particularly in young adults. Reporting additional well-documented cases contributes to a better understanding of their clinicopathological characteristics and long-term behavior. In this report, we present a case of a young male with a well-differentiated primary TNET and discuss its implications for prognosis.

Case presentation

A male in his early 20s with normal sexual development presented with a painless swelling in the left testis, gradually increasing in size over 2 months. The patient was admitted to Shariati Hospital, Tehran, Iran, in late 2024. Examination revealed a firm, non-tender mass in the left testis, with no associated inguinal lymphadenopathy. The right testis was unremarkable. The patient denied systemic symptoms, including fever, weight loss, or gastrointestinal complaints. His past medical history was unremarkable. Scrotal ultrasonography revealed a hypervascular lesion with heterogeneous parenchyma, and calcifications were noted in the left testis, measuring 38 × 27 mm, raising suspicion for malignancy. Spiral high-resolution CT of the lungs revealed no evidence of metastatic lesions. Abdominopelvic CT with intravenous contrast demonstrated normal findings, excluding lymphadenopathy or distant metastasis. All tumor markers were within normal ranges: AFP = 1.1 ng/mL; β-hCG <3 IU/L; and LDH = 411 IU/L. Additionally, markers such as vanillylmandelic acid (VMA) (7.4 mg/24 h) and urine metanephrines (210 mcg/24 h) were within the normal range.

The patient underwent radical orchiectomy. The specimen consisted of a testis measuring 7 × 5 × 4 cm. Cut sections demonstrated a well-circumscribed solid tumor that was 3 cm in the greatest dimension. The epididymis and spermatic cord findings were unremarkable. Histological sections revealed nests of monotonous tumor cells with round nuclei and characteristic “salt-and-pepper” chromatin. The monomorphic cells showed abundant granular eosinophilic cytoplasm. Mitotic activity was less than 1 mitosis/2 mm², and no necrosis was noted (Figure 1). The surrounding testicular parenchyma showed no evidence of germ cell neoplasia in situ (GCNIS), intratubular germ cell tumor, or teratomatous component. Several IHC tests were performed, which indicated that the tumor was positive for chromogranin, synaptophysin, INSM1, pancytokeratin, and Ki-67 (which was positive in less than 1% of the tumor cells), while EMA and SF1 were negative (Figure 2). The strong positivity for synaptophysin and chromogranin, along with the low Ki-67 expression, indicated that the tumor was derived from neuroendocrine cells. This combination of factors confirmed the diagnosis of a well-differentiated NET, typically associated with a better prognosis. The patient has been followed up for 18 months after surgery with no evidence of recurrence or metastasis on clinical examination and imaging studies. The reporting of this case conforms to the Case Report (CARE) guidelines, and written informed consent was obtained from the patient for treatment and publication of this case report. ¹⁰ All identifying information of the patient has been removed to protect patient privacy and ensure anonymity.

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Figure 1.

Histopathological features of the specimen. (a) Overall architecture of the tumor, revealing a well-defined tumor and normal testicular tissue. (b) Tumor cells which are organized in nests and trabeculae separated by thin fibrovascular septa. (c) Tumor cells with a uniform appearance with salt and pepper nuclear chromatin and fine granular cytoplasm.

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Figure 2.

Immunohistochemical staining. (a) Pancytokeratin, (b) Synaptophysin, (c) Chromogranin, (d) INSM1, (e) Ki-67.

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Discussion

Primary TNETs are extremely uncommon, representing less than 1% of all testicular malignancies. ¹¹ The rarity of these tumors emphasizes the importance of documenting each case to improve clinical understanding and management. Interestingly, these tumors can also develop in association with prepubertal teratomas. Approximately 75% are identified as pure NETs, whereas the remaining 25% are linked to other teratomatous components.^11–13 Additionally, rare cases of postpubertal-type TNETs have been reported. ¹⁴ According to a recent meta-analysis by Amine et al., the mean age at diagnosis was approximately 55 years for secondary TNETs and 41 years for pure primary TNETs. ⁴ Besides their rarity, primary TNETs often have a nonspecific clinical presentation, making them hard to distinguish from other common histopathologies, such as seminoma, Sertoli cell tumor, metastatic neuroendocrine carcinoma, and testicular teratoma with carcinoid.^7,15

TNETs typically do not cause discomfort and therefore often go unnoticed by the patient. Consequently, a considerable delay is often observed between the patient’s identification of a testicular swelling and their initial consultation.^11,16 These tumors do not lead to an elevation in the serum levels of standard markers associated with testicular tumors, such as AFP, β-HCG, and LDH. However, they may lead to an elevation in the serum levels of NSE, vanillylmandelic acid, serum serotonin, and its primary urinary metabolite, 5-HIAA, as assessed in a 24-h urine sample. ⁴ Scrotal ultrasonography is currently recognized as the gold standard for the morphological examination of the testis. TNETs typically present with dense punctate calcifications within a well-defined solid hypoechoic mass.^17,18 Pelvic CT plays a critical role in the staging of TNETs and in diagnosing tumors in an undescended testis. ¹⁹ Additionally, somatostatin receptor scintigraphy using octreotide demonstrates a sensitivity of 70%–90% for the detection of primary neuroendocrine tumors. ²⁰ Therefore, the conclusive diagnosis is primarily determined through careful histopathological analysis of the orchiectomy specimen, which demonstrates distinctive solid nests and insular, trabecular, and acinar growth patterns with luminal mucin in a fibrous or hyalinized stroma.^7,11,14 Neoplastic cells exhibit a monomorphic appearance with abundant granular eosinophilic-to-pale cytoplasm. The tumor cells have uniform round nuclei with fine “salt-and-pepper” chromatin. ¹¹ Mitotic figures, necrosis, and vascular invasion are rarely observed. ¹¹ The diagnosis is definitively established through IHC staining, demonstrating that the tumor cells exhibit strong positivity for neuroendocrine markers, including synaptophysin and chromogranin, while showing negativity for OCT3/4, SALL4, Kit, SF1, SOX2, alpha inhibin, and CDX2.^12,14,21

According to the 2016 WHO classification, TNETs were identified as “carcinoid tumors” and classified into the following categories: (a) pure primary forms, those associated with teratoma or epidermoid/dermoid cysts and (b) metastatic variants from extratesticular sites such as the ileum. By 2022, the terminology was revised to “prepubertal-type testicular neuroendocrine tumor,” replacing the previously used designations of carcinoid, atypical carcinoid, and neuroendocrine carcinoma. This change aligns the nomenclature with that of gastrointestinal NETs and emphasizes their usual lack of association with GCNIS. These tumors most commonly arise in conjunction with prepubertal-type teratomas, although rare cases have been reported with postpubertal-type teratomas. The updated classification eliminated subtypes and instead highlighted characteristic histopathological features, including insular and trabecular growth patterns and salt-and-pepper chromatin. Furthermore, it explicitly recognizes their germ cell derivation from intestinal-like neuroendocrine cells. Although these modifications are relatively modest, they improve diagnostic consistency and reinforce the generally indolent biological behavior of these tumors while acknowledging that atypical morphological features may be associated with metastatic potential.^22–25

Localized TNETs typically demonstrate a favorable outcome after surgical intervention.^11,16,26 Metastatic potential is present, with documented instances of metastasis occurring as late as 5–19 years after treatment.^16,27 Notably, approximately 50% of TNETs associated with carcinoid syndrome exhibit metastasis, and there is a correlation between larger tumors and an increased risk of metastasis. ¹² The outlook for TNETs is generally more favorable when the tumor is linked to a teratoma. However, the impact of this association on prognosis varies with the patient’s age. Specifically, in postpubertal patients, neuroendocrine tumors arising from teratomas are associated with a poorer prognosis.^11,12,28 Given the possibility of late metastasis, it is crucial to conduct long-term follow-up, which may involve regular physical examinations, urinary 5-HIAA monitoring, abdominal CT, and gastrointestinal evaluations.^11,16,26,27 According to a meta-analysis, the overall survival rate over 5 years is approximately 78.7%, while the disease-specific survival rate stands at 84.3%. ⁴ Adverse prognostic indicators encompass significant tumor size, low levels of tumor differentiation, and the occurrence of carcinoid syndrome.^12,29,30 In a metastatic context, retroperitoneal dissection and receptor-targeted radiotherapy may be employed; however, chemotherapy and radiotherapy are noted to offer limited advantages. Unfortunately, molecular testing such as detection of isochromosome 12p or other genomic alterations was not performed in this case due to limited availability. Future studies incorporating molecular profiling may provide further insights into the pathogenesis of primary TNETs.

Conclusion

Primary TNETs are very uncommon tumors that present diagnostic challenges owing to their vague clinical manifestations and similarities with other testicular neoplasms. Precise diagnosis is fundamentally dependent on histological assessment augmented by immunohistochemistry staining. Although uncommon, well-differentiated TNETs often have a positive prognosis after surgical intervention, with radical orchiectomy being the preferred therapy. The possibility of late metastasis requires prolonged monitoring using clinical evaluations, biochemical markers, and imaging tests. Continued documentation and study of TNET cases are crucial for deepening comprehension of their behavior, optimizing diagnostic methods, and refining management strategies to improve patient outcomes.