Clinical Features and Management of Primary Neuroendocrine Tumors in Rare Sites of the Urinary System: Two Case Reports and Literature Review

Clinical Features and Management of Primary Neuroendocrine Tumors in Rare Sites of the Urinary System: Two Case Reports and Literature Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Clinical Features and Management of Primary Neuroendocrine Tumors in Rare Sites of the Urinary System: Two Case Reports and Literature Review Rui Sun, Nanhe Lin, Guangyao Liang, Mingzhu Li, Yun Xie This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7357058/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background: Neuroendocrine tumors (NETs) primarily arising within the urinary system, particularly in the kidney or testis, are extremely rare. This rarity often results in diagnostic delays and therapeutic uncertainty. Heightened clinical vigilance is warranted for urogenital masses exhibiting atypical features and negative conventional tumor markers. Case presentation: We report two rare cases of primary urinary NETs. The first case involved a 52-year-old woman with an incidentally discovered left renal mass, ultimately diagnosed as a well-differentiated renal NET based on characteristic histological features and immunohistochemical (IHC) positivity for synaptophysin (Syn) and INSM1. The second case was a 21-year-old man who presented with painless right testicular enlargement, and was diagnosed with primary prepubertal-type testicular NET. Metastatic disease was excluded in both cases through comprehensive imaging and IHC analyses. Both patients underwent complete surgical excision and remained disease-free during follow-up. Conclusion: Primary renal and testicular NETs should be considered in differential diagnoses of atypical urogenital masses. Definitive diagnosis requires integrated histopathological assessment with targeted IHC and metastasis exclusion. Complete surgical resection remains the cornerstone of management, with mandatory long-term surveillance due to metastatic potential. Neuroendocrine tumor Kidney Testis Urinary system Figures Figure 1 Figure 2 Introduction Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms originating from neuroendocrine cells, which possess both neuronal and endocrine functions. These cells can secrete a variety of bioactive substances and typically express neuroendocrine markers such as synaptophysin and chromogranin A. NETs most commonly occur in the gastrointestinal (GI) and respiratory tracts, while primary NETs of the urogenital system are extremely rare, accounting for approximately 1% of all NETs. Within the urinary system, NETs are more frequently found in the adrenal glands, bladder, and prostate; cases originating from the kidney or testis are even less common. According to the SEER database, the incidence of primary renal NETs is about 0.13 per million people [ 1 ] , while the incidence of primary testicular NETs has not been reported. However, studies have indicated that testicular NETs constitute less than 1% of all testicular tumors [ 2 ] . Due to their low incidence, the diagnosis of primary urinary NETs is frequently delayed or missed, resulting in advanced disease at the time of detection, thereby greatly complicating treatment and severely impacting patient survival and quality of life. Here, we report two cases of NETs originating from the kidney and testis, respectively, and analyze their clinicopathological features and management, aiming to enhance clinicians’ understanding and diagnostic capabilities regarding rare primary NETs in the urinary system. Case Presentations Case 1 A 52-year-old female came with an incidentally detected left renal mass during a routine physical examination. She reported mild, persistent left lumbar pain for over three months without hematuria, fever, or other urinary symptoms. Her history was notable for hypertension and previous myomectomy. Physical examination was unremarkable, and urinalysis as well as blood biochemistry tests were within normal limits. Abdominal aortic CTA revealed a 51mm×55mm×60mm heterogeneous soft tissue lesion at the lower pole of the left kidney, with irregular enhancement and indistinct boundaries, suggestive of a malignant neoplasm(Fig. 1 A). No regional lymphadenopathy or obvious distant metastasis was observed. Following informed consent and preoperative optimization, the patient underwent robot-assisted laparoscopic partial nephrectomy under general anesthesia. The intraoperative findings confirmed a solid, encapsulated tumor at the lower pole of left kidney,which was completely resected under renal artery occlusion for 22 minutes. The operation was uneventful, with minimal blood loss and a good postoperative recovery. Gross pathology showed a soft, gray-red tumor closely adherent to the renal capsule but not invading the renal parenchyma. Histological examination(H&E) revealed tumor cells arranged in trabecular and glandular patterns, with uniform, round to oval nuclei, stippled chromatin, and mitotics counts 0/10 HPF(Fig. 1 B,C). Immunohistochemical(IHC) staining was positive for synaptophysin (Syn), CD56, cytokeratin (CK), INSM1, vimentin, and SATB2, with a Ki-67 proliferation index of approximately 5%. Stains for chromogranin A, PAX-8, GATA3, CK7, and CK20 were negative. The absence of PAX-8 and GATA3 excluded epithelial-derived renal tumors, and the positive neuroendocrine markers supported the diagnosis of NET. Postoperatively, ^68 Ga-DOTANOC showed mild increased uptake at the surgical site(likely reactive), and no confirmatory positive somatostatin receptor lesions elsewhere(Fig. 1 D). The final diagnosis was primary NET of the kidney. The patient did not receive adjuvant therapy and remained recurrence-free at one-month follow-up. Case 2 A 21-year-old male presented with a painless enlargement of the right testis for more than two weeks. He denied urinary irritative symptoms, hematuria, trauma, or radiating pain to the inguinal area. Physical examinatio n revealed right testicular enlargement, firmness, and no tenderness or scrotal skin changes; the left testis and epididymis were normal. Testicular ultrasound at another hospital revealed a 43mm×33 mm heterogeneous mass with vascularization. Serum tumor markers (AFP, β-HCG, CEA, CA-125, CA19-9) and serum LDH were all within normal limits. 3.0T MRI demonstrated an enlarged right testis measuring 36mm×29mm×35mm, exhibiting diffusely heterogeneous T2 hypointensity with preserved T1 isointensity(Fig. 2 A,B). Notably, diffusion restriction was evident as hyperintensity on Diffusion Weighted Imagin and corresponding hypointensity on the Apparent Diffusion Coefficient map. Post-contrast images revealed heterogeneous enhancement throughout the parenchyma. Spermatic veins on both sides appeared dilated, more so on the right. A linear fluid collection was noted along the right testis, accompanied by multiple enlarged bilateral inguinal lymph nodes (largest measuring 17mm×12mm) demonstrating post-contrast enhancement. The constellation of findings raised the possibility of a right seminoma. The patient underwent an immediate left radical orchidectomy under general anesthesia. On gross examination, the tumor appeared gray-yellow. The mass was confined to the testicular parenchyma, with no evidence of extension beyond the tunica albuginea or involvement of the spermatic cord. HE staining revealed tumor cells arranged in insular, rosette, or glandular patterns, with good differentiation and mitotic counts 1/10 HPF(Fig. 2 C-E). IHC analysis demonstrated the tumor was positive for Syn, CgA, CK, INSM1, CDX2, and a Ki-67 index of about 3%; negative for TTF1 and OCT3/4. The absence of OCT3/4 did not support a diagnosis of seminoma. Although CDX2 raised the possibility of an intestinal origin, ^68Ga-DOTANOC performed two weeks postoperatively showed only benign postoperative changes in the right scrotum, with no evidence of somatostatin receptor-positive lesions in the abdomen, retroperitoneum, or pelvis, thereby excluding metastatic disease(Fig. 2 F). Additionally, there was no histological evidence of a germ cell tumor in situ component. Taken together, these findings led to a final diagnosis of primary prepubertal-type NET of testis. The patient did not receive adjuvant therapy and remained disease-free at 1-year follow-up. Discussion NETs of the urinary system are rare, and those originating from the kidney or testis are exceedingly uncommon. According to the 2022 WHO classification, renal NETs are categorized by differentiation and proliferative activity into: well-differentiated NETs (formerly carcinoid tumors), neuroendocrine carcinomas (NEC, including small cell and large cell types) and mixed neuroendocrine-non-neuroendocrine tumors and paragangliomas [ 3 , 4 ] . Approximately 70% of primary renal NETs are well-differentiated (G1/G2); the rest are NECs. Testicular NETs, formerly termed "carcinoid tumor of the testis," are rare malignant tumors unrelated to germ cell tumors. The 2022 WHO classification redefined these as prepubertal-type testicular neuroendocrine tumors, divided into three categories: primary, mixed (with teratoma), and metastatic, of which primary accounts for most cases. Despite different sites, the diagnostic approach shared distinct similarities in the two cases. First, the clinical manifestations were nonspecific: renal NETs manifested as dull lumbar pain and an incidental mass, while testicular NETs presented with painless testicular enlargement; neither had features of carcinoid syndrome. Second, imaging could accurately localize and suggest malignancy but lacked specificity, making misdiagnosis likely (e.g., renal cell carcinoma was initially suspected in Case 1, seminoma in Case 2 ). Histomorphology and IHC are crucial for establishing a definitive diagnosis. In our cases, both tumors exhibited typical NET architecture on H&E staining (glandular/trabecular in renal NET, insular/rosette in testicular NET, both well differentiated). Pivovarcikova et al. reported 11 cases of renal NET, in which INSM1 was positive in 10 of 11 cases, CgA in 8 of 11 cases, and CD56 in 3 of 11 cases [ 5 ] . In the study by Romero et al., Syn exhibited a sensitivity of 100% (15/15), while CgA showed a sensitivity of 97.2% (35/36) [ 6 ] . And in our cases, IHC showed strong positivity for Syn and INSM1. As a recently established marker with high sensitivity and specificity for neuroendocrine tumors, INSM1 is now widely applied in routine diagnostics [ 7 ] . No specific grading system exists for urogenital NETs; GEP-NEN criteria are often referenced (G1: <2/10 HPF or Ki-67 20/10 HPF or Ki-67 > 20%) [ 8 ] . In our cases, the renal NET was G2, and the testicular NET was G1, both with indolent behavior and low metabolic activity on PET-CT, consistent with low-grade NETs. Therefore, in cases of urogenital masses with unclear origin, especially when imaging findings are atypical and the histomorphology does not match common carcinomas, the possibility of NETs should be considered. Early pathological biopsy combined with comprehensive IHC analysis including markers such as Syn, CgA, INSM1, and Ki-67 is crucial for accurate diagnosis and appropriate tumor grading. Primary renal NETs are exceedingly rare, and metastatic disease should be excluded. Most metastatic NETs arise from the pancreas, GI tract, or lung, often presenting with multifocal lesions or metastases. In Case 1, the following points supported a primary renal origin: (1) solitary intrarenal tumor with unique vascular supply; (2) negative CK7/CK20 (markers suggestive of metastasis); (3) thorough pre- and postoperative examination, including PET-CT, did not reveal an extrarenal primary lesion or other metastases. A comprehensive assessment should encompass a detailed review of any prior oncological history, pre- and postoperative imaging studies (such as CT, MRI, PET-CT, and gastrointestinal endoscopy), together with integrated analysis of pathological findings and IHC results. Of note, primary renal NETs lack organ-specific positive IHC markers, requiring multidimensional tumor analysis. For primary renal NETs, surgical resection is the preferred treatment modality. Some studies also suggest that cryoablation may serve as a therapeutic option. However, for patients with tumors confined to the kidney and without metastasis, there is still no consensus regarding the optimal approach among radical nephrectomy, partial nephrectomy, or minimally invasive techniques such as radiofrequency ablation [ 9 , 10 ] . Regional lymphadenectomy is recommended in patients with nodal disease [ 11 ] . Romero et al. reported that among patients with lymph node–metastatic renal NETs who underwent radical nephrectomy and perirenal lymphadenectomy, 50% showed no recurrence or further metastasis during a mean follow-up period of 43 months [ 6 ] . However, to date, no studies have demonstrated a direct survival benefit from such approaches as compared to adjuvant therapies. Prognostic factors for primary renal NETs remain unclear. Previous literature has suggested that age over 40 years, tumor size greater than 4 cm, mitotic activity exceeding 1/10 HPF, presence of initial metastasis, and perirenal capsular invasion may all be associated with poor prognosis [ 11 ] . In the study by Korkmaz T et al., cases with lymph node or distant metastases were always in patients over 40 years old, and tumor diameter in these cases exceeded 4 cm [ 12 ] . In addition, higher mitotic counts and Ki-67 indices have also been shown to correlate with increased risk of metastasis and poorer outcomes [ 3 , 13 ] , though these findings require further validation in larger cohorts. Given that some cases of metastasis may be detected several years after initial diagnosis, and that small primary lesions may be difficult to identify at early stages, long-term follow-up is recommended. This should include regular physical examinations, assessment of biochemical markers, serum CgA measurement, and imaging examination performed every 3–6 months [ 12 , 14 ] . Painless testicular enlargement most commonly suggests germ cell tumors, particularly seminomas. Primary testicular NETs are easily confused with these,yet the diagnosis, management, and prognosis differ markedly between the two, making accurate differentiation essential. In Case 2 , the patient was a young male, and seminoma was the primary clinical consideration. Distinguishing features include: (1) Tumor markers Serum LDH is often elevated in seminoma, with approximately 10–20% of patients exhibiting mildly increased β-HCG levels. In this case, laboratory values including LDH, AFP, β-HCG, and CEA, were all within normal ranges, arguing against classic seminoma; (2) Histopathology and IHC: These remain the gold standards for definitive diagnosis. Seminoma cells are large, uniform, with clear cytoplasm and prominent nucleoli, arranged in sheets or nests, and characteristically express OCT3/4, but are negative for neuroendocrine markers. In contrast, the testicular tumor in Case 2 exhibited insular, rosette-like, or glandular architectural patterns, with well-differentiated tumor cells showing strong, diffuse positivity for Syn, CgA, and INSM1, and negativity for germ cell markers, thus supporting a diagnosis of NET over seminoma. The Ki-67 index was also consistent with a neuroendocrine rather than a highly malignant germ cell tumor. Given the extreme rarity of primary testicular NETs, their classification and prognostic factors are not yet well defined. Some studies have reported that most well-differentiated primary testicular NETs have a favorable prognosis [ 15 – 17 ] , though considerable controversy remains regarding the need for adjuvant radiotherapy or chemotherapy following surgery [ 18 ] . In Case 2 , the patient was a primary testicular NET without carcinoid syndrome manifestations, and PET/CT revealed no distant metastasis, thus no adjuvant radiotherapy or chemotherapy was administered postoperatively. The patient remained disease-free without recurrence or metastasis during a one-year follow-up period. Despite the generally favorable outcomes associated with testicular NETs, rare cases of aggressive metastatic disease have been documented. For example, Hosking DH et al. described a patient with a primary testicular NET who developed metastatic NET and carcinoid syndrome 17 years after initial tumor resection [ 19 ] . Lee H.J. et al. reported a case of primary testicular carcinoid with significant lymphovascular invasion and a disease-free survival of 13 months following surgery [ 20 ] . Additionally, a meta-analysis by Amine MM et al. involving 132 cases of testicular NETs found lymph node metastases in 9% and visceral metastases in 6% of cases, most commonly hepatic [ 21 ] . Consequently, regular and long-term follow-up is recommended for patients with primary testicular NETs. In summary, although primary renal and testicular NETs are extremely rare, clinicians should maintain a high index of suspicion for NETs when encountering urogenital tumors of unknown origin, particularly those with atypical imaging features or negative conventional tumor markers such as AFP and β-HCG. A thorough clinical history and comprehensive systemic imaging are essential to exclude common primary NET sites elsewhere in the body, especially the gastrointestinal tract and lungs. Furthermore, the use of organ-specific IHC markers, such as TTF-1 and CDX2 which can aid in ruling out metastatic disease before a definitive diagnosis of primary NET is established. Once diagnosed, individualized follow-up and management plans should be developed based on tumor characteristics and grade, with close surveillance for potential recurrence and distant metastasis to optimize patient outcomes. Declarations Acknowledgements Not applicable. Authors’ contributions LGY collected the clinical data. SR drafted the manuscript, including the revision. LMZ collected the microscopic pictures. XY reviewed the manuscript. SR and LNH consulted the relevant literature. All authors read and approved the final manuscript. Funding This work was supported by Natural Science Foundation of Guangdong Province, 2023A1515012290, Guangzhou basic research planning for basic and applied basic research project, 2025A04J4171 and Fundamental Research Funds for the Central Universities, Sun Yat-sen University, 24qnpy350 Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Ethics approval and consent to participate The use of the patients’ data and histological results follows a written consent. Consent for publication Written informed consent for publication of their clinical details and clinical images was obtained from the patients. Competing interests The authors declare that they have no competing interests. References McGarrah PW, Westin GFM, Hobday TJ, et al. Renal neuroendocrine neoplasms: a single-center experience[J]. Clin Genitourin Cancer. 2020;18(4):e343–9. Yao JC, Hassan M, Phan A, et al. One hundred years after carcinoid: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States[J]. J Clin Oncology: Official J Am Soc Clin Oncol. 2008;26(18):3063–72. Yuan D, Wu J, Wang DY, et al. Clinical and pathological analysis of primary well-differentiated neuroendocrine tumors in the kidney- a case series[J]. BMC Urol. 2025;25(1):181. Moch H, Amin MB, Berney DM, et al. The 2022 world health organization classification of tumours of the urinary system and Male genital organs-part a: renal, penile, and testicular tumours[J]. Eur Urol. 2022;82(5):458–68. Pivovarcikova K, Agaimy A, Martinek P, et al. Primary renal well-differentiated neuroendocrine tumour (carcinoid): next-generation sequencing study of 11 cases[J]. Histopathology. 2019;75(1):104–17. Fr R, S R B SP et al. Primary carcinoid tumors of the kidney[J]. Journal of Urology, 2006, 176(6 Pt 1). Maleki Z, Nadella A, Nadella M et al. INSM1, a Novel Biomarker for Detection of Neuroendocrine Neoplasms: Cytopathologists’ View[J]. Diagnostics (basel, Switzerland), 2021, 11(12): 2172. Amin M, Trikalinos N, Chatterjee D. Single institutional experience on primary neuroendocrine neoplasms of the kidney: a rare distinct entity[J]. Hum Pathol. 2021;114:36–43. Rosenberg JE, Albersheim JA, Sathianathen NJ, et al. Five new cases of primary renal carcinoid tumor: case reports and literature review[J]. Pathol Oncol Research: POR. 2020;26(1):341–6. Virarkar M, Vulasala SS, Gopireddy D, et al. Neuroendocrine neoplasms of the female genitourinary tract: a comprehensive overview[J]. Cancers. 2022;14(13):3218. Le BK, McGarrah P, Paciorek A, et al. Urinary neuroendocrine neoplasms treated in the modern era: a multicenter retrospective review[J]. Clin Genitourin Cancer. 2023;21(3):403–e4145. Korkmaz T, Seber S, Yavuzer D, et al. Primary renal carcinoid: treatment and prognosis[J]. Crit Rev Oncol/Hematol. 2013;87(3):256–64. Kim B, Kim HS, Moon KC. Primary renal well-differentiated neuroendocrine tumors: report of six cases with an emphasis on the ki-67 index and mitosis[J]. Diagn Pathol. 2019;14(1):12. Hasteh F, Pu R, Michael CW. A metastatic renal carcinoid tumor presenting as breast mass: a diagnostic dilemma[J]. Diagn Cytopathol. 2007;35(5):306–10. Reyes A, Moran CA, Suster S, et al. Neuroendocrine carcinomas (carcinoid tumor) of the testis. A clinicopathologic and immunohistochemical study of ten cases[J]. Am J Clin Pathol. 2003;120(2):182–7. Stroosma OB, Delaere KPJ. Carcinoid tumours of the testis[J]. BJU Int. 2008;101(9):1101–5. Wang WP, Guo C, Berney DM, et al. Primary carcinoid tumors of the testis: a clinicopathologic study of 29 cases[J]. Am J Surg Pathol. 2010;34(4):519–24. Albalawi AA, Bedaiwi AK, Alotaibi MA, et al. Testicular Neuroendocrine Tumors: A Case Report and Literature Review[J]. Cureus. 2023;15(4):e37370. Hosking DH, Bowman DM, McMorris SL, et al. Primary carcinoid of the testis with metastases[J]. J Urol. 1981;125(2):255–6. Lee HJ, Park JY, Kim SY, et al. Primary testicular carcinoid tumor with marked lymphovascular invasion[J]. J Pathol Translational Med. 2021;55(6):410–4. Amine MM, Mohamed B, Mourad H, et al. Neuroendocrine testicular tumors: a systematic review and meta-analysis[J]. Curr Urol. 2017;10(1):15–25. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 07 Oct, 2025 Reviews received at journal 22 Sep, 2025 Reviewers agreed at journal 18 Sep, 2025 Reviews received at journal 16 Sep, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers agreed at journal 10 Sep, 2025 Reviewers invited by journal 10 Sep, 2025 Editor invited by journal 20 Aug, 2025 Editor assigned by journal 18 Aug, 2025 Submission checks completed at journal 18 Aug, 2025 First submitted to journal 12 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7357058","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":516097410,"identity":"40a6f381-31f5-4e9d-be91-c64f81226a6c","order_by":0,"name":"Rui Sun","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Sun","suffix":""},{"id":516097411,"identity":"eb742e4e-2a75-412d-a97b-c19506deff9a","order_by":1,"name":"Nanhe Lin","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Nanhe","middleName":"","lastName":"Lin","suffix":""},{"id":516097412,"identity":"938217be-0c14-4b4d-964b-29196af33932","order_by":2,"name":"Guangyao Liang","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Guangyao","middleName":"","lastName":"Liang","suffix":""},{"id":516097413,"identity":"be8a9243-c0f9-486f-8126-8cc03634ffee","order_by":3,"name":"Mingzhu Li","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Mingzhu","middleName":"","lastName":"Li","suffix":""},{"id":516097414,"identity":"04a3cee9-83c6-427f-8749-2278b9574243","order_by":4,"name":"Yun Xie","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYDACZiD+8MNGjoGBsfEATFCCkBbGmT1pxkCqgUgtIF08bIcSG4AM4rQYHGc+JsHDcyB9bfthoC1/DtsbHGA+eJuHwS4PlxbJZrY0CQmLO7nbziQ2HGBsO5y44QBbsjUPQ3IxLi38zDxmEgY8z3K3HQBpaTicYHCAx0yah+EA2KnYABsz/zeJBLbD6WbnH8Icxv8NrxagLWwSB9gOJ5jdANrCwHaYccMBHja8WoB+MbZs7Ekz3HYDaEtiW3rizMNAkTkGyTi1GJw//PD2nx828mbn0x8++PDH2p7vePPDG28q7HBqAQIWRCwkMDRD0gODAW71QMD8AYlTh1fpKBgFo2AUjEwAAM5GXQ+8h/6wAAAAAElFTkSuQmCC","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Yun","middleName":"","lastName":"Xie","suffix":""}],"badges":[],"createdAt":"2025-08-12 14:53:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7357058/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7357058/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91828956,"identity":"cf87fc9a-da6a-426c-8ed4-986b86d45322","added_by":"auto","created_at":"2025-09-22 08:54:22","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2525531,"visible":true,"origin":"","legend":"","description":"","filename":"ClinicalFeaturesandManagementofPrimaryNeuroendocrineTumorsinRareSitesoftheUrinarySystemTwoCaseReportsandLiteratureReview.docx","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/4b88c68b759a4ff2ecdadda4.docx"},{"id":91827262,"identity":"7ad204b0-ac3a-43cf-ba36-4d82d3f9f2e2","added_by":"auto","created_at":"2025-09-22 08:46:22","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6367,"visible":true,"origin":"","legend":"","description":"","filename":"378fd7b5d5fa4776b3ffa310fe9c5f3b.json","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/2dfb6aca1f906f77c8211d2e.json"},{"id":91827263,"identity":"8ef5fdb3-828a-489f-a92a-ab4098c83185","added_by":"auto","created_at":"2025-09-22 08:46:22","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":52373,"visible":true,"origin":"","legend":"","description":"","filename":"378fd7b5d5fa4776b3ffa310fe9c5f3b1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/53891261097d7298ebd79e3b.xml"},{"id":91830374,"identity":"b25a855d-6bce-44a1-9b6e-cc6bfe1beaff","added_by":"auto","created_at":"2025-09-22 09:02:22","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":205727,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/690064c13c11922ad0cd4ec6.png"},{"id":91828957,"identity":"ddd94363-6a90-4e6e-be80-01537405d46f","added_by":"auto","created_at":"2025-09-22 08:54:22","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":187917,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/005e6285d6493095d7d0edb8.png"},{"id":91828959,"identity":"df108760-b67f-4d67-bde8-e9d7be0cdddf","added_by":"auto","created_at":"2025-09-22 08:54:22","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":52087,"visible":true,"origin":"","legend":"","description":"","filename":"378fd7b5d5fa4776b3ffa310fe9c5f3b1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/6987f52c56973a5149557d0a.xml"},{"id":91827264,"identity":"30142426-3282-4e26-af07-75708dff70ce","added_by":"auto","created_at":"2025-09-22 08:46:22","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":55902,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/4aac202d3a9bc719389f83d4.html"},{"id":91827265,"identity":"8e9b9a18-f2ce-44e3-a984-8f947cb16c5f","added_by":"auto","created_at":"2025-09-22 08:46:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1320010,"visible":true,"origin":"","legend":"\u003cp\u003eImaging and pathological features of primary renal NET. \u003cstrong\u003e(A) \u003c/strong\u003eEnhanced CT showed a heterogeneous soft tissue lesion (arrow) at the lower pole of the left kidney. \u003cstrong\u003e(B,C)\u003c/strong\u003e H\u0026amp;E staining of the resected tumor demonstrating trabecular and glandular patterns of uniform tumor cells with stippled chromatin. \u003cstrong\u003e(D)\u003c/strong\u003e ^68Ga-DOTANOC whole-body PET/CT scan revealing mild uptake at the surgical site with no evidence of additional somatostatin receptor-positive lesions elsewhere.\u003c/p\u003e","description":"","filename":"floatimage110.png","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/3494c7de11fc661c7e609b51.png"},{"id":91827269,"identity":"689f5834-97cd-415e-a093-69cbce8d98a8","added_by":"auto","created_at":"2025-09-22 08:46:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1195157,"visible":true,"origin":"","legend":"\u003cp\u003eImaging and pathological features of primary testicular NET. \u003cstrong\u003e(A, B)\u003c/strong\u003e Axial T1-weight(A) and T2-weighted(B) MRI images of the pelvis reveal an enlarged right testis with heterogeneous low signal intensity and diffuse enhancement (A, black arrow; B, white arrow). \u003cstrong\u003e(C–E)\u003c/strong\u003eH\u0026amp;E staining of the testicular tumor shows insular, rosette-like, and glandular patterns of uniform neuroendocrine cells. The tumor is confined to the testicular parenchyma without involvement of the tunica albuginea or adjacent structures. \u003cstrong\u003e(F)\u003c/strong\u003e ^68Ga-DOTANOC PET/CT scan demonstrates no evidence of somatostatin receptor-positive lesions outside the surgical site, excluding metastasis.\u003c/p\u003e","description":"","filename":"floatimage28.png","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/1c17378ab82d769a7dce736c.png"},{"id":91830385,"identity":"57411962-4ccc-4bcd-93ea-ff015c1304c1","added_by":"auto","created_at":"2025-09-22 09:02:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3287292,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7357058/v1/ad9a39ad-61f5-43c6-b0dd-fdbaf2d02c18.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Features and Management of Primary Neuroendocrine Tumors in Rare Sites of the Urinary System: Two Case Reports and Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeuroendocrine tumors (NETs) are a heterogeneous group of neoplasms originating from neuroendocrine cells, which possess both neuronal and endocrine functions. These cells can secrete a variety of bioactive substances and typically express neuroendocrine markers such as synaptophysin and chromogranin A. NETs most commonly occur in the gastrointestinal (GI) and respiratory tracts, while primary NETs of the urogenital system are extremely rare, accounting for approximately 1% of all NETs. Within the urinary system, NETs are more frequently found in the adrenal glands, bladder, and prostate; cases originating from the kidney or testis are even less common. According to the SEER database, the incidence of primary renal NETs is about 0.13 per million people\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e, while the incidence of primary testicular NETs has not been reported. However, studies have indicated that testicular NETs constitute less than 1% of all testicular tumors\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Due to their low incidence, the diagnosis of primary urinary NETs is frequently delayed or missed, resulting in advanced disease at the time of detection, thereby greatly complicating treatment and severely impacting patient survival and quality of life. Here, we report two cases of NETs originating from the kidney and testis, respectively, and analyze their clinicopathological features and management, aiming to enhance clinicians\u0026rsquo; understanding and diagnostic capabilities regarding rare primary NETs in the urinary system.\u003c/p\u003e"},{"header":"Case Presentations","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eCase 1\u003c/h2\u003e\u003cp\u003eA 52-year-old female came with an incidentally detected left renal mass during a routine physical examination. She reported mild, persistent left lumbar pain for over three months without hematuria, fever, or other urinary symptoms. Her history was notable for hypertension and previous myomectomy. Physical examination was unremarkable, and urinalysis as well as blood biochemistry tests were within normal limits. Abdominal aortic CTA revealed a 51mm\u0026times;55mm\u0026times;60mm heterogeneous soft tissue lesion at the lower pole of the left kidney, with irregular enhancement and indistinct boundaries, suggestive of a malignant neoplasm(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). No regional lymphadenopathy or obvious distant metastasis was observed.\u003c/p\u003e\u003cp\u003eFollowing informed consent and preoperative optimization, the patient underwent robot-assisted laparoscopic partial nephrectomy under general anesthesia. The intraoperative findings confirmed a solid, encapsulated tumor at the lower pole of left kidney,which was completely resected under renal artery occlusion for 22 minutes. The operation was uneventful, with minimal blood loss and a good postoperative recovery. Gross pathology showed a soft, gray-red tumor closely adherent to the renal capsule but not invading the renal parenchyma. Histological examination(H\u0026amp;E) revealed tumor cells arranged in trabecular and glandular patterns, with uniform, round to oval nuclei, stippled chromatin, and mitotics counts 0/10 HPF(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB,C). Immunohistochemical(IHC) staining was positive for synaptophysin (Syn), CD56, cytokeratin (CK), INSM1, vimentin, and SATB2, with a Ki-67 proliferation index of approximately 5%. Stains for chromogranin A, PAX-8, GATA3, CK7, and CK20 were negative. The absence of PAX-8 and GATA3 excluded epithelial-derived renal tumors, and the positive neuroendocrine markers supported the diagnosis of NET. Postoperatively, ^68 Ga-DOTANOC showed mild increased uptake at the surgical site(likely reactive), and no confirmatory positive somatostatin receptor lesions elsewhere(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). The final diagnosis was primary NET of the kidney. The patient did not receive adjuvant therapy and remained recurrence-free at one-month follow-up.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003cp\u003eA 21-year-old male presented with a painless enlargement of the right testis for more than two weeks. He denied urinary irritative symptoms, hematuria, trauma, or radiating pain to the inguinal area. Physical examinatio n revealed right testicular enlargement, firmness, and no tenderness or scrotal skin changes; the left testis and epididymis were normal. Testicular ultrasound at another hospital revealed a 43mm\u0026times;33 mm heterogeneous mass with vascularization. Serum tumor markers (AFP, β-HCG, CEA, CA-125, CA19-9) and serum LDH were all within normal limits. 3.0T MRI demonstrated an enlarged right testis measuring 36mm\u0026times;29mm\u0026times;35mm, exhibiting diffusely heterogeneous T2 hypointensity with preserved T1 isointensity(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA,B). Notably, diffusion restriction was evident as hyperintensity on Diffusion Weighted Imagin and corresponding hypointensity on the Apparent Diffusion Coefficient map. Post-contrast images revealed heterogeneous enhancement throughout the parenchyma. Spermatic veins on both sides appeared dilated, more so on the right. A linear fluid collection was noted along the right testis, accompanied by multiple enlarged bilateral inguinal lymph nodes (largest measuring 17mm\u0026times;12mm) demonstrating post-contrast enhancement. The constellation of findings raised the possibility of a right seminoma.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eThe patient underwent an immediate left radical orchidectomy under general anesthesia. On gross examination, the tumor appeared gray-yellow. The mass was confined to the testicular parenchyma, with no evidence of extension beyond the tunica albuginea or involvement of the spermatic cord. HE staining revealed tumor cells arranged in insular, rosette, or glandular patterns, with good differentiation and mitotic counts 1/10 HPF(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC-E). IHC analysis demonstrated the tumor was positive for Syn, CgA, CK, INSM1, CDX2, and a Ki-67 index of about 3%; negative for TTF1 and OCT3/4. The absence of OCT3/4 did not support a diagnosis of seminoma. Although CDX2 raised the possibility of an intestinal origin, ^68Ga-DOTANOC performed two weeks postoperatively showed only benign postoperative changes in the right scrotum, with no evidence of somatostatin receptor-positive lesions in the abdomen, retroperitoneum, or pelvis, thereby excluding metastatic disease(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF). Additionally, there was no histological evidence of a germ cell tumor in situ component. Taken together, these findings led to a final diagnosis of primary prepubertal-type NET of testis. The patient did not receive adjuvant therapy and remained disease-free at 1-year follow-up.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eNETs of the urinary system are rare, and those originating from the kidney or testis are exceedingly uncommon. According to the 2022 WHO classification, renal NETs are categorized by differentiation and proliferative activity into: well-differentiated NETs (formerly carcinoid tumors), neuroendocrine carcinomas (NEC, including small cell and large cell types) and mixed neuroendocrine-non-neuroendocrine tumors and paragangliomas\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Approximately 70% of primary renal NETs are well-differentiated (G1/G2); the rest are NECs. Testicular NETs, formerly termed \"carcinoid tumor of the testis,\" are rare malignant tumors unrelated to germ cell tumors. The 2022 WHO classification redefined these as prepubertal-type testicular neuroendocrine tumors, divided into three categories: primary, mixed (with teratoma), and metastatic, of which primary accounts for most cases.\u003c/p\u003e\u003cp\u003eDespite different sites, the diagnostic approach shared distinct similarities in the two cases. First, the clinical manifestations were nonspecific: renal NETs manifested as dull lumbar pain and an incidental mass, while testicular NETs presented with painless testicular enlargement; neither had features of carcinoid syndrome. Second, imaging could accurately localize and suggest malignancy but lacked specificity, making misdiagnosis likely (e.g., renal cell carcinoma was initially suspected in Case 1, seminoma in Case \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Histomorphology and IHC are crucial for establishing a definitive diagnosis. In our cases, both tumors exhibited typical NET architecture on H\u0026amp;E staining (glandular/trabecular in renal NET, insular/rosette in testicular NET, both well differentiated). Pivovarcikova et al. reported 11 cases of renal NET, in which INSM1 was positive in 10 of 11 cases, CgA in 8 of 11 cases, and CD56 in 3 of 11 cases\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. In the study by Romero et al., Syn exhibited a sensitivity of 100% (15/15), while CgA showed a sensitivity of 97.2% (35/36)\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. And in our cases, IHC showed strong positivity for Syn and INSM1. As a recently established marker with high sensitivity and specificity for neuroendocrine tumors, INSM1 is now widely applied in routine diagnostics\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. No specific grading system exists for urogenital NETs; GEP-NEN criteria are often referenced (G1: \u0026lt;2/10 HPF or Ki-67\u0026thinsp;\u0026lt;\u0026thinsp;3%; G2: 2\u0026ndash;20/10 HPF or Ki-67 3\u0026ndash;20%; G3: \u0026gt;20/10 HPF or Ki-67\u0026thinsp;\u0026gt;\u0026thinsp;20%)\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. In our cases, the renal NET was G2, and the testicular NET was G1, both with indolent behavior and low metabolic activity on PET-CT, consistent with low-grade NETs. Therefore, in cases of urogenital masses with unclear origin, especially when imaging findings are atypical and the histomorphology does not match common carcinomas, the possibility of NETs should be considered. Early pathological biopsy combined with comprehensive IHC analysis including markers such as Syn, CgA, INSM1, and Ki-67 is crucial for accurate diagnosis and appropriate tumor grading.\u003c/p\u003e\u003cp\u003ePrimary renal NETs are exceedingly rare, and metastatic disease should be excluded. Most metastatic NETs arise from the pancreas, GI tract, or lung, often presenting with multifocal lesions or metastases. In Case 1, the following points supported a primary renal origin: (1) solitary intrarenal tumor with unique vascular supply; (2) negative CK7/CK20 (markers suggestive of metastasis); (3) thorough pre- and postoperative examination, including PET-CT, did not reveal an extrarenal primary lesion or other metastases. A comprehensive assessment should encompass a detailed review of any prior oncological history, pre- and postoperative imaging studies (such as CT, MRI, PET-CT, and gastrointestinal endoscopy), together with integrated analysis of pathological findings and IHC results. Of note, primary renal NETs lack organ-specific positive IHC markers, requiring multidimensional tumor analysis. For primary renal NETs, surgical resection is the preferred treatment modality. Some studies also suggest that cryoablation may serve as a therapeutic option. However, for patients with tumors confined to the kidney and without metastasis, there is still no consensus regarding the optimal approach among radical nephrectomy, partial nephrectomy, or minimally invasive techniques such as radiofrequency ablation\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Regional lymphadenectomy is recommended in patients with nodal disease\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Romero et al. reported that among patients with lymph node\u0026ndash;metastatic renal NETs who underwent radical nephrectomy and perirenal lymphadenectomy, 50% showed no recurrence or further metastasis during a mean follow-up period of 43 months\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. However, to date, no studies have demonstrated a direct survival benefit from such approaches as compared to adjuvant therapies. Prognostic factors for primary renal NETs remain unclear. Previous literature has suggested that age over 40 years, tumor size greater than 4 cm, mitotic activity exceeding 1/10 HPF, presence of initial metastasis, and perirenal capsular invasion may all be associated with poor prognosis\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. In the study by Korkmaz T et al., cases with lymph node or distant metastases were always in patients over 40 years old, and tumor diameter in these cases exceeded 4 cm\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. In addition, higher mitotic counts and Ki-67 indices have also been shown to correlate with increased risk of metastasis and poorer outcomes\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, though these findings require further validation in larger cohorts. Given that some cases of metastasis may be detected several years after initial diagnosis, and that small primary lesions may be difficult to identify at early stages, long-term follow-up is recommended. This should include regular physical examinations, assessment of biochemical markers, serum CgA measurement, and imaging examination performed every 3\u0026ndash;6 months\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003ePainless testicular enlargement most commonly suggests germ cell tumors, particularly seminomas. Primary testicular NETs are easily confused with these,yet the diagnosis, management, and prognosis differ markedly between the two, making accurate differentiation essential. In Case \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the patient was a young male, and seminoma was the primary clinical consideration. Distinguishing features include: (1) Tumor markers Serum LDH is often elevated in seminoma, with approximately 10\u0026ndash;20% of patients exhibiting mildly increased β-HCG levels. In this case, laboratory values including LDH, AFP, β-HCG, and CEA, were all within normal ranges, arguing against classic seminoma; (2) Histopathology and IHC: These remain the gold standards for definitive diagnosis. Seminoma cells are large, uniform, with clear cytoplasm and prominent nucleoli, arranged in sheets or nests, and characteristically express OCT3/4, but are negative for neuroendocrine markers. In contrast, the testicular tumor in Case \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e2\u003c/span\u003e exhibited insular, rosette-like, or glandular architectural patterns, with well-differentiated tumor cells showing strong, diffuse positivity for Syn, CgA, and INSM1, and negativity for germ cell markers, thus supporting a diagnosis of NET over seminoma. The Ki-67 index was also consistent with a neuroendocrine rather than a highly malignant germ cell tumor. Given the extreme rarity of primary testicular NETs, their classification and prognostic factors are not yet well defined. Some studies have reported that most well-differentiated primary testicular NETs have a favorable prognosis\u003csup\u003e[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e, though considerable controversy remains regarding the need for adjuvant radiotherapy or chemotherapy following surgery\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. In Case \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the patient was a primary testicular NET without carcinoid syndrome manifestations, and PET/CT revealed no distant metastasis, thus no adjuvant radiotherapy or chemotherapy was administered postoperatively. The patient remained disease-free without recurrence or metastasis during a one-year follow-up period. Despite the generally favorable outcomes associated with testicular NETs, rare cases of aggressive metastatic disease have been documented. For example, Hosking DH et al. described a patient with a primary testicular NET who developed metastatic NET and carcinoid syndrome 17 years after initial tumor resection\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Lee H.J. et al. reported a case of primary testicular carcinoid with significant lymphovascular invasion and a disease-free survival of 13 months following surgery\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Additionally, a meta-analysis by Amine MM et al. involving 132 cases of testicular NETs found lymph node metastases in 9% and visceral metastases in 6% of cases, most commonly hepatic\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Consequently, regular and long-term follow-up is recommended for patients with primary testicular NETs.\u003c/p\u003e\u003cp\u003eIn summary, although primary renal and testicular NETs are extremely rare, clinicians should maintain a high index of suspicion for NETs when encountering urogenital tumors of unknown origin, particularly those with atypical imaging features or negative conventional tumor markers such as AFP and β-HCG. A thorough clinical history and comprehensive systemic imaging are essential to exclude common primary NET sites elsewhere in the body, especially the gastrointestinal tract and lungs. Furthermore, the use of organ-specific IHC markers, such as TTF-1 and CDX2 which can aid in ruling out metastatic disease before a definitive diagnosis of primary NET is established. Once diagnosed, individualized follow-up and management plans should be developed based on tumor characteristics and grade, with close surveillance for potential recurrence and distant metastasis to optimize patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLGY collected the clinical data. SR drafted the manuscript, including the revision. LMZ collected the microscopic pictures. XY reviewed the manuscript. SR and LNH consulted the relevant literature. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Natural Science Foundation of Guangdong Province, 2023A1515012290, Guangzhou basic research planning for basic and applied basic research project, 2025A04J4171 and Fundamental Research Funds for the Central Universities, Sun Yat-sen University, 24qnpy350\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe use of the patients\u0026rsquo; data and histological results follows a written consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of their clinical details and clinical images was obtained from the patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMcGarrah PW, Westin GFM, Hobday TJ, et al. Renal neuroendocrine neoplasms: a single-center experience[J]. Clin Genitourin Cancer. 2020;18(4):e343\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYao JC, Hassan M, Phan A, et al. One hundred years after carcinoid: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States[J]. J Clin Oncology: Official J Am Soc Clin Oncol. 2008;26(18):3063\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYuan D, Wu J, Wang DY, et al. Clinical and pathological analysis of primary well-differentiated neuroendocrine tumors in the kidney- a case series[J]. BMC Urol. 2025;25(1):181.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoch H, Amin MB, Berney DM, et al. The 2022 world health organization classification of tumours of the urinary system and Male genital organs-part a: renal, penile, and testicular tumours[J]. Eur Urol. 2022;82(5):458\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePivovarcikova K, Agaimy A, Martinek P, et al. Primary renal well-differentiated neuroendocrine tumour (carcinoid): next-generation sequencing study of 11 cases[J]. Histopathology. 2019;75(1):104\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFr R, S R B SP et al. Primary carcinoid tumors of the kidney[J]. Journal of Urology, 2006, 176(6 Pt 1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaleki Z, Nadella A, Nadella M et al. INSM1, a Novel Biomarker for Detection of Neuroendocrine Neoplasms: Cytopathologists\u0026rsquo; View[J]. Diagnostics (basel, Switzerland), 2021, 11(12): 2172.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAmin M, Trikalinos N, Chatterjee D. Single institutional experience on primary neuroendocrine neoplasms of the kidney: a rare distinct entity[J]. Hum Pathol. 2021;114:36\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosenberg JE, Albersheim JA, Sathianathen NJ, et al. Five new cases of primary renal carcinoid tumor: case reports and literature review[J]. Pathol Oncol Research: POR. 2020;26(1):341\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVirarkar M, Vulasala SS, Gopireddy D, et al. Neuroendocrine neoplasms of the female genitourinary tract: a comprehensive overview[J]. Cancers. 2022;14(13):3218.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLe BK, McGarrah P, Paciorek A, et al. Urinary neuroendocrine neoplasms treated in the modern era: a multicenter retrospective review[J]. Clin Genitourin Cancer. 2023;21(3):403\u0026ndash;e4145.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKorkmaz T, Seber S, Yavuzer D, et al. Primary renal carcinoid: treatment and prognosis[J]. Crit Rev Oncol/Hematol. 2013;87(3):256\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim B, Kim HS, Moon KC. Primary renal well-differentiated neuroendocrine tumors: report of six cases with an emphasis on the ki-67 index and mitosis[J]. Diagn Pathol. 2019;14(1):12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHasteh F, Pu R, Michael CW. A metastatic renal carcinoid tumor presenting as breast mass: a diagnostic dilemma[J]. Diagn Cytopathol. 2007;35(5):306\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eReyes A, Moran CA, Suster S, et al. Neuroendocrine carcinomas (carcinoid tumor) of the testis. A clinicopathologic and immunohistochemical study of ten cases[J]. Am J Clin Pathol. 2003;120(2):182\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStroosma OB, Delaere KPJ. Carcinoid tumours of the testis[J]. BJU Int. 2008;101(9):1101\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang WP, Guo C, Berney DM, et al. Primary carcinoid tumors of the testis: a clinicopathologic study of 29 cases[J]. Am J Surg Pathol. 2010;34(4):519\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlbalawi AA, Bedaiwi AK, Alotaibi MA, et al. Testicular Neuroendocrine Tumors: A Case Report and Literature Review[J]. Cureus. 2023;15(4):e37370.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHosking DH, Bowman DM, McMorris SL, et al. Primary carcinoid of the testis with metastases[J]. J Urol. 1981;125(2):255\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee HJ, Park JY, Kim SY, et al. Primary testicular carcinoid tumor with marked lymphovascular invasion[J]. J Pathol Translational Med. 2021;55(6):410\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAmine MM, Mohamed B, Mourad H, et al. Neuroendocrine testicular tumors: a systematic review and meta-analysis[J]. Curr Urol. 2017;10(1):15\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"buro","sideBox":"Learn more about [BMC Urology](http://bmcurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/buro/default.aspx","title":"BMC Urology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Neuroendocrine tumor, Kidney, Testis, Urinary system","lastPublishedDoi":"10.21203/rs.3.rs-7357058/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7357058/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eNeuroendocrine tumors (NETs) primarily arising within the urinary system, particularly in the kidney or testis, are extremely rare.\u003cstrong\u003e \u003c/strong\u003eThis rarity often results in diagnostic delays and therapeutic uncertainty. Heightened clinical vigilance is warranted for urogenital masses exhibiting atypical features and negative conventional tumor markers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003eWe report two rare cases of primary urinary NETs. The first case involved a 52-year-old woman with an incidentally discovered left renal mass, ultimately diagnosed as a well-differentiated renal NET based on characteristic histological features and immunohistochemical (IHC) positivity for synaptophysin (Syn) and INSM1. The second case was a 21-year-old man who presented with painless right testicular enlargement, and was diagnosed with primary prepubertal-type testicular NET. Metastatic disease was excluded in both cases through comprehensive imaging and IHC analyses. Both patients underwent complete surgical excision and remained disease-free during follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003ePrimary renal and testicular NETs should be considered in differential diagnoses of atypical urogenital masses. Definitive diagnosis requires integrated histopathological assessment with targeted IHC and metastasis exclusion. Complete surgical resection remains the cornerstone of management, with mandatory long-term surveillance due to metastatic potential.\u003c/p\u003e","manuscriptTitle":"Clinical Features and Management of Primary Neuroendocrine Tumors in Rare Sites of the Urinary System: Two Case Reports and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 08:46:18","doi":"10.21203/rs.3.rs-7357058/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-07T16:08:57+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-22T23:55:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"254489508586694847949388034598705842273","date":"2025-09-18T19:09:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-16T17:40:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"312286963426556457586789421100506170631","date":"2025-09-15T18:01:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47629512182502210546814608852445361752","date":"2025-09-10T13:34:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-10T13:20:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-20T08:07:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-18T06:46:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-18T06:45:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Urology","date":"2025-08-12T14:50:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"buro","sideBox":"Learn more about [BMC Urology](http://bmcurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/buro/default.aspx","title":"BMC Urology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"24534cd0-0027-4a91-8672-1217471de5bc","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-18T16:23:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-22 08:46:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7357058","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7357058","identity":"rs-7357058","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}