Metastatic Yolk Sac Tumor in the Urinary System: a Case Report and Literature Review

Metastatic Yolk Sac Tumor in the Urinary System: a Case Report 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 Metastatic Yolk Sac Tumor in the Urinary System: a Case Report and Literature Review serhat yentur, ibrahim hacibey, yunus emre dusunus, sule ozsoy, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5783893/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract A testicular cancer is one of the most common malignancies observed in males between the ages of 15 and 35. Testicular-origin yolk sac tumors typically manifest as large, painless, voluminous masses. In nearly all cases with pure or mixed forms of yolk sac tumors, significantly elevated serum alpha-fetoprotein (AFP) levels are detected. Microscopically, the appearance of a yolk sac tumor is the same regardless of patient age and primary site. Observation of Schiller-Duvall bodies is pathognomic for yolk sac tumors. Immunohistochemically, yolk sac tumors are positive for AFP, CK AE1/AE3, Glypican-3 and SALL4, and negative for EMA and CK7. Pure yolk sac tumors are very rare in adults, and only a few cases have been reported in the literature. While adult and prepubertal yolk sac tumors may be histologically similar, it is noted that they tend to metastasize more frequently in adults and exhibit a poorer prognosis. This phenomenon is attributed to the tumor being poorly differentiated in adults. The preferred primary treatment for advanced disease is three to four cycles of BEP (bleomycin, etoposide, cisplatin) chemotherapy followed by resection of residual tumor In our case, we observe a yolk sac tumor that has metastasized synchronously to the renal pelvis, ureter, and bladder. In these patients, elevated serum AFP levels are noted. Given that enzyme levels are not routinely assessed in preoperative and postoperative monitoring of adult patients with urothelial carcinoma, it is important to recognize that uncommon histological patterns in urothelial neoplasms may be unnoticed. Testis Tumor Yolk Sac Urinary System Figures Figure 1 Figure 2 Figure 3 Figure 4 1. INTRODUCTION Testicular cancer is among the most common malignancies observed in males between the ages of 15 and 35. However, it constitutes only 1% of all male malignancies. It is estimated that 0.2% of men will develop a testicular tumor during their lifetime. Approximately 90–95% of these tumors originate from germinal tissue. Testicular tumors can be classified into various histological types, including germ cell tumors (seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, mixed germ cell tumors), sex cord-stromal cell tumors (Leydig cell, Sertoli cell, granulosa cell, thecoma-fibroma), and miscellaneous tumors (lymphoma, leukemia, sarcoma, leiomyoma, vascular tumor, fibroma, neurofibroma). 90–95% of all testicular tumors are germ cell tumors, with mixed cell types being the most common type [ 1 , 2 ]. Mixed germ cell tumors contain up to 42% yolk sac components, whereas adults with pure yolk sac tumors only account for 2.4% [ 3 ]. Yolk sac tumors originating from the testicles typically present as large, painless, and voluminous masses. In almost all cases involving pure or mixed forms of yolk sac tumors, markedly elevated serum alpha-fetoprotein (AFP) levels are observed [ 4 ]. AFP is released from yolk sac cells, exhibiting a serum half-life of 5–7 days [ 5 ]. Assessing serum AFP levels is valuable for diagnosing yolk sac tumors and proves useful in monitoring response to treatment and prognosis [ 6 ]. AFP, genereated by the yolk sac and liver during the embryonic period, decreases to normal adult levels within 1 year after birth [ 7 , 8 ]. Beyond primary liver cancer, elevated serum AFP concentrations may be observed in a significant proportion of ovarian and testicular cancers (23%), pancreatic cancers (18%), stomach cancers (7%), bronchogenic cancers (7%), and colon cancers (5%) [ 9 , 10 ]. It has been associated with elevated serum AFP levels in various types of renal neoplasms across different age groups. These include Wilms tumors, hepatoid carcinoma, renal cell carcinoma, collecting duct carcinomas, and non-invasive bladder tumor subtypes [ 11 ]. Serum AFP levels typically decrease within 2 to 3 weeks after treatment. Extragonadal GCTs are relatively rare, comprising 1–5% of all germ cell tumors. A few cases have been reported in the mediastinum, liver, lung, brain, nasopharynx, sinonasal tract, orbit, ear, and parotid gland [ 12 ]. Microscopically, the appearance of a yolk sac tumor remains consistent regardless of patient age and primary site. The presence of Schiller-Duvall bodies is pathognomonic for yolk sac tumors. Additionally, yolk sac tumors exhibit intracellular and extracellular PAS-positive hyaline globules [ 3 , 13 ]. Immunohistochemically, yolk sac tumors show positivity for AFP, CK AE1/AE3, Glypican-3, and SALL4, and negativity for EMA and CK7. A negative CD30 and beta-HCG on immunohistochemistry may aid in excluding mixed components of embryonal carcinoma and choriocarcinoma, respectively [ 14 ]. The prognosis in adults is poorer, and three adult cases of pure yolk sac tumors have been documented, featuring local (lymph nodes) and/or distant (lungs, brain) massive metastases at the time of diagnosis [ 15 – 17 ]. The preferred primary treatment for advanced disease involves three to four cycles of BEP (bleomycin, etoposide, cisplatin) chemotherapy, followed by the resection of residual tumors [ 4 ]. 2. CASE PRESENTATION A 33-year-old male patient with history of left orchiectomy presented with left flank pain. The pathology report from the orchiectomy performed abroad 2 years ago could not be obtained. Ultrasonography revealed a suspicious lesion on the renal pelvis and severe hydronephrosis. On the Computer Tomography (CT), a hypodense lesion, approximately 27x21 mm in size, with a density higher than that of urine in the calyceal system, was observed in the area extending from the distal renal pelvis to the proximal ureter. Then the patient received 4 cycles of BEP chemotherapy. In the 1 month follow-up CT scan, grade 3 hydronephrosis on the left, a 2 cm lesion on the left posterolateral wall of the bladder, and a 38x25 mm conglomerate lymphadenopathy (LAP) in the left paraaortic area were observed (Fig. 1 ). In the lab evaluation, beta HCG was found to be < 0.1 ng/ml, LDH: 278 ng/ml and AFP: 668 ng/ml. Subsequently, complete resection of the bladder lesion, nephroureterectomy, and retroperitoneal lymph node dissection were performed. All pathologies were reported as pure yolk sac tumor infiltration. 2.1 Pathological Findings Macroscopically, tumors exhibiting similar characteristics were identified in the renal pelvis, four distinct foci along the ureter, bladder, and lymph node. In the microscopic examination of tumor tissues, atypical pleomorphic cells with vesicular nuclei, prominent nucleoli, and narrow eosinophilic cytoplasm were observed. In some areas, these cells formed microcysts in the myxoid stroma (Fig. 2 ), while in other areas, they were arranged around vessels, forming solid islands and Schiller duval bodies (Fig. 3 ). Immunohistochemically, positivity for SALL4 and glypican was observed in these cells, while no staining with p63 and GATA3 was detected (Fig. 4 ). Based on these histomorphological and immunohistochemical findings, the patient was diagnosed with yolk sac metastasis. 2.2 Follow-up At the 3-week postoperative follow-up, the AFP level was 110 ng/ml, while B-HCG and LDH levels were within the normal range. At the 6-month postoperative follow-up, it was observed that the disease had progressed, and the AFP level was > 60,000 ng/ml. Ultrasonographic examination revealed a 10 cm LAP in the para-aortic area and liver metastasis. When the oncological medical records were reviewed, it was noted that the clinical condition progressed, leading to the patient's death in the seventh month postoperatively. 3. DISCUSSION Approximately 60% of prepubertal testicular tumors are comprised of yolk sac tumors [ 15 ]. Pure yolk sac tumors are very rare in adults, and only a few cases have been reported in the literature [ 15 , 18 – 20 ]. While adult and prepubertal yolk sac tumors may be histologically similar, it is noted that they tend to metastasize more frequently in adults and exhibit a poorer prognosis. This phenomenon is attributed to the tumor being poorly differentiated in adults [ 21 ]. Diagnosis of yolk sac tumors requires confirmation by a characteristic immunohistochemistry profile. The majority of these neoplasms show positivity for AFP, SALL4, and negativity for markers of differentiated epithelium such as CK7 and EMA [ 22 ]. Yolk sac tumors are not recognized as a histological variant in the current WHO classifications of urothelial carcinoma. However, there are reports in the literature of certain urinary neoplasms exhibiting features similar to yolk sac tumors. Most of these cases have been summarized in a previous publication by Samaratunga et al. [ 23 ]. Miettinen et al have also reported cases of urothelial carcinoma demonstrating SALL4 positivity [ 24 ]. 4. CONCLUSION A yolk sac tumor metastasizing to the urothelial tract is extremely rare. For the diagnosis, confirmation through immunohistochemistry is essential, involving positivity for AFP, GLP3, and SALL4, and negativity for epithelial markers such as CK7 and EMA. Elevated serum AFP levels can provide supporting evidence for this diagnosis. In our case, we observe a yolk sac tumor that has metastasized synchronously to the renal pelvis, ureter, and bladder. In these patients, elevated serum AFP levels are noted. Given that enzyme levels are not routinely assessed in preoperative and postoperative monitoring of adult patients with urothelial carcinoma, it is important to recognize that uncommon histological patterns in urothelial neoplasms may be unnoticed. Abbreviations AFP: Alpha-fetoprotein CK AE1/AE3: CytokeratinAE1/AE3 CK7: Cytokeratin 7 SALL4: Sal-like protein 4 GLP3: Glypican-3 EMA: Epithelial membrane antigen BEP: Bleomycin, Etoposide, Cisplatin GCT: Germ Cell Tumor PAS: Periodic-Acid-Schiff CT: Computer Tomography HCG: Human chorionic gonadotropin LDH: Lactate dehydrogenase LAP: Lymphadenopathy WHO: World Health Organization Declarations 1.Funding The study was not supported financially by anybody. 2. Conflicts of interest/Competing interests The authors declare no conflicts of interest. 3. Ethics approval The study is case report, so ethics approval is not applicable. 4. Consent to participate Consent was obtained from patient for the study. 5. Written Consent for publication Written consent for publication was obtained from the patient. 6. Availability of data and material The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. 7. Code availability Not applicable 8. Authors' contributions Y.D., I.H. and S.Y wrote the main manuscript text. S.O. prepared figures 1-4. I.K. coordinated the research. All authors reviewed the manuscript. References Coursey Moreno C, Small WC, Camacho JC, et al. Testicular tumors: what radiologists need to know--differential diagnosis, staging, and management. Radiographics 2015;35:400-415. Richie JP. Detection and treatment of testicular cancer. CA Cancer J Clin. 43(3): 151-75, 1993. Khan S, Jetley S, Pujani M, et al.. Pure yolk sac tumor of testis in an adult: a rare occurrence. J Postgrad Med 2014;60:351–3 Hemant J, Jeffrey M and Shekhar G. Pure yolk sac tumour, post-pubertal type, arising from cryptorchid testes BMJ Case Rep. 2019 Jul 22;12(7):e229541. Wanderas EH, Trettli S, Fossa SD. Trends in incidence of testicular cancer in Norway 1955-1992. Eur J Cancer 1995;31A(12):2044-8. Eble J. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press, 2004:237–40. Harper ME, Dugaiczyk A: Linkage of the evolutionarily-related serum albumin and alpha-fetoprotein genes within q11-22 of human chromosome 4”. Am J Hum Genet 35: 565-572, 1983. Seregni E, Botti C, Bombardieri E: Biochemical characteristics and clinical applications of alpha-fetoprotein isoforms. Anticancer Res 15: 1491-1499, 1995. Ball D, Rose E, Alpert E: Alpha-fetoprotein levels in normal adults. Am J Med Sci 303: 157-159, 1992. Sizaret P, Martel N, Tuyns A, Reynaud S: Mean alpha-fetoprotein values of 1,333 males over 15 years by age groups. Digestion 15: 97-103, 1977. Mona El-Bahrawy. AFP producing non-germ celltumors of the urological system. Reviews in urology vol.13 no.1 2011 Arumugam D, Thandavarayan P, Chidambaram L, et al.. Primary nasopharngeal yolk sac tumor: a case report Hashimoto Y, Iwase Y, Mogami T, Hayashi Y, Sasaki S, Kato M, et al. A case of adult pure yolk sac tumor of the testis achieving pathological complete response by chemotherapy. [Article in Japanese]. Hinyokika Kiyo 1995;41:813-6. Dabbs D. Diagnostic immunohistochemistry. 3rd edn Philadelphia, PA: Saunders/Elsevier, 2010:737–9. Talerman A: The incidence of yolk sac tumor (endodermal sinus tumor) elements in germ cell tumors of the testis in adults. Cancer 1975; 36:211–215. Izumi H, Shiokawa H, Shibata Y, Kurokawa J, Ohbu M. Pure yolk sac tumor of the testis with brain metastasis: Report of an adult case. [Article in Japanese]. Hinyokika Kiyo 1992;38:1071-4. Dadalı M, Sunay M, Büyükşerbetçi M, Emir L, Özer E, Erol D. Pure yolk sac tumor of testis in an adult patient: case report. Turkish Journal of Urology 2010;36(3):322-325 Foster RS, Hermans B, Bihrle R, Donohue JP. Clinical stage I pure yolk sac tumor of the testis in adults has different clinical behavior than juvenile yolk sac tumor. J Urol 2000;164:1943-4. Munver R, Donehower RC, Kronz JD, Polascik TJ. HIV infection presenting as an unusually large pure yolk sac tumor of the testis. J Urol 2000;164:1653-4. Espejo-Herrera and Condom-Mundó. Yolk sac tumor differentiation in urothelial carcinoma of the urinary bladder: a case report and differential diagnosis. Diagnostic Pathology (2020) 15:68 https://doi.org/10.1186/s13000-020-00983-3 Baniel J, Foster RS, Einhorn LH. Late relapse of clinical stage I testicular cancer. J Urol 1995;154:1370-2 McNamee T, Damato S, McCluggage WG. Yolk sac tumours of the female genital tract in older adults derive commonly from somatic epithelial neoplasms:somatically derived yolk sac tumours. Histopathology. 2016;69(5):739–51. Samaratunga H, Samaratunga D, Dunglison N, Perry-Keene J, Nicklin J, Delahunt B. Alpha-fetoprotein-producing carcinoma of the renal pelvis exhibiting hepatoid and urothelial differentiation. Anticancer Res. 2012;32(11):4987–91. Miettinen M, Wang Z, McCue PA, Sarlomo-Rikala M, Rys J, Biernat W, Lasota J, Lee YS. SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases. Am J Surg Pathol. 2014;38(3):410–20. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 31 May, 2025 Reviews received at journal 31 May, 2025 Reviewers agreed at journal 31 May, 2025 Reviews received at journal 08 Apr, 2025 Reviewers agreed at journal 31 Mar, 2025 Reviewers invited by journal 02 Mar, 2025 Editor assigned by journal 27 Feb, 2025 Submission checks completed at journal 27 Feb, 2025 First submitted to journal 07 Jan, 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. 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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-5783893","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":422917706,"identity":"2be8b453-6cc6-4358-9163-2e8ffb54938a","order_by":0,"name":"serhat yentur","email":"","orcid":"","institution":"Bağcılar Eğitim ve Araştırma Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"serhat","middleName":"","lastName":"yentur","suffix":""},{"id":422917707,"identity":"9a9b4c30-7c29-453b-920f-cdc9c11b0d8b","order_by":1,"name":"ibrahim hacibey","email":"","orcid":"","institution":"Bağcılar Eğitim ve Araştırma 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1","display":"","copyAsset":false,"role":"figure","size":458968,"visible":true,"origin":"","legend":"\u003cp\u003eThe preoperative CT scan revealed a mass in the left renal pelvis and a left para-aortic LAP\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5783893/v1/3eac3ec37649c7ec0297b723.png"},{"id":77669929,"identity":"138faab2-814e-4fc6-ac79-1e0694e0ac54","added_by":"auto","created_at":"2025-03-04 06:46:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1280152,"visible":true,"origin":"","legend":"\u003cp\u003eCells formed microcysts in the myxoid stroma (HEx40)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5783893/v1/7aebe8da33ad806a03d17f9a.png"},{"id":77669904,"identity":"fe02055d-a5ac-4436-b7ed-60da56b6fac9","added_by":"auto","created_at":"2025-03-04 06:46:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1558004,"visible":true,"origin":"","legend":"\u003cp\u003eSchiller-Duval bodies (HEx40)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5783893/v1/d51323f06f35913430009c58.png"},{"id":77671141,"identity":"c2e11cf1-bed3-42d1-8458-08d6daa92708","added_by":"auto","created_at":"2025-03-04 07:02:28","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1050106,"visible":true,"origin":"","legend":"\u003cp\u003ePositivity for SALL4 (SALL4x200)\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5783893/v1/f18f2e6c358cdbbecfb78210.png"},{"id":77672410,"identity":"c1ee05cf-558c-41d3-a56e-b0fcb45ea1e8","added_by":"auto","created_at":"2025-03-04 07:18:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5693194,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5783893/v1/ec98bb24-03b5-4ce6-a373-a5302635b2b2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eMetastatic Yolk Sac Tumor in the Urinary System: a Case Report and Literature Review\u003c/p\u003e","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eTesticular cancer is among the most common malignancies observed in males between the ages of 15 and 35. However, it constitutes only 1% of all male malignancies. It is estimated that 0.2% of men will develop a testicular tumor during their lifetime. Approximately 90\u0026ndash;95% of these tumors originate from germinal tissue. Testicular tumors can be classified into various histological types, including germ cell tumors (seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, mixed germ cell tumors), sex cord-stromal cell tumors (Leydig cell, Sertoli cell, granulosa cell, thecoma-fibroma), and miscellaneous tumors (lymphoma, leukemia, sarcoma, leiomyoma, vascular tumor, fibroma, neurofibroma). 90\u0026ndash;95% of all testicular tumors are germ cell tumors, with mixed cell types being the most common type [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMixed germ cell tumors contain up to 42% yolk sac components, whereas adults with pure yolk sac tumors only account for 2.4% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eYolk sac tumors originating from the testicles typically present as large, painless, and voluminous masses. In almost all cases involving pure or mixed forms of yolk sac tumors, markedly elevated serum alpha-fetoprotein (AFP) levels are observed [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. AFP is released from yolk sac cells, exhibiting a serum half-life of 5\u0026ndash;7 days [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Assessing serum AFP levels is valuable for diagnosing yolk sac tumors and proves useful in monitoring response to treatment and prognosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAFP, genereated by the yolk sac and liver during the embryonic period, decreases to normal adult levels within 1 year after birth [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Beyond primary liver cancer, elevated serum AFP concentrations may be observed in a significant proportion of ovarian and testicular cancers (23%), pancreatic cancers (18%), stomach cancers (7%), bronchogenic cancers (7%), and colon cancers (5%) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. It has been associated with elevated serum AFP levels in various types of renal neoplasms across different age groups. These include Wilms tumors, hepatoid carcinoma, renal cell carcinoma, collecting duct carcinomas, and non-invasive bladder tumor subtypes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Serum AFP levels typically decrease within 2 to 3 weeks after treatment. Extragonadal GCTs are relatively rare, comprising 1\u0026ndash;5% of all germ cell tumors. A few cases have been reported in the mediastinum, liver, lung, brain, nasopharynx, sinonasal tract, orbit, ear, and parotid gland [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMicroscopically, the appearance of a yolk sac tumor remains consistent regardless of patient age and primary site. The presence of Schiller-Duvall bodies is pathognomonic for yolk sac tumors. Additionally, yolk sac tumors exhibit intracellular and extracellular PAS-positive hyaline globules [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Immunohistochemically, yolk sac tumors show positivity for AFP, CK AE1/AE3, Glypican-3, and SALL4, and negativity for EMA and CK7. A negative CD30 and beta-HCG on immunohistochemistry may aid in excluding mixed components of embryonal carcinoma and choriocarcinoma, respectively [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe prognosis in adults is poorer, and three adult cases of pure yolk sac tumors have been documented, featuring local (lymph nodes) and/or distant (lungs, brain) massive metastases at the time of diagnosis [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The preferred primary treatment for advanced disease involves three to four cycles of BEP (bleomycin, etoposide, cisplatin) chemotherapy, followed by the resection of residual tumors [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e"},{"header":"2. CASE PRESENTATION","content":"\u003cp\u003eA 33-year-old male patient with history of left orchiectomy presented with left flank pain. The pathology report from the orchiectomy performed abroad 2 years ago could not be obtained. Ultrasonography revealed a suspicious lesion on the renal pelvis and severe hydronephrosis. On the Computer Tomography (CT), a hypodense lesion, approximately 27x21 mm in size, with a density higher than that of urine in the calyceal system, was observed in the area extending from the distal renal pelvis to the proximal ureter. Then the patient received 4 cycles of BEP chemotherapy. In the 1 month follow-up CT scan, grade 3 hydronephrosis on the left, a 2 cm lesion on the left posterolateral wall of the bladder, and a 38x25 mm conglomerate lymphadenopathy (LAP) in the left paraaortic area were observed (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In the lab evaluation, beta HCG was found to be \u0026lt;\u0026thinsp;0.1 ng/ml, LDH: 278 ng/ml and AFP: 668 ng/ml. Subsequently, complete resection of the bladder lesion, nephroureterectomy, and retroperitoneal lymph node dissection were performed. All pathologies were reported as pure yolk sac tumor infiltration.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Pathological Findings\u003c/h2\u003e \u003cp\u003eMacroscopically, tumors exhibiting similar characteristics were identified in the renal pelvis, four distinct foci along the ureter, bladder, and lymph node. In the microscopic examination of tumor tissues, atypical pleomorphic cells with vesicular nuclei, prominent nucleoli, and narrow eosinophilic cytoplasm were observed. In some areas, these cells formed microcysts in the myxoid stroma (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), while in other areas, they were arranged around vessels, forming solid islands and Schiller duval bodies (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Immunohistochemically, positivity for SALL4 and glypican was observed in these cells, while no staining with p63 and GATA3 was detected (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Based on these histomorphological and immunohistochemical findings, the patient was diagnosed with yolk sac metastasis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Follow-up\u003c/h2\u003e \u003cp\u003eAt the 3-week postoperative follow-up, the AFP level was 110 ng/ml, while B-HCG and LDH levels were within the normal range.\u003c/p\u003e \u003cp\u003eAt the 6-month postoperative follow-up, it was observed that the disease had progressed, and the AFP level was \u0026gt;\u0026thinsp;60,000 ng/ml. Ultrasonographic examination revealed a 10 cm LAP in the para-aortic area and liver metastasis.\u003c/p\u003e \u003cp\u003eWhen the oncological medical records were reviewed, it was noted that the clinical condition progressed, leading to the patient's death in the seventh month postoperatively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"3. DISCUSSION","content":"\u003cp\u003eApproximately 60% of prepubertal testicular tumors are comprised of yolk sac tumors [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Pure yolk sac tumors are very rare in adults, and only a few cases have been reported in the literature [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. While adult and prepubertal yolk sac tumors may be histologically similar, it is noted that they tend to metastasize more frequently in adults and exhibit a poorer prognosis. This phenomenon is attributed to the tumor being poorly differentiated in adults [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Diagnosis of yolk sac tumors requires confirmation by a characteristic immunohistochemistry profile. The majority of these neoplasms show positivity for AFP, SALL4, and negativity for markers of differentiated epithelium such as CK7 and EMA [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eYolk sac tumors are not recognized as a histological variant in the current WHO classifications of urothelial carcinoma. However, there are reports in the literature of certain urinary neoplasms exhibiting features similar to yolk sac tumors. Most of these cases have been summarized in a previous publication by Samaratunga et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Miettinen et al have also reported cases of urothelial carcinoma demonstrating SALL4 positivity [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e"},{"header":"4. CONCLUSION","content":"\u003cp\u003eA yolk sac tumor metastasizing to the urothelial tract is extremely rare. For the diagnosis, confirmation through immunohistochemistry is essential, involving positivity for AFP, GLP3, and SALL4, and negativity for epithelial markers such as CK7 and EMA. Elevated serum AFP levels can provide supporting evidence for this diagnosis. In our case, we observe a yolk sac tumor that has metastasized synchronously to the renal pelvis, ureter, and bladder. In these patients, elevated serum AFP levels are noted. Given that enzyme levels are not routinely assessed in preoperative and postoperative monitoring of adult patients with urothelial carcinoma, it is important to recognize that uncommon histological patterns in urothelial neoplasms may be unnoticed.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAFP: Alpha-fetoprotein \u003c/p\u003e\n\n\u003cp\u003eCK AE1/AE3: CytokeratinAE1/AE3\u003c/p\u003e\n\n\u003cp\u003eCK7: Cytokeratin 7 \u003c/p\u003e\n\n\u003cp\u003eSALL4: Sal-like protein 4\u003c/p\u003e\n\n\u003cp\u003eGLP3: Glypican-3\u003c/p\u003e\n\n\u003cp\u003eEMA: \u003cem\u003eEpithelial membrane antigen\u003c/em\u003e\u003c/p\u003e\n\n\u003cp\u003eBEP: Bleomycin, Etoposide, Cisplatin\u003c/p\u003e\n\n\u003cp\u003eGCT: Germ Cell Tumor\u003c/p\u003e\n\n\u003cp\u003ePAS: Periodic-Acid-Schiff\u003c/p\u003e\n\n\u003cp\u003eCT: Computer Tomography \u003c/p\u003e\n\n\u003cp\u003eHCG: Human chorionic gonadotropin \u003c/p\u003e\n\n\u003cp\u003eLDH: Lactate dehydrogenase\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003eLAP: \u003c/em\u003eLymphadenopathy\u003c/p\u003e\n\n\u003cp\u003eWHO: World Health Organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e1.Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was not supported financially by anybody.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Conflicts of interest/Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Ethics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is case report, so ethics approval is not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4. Consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent was obtained from patient for the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5. Written Consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten consent for publication was obtained from the patient.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6. Availability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe \u0026nbsp;datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7. Code availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e8.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY.D., I.H. and S.Y wrote the main manuscript text.\u003c/p\u003e\n\u003cp\u003eS.O. \u0026nbsp;prepared figures 1-4.\u003c/p\u003e\n\u003cp\u003eI.K. coordinated the research.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCoursey Moreno C, Small WC, Camacho JC, et al. Testicular tumors: what radiologists need to know--differential diagnosis, staging, and management. Radiographics 2015;35:400-415.\u003c/li\u003e\n \u003cli\u003eRichie JP. Detection and treatment of testicular cancer. CA Cancer J Clin. 43(3): 151-75, 1993.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKhan S, Jetley S, Pujani M, et al..\u0026nbsp;Pure yolk sac tumor of testis in an adult: a rare occurrence.\u0026nbsp;J Postgrad Med\u0026nbsp;2014;60:351\u0026ndash;3\u003c/li\u003e\n \u003cli\u003eHemant J, Jeffrey M and Shekhar G.\u0026nbsp;Pure yolk sac tumour, post-pubertal type, arising from cryptorchid testes BMJ Case Rep. 2019 Jul 22;12(7):e229541.\u003c/li\u003e\n \u003cli\u003eWanderas EH, Trettli S, Fossa SD. Trends in incidence of testicular cancer in Norway 1955-1992. Eur J Cancer 1995;31A(12):2044-8.\u003c/li\u003e\n \u003cli\u003eEble J. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press, 2004:237\u0026ndash;40.\u003c/li\u003e\n \u003cli\u003eHarper ME, Dugaiczyk A: Linkage of the evolutionarily-related serum albumin and alpha-fetoprotein genes within q11-22 of human chromosome 4\u0026rdquo;. Am J Hum Genet 35: 565-572, 1983.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSeregni E, Botti C, Bombardieri E:\u0026nbsp;Biochemical characteristics and clinical applications of alpha-fetoprotein isoforms. Anticancer Res 15: 1491-1499, 1995.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBall D, Rose E, Alpert E: Alpha-fetoprotein levels in normal adults. Am J Med Sci 303: 157-159, 1992.\u003c/li\u003e\n \u003cli\u003eSizaret P, Martel N, Tuyns A, Reynaud S: Mean alpha-fetoprotein values of 1,333 males over 15 years by age groups. Digestion 15: 97-103, 1977.\u003c/li\u003e\n \u003cli\u003eMona El-Bahrawy. AFP producing non-germ celltumors of the urological system. Reviews in urology vol.13 no.1 2011\u003c/li\u003e\n \u003cli\u003eArumugam D, Thandavarayan P, Chidambaram L, et al.. Primary nasopharngeal yolk sac tumor: a case report\u003c/li\u003e\n \u003cli\u003eHashimoto Y, Iwase Y, Mogami T, Hayashi Y, Sasaki S, Kato M, et al. A case of adult pure yolk sac tumor of the testis achieving pathological complete response by chemotherapy. [Article in Japanese]. Hinyokika Kiyo 1995;41:813-6.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDabbs D. Diagnostic immunohistochemistry. 3rd edn Philadelphia, PA: Saunders/Elsevier, 2010:737\u0026ndash;9.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTalerman A: The incidence of yolk sac tumor (endodermal sinus tumor) elements in germ cell tumors of the testis in adults. Cancer 1975; 36:211\u0026ndash;215.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eIzumi H, Shiokawa H, Shibata Y, Kurokawa J, Ohbu M. Pure yolk sac tumor of the testis with brain metastasis: Report of an adult case. [Article in Japanese]. Hinyokika Kiyo 1992;38:1071-4.\u003c/li\u003e\n \u003cli\u003eDadalı M, Sunay M, B\u0026uuml;y\u0026uuml;kşerbet\u0026ccedil;i M, Emir L, \u0026Ouml;zer E, Erol D. Pure yolk sac tumor of testis in an adult patient: case report. Turkish Journal of Urology 2010;36(3):322-325\u003c/li\u003e\n \u003cli\u003eFoster RS, Hermans B, Bihrle R, Donohue JP. Clinical stage I pure yolk sac tumor of the testis in adults has different clinical behavior than juvenile yolk sac tumor. J Urol 2000;164:1943-4.\u003c/li\u003e\n \u003cli\u003eMunver R, Donehower RC, Kronz JD, Polascik TJ. HIV infection presenting as an unusually large pure yolk sac tumor of the testis. J Urol 2000;164:1653-4.\u003c/li\u003e\n \u003cli\u003eEspejo-Herrera and Condom-Mund\u0026oacute;. Yolk sac tumor differentiation in urothelial carcinoma of the urinary bladder: a case report and differential diagnosis. Diagnostic Pathology (2020) 15:68 https://doi.org/10.1186/s13000-020-00983-3\u003c/li\u003e\n \u003cli\u003eBaniel J, Foster RS, Einhorn LH. Late relapse of clinical stage I testicular cancer. J Urol 1995;154:1370-2\u003c/li\u003e\n \u003cli\u003eMcNamee T, Damato S, McCluggage WG. Yolk sac tumours of the female genital tract in older adults derive commonly from somatic epithelial neoplasms:somatically derived yolk sac tumours. Histopathology. 2016;69(5):739\u0026ndash;51.\u003c/li\u003e\n \u003cli\u003eSamaratunga H, Samaratunga D, Dunglison N, Perry-Keene J, Nicklin J, Delahunt B. Alpha-fetoprotein-producing carcinoma of the renal pelvis exhibiting hepatoid and urothelial differentiation. Anticancer Res. 2012;32(11):4987\u0026ndash;91.\u003c/li\u003e\n \u003cli\u003eMiettinen M, Wang Z, McCue PA, Sarlomo-Rikala M, Rys J, Biernat W, Lasota J, Lee YS. SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases. Am J Surg Pathol. 2014;38(3):410\u0026ndash;20.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Testis Tumor, Yolk Sac, Urinary System","lastPublishedDoi":"10.21203/rs.3.rs-5783893/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5783893/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA testicular cancer is one of the most common malignancies observed in males between the ages of 15 and 35. Testicular-origin yolk sac tumors typically manifest as large, painless, voluminous masses. In nearly all cases with pure or mixed forms of yolk sac tumors, significantly elevated serum alpha-fetoprotein (AFP) levels are detected.\u003c/p\u003e \u003cp\u003eMicroscopically, the appearance of a yolk sac tumor is the same regardless of patient age and primary site. Observation of Schiller-Duvall bodies is pathognomic for yolk sac tumors. Immunohistochemically, yolk sac tumors are positive for AFP, CK AE1/AE3, Glypican-3 and SALL4, and negative for EMA and CK7.\u003c/p\u003e \u003cp\u003ePure yolk sac tumors are very rare in adults, and only a few cases have been reported in the literature. While adult and prepubertal yolk sac tumors may be histologically similar, it is noted that they tend to metastasize more frequently in adults and exhibit a poorer prognosis. This phenomenon is attributed to the tumor being poorly differentiated in adults. The preferred primary treatment for advanced disease is three to four cycles of BEP (bleomycin, etoposide, cisplatin) chemotherapy followed by resection of residual tumor\u003c/p\u003e \u003cp\u003eIn our case, we observe a yolk sac tumor that has metastasized synchronously to the renal pelvis, ureter, and bladder. In these patients, elevated serum AFP levels are noted. Given that enzyme levels are not routinely assessed in preoperative and postoperative monitoring of adult patients with urothelial carcinoma, it is important to recognize that uncommon histological patterns in urothelial neoplasms may be unnoticed.\u003c/p\u003e","manuscriptTitle":"Metastatic Yolk Sac Tumor in the Urinary System: a Case Report and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-04 06:46:23","doi":"10.21203/rs.3.rs-5783893/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-31T15:22:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-31T14:47:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6853553468143785874883020014845106553","date":"2025-05-31T13:41:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-08T17:31:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"135483513796945220475702208159366224765","date":"2025-03-31T14:32:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-02T13:53:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-27T07:41:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-02-27T07:36:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"SN Comprehensive Clinical Medicine","date":"2025-01-07T19:26:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"eba842cb-22ba-4220-b5a2-01ae5aff418e","owner":[],"postedDate":"March 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-06-19T05:53:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-04 06:46:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5783893","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5783893","identity":"rs-5783893","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}