Gastric Neuroendocrine Tumor Presenting Atypically in von Hippel– Lindau Disease A Case Report
Main Article Content
Keywords
von Hippel-Lindau disease, neuroendocrine tumor, germline mutation
Abstract
von Hippel–Lindau (VHL) disease, an autosomal dominant inherited disorder resulting from mutations in the VHL gene, is known to be asso-ciated with the development of neuroendocrine tumors (NET) in various organs, including the adrenal gland, pancreas, and paraganglion. However, the development of gastric NET (gNET) in VHL disease has not been reported. Limited studies have suggested that clear cell change is a distinctive feature of VHL-associated tumors. Herein, we first report a case of a patient with VHL syndrome who presented with a gNET showing clear cell change, an unusual morphological characteristic of gNET, and harbored a pathogenic germline VHL mutation (c.351 G>T). The patient underwent surgical treatment for retinal hemangioblastoma, gNET, and renal cell carcinoma, in addition to receiving endocrine therapy and antiangiogenic drugs. The patient survived for 17 years. Our case highlights the possibility of VHL-associated NET development in uncommon locations. Further studies are required to elucidate the correlation between VHL mutation sites and the clinical manifestation of the disease.
References
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17. Tirosh A, Killian JK, Petersen D, Zhu YJ, Walker RL, Blau JE, et al. Distinct DNA methylation signatures in neuroendocrine tumors specific for primary site and inherited predisposition. J Clin Endocrinol Metab. 2020;105(10):3285–94. https://doi.org/10.1210/clinem/dgaa477
18. Wang Y, Wang W, Jin K, Fang C, Lin Y, Xue L, et al. Somatostatin receptor expression indicates improved prognosis in gastroenteropancreatic neuroendocrine neoplasm, and octreotide long-acting release is effective and safe in Chinese patients with advanced gastroenteropancreatic neuroendocrine tumors. Oncol Lett. 2017;13(3):1165–74. https://doi.org/10.3892/ol.2017.5591
19. Petrella BL, Lohi J, Brinckerhoff CE. D10Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2 alpha in von Hippel–Lindau renal cell carcinoma. Oncogene. 2005;24(6):1043–52. https://doi.org/10.1038/sj.onc.1208305
20. Maher ER. D11Von Hippel–Lindau disease. Eur J Cancer. 1994;30A(13):1987–90. https://doi.org/10.1016/0959-8049(94)00391-H
2. Forman JR, Worth CL, Bickerton GRJ, Eisen TG, Blundell TL. intro2Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel–Lindau disease and suggests molecular mechanisms of tumorigenesis. Proteins. 2009;77(1):84–96. https://doi.org/10.1002/prot.22419
3. Mete O, Asa SL. intro3Precursor lesions of endocrine system neoplasms. Pathology. 2013;45(3):316–30. https://doi.org/10.1097/PAT.0b013e32835f45c5
4. Yamasaki I, Nishimori I, Ashida S, Kohsaki T, Onishi S, Shuin T. intro4Clinical characteristics of pancreatic neuroendocrine tumors in Japanese patients with von Hippel–Lindau disease. Pancreas. 2006;33(4):382–5. https://doi.org/10.1097/01.mpa.0000240604.26312.e4
5. Foster K, Prowse A, van den Berg A, Fleming S, Hulsbeek MM, Crossey PA, et al. intro5Somatic mutations of the von Hippel–Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet. 1994;3(12):2169–73. https://doi.org/10.1093/hmg/3.12.2169
6. Crona J, Skogseid B. GEP- NETS UPDATE: Genetics of neuroendocrine tumors. Eur J Endocrinol. 2016;174(6):R275–290. https://doi.org/10.1530/EJE-15-0972
7. Minervini G, Quaglia F, Tabaro F, Tosatto SCE. Genotype-phenotype relations of the von Hippel–Lindau tumor suppressor inferred from a large-scale analysis of disease mutations and interactors. PLoS Comput Biol. 2019;15(4):e1006478. https://doi.org/10.1371/journal.pcbi.1006478
8. Kawaguchi K, Yashima K, Ikebuchi Y, Yoshida A, Kuwamoto S, Isomoto H. The first case of gastric neuroendocrine tumors induced by a proton pump inhibitor in von Hippel–Lindau disease. Intern Med. 2022;61(17):2587–92. https://doi.org/10.2169/internalmedicine.8701-21
9. Alexandraki KI, Spyroglou A, Xekouki P, Bramis KI, Kyriakopoulos G, Barkas K, et al. When rare diseases crisscross within the same patient: von Hippel–Lindau and type 1 gastric neuroendocrine tumor. Hormones (Athens). 2024;23(3):585–90. https://doi.org/10.1007/s42000-024-00556-9
10. Mahon PC, Hirota K, Semenza GL. FIH-1: A novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001;15(20):2675–86. https://doi.org/10.1101/gad.924501
11. Gong K, Zhang K, Zhang N, Na QY. Relationship of EPO over-expression to VHL mutations and Hif1α and 2α in sCCRCC. J Urol. 2008;179(4):91. https://doi.org/10.1016/S0022-5347(08)60266-9
12. Migliorini D, Haller S, Merkler D, Pugliesi-Rinaldi A, Koka A, Schaller K, et al. Recurrent multiple CNS hemangioblastomas with VHL disease treated with pazopanib: A case report and literature review. CNS Oncol. 2015;4(6):387–92. https://doi.org/10.2217/cns.15.22
13.Srinivasan R, Iliopoulos O, Beckermann KE, et al. Belzutifan for von Hippel–Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study. Lancet Oncol. 2025;26(5):571–82. https://doi.org/10.1016/S1470-2045(25)00099-3
14. van der Graaf WTA, Tesselaar MET, McVeigh TP, Oyen WJG, Fröhling S. D07biology guided precision medicine in rare cancers: Lessons from sarcomas and neuroendocrine tumours. Semin Cancer Biol. 2022;84:228–41. https://doi.org/10.1016/j.semcancer.2022.05.011
15. Kim JY, Hong SM, Ro JY. D08Recent updates on grading and classification of neuroendocrine tumors. Ann Diagn Pathol. 2017;29:11–6. https://doi.org/10.1016/j.anndiagpath.2017.04.005
16. Hoffman SE, Dowrey TW, Villacorta Martin C, Bi K, Titchen B, Johri S, et al. Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors. Sci Adv. 2023;9(39):eadd9668. https://doi.org/10.1126/sciadv.add9668
17. Tirosh A, Killian JK, Petersen D, Zhu YJ, Walker RL, Blau JE, et al. Distinct DNA methylation signatures in neuroendocrine tumors specific for primary site and inherited predisposition. J Clin Endocrinol Metab. 2020;105(10):3285–94. https://doi.org/10.1210/clinem/dgaa477
18. Wang Y, Wang W, Jin K, Fang C, Lin Y, Xue L, et al. Somatostatin receptor expression indicates improved prognosis in gastroenteropancreatic neuroendocrine neoplasm, and octreotide long-acting release is effective and safe in Chinese patients with advanced gastroenteropancreatic neuroendocrine tumors. Oncol Lett. 2017;13(3):1165–74. https://doi.org/10.3892/ol.2017.5591
19. Petrella BL, Lohi J, Brinckerhoff CE. D10Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2 alpha in von Hippel–Lindau renal cell carcinoma. Oncogene. 2005;24(6):1043–52. https://doi.org/10.1038/sj.onc.1208305
20. Maher ER. D11Von Hippel–Lindau disease. Eur J Cancer. 1994;30A(13):1987–90. https://doi.org/10.1016/0959-8049(94)00391-H
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Published
Apr 1, 2026
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Gastric Neuroendocrine Tumor Presenting Atypically in von Hippel– Lindau Disease: A Case Report. (2026). Journal of Kidney Cancer, 13(1), 21–26. https://doi.org/10.15586/jkcvhl.v13i1.420
Section
Kidney Cancer: Case Reports
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How to Cite
Gastric Neuroendocrine Tumor Presenting Atypically in von Hippel– Lindau Disease: A Case Report. (2026). Journal of Kidney Cancer, 13(1), 21–26. https://doi.org/10.15586/jkcvhl.v13i1.420