Open AccessCase Report Life-Threatening Gastrointestinal Bleeding Revealing a Rare Coexistence of Ampullary Ganglioneuroma and Pancreatic Neuroendocrine Tumor: A Case Report 1 Second Department of Surgery, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece 2 Department of Surgery, Medical School, University of Patras, 26504 Patras, Greece 3 Department of Pathology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece 4 Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK * Author to whom correspondence should be addressed. Diagnostics 2026, 16(12), 1778; https://doi.org/10.3390/diagnostics16121778 (registering DOI) Submission received: 24 April 2026 / Revised: 4 June 2026 / Accepted: 7 June 2026 / Published: 9 June 2026 Abstract Background and Clinical Significance: Ganglioneuromas are rare benign tumors of neural crest origin, with gastrointestinal involvement being uncommon and ampullary localization exceptionally rare. Pancreatic neuroendocrine tumors (NETs) are also uncommon neoplasms with variable biological behavior. The coexistence of these two entities is unusual, particularly in the absence of an identifiable hereditary syndrome. Case Presentation: A 38-year-old man presented with hematemesis and multiple episodes of melena over 18 h and was found to have significant anemia with borderline hemodynamic stability. Upper gastrointestinal endoscopy revealed an enlarged, actively bleeding papilla of Vater, and initial hemostasis was achieved with adrenaline injection and endoscopic clipping. However, recurrent massive bleeding developed within 36 h, accompanied by hemodynamic instability. Repeat endoscopy confirmed ongoing hemorrhage, and the patient subsequently underwent emergency pancreaticoduodenectomy. Histopathological examination demonstrated an ampullary ganglioneuroma and an incidental well-differentiated pancreatic neuroendocrine tumor (WHO Grade 2). Surgical margins were negative, and no lymph node metastases were identified. Further evaluation for hereditary endocrine syndromes was unremarkable. The patient remains asymptomatic, with no evidence of recurrence during a 10-year follow-up period. This case highlights the diagnostic and therapeutic challenges associated with rare periampullary tumors. Although ganglioneuromas are typically benign, their anatomical location may result in severe clinical manifestations such as life-threatening bleeding. The coexistence with a pancreatic NET raises questions regarding potential shared pathogenesis, although no genetic syndrome was identified. Limitations of endoscopic management in uncontrolled bleeding and the importance of definitive surgical intervention are emphasized. Conclusions: This case highlights an exceptionally rare coexistence of ampullary ganglioneuroma and pancreatic neuroendocrine tumor presenting with life-threatening gastrointestinal bleeding. Although ganglioneuromas are benign, their anatomical location may result in severe clinical manifestations. Early recognition and decisive surgical management are crucial when endoscopic control fails. Favorable long-term outcomes can be achieved following complete resection. 1. Introduction We report a rare case of ampullary ganglioneuroma coexisting with a well-differentiated pancreatic neuroendocrine tumor, presenting with acute upper gastrointestinal bleeding refractory to endoscopic management and ultimately requiring emergency pancreaticoduodenectomy. This case highlights the diagnostic and therapeutic challenges associated with unusual ampullary lesions. It contributes to the limited body of literature on synchronous neurogenic and neuroendocrine tumors of the periampullary region. 2. Case Presentation A 38-year-old man presented to the emergency department with hematemesis and four episodes of melena over the preceding 18 h. On admission, he was hemodynamically borderline stable, with a blood pressure of 105/60 mmHg and a heart rate of 92 beats per minute. His medical history was unremarkable, with no prior history of peptic ulcer disease or use of non-steroidal anti-inflammatory drugs. Physical examination did not reveal any significant abnormalities. Initial laboratory investigations revealed marked anemia, with a hemoglobin level of 8.1 g/dL (reference range: 11.0–15.0 g/dL) and a hematocrit of 22.8%. The patient was promptly resuscitated with intravenous crystalloids and colloids, along with transfusion of three units of packed red blood cells. Following hemodynamic stabilization, an upper gastrointestinal endoscopy was performed. Duodenoscopic evaluation demonstrated an enlarged papilla of Vater with active bleeding ( Figure 1). Endoscopic hemostasis was achieved using injection of diluted adrenaline (1:10,000) in combination with application of hemostatic clips ( Figure 2A,B). Subsequent contrast-enhanced abdominal computed tomography revealed a prominent, bulging ampulla of Vater, without evidence of additional intra-abdominal pathology ( Figure 3 Thirty-six hours later, the patient experienced recurrent, massive gastrointestinal bleeding accompanied by hemodynamic instability. After aggressive resuscitation, repeat duodenoscopy confirmed ongoing, profuse bleeding originating from the second part of the duodenum ( Figure 4). In view of the failure of endoscopic management and the severity of the hemorrhage, the decision was made to proceed with emergency surgical intervention. Trans-arterial embolization (TAE) was considered as an alternative treatment strategy; however, this option was not available at our institution at the time, as interventional radiology services were not provided as an out of hours service. Patient transfer to a regional referral centre with interventional radiology capability was discussed but was judged to carry an unacceptable risk given the severity of ongoing haemorrhage and the patient’s repeated haemodynamic instability. We acknowledge that in centres where on-site interventional radiology is available, TAE of the gastroduodenal artery would represent a valid and less invasive first-line option before proceeding to surgery. The patient underwent an emergency pancreaticoduodenectomy (Whipple procedure). Reconstruction was performed with a duct-to-mucosa pancreaticojejunostomy and an antecolic gastrojejunostomy. Pancreaticoduodenectomy was selected as the most appropriate definitive intervention, offering simultaneous haemorrhage control, oncologically complete resection of the ampullary lesion, and accurate histopathological staging, goals that could not reliably be achieved by attempted suture ligation of the bleeding point alone, which would likely have been an insufficient measure altogether given the anatomical location and haemodynamic severity of the haemorrhage. The postoperative course was uneventful. The surgical drain was removed on postoperative day six, and the patient was discharged in good clinical condition on postoperative day ten. Histopathological examination identified two distinct lesions. A well-circumscribed lesion measuring 1 cm in diameter was located at the ampulla of Vater. Microscopically, this lesion was composed of spindle-shaped Schwann cells arranged in intersecting fascicles, showing strong immunoreactivity for S100 protein. Scattered mature ganglion cells, positive for neuron-specific enolase (NSE), were also present. There was no evidence of cytological atypia, mitotic activity, or necrosis ( Figure 5A–C). There was no invasion past the submucosal plane. These features comply with an ampullary ganglioneuroma. In addition, an incidental lesion measuring 1.2 cm was identified in the head of the pancreas. Although slightly larger than the ampullary ganglioneuroma, this lesion had not been identified on preoperative contrast-enhanced CT. This is consistent with the well-recognised limited sensitivity of CT for small, non-functional pancreatic NETs, which are frequently iso-attenuating relative to the surrounding parenchyma and may lack a discrete hypervascular blush on arterial-phase imaging, particularly below 2 cm in diameter. Its detection was therefore an incidental intraoperative and histopathological finding. Histological examination revealed a neoplasm composed of uniform, medium-sized round cells with coarse chromatin, inconspicuous nucleoli, and minimal cytological atypia. The tumor exhibited a solid and gyriform architectural pattern within a densely collagenized stroma. Mitotic activity was low, with fewer than 3 mitoses per 10 high-power fields. Immunohistochemical analysis demonstrated diffuse positivity for chromogranin, synaptophysin, and CD56. The Ki-67 proliferation index was less than 10%, consistent with a well-differentiated pancreatic neuroendocrine tumor (WHO Grade 2) ( Figure 6A–C). All surgical margins were free of tumor involvement (R0 resection), and no metastatic disease was identified in the examined peripancreatic lymph nodes. Given the known association of ganglioneuromas with hereditary syndromes, further evaluation for multiple endocrine neoplasia type 2 and PTEN hamartoma tumor syndrome (Cowden’s disease) was undertaken. Neck ultrasonography showed no abnormalities of the thyroid or parathyroid glands, thyroid function tests were within normal limits, and functional imaging with 111In-octreotide scintigraphy did not demonstrate any pathological uptake. No other features of neurofibromatosis syndromes were present, and the patient was referred to the Clinical Geneticist for germline testing, which did not result in a genetic syndrome diagnosis. Therefore, this was deemed a sporadic case of rare tumors of neural crest origin. At long-term follow-up, the patient remains asymptomatic, with no clinical or radiological evidence of recurrence over 10 years. The latest follow-up CT scan performed at 10 years was unremarkable. 3. Discussion A review of the recent literature (last 10 years) shows that ampullary ganglioneuromas and related entities, such as gangliocytic paragangliomas, are rare tumors, most commonly located in the periampullary region. Fewer than 60 cases have been reported in the literature in this period, with gastrointestinal bleeding being the most frequent presenting symptom. However, life-threatening hemorrhage requiring emergency surgery remains exceptionally rare. A summary of representative cases from the recent literature is presented in . Given the rarity of strictly ampullary lesions, selected periampullary cases were included for comparison. The diagnostic evaluation of periampullary ganglioneuromas remains challenging. Imaging modalities such as computed tomography and endoscopic ultrasound are useful for lesion localization but lack specificity. In addition, endoscopic biopsies are often inconclusive due to the submucosal nature of these tumors, and misclassification as neuroendocrine or other subepithelial lesions is not uncommon [ 23, 24]. In our case, a definitive diagnosis was only established following surgical resection, highlighting the limitations of preoperative assessment in such settings. A particularly noteworthy aspect of our case is the synchronous presence of an ampullary ganglioneuroma and a pancreatic neuroendocrine tumor in the absence of a hereditary syndrome. To our knowledge, such synchronous occurrences have been described in only an extremely limited number of cases. The pancreatic NET most likely represents an incidental finding, given the absence of any identifiable hereditary syndrome and the lack of a defined mechanistic link between these two entities. We therefore use the term “coexistence” in a purely descriptive and clinicopathological sense, to denote the simultaneous presence of two rare tumours in the same patient, without implying a causal or syndromic relationship. Any allusion to a shared pathogenetic pathway should be understood as speculative and hypothesis-generating rather than as an established biological association, particularly given the high prevalence of small, incidental NETs in the general population. Management should be tailored to tumor characteristics and clinical presentation. Endoscopic resection may be appropriate for small, localized lesions confined to the submucosa [ 24]. However, this approach is limited by the potential for incomplete excision and the inability to assess lymph node status. In our patient, initial endoscopic hemostasis was unsuccessful, and ongoing hemorrhage necessitated emergency surgical intervention. Pancreaticoduodenectomy allowed definitive control of bleeding, complete tumor removal, and accurate histopathological evaluation. Recently, minimally invasive endoscopic techniques have expanded the therapeutic options for selected periampullary lesions. Underwater endoscopic mucosal resection (UEMR) has been reported as a safe and effective approach for en bloc resection of small periampullary subepithelial tumors, although experience remains limited and careful patient selection is required [ 30 Compared to previously reported cases, our case is distinguished by the severity and rapid recurrence of hemorrhage, necessitating emergency pancreaticoduodenectomy despite initial endoscopic control. This highlights a rare but important clinical scenario and expands the current understanding of the potential behavior of periampullary ganglioneuromas. This report has certain limitations. As a single case report, it does not allow firm conclusions regarding the relationship between ampullary ganglioneuromas and pancreatic neuroendocrine tumors. In addition, molecular or genetic analyses were not performed, which might have provided further insight into potential shared pathogenetic mechanisms. Nonetheless, the rarity of this presentation, combined with the detailed clinical and pathological documentation, adds useful information to the existing literature. Future studies focusing on molecular profiling and larger case series are required to better define the biological behavior and optimal management strategies of these rare tumors. Improved understanding of their pathogenesis may also help clarify the relationship between neurogenic and neuroendocrine components, particularly in cases presenting with synchronous lesions [ 34, 35 Our case describes a rare coexistence of ampullary ganglioneuroma and pancreatic neuroendocrine tumor presenting with life-threatening gastrointestinal bleeding. Although ganglioneuromas are generally considered benign, their anatomical location in the ampullary region may lead to severe and rapidly evolving clinical manifestations. It also illustrates the limitations of endoscopic management in the setting of uncontrolled bleeding. In addition, this case highlights the need for timely surgical intervention when initial measures fail or when diagnostic uncertainty persists. The favorable long-term outcome observed in this patient suggests that complete surgical resection can be curative, even in complex and emergent scenarios. It adds to the limited literature on rare periampullary tumors and supports the importance of individualized management and careful follow-up. Further studies are needed to define the biological relationship between these entities better. Author Contributions Conceptualization, F.M. and G.-I.V.; methodology, M.K.; software, A.-M.M.; validation, H.B., I.T. and A.G.; formal analysis, A.J.K.; investigation, F.M.; resources, M.K.; data curation, G.-I.V.; writing—original draft preparation, F.M., M.K., A.-M.M., H.B. and I.T.; writing—review and editing, G.-I.V., A.G. and A.J.K.; visualization, F.M.; supervision, A.J.K.; project administration, H.B.; funding acquisition, A.J.K. All authors have read and agreed to the published version of the manuscript. This research received no external funding. Institutional Review Board Statement This submission does not report prospective research on human subjects, nor does it involve experimental procedures. It represents a single clinical case that falls within routine clinical practice. Under institutional policy, the manuscript does not require Institutional Ethics Committee approval and therefore the manuscript is exempted from ethics-committee review. Informed Consent Statement Written informed consent for publication of this case report and accompanying images was obtained from the patient. Data Availability Statement The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author. Conflicts of Interest The authors declare that they have no competing interests. References He, W.; Yan, Y.; Tang, W.; Cai, R.; Ren, G. Clinical and biological features of neuroblastic tumors: A comparison of neuroblastoma and ganglioneuroblastoma. Oncotarget 2017, 8, 37730–37739. [ Google Scholar] [ CrossRef] [ PubMed] Geoerger, B.; Hero, B.; Harms, D.; Grebe, J.; Scheidhauer, K.; Berthold, F. Metabolic activity and clinical features of primary ganglioneuromas. Cancer 2001, 91, 1905–1913. [ Google Scholar] [ CrossRef] [ PubMed] Shekitka, K.M.; Sobin, L.H. Ganglioneuromas of the gastrointestinal tract. Relation to Von Recklinghausen disease and other multiple tumor syndromes. Am. J. Surg. Pathol. 1994, 18, 250–257. [ Google Scholar] [ CrossRef] [ PubMed] Levy, A.D.; Remotti, H.E.; Thompson, W.M.; Sobin, L.H.; Miettinen, M. Gastrointestinal stromal tumors: Radiologic features with pathologic correlation. Radiographics 2003, 23, 283–304, 456; quiz 532. [ Google Scholar] [ CrossRef] [ PubMed] Carter, J.T.; Grenert, J.P.; Rubenstein, L.; Stewart, L.; Way, L.W. Tumors of the ampulla of Vater: Histopathologic classification and predictors of survival. J. Am. Coll. Surg. 2008, 207, 210–218. [ Google Scholar] [ CrossRef] [ PubMed] Futakawa, N.; Kimura, W.; Wada, Y.; Muto, T. Clinicopathological characteristics and surgical procedures for carcinoma of the papilla of Vater. Hepatogastroenterology 1996, 43, 260–267. [ Google Scholar] [ PubMed] Dasari, A.; Shen, C.; Halperin, D.; Zhao, B.; Zhou, S.; Xu, Y.; Shih, T.; Yao, J.C. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients with Neuroendocrine Tumors in the United States. JAMA Oncol. 2017, 3, 1335–1342. [ Google Scholar] [ CrossRef] Cives, M.; Strosberg, J.R. Gastroenteropancreatic Neuroendocrine Tumors. CA Cancer J. Clin. 2018, 68, 471–487. [ Google Scholar] [ CrossRef] [ PubMed] Hobert, J.; Eng, C. PTEN hamartoma tumor syndrome: An overview. Genet. Med. 2009, 11, 687–694. [ Google Scholar] [ CrossRef] Ferner, R.E.; Gutmann, D.H. Neurofibromatosis type 1 (NF1): Diagnosis and management. Handb. Clin. Neurol. 2013, 115, 939–955. [ Google Scholar] [ CrossRef] [ PubMed] Alfouzan, M.; Alrubaiaan, A.; Alshamlan, B.; Fekry, T.; AlGhadban, M.; Hayati, H. Surgical management of duodenal gangliocytic paraganglioma causing upper gastrointestinal bleeding: A case report. Int. J. Surg. Case Rep. 2026, 138, 1051–1056. [ Google Scholar] [ CrossRef] Nova-Camacho, L.M.; Ma, C.; Abukhiran, I.; Shaker, N.; Abdul Baki, M.N.; Collins, K.; González, I.; Chao, T.; Yang, Z.; Vyas, M.; et al. Composite gangliocytoma/neuroma and neuroendocrine tumour: A contemporary analysis of 71 cases shows risk factors for metastasis. Histopathology 2025, 87, 933–942. [ Google Scholar] [ CrossRef] Zhang, M.L.; Meredith, D.M.; Bellizzi, A.M.; Nowak, J.A.; Papke, D.J., Jr. Composite gangliocytoma/neuroma and neuroendocrine tumor: A clinicopathologic, immunohistochemical, and molecular genetic study of 11 cases. Virchows Arch. 2025, 1–11. [ Google Scholar] [ CrossRef] Karam, E.; Hollenbach, M.; Heise, C.; Ali, E.A.; Gulla, A.; Auriemma, F.; Terris, B.; Souche, F.R.; de Ponthaud, C.; Hank, T.; et al. Ampullary composite gangliocytoma/neuroma and neuroendocrine tumor management. Endocr. Relat. Cancer 2025, 32, e240238. [ Google Scholar] [ CrossRef] [ PubMed] Okubo, Y.; Yoshioka, E.; Suzuki, M.; Washimi, K.; Kawachi, K.; Kameda, Y.; Yokose, T. Diagnosis, pathological findings, and clinical management of gangliocytic paraganglioma: A systematic review. Front. Oncol. 2018, 8, 291. [ Google Scholar] [ CrossRef] [ PubMed] Chiang, C.S.; Shyr, B.U.; Chen, S.C.; Shyr, Y.M.; Wang, S.E. Periampullary gangliocytic paraganglioma. J. Gastrointest. Surg. 2019, 23, 2247–2254. [ Google Scholar] [ CrossRef] [ PubMed] Park, S.J.; Kim, D.H.; Lim, H.; Lee, J.H.; Choi, K.D.; Song, H.J.; Lee, G.H.; Jung, H.Y.; Kim, J.H.; Park, J.Y. Endoscopic resection as a possible radical treatment for duodenal gangliocytic paraganglioma: A report of four cases. Korean J. Gastroenterol. 2014, 63, 114–119. [ Google Scholar] [ CrossRef] [ PubMed] Scheithauer, B.W.; Nora, F.E.; LeChago, J.; Wick, M.R.; Crawford, B.G.; Weiland, L.H.; Carney, J.A. Duodenal gangliocytic paraganglioma. Clinicopathologic and immunocytochemical study of 11 cases. Am. J. Clin. Pathol. 1986, 86, 559–565. [ Google Scholar] [ CrossRef] [ PubMed] Barret, M.; Rahmi, G.; Duong van Huyen, J.P.; Landi, B.; Cellier, C.; Berger, A. Duodenal gangliocytic paraganglioma with lymph node metastasis and an 8-year follow-up: A case report. Eur. J. Gastroenterol. Hepatol. 2012, 24, 90–94. [ Google Scholar] [ CrossRef] [ PubMed] Sánchez-Pérez, M.A.; Luque-de León, E.; Muñoz-Juárez, M.; Moreno-Paquentin, E.; Genovés-Gómez, H.; Torreblanca-Marín, M.A. Duodenal gangliocytic paraganglioma. Can. J. Surg. 2009, 52, E27–E28. [ Google Scholar] [ PubMed] [ PubMed Central] Witkiewicz, A.; Galler, A.; Yeo, C.J.; Gross, S.D. Gangliocytic paraganglioma: Case report and review of the literature. J. Gastrointest. Surg. 2007, 11, 1351–1354. [ Google Scholar] [ CrossRef] [ PubMed] Scarpa, A.; Chang, D.K.; Nones, K.; Corbo, V.; Patch, A.M.; Bailey, P.; Lawlor, R.T.; Johns, A.L.; Miller, D.K.; Mafficini, A.; et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 2017, 543, 65–71. [ Google Scholar] [ CrossRef] Mete, O. Special Issue on Molecular Pathology of Endocrine Neoplasms: Understanding the Basis of Endocrine Pathology Practice. Endocr. Pathol. 2021, 32, 1–2. [ Google Scholar] [ CrossRef] Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Share and Cite MDPI and ACS Style Mulita, F.; Kouroupi, M.; Verras, G.-I.; Mitropoulou, A.-M.; Bolanaki, H.; Tzimagiorgis, I.; Giatromanolaki, A.; Karayiannakis, A.J. Life-Threatening Gastrointestinal Bleeding Revealing a Rare Coexistence of Ampullary Ganglioneuroma and Pancreatic Neuroendocrine Tumor: A Case Report. Diagnostics 2026, 16, 1778. https://doi.org/10.3390/diagnostics16121778 AMA Style Mulita F, Kouroupi M, Verras G-I, Mitropoulou A-M, Bolanaki H, Tzimagiorgis I, Giatromanolaki A, Karayiannakis AJ. Life-Threatening Gastrointestinal Bleeding Revealing a Rare Coexistence of Ampullary Ganglioneuroma and Pancreatic Neuroendocrine Tumor: A Case Report. Diagnostics. 2026; 16(12):1778. https://doi.org/10.3390/diagnostics16121778 Chicago/Turabian Style Mulita, Francesk, Maria Kouroupi, Georgios-Ioannis Verras, Anna-Maria Mitropoulou, Helen Bolanaki, Ioannis Tzimagiorgis, Alexandra Giatromanolaki, and Anastasios J. Karayiannakis. 2026. "Life-Threatening Gastrointestinal Bleeding Revealing a Rare Coexistence of Ampullary Ganglioneuroma and Pancreatic Neuroendocrine Tumor: A Case Report" Diagnostics 16, no. 12: 1778. https://doi.org/10.3390/diagnostics16121778 APA Style Mulita, F., Kouroupi, M., Verras, G.-I., Mitropoulou, A.-M., Bolanaki, H., Tzimagiorgis, I., Giatromanolaki, A., & Karayiannakis, A. J. (2026). Life-Threatening Gastrointestinal Bleeding Revealing a Rare Coexistence of Ampullary Ganglioneuroma and Pancreatic Neuroendocrine Tumor: A Case Report. 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