Mixed adenoneuroendocrine carcinoma of the stomach – a case report

Czech version

Authors: M. Drab ¹; E. Tomsová ¹; J. Marček ¹; T. Klinger ²
Authors‘ workplace: Gastroenterologické oddělení, Oblastní nemocnice Mladá Boleslav, a. s., nemocnice Středočeského kraje ¹; Oddělení patologie, Krajská nemocnice Liberec, a. s. ²
Published in: Gastroent Hepatol 2023; 77(5): 409-418
Category: Gastrointestinal Oncology: Case Report
doi: https://doi.org/10.48095/ccgh2023409

Overview

Neuroendocrine tumours represent a heterogeneous group of neoplasia arising from different anatomical locations, with approximately 50% of gastrointestinal origin. Main parameters in the evaluation of each case include tumour morphology, mitotic cell count, and Ki-67 index. Mixed adeno-neuroendocrine carcinomas (MANECs) are rare aggressive neoplasms consisting of both adenocarcinomatous and neuroendocrine cells, each component constituting at least 30% of the lesion. Our case represents 77-year-old polymorbid patient who, due to signs of acute bleeding in the upper gastrointestinal tract with anaemic syndrome, underwent a gastroscopic examination for melena with the finding of an ulcer lesion on the front wall of the stomach at the junction of the body and the antrum. The control gastroscopic examinations with biopsies, at first only signs of chronic gastritis with Helicobacter pylori positivity were histologically proven, then fragments of high-grade tubular to tubulovillous adenoma and structures of moderately differentiated tubular adenocarcinoma were found. Histological analysis of the gastric resection showed mixed adeno-neuroendocrine carcinoma with lymphangioinvasion.

Keywords:

neuroendocrine tumour – mixed adenoneuroendocrine carcinoma – MANEC – synaptophysin – chromogranin

Sources

1. Hallet J, Law CH, Cukier M et al. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015; 121 (4): 589–597. doi: 10.1002/cncr.29099.

2. Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011; 30 (1): 3–7. doi: 10.1007/s10555-011-9292-1.

3. Fraenkel M, Kim MK, Faggiano A et al. Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol 2012; 26 (6): 691–703. doi: 10.1016/j.bpg.2013.01.006.

4. Fraenkel M, Kim M, Faggiano A et al. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer 2014; 21 (3): eR153–eR163. doi: 10.1530/ERC-13-0125.

5. Leoncini E, Boffetta P, Shafir M et al. Increased incidence trend of low-grade and high-grade neuroendocrine neoplasms. Endocrine 2017; 58 (2): 368–379. doi: 10.1007/s12020-017-12 73-x.

6. Huguet I, Grossman AB, O’Toole D. Changes in the epidemiology of neuroendocrine tumours. Neuroendocrinology 2017; 104 (2): 105–111. doi: 10.1159/000441897.

7. Maggard MA, O‘Connell JB, Ko CY. Updated population-based review of carcinoid tumors. Ann Surg 2004; 240 (1): 117–122. doi: 10.1097/01.sla.0000129342.67174.67.

8. Modlin IM, Oberg K, Chung DC et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008; 9 (1): 61–72. doi: 10.1016/S1470-2045 (07) 70410-2.

9. Oberg K, Knigge U, Kwekkeboom D et al. Neuroendocrine gastro-entero- pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (7): 124–130. doi: 10.1093/annonc/mds295.

10. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999; 340 (11): 858–868. doi: 10.1056/NEJM199903183401107.

11. Schnirer II, Yao JC, Ajani JA. Carcinoid – a comprehensive review. Acta Oncol 2003; 42 (7): 672–692. doi: 10.1080/02841860310010547.

12. Sato Y. Endoscopic diagnosis and management of type I neuroendocrine tumors. World J Gastrointest Endosc 2015; 7 (4): 346–353. doi: 10.4253/wjge.v7.i4.346.

13. Rindi G, Klöppel G. Endocrine tumors of the gut and pancreas tumor biology and classification. Neuroendocrinology 2004; 80 (Suppl 1): 12–15. doi: 10.1159/000080733.

14. Sheibani S, Kim JJ, Chen B et al. Natural history of acute upper GI bleeding due to tumours: short-term success and long-term recurrence with or without endoscopic therapy. Aliment Pharmacol Ther 2013; 38 (2): 144–150. doi: 10.1111/apt.12347.

15. Bhattacharyya S, Davar J, Dreyfus G et al. Carcinoid heart disease. Circulation 2007; 116 (24): 2860–2865. doi: 10.1161/CIRCULATIONAHA. 107.701367.

16. Klimstra DS, Modlin IR, Adsay NV et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol 2010; 34 (3): 300–313. doi: 10.1097/PAS.0b013e3181ce1447.

17. Sorbye H, Welin S, Langer SW et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013; 24 (1): 152–160. doi: 10.1093/annonc/mds276.

18. Chan ES, Alexander J, Swanson PE et al. PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrine neoplasms. Am J Surg Pathol 2012; 36 (5): 737–743. doi: 10.1097/PAS.0b013e31824aba59.

19. Graham RP, Shrestha B, Caron BL et al. Islet-1 is a sensitive but not entirely specific marker for pancreatic neuroendocrine neoplasms and their metastases. Am J Surg Pathol 2013; 37 (3): 399–405. doi: 10.1097/PAS.0b013e31826f042c.

20. Srivastava A, Hornick JL. Immunohistochemical staining for CDX-2, PDX-1, NESP-55, and TTF-1 can help distinguish gastrointestinal carcinoid tumors from pancreatic endocrine and pulmonary carcinoid tumors. Am J Surg Pathol 2009; 33 (4): 626–632. doi: 10.1097/PAS. 0b013e31818d7d8b.

21. Vinik AI, Woltering EA, Warner RR et al. NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas 2010; 39 (6): 713–734. doi: 10.1097/MPA.0b013e3181ebaffd.

22. Uccella S, Sessa F, La Rosa S. Diagnostic approach to neuroendocrine neoplasms of the gastrointestinal tract and pancreas. Turk Patoloji Derg 2015; 31 (Suppl 1): 113–127. doi: 10.5146/tjpath.2015.01319.

23. Kim JY, Kim KS, Kim KJ et al. Non-L-cell immunophenotype and large tumor size in rectal neuroendocrine tumors are associated with aggressive clinical behavior and worse prognosis. Am J Surg Pathol 2015; 39 (5): 632–643. doi: 10.1097/PAS.0000000000000400.

24. Tsolakis AV, Grimelius L, Granerus G et al. Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours. World J Gastroenterol 2015; 21 (47): 13240–13249. doi: 10.3748/wjg.v21.i47.13240.

25. Ganeshan D, Bhosale P, Yang T et al. Imaging features of carcinoid tumors of the gastrointestinal tract. AJR Am J Roentgenol 2013; 201 (4): 773–786. doi: 10.2214/AJR.12.9758.

26. Koopmans KP, de Vries EG, Kema IP et al. Staging of carcinoid tumours with 18F-DOPA PET: a prospective, diagnostic accuracy study. Lancet Oncol 2006; 7 (9): 728–734. doi: 10.1016/S1470-2045 (06) 70801-4.

27. Koopmans KP, Neels OC, Kema IP et al. Improved staging of patients with carcinoid and islet cell tumors with 18F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan positron emission tomography. J Clin Oncol 2008; 26 (9): 1489–1495. doi: 10.1200/JCO.2007.15.1126.

28. Hoegerle S, Altehoefer C, Ghanem N et al. Whole-body 18F dopa PET for detection of gastrointestinal carcinoid tumors. Radiology 2001; 220 (3): 373–380. doi: 10.1148/radiology. 220.2.r01au25373.

29. Eisenhofer G, Huynh TT, Hiroi M et al. Understanding catecholamine metabolism as a guide to the biochemical diagnosis of pheochromocytoma. Rev Endocr Metab Disord 2001; 2 (3): 297–311. doi: 10.1023/A: 1011572617314.

30. Treglia G, Castaldi P, Rindi G et al. Diagnostic performance of Gallium-68 somatostatin receptor PET and PET/CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours: a meta-analysis. Endocrine 2012; 42 (1): 80–87. doi: 10.1007/s12020-012-9631-1.

31. Binderup T, Knigge U, Loft A et al. 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendo – crine tumors. Clin Cancer Res. 2010; 16: 978e985.

32. Giesel FL, Kratochwil C, Mehndiratta A et al. Comparison of neuroendocrine tumor detection and characterization using DOTATOC-PET in correlation with contrast enhanced CT and delayed contrast enhanced MRI. Eur J Radiol 2012; 81 (10): 2820–2825. doi: 10.1016/ j.ejrad.2011.11.007.

33. Dromain C, de Baere T, Lumbroso J et al. Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol 2005; 23 (1): 70–78. doi: 10.1200/JCO.2005.01.013.

34. Kunz PL, Reidy-Lagunes D, Anthony LB et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 2013; 42 (4): 557–577. doi: 10.1097/MPA.0b013e31828e34a4.

35. Delle Fave G, Kwekkeboom DJ, Van Cutsem E et al. ENETS consensus guidelines for the management of patients with gastroduodenal neoplasms. Neuroendocrinology 2012; 95 (2): 74–87. doi: 10.1159/000335595.

36. Yao JC, Lagunes DR, Kulke MH. Targeted therapies in neuroendocrine tumors (NET): clinical trial challenges and lessons learned. Oncologist 2013; 18 (5): 525–532. doi: 10.1634/theoncologist.2012-0434.

37. Wilson MK, Karakasis K, Oza AM. Outcomes and endpoints in trials of cancer treatment: the past, present, and future. Lancet Oncol 2015; 16 (1): e32–e42. doi: 10.1016/S1470-204 5 (14) 70375-4.

38. Caplin ME, Pavel M, Cwikla JB et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371 (16): 224–233. doi: 10.1056/NEJMc1409757.

39. Rinke A, Muller HH, Schade-Brittinger C et al. Placebo-controlled, double- blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. J Clin Oncol 2009; 27 (28): 4656–4663. doi: 10.1200/JCO.2009.22.8510.

40. Pavel ME, Hainsworth JD, Baudin E et al. Everolimus plus octreotide long- acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo- controlled, phase 3 study. Lancet 2011; 378 (9808): 2005–2012. doi: 10.1016/S0140-6736 (11) 617 42-X.

41. Yao JC, Fazio N, Singh S et al. Everolimus in advanced, non-functional neuroendocrine tumors of lung or gastrointestinal origin: efficacy and safety results from the placebo-controlled, double-blind, multicenter, phase 3 study. Lancet 2016; 387 (10022): 968–977. doi: 10.1016/S0140-6736 (15) 00817-X.

42. Rinke A, Wittenberg M, Schade-Brittinger C et al. Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): results on long term survival. Neuroendocrinology 2017; 104 (1): 26–32. doi: 10.1159/000443612.

43. Yao JC, Fazio N, Singh S et al. Everolimus for the treatment of advanced, non- functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016; 387 (10022): 968–977. doi: 10.1016/S0140-6736 (15) 00817-X.

44. Kam BLR, Teunissen JJM, Krenning EP et al. Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2012; 39 (1): S103–112. doi: 10.1007/s002 59-011-2039-y.

45. Strosberg J, Wolin E, Chasen B. 177Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours: results of the phase III NETTER-1 trial. Pancreas 2016; 45 (3): 783. doi: 10.1097/MPA.0000000000000615.

46. Wang J, He A, Feng Q et al. Gastrointestinal mixed adenoneuroendocrine carcinoma: a population level analysis of epidemiological trends. J Transl Med 2020; 18 (1): 128. doi: 10.1186/s12967-020-02293-0.

47. Rindi G, Arnold R, Bosman F. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. WHO classification of tumours of the digestive system; 2010: 13–14.

48. La Rosa S, Marando A, Sessa F et al. Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract: an update. Cancers (Basel) 2012; 4 (1): 11–30. doi: 10.3390/cancers4010 011.

49. Takahashi K, Fujiya M, Sasaki T et al. Endoscopic findings of gastric mixed adenoneuroendocrine carcinoma: a case report. Medicine (Baltimore) 2020; 99 (38): e22306. doi: 10.1097/MD.0000000000022306.

50. Lin J, Zhao Y, Zhou Y et al. Comparison of survival and patterns of recurrence in gastric neuroendocrine carcinoma, mixed adenoneuroendocrine carcinoma and adenocarcinoma: A multicenter study from China. JAMA Netw Open 2021; 4 (7): e2114180. doi: 10.1001/jama networkopen.2021.14180.

51. Rindi G, Bordi C, La RS et al. Gastroenteropancreatic (neuro) endocrine neoplasms: the histology report. Dig Liver Dis 2011; 43 (4): S356–S360. doi: 10.1016/S1590-8658 (11) 60 591-4.

52. Tanaka T, Kaneko M, Nozawa H et al. Diagnosis, assessment, and therapeutic strategy for colorectal mixed adenoneuroendocrine carcinoma. Neuroendocrinology 2017; 105 (4): 426–434. doi: 10.1159/000478743.

53. Watanabe J, Suwa Y, Ota M et al. Clinicopathological and prognostic evaluations of mixed adenoneuroendocrine carcinoma of the colon and rectum: a case-matched study. Dis Colon Rectum 2016; 59 (12): 1160–1167. doi: 10.1097/DCR.0000000000000702.

54. Spada F, Gervaso L, Pisa E et al. Molecular characterization of gastro-entero-pancreatic advanced mixed adeno-neuroendocrine carcinomas: NIRVANA sub-study. Ann Oncol 2022; 33 (7): S410–S416. 10.1016/annonc/annonc1060.

55. Xie JW, Lu J, Wang JB et al. Prognostic factors for survival after curative resection of gastric mixed adenoneuroendocrine carcinoma: a series of 80 patients. BMC Cancer 2018; 18 (1): 1021. doi: 10.1186/s12885-018-49 43-z.

56. Rosa SL, Sessa F, Uccella S. Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol 2016; 27 (4): 284–311. doi: 10.1007/s12022-016-9432-9.

57. La Rosa S, Marando A, Furlan D et al. Colorectal poorly differentiated neuroendocrine carcinomas and mixed adenoneuroendocrine carcinomas: insights into the diagnostic immunophenotype, assessment of methylation profile, and search for prognostic markers. Am J Surg Pathol 2012; 36 (4): 601–611. doi: 10.1097/PAS.0b013e318242e21c.

58. Power DG, Asmis TR, Tang LH et al. High-grade neuroendocrine carcinoma of the colon, long-term survival in advanced disease. Med Oncol 2011; 28 (1): S169–S174. doi: 10.1007/s120 32-010-9674-1.

59. Romeo M, Quer A, Tarrats A et al. Appendiceal mixed adenoneuroendocrine carcinomas, a rare entity that can present as a Krukenberg tumor: case report and review of the literature. World J Surg Oncol 2015; 13: 325. doi: 10.1186/s12957-015-0740-1.