Progress of Diagnosis and Treatment of Gastrointestinal Neuroendocrine Tumors_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

FENG Jinyan ,  WU Xiaoting

Surgery Center of Gastroenterology， West China Hospital， Sichuan University， Chengdu 610041， Sichuan Province， China;

Corresponding author：

WU Xiaoting, Email: wxt402214359@163.com

Keywords：

Neuroendocrine tumors; Gastrointestinal tract; Diagnosis; Treatment; Classification

Video：

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Objective 　To summary the pathological classification， clinical manifestations， diagnosis， and treatments of gastrointestinal neuroendocrine tumors （GE-NETs）.
Methods 　Domestic and international literatures were collected to summary the status of clinical researches and treatments of GE-NETs.
Results 　GE-NETs derived from enterochromaffin cells throughout the gut which had the function of amine precursor uptake decarboxylase （APUD）. These tumors secreted discrete bioactive substances and produced characteristic immunohistochemical patterns， making patients to manifest endocrine syndrome. But there were no unified standards on the diagnosis， grade， TNM classification， and prognosis of GE-NETs. Early diagnosis rate of GE-NETs was low， and most of tumors were asymptomatic and detected at late stage， with a tendency to metastasize to the liver. Imaging examation was important in early diagnosis of GE-NETs. Surgery was the traditional first-line therapy and the only possible curative approach. Somatostatin analogues， such as long-term-release （LAR） octreotide， could relieve the hormonal symptoms， slow down the tumor growth， and had shown synergistic antiproliferative activity in combination with biological agent everolimus.
Conclusions 　The lack of standardized classification and an incomplete understanding of this disease are some of the impediments to the progress of treatment. Individualized comprehensive therapy is the aim of the future treatment.

Citation： FENG Jinyan,WU Xiaoting,.. Progress of Diagnosis and Treatment of Gastrointestinal Neuroendocrine Tumors. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(3): 334-339. doi: Copy

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2.	Soga J. Early-stage carcinoids of the gastrointestinal tract：an analysis of 1 914 reported cases[J]. Cancer， 2005， 103(8)：1587-1595.
3.	Srirajaskanthan R， Shanmugabavan D， Ramage JK. Carcinoid syndrome[J]. BMJ， 2010， 341：c3941.
4.	Shebani KO， Souba WW， Finkelstein DM， et al. Prognosis and survival in patients with gastrointestinal tract carcinoid tumors[J]. Ann Surg， 1999， 229(6)：815-821.
5.	Modlin IM， Moss SF， Chung DC， et al. Priorities for improvingthe management of gastroenteropancreatic neuroendocrine tumors[J]. J Natl Cancer Inst， 2008， 100(18)：1282-1289.
6.	Ramage JK， Ahmed A， Ardill J， et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)[J]. Gut， 2012， 61(1)：6-32.
7.	Oberndorfer S， Karzinoide tumoren des dünndarms[J]. Frankf Z Pathol， 1907， 1：426-432.
8.	Klöppel G， Perren A， Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors：the WHO classification[J]. Ann N Y Acad Sci， 2004， 1014：13-27.
9.	Jensen RT， Berna MJ， Bingham DB， et al. Inherited pancreatic endocrine tumor syndromes：advances in molecular pathogenesis， diagnosis， management， and controversies[J]. Cancer， 2008， 113(7 Suppl)：1807-1843.
10.	Turaga KK， Kvols LK. Recent progress in the understanding，diagnosis， and treatment of gastroenteropancreatic neuroendocrine tumors[J]. CA Cancer J Clin， 2011， 61(2)：113-132.
11.	中国胃肠胰神经内分泌肿瘤病理专家组. 中国胃肠胰神经内分泌肿瘤病理学诊断共识[J]. 中华病理学杂志， 2011， 40(4)：257-262.
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13.	Rindi G， Klöppel G， Couvelard A， et al. TNM staging of midgutand hindgut (neuro) endocrine tumors：a consensus proposal including a grading system[J]. Virchows Arch， 2007， 451(4)：757-762.
14.	Klöppel G， Couvelard A， Perren A， et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors：towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification[J]. Neuroendocrinology， 2009， 90(2)：162-166.
15.	Gastrointestinal Pathology Study Group of Korean Society of Pathologists； Cho MY， Kim JM， et al. Current trends of the incidence and pathological diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Korea 2000-2009：multicenter study[J]. Cancer Res Treat， 2012， 44(3)：157-165.
16.	Leja J， Essaghir A， Essand M， et al. Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas[J]. Mod Pathol， 2009， 22(2)：261-272.
17.	Tormey WP， Fitzgerald RJ. The clinical and laboratory correlates of an increased urinary 5-hydroxyindoleacetic acid[J]. Postgrad Med J， 1995， 71(839)：542-545.
18.	Oberg K， Eriksson B. Nuclear medicine in the detection， stagingand treatment of gastrointestinal carcinoid tumours[J]. Best Pract Res Clin Endocrinol Metab， 2005， 19(2)：265-276.
19.	Ghevariya V， Malieckal A， Ghevariya N， et al. Carcinoid tumors of the gastrointestinal tract[J]. South Med J， 2009， 102(10)：1032-1040.
20.	Coates SW Jr， Demarco DC. Metastatic carcinoid tumor discovered by capsule endoscopy and not detected by esophagogastroduodenoscopy[J]. Dig Dis Sci， 2004， 49(4)：639-641.
21.	Oberg K， Kvols L， Caplin M， et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system[J]. Ann Oncol， 2004， 15(6)：966-973.
22.	Nikolaou A， Thomas D， Kampanellou C， et al. The value of 11C-5-hydroxy-tryptophan positron emission tomography in neuroendocrine tumor diagnosis and management：experience from one center[J]. J Endocrinol Invest， 2010， 33(11)：794-799.
23.	Modlin IM， Tang LH. Approaches to the diagnosis of gut neuroendocrine tumors：the last word (today)[J]. Gastroenterology，.
24.	Oberg K. Interferon in the management of neuroendocrine GEP-tumors：a review[J]. Digestion， 2000， 62 Suppl 1：92-97.
25.	Kunz PL， Fisher GA. Advances in the treatment of gastroenteropancreatic neuroendocrine tumors[J]. Clin Exp Gastroenterol， 2010， 3(1)：79-86.
26.	Fendrich V， Bartsch DK. Surgical treatment of gastrointestinal neuroendocrine tumors[J]. Langenbecks Arch Surg， 2011， 396(3)：299-311.
27.	Stinner B， Kisker O， Zielke A， et al. Surgical management for carcinoid tumors of small bowel， appendix， colon， and rectum[J]. World J Surg， 1996， 20(2)：183-188.
28.	Sutton R， Doran HE， Williams EM， et al. Surgery for midgut carcinoid[J]. Endocr Relat Cancer， 2003， 10(4)：469-481.
29.	Susini C， Buscail L. Rationale for the use of somatostatin analogs as antitumor agents[J]. Ann Oncol， 2006， 17(12)：1733-1742.
30.	Mejias M， Garcia-Pras E， Tiani C， et al. The somatostatin analogue octreotide inhibits angiogenesis in the earliest， but not in advanced， stages of portal hypertension in rats[J]. J Cell Mol Med， 2008， 12(5A)：1690-1699.
31.	Bruns C， Lewis I， Briner U， et al. SOM230：a novel somatostatinpeptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile[J]. Eur J Endocrinol， 2002， 146(5)：707-716.
32.	Kwekkeboom DJ， Teunissen JJ， Bakker WH， et al. Radiolabeled somatostatin analog [177Lu-DOTA0，Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors[J]. J Clin Oncol， 2005， 23(12)：2754-2762.
33.	Kulke MH， Kim H， Clark JW， et al. A phase Ⅱ trial of gemcitabine for metastatic neuroendocrine tumors[J]. Cancer， 2004， 101(5)：934-939.
34.	Oberg K， Norheim I， Lundqvist G， et al. Cytotoxic treatment in patients with malignant carcinoid tumors. Response to streptozocin——alone or in combination with 5-FU[J]. Acta Oncol， 1987， 26(6)：429-432.
35.	Eriksson J， Stålberg P， Nilsson A， et al. Surgery and radiofrequency ablation for treatment of liver metastases from midgut and foregut carcinoids and endocrine pancreatic tumors[J]. World J Surg， 2008， 32(5)：930-938.
36.	Le Treut YP， Delpero JR， Dousset B， et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report[J]. Ann Surg， 1997， 225(4)：355-364.
37.	Sutcliffe R， Maguire D， Ramage J， et al. Management of neuroendocrine liver metastases[J]. Am J Surg， 2004， 187(1)：39-46.
38.	Yao JC， Phan AT， Chang DZ， et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low to intermediate-grade neuroendocrine tumors：results of a phase Ⅱstudy[J]. J Clin Oncol， 2008， 26(26)：4311-4318.
39.	， 112(2)：583-590.

1. Toumpanakis CG， Caplin ME. Molecular genetics of gastroenteropancreatic neuroendocrine tumors[J]. Am J Gastroenterol， 2008， 103(3)：729-732.
2. Soga J. Early-stage carcinoids of the gastrointestinal tract：an analysis of 1 914 reported cases[J]. Cancer， 2005， 103(8)：1587-1595.
3. Srirajaskanthan R， Shanmugabavan D， Ramage JK. Carcinoid syndrome[J]. BMJ， 2010， 341：c3941.
4. Shebani KO， Souba WW， Finkelstein DM， et al. Prognosis and survival in patients with gastrointestinal tract carcinoid tumors[J]. Ann Surg， 1999， 229(6)：815-821.
5. Modlin IM， Moss SF， Chung DC， et al. Priorities for improvingthe management of gastroenteropancreatic neuroendocrine tumors[J]. J Natl Cancer Inst， 2008， 100(18)：1282-1289.
6. Ramage JK， Ahmed A， Ardill J， et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)[J]. Gut， 2012， 61(1)：6-32.
7. Oberndorfer S， Karzinoide tumoren des dünndarms[J]. Frankf Z Pathol， 1907， 1：426-432.
8. Klöppel G， Perren A， Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors：the WHO classification[J]. Ann N Y Acad Sci， 2004， 1014：13-27.
9. Jensen RT， Berna MJ， Bingham DB， et al. Inherited pancreatic endocrine tumor syndromes：advances in molecular pathogenesis， diagnosis， management， and controversies[J]. Cancer， 2008， 113(7 Suppl)：1807-1843.
10. Turaga KK， Kvols LK. Recent progress in the understanding，diagnosis， and treatment of gastroenteropancreatic neuroendocrine tumors[J]. CA Cancer J Clin， 2011， 61(2)：113-132.
11. 中国胃肠胰神经内分泌肿瘤病理专家组. 中国胃肠胰神经内分泌肿瘤病理学诊断共识[J]. 中华病理学杂志， 2011， 40(4)：257-262.
12. 徐建明，杨晨. 胃肠胰腺神经内分泌肿瘤国际诊断共识的解读[J]. 临床肿瘤学杂志， 2011， 16(11)：1033-1038.
13. Rindi G， Klöppel G， Couvelard A， et al. TNM staging of midgutand hindgut (neuro) endocrine tumors：a consensus proposal including a grading system[J]. Virchows Arch， 2007， 451(4)：757-762.
14. Klöppel G， Couvelard A， Perren A， et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors：towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification[J]. Neuroendocrinology， 2009， 90(2)：162-166.
15. Gastrointestinal Pathology Study Group of Korean Society of Pathologists； Cho MY， Kim JM， et al. Current trends of the incidence and pathological diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Korea 2000-2009：multicenter study[J]. Cancer Res Treat， 2012， 44(3)：157-165.
16. Leja J， Essaghir A， Essand M， et al. Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas[J]. Mod Pathol， 2009， 22(2)：261-272.
17. Tormey WP， Fitzgerald RJ. The clinical and laboratory correlates of an increased urinary 5-hydroxyindoleacetic acid[J]. Postgrad Med J， 1995， 71(839)：542-545.
18. Oberg K， Eriksson B. Nuclear medicine in the detection， stagingand treatment of gastrointestinal carcinoid tumours[J]. Best Pract Res Clin Endocrinol Metab， 2005， 19(2)：265-276.
19. Ghevariya V， Malieckal A， Ghevariya N， et al. Carcinoid tumors of the gastrointestinal tract[J]. South Med J， 2009， 102(10)：1032-1040.
20. Coates SW Jr， Demarco DC. Metastatic carcinoid tumor discovered by capsule endoscopy and not detected by esophagogastroduodenoscopy[J]. Dig Dis Sci， 2004， 49(4)：639-641.
21. Oberg K， Kvols L， Caplin M， et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system[J]. Ann Oncol， 2004， 15(6)：966-973.
22. Nikolaou A， Thomas D， Kampanellou C， et al. The value of 11C-5-hydroxy-tryptophan positron emission tomography in neuroendocrine tumor diagnosis and management：experience from one center[J]. J Endocrinol Invest， 2010， 33(11)：794-799.
23. Modlin IM， Tang LH. Approaches to the diagnosis of gut neuroendocrine tumors：the last word (today)[J]. Gastroenterology，.
24. Oberg K. Interferon in the management of neuroendocrine GEP-tumors：a review[J]. Digestion， 2000， 62 Suppl 1：92-97.
25. Kunz PL， Fisher GA. Advances in the treatment of gastroenteropancreatic neuroendocrine tumors[J]. Clin Exp Gastroenterol， 2010， 3(1)：79-86.
26. Fendrich V， Bartsch DK. Surgical treatment of gastrointestinal neuroendocrine tumors[J]. Langenbecks Arch Surg， 2011， 396(3)：299-311.
27. Stinner B， Kisker O， Zielke A， et al. Surgical management for carcinoid tumors of small bowel， appendix， colon， and rectum[J]. World J Surg， 1996， 20(2)：183-188.
28. Sutton R， Doran HE， Williams EM， et al. Surgery for midgut carcinoid[J]. Endocr Relat Cancer， 2003， 10(4)：469-481.
29. Susini C， Buscail L. Rationale for the use of somatostatin analogs as antitumor agents[J]. Ann Oncol， 2006， 17(12)：1733-1742.
30. Mejias M， Garcia-Pras E， Tiani C， et al. The somatostatin analogue octreotide inhibits angiogenesis in the earliest， but not in advanced， stages of portal hypertension in rats[J]. J Cell Mol Med， 2008， 12(5A)：1690-1699.
31. Bruns C， Lewis I， Briner U， et al. SOM230：a novel somatostatinpeptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile[J]. Eur J Endocrinol， 2002， 146(5)：707-716.
32. Kwekkeboom DJ， Teunissen JJ， Bakker WH， et al. Radiolabeled somatostatin analog [177Lu-DOTA0，Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors[J]. J Clin Oncol， 2005， 23(12)：2754-2762.
33. Kulke MH， Kim H， Clark JW， et al. A phase Ⅱ trial of gemcitabine for metastatic neuroendocrine tumors[J]. Cancer， 2004， 101(5)：934-939.
34. Oberg K， Norheim I， Lundqvist G， et al. Cytotoxic treatment in patients with malignant carcinoid tumors. Response to streptozocin——alone or in combination with 5-FU[J]. Acta Oncol， 1987， 26(6)：429-432.
35. Eriksson J， Stålberg P， Nilsson A， et al. Surgery and radiofrequency ablation for treatment of liver metastases from midgut and foregut carcinoids and endocrine pancreatic tumors[J]. World J Surg， 2008， 32(5)：930-938.
36. Le Treut YP， Delpero JR， Dousset B， et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report[J]. Ann Surg， 1997， 225(4)：355-364.
37. Sutcliffe R， Maguire D， Ramage J， et al. Management of neuroendocrine liver metastases[J]. Am J Surg， 2004， 187(1)：39-46.
38. Yao JC， Phan AT， Chang DZ， et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low to intermediate-grade neuroendocrine tumors：results of a phase Ⅱstudy[J]. J Clin Oncol， 2008， 26(26)：4311-4318.
39. ， 112(2)：583-590.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Progress of Diagnosis and Treatment of Gastrointestinal Neuroendocrine Tumors

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