Top

World Journal of Surgery

Published in:

01-06-2014

Role of Ki-67 Proliferation Index in the Assessment of Patients with Neuroendocrine Neoplasias Regarding the Stage of Disease

Authors: H. C. Miller, P. Drymousis, R. Flora, R. Goldin, D. Spalding, A. Frilling

Published in: World Journal of Surgery | Issue 6/2014

Abstract

Background

Neuroendocrine neoplasias (NEN) of the gastroenteropancreatic (GEP) system frequently present with metastatic deposits. The proliferation marker Ki-67 is used for diagnosis and to assess the prognosis of disease. The aim of our study was to evaluate the usefulness of Ki-67 % in the assessment of NEN patients with regard to their disease stage in clinical practice. Additionally, a comparative analysis of Ki-67 levels among different sites of disease was performed.

Methods

This retrospective study included patients with GEP NEN referred to our center from 2010 to 2012. The NEN diagnosis was confirmed by standard histopathology. Ki-67 immunohistochemistry was done on paraffin-embedded sections using an automated Leica immunohistochemistry machine. NEN grading was carried out according to European Neuroendocrine Tumor Society recommendations (low grade [G1] to intermediate grade [G2], well to moderately differentiated neuroendocrine neoplasms; high-grade [G3], moderately to poorly differentiated neuroendocrine neoplasms). Results of tumor staging and grading were correlated. In a subgroup of cases, comparative analysis of Ki-67 levels in different sites of disease was carried out.

Results

One hundred sixty-one GEP NEN patients were included in the study. Metastatic disease was seen in 46.1 % (53/115) of G1 tumors, 77.8 % (28/36) of G2 tumors, and 100 % of (10/10) G3 tumors (p = 0.0002). When stratified according to primary tumor site, metastatic disease was documented in 42.9 % (36/84) of patients with pancreatic NEN and in 91.9 % (34/37) of those with small intestinal primary. Stage IV metastatic disease was present in 27.8 % (32/115) and 72.2 % (26/36) of the G1 and G2 tumors, respectively, and in 90 % (9/10) of the G3 tumors. Assessment of the Ki-67 index for a subset of cases at metastatic sites as well as the primary tumor site showed discrepancies in 35.3 % cases. In 7/9 (77.8 %) patients with liver metastases, Ki-67 % was higher in the liver lesions than in the primary tumor.

Conclusions

Patients with GEP NEN exhibiting a high Ki-67 proliferation index present with metastatic disease in the vast majority of cases. Depending upon the primary tumor site, metastases are to be expected also in tumors with low Ki-67 %, although they are considered less aggressive. Different disease sites may express heterogeneous Ki-67 levels.

Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM (2011) The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 40(1):1–18 viiPubMedCrossRef

Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE et al (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26(18):3063–3072PubMedCrossRef

Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, Diaz-Perez JA, Martinez Del Prado MP, Alonso Orduna V et al (2010) Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol 21(9):1794–1803PubMedCrossRef

Lombard-Bohas C, Mitry E, O’Toole D, Louvet C, Pillon D, Cadiot G et al (2009) Thirteen-month registration of patients with gastroenteropancreatic endocrine tumours in France. Neuroendocrinology 89(2):217–222PubMedCrossRef

Ahmed A, Turner G, King B, Jones L, Culliford D, McCance D et al (2009) Midgut neuroendocrine tumours with liver metastases: results of the UKINETS study. Endocr Relat Cancer 16(3):885–894PubMedCrossRef

Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B (2008) Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Research 14(23):7798–7803CrossRef

Jann H, Roll S, Couvelard A, Hentic O, Pavel M, Muller-Nordhorn J et al (2011) Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. Cancer 117(15):3332–3341PubMedCrossRef

Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW et al (2012) TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 104(10):764–777PubMedCrossRef

Beasley MB, Thunnissen FB, Brambilla E, Hasleton P, Steele R, Hammar SP et al (2000) Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 31(10):1255–1265PubMedCrossRef

10.

Hotta K, Shimoda T, Nakanishi Y, Saito D (2006) Usefulness of Ki-67 for predicting the metastatic potential of rectal carcinoids. Pathol Int 56(10):591–596PubMedCrossRef

11.

Jamali M, Chetty R (2008) Predicting prognosis in gastroentero-pancreatic neuroendocrine tumors: an overview and the value of Ki-67 immunostaining. Endocr Pathol 19(4):282–288PubMedCrossRef

12.

Rindi G, Kloppel G, Ahlman H, Caplin M, Couvelard A, de Herder WW et al (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449(4):395–401PubMedCentralPubMedCrossRef

13.

Rindi G, Kloppel G, Couvelard A, Komminoth P, Korner M, Lopes JM et al (2007) TNM staging of midgut and hindgut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 451(4):757–762PubMedCrossRef

14.

Bosman FT, World Health Organization, International Agency for Research on Cancer (2010) WHO classification of tumours of the digestive system, 4th edn. International Agency for Research on Cancer, Lyon, p 417

15.

Khan MS, Luong TV, Watkins J, Toumpanakis C, Caplin ME, Meyer T (2013) A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms. Br J Cancer 108(9):1838–1845PubMedCrossRef

16.

Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R et al (2010) Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 23(6):824–833PubMedCrossRef

17.

Hentic O, Couvelard A, Rebours V, Zappa M, Dokmak S, Hammel P et al (2011) Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with liver metastases of digestive endocrine carcinomas. Endocr Relat Cancer 18(1):51–59PubMedCrossRef

18.

Boninsegna L, Panzuto F, Partelli S, Capelli P, Delle Fave G, Bettini R et al (2012) Malignant pancreatic neuroendocrine tumour: lymph node ratio and Ki67 are predictors of recurrence after curative resections. Eur J Cancer 48(11):1608–1615PubMedCrossRef

19.

Dhall D, Mertens R, Bresee C, Parakh R, Wang HL, Li M et al (2012) Ki-67 proliferative index predicts progression-free survival of patients with well-differentiated ileal neuroendocrine tumors. Hum Pathol 43(4):489–495PubMedCrossRef

20.

La Rosa S, Klersy C, Uccella S, Dainese L, Albarello L, Sonzogni A et al (2009) Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors. Hum Pathol 40(1):30–40PubMedCrossRef

21.

Durante C, Boukheris H, Dromain C, Duvillard P, Leboulleux S, Elias D et al (2009) Prognostic factors influencing survival from metastatic (stage IV) gastroenteropancreatic well-differentiated endocrine carcinoma. Endocr Relat Cancer 16(2):585–597PubMedCrossRef

22.

Haug AR, Cindea-Drimus R, Auernhammer CJ, Reincke M, Wangler B, Uebleis C et al (2012) The role of 68 Ga-DOTATATE PET/CT in suspected neuroendocrine tumors. J Nucl Med 53(11):1686–1692PubMedCrossRef

23.

Frilling A, Sotiropoulos GC, Radtke A, Malago M, Bockisch A, Kuehl H et al (2010) The impact of 68 Ga-DOTATOC positron emission tomography/computed tomography on the multimodal management of patients with neuroendocrine tumors. Ann Surg 252(5):850–856PubMedCrossRef

24.

Baum RP, Kulkarni HR, Carreras C (2012) Peptides and receptors in image-guided therapy: theranostics for neuroendocrine neoplasms. Semin Nucl Med 42(3):190–207PubMedCrossRef

25.

Pavel M, Baudin E, Couvelard A, Krenning E, Oberg K, Steinmuller T et al (2012) ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 95(2):157–176PubMedCrossRef

26.

Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6):514–523PubMedCrossRef

27.

Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6):501–513PubMedCrossRef

28.

Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M et al (2009) 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 27(28):4656–4663PubMedCrossRef

29.

Pape UF, Berndt U, Muller-Nordhorn J, Bohmig M, Roll S, Koch M et al (2008) Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 15(4):1083–1097PubMedCrossRef

30.

Panzuto F, Boninsegna L, Fazio N, Campana D, Pia Brizzi M, Capurso G et al (2011) Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol 29(17):2372–2377PubMedCrossRef

31.

Landerholm K, Zar N, Andersson RE, Falkmer SE, Jarhult J (2011) Survival and prognostic factors in patients with small bowel carcinoid tumour. Br J Surg 98(11):1617–1624PubMedCrossRef

32.

Norlen O, Stalberg P, Oberg K, Eriksson J, Hedberg J, Hessman O et al (2012) Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World J Surg 36(6):1419–1431. doi:10.1007/s00268-011-1296-z PubMedCrossRef

33.

Panzuto F, Nasoni S, Falconi M, Corleto VD, Capurso G, Cassetta S et al (2005) Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 12(4):1083–1092PubMedCrossRef

34.

Ruf J, Heuck F, Schiefer J, Denecke T, Elgeti F, Pascher A et al (2010) Impact of multiphase 68 Ga-DOTATOC-PET/CT on therapy management in patients with neuroendocrine tumors. Neuroendocrinology 91(1):101–109PubMedCrossRef

35.

Frilling A, Li J, Malamutmann E, Schmid KW, Bockisch A, Broelsch CE (2009) Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease. Br J Surg 96(2):175–184PubMedCrossRef

36.

Frilling A, Modlin IM, Kidd M, Russell C, Breitenstein S, Salem R, Kwekkeboom D, Lau WY, Klersy C, Vilgrain V, Davidson B, Siegler M, Caplin M, Solcia E, Schilsky R, Working Group Neuroendocrine Metastasis (2014) Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol 15(1):e8–e21PubMedCrossRef

37.

Yang Z, Tang LH, Klimstra DS (2011) Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification. Am J Surg Pathol 35(6):853–860PubMedCrossRef

38.

Couvelard A, Deschamps L, Ravaud P, Baron G, Sauvanet A, Hentic O et al (2009) Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors. Mod Pathol 22(2):273–281PubMedCrossRef

39.

Remes SM, Tuominen VJ, Helin H, Isola J, Arola J (2012) Grading of neuroendocrine tumors with Ki-67 requires high-quality assessment practices. Am J Surg Pathol 36(9):1359–1363PubMedCrossRef

40.

Tang LH, Gonen M, Hedvat C, Modlin IM, Klimstra DS (2012) Objective quantification of the Ki-67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system: a comparison of digital image analysis with manual methods. Am J Surg Pathol 36(12):1761–1770PubMedCrossRef

41.

Young HT, Carr NJ, Green B, Tilley C, Bhargava V, Pearce N (2013) Accuracy of visual assessments of proliferation indices in gastroenteropancreatic neuroendocrine tumours. J Clin Pathol 66(8):700–704PubMedCrossRef

42.

Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA et al (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467(7319):1109–1113PubMedCentralPubMedCrossRef

43.

Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J et al (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94PubMedCrossRef

44.

Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892PubMedCrossRef

45.

Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW et al (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464(7291):999–1005PubMedCentralPubMedCrossRef

46.

Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B et al (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1147PubMedCentralPubMedCrossRef

47.

Habal N, Sims C, Bilchik AJ (2000) Gastrointestinal carcinoid tumors and second primary malignancies. J Surg Oncol 75(4):310–316PubMed

48.

Kothari T, Mangla JC (1981) Malignant tumors associated with carcinoid tumors of the gastrointestinal tract. J Clin Gastroenterol 3(Suppl 1):43–46PubMedCrossRef

49.

Kim JY, Jang WY, Heo MH, Lee KK, Do YR, Park KU et al (2012) Metachronous double primary cancer after diagnosis of gastric cancer. Cancer Res Treat 44(3):173–178PubMedCentralPubMedCrossRef

50.

Liu L, Lemmens VE, De Hingh IH, de Vries E, Roukema JA, van Leerdam ME et al (2013) Second primary cancers in subsites of colon and rectum in patients with previous colorectal cancer. Dis Colon Rectum 56(2):158–168PubMedCrossRef

51.

Watanabe M, Kochi M, Fujii M, Kaiga T, Mihara Y, Funada T et al (2012) Dual primary gastric and colorectal cancer: is the prognosis better for synchronous or metachronous? Am J Clin Oncol 35(5):407–410PubMedCrossRef

52.

Schimmack S, Svejda B, Lawrence B, Kidd M, Modlin IM (2011) The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbecks Arch Surg 396(3):273–298PubMedCrossRef

53.

Zucker KA, Longo WE, Modlin IM, Bilchik AJ, Adrian TE (1989) Malignant diathesis from jejunal-ileal carcinoids. Am J Gastroenterol 84(2):182–186PubMed

54.

Reubi JC, Gugger M, Waser B, Schaer JC (2001) Y(1)-mediated effect of neuropeptide Y in cancer: breast carcinomas as targets. Cancer Res 61(11):4636–4641PubMed

55.

Chave HS, Gough AC, Palmer K, Preston SR, Primrose JN (2000) Bombesin family receptor and ligand gene expression in human colorectal cancer and normal mucosa. Br J Cancer 82(1):124–130PubMedCentralPubMedCrossRef

Title: Role of Ki-67 Proliferation Index in the Assessment of Patients with Neuroendocrine Neoplasias Regarding the Stage of Disease
Authors: H. C. Miller
P. Drymousis
R. Flora
R. Goldin
D. Spalding
A. Frilling
Publication date: 01-06-2014
Publisher: Springer US
Published in: World Journal of Surgery / Issue 6/2014
Print ISSN: 0364-2313
Electronic ISSN: 1432-2323
DOI: https://doi.org/10.1007/s00268-014-2451-0

ACC 2024 Congress

Springer Medicine

Role of Ki-67 Proliferation Index in the Assessment of Patients with Neuroendocrine Neoplasias Regarding the Stage of Disease

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2014

The Acute Surgical Unit Model Verses the Traditional “On Call” Model: A Systematic Review and Meta-Analysis

Trends in Incidentally Identified Thyroid Cancers Over a Decade: A Retrospective Analysis of 2,090 Surgical Patients

Surgery Indeed has an Important Role in Long-Term Outcome in Patients with Pancreatic Head Cancer

Quality of Life After Surgical Treatment of Early Barrett’s Cancer: A Prospective Comparison of the Ivor-Lewis Resection Versus the Modified Merendino Resection

Factors Affecting Success Rate of Advanced Trauma Life Support (ATLS) Courses

Enhancing Surgical Performance Outcomes Through Process-driven Care: A Systematic Review