Abstract
The Ki-67 labeling index has been found to bear prognostic significance in gastrointestinal neuroendocrine tumors (NETs), and it was recently incorporated in NET histological grading. Nevertheless, a reliable preoperative determination of NET grading could be useful in clinical practice. The aim of this study is to compare the results of Ki-67 labeling index, as measured on cytological samples and on surgical specimens of patients with pancreatic NETs (P-NETs). We also investigated whether concordance might be improved, using a 5 % (instead of 2 %) cutoff value for defining G2 tumors. We retrospectively identified 48 consecutive patients with 53 P-NETs, from our five institutions, and we measured Ki-67 labeling index on their cytological samples and surgical specimens. The traditional 2 % and the alternative 5 % cutoff values were used to classify G2 tumors. The concordance rate between cytological and histological grading was 46/53 (86.8 %; weighted κ statistic 0.77; 95 % confidence interval (95 % CI) 0.60–0.94). No cases of cytological G1-G2 NETs were upgraded to G3 neuroendocrine carcinoma (NEC) at histological grading. Cytology was found to be highly specific in the diagnosis of both G2 (94.1 %; 95 % CI 80.3–99.3) and G3 tumors (100.0 %; 95 % CI 92.8–100), but the sensitivity was poor for G2 NETs (66.7 %; 95 % CI 38.4–88.2) and high for the prediction of G3 NECs (100 %; 95 % CI 39.8–100.0). When the 5 % cutoff value was adopted, concordance rate was 49/53 (92.4 %; weighted κ 0.82; 95 % CI 0.64–1.00). In conclusion, Ki-67 cytological expression can distinguish well-differentiated (both G1 and G2) from poorly differentiated P-NETs, and it may be useful for their preoperative classification.
Similar content being viewed by others
References
Rindi G, Klöppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth M, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B, Frascati Consensus Conference participants (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449:395–401
Rindi G, Arnold R, Bosman FT, Capella C, Klimstra DS, Klöppel G, Komminoth P, Solcia E (2010) Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumours of the digestive system, 4th edn. IARC Press, Lyon, France, pp 13–14
Pape UF, Jann H, Mueller-Nordhorn J, Bockelbrink A, Berndt U, Willich SN, Koch M, Roecken C, Rindi G, Wiedenmann B (2008) Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 113:256–265
Strosberg J, Nasir A, Coppola D, Wick M, Kvols L (2009) Correlation between grade and prognosis in metastatic gastroenteropancreatic neuroendocrine tumors. Hum Pathol 40:1262–1268
Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R, Panzuto F, Pederzoli P, Delle Fave G, Falconi M (2010) Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 23:824–833
Panzuto F, Boninsegna L, Fazio N, Campana D, Pia Brizzi M, Capurso G, Scarpa A, De Braud F, Dogliotti L, Tomassetti P, Delle Fave G, Falconi M (2011) Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol 29:2372–2377
Boninsegna L, Panzuto F, Partelli S, Capelli P, Delle Fave G, Bettini R, Pederzoli P, Scarpa A, Falconi M (2012) Malignant pancreatic neuroendocrine tumour: lymph node ratio and Ki-67 are predictors of recurrence after curative resections. Eur J Cancer 48:1608–1615
Couvelard A, Deschamps L, Ravaud P, Baron G, Sauvanet A, Hentic O, Colnot N, Paradis V, Belghiti J, Bedossa P, Ruszniewski P (2009) Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors. Mod Pathol 22:273–281
Klimstra DS, Modlin IR, Adsay V, Chetty R, Deshpande V, Goenen M, Jensen RT, Kidd M, Kulke MH, Lloyd RV, Moran C, Moss SF, Oberg K, O’Toole D, Rindi G, Robert ME, Suster S, Tang LH, Tzen CY, Washington MK, Wiedenmann B, Yao J (2010) Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol 34:300–313
Rindi G, Bordi C, La Rosa S, Solcia E, Delle Fave G on behalf of the “Gruppo Italiano Patologi Apparato Digerente (GIPAD)” and of the “Società Italiana di Anatomia Patologica e Citopatologia Diagnostica”/International Academy of Pathology, Italian division (SIAPEC/IAP) (2011) Gastroenteropancreatic (neuro)endocrine neoplasms: the histology report. Dig Liver Dis 43S:S356–S360
Goodell PP, Krasinskas AM, Davison JM, Hartman DJ (2012) Comparison of methods for proliferative index analysis for grading pancreatic well-differentiated neuroendocrine tumors. Am J Clin Pathol 137:576–582
Bettini R, Partelli S, Boninsegna L, Capelli P, Crippa S, Pederzoli P, Scarpa A, Falconi M (2011) Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 150:75–82
Oeberg K (2012) Neuroendocrine tumors of the digestive tract: impact of new classifications and new agents on therapeutic approaches. Curr Opin Oncol 24:433–440
Piani P, Franchi GM, Cappelletti C, Scavini M, Albarello L, Zerbi Z, Arcidiacono PG, Bosi E, Manzoni MF (2008) Cytological Ki-67 in pancreatic endocrine tumours: an opportunity for pre-operative grading. Endocr Relat Cancer 15:175–181
Figueiredo FAF, Giovannini M, Monges G, Bories E, Pesenti C, Caillol F, Delpero JR (2009) EUS-FNA predicts 5-year survival in pancreatic endocrine tumors. Gastrointest Endosc 70:907–914
Kaklamatos M, Dimitrios T, Kanakis G, Alexandrakis K, Sougioultzis S, Kaltsas G, Karoumpalis I, Salla C, Diakatou E, Kontogeorgos G (2011) Diagnostic accuracy and clinical significance of the fine needle aspiration Ki-67 labeling index in pancreatic endocrine tumours. Endocr Relat Cancer 18:L1–L3
De Angelis C, Pacchioni D, Carucci P, Bruno M, Allegranza P, Barreca A, Brizzi F, Valente V, Mezzabotta L, Reggio D, Rizzetto M (2011) Role of EUS-FNA in the diagnosis of pancreatic neuroendocrine tumors and value of Ki-67. Dig Liver Dis 43S:S143, Abs
Larghi A, Capurso G, Carnuccio A, Ricci R, Alfieri S, Galasso D, Lugli F, Bianchi A, Panzuto F, De Marinis L, Falconi M, Delle Fave Doglietto GB, Costamagna G, Rindi G (2012) Ki-67 grading of nonfunctioning pancreatic neuroendocrine tumors on histologic samples obtained by EUS-guided fine-needle tissue acquisition: a prospective study. Gastrointest Endosc 76:570–577
Tatsumoto S, Kodama Y, Sakurai Y, Shinohara T, Katanuma A, Maguchi H (2013) Pancreatic neuroendocrine neoplasm: correlation between computed tomography enhancement patterns and prognostic factors of surgical and endoscopic ultrasound-guided fine-needle aspiration biopsy specimens. Abdom Imaging 38:358–366
Hasegawa T, Yamao K, Hijioka S, Bhatia V, Mizuno N, Hara K, Imaoka H, Niwa Y, Tajika M, Kondo S, Tanaka T, Shimizu Y, Kinoshita T, Kohsaki T, Nishimori I, Iwasaki S, Saibara T, Hosoda W, Yatabe Y (2013) Evaluation of Ki-67 index in EUS-FNA specimens for the assessment of malignancy risk in pancreatic neuroendocrine tumors. Endoscopy. [Epub ahead of print]
McKee GT, Tambouret RH, Finkelstein D (2001) A reliable method of demonstrating HER-2/neu, estrogen receptors, and progesterone receptors on routinely processed cytologic material. Appl Immunohistochem Mol Morphol 9:352–357
Krishnamurthy S, Dimashkieh H, Patel S, Sneige N (2003) Immunocytochemical evaluation of estrogen receptor on archival Papanicolau-stained fine needle aspirate smears. Diagn Cytopathol 29:309–314
Nadji M, Gomez-Fernandez C, Ganjei-Azar P, Morales AR (2005) Immunohistochemistry of estrogen and progesterone receptors reconsidered. Am J Clin Pathol 123:21–27
McCall CM, Shi C, Cornish TC, Klimstra DS, Tang LH, Basturk O, Jun Mun L, Ellison TA, Wolfgang CL, Choti MA, Schulick RD, Edil BH, Hruban RH (2013) Grading of well differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. Am J Surg Pathol 37:1671–1677
Tang LH, Gonen M, Hedvat C, Modlin IM, Klimstra DS (2012) Objective quantification of the Ki67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system. A comparison of digital image analysis with manual methods. Am J Surg Pathol 36:1761–1770
Yang Z, Tang LH, Klimstra DS (2011) Effect of Tumor Heterogeneity on the assessment of Ki-67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification. Am J Surg Pathol 35:853–860
Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler W, Capella C, Caplin M, Couvelard A, Doglioni C, Delle Fave G, Fisher L, Fusai G, de Herder WW, Jann H, Komminoth P, de Krijer RR, La Rosa S, Luong TV, Pape U, Perren A, Ruszniewski P, Scarpa A, Schmitt A, Solcia E, Wiedenmann B (2012) TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 104:764–777
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Carlinfante, G., Baccarini, P., Berretti, D. et al. Ki-67 cytological index can distinguish well-differentiated from poorly differentiated pancreatic neuroendocrine tumors: a comparative cytohistological study of 53 cases. Virchows Arch 465, 49–55 (2014). https://doi.org/10.1007/s00428-014-1585-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-014-1585-7