ORIGINAL ARTICLE
Tissue heterogeneity contributes to suboptimal precision of WHO 2010 scoring criteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreas
Submission date: 2016-10-03
Final revision date: 2016-12-08
Acceptance date: 2016-12-09
Publication date: 2017-02-10
Pol J Pathol 2016;67(4):318-331
KEYWORDS
Ki-67 antigenneoplasm gradingneuroendocrine tumorsneuroendocrine carcinomapancreaspancreatic neoplasms
TOPICS
ABSTRACT
Reporting of Ki67 labeling index (LI) is a routine in diagnostics of neuroendocrine neoplasms of the pancreas. The aim of the study was to examine whether heterogeneity of Ki67 LI distribution in primary tumoral tissue influences precision of reporting of Ki67 LI and Ki67-LI-based grade, both established in adherence to WHO 2010 guidelines. Seventy-one samples of neuroendocrine tumours (NET) and 6 samples of neuroendocrine carcinomas (NEC) of the pancreas were taken for manual counting of Ki67 LI in 25 portions of 100 cells (2500 cells in total) in 3 hot spots an in a single area of lower proliferation rate (cold spot) in each case. Both NET and NEC showed Ki67 LI heterogeneity within primary tumour. Almost 20% of NET showed higher grade when 500 cells rather than 2000 cells were counted in hot spot area. Suboptimal choice of hot spot resulted in under-grading of approximately 20% of NET. Cold spots were constantly present in NET. Heterogeneity of Ki67 LI was also present in NEC, but it virtually never resulted in under-grading. Concept and methodology of Ki67 LI counting in neuroendocrine neoplasms of the pancreas requires clarification. Efforts aiming to improve precision of assessment of Ki67 LI are needed.
REFERENCES (88)
1.
Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: WHO classification of tumours of the digestive system. Bosman FT, Carneiro F, Hruban RH, Theise ND (eds). 4th ed. International Agency for Research on Cancer, Lyon 2010; 13-14.
2.
Adsay V. Ki67 labeling index in neuroendocrine tumors of the gastrointestinal and pancreatobiliary tract: to count or not to count is not the question, but rather how to count. Am J Surg Pathol 2012; 36: 1743-1746.
3.
Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol 2000; 182: 311-322.
4.
Rindi G, Klöppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006; 449: 395-401.
5.
Kunz PL, Reidy-Lagunes D, Anthony LB, et al. North American Neuroendocrine Tumor Society. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 2013; 42: 557-577.
6.
Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology 2016; 103: 153-171.
7.
Pavel M, O’Toole D, Costa F, et al. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 2016; 103: 172-185.
8.
Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 2012; 12: 323-334.
9.
Tang LH, Untch BR, Reidy DL, et al. Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: A pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res 2016; 22: 1011-1017.
10.
Valous NA, Lahrmann B, Halama N, et al. Spatial intratumoral heterogeneity of proliferation in immunohistochemical images of solid tumors. Med Phys 2016; 43: 2936.
11.
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: 300-313.
12.
Hasegawa T, Yamao K, Hijioka S, et al. Evaluation of Ki-67 index in EUS-FNA specimens for the assessment of malignancy risk in pancreatic neuroendocrine tumors. Endoscopy 2014; 46: 32-38.
13.
Adesoye T, Daleo MA, Loeffler AG, et al. Discordance of histologic grade between primary and metastatic neuroendocrine carcinomas. Ann Surg Oncol 2015; 22 Suppl 3: S817-S821.
14.
Zen Y, Heaton N. Elevated Ki-67 labeling index in ‘synchronous liver metastases’ of well differentiated enteropancreatic neuroendocrine tumor. Pathol Int 2013; 63: 532-538.
15.
Grillo F, Albertelli M, Brisigotti MP, et al. Grade increases in gastroenteropancreatic neuroendocrine tumor metastases compared to the primary tumor. Neuroendocrinology 2016; 103: 452-459.
16.
Couvelard A, Deschamps L, Ravaud P, et al. Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors. Mod Pathol 2009; 22: 273-281.
17.
Yang Z, Tang LH, Klimstra DS. 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 2011; 35: 853-860.
19.
Li J, Lin JP, Shi LH, et al. How reliable is the Ki-67 cytological index in grading pancreatic neuroendocrine tumors? A meta-analysis. Dig Dis 2016; 17: 95-103.
20.
Young HT, Carr NJ, Green B, et al. Accuracy of visual assessments of proliferation indices in gastroenteropancreatic neuroendocrine tumours. J Clin Pathol 2013; 66: 700-704.
21.
Reid MD, Bagci P, Ohike N, et al. Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies. Mod Pathol 2015; 28: 686-694.
22.
Blank A, Wehweck L, Marinoni I, et al. Interlaboratory variability of MIB1 staining in well-differentiated pancreatic neuroendocrine tumors. Virchows Arch 2015; 467: 543-550.
23.
Nadler A, Cukier M, Rowsell C, et al. Ki-67 is a reliable pathological grading marker for neuroendocrine tumors. Virchows Arch 2013; 462: 501-505.
24.
Goodell PP, Krasinskas AM, Davison JM, et al. Comparison of methods for proliferative index analysis for grading pancreatic well-differentiated neuroendocrine tumors. Am J Clin Pathol 2012; 137: 5765-5782.
25.
Tang LH, Gonen M, Hedvat C, et al. 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 2012; 36: 1761-1770.
26.
McCall CM, Shi C, Cornish TC, et al. Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. Am J Surg Pathol 2013; 37: 1671-1677.
27.
van Velthuysen ML, Groen EJ, Sanders J, et al. Reliability of proliferation assessment by Ki-67 expression in neuroendocrine neoplasms: eyeballing or image analysis? Neuroendocrinology 2014; 100: 288-292.
28.
Kroneman TN, Voss JS, Lohse CM, et al. Comparison of three Ki-67 index quantification methods and clinical significance in pancreatic neuroendocrine tumors. Endocr Pathol 2015; 26: 255-262.
29.
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. Neuroendocrinology 2009; 90: 162-166.
30.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine Tumors. Version 2.2016. https://www.nccn.org/professio... (Assessed: 24th July 2016).
31.
College of American Pathologists. Protocol for the Examination of Specimens From Patients With Tumors of the Endocrine Pancreas. Pancreas Endocrine 3.3.0.0. January 2016 Asessed: http://www.cap.org/ShowPropert... Folders/WebContent/pdf/cp-pancreasendo-16protocol-3300.pdf (30th July 2016).
32.
Weynand B, Borbath I, Bernard V, et al. Pancreatic neuroendocrine tumour grading on endoscopic ultrasound-guided fine needle aspiration: high reproducibility and inter-observer agreement of the Ki-67 labelling index. Cytopathology 2014; 25: 389-395.
33.
Liszka Ł, Pająk J, Mrowiec S, et al. Discrepancies between two alternative staging systems (European Neuroendocrine Tumor Society 2006 and American Joint Committee on Cancer/Union for International Cancer Control 2010) of neuroendocrine neoplasms of the pancreas. A study of 50 cases. Pathol Res Pract 2011; 207: 220-224.
34.
Liszka Ł, Mrowiec S, Kuśnierz K, et al. Standardized grossing protocol is useful for the pathology reporting of malignant neoplasms other than adenocarcinomas treated with pancreaticoduodenectomy. Histol Histopathol 2017; 32: 177-192.
35.
Tang LH, Basturk O, Sue JJ, et al. A practical approach to the classification of WHO grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol 2016; 40: 1192-1202.
36.
Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol 2014; 38: 437-447.
37.
Vélayoudom-Céphise FL, Duvillard P, Foucan L, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer 2013; 20: 649-657.
38.
Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol 2015; 39: 683-690.
39.
Dowsett M, Nielsen TO, A’Hern R, et al. International Ki-67 in Breast Cancer Working Group. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 2011; 103: 1656-1664.
40.
Reid MD, Balci S, Saka B, et al. Neuroendocrine tumors of the pancreas: current concepts and controversies. Endocr Pathol 2014; 25: 65-79.
41.
Knijn N, Nagtegaal ID. Guidelines for reporting histopathology studies. J Clin Pathol 2015; 68: 173-174.
42.
Romero Q, Bendahl PO, Klintman M, et al. Ki67 proliferation in core biopsies vs. surgical samples - a model for neo-adjuvant breast cancer studies. BMC Cancer 2011; 11: 341.
43.
Hashim YM, Trinkaus KM, Linehan DC, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg 2014; 259: 197-203.
44.
Partelli S, Gaujoux S, Boninsegna L, et al. Pattern and clinical predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). JAMA Surg 2013; 148: 932-939.
45.
Jiang Y, Jin JB, Zhan Q, et al. Impact and Clinical Predictors of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors. Chin Med J (Engl) 2015; 128: 3335-3344.
46.
Rindi G, Falconi M, Klersy C, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 2012; 104: 764-777.
47.
Scarpa A, Mantovani W, Capelli P, et al. Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 2010; 23: 824-833.
48.
Bettini R, Boninsegna L, Mantovani W, et al. Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours. Ann Oncol 2008; 19: 903-908.
49.
Richards-Taylor S, Ewings SM, Jaynes E, et al. The assessment of Ki-67 as a prognostic marker in neuroendocrine tumours: a systematic review and meta-analysis. J Clin Pathol 2016; 69: 612-618.
50.
Teutsch SM, Bradley LA, Palomaki GE, et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med 2009; 11: 3-14.
51.
Guiu S, Michiels S, André F, et al. Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement. Ann Oncol 2012; 23: 2997-3006.
52.
Duffy MJ, Sturgeon CM, Sölétormos G, et al. Validation of new cancer biomarkers: a position statement from the European group on tumor markers. Clin Chem 2015; 61: 809-820.
53.
Polley MY, Leung SC, McShane LM, et al. An international Ki67 reproducibility study. J Natl Cancer Inst 2013; 105: 1897-1906.
54.
Jennings L, Van Deerlin VM, Gulley ML. Recommended principles and practices for validating clinical molecular pathology tests. Arch Pathol Lab Med 2009; 133: 743-755.
55.
Fitzgibbons PL, Bradley LA, Fatheree LA, et al. Principles of analytic validation of immunohistochemical assays: Guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med 2014; 138: 1432-1443.
56.
Varga Z, Diebold J, Dommann-Scherrer C, et al. How reliable is Ki-67 immunohistochemistry in grade 2 breast carcinomas? A QA study of the Swiss Working Group of Breast- and Gynecopathologists. PLoS One 2012; 7: e37379.
57.
Arima N, Nishimura R, Osako T, et al. The importance of tissue handling of surgically removed breast cancer for an accurate assessment of the Ki-67 index. J Clin Pathol 2016; 69: 255-259.
58.
Vyberg M, Nielsen S. Proficiency testing in immunohistochemistry--experiences from Nordic Immunohistochemical Quality Control (NordiQC). Virchows Arch 2016; 468: 19-29.
59.
Romero Q, Bendahl PO, Fernö M, et al. A novel model for Ki67 assessment in breast cancer. Diagn Pathol 2014; 9: 118.
60.
Sato M, Kojima M, Nagatsuma AK, et al. Optimal fixation for total preanalytic phase evaluation in pathology laboratories: a comprehensive study including immunohistochemistry, DNA, and mRNA assays. Pathol Int 2014; 64: 209-215.
61.
Polley MY, Leung SC, Gao D, et al. An international study to increase concordance in Ki67 scoring. Mod Pathol 2015; 28: 778-786.
62.
Denkert C, Budczies J, von Minckwitz G, et al. Strategies for developing Ki67 as a useful biomarker in breast cancer. Breast 2015; 24 Suppl 2: S67-S72.
63.
Vörös A, Csörgő E, Nyári T, et al. An intra- and interobserver reproducibility analysis of the Ki-67 proliferation marker assessment on core biopsies of breast cancer patients and its potential clinical implications. Pathobiology 2013; 80: 111-118.
64.
Coates AS, Winer EP, Goldhirsch A, et al. Tailoring therapies – improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol 2015; 26: 1533-1546.
65.
Garcia-Carbonero R, Sorbye H, Baudin E, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology 2016; 103: 186-194.
66.
Pezzilli R, Partelli S, Cannizzaro R, et al. Ki-67 prognostic and therapeutic decision driven marker for pancreatic neuroendocrine neoplasms (PNENs): A systematic review. Adv Med Sci 2016; 61: 147-153.
67.
Panzuto F, Boninsegna L, Fazio N, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol 2011; 29: 2372-2377.
68.
La Rosa S, Klersy C, Uccella S, et al. Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors. Hum Pathol 2009; 40: 30-40.
69.
Pape UF, Jann H, Müller-Nordhorn J, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 2008; 113: 256-255.
70.
Öberg 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 Suppl 7: vii124-vii130.
71.
O’Toole D, Couvelard A, Rebours V, et al. Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors. Endocr Relat Cancer 2010; 17: 847-856.
72.
Singla S, LeVea CM, Pokuri VK, et al. Ki67 score as a potential predictor in the selection of liver-directed therapies for metastatic neuroendocrine tumors: a single institutional experience. J Gastrointest Oncol 2016; 7: 441-448.
73.
Gudlaugsson E, Skaland I, Janssen EA, et al. Comparison of the effect of different techniques for measurement of Ki67 proliferation on reproducibility and prognosis prediction accuracy in breast cancer. Histopathology 2012; 61: 1134-1144.
74.
Plancoulaine B, Laurinaviciene A, Herlin P, et al. A methodology for comprehensive breast cancer Ki67 labeling index with intra-tumor heterogeneity appraisal based on hexagonal tiling of digital image analysis data. Virchows Arch 2016; DOI: 10.1007/s00428-015-1865-x.
75.
Mikami Y, Ueno T, Yoshimura K, et al. Interobserver concordance of Ki67 labeling index in breast cancer: Japan Breast Cancer Research Group Ki67 ring study. Cancer Sci 2013; 104: 1539-1543.
76.
Lopez XM, Debeir O, Maris C, et al. Clustering methods applied in the detection of Ki67 hot-spots in whole tumor slide images: an efficient way to characterize heterogeneous tissue-based biomarkers. Cytometry A 2012; 81: 765-775.
77.
Khan Niazi MK, Yearsley MM, Zhou X, et al. Perceptual clustering for automatic hotspot detection from Ki-67-stained neuroendocrine tumour images. J Microsc 2014; 256: 213-225.
78.
Christgen M, von Ahsen S, Christgen H, et al. The region-of-interest size impacts on Ki67 quantification by computer-assisted image analysis in breast cancer. Hum Pathol 2015; 46: 1341-1349.
79.
Lu H, Papathomas TG, van Zessen D, et al. Automated Selection of Hotspots (ASH): enhanced automated segmentation and adaptive step finding for Ki67 hotspot detection in adrenal cortical cancer. Diagnostic Pathology 2014; 9: 216.
80.
Świderska Z, Korzyńska A, Markiewicz T, et al. Comparison of the manual, semiautomatic, and automatic selection and leveling of hot spots in whole slide images for Ki-67 quantification in meningiomas. Anal Cell Pathol (Amst) 2015; 2015: 498746.
81.
Couvelard A. Neuroendocrine tumours of the pancreas: recent developments in staging and grading. Diagn Histopathol 2011; 18: 1.
82.
Coriat R, Walter T, Terris B, et al. Gastroenteropancreatic well-differentiated grade 3 neuroendocrine tumors: review and position statement. Oncologist 2016; 21: 1191-1199.
83.
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 2014; 465: 49-55.
84.
Focke CM, Decker T, van Diest PJ. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours. Histopathology 2016; 69: 849-861.
85.
Voss SM, Riley MP, Lokhandwala PM, et al. Mitotic count by phosphohistone H3 immunohistochemical staining predicts survival and improves interobserver reproducibility in well-differentiated neuroendocrine tumors of the pancreas. Am J Surg Pathol 2015; 39: 13-24.
86.
Cserni G, Vörös A, Liepniece-Karele I, et al. Distribution pattern of the Ki67 labelling index in breast cancer and its implications for choosing cut-off values. Breast 2014; 23: 259-263.
87.
Vörös A, Csörgő E, Kővári B, et al. Different methods of pretreatment Ki-67 labeling index evaluation in core biopsies of breast cancer patients treated with neoadjuvant chemotherapy and their relation to response to therapy. Pathol Oncol Res 2015; 21: 147-155.
88.
Klimstra DS. Pathology reporting of neuroendocrine tumors: essential elements for accurate diagnosis, classification, and staging. Semin Oncol 2013; 40: 23-36.
Share
RELATED ARTICLE
| eISSN: | 2084-9869 |
| ISSN: | 1233-9687 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
