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Neuroendocrine Neoplasms of the Pancreas: the Pathological Viewpoint

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Neuroendocrine Neoplasms of the Pancreas: the Pathological Viewpoint JOP. J Pancreas (Online) 2018 Dec 31; S(3):328-334. REVIEW ARTICLE PANCREATIC NEUROENDOCRINE TUMORS Neuroendocrine Neoplasms of the Pancreas: The Pathological Viewpoint Noriyoshi Fukushima Department of Diagnostic Pathology, Jichi Medical University Hospital, Tochigi, Japan ABSTRACT Neuroendocrine neoplasms of the pancreas are relatively rare, accounting for approximately 1–2% of all pancreatic neoplasms, and are composed of epithelial neoplastic cells with neuroendocrine differentiation. Neuroendocrine neoplasms are potentially malignant neoplasms including well-differentiated types (neuroendocrine tumors, neuroendocrine tumors) and poorly differentiated types neoplasms of the digestive system. “Endocrine neoplasm” was changed to “neuroendocrine neoplasm”. Neuroendocrine neoplasms are (neuroendocrine carcinomas). The WHO classification released in 2010 led to a significant change in the grading system of neuroendocrine graded according to the number of mitoses and/or Ki-67 index. These changes simplified the classification scheme. However, there are a number of remaining issues. Neuroendocrine tumors meeting the WHO criteria for neuroendocrine carcinoma (>20 mitoses/10 high (gradepower fields3) neuroendocrine and/or Ki67 neoplasms,index > 20%) they with are a divided well-differentiated into pancreatic morphology, neuroendocrine known tumors, as an “organoid grade 3 (PanNET pattern” G3) have and been neuroendocrine identified. In carcinomas,the revised version grade 3of (PanNEC the “WHO G3) Classification depending ofon Tumours their histo-morphologic of Endocrine Organs” characteristics. published inThe 2017, neuroendocrine to solve the problems tumor G3 of categoryhigh-grade is using a combination of tumor morphology and cell proliferation is important. Better strategies to treat and improve the outcomes of patientsassociated with with pancreatic a better prognosis neuroendocrine and does neoplasms not significantly are required. responds to cisplatin-based chemotherapy. Defining that subgroup of patients INTRODUCTION pancreatic NENs tend to be diagnosed at more advanced Neuroendocrine neoplasms (NENs) of the pancreas are stages4]. Because of disease of lacking compared specific with symptoms, functional non-functional pancreatic composed of epithelial neoplastic cells with phenotypic neuroendocrine differentiation. NENs are potentially 1–2% of patients with these tumors have predisposing malignant tumors including well-differentiated types familialNENs such syndromes. as insulinoma However, and gastrinoma. patients with Approximately NEC tend (neuroendocrine tumors, NETs) and poorly differentiated to be older, similar to patients with pancreatic ductal types (neuroendocrine carcinomas, NECs) [1]. These adenocarcinoma. tumors are relatively rare, but are the second most common neoplasm of the pancreas, accounting for approximately 1–2% of all pancreatic neoplasms [1, 2]. The incidence of In addition to a physical examination, imaging studies including US, CT and MRI are useful to diagnose as NEN. NETs of the pancreas has increased recently [3, 4]. pathologicalIn addition, thediagnosis endoscopic and ultrasonography-guidedsuitable treatment for fine-the and grading system of the pancreatic NEN are described. tumors.needle aspiration (EUS-FNA) biopsy has enabled correct In this short review updated clinicopathological features Patients’ Characteristics and Clinical Diagnosis Histologic Grading and Classification Patients with NETs are typically from 30 to 60 years The WHO tumor classification of endocrine organs [5] old, and show no significant gender predilection [1, 2, 3, NETs and well- and poorly differentiated neuroendocrine published in 2004 divided NENs into well-differentiated into benign and borderline tumors according to tumor Keywords carcinoma (NEC), and the former NETs were sub-classified PancreasReceived October 11th, 2017 - Accepted November 15th, 2017 size, mitotic rate, lymphovascular invasion and perineural Abbreviations Carcinoma; NEC neuroendocrine Classification; carcinoma;Neuroendocrine NENs Tumors;neuroendocrine neoplasms; NET neuroendocrine tumors Correspondence neoplasmsinvasion [5]. of The the 2010 digestive WHO system. classification “Endocrine included neoplasm” several Department of Diagnostic Pathology, Jichi Medical University Noriyoshi Hospital, Fukushima wasmajor changed changes to in “neuroendocrinethe grading system neoplasm”, of neuroendocrine NENs are now graded according to the number of mitoses and/or Tel3311-1 Yakushiji, Shimotsuke, FaxTochigi 329-0498, Japan system is applied to NENs arising in any organ of the E-mail +81 285587330 digestiveKi-67 index system (using [1]. the These MIB1 changesantibody), were and based this gradingon the +81 285448467 [email protected] JOP. Journal of the Pancreas - http://pancreas.imedpub.com/ - Special Issue No. 3 – Dec 2018. [ISSN 1590-8577] 328 JOP. J Pancreas (Online) 2018 Dec 31; S(3):328-334. predictors of response to platinum-based chemotherapy for NEN G3 tumors, and Rb for PanNEC (G3) [8]. dividedEuropian into Neuroendocrine well-differentiated Tumor NETs (NET Society G1 and (ENETS) G2) and consensus guideline [6]. In this classification, NENs were The Japanese classification of pancreatic cancer, 7th poorly differentiated NEC. NET G1 was defined as having a edition, was released by Japan Pancreas Society (JPS) in Ki 67 index of ≤2% and <2 mitoses/10 high power fields July 2016 and English version of it was in 2017 [11]. In this (HPF). NET G2 was defined as a Ki-67 index of 3 to 20% or concerning to so-called “NET G3-issue” they commented book, 2010 WHO grading system of NENs was adopted and 2 to 20 mitoses/10HPFs. NEC was defined as a Ki-67 index on it as “… some NETs with organoid structures may also of >20% and >20 mitoses/10HPFs. The WHO recommends demonstrate a high proliferative potential (Ki67 index bethat counted for mitotic in tumor counts, hot at spots. least 50For HPFs grade-discordant should be counted, cases and for Ki-67 index, a minimum of 500 tumor cells should called well differentiated NECs or NET G3.” (based on differences in mitotic count and Ki-67 index), >20%, mitotic count >20 per HPF). These are sometimes the higher grade should be used. ENETS first proposed a staging system for NETs, and however several issues remain. NECs of the pancreas are this was accepted in the 7th edition of the American Joint These changes simplified the classification scheme, Committee on Cancer (AJCC)/ Union for International meeting the WHO criteria for NEC (described above) Cancer Control (UICC) TNM staging manual [12]. Recently withdefined a well-differentiated by cell proliferation morphology criteria only, and however an “organoid NENs colonrevised and AJCC/UICC rectum [13]. system divided it each organ such as stomach, duodenum/ampullary, jejunum/ileum, appendix, components of a well differentiated NET with a low proliferativepattern” have rate, been and identified are admixed [7, 8]. Otherwith alesions high-grade have NEN within the specimen from the same patient. These Unlike in the case of digestive organ, the ENETS cases have been interpreted as high-grade progression recommendations and WHO 2015 classifications of lung of a well differentiated NEN [9]. Heterogeneity within the carcinoid,and thymus atypical NENs takecarcinoid into account(that would the gradecorrespond of necrosis to NET in addition to Ki-67, and define three distinct subgroups: typical neoplasm should be noted, especially in FNA samples. The G1Gross and G2,Findings respectively) and large- and small-cell NECs [14]. graderevised NENs version into neuroendocrineof the “WHO Classification tumor, Grade of 3 Tumours(PanNET Grossly, NETs (well-differentiated NENs) are usually G3)of Endocrine and neuroendocrine Organs”, published carcinomas, in 2017, Grade divided 3 (PanNEC high G3) according to their histo-morphologic characteristics homogeneous soft tumors, however they may be hard (Table 1) (sclerotic)solitary, well with circumscribed, gray-white nodules tan to (Figure pink, and1a), yellowishrelatively nodules (Figure 1b) or cystic tumors. NECs (poorly [10]. Tumors in the NET G3 category are associated differentiated NENs) are usually tan-red or yellowish, solid with a better prognosis and do not significantly respond to Tablecisplatin-based 1. chemotherapy. Rb and KRAS are promising 2004 2010 2017 WHO classification and grading of pancreatic neuroendocrine neoplasms. Neuriendocrine tumor (NET) G1 Well-differentiated endocrine tumor PanNETs (carcinoid) PanNETWell-differentiated G1 PanNENs: Benign' behavior ≤2% Ki-67* Confined to the pancreas, non-angioinvasive, <2 mitoses/10HPF, <2 mitoses/10HPFx, <3% Ki-67 no Uncertain perineural behavior invasion, <2 cm in diameter, <2 mitoses/10HPF and <2% Ki-67 positive cells Neuriendocrine tumor (NET) G2 PanNET G2 ≥2 cm in diameter, Confined to the pancreas and one or more of the following features: angioinvasion, perineural invasion. 2-20 mitoses/10HPF, 3-20% Ki-67 2-20 mitoses/10HPF, 3-20% Ki-67 Well-differentiated2-10 mitoses/10 HPF, endocrine >2% Ki-67positive carcinoma cells, PanNET G3 Low grade malignant Gross local invasion and/or metastases Poorly-differentiated endocrine carcinoma Neuroendocrine carcinoma (NEC) >20 mitoses/10HPF, >20% Ki-67 PanNECs ≥ Poorly differentiated PanNENs: High grade malignant • • 20 mitoses/10HPF,Large cell neuroendocrine >20% Ki-67 carcinoma positive cells Large>20 mitoses/10HPF, cell type >20% Ki-67 Small cell neuroendocrine carcinoma MixedSmall cell neuroendocrine-non-neuroendocrine
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