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JOP. J Pancreas (Online) 2018 Dec 31; S(3):328-334.

REVIEW ARTICLE PANCREATIC NEUROENDOCRINE TUMORS

Neuroendocrine of the Pancreas: The Pathological Viewpoint

Noriyoshi Fukushima

Department of Diagnostic , 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 ” was changed to “neuroendocrine neoplasm”. Neuroendocrine neoplasms are (neuroendocrine ). The WHO classification released in 2010 led to a significant change in the 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 (>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 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 -based . 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 However, and . 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 . 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) 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 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 “neuroendocrine the 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 of the E-mail +81 285587330 digestiveKi-67 index system (using [1]. the These MIB1 changes antibody), 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 Neuroendocrinewell-differentiated Tumor NETs (NET Society G1 and (ENETS) G2) and consensus guideline [6]. In this classification, NENs were The Japanese classification of pancreatic , 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 a lesions 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 ,and 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 neuroendocrine of 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), yellowish relatively 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 cisplatin-basedTable 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 type Mixed>10 mitoses/ exocrine-endocrine 10 HPF carcinoma neoplasm(MiNEN) Mixed adenoneuroendocrine carcinoma(MANEC)

PanNEN pancreatic neuroendocrine neoplasm; PanNET pancreatic *Ki-67 proliferation index is based on the evaluation of ≥ 500 (Ki-67cells in orareas mitotic) of higher places nuclear the tumour labelling in the(so-called highest hotspots). grade category. The mitotic For assessing index is basedKi-67, on casual the evaluation visual estimation of mitoses (eyeballing) in 50 high-power is not recommended; fields (HPF; 0.2 manual mm2 countingeach) in areas using of printed higher images density, is and advocated. is expressed as mitoses per 10 high-power fields (2.0 mm2). The final grade is determined based on whichever index

JOP. Journal of the Pancreas - http://pancreas.imedpub.com/ - Special Issue No. 3 – Dec 2018. [ISSN 1590-8577] 329 JOP. J Pancreas (Online) 2018 Dec 31; S(3):328-334. masses and frequently have hemorrhagic and/or necrotic and are composed of monotonous epithelial cells with a areas. fair amount of cytoplasm and regular round nuclei with a so-called “salt and pepper” appearance (Figures 2a and 2b) Well-Differentiated and Low Grade NENs (Nets G1 and G2) HPF. Most(Figure tumors 2c). haveVascular rich invasionvascular networks.is often found, NETs even in this in thesecategory low have grade a tumorsKi-67 index of ≤20%. and ≤20 mitoses/10 Well-differentiated NENs usually have an organoid (Figure 2d) architecture including solid nests, trabeculae, ribbon-like, Several functioning NETs show characteristic histologic glandular, acinar, and rosette formations, lacking necrosis, findings [2]. Stromal amyloid deposition is frequently seen a b

Figure 1. Macroscopic features of pancreatic neuroendocrine tumors (NETs). (a). Gray-white and well-demarcated . (b). The tumor is yellowish with a well-demarcated border. a b

a

c d

Figure 2. Histologic features of pancreatic neuroendocrine tumors (NETs). (a). The tumor has a so-called “organoid structure” including ribbon- (b). (c). Ki-67 (WHO NET G2). (d). Vascular invasion. like and pseudo- rosette patterns. The tumor has a so-called “organoid structure” including trabeculae with a thin vascular network.

JOP. Journal of the Pancreas - http://pancreas.imedpub.com/ - Special Issue No. 3 – Dec 2018. [ISSN 1590-8577]

330 JOP. J Pancreas (Online) 2018 Dec 31; S(3):328-334. in . Glandular formation with psammomatous are neoplastic glandular components of NETs or entrapped tumors (Figure 3a) components have apparent histologic atypia, mixed calcification is sometimes noted in somatostatin-producing(Figure 3b). ductal-neuroendocrineproliferating non-neoplastic carcinoma ductules. should If be the considered. ductular These NETs are often. Approximatelyserotonin positive 10% and of sometimes NETs are However these are exceedingly uncommon [19]. showaccompanied duct involvement. with dense stromal fibrosis Well-Differentiated and High Grade NENs, (NET G3) There are also many histo-morphologic variants Pancreatic NET G3 lesions are defined by a Ki- including clear cell/lipid rich, oncocytic, pleomorphic, rhabdoid, glandular, and others. NETs with morphologically abundant clear cytoplasm (“lipid-rich”) (Figure 3c), described67 proliferation above (Figures index >20% 4a and and/or 4b) a mitotic index grossly mimic adrenal cortical neoplasms, and are seen limit>20/10HPF for the andproliferation also have index organoid has not structuresbeen defined, as [10]. The upper sporadic cases have also been reported [16]. “Pigmented especially in patients with VHL syndrome [15], but Rbhowever is observed. the Ki-67 Due index to their is usually morphological less than 55%.similarity, Only of intracytoplasmic lipofuscin and mimic metastatic itlow is immunohistochemicalnecessary to differentiate expression them offrom p53 acinar or loss cell of melanomablack” pancreatic [17]. Oncocytic neuroendocrine NETs are tumors characterized are composed by cells carcinomas by immunohistochemistry (Figures 4c and with abundant granular eosinophilic cytoplasm because 4d). of accumulation of mitochondria (Figure 3d) [18]. Poorly Differentiated and High Grade NENs (NEC G3) possibilitySome NETs of show being markedundifferentiated nuclear atypia/pleomorphismcarcinomas or poorly differentiatedthroughout the ductal tumor. carcinomas, Although theseno elevated NETs have mitotic the Poorly differentiated NECs (NEC G3) are defined by a Ki-67 proliferation index >20% and/or a mitotic index abundant ductal components with obvious benign cytology >20/10HPF with no differentiated morphology (organoid rate or aggressive biology is seen [19]. Some NETs have similarstructures) morphology [10]. NECs with G3 small are divided cell carcinoma into small of thecell lung,NEC and large cell NEC. Small cell NEC of the pancreas share a [2, 19]. It is sometimes debatable whether those ductules a b

a

c d

Figure 3. Histologic variants of pancreatic neuroendocrine tumors (NETs). (a). (b). Pancreatic NET (c). Clear cell pancreatic NET. (d). Oncocytic pancreatic NET. Glandular formation with psammomatous calcification. with dense stromal fibrosis.

JOP. Journal of the Pancreas - http://pancreas.imedpub.com/ - Special Issue No. 3 – Dec 2018. [ISSN 1590-8577] 331 JOP. J Pancreas (Online) 2018 Dec 31; S(3):328-334.

a b

c d

Figure 4. Histologic features of pancreatic neuroendocrine tumors (NETs)(WHO PanNET G3). (a). (b). (c). (d). Tumor cells are diffusely positive for . The tumor has a glandular or acinar-like structure. Ki-67 immunohistochemistry (>20%/HPF). Tumor cells are partially positive for .

Figure 5. Histologic features of pancreatic neuroendocrine carcinoma (NEC)(WHO PanNEC G3). and it is important to rule out metastases to the pancreas IMMUNOHISTOCHEMISTRY before establishing the diagnosis. NEC G3 tumors typically Diagnostic Markers have sheets or nests of carcinoma cells with pleomorphic,

(Figure 5). The so-called "salt and pepper" chromatin of cytoplasmic neuroendocrine granules, and the patternhyperchromatic is lost. Necrosis nuclei andis often abundant present mitotic in these figures solid Well differentiated-NENs are defined by the existence nests. Mixed tumors with exocrine differentiation are tocurrently show stronger accepted and reliable more markersdiffuse are synaptophysin with these endocrine carcinomas. and chromogranin A. Well-differentiated NENs tend aggressive lesions that behave more like exocrine than neuroendocrine markers than poorly differentiated NENs. JOP. Journal of the Pancreas - http://pancreas.imedpub.com/ - Special Issue No. 3 – Dec 2018. [ISSN 1590-8577] 332 JOP. J Pancreas (Online) 2018 Dec 31; S(3):328-334.

CD56 antibody, against neural cell adhesion molecules, is Solid pseudopapillary neoplasms (SPNs), showing solid less specific as a neuroendocrine marker. stainingsheet-like, of nestbeta-catenin and sometimes is very auseful rosette-like to diagnose appearance, it as a also resemble NETs. Immunohistochemical nuclear immunohistochemically,Approximately 45% of sporadicwhich wellcorrelates differentiated- with NENs show loss of expression of DAXX and ATRX carcinoma may be challenging. SPN. Distinguishing from a mixed acinar-neuroendocrine thatmutations the patient in the has DAXXclinical andsymptoms, ATRX and the [20,opposite 21]. most frequent tumors to metastasize only to the pancreas, situationImmunohistochemically may occur, probably detected due to peptides the rapid do release not imply and resembleMetastatic the clear cell carcinomas,or lipid-rich knownvariant as of oneNET. of Thethe dispersal of the hormone product without intracytoplasmic oncocytic variant of NET may resemble hepatocellular accumulation [2]. carcinoma. Prognostic or Therapy Related Markers Prognosis

curative treatment for low grade NETs (NET G1 or G2). The mitotic count and the Ki-67/MIB-1-labeling Surgical complete resection of the tumor is an only ofindex ductal are theepithelial most reliable cells and prognostic is expressed markers not for only NENs. by metastasize to the liver. Recently, several treatment options poorlyCytokeratin differentiated 19 (CK 19)but isalso usually by well-differentiated regarded as a marker NENs. inIf untreated,the setting mostof metastatic pancreatic disease NETs have grow been and developed, eventually which include systemic treatment with somatostatin

Several studies reported that CK 19 is a marker of more radiotargeted therapy (PRRT), cytotoxic chemotherapy or aggressive behavior [22, 23, 24]. c-Kit has also reported molecularanalogs (SSAs), target agents interferon-α such as (INF-α), everolimus peptide and sunitinib receptor as a worse prognostic marker [22, 24]. There are several hepatocyteother prognostic growth markers factor which receptors were (HGFR),previously E-cadherin, reported such as CD99, CD44, p27, epidermal growth factor (EGF), [30,Most 31]. PNETs are indolent but have malignant potential.

CEACAM1, HER-2 and c-MET. However, they have not been Overall 10-year survival of the patients with low grade validated in clinical use [22, 25, 26, 27, 28]. NENs (NET G1 or G2) is 60-70%, and with both low grade hormone.Somatostatin, The expressionwhich binds ofto asomatostatin family of five G--receptors NEC(G1) G3 and is 61%, low stage 22%, (T1N0M0)and 17%, respectively is more than [19]. 95% [19]. coupled receptors, was identified as an important inhibitory Overall 5-year survival of the patients with NET G2, G3 and and immunocytochemistry, led to the application of this CONCLUSION inhibitor(SSTRs) inin the NETs, treatment as shown of patients by octreotide with NETs scintigraphy [29]. The development of long-acting somatostatin analogs allowed for clinical use because the native somatostatin has a very pancreaticThe WHO NENs. classification However, a published number of in issues 2010 remain. had a significant impact on the classification and grading of short half-life of only 2 minutes. SSTR2 is expressed by most cellThe revisedproliferation version and of themorphology. WHO classification Better strategies, published pancreatic NETs and shows high affinity for somatostatin dependingin 2017 proposedon appropriate grading pathological criteria evaluation, based on to treat both analogs. It has been used as a target for molecular imaging and improve the outcomes of the patients with pancreatic and treatment of NETs [29]. Immunohistochemistry for NENs are required. SSTR2ADifferential is widely Diagnosis performed. The histologic differential diagnosis of pancreatic NETs includes pancreatic neoplasms showing solid or diffuse Acknowledgements cellular proliferation as well as metastatic neoplasms. Furthermore, it is not always easy to distinguish a NET Medical Education, Jichi Medical University, for comments G3 from NEC G3 tumors by morphology only. Tang et al. thatWe greatly thank improved Professor the Alan manuscript. Lefor, The Center for Graduate proposed a diagnostic algorithm for high-grade NENs using a combination of histology and immunohistochemistry for Conflict of Interest

DAXX/ATRX, Rb and p53 [5]. All authors declare having no conflict of interests. macroscopicIn primary andpancreatic microscopic neoplasms, morphology acinar cell carcinomaresembles References (ACC) should first be ruled out because their radiologic/ 1.

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