|
1
|
Rokutan H, Fukasawa-Hokazono M, Hokazono Y, Ushiku T. Mixed adenoma-neuroendocrine tumor of the stomach: analysis of nine cases with literature review. Virchows Arch 2025; 486:521-530. [PMID: 38922356 PMCID: PMC11950016 DOI: 10.1007/s00428-024-03851-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 06/13/2024] [Accepted: 06/14/2024] [Indexed: 06/27/2024]
Abstract
Mixed adenoma-neuroendocrine tumor (MANET) comprises adenoma and well-differentiated neuroendocrine tumor (NET) components. Given the limited information on this due to its rarity, we aimed to clarify the clinicopathologic features and optimal management of gastric MANETs in a case series and literature review. Nine patients with gastric MANETs, including eight male and one female patient (mean age, 72 years), were identified from the institutional pathology archive. Endoscopically, the tumors appeared as flat elevated lesions with sizes ranging from 0.8 to 4.4 cm. One patient had familial adenomatous polyposis, and no patient had autoimmune gastritis. All MANETs developed in the gastric body mucosa exhibiting chronic metaplastic atrophic gastritis. The glandular components were intestinal-type low-grade adenoma, and focal high-grade dysplasia was also recognized in three cases. The NET component was in middle/deep lamina propria in six cases and confined to deep lamina propria in the remaining three cases. Minimal cytologic atypia was found in the NET component, with no recognizable mitosis and a Ki-67 labeling index of < 2%. The NET component mostly showed diffuse positivity for serotonin and CDX2, suggesting that it consists of enterochromaffin cells. Diffuse p53 immunostaining was observed only in the high-grade adenomatous component of one case. No recurrence was observed during the follow-up period of 2-94 months. Correct distinction between the NET and poorly differentiated carcinoma components is crucial to prevent overtreatment of gastric MANETs. Considering its indolent nature, endoscopic resection is the primary recommendation for gastric MANETs as well as for pure adenomas.
Collapse
Affiliation(s)
- Hirofumi Rokutan
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Miyako Fukasawa-Hokazono
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
- Department of Pathology, Yaizu City Hospital, Shizuoka, Japan
| | - Yukio Hokazono
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan.
| |
Collapse
|
|
2
|
Liu Y, Esnakula AK, Jain S, Lin J, Panarelli N, Pyatibrat S, Karamchandani DM. Spectra of well-differentiated neuroendocrine lesions in the extrahepatic biliary system: a case series. Histopathology 2025; 86:285-293. [PMID: 39267205 DOI: 10.1111/his.15316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/14/2024]
Abstract
AIMS Neuroendocrine tumours (NETs) occurring in the extrahepatic biliary system are exceedingly rare. While NETs typically manifest as mass lesions, the occurrence of microscopic neuroendocrine cell proliferation without a distinct mass remains undocumented at this location. This study aims to characterise the clinicopathological features of a series of well-differentiated neuroendocrine lesions involving the extrahepatic biliary tree, including mass forming NETs and microscopic non-mass-forming neuroendocrine cell proliferation, designated neuroendocrine cell micronests (NCMs). METHODS AND RESULTS Surgical resections of NETs/NCMs involving the extrahepatic bile ducts and gallbladder were identified from electronic pathology databases among seven institutions spanning from January 2011 to September 2023. Clinical and histological findings were recorded. Ten patients (four female, six male: age range = 34-75 years) were included in the study. Histopathological examination revealed visible mass-forming lesions in four cases (1.6-14.0 cm in size), identified in the gallbladder (n = two) or extrahepatic bile duct (n = two), all diagnosed as well-differentiated NETs. The remaining six cases revealed incidental non-mass-forming NCMs in either the cystic duct (n = two), common bile duct (n = three) or gallbladder (n = one), ranging from < 0.1 to 0.4 cm; four were associated with biliary lithiasis. No evidence of metastasis or recurrence was seen in the follow-up period (range = 0.1-11.2 years). CONCLUSIONS This study highlights the spectrum of extrahepatic biliary well-differentiated neuroendocrine lesions, ranging from incidental microscopic NCMs to grossly apparent mass-forming NETs, potentially requiring different clinical management. Noteworthy is the frequent association of incidental microscopic neuroendocrine cell proliferations with biliary lithiasis, indicating a potential neuroendocrine metaplastic pathogenesis that merits further exploration.
Collapse
Affiliation(s)
- Yongjun Liu
- Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, WA, USA
| | - Ashwini K Esnakula
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Shilpa Jain
- Department of Pathology, Baylor College of Medicine, Houston, TX, USA
| | - Jingmei Lin
- Department of Pathology and Laboratory Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA
| | - Nicole Panarelli
- Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, USA
| | - Sergey Pyatibrat
- Department of Pathology and Laboratory Medicine, Royal Columbian Hospital, University of British Columbia, New Westminster, BC, Canada
| | | |
Collapse
|
|
3
|
Carr HS, Zuo Y, Frost JA. The Wnt pathway protein Dvl1 targets somatostatin receptor 2 for lysosome-dependent degradation. J Biol Chem 2023; 299:104645. [PMID: 36965619 PMCID: PMC10164914 DOI: 10.1016/j.jbc.2023.104645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 03/15/2023] [Accepted: 03/16/2023] [Indexed: 03/27/2023] Open
Abstract
The Somatostatin receptor 2 (Sstr2) is a heterotrimeric G protein-coupled receptor that is highly expressed in neuroendocrine tumors and is a common pharmacological target for intervention. Unfortunately, not all neuroendocrine tumors express Sstr2, and Sstr2 expression can be downregulated with prolonged agonist use. Sstr2 is rapidly internalized following agonist stimulation and, in the short term, is quantitatively recycled back to the plasma membrane. However, mechanisms controlling steady state expression of Sstr2 in the absence of agonist are less well described. Here, we show that Sstr2 interacts with the Wnt pathway protein Dvl1 in a ligand-independent manner to target Sstr2 for lysosomal degradation. Interaction of Sstr2 with Dvl1 does not affect receptor internalization, recycling, or signaling to adenylyl cyclase but does suppress agonist-stimulated ERK1/2 activation. Importantly, Dvl1-dependent degradation of Sstr2 can be stimulated by overexpression of Wnts and treatment of cells with Wnt pathway inhibitors can boost Sstr2 expression in neuroendocrine tumor cells. Taken together, this study identifies for the first time a mechanism that targets Sstr2 for lysosomal degradation that is independent of Sstr2 agonist and can be potentiated by Wnt ligand. Intervention in this signaling mechanism has the potential to elevate Sstr2 expression in neuroendocrine tumors and enhance Sstr2-directed therapies.
Collapse
Affiliation(s)
- Heather S Carr
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, USA
| | - Yan Zuo
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, USA
| | - Jeffrey A Frost
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, USA.
| |
Collapse
|
|
4
|
Fu ZY, Kmeid M, Aldyab M, Lagana SM, Lee H. Composite intestinal adenoma-microcarcinoid: An update and literature review. World J Gastrointest Endosc 2021; 13:593-606. [PMID: 35070021 PMCID: PMC8716980 DOI: 10.4253/wjge.v13.i12.593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 10/19/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
Composite intestinal adenoma-microcarcinoid (CIAM) is a rare intestinal lesion consisting of conventional adenoma and small, well differentiated carcinoid [microcarcinoid (MC)] at its base. The incidence of CIAM is 3.8% in surgically resected colorectal polyps. While its pathogenesis is unknown, studies support the role of Wnt/β-catenin pathway in the tumorigenesis of CIAM. CIAMs have been primarily reported in the colon wherein they present as polyps with well-defined margins, similar to conventional adenomatous polyps. MC is usually found in adenomatous polyps with high-risk features such as large size, villous architecture, or high grade dysplasia. Histologically, the MC component is often multifocal and spans 3.9 to 5.8 millimeters in size. MC is usually confined within the mucosa but occasional CIAM cases with MC extending to the submucosa have been reported. MC of CIAM demonstrates bland cytology and inconspicuous proliferative activity. The lesional cells are positive for synaptophysin and 60% to 100% of cases show nuclear β-catenin positivity. MC poses a diagnostic challenge with its morphologic and immunohistochemical resemblance to both benign and malignant lesions, including squamous morules/metaplasia, adenocarcinoma, squamous cell carcinoma, sporadic neuroendocrine tumor and goblet cell adenocarcinoma. CIAM is an indolent lesion with a favorable outcome. Complete removal by polypectomy is considered curative. Awareness and recognition of this rare entity will help arrive at correct diagnosis and improve patient care. Currently, CIAM is not recognized as a subtype of mixed neuroendocrine-non-neuroendocrine neoplasm by WHO.
Collapse
Affiliation(s)
- Zhi-Yan Fu
- Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, United States
| | - Michel Kmeid
- Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, United States
| | - Mahmoud Aldyab
- Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, United States
| | - Stephen M Lagana
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, United States
| | - Hwajeong Lee
- Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, United States
| |
Collapse
|
|
5
|
Dabir PD, van der Post RS, Nagtegaal ID. Incidental morphological findings in colorectal adenomas. Histopathology 2020; 78:348-357. [PMID: 32981102 PMCID: PMC7894322 DOI: 10.1111/his.14263] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/01/2020] [Accepted: 09/21/2020] [Indexed: 12/14/2022]
Abstract
Owing to a sharp increase in the frequency of diagnosis of colorectal adenomas in the current era of population screening, distinctive morphological features are increasingly being observed. These may present diagnostic challenges and cause clinical management issues. Paneth cell metaplasia is a more common occurrence, but the incidence rates of squamous metaplasia, clear cell metaplasia, osseous metaplasia, neuroendocrine differentiation and signet‐ring cell‐like lesion are low, and they can be seen in <1% of colorectal adenomas. Their histomorphological characteristics are quite unique; ancillary studies are not very helpful and often not needed. In this review, we give an overview and describe the potential clinical consequences of such incidental and special morphological findings in colorectal adenomas.
Collapse
Affiliation(s)
- Parag D Dabir
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.,Institute of Pathology, Randers Regional Hospital, Randers, Denmark
| | - Rachel S van der Post
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| |
Collapse
|
|
6
|
Kanthan R, Tharmaradinam S, Asif T, Ahmed S, Kanthan SC. Mixed epithelial endocrine neoplasms of the colon and rectum - An evolution over time: A systematic review. World J Gastroenterol 2020; 26:5181-5206. [PMID: 32982118 PMCID: PMC7495040 DOI: 10.3748/wjg.v26.i34.5181] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/18/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mixed tumors of the colon and rectum, composed of a combination of epithelial and endocrine elements of benign and malignant potential are rare neoplasms. These can occur anywhere in the gastrointestinal tract and are often diagnosed incidentally. Though they have been a well-documented entity in the pancreas, where the exocrine-endocrine mixed tumors have been known for a while, recognition and accurate diagnosis of these tumors in the colon and rectum, to date, remains a challenge. This is further compounded by the different terminologies that have been attributed to these lesions over the years adding to increased confusion and misclassification. Therefore, dedicated literature reviews of these lesions in the colon and rectum are inconsistent and are predominantly limited to case reports and case series of limited case numbers. Though, most of these tumors are high grade and of advanced stage, intermediate and low grade lesions of these mixed tumors are also increasingly been reported. There are no established independent consensus based guidelines for the therapeutic patient management of these unique lesions. AIM To provide a comprehensive targeted literature review of these complex mixed tumors in the colon and rectum that chronicles the evolution over time with summarization of historical perspectives of terminology and to further our understanding regarding their pathogenesis including genomic landscape, clinicoradiological features, pathology, treatment, prognosis, the current status of the management of the primary lesions, their recurrences and metastases. METHODS A comprehensive review of the published English literature was conducted using the search engines PubMed, MEDLINE and GOOGLE scholar. The following search terms ["mixed tumors colon" OR mixed endocrine/neuroendocrine tumor/neoplasm/lesion colon OR adenocarcinoma and endocrine/neuroendocrine tumor colon OR mixed adenocarcinoma and endocrine/neuroendocrine carcinoma colon OR Amphicrine tumors OR Collision tumors] were used. Eligibility criteria were defined and all potential relevant items, including full articles and/or abstracts were independently reviewed, assessed and agreed upon items were selected for in-depth analysis. RESULTS In total 237 full articles/abstracts documents were considered for eligibility of which 45 articles were illegible resulting in a total of 192 articles that were assessed for eligibility of which 139 have been selected for reference in this current review. This seminal manuscript is a one stop article that provides a detailed outlook on the evolution over time with summarization of historical perspectives, nomenclature, clinicoradiological features, pathology, treatment, prognosis and the current status of the management of both the primary lesions, their recurrences and metastases. Gaps in knowledge have also been identified and discussed. An important outcome of this manuscript is the justified proposal for a new, simple, clinically relevant, non-ambiguous terminology for these lesions to be referred to as mixed epithelial endocrine neoplasms (MEENs). CONCLUSION MEEN of the colon and rectum are poorly understood rare entities that encompass an extensive range of heterogeneous tumors with a wide variety of combinations leading to tumors of high, intermediate or low grade malignant potential. This proposed new revised terminology of MEEN will solve the biggest hurdle of confusion and misclassification that plagues these rare unique colorectal neoplasms thus facilitating the future design of multi institutional prospective randomized controlled clinical trials to develop and evaluate newer therapeutic strategies that are recommended for continued improved understanding and personal optimization of clinical management of these unique colorectal neoplasms.
Collapse
Affiliation(s)
- Rani Kanthan
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon S7N 0W8, SK, Canada
| | - Suresh Tharmaradinam
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon S7N 0W8, SK, Canada
| | - Tehmina Asif
- Division of Oncology, Saskatoon Cancer Centre, Saskatoon S7N 0W8, SK, Canada
| | - Shahid Ahmed
- Division of Oncology, Saskatoon Cancer Centre, Saskatoon S7N 0W8, SK, Canada
| | - Selliah C Kanthan
- Division of General Surgery, University of Saskatchewan, Saskatoon S7N 0W8, SK, Canada
| |
Collapse
|
|
7
|
Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
8
|
Mixed Adenoma Well-differentiated Neuroendocrine Tumor (MANET) of the Digestive System: An Indolent Subtype of Mixed Neuroendocrine-NonNeuroendocrine Neoplasm (MiNEN). Am J Surg Pathol 2019; 42:1503-1512. [PMID: 30001239 DOI: 10.1097/pas.0000000000001123] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) consisting of adenoma and well-differentiated neuroendocrine tumor (NET) has been recently defined as "MANET." However, the clinico-pathologic and pathogenetic features of this entity are not thoroughly studied. We examined the clinico-pathologic features of 12 MANETs by expanding their p53 and β-catenin expression profiles as well as the presence of microsatellite instability and KRAS, BRAF, and PIK3CA mutations in the 2 tumor components. In all cases, the adenomatous component represented the larger part of the lesions and the NET was localized in the deep central portion of polyps. In 9 cases the latter was represented by NET G1, in 2 by NET G2, and in 1 by NET G3. In all cases, the glandular and NET components were intimately admixed, with zone of transition between the tumor components. The NET component was p53 negative in all cases and 3 of 8 cases showed variable nuclear positivity for β-catenin. All patients with follow-up data were alive and free of disease after a mean follow-up time of 9 years. No mutations in KRAS, BRAF, and PIK3CA genes and no microsatellite instability were found in both tumor components. Review of the literature also identified 59 previously reported MANETs and no tumor-related death has been found. Like mixed adenoneuroendocrine carcinomas, a high-grade malignant form of MiNENs with a poorly differentiated neuroendocrine carcinoma component, a common origin for both tumor constituents may be hypothesized. Moreover, the current series provides evidence that MANET is an indolent disease that needs to be distinguished from aggressive high-grade MiNENs.
Collapse
|
|
9
|
Tamura H, Ando H, Doi R, Adachi S. Combined Intestinal Adenomas/Microcarcinoids. Case Rep Gastroenterol 2019; 13:410-417. [PMID: 39263603 PMCID: PMC11387879 DOI: 10.1159/000503169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 09/04/2019] [Indexed: 09/13/2024] Open
Abstract
The combined colonic adenoma/microcarcinoid tumor is a rare intestinal neoplasm featuring intermingled adenomatous and carcinoid components. A few case reports and small case series have suggested that this entity exhibits an indolent clinical course. Here, we report two cases with these tumors, and describe the morphological features and clinical follow-up. A 61-year-old male and 78-year-old male presented with heme-positive stools at their medical checkups. Colonoscopy revealed masses in the colons; we performed endoscopic mucosal resection. Both lesions featured low-grade adenomas and low-grade neuroendocrine tumors. We diagnosed combined colonic adenomas/microcarcinoids. The clinical courses of both patients were benign at follow-up at 2.5 and 6 years. Awareness of this rare colonic tumor should prevent potential diagnostic pitfalls and may help clarify the natural history of these tumors and their possible relationships with composite glandular/carcinoid tumors.
Collapse
Affiliation(s)
- Hiromi Tamura
- Department of Pathology, Toyonaka Municipal Hospital, Toyonaka, Japan
| | - Hiroka Ando
- Department of Pathology, Toyonaka Municipal Hospital, Toyonaka, Japan
| | - Reiko Doi
- Department of Pathology, Toyonaka Municipal Hospital, Toyonaka, Japan
| | - Shiro Adachi
- Department of Pathology, Toyonaka Municipal Hospital, Toyonaka, Japan
| |
Collapse
|
|
10
|
Fu Z, Saade R, Koo BH, Jennings TA, Lee H. Incidence of composite intestinal adenoma-microcarcinoid in 158 surgically resected polyps and its association with squamous morule. Ann Diagn Pathol 2019; 42:69-74. [PMID: 31326865 DOI: 10.1016/j.anndiagpath.2019.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/03/2019] [Accepted: 07/13/2019] [Indexed: 12/19/2022]
Abstract
Composite intestinal adenoma-microcarcinoid (CIAM) is a rare colorectal lesion consisting of adenoma and small well-differentiated neuroendocrine cell clusters at its base. Its incidence is unknown. Benign squamous morule may demonstrate a neuroendocrine phenotype by immunohistochemistry. We investigated the incidence and clinicopathologic features of CIAM in endoscopically unresectable, surgically removed colorectal adenomas and evaluated its association with squamous morule. Archived pathology materials from 158 surgically resected colorectal adenomas were reviewed. 139 (88%) polyps were entirely submitted for microscopic examination. All lymph nodes were negative for adenocarcinoma and neuroendocrine tumor. CIAM was identified in 6 (3.8%) cases. The microcarcinoid (MC) was distributed over a mean of 5.8 mm (range < 1 to 12 mm), and was multifocal in 5 cases. The MC component was positive for synaptophysin in 6, CK5/6 in 4, and β-catenin in 3 cases. Two of 6 (33.3%) CIAM showed concurrent squamous morule, compared to 4.0% (6 of 152) of adenomas without MC (p < 0.05). At the end of the mean follow-up of 53 months, 4 were free of disease and one patient with previous history of pulmonary large cell neuroendocrine carcinoma (NEC) had a recurrence of NEC. One patient died of an unrelated disease. The incidence of CIAM in surgically removed colorectal adenomas is 3.8%, with an indolent clinical course. Frequent co-expression of CK5/6 and β-catenin in MC combined with common co-existence of squamous morule in the same polyp suggests shared pathogenesis of MC in CIAM and squamous morule, likely representing altered Wnt/β-catenin signaling pathway.
Collapse
Affiliation(s)
- Zhiyan Fu
- Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA.
| | - Rayan Saade
- Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA.
| | | | - Timothy A Jennings
- Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA.
| | - Hwajeong Lee
- Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA.
| |
Collapse
|
|
11
|
Ramage JK, Valle JW, Nieveen van Dijkum EJM, Sundin A, Pascher A, Couvelard A, Kloeppel G. Colorectal Neuroendocrine Neoplasms: Areas of Unmet Need. Neuroendocrinology 2019; 108:45-53. [PMID: 30219817 DOI: 10.1159/000493767] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 09/14/2018] [Indexed: 12/15/2022]
Abstract
The subject of colorectal neuroendocrine neoplasms (NENs), subdivided into well-differentiated NENs, termed neuroendocrine tumours (NETs; grade (G) 1 and 2), and poorly differentiated NENs, termed neuroendocrine carcinomas (NECs; G3) according to the 2010 World Health Organisation (WHO) classification, has arguably not had as much attention or study as NENs occurring in other sites. Colorectal NETs and NECs are however easier to study than many others since they are usually not difficult to remove and are increasingly detected because of intensified colorectal cancer screening and surveillance programmes. Colorectal NETs and NECs show site-specific heterogeneity with variable behaviour and different therapeutic options; these various aspects provide unique challenges. Because of bowel cancer screening programmes, colorectal NENs, like conventional adenocarcinomas, may be diagnosed at a stage that is associated with improved survival. In this article we intend to describe and define areas of unmet needs relating to the epidemiology, classification, pathology, diagnosis and therapy of colorectal NETs (including NETs G3), colorectal NECs, and finally, mixed adeno-neuroendocrine carcinomas (MANECs) by reviewing and discussing the relevant literature.
Collapse
Affiliation(s)
- John K Ramage
- Department Gastroenterology, Hampshire Hospitals NHS Trust, Kings College Hospital ENETS centre of Excellence, Basingstoke, United
| | - Juan W Valle
- Department of Medical Oncology, University of Manchester, The Christie ENETS Centre of Excellence, Manchester, United Kingdom
| | | | - Anders Sundin
- Department of Radiology, Institution Surgical Sciences, Uppsala University and ENETS centre of excellence, Uppsala University Hopsital, Uppsala, Sweden
| | - Andreas Pascher
- Department of Surgery, Charité Universitaetsmedizin Berlin, Berlin, Germany
- Department of Visceral and Transplant Surgery, University of Muenster, Muenster, Germany
| | - Anne Couvelard
- Department of Pathology, Bichat Hospital AP-HP and University of Paris Diderot, Paris, France
| | - Guenter Kloeppel
- Department of Pathology, Technical University Munich, Munich, Germany
| |
Collapse
|
|
12
|
Kidambi TD, Pedley C, Blanco A, Bergsland EK, Terdiman JP. Lower gastrointestinal neuroendocrine neoplasms associated with hereditary cancer syndromes: a case series. Fam Cancer 2018; 16:537-543. [PMID: 28283864 DOI: 10.1007/s10689-017-9979-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Lower gastrointestinal (GI) neuroendocrine neoplasms (NENs) of the colon and rectum are uncommon and not traditionally associated with hereditary GI cancer syndromes. However, with widespread implementation of colorectal cancer screening programs, lower GI NENs are being identified with increasing frequency. We report the first case series of six patients with lower GI NENs who were diagnosed with hereditary GI cancer syndromes by germline testing. Two patients presented with poorly differentiated rectal neuroendocrine carcinoma (NECs) with colonic polyposis and were found to have Familial Adenomatous Polyposis and MYH-Associated Polyposis, respectively. Three patients with colorectal NENs (one well differentiated neuroendocrine tumor, NET, and two NECs), all of which displayed abnormal immunohistochemistry for mismatch repair proteins, were diagnosed with Lynch syndrome. One patient with a goblet cell carcinoid was diagnosed with CHEK2 mutations. All patients met genetic testing guidelines and the diagnosis was made utilizing next generation sequencing gene panel tests. Lower GI NETs should therefore be considered a potential hereditary GI cancer syndrome-associated malignancy in patients who otherwise meet criteria for genetic evaluation.
Collapse
Affiliation(s)
- Trilokesh D Kidambi
- Division of Gastroenterology, University of California, San Francisco, San Francisco, CA, USA
| | - Christina Pedley
- Hereditary GI Cancer Prevention Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Amie Blanco
- Hereditary GI Cancer Prevention Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Emily K Bergsland
- Hereditary GI Cancer Prevention Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Division of Medical Oncology, University of California, San Francisco, San Francisco, CA, USA
| | - Jonathan P Terdiman
- Division of Gastroenterology, University of California, San Francisco, San Francisco, CA, USA. .,Hereditary GI Cancer Prevention Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. .,Clinical Medicine and Surgery, University of California, San Francisco, 1701 Divisadero, San Francisco, CA, 94115, USA.
| |
Collapse
|
|
13
|
Gonzalez P, Kelly J, Nassif G, Tran TAN. Neuroendocrine hyperplasia in a large composite adenoma-microcarcinoid case report and literature review on colonic adenoma-microcarcinoids/carcinoids. HUMAN PATHOLOGY: CASE REPORTS 2018. [DOI: 10.1016/j.ehpc.2018.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
|
|
14
|
Small Intestine Neuroendocrine Tumor in a Patient With MUTYH Adenomatous Polyposis-Case Report and SEER Analysis. Clin Colorectal Cancer 2018; 17:e545-e548. [PMID: 29843990 DOI: 10.1016/j.clcc.2018.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 04/30/2018] [Accepted: 05/03/2018] [Indexed: 12/17/2022]
|
|
15
|
Aristizabal Prada ET, Auernhammer CJ. Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets. Endocr Connect 2018; 7:R1-R25. [PMID: 29146887 PMCID: PMC5754510 DOI: 10.1530/ec-17-0286] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 11/16/2017] [Indexed: 12/12/2022]
Abstract
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras-Raf-MEK-ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.
Collapse
Affiliation(s)
- E T Aristizabal Prada
- Department of Internal Medicine IVCampus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - C J Auernhammer
- Department of Internal Medicine IVCampus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany
| |
Collapse
|
|
16
|
Scoazec JY, Couvelard A. [Classification of pancreatic neuroendocrine tumours: Changes made in the 2017 WHO classification of tumours of endocrine organs and perspectives for the future]. Ann Pathol 2017; 37:444-456. [PMID: 29169836 DOI: 10.1016/j.annpat.2017.10.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 10/08/2017] [Indexed: 02/01/2023]
Abstract
The WHO classification of the tumors of endocrine organs, published in July 2017, has introduced significant changes in the classification of pancreatic neuroendocrine tumors, the previous version of which has appeared in 2010, within the WHO classification of the tumors of the digestive system. The main change is the introduction of a new category of well-differentiated neoplasms, neuroendocrine tumors G3, in addition to the previous categories of neuroendocrine tumors G1 and G2. The differential diagnosis between neuroendocrine tumors G3 (well-differentiated) and neuroendocrine carcinomas (poorly-differentiated) might be difficult; the authors of the WHO classification therefore suggest the use of a number of immunohistochemical markers to facilitate the distinction between the two entities. The other changes are: (a) the modification of the threshold between neuroendocrine tumors G1 and G2, now set at 3%; (b) the terminology used for mixed tumors: the previous term mixed adeno-neuroendocrine carcinoma (MANEC) is substituted by the term mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Finally, the recommendations for Ki-67 index evaluation are actualized. Even if these changes only concern, stricto sensu, the neuroendocrine tumors of pancreatic location, they will probably be applied, de facto, for all digestive neuroendocrine tumors. The revision of the histological classification of pancreatic neuroendocrine tumors coincides with the revision of their UICC TNM staging; significant changes have been made in the criteria for T3 and T4 stages. Our professional practices have to take into account all these modifications.
Collapse
Affiliation(s)
- Jean-Yves Scoazec
- Département de biologie et pathologie médicales, Gustave-Roussy Cancer Campus, 114, rue Edouard-Vaillant, 94805 Villejuif cedex, France; Faculté de médecine de Bicêtre, université Paris Sud, 94270 Le Kremlin-Bicêtre, France.
| | - Anne Couvelard
- DHU Unity, département de pathologie, hôpital Bichat, Assistance publique-Hôpitaux de Paris, 75018 Paris, France; Faculté de médecine Bichat, université Paris Diderot, 75018 Paris, France
| | | |
Collapse
|
|
17
|
Kim MJ, Lee EJ, Kim DS, Lee DH, Youk EG, Kim HJ. Composite intestinal adenoma-microcarcinoid in the colon and rectum: a case series and historical review. Diagn Pathol 2017; 12:78. [PMID: 29116005 PMCID: PMC5688820 DOI: 10.1186/s13000-017-0665-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 10/19/2017] [Indexed: 12/18/2022] Open
Abstract
Background Composite intestinal adenoma-microcarcinoid (CIAM) is a rare colorectal lesion that mostly comprises a conventional adenomatous component with a minute proportion of neuroendocrine (NE) component. Although microcarcinoids are well-recognized in the setting of chronic inflammatory disorders of the gastrointestinal tract, large intestinal microcarcinoids associated with intestinal adenoma are exceedingly rare and their clinicopathologic characteristics are yet to be elucidated. This study was performed to clarify their clinicopathologic characteristics and to review the relevant literature. Methods In total, 24 cases of CIAM in which tumors were excised endoscopically (n = 22) or surgically (n = 2) were retrieved from the Department of Pathology, Daehang Hospital. We analyzed their clinicopathologic characteristics and performed immunohistochemical staining for NE markers to determine their endocrine nature. Results CIAM usually developed in middle-aged and elderly patients, with a mean age of 62.0 years (range, 44–81 years). Thirteen patients were men and 11 were women, indicating a nearly equal sex ratio. Unlike classic carcinoid tumors, CIAMs occurred mostly in the colon (83.3% of cases), particularly in the proximal colon. Histologically, the microcarcinoid component consisted of low-grade NE cells arranged in small nests, glands or cords interspersed with glandular elements or less frequently resembled squamous morules. There was no expansile nodular or organoid growth pattern, which is typical of carcinoid tumors. The microcarcinoids were 1–20 mm in size (mean size, 4.7 mm) and were mostly situated in the basal lamina propria with no submucosal layer involvement; none showed desmoplastic reaction or increased proliferative activity. Follow-up data (mean, 23.1 months) were available for 18 patients; all patients are alive and well. Conclusions To the best of our knowledge, ours is the largest series of patients with CIAM in the English-language literature. Microcarcinoids found in CIAMs appear to show favorable clinical outcomes regardless of their size, likely due to the absence of submucosal extension and/or increased proliferative activity. We recommend avoiding additional radical surgeries in patients who have endoscopically undergone complete CIAM excision unless they exhibit ominous histologic features such as submucosal extension or increased proliferative activity.
Collapse
Affiliation(s)
- Mi-Jung Kim
- Department of Pathology, Daehang hospital, 481-10 BangBae3-dong, Seocho-gu, 137-820, Seoul, Republic of Korea
| | - Eun-Jung Lee
- Department of Surgery, Daehang hospital, 481-10 BangBae3-dong, Seocho-gu, 137-820, Seoul, Republic of Korea
| | - Do Sun Kim
- Department of Surgery, Daehang hospital, 481-10 BangBae3-dong, Seocho-gu, 137-820, Seoul, Republic of Korea
| | - Doo Han Lee
- Department of Surgery, Daehang hospital, 481-10 BangBae3-dong, Seocho-gu, 137-820, Seoul, Republic of Korea
| | - Eui Gon Youk
- Department of Surgery, Daehang hospital, 481-10 BangBae3-dong, Seocho-gu, 137-820, Seoul, Republic of Korea
| | - Hyun-Jung Kim
- Department of Pathology, University of Inje College of Medicine, Sanggye Paik hospital, Dongil-ro 1342, Nowon-gu, Seoul, Republic of Korea.
| |
Collapse
|
|
18
|
La Rosa S, Sessa F, Uccella S. Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs): Unifying the Concept of a Heterogeneous Group of Neoplasms. Endocr Pathol 2016; 27:284-311. [PMID: 27169712 DOI: 10.1007/s12022-016-9432-9] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The wide application of immunohistochemistry to the study of tumors has led to the recognition that epithelial neoplasms composed of both a neuroendocrine and nonneuroendocrine component are not as rare as traditionally believed. It has been recommended that mixed neuroendocrine-nonneuroendocrine epithelial neoplasms are classified as only those in which either component represents at least 30 % of the lesion but this cutoff has not been universally accepted. Moreover, since their pathogenetic and clinical features are still unclear, mixed neuroendocrine-nonneuroendocrine epithelial neoplasms are not included as a separate clinicopathological entity in most WHO classifications, although they have been observed in virtually all organs. In the WHO classification of digestive tumors, mixed neuroendocrine-nonneuroendocrine neoplasm is considered a specific type and is defined as mixed adenoneuroendocrine carcinoma, a definition that has not been accepted for other organs. In fact, this term does not adequately convey the morphological and biological heterogeneity of digestive mixed neoplasms and has created some misunderstanding among both pathologists and clinicians. In the present study, we have reviewed the literature on mixed neuroendocrine-nonneuroendocrine epithelial neoplasms reported in the pituitary, thyroid, nasal cavity, larynx, lung, digestive system, urinary system, male and female genital organs, and skin to give the reader an overview of the most important clinicopathological features and morphological criteria for diagnosing each entity. We also propose to use the term "mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN)" to define and to unify the concept of this heterogeneous group of neoplasms, which show different characteristics mainly depending on the type of neuroendocrine and nonneuroendocrine components.
Collapse
Affiliation(s)
- Stefano La Rosa
- Department of Pathology, Ospedale di Circolo, viale Borri 57, 21100, Varese, Italy.
| | - Fausto Sessa
- Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Silvia Uccella
- Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| |
Collapse
|
|
19
|
Weiss V, Dueber J, Wright JP, Cates J, Revetta F, Parikh AA, Merchant NB, Shi C. Immunohistochemical analysis of the Wnt/β-catenin signaling pathway in pancreatic neuroendocrine neoplasms. World J Gastrointest Oncol 2016; 8:615-622. [PMID: 27574554 PMCID: PMC4980652 DOI: 10.4251/wjgo.v8.i8.615] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/24/2016] [Accepted: 06/03/2016] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the role of the Wnt/β-catenin pathway in pancreatic neuroendocrine neoplasms (PanNENs).
METHODS: Tissue microarrays containing 88 PanNENs were immunohistochemically labeled with antibodies to β-catenin, E-cadherin, adenomatous polyposis coli (APC), chromogranin and synaptophysin. One case had only metastatic tumors resected, whereas others (n = 87) received pancreatectomy with or without partial hepatectomy. Pathology slides, demographic, clinicopathologic, and follow up data were reviewed. Patients’ demographics, clinicopathologic features, and immunohistochemical results from 87 primary tumors were compared between patients with low stage (stage I/II) and high stage (stage III/IV) tumors. In addition, correlation of immunohistochemical results from primary tumors with disease-specific survival (DSS) was evaluated.
RESULTS: Strong membranous β-catenin staining in the primary tumor was observed in all 13 stage III/IV PanNENs as compared to 47% (35/74) of stage I/II tumors (P < 0.01). However, the strong membranous β-catenin staining was unassociated with tumor grade or DSS. Decreased membranous β-catenin staining was associated with decreased membranous E-cadherin labeling. Nuclear β-catenin staining was seen in 15% (2/13) of stage III/IV PanNENs as compared to 0% (0/74) of stage I/II tumors (P = 0.02). The case with metastasectomy also only showed nuclear β-catenin staining. Two of the three cases with nuclear β-catenin staining were familial adenomatous polyposis (FAP) patients. Lack of APC expression was seen in 70% (57/81) of the cases, including the 3 cases with nuclear β-catenin staining. Expression of E-cadherin and APC in primary tumor was not correlated with tumor grade, tumor stage, or disease specific survival.
CONCLUSION: The Wnt/β-catenin pathway was altered in some PanNENs, but did not Impact DSS. PanNENs in FAP patients demonstrated nuclear β-catenin accumulation and loss of APC.
Collapse
|
|
20
|
Lee SH, Lee TH, Jang SH, Choi CY, Lee WM, Min JH, Cho HD, Park SH. Ampullary neuroendocrine tumor diagnosed by endoscopic papillectomy in previously confirmed ampullary adenoma. World J Gastroenterol 2016; 22:3687-3692. [PMID: 27053861 PMCID: PMC4814655 DOI: 10.3748/wjg.v22.i13.3687] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/17/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Ampullary adenoma is a common indication for endoscopic papillectomy. Ampullary neuroendocrine tumor (NET) is a rare disease for which complete surgical resection is the treatment of choice. However, because of the morbidity and mortality associated with surgical resection, endoscopic papillectomy is increasingly used in selected cases of low grade, with no metastasis and no invasion of the pancreatic or bile duct. Also, confirmed and complete endoscopic resection of ampullary NET accompanied by adenoma has not been reported to date. We report herein a rare case of an ampullary NET accompanied with adenoma, which was successfully and completely resected via endoscopic papillectomy. Prior to papillectomy, this case was diagnosed as an ampullary adenoma.
Collapse
|
|
21
|
Rengifo-Cam W, Jasperson KW, Burt RW, Samadder NJ. Familial Adenomatous Polyposis. INTESTINAL POLYPOSIS SYNDROMES 2016:173-195. [DOI: 10.1007/978-3-319-28103-2_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|