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Hong R, Wang H, Lin Y, Yin X, Fang J, Pang J, Chen L, Wu H, Liang Z. The clinicopathological and molecular features of primary high-grade neuroendocrine tumour in the breast. Histopathology 2025; 86:900-915. [PMID: 39688109 DOI: 10.1111/his.15398] [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: 04/09/2024] [Revised: 09/17/2024] [Accepted: 11/30/2024] [Indexed: 12/18/2024]
Abstract
AIMS Nottingham grade for breast cancers, rather than gastro-entero-pancreatic (GEP) grade for neuroendocrine tumours (NETs), is currently applied to primary breast NETs, which need further clarification. High-grade NETs in breast also remain poorly recognised. METHODS AND RESULTS Among 595 breast carcinomas with diffuse synaptophysin (Syn) or chromogranin A (CgA) immunostaining (≥ 90%), 197 eligible cases were selected, including 69 NETs, 123 invasive breast carcinomas of no special type (IBC-NSTs) and five neuroendocrine carcinomas (NECs). The prognostic significance of these two grading systems in breast NETs was assessed. Furthermore, the clinicopathological features were compared in Nottingham G3 cases among three entities. Targeted sequencing and immunostaining (INSM1/p53/Rb/p16) were also performed in all Nottingham G3 NETs, NECs and 10 Nottingham G3 IBC-NSTs. All Nottingham G3 NETs (9 of 69, 13.0%) fell into GEP G3 cases (20 of 69, 29.0%). Nottingham grade provided better prognostic discrimination between G1/G2 and G3 NETs than GEP grade. Among Nottingham G3 cases, there was a trend towards reduced progression-free survival (PFS) in NETs compared with IBC-NSTs (P = 0.057), and the former were more often immunoreactive for INSM1 (44.4 versus 0%, P = 0.033). Nottingham G3 NETs were all of luminal-like phenotype (P < 0.001) and exhibited less aberrant p53 patterns (11.1 versus 80.0%, P = 0.023) as well as more favourable PFS (P = 0.012) and disease-specific survival (P = 0.002) than NECs. Rb loss (4 of 5, 80%), p16 overexpression (5 of 5, 100%) and RB1 mutation (2 of 5, 40%) were observed exclusively in NECs. Based on expression data, epithelial-mesenchymal transition and KRAS signalling pathways were significantly up-regulated in Nottingham G3 NETs (P < 0.05). CONCLUSIONS Nottingham grade, rather than GEP grade, holds important prognostic significance in primary breast NETs. Nottingham G3 NETs represent a small proportion of breast NETs, and may demonstrate distinct clinicopathological and molecular features from other high-grade breast carcinomas with diffuse neuroendocrine markers expression.
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Affiliation(s)
- Ruping Hong
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hao Wang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yan Lin
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xianglin Yin
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Jiuyuan Fang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Junyi Pang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Longyun Chen
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Huanwen Wu
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Zhiyong Liang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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Lv HY, Liu MX, Hong WT, Li XW. Primary hepatic neuroendocrine tumor with a suspicious pulmonary nodule: A case report and literature review. World J Clin Oncol 2025; 16:101236. [PMID: 40130063 PMCID: PMC11866086 DOI: 10.5306/wjco.v16.i3.101236] [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: 09/08/2024] [Revised: 12/07/2024] [Accepted: 12/27/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare tumors originating from neuroendocrine cells. Due to lack of neuroendocrine symptoms and specific radiographic characteristics, PHNETs are challenging to differentiate from other liver tumors. CASE SUMMARY This case involved a 67-year-old male who was admitted with a discovered hepatic mass and a suspicious lung lesion. Primary hepatic carcinoma was initially speculated based on the characteristic magnetic resonance imaging findings. The patient underwent a laparoscopic right partial hepatectomy, and subsequent immunohistochemical examination revealed a HNET. To exclude other potential origins, a positron emission tomography-computed tomography scan and gastrointestinal endoscopy were performed, leading to a final diagnosis of PHNETs. Then we conducted a literature review using the PubMed database, identifying 99 articles and 317 cases related to PHNETs. The characteristics, diagnostic methods, and treatment of PHNETs have been described. Finally, we elaborate on the presumed origins, pathological grades, clinical features, diagnosed methods, and treatments associated with PHNETs. CONCLUSION The diagnosis of PHNETs was primarily an exclusionary process. A definitive diagnosis of PHNETs relied mainly on immunohistochemical markers (chromogranin A, synaptophysin, and cluster of differentiation 56) and exclusion of primary foci in other organs. Radical surgery was the preferred treatment for early-stage tumors.
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Affiliation(s)
- Hai-Yan Lv
- Department of Nursing, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Mei-Xuan Liu
- Department of Burns and Wound Care Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Wen-Ting Hong
- Department of Nursing Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Xia-Wei Li
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Department of Cancer Center, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
- Harvard T.H. Chan School of Public Health, Harvard University, Cambridge, MA 02138, United States
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Mattiolo P. Practical hints for the diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasms of the digestive system. World J Gastrointest Oncol 2024; 16:4326-4332. [PMID: 39554731 PMCID: PMC11551634 DOI: 10.4251/wjgo.v16.i11.4326] [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: 03/26/2024] [Revised: 06/06/2024] [Accepted: 07/15/2024] [Indexed: 10/25/2024] Open
Abstract
In this editorial, a comment on the article by Díaz-López et al published in the recent issue of the 2024 is provided. We focus on the practical implications critical for providing a correct and complete diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) in the gastrointestinal system. The diagnosis of MiNEN begins with the recognition of neuroendocrine features in one component of a biphasic tumor. The non-neuroendocrine counterpart can be virtually represented by any neoplastic type, even though the most frequent histologies are glandular and squamous. However, qualification of the neuroendocrine component requires histological and immunohistochemical confirmation. Neuroendocrine tumors are characterized by a peculiar architectural organization and bland nuclei with granular "salt and pepper" chromatin. Although neuroendocrine carcinomas have multiple and variable presentations, they typically show a solid or organoid architecture. The histological aspect needs to be confirmed by immunohistochemistry, and a diagnosis is confirmed whenever the expression of keratin and neuroendocrine markers is observed. Once both histopathological and immunohistochemical features of neuroendocrine neoplasms are identified, it is important to consider the three major pitfalls of MiNEN diagnostics: (1) Entrapment of neuroendocrine non-neoplastic cells within the tumor mass; (2) Differential diagnosis with amphicrine neoplasms; and (3) Differential diagnosis of tumors that partially express neuroendocrine markers. According to the current guidelines for diagnosing digestive MiNEN, each component must represent at least 30% of the entire neoplastic mass. Although the high-grade histopathological subtype frequently determines disease prognosis, both components can significantly affect prognosis. Thus, if one of the components, either neuroendocrine or non-neuroendocrine, does not fulfill the volumetric criteria, the guidelines still encourage reporting it. These strict criteria are essential for correctly recognizing and characterizing digestive MiNENs. This task is essential because it has prognostic relevance and substantial potential value for guiding further studies in this field. In the future, systematic analyses should be performed to validate or reconsider the current 30% cutoff value.
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Affiliation(s)
- Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, University and Hospital Trust of Verona, Verona 37134, Italy
- Department of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf 40225, Germany
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Pini GM, Giordano M, Colecchia M, Patriarca C. The pitfalls of an invasive non-neuroendocrine GATA3- and TTF1+ urothelial carcinoma. Pathologica 2024; 116:335-337. [PMID: 39748718 DOI: 10.32074/1591-951x-1102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 01/04/2025] Open
Affiliation(s)
| | | | - Maurizio Colecchia
- Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy
- IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Carlo Patriarca
- Pathology Unit, St. Anna Hospital (ASST Lariana), Como, Italy
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Laffi A, Bertuzzi AF, Carrara S, Zerbi A, Lania A, Lavezzi E, Ferrillo G, Jandric J, Carnaghi C, Rossi RE, Grimaudo MS, Spaggiari P, Uccella S. Co-existing Neuroendocrine Tumors in the Ileum and Pancreas: A Clinico-Pathological Challenge. Endocr Pathol 2024; 35:256-266. [PMID: 38848012 DOI: 10.1007/s12022-024-09814-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/30/2024] [Indexed: 06/18/2024]
Abstract
Ileal (I) and pancreatic (Pan) neuroendocrine tumors (NETs) are among the most common digestive neuroendocrine neoplasms (NENs). Coexisting NETs at both sites are rare, and establishing the primary or metastatic nature of the two lesions may be crucial for the appropriate treatment. We reviewed all the clinical reports of patients with INETs or PanNETs, diagnosed and treated in our ENETS Center of Excellence between 2012 and 2022. We selected patients with a history of synchronous or metachronous neuroendocrine (NE) lesions at the ileum and pancreas. For those with available histological samples from both sites, an immunohistochemistry (IHC) analysis for CDX2, Islet1, and serotonin has been performed. We found seven patients with NET in both the ileum and pancreas. F to M ratio was 4:3, and the median age at first diagnosis was 54 years (42-79). Five cases had synchronous lesions; in 2 cases, PanNETs were diagnosed respectively 8 and 56 months, after INETs. In four patients, with available histological samples from both the sites, a pathologic review and the IHC analysis have been performed, identifying three different scenarios: (i) primary INET metastatic to the pancreas, (ii) primary PanNET metastatic to the ileum, and (iii) synchronous primary PanNET and INET. In our experience, coexisting ileal and pancreatic NENs are rare occurrences. A multidisciplinary evaluation case-by-case and, whenever feasible, a comprehensive histopathological examination are needed to distinguish between metastatic and primary disease, in order to properly treat the patient.
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Affiliation(s)
- Alice Laffi
- Department of Oncology & Hematology, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | - Silvia Carrara
- Gastroenterology Department, Endoscopic Unit, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alessandro Zerbi
- Pancreatic Surgery Unit, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Andrea Lania
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Medical Andrology Unit, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Elisabetta Lavezzi
- Endocrinology, Diabetology and Medical Andrology Unit, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Giuseppe Ferrillo
- Radiology Department, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Jelena Jandric
- Nuclear Medicine Department, IRCCS, Humanitas Research Hospital, Rozzano Milan, Italy
| | | | - Roberta Elisa Rossi
- Gastroenterology Department, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Maria Susanna Grimaudo
- Department of Oncology & Hematology, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Paola Spaggiari
- Pathology Department, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Silvia Uccella
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
- Pathology Department, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy.
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Kelly N, Wu YT, Johnston AN. Gallbladder Neuroendocrine Neoplasms in Dogs and Humans. Vet Sci 2024; 11:371. [PMID: 39195825 PMCID: PMC11360110 DOI: 10.3390/vetsci11080371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/28/2024] [Accepted: 08/09/2024] [Indexed: 08/29/2024] Open
Abstract
Gallbladder neuroendocrine neoplasms (GB NENs) are among the rarest cancers reported in humans and dogs. This review provides a detailed review of the canine GB NEN literature and an interspecies comparison of demographics, clinical pathophysiology, pathobiology, and therapeutic response of GB NENs. The aim of this work is to explore the relevance of dogs as a spontaneous model for human GB NENs.
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Affiliation(s)
- Nadia Kelly
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (N.K.); (Y.-T.W.)
| | - Yen-Tse Wu
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (N.K.); (Y.-T.W.)
- Emergency & Critical Care, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
| | - Andrea N. Johnston
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (N.K.); (Y.-T.W.)
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Chi Z, Xu J, Karamchandani DM, Peng L. INSM1 is a useful neuroendocrine marker to differentiate pancreatic serous cystadenoma from pancreatic well-differentiated neuroendocrine tumors in cytology and surgical specimens. Ann Diagn Pathol 2024; 71:152304. [PMID: 38614035 DOI: 10.1016/j.anndiagpath.2024.152304] [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: 03/19/2024] [Revised: 04/04/2024] [Accepted: 04/06/2024] [Indexed: 04/15/2024]
Abstract
INTRODUCTION Differentiating pancreatic serous cystadenoma (SCA) from well-differentiated neuroendocrine tumors (WDNETs) based on histomorphology is critical yet challenging, particularly in small biopsy samples. Our study aimed to examine the expression profile of INSM1 in cytologic and surgical resection specimens from pancreatic SCA to evaluate its potential as a discriminative marker against pancreatic WDNET. METHODS We characterized INSM1 immunohistochemistry in 34 patients with pancreatic SCA, comprising 23 surgical resections and 11 cytology specimens. As a control, we used 28 cytology specimens from pancreatic WDNET. Clinical information was retrieved through a review of electronic medical records. RESULTS All 11 pancreatic SCA cytology specimens and 15 of 23 pancreatic SCA surgical resections exhibited absent INSM1 immunostaining. Each of the remaining eight surgical resection specimens demonstrated 1 % immunoreactivity. In contrast, 27 out of 28 (96 %) pancreatic WDNET cytology specimens were positive for INSM1 immunostaining, with a median immunoreactivity of 90 % and a range of 30-90 %. Overall, INSM1 immunostains perform similarly to chromogranin and synaptophysin in pancreatic SCA. CONCLUSIONS The results indicate that INSM1 immunohistochemistry staining may serve as a useful neuroendocrine marker to differentiate pancreatic SCA from pancreatic WDNET in clinical practice. To our knowledge, this represents the first large-scale study to evaluate INSM1 immunostaining in surgical and cytology specimens from pancreatic SCA.
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Affiliation(s)
- Zhikai Chi
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Jing Xu
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Dipti M Karamchandani
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lan Peng
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Cheng Z, Yu F, Chen R, Cui L, Chen Y, Deng C, Shi Y, Tan H. Treatment, Prognostic Markers, and Survival in Thymic Neuroendocrine Tumors, with Special Reference to Temozolomide-Based Chemotherapy. Cancers (Basel) 2024; 16:2502. [PMID: 39061142 PMCID: PMC11275075 DOI: 10.3390/cancers16142502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/01/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Thymic neuroendocrine tumors (Th-NETs) are rare and aggressive, with a scarcity of research on predicting patient prognosis. Our study aimed to assess the impact of prognostic markers and temozolomide (TMZ)-based chemotherapy on survival in Th-NETs. METHODS We retrospectively reviewed the medical records of patients diagnosed with Th-NETs between 2013 and 2023 at our institution. We collected clinicopathological data, including tumor pathological grading, staging, serum concentrations of neuron-specific enolase (NSE) and pro-gastrin-releasing peptide, levels of inflammatory factors, and expression of oxygen 6-methylguanine-DNA methyltransferase (MGMT). Treatment details (such as surgery and chemotherapy) and survival outcomes were also documented. RESULTS A total of 32 patients were included in our study after excluding those without complete available information. The median progression-free survival (PFS) was 12.5 months (95%CI, 8-16 months) for 19 patients who received TMZ-based chemotherapy. Twenty-one patients underwent surgery as the primary treatment, demonstrating a median disease-free survival (DFS) of 51.0 months. The inflammatory factor neutrophil-to-lymphocyte ratio (NLR) was an independent prognostic indicator of DFS in postoperative patients and PFS in TMZ-treated patients. The overall 3-, 5-, and 10-year survival rates were 86.6%, 69.5%, and 33.8%, respectively. Ki67 level exceeding 10% (p = 0.048) and absence of surgical resection (p = 0.003) were significantly associated with worse overall survival (OS). CONCLUSION Surgical treatment was currently the primary method for treating Th-NETs, and postoperative adjuvant therapy was an essential consideration for specific patient cohorts. Despite widespread positive MGMT expression, TMZ-based chemotherapy showed promise. Some potential prognostic biomarkers such as NLR and NSE need more attention.
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Affiliation(s)
- Zixuan Cheng
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China; (Z.C.)
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Fuhuan Yu
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China; (Z.C.)
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Ruao Chen
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China; (Z.C.)
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Lingjun Cui
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China; (Z.C.)
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yingying Chen
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China; (Z.C.)
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Chao Deng
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yanfen Shi
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Huangying Tan
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
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9
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Liu L, Li Q, Liu W, Qiu Z, Wu Z, Yu D, Deng W. Gastric mixed neuroendocrine non-neuroendocrine neoplasms. Front Oncol 2024; 14:1335760. [PMID: 38655135 PMCID: PMC11036886 DOI: 10.3389/fonc.2024.1335760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
The uncommon tumour known as gastric mixed neuroendocrine-non-neuroendocrine neoplasms (G-MiNENs) is made up of parts of neuroendocrine carcinoma and adenocarcinoma. The biological and clinical features are different from those of gastric adenocarcinoma. Their pathophysiology, diagnostic standards, and clinical behaviour have all been the subject of lengthy debates, and their nomenclature has undergone multiple changes. Its emergence has created new challenges in the classification and diagnosis of gastric tumours. This review will update information on the topic, covering molecular aspects, diagnostic criteria, treatment, and prognostic factor discovery. It will also provide a historical context that will aid in understanding the evolution of the idea and nomenclature of mixed gastric tumours. Additionally, it will provide the reader a thorough understanding of this difficult topic of cancer that is applicable to real-world situations.
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Affiliation(s)
- Li Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Qian Li
- Department of Ultrasound Imaging, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenxuan Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhendong Qiu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhongkai Wu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Danli Yu
- Department of Ultrasound Imaging, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenhong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Karamitopoulou-Diamantis E. [Exocrine meets neuroendocrine: mimickers of pancreatic neuroendocrine neoplasms]. PATHOLOGIE (HEIDELBERG, GERMANY) 2024; 45:42-49. [PMID: 38091082 DOI: 10.1007/s00292-023-01286-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/07/2023] [Indexed: 01/31/2024]
Abstract
Neuroendocrine neoplasms (NENs) originate from various epithelial or neuroectodermal tissues, can occur in any organ, including the pancreas, and are characterized by the expression of the neuroendocrine markers synaptophysin and chromogranin A. Pancreatic neuroendocrine tumors (PanNETs) are well-differentiated epithelial neoplasms with morphological and immunohistochemical features of neuroendocrine differentiation of low, intermediate, or high grade. Pancreatic neuroendocrine carcinomas (PanNECs) are clinically aggressive, high-grade (poorly differentiated) carcinomas with morphologic features suggesting neuroendocrine differentiation, a high proliferative rate (> 20 mitoses per 2 mm2 and Ki67 index > 20%), and immunohistochemical labeling for neuroendocrine markers. They include the small cell neuroendocrine carcinoma and the large cell neuroendocrine carcinoma categories.Neuroendocrine-like morphology coupled with immunohistochemical markers of neuroendocrine differentiation are highly specific. However, neuroendocrine markers may also be expressed in non-neuroendocrine neoplasms, which can therefore be confused with NENs. Mimickers of pancreatic NENs comprise a number of important pitfall tumors, including epithelial and non-epithelial neoplasms, such as acinar cell carcinomas, solid pseudopapillary neoplasms (SPNs), or even non-neoplastic lesions. All of these lesions have the expression of neuroendocrine markers in common, such as synaptophysin and chromogranin A, and although they are comparatively rare, they can cause considerable diagnostic problems. This review article deals with some of the most important mimickers of pancreatic neuroendocrine neoplasms and even non-neoplastic lesions, such as islet aggregation. The similarities and differences between these entities and pancreatic neuroendocrine neoplasms are highlighted, and key findings that facilitate the correct diagnosis are discussed.
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Affiliation(s)
- Eva Karamitopoulou-Diamantis
- Institut für Gewebemedizin und Pathologie, Universität Bern, Bern, Schweiz.
- PATHOLOGIE INSTITUT ENGE, Hardturmstr. 133, 8005, Zürich, Schweiz.
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11
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Vocino Trucco G, Righi L, Volante M, Papotti M. Updates on lung neuroendocrine neoplasm classification. Histopathology 2024; 84:67-85. [PMID: 37794655 DOI: 10.1111/his.15058] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 09/08/2023] [Accepted: 09/14/2023] [Indexed: 10/06/2023]
Abstract
Lung neuroendocrine neoplasms (NENs) are a heterogeneous group of pulmonary neoplasms showing different morphological patterns and clinical and biological characteristics. The World Health Organisation (WHO) classification of lung NENs has been recently updated as part of the broader attempt to uniform the classification of NENs. This much-needed update has come at a time when insights from seminal molecular characterisation studies revolutionised our understanding of the biological and pathological architecture of lung NENs, paving the way for the development of novel diagnostic techniques, prognostic factors and therapeutic approaches. In this challenging and rapidly evolving landscape, the relevance of the 2021 WHO classification has been recently questioned, particularly in terms of its morphology-orientated approach and its prognostic implications. Here, we provide a state-of-the-art review on the contemporary understanding of pulmonary NEN morphology and the potential contribution of artificial intelligence, the advances in NEN molecular profiling with their impact on the classification system and, finally, the key current and upcoming prognostic factors.
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Affiliation(s)
| | - Luisella Righi
- Department of Oncology, University of Turin, Turin, Italy
| | - Marco Volante
- Department of Oncology, University of Turin, Turin, Italy
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy
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Asa SL, Uccella S, Tischler A. The Unique Importance of Differentiation and Function in Endocrine Neoplasia. Endocr Pathol 2023; 34:382-392. [PMID: 37043101 DOI: 10.1007/s12022-023-09762-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/13/2023]
Abstract
The assessment of cell differentiation in endocrine neoplasms involves not only the identification of a cell's structure and expression of specific transcription factors which regulate that cell, but also the identification of hormones and/or enzymes involved in hormone synthesis. The importance of this functional characterization is emphasized by the fact that the hormones serve as biomarkers for clinical surveillance to identify persistence, recurrence, or progression of disease. Sometimes, unusual patterns of hormone expression lead to unexpected clinical signs and symptoms. Loss of differentiated hormone production can be a sign of dedifferentiation as a tumor becomes more aggressive. In addition to prognostic information, cell differentiation can be predictive, since differentiated endocrine cells express targets for therapy, such as the sodium iodide symporter in thyroid cancers and somatostatin receptors in neuroendocrine tumors. The salient features of differentiation in the three main types of endocrine cells can be used to determine prognosis and to tailor management of patients with endocrine neoplasms.
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Affiliation(s)
- Sylvia L Asa
- Department of Pathology, University Hospitals Cleveland, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, 44106, USA.
| | - Silvia Uccella
- Unit of Pathology, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Department of Pathology, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Arthur Tischler
- Department of Pathology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, 02111, USA
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Couvelard A, Cazes A, Cros J. Updates in histopathological classification and tissue biomarkers of digestive neuroendocrine neoplasms: What the clinician should know. Best Pract Res Clin Endocrinol Metab 2023; 37:101795. [PMID: 37429760 DOI: 10.1016/j.beem.2023.101795] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/12/2023]
Abstract
Histopathological classifications of neuroendocrine neoplasms (NEN) change regularly and the latest WHO classification published in 2022, which concerns all NEN in the body, attempts to standardize classifications in the different locations. Differentiation and proliferation mainly assessed by Ki-67 index are still the cornerstone of those classifications. However, many markers are now used for diagnostic (to check neuroendocrine differentiation, to identify the site of origin of a metastasis, to help separating high-grade neuroendocrine tumors/NET and neuroendocrine carcinoma/NEC), prognostic or theranostic purposes. NENs are often heterogeneous and this can lead to difficulties in classifications, biomarker and prognostic assessment. These different points are discussed successively in this review, insisting especially on the frequent digestive, gastro-entero-pancreatic (GEP) localizations.
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Affiliation(s)
- Anne Couvelard
- Department of Pathology, ENETS Centre of Excellence, Beaujon-Bichat Hospitals, AP-HP, Paris, France; Université Paris Cité, Paris, France; INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
| | - Aurélie Cazes
- Department of Pathology, ENETS Centre of Excellence, Beaujon-Bichat Hospitals, AP-HP, Paris, France; Université Paris Cité, Paris, France; INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France
| | - Jérôme Cros
- Department of Pathology, ENETS Centre of Excellence, Beaujon-Bichat Hospitals, AP-HP, Paris, France; Université Paris Cité, Paris, France; INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France
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14
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Cattaneo L, Centonze G, Sabella G, Lagano V, Angerilli V, Pardo C, Bertani E, Spada F, Prinzi N, Pusceddu S, Fassan M, Fazio N, Milione M. Digestive MiNENs: Could histological classification and molecular characterization drive clinical outcome and therapeutic approach? Crit Rev Oncol Hematol 2023; 188:104044. [PMID: 37268174 DOI: 10.1016/j.critrevonc.2023.104044] [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: 03/01/2023] [Revised: 05/19/2023] [Accepted: 05/30/2023] [Indexed: 06/04/2023] Open
Abstract
Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are epithelial neoplasms in which neuroendocrine and non-neuroendocrine discrete components are combined, each of which constitutes ≥ 30% of the neoplasm. The finding of an additional neuroendocrine component seems to characterize the tumor's biological behavior. Few studies have proved MiNENs histogenetic and molecular characterization, and the development of molecular markers for more accurate classification of MiNENs represents a clinical need. However, a common origin of the neuroendocrine and non-neuroendocrine components from a pluripotent cancer stem cell could be suggested. The optimal clinical management of MiNENS is largely unknown. Whenever feasible, curative-intent resection should be performed for localized disease; in advanced disease, the treatment should be targeted to the component responsible for the metastatic spreading. This paper provides a revision of the current knowledge on MiNENs, focusing on available evidence about their molecular characterization to suggest a prognostic stratification of these rare forms.
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Affiliation(s)
- Laura Cattaneo
- Pathology First Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- Pathology First Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; Department of Research, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanna Sabella
- Pathology First Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Vincenzo Lagano
- Pathology First Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Valentina Angerilli
- Department of Medicine - DIMED, University of Padua, Padua, Italy; Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Carlotta Pardo
- Pathology First Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Emilio Bertani
- Division of Gastrointestinal Surgery, European Institute of Oncology, Milan, Italy
| | - Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Natalie Prinzi
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Sara Pusceddu
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padua, Padua, Italy; Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Massimo Milione
- Pathology First Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy.
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15
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Abstract
PURPOSE OF REVIEW Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) represent a heterogenous group of rare tumors emanating from neuroendocrine cells that are clinically silent for prolonged periods of time without detection. Traditional biomarkers lack sufficiently high enough specificity and sensitivity for these tumors and their secreted products. New molecules are sought to improve accuracy of detection and monitoring of GEP-NENs. The purpose of this review is to highlight recent advances in the discovery of novel biomarkers and their potential characteristics and utility as markers of GEP-NENs. RECENT FINDINGS Several recent GEP-NEN investigations regarding NETest demonstrate superior sensitivity and specificity in diagnosis and disease monitoring as compared with chromogranin A. Among several tissue-based emergent candidate molecules as biomarkers for GEP-NEN INSM1 has demonstrated consistently excellent characteristics when compared with traditional markers including chromogranin A, synaptophysin, and CD56. SUMMARY For the diagnosis and clinical monitoring of NEN, there still exists a considerable need for better biomarkers. Novel technology has resulted in a promising liquid biopsy for the detection and monitoring of GEP-NENs. The search for improved tissue biomarkers has resulted in identification of one potential candidate whereas several others remain in the investigatory phase.
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Affiliation(s)
- Isa Mulingbayan Jacoba
- Boston Medical Center/Boston University Chobanian & Avedisian School of Medicine, Department of Pathology & Laboratory Medicine
| | - H Christian Weber
- Boston Medical Center/Boston University Chobanian & Avedisian School of Medicine, Department of Pathology & Laboratory Medicine
- Department of Medicine
- VA Boston Healthcare System, Section of Gastroenterology and Hepatology, Boston, Massachusetts, USA
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16
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Maragliano R, Libera L, Carnevali I, Pensotti V, De Vecchi G, Testa M, Amaglio C, Leoni E, Formenti G, Sessa F, Furlan D, Uccella S. Mixed Neuroendocrine/Non-neuroendocrine Neoplasm (MiNEN) of the Ovary Arising from Endometriosis: Molecular Pathology Analysis in Support of a Pathogenetic Paradigm. Endocr Pathol 2022; 33:400-410. [PMID: 34342838 PMCID: PMC9420090 DOI: 10.1007/s12022-021-09689-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/19/2021] [Indexed: 12/19/2022]
Abstract
Primary ovarian neuroendocrine neoplasms (Ov-NENs) are infrequent and mainly represented by well-differentiated forms (neuroendocrine tumors - NETs - or carcinoids). Poorly differentiated neuroendocrine carcinomas (Ov-NECs) are exceedingly rare and only few cases have been reported in the literature. A subset of Ov-NECs are admixed with non-neuroendocrine carcinomas, as it occurs in other female genital organs, as well (mostly endometrium and uterine cervix), and may be assimilated to mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs) described in digestive and extra-digestive sites. Here, we present a case of large cell Ov-NEC admixed with an endometrioid carcinoma of the ovary, arising in the context of ovarian endometriosis, associated with a uterine endometrial atypical hyperplasia (EAH). We performed targeted next-generation sequencing analysis, along with a comprehensive immunohistochemical study and FISH analysis for TP53 locus, separately on the four morphologically distinct lesions (Ov-NEC, endometrioid carcinoma, endometriosis, and EAH). The results of our study identified molecular alterations of cancer-related genes (PIK3CA, CTNNB1, TP53, RB1, ARID1A, and p16), which were present with an increasing gradient from preneoplastic lesions to malignant proliferations, both neuroendocrine and non-neuroendocrine components. In conclusion, our findings underscored that the two neoplastic components of this Ov-MiNEN share a substantially identical molecular profile and they progress from a preexisting ovarian endometriotic lesion, in a patient with a coexisting preneoplastic proliferation of the endometrium, genotypically and phenotypically related to the ovarian neoplasm. Moreover, this study supports the inclusion of MiNEN in the spectrum ovarian and, possibly, of all gynecological NENs, among which they are currently not classified.
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Affiliation(s)
- Roberta Maragliano
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
- Dept. of Pathology, ASST Dei Sette Laghi, Varese, Italy
| | - Laura Libera
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | | | | | | | - Margherita Testa
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Cristina Amaglio
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Eleonora Leoni
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Giorgio Formenti
- Dept. of Obstetrics and Gynecology, ASST Dei Sette Laghi, Varese, Italy
| | - Fausto Sessa
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Daniela Furlan
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Silvia Uccella
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy.
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17
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Willner J, Zhou F, Moreira AL. Diagnostic Challenges in the Cytology of Thymic Epithelial Neoplasms. Cancers (Basel) 2022; 14:cancers14082013. [PMID: 35454918 PMCID: PMC9024685 DOI: 10.3390/cancers14082013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/12/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Thymic epithelial neoplasms, including thymoma, thymic carcinoma, and thymic neuroendocrine neoplasms, constitute the majority of anterior mediastinal masses. Fine needle aspirations (FNA) of mediastinal masses are infrequently encountered and are highly challenging to interpret. Thymic neoplasms display a significant degree of histologic diversity and have overlapping morphologic features with tumors from other sites. However, when properly interpreted alongside ancillary studies and radiologic findings, FNAs can yield clinically actionable results. This review aims to illustrate the usefulness and diagnostic pitfalls of thymic FNAs to assist pathologists in analyzing these specimens. Abstract Thymic epithelial neoplasms are rare tumors that constitute the majority of anterior mediastinal masses. They are classified as thymomas, thymic carcinomas, and thymic neuroendocrine neoplasms. Biopsy diagnosis is not common, and most tumors are surgically resected. Biopsy, including cytology, is indicated when a non-surgical entity is suspected or in cases of locally advanced disease. Smears of thymomas consist of round or spindle epithelial cells admixed with varying amounts of lymphocytes depending on the type of thymoma. Smears of thymic carcinoma and thymic neuroendocrine neoplasms are often indistinguishable from corresponding tumor types from other organs. Accurate cytological diagnosis can be difficult due to the histological diversity of thymomas, as well as the morphological features that certain thymic tumors share with similar tumors from other organs. However, fine needle aspiration (FNA) of anterior mediastinal masses can provide clinically actionable information and can be used to determine whether lesions require surgical, systemic, or local noninvasive treatments. Ancillary studies, namely, immunocytochemical stains, flow cytometry, and radiology, are important tools in the evaluation of thymic aspirates. This review discusses the utility and limitations of thymic FNAs and illustrates the diagnostic features and pitfalls of these specimens.
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Mete O, Wenig BM. Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Overview of the 2022 WHO Classification of Head and Neck Neuroendocrine Neoplasms. Head Neck Pathol 2022; 16:123-142. [PMID: 35312985 PMCID: PMC9018952 DOI: 10.1007/s12105-022-01435-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 02/21/2022] [Indexed: 12/17/2022]
Abstract
This review article provides a brief overview of the new WHO classification by adopting a question-answer model to highlight the spectrum of head and neck neuroendocrine neoplasms which includes epithelial neuroendocrine neoplasms (neuroendocrine tumors and neuroendocrine carcinomas) arising from upper aerodigestive tract and salivary glands, and special neuroendocrine neoplasms including middle ear neuroendocrine tumors (MeNET), ectopic or invasive pituitary neuroendocrine tumors (PitNET; formerly known as pituitary adenoma) and Merkel cell carcinoma as well as non-epithelial neuroendocrine neoplasms (paragangliomas). The new WHO classification follows the IARC/WHO nomenclature framework and restricts the diagnostic term of neuroendocrine carcinoma to poorly differentiated epithelial neuroendocrine neoplasms. In this classification, well-differentiated epithelial neuroendocrine neoplasms are termed as neuroendocrine tumors (NET), and are graded as G1 NET (no necrosis and < 2 mitoses per 2 mm2; Ki67 < 20%), G2 NET (necrosis or 2-10 mitoses per 2 mm2, and Ki67 < 20%) and G3 NET (> 10 mitoses per 2 mm2 or Ki67 > 20%, and absence of poorly differentiated cytomorphology). Neuroendocrine carcinomas (> 10 mitoses per 2 mm2, Ki67 > 20%, and often associated with a Ki67 > 55%) are further subtyped based on cytomorphological characteristics as small cell and large cell neuroendocrine carcinomas. Unlike neuroendocrine carcinomas, head and neck NETs typically show no aberrant p53 expression or loss of RB reactivity. Ectopic or invasive PitNETs are subtyped using pituitary transcription factors (PIT1, TPIT, SF1, GATA3, ER-alpha), hormones and keratins (e.g., CAM5.2). The new classification emphasizes a strict correlation of morphology and immunohistochemical findings in the accurate diagnosis of neuroendocrine neoplasms. A particular emphasis on the role of biomarkers in the confirmation of the neuroendocrine nature of a neoplasm and in the distinction of various neuroendocrine neoplasms is provided by reviewing ancillary tools that are available to pathologists in the diagnostic workup of head and neck neuroendocrine neoplasms. Furthermore, the role of molecular immunohistochemistry in the diagnostic workup of head and neck paragangliomas is discussed. The unmet needs in the field of head and neck neuroendocrine neoplasms are also discussed in this article. The new WHO classification is an important step forward to ensure accurate diagnosis that will also form the basis of ongoing research in this field.
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Affiliation(s)
- Ozgur Mete
- Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, Canada.
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
- Endocrine Oncology Site, The Princess Margaret Cancer Center, Toronto, ON, Canada.
| | - Bruce M Wenig
- Department of Pathology Moffitt Cancer Center, Tampa, FL, USA
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19
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Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, Ezzat S, de Herder WW, Klimstra DS, Papotti M, Asa SL. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr Pathol 2022; 33:115-154. [PMID: 35294740 DOI: 10.1007/s12022-022-09708-2] [Citation(s) in RCA: 433] [Impact Index Per Article: 144.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/28/2022] [Indexed: 02/07/2023]
Abstract
In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.
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Affiliation(s)
- Guido Rindi
- Department of Life Sciences and Public Health, Section of Anatomic Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.
- Department of Woman and Child Health Sciences and Public Health, Anatomic Pathology Unit, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Largo A. Gemelli, 8, 00168, Rome, Italy.
- ENETS Center of Excellence, Rome, Italy.
| | - Ozgur Mete
- Department of Pathology, University Health Network, University of Toronto, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G 2C4, Canada.
| | - Silvia Uccella
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Stefano La Rosa
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Lodewijk A A Brosens
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Shereen Ezzat
- Department of Medicine, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Wouter W de Herder
- Department of Internal Medicine, Sector of Endocrinology, Erasmus MC Cancer Institute, ENETS Center of Excellence Rotterdam, Erasmus MC, Rotterdam, The Netherlands
| | - David S Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Paige.AI, New York, NY, USA
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy
| | - Sylvia L Asa
- Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA
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20
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Elpek GO. Mixed neuroendocrine-nonneuroendocrine neoplasms of the gastrointestinal system: An update. World J Gastroenterol 2022; 28:794-810. [PMID: 35317101 PMCID: PMC8900574 DOI: 10.3748/wjg.v28.i8.794] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/15/2021] [Accepted: 01/22/2022] [Indexed: 02/06/2023] Open
Abstract
Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) of the digestive tract are a rare heterogeneous group of tumors that present many challenges in terms of diagnosis and treatment. Over the years, the diagnostic criteria, classification, and clinical behavior of these tumors have been the subjects of ongoing debate, and the various changes in their nomenclature have strengthened the challenges associated with MiNENs. This review is performed to provide an understanding of the key factors involved in the evolution of the designation of these tumors as MiNEN, highlight the current diagnostic criteria, summarize the latest data on pathogenesis and provide information on available treatments. Moreover, this work seeks to increase the awareness about these rare neoplasms by presenting the clinicopathological features and prognostic factors that play important roles in their behavior and discussing their different regions of origin in the gastrointestinal system (GIS). Currently, the MiNEN category also includes tumors in the GIS with a nonneuroendocrine component and epithelial tumors other than adenocarcinoma, depending on the organ of origin. Diagnosis is based on the presence of both morphological components in more than 30% of the tumor. However, this value needs to be reconfirmed with further studies and may be a limiting factor in the diagnosis of MiNEN by biopsy. Furthermore, available clinicopathological data suggest that the inclusion of amphicrine tumors in the definition of MiNEN is not supportive and warrants further investigation. The diagnosis of these tumors is not solely based on immunohistochemical findings. They are not hybrid tumors and both components can act independently; thus, careful grading of each component separately is required. In addition to parameters such as the metastatic state of the tumor at the time of diagnosis and the feasibility of surgical resection, the aggressive potential of both components has paramount importance in the choice of treatment. Regardless of the organ of origin within the GIS, almost MiNENs are tumors with poor prognosis and are frequently encountered in the elderly and men. They are most frequently reported in the colorectum, where data from molecular studies indicate a monoclonal origin; however, further studies are required to provide additional support for this origin.
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21
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Levy S, Verbeek WH, Eskens FA, van den Berg JG, de Groot DJA, van Leerdam ME, Tesselaar ME. First-line everolimus and cisplatin in patients with advanced extrapulmonary neuroendocrine carcinoma: a nationwide phase 2 single-arm clinical trial. Ther Adv Med Oncol 2022; 14:17588359221077088. [PMID: 35251315 PMCID: PMC8891910 DOI: 10.1177/17588359221077088] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/12/2022] [Indexed: 11/23/2022] Open
Abstract
Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) are an aggressive subgroup of neuroendocrine neoplasms (NEN). Advanced EP-NEC is generally treated with platinum-based cytotoxic regimens, but progressive disease occurs rapidly, resulting in a poor prognosis. Genetic alterations in the mammalian target for rapamycin (mTOR) pathway have been identified in NEN, providing a rationale for treatment with the mTOR-inhibitor everolimus. Methods: A prospective phase 2 single-arm study included patients with advanced EP-NEC from three Dutch NEN expertise centres between March 2016 and January 2020. Treatment consisted of cisplatin 75 mg/m2 every 3 weeks in combination with daily everolimus 7.5 mg for a maximum of six cycles, followed by maintenance everolimus until disease progression. Primary endpoint was disease control rate (DCR), defined as the sum of overall response rate (ORR) plus the rate of stable disease according to RECIST 1.1, assessed at 9-week intervals. Toxicity was evaluated according to CTCAE version 5.0. Results: Thirty-nine patients, with a median age of 64 years (range: 28–74), of whom 20 (51%) were male, were enrolled. DCR was 82.1% (95% confidence interval (CI): 66.4–92.4), with an ORR of 58.9% (CI: 42.1–74.4). Median duration of response was 6.4 (CI: 5.8–7.0) months and median progression-free survival was 6.0 (CI: 4.3–7.8) months. Three patients (8%) had durable responses lasting > 12 months. Median overall survival was 8.7 (CI: 7.8–9.6) months. Most common grade 3/4 toxicities were haematological (36%) and renal (21%). Conclusion: Everolimus in combination with cisplatin is an effective first-line treatment option for advanced EP-NEC, especially in highly selected patients. Trial registration: Clinicaltrials.gov, NCT02695459, https://clinicaltrials.gov/ct2/show/NCT02695459.
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Affiliation(s)
- Sonja Levy
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Wieke H.M. Verbeek
- Department of Gastroenterological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ferry A.L.M. Eskens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - José G. van den Berg
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Derk Jan A. de Groot
- Department of Medical Oncology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Monique E. van Leerdam
- Department of Gastroenterological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Margot E.T. Tesselaar
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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22
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Abstract
Purpose of Review Gastric neuroendocrine neoplasms (g-NENs) are a rare type of stomach cancer. The three main subtypes have different pathogeneses, biological behaviours and clinical characteristics, so they require different management strategies. This article will provide an overview of g-NENs and highlight recent advances in the field. Recent Findings Molecular profiling has revealed differences between indolent and aggressive g-NENs, as well as a new somatic mutation responsible for some familial type I g-NENs. Novel biomarkers have been developed which will hopefully improve diagnosis, treatment, risk stratification and follow-up. Patient treatment is also changing, as evidence supports the use of less aggressive options (e.g. endoscopic surveillance or resection) in some patients with more indolent tumours. Summary g-NEN heterogeneity poses challenges in understanding and managing this rare disease. More basic science research is needed to investigate molecular pathogenesis, and future larger clinical studies will hopefully also further improve treatment and patient outcomes.
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Rekhtman N. Lung neuroendocrine neoplasms: recent progress and persistent challenges. Mod Pathol 2022; 35:36-50. [PMID: 34663914 PMCID: PMC8695375 DOI: 10.1038/s41379-021-00943-2] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/28/2021] [Accepted: 09/28/2021] [Indexed: 02/07/2023]
Abstract
This review summarizes key recent developments relevant to the pathologic diagnosis of lung neuroendocrine neoplasms, including carcinoids, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC). Covered are recent insights into the biological subtypes within each main tumor type, progress in pathological diagnosis and immunohistochemical markers, and persistent challenging areas. Highlighted topics include highly proliferative carcinoids and their distinction from small cell and large cell neuroendocrine carcinomas (NECs), the evolving role of Ki67, the update on the differential diagnosis of NEC to include thoracic SMARCA4-deficient undifferentiated tumors, the recent data on SCLC transcriptional subtypes with the emergence of POU2F3 as a novel marker for the diagnosis of SCLC with low/negative expression of standard neuroendocrine markers, and the update on the diagnosis of LCNEC, particularly in biopsies. There has been remarkable recent progress in the understanding of the genetic and expression-based profiles within each type of lung neuroendocrine neoplasm, and it is hoped that these insights will enable the development of novel diagnostic, prognostic, and predictive biomarkers to aid in the pathologic assessment of these tumors in the future.
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Affiliation(s)
- Natasha Rekhtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
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Mühlethaler-Mottet A, Uccella S, Marchiori D, La Rosa S, Daraspe J, Balmas Bourloud K, Beck Popovic M, Eugster PJ, Grouzmann E, Abid K. Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension. Front Endocrinol (Lausanne) 2022; 13:1027856. [PMID: 36531507 PMCID: PMC9751011 DOI: 10.3389/fendo.2022.1027856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 11/11/2022] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION Neuroblastoma (NB) is a pediatric cancer of the developing sympathetic nervous system. It produces and releases metanephrines, which are used as biomarkers for diagnosis in plasma and urine. However, plasma catecholamine concentrations remain generally normal in children with NB. Thus, unlike pheochromocytoma and paraganglioma (PHEO/PGL), two other non-epithelial neuroendocrine tumors, hypertension is not part of the usual clinical picture of patients with NB. This suggests that the mode of production and secretion of catecholamines and metanephrines in NB is different from that in PHEO/PGL, but little is known about these discrepancies. Here we aim to provide a detailed comparison of the biosynthesis, metabolism and storage of catecholamines and metanephrines between patients with NB and PHEO. METHOD Catecholamines and metanephrines were quantified in NB and PHEO/PGL patients from plasma and tumor tissues by ultra-high pressure liquid chromatography tandem mass spectrometry. Electron microscopy was used to quantify neurosecretory vesicles within cells derived from PHEO tumor biopsies, NB-PDX and NB cell lines. Chromaffin markers were detected by qPCR, IHC and/or immunoblotting. RESULTS Plasma levels of metanephrines were comparable between NB and PHEO patients, while catecholamines were 3.5-fold lower in NB vs PHEO affected individuals. However, we observed that intratumoral concentrations of metanephrines and catecholamines measured in NB were several orders of magnitude lower than in PHEO. Cellular and molecular analyses revealed that NB cell lines, primary cells dissociated from human tumor biopsies as well as cells from patient-derived xenograft tumors (NB-PDX) stored a very low amount of intracellular catecholamines, and contained only rare neurosecretory vesicles relative to PHEO cells. In addition, primary NB expressed reduced levels of numerous chromaffin markers, as compared to PHEO/PGL, except catechol O-methyltransferase and monoamine oxidase A. Furthermore, functional assays through induction of chromaffin differentiation of the IMR32 NB cell line with Bt2cAMP led to an increase of neurosecretory vesicles able to secrete catecholamines after KCl or nicotine stimulation. CONCLUSION The low amount of neurosecretory vesicles in NB cytoplasm prevents catecholamine storage and lead to their rapid transformation by catechol O-methyltransferase into metanephrines that diffuse in blood. Hence, in contrast to PHEO/PGL, catecholamines are not secreted massively in the blood, which explains why systemic hypertension is not observed in most patients with NB.
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Affiliation(s)
- Annick Mühlethaler-Mottet
- Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Silvia Uccella
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Pathology Service, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Deborah Marchiori
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Stefano La Rosa
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy
- Institute of Pathology, Department of Laboratory Medicine and Pathology, University of Lausanne, Lausanne, Switzerland
| | - Jean Daraspe
- Electron Microscopy Facility (EMF), University of Lausanne, Lausanne, Switzerland
| | - Katia Balmas Bourloud
- Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Maja Beck Popovic
- Pediatric Hematology Oncology Unit, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Philippe J. Eugster
- Service of Clinical Pharmacology and Toxicology, Lausanne University Hospital, Lausanne, Switzerland
| | - Eric Grouzmann
- Service of Clinical Pharmacology and Toxicology, Lausanne University Hospital, Lausanne, Switzerland
| | - Karim Abid
- Service of Clinical Pharmacology and Toxicology, Lausanne University Hospital, Lausanne, Switzerland
- *Correspondence: Karim Abid,
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Behzatoğlu K, Schmitt F. Primary Small Cell Malignancies of the Breast: Are They Rare Malignancies? Acta Cytol 2021; 66:347-356. [PMID: 34923492 DOI: 10.1159/000520875] [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: 10/10/2021] [Accepted: 11/08/2021] [Indexed: 11/19/2022]
Abstract
In contrast with the other organs such as the lung, small cell tumors have been less studied in the breast due to their relatively less frequency. Although rare, neuroendocrine neoplasms, some lymphomas, and some small cell sarcomas such as undifferentiated small round cell sarcoma and rhabdomyosarcoma can be seen in small cell morphology in the breast. Many cytological specimens such as fine-needle aspiration biopsies and touch imprint cytology are used for diagnosis and further prognostic/predictive marker determination in primary breast masses, sentinel and axillary lymph nodes, and metastatic masses. Lobular carcinoma deserves to be considered in the small cell tumor group because of its small, monomorphic, discohesive, scant cytoplasmic cytological features. Since so many different types of tumors in the breast can have small cell characteristics, they should be divided into small cell neuroendocrine tumors and small cell nonneuroendocrine tumors. When evaluating small cell breast tumors cytologically, wide tumor diversity should be kept in mind, and clinical, hematological, and radiological features should be taken into consideration.
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Affiliation(s)
- Kemal Behzatoğlu
- Pathology Department, Atakent Acibadem University, Istanbul, Turkey
| | - Fernando Schmitt
- Department of Pathology, Medical Faculty of Porto University, Porto, Portugal
- Molecular Pathology Unit, Institute of Molecular Pathology and Immunology of Porto University, Porto, Portugal
- CINTESIS@RISE, Porto, Portugal
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Uccella S. The classification of neuroendocrine neoplasms of the breast and its clinical relevance. Virchows Arch 2021; 481:3-12. [PMID: 34698887 DOI: 10.1007/s00428-021-03223-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/04/2021] [Accepted: 10/19/2021] [Indexed: 02/06/2023]
Abstract
Neuroendocrine neoplasms of the breast (Br-NENs) are rare tumors of the mammary gland. Their definition and classification have been a matter of discussion for more than half a century, as they present some degree of overlap with other malignancies in the mammary gland. The recent evolutions in the understanding of the pathogenesis of neuroendocrine neoplasms (NENs) as well as the novel tools in the diagnostic arsenal of the pathologists, and a better correlation with clinical data, have led to improved classification schemes for these entities, beginning from those arising in digestive and thoracic organs. These new classification concepts have been recently expanded to NENs arising in every anatomical site, with the proposal of a common classification framework that has been applied in the 5th edition of the WHO classification of tumors. These concepts include the recognition of two distinct families of NENs (neuroendocrine tumors, NETs, and neuroendocrine carcinomas, NECs), the identification of mixed neuroendocrine/non-neuroendocrine neoplasms, and the application of definite morphological and immunohistochemical criteria for the diagnosis of NENs. The last WHO classification of Br-NENs, however, still seems to leave several unanswered questions and unmet needs in the understanding of diagnostic and clinical features of these entities. This review will critically revise the current classification of Br-NENs, underlining its lights and shadows and focusing on the identification of diagnostic histopathological criteria that can help the univocal recognition of Br-NET, Br-NEC, and Br-MiNEN.
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Affiliation(s)
- Silvia Uccella
- Department of Medicine and Surgery, Unit of Pathology, University of Insubria, via Ottorino Rossi 9 21100, Varese, Italy.
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27
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Pelosi G, Bianchi F, Dama E, Metovic J, Barella M, Sonzogni A, Albini A, Papotti M, Gong Y, Vijayvergia N. A Subset of Large Cell Neuroendocrine Carcinomas in the Gastroenteropancreatic Tract May Evolve from Pre-existing Well-Differentiated Neuroendocrine Tumors. Endocr Pathol 2021; 32:396-407. [PMID: 33433886 DOI: 10.1007/s12022-020-09659-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/16/2020] [Indexed: 02/06/2023]
Abstract
In the gastro-entero-pancreatic (GEP) tract, neuroendocrine neoplasms (NENs) include well differentiated neuroendocrine tumors (NETs) and high-grade NE carcinomas (NECs), which are thought to make up separate and mutually exclusive tumor entities. Little is known, however, as to whether there may be any pathogenetic link between them. Clustering analysis of a 10-gene panel generated from a previously reported next-generation sequencing analysis on 48 GEP-NENs with clinical annotations was used in the study. Unsupervised cluster analysis showed three histology-independent clusters, namely, C1, C2, and C3, which accounted for 44% of patients but the entire array of mutations. All but two NECs fell into the clusters, yet with different prevalence rates (p < 0.0001). A model was devised according to which NETs were likely to evolve into NECs upon progression of C3 into C1 and C2, despite different morphology. The median Ki-67 labeling index was 5% in C3 showing better prognosis and 50% in C1 and C2 experiencing worse prognosis, with an impressive intra-tumor heterogeneity of diversely proliferating tumor areas. This study suggests that a subset of large cell NECs in the gastroenteropancreatic tract may evolve from pre-existing well-differentiated NETs.
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Affiliation(s)
- Giuseppe Pelosi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
- Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy.
| | - Fabrizio Bianchi
- Cancer Biomarker Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy
| | - Elisa Dama
- Cancer Biomarker Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy
| | - Jasna Metovic
- Department of Oncology, University of Turin, Turin, Italy
| | - Marco Barella
- Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy
| | - Angelica Sonzogni
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Adriana Albini
- Laboratory of Vascular Biology and Angiogenesis, IRCCS MultiMedica, Milan, Italy
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy
| | - Yulan Gong
- Department of Pathology, Fox Chase Cancer Centre, Philadelphia, PA, USA
| | - Namrata Vijayvergia
- Department of Medical Oncology, Fox Chase Cancer Centre, Philadelphia, PA, USA
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Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplastic proliferations showing different morphological features, immunophenotype, molecular background, clinical presentation, and outcome. They can virtually originate in every organ of the human body and their classification is not uniform among different sites. Indeed, as they have historically been classified according to the organ in which they primarily arise, the different nomenclature that has resulted have created some confusion among pathologists and clinicians. Although a uniform terminology to classify neuroendocrine neoplasms arising in different systems has recently been proposed by WHO/IARC, some issues remain unsolved or need to be clarified. In this review, we discuss the lights and shadows of the current WHO classifications used to define and characterize NENs of the pituitary gland, lung, breast and those of the head and neck region, and digestive and urogenital systems.
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Affiliation(s)
- Stefano La Rosa
- Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.
- Institut Universitaire de Pathologie, CHUV, 25 rue du Bugnon, CH-1011, Lausanne, Switzerland.
| | - Silvia Uccella
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy
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Pini GM, Uccella S, Corinti M, Colecchia M, Pelosi G, Patriarca C. Primary MiNEN of the urinary bladder: an hitherto undescribed entity composed of large cell neuroendocrine carcinoma and adenocarcinoma with a distinct clinical behavior : Description of a case and review of the pertinent literature. Virchows Arch 2021; 479:69-78. [PMID: 33454836 PMCID: PMC8298318 DOI: 10.1007/s00428-021-03023-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/28/2020] [Accepted: 01/06/2021] [Indexed: 12/12/2022]
Abstract
Neuroendocrine carcinomas (NECs) of the urinary bladder are very rare and can be observed in the context of mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs), most frequently in association with urothelial carcinoma. Small cell NECs are far more common than large cell NECs (LCNECs), which are exceedingly rare. We describe a primary MiNEN of the urinary bladder, composed of a LCNEC and of an adenocarcinoma, in which the neuroendocrine component reached complete pathological regression after neoadjuvant M-VAC chemotherapy, whereas the non-neuroendocrine component of the tumor progressed to metastatic disease. Compared to mixed neuroendocrine/non-neuroendocrine neoplasms described in the literature until now, this appears to be a unique case that expands the spectrum of neuroendocrine neoplasia of the urinary bladder.
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Affiliation(s)
- Giacomo Maria Pini
- Department of Medicine and Surgery, Unit of Pathology, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Silvia Uccella
- Department of Medicine and Surgery, Unit of Pathology, University of Insubria, via O. Rossi 9, 21100, Varese, Italy.
| | | | - Maurizio Colecchia
- Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giuseppe Pelosi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy
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30
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La Rosa S. Challenges in High-grade Neuroendocrine Neoplasms and Mixed Neuroendocrine/Non-neuroendocrine Neoplasms. Endocr Pathol 2021; 32:245-257. [PMID: 33786701 PMCID: PMC8116295 DOI: 10.1007/s12022-021-09676-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/23/2021] [Indexed: 12/13/2022]
Abstract
The growth in knowledge of the pathogenesis, molecular background, and immunohistochemical profile of neuroendocrine neoplasms (NENs) has led not only to an increased awareness of these diseases but also to several changes of the nomenclature. In particular, the concept and terminology of high-grade (grade 3) NENs and mixed neoplasms have changed considerably over the last 20 years, creating some confusion among pathologists and clinicians. The aim of this review is to elucidate the diagnostic criteria, including the most important differential diagnoses of high-grade NENs and mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs). The role of the Ki67 labelling index and morphology, used to define grade 3 NENs of the digestive system and lungs, is also discussed. The evolution of the concepts and terminology of MiNENs is revised, including the most important differential diagnoses.
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Affiliation(s)
- Stefano La Rosa
- Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.
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31
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Gambella A, Falco EC, Metovic J, Maletta F, De Angelis C, Maragliano R, Uccella S, Pacchioni D, Papotti M. Amyloid-Rich Pancreatic Neuroendocrine Tumors: a Potential Diagnostic Pitfall in Endoscopic Ultrasound-Guided Fine Needle Aspiration Cytology (EUS-FNAC). Endocr Pathol 2021; 32:318-325. [PMID: 32399832 DOI: 10.1007/s12022-020-09625-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms that include even rarer variants that may pose different diagnostic problems, especially in fine needle aspiration cytology (FNAC). We describe the diagnostic clues of the amyloid-rich variant of PanNETs in endoscopic ultrasound (EUS)-guided fine needle aspiration cytology (EUS-FNAC). Three cases of PanNETs with an amyloid-rich stromal component were retrieved and retrospectively reviewed. For every case, the pancreatic lesion was investigated by a EUS-FNAC procedure. The final diagnosis was supported by immunocytochemistry and Congo red staining. All cases had similar EUS-FNAC features: neoplastic cells were entrapped in an eosinophilic, homogeneous dense and amorphous matrix. The neuroendocrine nature was confirmed by immunoexpression of synaptophysin and chromogranin A, while the amorphous stroma was characterized as amyloid based on positive Congo red staining. Regarding the hormonal profile, no insulin or proinsulin reactivity was observed, but all cases were diffusely positive for amylin. The diagnosis of uncommon variants of PanNETs, such as the amyloid-rich, is challenging especially in EUS-FNAC procedures because of a unique and misleading morphology, potentially mimicking fibrotic conditions and amyloid deposition within systemic amyloidosis. In cytology specimens, the presence of amorphous material requires amyloid deposition to be considered in the differential diagnosis of pancreatic neoplasms with neuroendocrine phenotype.
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Affiliation(s)
- Alessandro Gambella
- Division of Pathology, Città della Salute e della Scienza Hospital, Turin, Italy
| | | | - Jasna Metovic
- Department of Oncology, University of Turin, Turin, Italy
| | - Francesca Maletta
- Division of Pathology, Città della Salute e della Scienza Hospital, Turin, Italy
| | - Claudio De Angelis
- Division of Gastroenterology, Città della Salute e della Scienza Hospital, Turin, Italy
| | - Roberta Maragliano
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Silvia Uccella
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Donatella Pacchioni
- Division of Pathology, Città della Salute e della Scienza Hospital, Turin, Italy
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy.
- Anatomia Patologica, Università di Torino, Via Santena 7, I-10126, Torino, Italy.
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Vitale G, Barrea L, Aversa A. Neuroendocrine neoplasms: what we have learned and what the future holds in the pharmacological treatment. Minerva Med 2021; 112:315-317. [PMID: 33616378 DOI: 10.23736/s0026-4806.21.07450-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Giovanni Vitale
- IRCCS Istituto Auxologico Italiano, Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Cusano Milanino, Milan, Italy - .,Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy -
| | - Luigi Barrea
- Unit of Endocrinology, Department of Clinical Medicine and Surgery, Medical School of Naples, Federico II University, Naples, Italy.,Unit of Endocrinology, Department of Clinical Medicine and Surgery, Centro Italiano per la Cura e il Benessere del Paziente con Obesità (C.I.B.O), Medical School of Naples, Federico II University, Naples, Italy
| | - Antonio Aversa
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
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Recent advances and conceptual changes in the classification of neuroendocrine tumors of the thymus. Virchows Arch 2021; 478:129-135. [PMID: 33555458 PMCID: PMC7965853 DOI: 10.1007/s00428-021-03037-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/09/2020] [Accepted: 01/17/2021] [Indexed: 01/18/2023]
Abstract
Neuroendocrine tumors of the thymus (TNET) are exceedingly rare neoplasms. Their histomorphology is identical to neuroendocrine tumors elsewhere in the body (in particular the lungs) and bears no similarity with thymomas and thymic carcinomas. Recent molecular findings have profoundly changed our perception of these tumors and may impact future histological classification systems.
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Luchini C, Pelosi G, Scarpa A, Mattiolo P, Marchiori D, Maragliano R, Sessa F, Uccella S. Neuroendocrine neoplasms of the biliary tree, liver and pancreas: a pathological approach. Pathologica 2021; 113:28-38. [PMID: 33686308 PMCID: PMC8138696 DOI: 10.32074/1591-951x-231] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 11/30/2020] [Indexed: 12/14/2022] Open
Abstract
Neuroendocrine neoplasms of the pancreatobiliary tract and liver are a heterogeneous group that encompass a spectrum of entities with distinct morphological, biological and clinical features. Although in the various anatomical sub-sites of this region they show specific characteristics, these tumors, as a whole, share several etiological and clinical aspects. This review systematically addresses NENs arising in the extrahepatic bile ducts, gallbladder, liver and pancreas, with the principal aim of pinpointing essential diagnostic and classification issues. In addition, the section on hepatic NENs has been expanded to include metastatic disease of unknown primary site.
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Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Italy
| | - Giuseppe Pelosi
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
- Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Italy
- ARC-NET Research Centre, University of Verona, Italy
| | - Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Italy
| | - Deborah Marchiori
- Department of Medicine and Surgery, Unit of Pathology, University of Insubria, Varese, Italy
| | - Roberta Maragliano
- Department of Medicine and Surgery, Unit of Pathology, University of Insubria, Varese, Italy
| | - Fausto Sessa
- Department of Medicine and Surgery, Unit of Pathology, University of Insubria, Varese, Italy
| | - Silvia Uccella
- Department of Medicine and Surgery, Unit of Pathology, University of Insubria, Varese, Italy
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35
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Zombori T, Turkevi-Nagy S, Sejben A, Juhász-Nagy G, Cserni G, Furák J, Tiszlavicz L, Krenács L, Kővári B. The panel of syntaxin 1 and insulinoma-associated protein 1 outperforms classic neuroendocrine markers in pulmonary neuroendocrine neoplasms. APMIS 2021; 129:186-194. [PMID: 33417719 DOI: 10.1111/apm.13113] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 01/04/2021] [Indexed: 11/26/2022]
Abstract
Syntaxin-1 (STX1) is a recently described highly sensitive and specific neuroendocrine marker. We evaluated the applicability of STX1 as an immunohistochemical marker in pulmonary neuroendocrine neoplasms (NENs). We compared STX1 with established neuroendocrine markers, including insulinoma-associated protein 1 (INSM1). Typical carcinoids (n = 33), atypical carcinoids (n = 7), small cell lung carcinomas ([SCLCs] n = 30), and large cell neuroendocrine lung carcinomas (n = 17) were immunostained using tissue microarray for STX1, chromogranin A, synaptophysin, CD56, and INSM1. Eighty-four of eighty-seven (96.5%) NENs showed STX1 positivity. Carcinoids and LCNECs typically presented a combined strong membranous and weak cytoplasmic staining pattern; cytoplasmic expression was predominately observed in SCLCs. The sensitivity of STX1 was 90% in SCLCs and 100% in typical carcinoids, atypical carcinoids, and large cell neuroendocrine lung carcinomas. The overall sensitivity of STX1 in pulmonary NENs was 96.6%, and the sensitivity of the other markers was as follows: chromogranin A (85.2%), synaptophysin (85.2%), CD56 (92.9%), and INSM1 (97.7%). STX1 was found to be an excellent neuroendocrine marker of pulmonary NENs, with sensitivity and specificity surpassing that of classic markers. We propose a panel of STX1 and INSM1 for the routine immunohistochemical workup of pulmonary NENs.
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Affiliation(s)
- Tamás Zombori
- Department of Pathology, University of Szeged, Szeged, Hungary
| | | | - Anita Sejben
- Department of Pathology, University of Szeged, Szeged, Hungary
| | | | - Gábor Cserni
- Department of Pathology, University of Szeged, Szeged, Hungary.,Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary
| | - József Furák
- Department of Surgery, University of Szeged, Szeged, Hungary
| | | | - László Krenács
- Laboratory of Tumor Pathology and Molecular Diagnostics, Szeged, Hungary
| | - Bence Kővári
- Department of Pathology, University of Szeged, Szeged, Hungary.,Department of Pathology, Henry Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
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La Rosa S, Uccella S, Rindi G. Neuroendocrine Neoplasms of the Gut. THE SPECTRUM OF NEUROENDOCRINE NEOPLASIA 2021:207-244. [DOI: 10.1007/978-3-030-54391-4_10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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37
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Qiu J, Xin Y. Incidence and prognosis of undifferentiated cancers of the digestive system: a population-based cohort study. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:15. [PMID: 33553308 PMCID: PMC7859808 DOI: 10.21037/atm-20-1615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Cases of undifferentiated cancers of the digestive system (UCDS) are occasionally encountered in clinical practice; however, no large-scale studies have described their characteristics. This study aimed to investigate the incidence, prognosis, and treatment strategies of UCDS. Methods We used the data from the Surveillance, Epidemiology, and End Results database to evaluate clinical characteristics in UCDS patients. A cohort of 1,372 patients was included to estimate UCDS incidence; another cohort of 1,816 patients was followed up until December 31, 2017 to evaluate treatment and prognosis. The incidence, trends, treatments, overall survival, and cause-specific survival were assessed. Results The estimated incidence of UCDS was 0.136 per 100,000 people-years [95% confidence interval (CI): 0.129-0.143] from 1975 to 2016 with respect to sex, age, year of diagnosis, race, region, site, income, and education. The age-adjusted rates of UCDS dropped from 0.567 per 100,000 people-years in 1978 to 0.031 per 100,000 people-years in 2016. The rates of surgery, beam radiation, and chemotherapy in patients with UCDS were 37.3%, 17.3%, and 30.7%, respectively. Overall, the 5-year cause-specific survival rate was 18%, with a median cause-specific survival of 4 months. Patient prognosis improved significantly over the decades; stage, site, year of diagnosis, surgery, beam radiation, and chemotherapy were independent prognostic factors for UCDS mortality. Conclusions The incidence of UCDS has decreased in the United States over the past 40 years. Patients benefited from surgery, beam radiation, and chemotherapy. The survival of patients with UCDS has improved. Further research on developing decision-making recommendations for UCDS treatment is crucial.
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Affiliation(s)
- Jingping Qiu
- Department of Radiation oncology, The First Hospital of China Medical University, Shenyang, China.,Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Hospital of China Medical University, Shenyang, China
| | - Yan Xin
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Hospital of China Medical University, Shenyang, China
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Liberini V, Huellner MW, Grimaldi S, Finessi M, Thuillier P, Muni A, Pellerito RE, Papotti MG, Piovesan A, Arvat E, Deandreis D. The Challenge of Evaluating Response to Peptide Receptor Radionuclide Therapy in Gastroenteropancreatic Neuroendocrine Tumors: The Present and the Future. Diagnostics (Basel) 2020; 10:E1083. [PMID: 33322819 PMCID: PMC7763988 DOI: 10.3390/diagnostics10121083] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/09/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023] Open
Abstract
The NETTER-1 study has proven peptide receptor radionuclide therapy (PRRT) to be one of the most effective therapeutic options for metastatic neuroendocrine tumors (NETs), improving progression-free survival and overall survival. However, PRRT response assessment is challenging and no consensus on methods and timing has yet been reached among experts in the field. This issue is owed to the suboptimal sensitivity and specificity of clinical biomarkers, limitations of morphological response criteria in slowly growing tumors and necrotic changes after therapy, a lack of standardized parameters and timing of functional imaging and the heterogeneity of PRRT protocols in the literature. The aim of this article is to review the most relevant current approaches for PRRT efficacy prediction and response assessment criteria in order to provide an overview of suitable tools for safe and efficacious PRRT.
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Affiliation(s)
- Virginia Liberini
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
- Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Martin W. Huellner
- Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Serena Grimaldi
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
| | - Monica Finessi
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
| | - Philippe Thuillier
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
- Department of Endocrinology, University Hospital of Brest, 29200 Brest, France
| | - Alfredo Muni
- Department of Nuclear Medicine, S.S. Biagio e Antonio e C. Arrigo Hospital, 15121 Alessandria, Italy;
| | | | - Mauro G. Papotti
- Pathology Unit, City of Health and Science University Hospital, 10126 Turin, Italy;
- Department of Oncology, University of Turin at Molinette Hospital, 10126 Turin, Italy
| | - Alessandro Piovesan
- Department of Endocrinology, A. O. U. Città della Salute della Scienza of Turin, 10126 Turin, Italy;
| | - Emanuela Arvat
- Oncological Endocrinology, Department of Medical Sciences, University of Turin, 10126 Turin, Italy;
| | - Désirée Deandreis
- Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.G.); (M.F.); (P.T.); (D.D.)
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Juhlin CC, Zedenius J, Höög A. Clinical Routine Application of the Second-generation Neuroendocrine Markers ISL1, INSM1, and Secretagogin in Neuroendocrine Neoplasia: Staining Outcomes and Potential Clues for Determining Tumor Origin. Endocr Pathol 2020; 31:401-410. [PMID: 32813226 PMCID: PMC7665972 DOI: 10.1007/s12022-020-09645-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/10/2020] [Indexed: 12/13/2022]
Abstract
Neuroendocrine neoplasms (NENs) have traditionally been identified via expression of proteins associated to the regulation of secretory vesicles and granules. We report the clinical usage of the "second-generation" proteins ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSM1), and secretagogin (SECG) as immunohistochemical markers of neuroendocrine differentiation since their introduction in clinical routine and compare the results with the established proteins chromogranin A (CGA) and synaptophysin (SYP). In total, 161 tumors, including 139 NENs and 22 "non-NENs" (unrelated tumors with an initial suspicion of NEN), were informatively stained for ISL1, and subsets were also interrogated for INSM1 and/or SECG. Diffuse or focal positive immunoreactivity was noted for ISL1 in 91/139 NENs (65%) and in 6/22 (27%) non-NENs, for INSM1 in 76/85 NENs (89%) and in 2/5 (40%) non-NENs, and for SECG in 49 out of 64 NENs (77%) and in 0/5 non-NENs (0%). Generally, ISL1, INSM1, and SECG exhibited sensitivities in line with or slightly below that of CGA and SYP-largely attributable to tissue-specific patterns regarding tumoral origin. Moreover, for pancreatic and small intestinal NENs, the two largest subgroups, ISL1 staining results were consistent irrespectively of tumor source and WHO grade. We verify previously suggested immunohistochemical schemes of neuroendocrine markers of first- and second-generations to facilitate the diagnostic process for NENs and confirm that the second-generation neuroendocrine markers display tissue-specific patterns. We therefore recommend their implementation in tertiary endocrine pathology centers, not least to aid in the identification of primary tumors when analyzing metastases.
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Affiliation(s)
- Carl Christofer Juhlin
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden
| | - Jan Zedenius
- Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden
| | - Anders Höög
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden
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Uccella S, Finzi G, Sessa F, La Rosa S. On the Endless Dilemma of Neuroendocrine Neoplasms of the Breast: a Journey Through Concepts and Entities. Endocr Pathol 2020; 31:321-329. [PMID: 32613538 DOI: 10.1007/s12022-020-09637-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Neuroendocrine differentiation in breast carcinomas has been a matter of discussion since it was first described almost 60 years ago. Indeed, so-called neuroendocrine neoplasms of the breast (Br-NENs) are a less well-defined group of neoplasms than analogous entities in other anatomic sites, such as the lung and the gastroenteropancreatic (GEP) tract. Pure neuroendocrine phenotype is extremely rare, whereas the expression of neuroendocrine markers in usual breast carcinomas, both of special and of non-special type, without evident neuroendocrine morphology, is more common. In this context, the diagnostic criteria and the classification scheme for Br-NENs have been continuously changing over time and real consensus on this topic is still lacking, despite the recent publication of the 5th edition of the WHO classification of breast tumors. In this review, we will recapitulate the evolution of the concept of Br-NEN; revise the available knowledge on their morphological, molecular, and clinical features; and critically discuss the current classification scheme.
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Affiliation(s)
- Silvia Uccella
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy.
| | - Giovanna Finzi
- Department of Pathology, ASST dei Sette Laghi, Varese, Italy
| | - Fausto Sessa
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Stefano La Rosa
- Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland
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Wan X, Zhang H, Zhang Y, Peng Y. Metastases to the Breast from Extramammary Nonhematological Malignancies: Case Series. Int J Gen Med 2020; 13:1105-1114. [PMID: 33209053 PMCID: PMC7670084 DOI: 10.2147/ijgm.s276602] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/21/2020] [Indexed: 02/05/2023] Open
Abstract
Objective This article aims to provide a better understanding of ultrasonography and immunohistochemistry of secondary nonhematological tumors of breast. Methods The study reviewed the ultrasound findings and immunohistochemical features of nonhematological metastatic breast tumor cases found in patients of West China Hospital, Sichuan University from 2007 to 2019. Each case was categorized as secondary breast malignancy using histopathological results. Results Fourteen cases were identified from West China Hospital database. Ten cases originated in the lung, 2 cases in the stomach, 1 case in the ovary and 1 case of neuroendocrine carcinomas. Fourteen masses were evaluated. Ultrasound findings showed that tumors were hypoechoic (14/14), irregular (13/14), indistinct margin (13/14), along a long axis parallel to the skin (11/14), lacked vascularity via color doppler flow imaging (9/14). Eight cases showed no posterior features. Calcification was found in 1 case of lung adenocarcinoma that had metastasized to the breast. Abnormal axillary lymph nodes were detected in 5 cases. Immunohistochemical analysis showed that estrogen receptor (ER) and progesterone receptor (PR) were both negative in 11 cases, including gastric and lung cancer metastasis. One case of ovarian metastasis was positive for ER and negative for PR. Six patients were positive for cytokeratin 7 (CK7) and negative for cytokeratin 20 (CK20), including lung and ovarian carcinoma metastasis. Thyroid transcription factor-1 (TTF-1) was positive in 9 of 10 pulmonary carcinoma metastases. The patient of ovarian metastasis was positive for Wilms' tumour 1 (WT-1) and carbohydrate antigen 125 (CA125). Two cases from gastric metastasis were positive for caudal-type homeobox 2 (CDX2). Conclusion Although breast ultrasound is not useful in distinguishing metastases from primary breast cancer, it is helpful in diagnosing breast lesions as oncological diseases and provide evidence for further examination of patients. Immunohistochemistry plays an important role in distinguishing secondary breast cancer from primary, especially in patients without tumor history.
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Affiliation(s)
- Xue Wan
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Heqing Zhang
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Yahan Zhang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Yulan Peng
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
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Uccella S, La Rosa S. Looking into digestive mixed neuroendocrine - nonneuroendocrine neoplasms: subtypes, prognosis, and predictive factors. Histopathology 2020; 77:700-717. [PMID: 32538468 DOI: 10.1111/his.14178] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mixed neuroendocrine - nonneuroendocrine neoplasms (MiNENs) of the digestive system represent a challenge for both pathologists and clinicians. Their nomenclature has changed several times, and their diagnostic criteria, classification and clinical behaviour have been matter of debate over the years. Although several attempts have been made to elucidate the pathogenesis and biology of MiNENs, some issues remain open. This review will provide: a historical background that helps in understanding the evolution of the concept and nomenclature of mixed neoplasms; a revision of the knowledge on this topic, including molecular aspects, to give the reader a comprehensive and practical overview on this challenging field of pathology; a focus on the diagnostic criteria and on the determination of prognostic and predictive factors; and a description of the different tumour types in the different sites of origin.
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Affiliation(s)
- Silvia Uccella
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Stefano La Rosa
- Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland
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Shi H, Jiang C, Zhang Q, Qi C, Yao H, Lin R. Clinicopathological heterogeneity between primary and metastatic sites of gastroenteropancreatic neuroendocrine neoplasm. Diagn Pathol 2020; 15:108. [PMID: 32917216 PMCID: PMC7488304 DOI: 10.1186/s13000-020-01030-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 09/04/2020] [Indexed: 12/11/2022] Open
Abstract
Background Chromogranin A (CgA), synaptophysin (Syn) and the Ki-67 index play significant roles in diagnosis or the evaluation of the proliferative activity of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, little is known about whether these biological markers change during tumor metastasis and whether such changes have effect on prognosis. Methods We analyzed 35 specimens of both primary and metastatic tumor from 779 patients who had been diagnosed as GEP-NENs at Wuhan Union Hospital from August 2011 to October 2019. The heterogeneity of CgA, Syn and Ki-67 index was evaluated by immunohistochemical analysis. Results Among these 779 patients, the three most common sites of NENs in the digestive tract were the pancreas, rectum and stomach. Metastases were found in 311 (39.9%) patients. Among the 35 patients with both primary and metastatic pathological specimens, differences in the Ki-67 level were detected in 54.3% of the patients, while 37.1% showed a difference in CgA and only 11.4% showed a difference in Syn. Importantly, due to the difference in the Ki-67 index between primary and metastatic lesions, the WHO grade was changed in 8.6% of the patients. In addition, a Kaplan–Meier survival analysis showed that patients with Ki-67 index variation had a shorter overall survival (p = 0.0346), while neither Syn variation nor CgA variation was related to patient survival (p = 0.7194, p = 0.4829). Conclusions Our data indicate that primary and metastatic sites of GEP-NENs may exhibit pathological heterogeneity. Ki-67 index variation is closely related to the poor prognosis of patients with tumor metastasis, but neither Syn variation nor CgA variation is related to patient prognosis. Therefore, clinicopathologic evaluation of the primary tumor and metastatic sites could be helpful for predicting the prognosis.
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Affiliation(s)
- Huiying Shi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chen Jiang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qin Zhang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Cuihua Qi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hailing Yao
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Hodgson A, Pakbaz S, Shenouda C, Francis JA, Mete O. Mixed Sparsely Granulated Lactotroph and Densely Granulated Somatotroph Pituitary Neuroendocrine Tumor Expands the Spectrum of Neuroendocrine Neoplasms in Ovarian Teratomas: the Role of Pituitary Neuroendocrine Cell Lineage Biomarkers. Endocr Pathol 2020; 31:315-319. [PMID: 32632841 DOI: 10.1007/s12022-020-09639-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/01/2020] [Indexed: 12/24/2022]
Affiliation(s)
- Anjelica Hodgson
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G 2C4, Canada
| | - Caroline Shenouda
- Department of Obstetrics and Gynecology, Mackenzie Health, Richmond Hill, ON, Canada
| | - Julie-Ann Francis
- Gynecologic Oncology Program, Lakeridge Health - The Oshawa Hospital, Oshawa, ON, Canada
| | - Ozgur Mete
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G 2C4, Canada.
- Endocrine Oncology Site, The Princess Margaret Cancer Centre, Toronto, ON, Canada.
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Han XY, Wang YY, Wei HQ, Yang GZ, Wang J, Jia YZ, Ao WQ. Multifocal neuroendocrine cell hyperplasia accompanied by tumorlet formation and pulmonary sclerosing pneumocytoma: A case report. World J Clin Cases 2020; 8:3583-3590. [PMID: 32913868 PMCID: PMC7457093 DOI: 10.12998/wjcc.v8.i16.3583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 07/06/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pulmonary tumorlets are nodular hyperplastic neuroendocrine cells (NECs) that extend beyond the basement membrane. They often coexist with other lung diseases such as fibrosis and bronchiectasis, but rarely accompanied by pulmonary sclerosing pneumocytoma (PSP), which has not been reported in the literature.
CASE SUMMARY A 54-year-old woman was admitted to the hospital because she had symptoms of bloody sputum for more than 4 mo and hemoptysis for 1 wk. Computed tomography images showed atrophy accompanied by infections in the middle lobe of her right lung. Moreover, numerous nodules were identified in the middle lobe of the right lung. The patient underwent thoracoscopic pneumonectomy of the middle lobe of the right lung, and the resected mass was pathologically confirmed to have bronchiectasis, multifocal NEC hyperplasia accompanied by tumorlet, and PSP.
CONCLUSION Our report presents a rare clinical case of bronchiectasis complicated with multifocal NEC hyperplasia, tumorlet, and PSP.
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Affiliation(s)
- Xiao-Yu Han
- Department of Pathology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Yuan-Yuan Wang
- Department of Pathology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Hong-Quan Wei
- Department of Pathology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Guang-Zhao Yang
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Jian Wang
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Yu-Zhu Jia
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Wei-Qun Ao
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
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Nanayakkara J, Tyryshkin K, Yang X, Wong JJM, Vanderbeck K, Ginter PS, Scognamiglio T, Chen YT, Panarelli N, Cheung NK, Dijk F, Ben-Dov IZ, Kim MK, Singh S, Morozov P, Max KEA, Tuschl T, Renwick N. Characterizing and classifying neuroendocrine neoplasms through microRNA sequencing and data mining. NAR Cancer 2020; 2:zcaa009. [PMID: 32743554 PMCID: PMC7380486 DOI: 10.1093/narcan/zcaa009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/22/2020] [Accepted: 06/06/2020] [Indexed: 12/13/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are clinically diverse and incompletely characterized cancers that are challenging to classify. MicroRNAs (miRNAs) are small regulatory RNAs that can be used to classify cancers. Recently, a morphology-based classification framework for evaluating NENs from different anatomical sites was proposed by experts, with the requirement of improved molecular data integration. Here, we compiled 378 miRNA expression profiles to examine NEN classification through comprehensive miRNA profiling and data mining. Following data preprocessing, our final study cohort included 221 NEN and 114 non-NEN samples, representing 15 NEN pathological types and 5 site-matched non-NEN control groups. Unsupervised hierarchical clustering of miRNA expression profiles clearly separated NENs from non-NENs. Comparative analyses showed that miR-375 and miR-7 expression is substantially higher in NEN cases than non-NEN controls. Correlation analyses showed that NENs from diverse anatomical sites have convergent miRNA expression programs, likely reflecting morphological and functional similarities. Using machine learning approaches, we identified 17 miRNAs to discriminate 15 NEN pathological types and subsequently constructed a multilayer classifier, correctly identifying 217 (98%) of 221 samples and overturning one histological diagnosis. Through our research, we have identified common and type-specific miRNA tissue markers and constructed an accurate miRNA-based classifier, advancing our understanding of NEN diversity.
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Affiliation(s)
- Jina Nanayakkara
- Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON K7L 3N6, Canada
| | - Kathrin Tyryshkin
- Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON K7L 3N6, Canada
| | - Xiaojing Yang
- Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON K7L 3N6, Canada
| | - Justin J M Wong
- Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON K7L 3N6, Canada
| | - Kaitlin Vanderbeck
- Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON K7L 3N6, Canada
| | - Paula S Ginter
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Theresa Scognamiglio
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Yao-Tseng Chen
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Nicole Panarelli
- Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Nai-Kong Cheung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Frederike Dijk
- Department of Pathology, Amsterdam University Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Iddo Z Ben-Dov
- Department of Nephrology and Hypertension, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Michelle Kang Kim
- Center for Carcinoid and Neuroendocrine Tumors of Mount Sinai, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Simron Singh
- Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, ON M4N 3M5, Canada
| | - Pavel Morozov
- Laboratory of RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Klaas E A Max
- Laboratory of RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Thomas Tuschl
- Laboratory of RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Neil Renwick
- Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON K7L 3N6, Canada
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Tang JY, Gao HJ, Shi GD, Guo XK, Yu WQ, Wang HF, Wei YC. Development and validation of a nomogram prognostic model for patients with neuroendocrine tumors of the thymus. Thorac Cancer 2020; 11:2457-2464. [PMID: 32656987 PMCID: PMC7471026 DOI: 10.1111/1759-7714.13556] [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: 04/17/2020] [Revised: 06/08/2020] [Accepted: 06/11/2020] [Indexed: 12/05/2022] Open
Abstract
Background The purpose of this study was to analyze the clinical characteristics and prognostic survival of patients with neuroendocrine tumors of the thymus (NETTs), and to develop and validate a nomogram model for predicting the prognosis of patients. Methods We conducted a retrospective analysis of patients with neuroendocrine tumors of the thymus in the Surveillance, Epidemiology, and End Results (SEER) database in the United States between 1988 and 2016. Cox scale risk regression analysis, the Kaplan‐Meier method and log‐rank test were used to carry out the significance test to determine the independent prognostic factors, from which a nomogram for NETTs was established. C‐index and calibration curve were used to evaluate the prediction accuracy of the model. External validation of the nomogram was performed using data from our center. Results A total of 254 patients with NETTs were collected in the SEER database. In the multivariable analysis, T stage, tumor grade, surgery, and chemotherapy were found to be independent factors affecting the prognosis of patients (all P < 0.05). A nomogram model was constructed based on these variables, and its c‐index was 0.707 (0.661–0.752). The c‐index results showed that the nomogram model had better authentication capability than the eighth edition of the tumor, node, metastasis (TNM) staging system and Masaoka‐Koga (MK) staging system. The calibration curve showed that the model could accurately predict patient prognosis. Conclusions The study established a nomogram model that predicted the overall survival rate of one‐, three‐ and five‐years, and used the survival prediction model to optimize individualized therapy and prognostic follow‐up through risk stratification.
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Affiliation(s)
- Jia-Yu Tang
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Hui-Jiang Gao
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Guo-Dong Shi
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Xiao-Kang Guo
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Wen-Quan Yu
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Hua-Feng Wang
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Yu-Cheng Wei
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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Baine MK, Rekhtman N. Multiple faces of pulmonary large cell neuroendocrine carcinoma: update with a focus on practical approach to diagnosis. Transl Lung Cancer Res 2020; 9:860-878. [PMID: 32676352 PMCID: PMC7354156 DOI: 10.21037/tlcr.2020.02.13] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive malignancy that is strongly linked to smoking and notoriously difficult to diagnose and treat. Recent molecular data reveal that it represents a biologically heterogeneous group of tumors, characterized by morphologic and genomic diversity that straddles small cell and non-small cell lung carcinomas (NSCLCs), and in a minority of cases atypical carcinoids. This review provides an update on recent molecular and clinical developments in LCNEC with the main focus on practical approach to pathologic diagnosis using illustrative examples of the main differential diagnostic considerations.
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Affiliation(s)
- Marina K Baine
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Natasha Rekhtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Syntaxin 1: A Novel Robust Immunophenotypic Marker of Neuroendocrine Tumors. Int J Mol Sci 2020; 21:ijms21041213. [PMID: 32059362 PMCID: PMC7072745 DOI: 10.3390/ijms21041213] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/03/2020] [Accepted: 02/10/2020] [Indexed: 12/26/2022] Open
Abstract
Considering the specific clinical management of neuroendocrine (NE) neoplasms (NENs), immunohistochemistry (IHC) is required to confirm their diagnosis. Nowadays, synaptophysin (SYP), chromogranin A (CHGA), and CD56 are the most frequently used NE immunohistochemical markers; however, their sensitivity and specificity are less than optimal. Syntaxin 1 (STX1) is a member of a membrane-integrated protein family involved in neuromediator release, and its expression has been reported to be restricted to neuronal and NE tissues. In this study, we evaluated STX1 as an immunohistochemical marker of NE differentiation. STX1, SYP, CHGA, and CD56 expression was analyzed in a diverse series of NE tumors (NETs), NE carcinomas (NECs), and non-NE tumors. All but one (64/65; 98%) NETs and all (54/54; 100%) NECs revealed STX1 positivity in at least 50% of the tumor cells. STX1 showed the highest sensitivity both in NETs (99%) and NECs (100%) compared to CHGA (98% and 91%), SYP (96% and 89%), and CD56 (70% and 93%), respectively. A wide variety of non-NE tumors were tested and found to be uniformly negative, yielding a perfect specificity. We established that STX1 is a robust NE marker with an outstanding sensitivity and specificity. Its expression is independent of the site and grade of the NENs.
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50
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Jin XF, Spöttl G, Maurer J, Nölting S, Auernhammer CJ. Inhibition of Wnt/β-Catenin Signaling in Neuroendocrine Tumors in vitro: Antitumoral Effects. Cancers (Basel) 2020; 12:cancers12020345. [PMID: 32033025 PMCID: PMC7072467 DOI: 10.3390/cancers12020345] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/18/2020] [Accepted: 01/30/2020] [Indexed: 12/17/2022] Open
Abstract
Background and aims: Inhibition of Wnt/β-catenin signaling by specific inhibitors is currently being investigated as an antitumoral strategy for various cancers. The role of Wnt/β-catenin signaling in neuroendocrine tumors still needs to be further investigated. Methods: This study investigated the antitumor activity of the porcupine (PORCN) inhibitor WNT974 and the β-catenin inhibitor PRI-724 in human neuroendocrine tumor (NET) cell lines BON1, QGP-1, and NCI-H727 in vitro. NET cells were treated with WNT974, PRI-724, or small interfering ribonucleic acids against β-catenin, and subsequent analyses included cell viability assays, flow cytometric cell cycle analysis, caspase3/7 assays and Western blot analysis. Results: Treatment of NET cells with WNT974 significantly reduced NET cell viability in a dose- and time-dependent manner by inducing NET cell cycle arrest at the G1 and G2/M phases without inducing apoptosis. WNT974 primarily blocked Wnt/β-catenin signaling by the dose- and time-dependent downregulation of low-density lipoprotein receptor-related protein 6 (LRP6) phosphorylation and non-phosphorylated β-catenin and total β-catenin, as well as the genes targeting the latter (c-Myc and cyclinD1). Furthermore, the WNT974-induced reduction of NET cell viability occurred through the inhibition of GSK-3-dependent or independent signaling (including pAKT/mTOR, pEGFR and pIGFR signaling). Similarly, treatment of NET cells with the β-catenin inhibitor PRI-724 caused significant growth inhibition, while the knockdown of β-catenin expression by siRNA reduced NET tumor cell viability of BON1 cells but not of NCI-H727 cells. Conclusions: The PORCN inhibitor WNT974 possesses antitumor properties in NET cell lines by inhibiting Wnt and related signaling. In addition, the β-catenin inhibitor PRI-724 possesses antitumor properties in NET cell lines. Future studies are needed to determine the role of Wnt/β-catenin signaling in NET as a potential therapeutic target.
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Affiliation(s)
- Xi-Feng Jin
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany; (X.-F.J.); (G.S.); (J.M.); (S.N.)
| | - Gerald Spöttl
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany; (X.-F.J.); (G.S.); (J.M.); (S.N.)
| | - Julian Maurer
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany; (X.-F.J.); (G.S.); (J.M.); (S.N.)
| | - Svenja Nölting
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany; (X.-F.J.); (G.S.); (J.M.); (S.N.)
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Marchioninistr. 15, 81377 Munich, Germany
| | - Christoph Josef Auernhammer
- Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany; (X.-F.J.); (G.S.); (J.M.); (S.N.)
- Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Marchioninistr. 15, 81377 Munich, Germany
- Correspondence:
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