|
1
|
Mukherjee S, Vagha S, Mukherjee M. Various Markers of Neuroendocrine Tumor: A Narrative Review. Cureus 2024; 16:e67493. [PMID: 39314560 PMCID: PMC11417284 DOI: 10.7759/cureus.67493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
Neuroendocrine tumors (NETs) are uncommon tumors that develop from specialized endocrine cells. Thyroid medullary carcinoma, phaeochromocytomas, pituitary tumors, carcinoid, and gastroenteropancreatic NET are just a few examples of the diverse group known as NET. In recent times, they have garnered significant interest due to their ease of palliation and ability to reveal the long-term impact of the specific hormone raised. Neuroendocrine indicators, particularly chromogranin A, are very helpful in the diagnostic process. Accurate biomarkers that can be employed for NET diagnosis, prognosis and follow-up, therapy stratification, and treatment response evaluation are greatly needed. Due to the great diversity of neuroendocrine neoplasms, particular biomarkers must be developed in order to diagnose, treat, and identify them. The several NET biomarkers covered in this review will aid in the fight against this uncommon illness.
Collapse
Affiliation(s)
- Sreetama Mukherjee
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sunita Vagha
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | | |
Collapse
|
|
2
|
Abstract
Most pancreatic neuroendocrine neoplasms are slow-growing, and the patients may survive for many years, even after distant metastasis. The tumors usually display characteristic organoid growth patterns with typical neuroendocrine morphology. A smaller portion of the tumors follows a more precipitous clinical course. The classification has evolved from morphologic patterns to the current World Health Organization classification, with better-defined grading and prognostic criteria. Recent advances in molecular pathology have further improved our understanding of the pathogenesis of these tumors. Various issues and challenges remain, including the correct recognition of a neuroendocrine neoplasm, accurate classification and grading of the tumor, and differentiation from mimickers. This review focuses on the practical aspects during the workup of pancreatic neuroendocrine neoplasms and attempts to provide a general framework to help achieve an accurate diagnosis, classification, and grading.
Collapse
|
|
3
|
Van Treeck BJ, Dasari S, Kurtin PJ, Theis JD, Nasr SH, Zhang L, Yasir S, Graham RP, McPhail ED, Said S. Somatostatin-derived amyloidosis: a novel type of amyloidosis associated with well-differentiated somatostatin-producing neuroendocrine tumours. Amyloid 2022; 29:58-63. [PMID: 34541974 DOI: 10.1080/13506129.2021.1979512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To report the clinicopathologic and proteomic characteristics of a novel form of amyloidosis derived from the precursor protein somatostatin. MATERIALS AND METHODS Cases were identified by searching the Mayo Clinic amyloid liquid chromatography and tandem mass spectrometry (LC-MS/MS) typing database from 1 January 2008 to 1 September 2020 for specimens with the amyloid signature proteins and abundant somatostatin, in the absence of other amyloid precursor proteins. All available medical records and pathologic materials were examined. RESULTS Somatostatin-derived amyloid deposits were found in four patients, two females and two males, with a median age of 61.5 years (range 47-73 years). One patient also had neurofibromatosis-1. The amyloid in each case was associated with a well-differentiated, somatostatin-producing neuroendocrine tumour arising in the small bowel or pancreas. The amyloid deposits were Congo Red-positive and were readily identified by LC- MS/MS analysis. Somatostatin was present exclusively in somatostatin-associated amyloid cases (p < .001), compared to small bowel and pancreas amyloidosis cases of other types. Long-term follow-up is available for one patient who is alive 6 years after initial presentation. CONCLUSION We propose that somatostatin-related amyloidosis is a novel localised human amyloid type that arises in association with well-differentiated somatostatin-producing enteropancreatic neuroendocrine tumours. Treatment of the associated neuroendocrine tumour may be adequate therapy for these patients.
Collapse
Affiliation(s)
| | - Surendra Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Paul J Kurtin
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Jason D Theis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Lizhi Zhang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Saba Yasir
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Ellen D McPhail
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Samar Said
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
Kidd M, Kitz A, Drozdov I, Modlin I. Neuroendocrine Tumor Omic Gene Cluster Analysis Amplifies the Prognostic Accuracy of the NETest. Neuroendocrinology 2021; 111:490-504. [PMID: 32392558 DOI: 10.1159/000508573] [Citation(s) in RCA: 16] [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] [Received: 02/04/2020] [Accepted: 05/11/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND The NETest is a multigene assay comprising 51 circulating neuroendocrine tumor (NET)-specific transcripts. The quotient of the 51-gene assay is based upon an ensemble of machine learning algorithms. Eight cancer hallmarks or "omes" (apoptome, epigenome, growth factor signalome, metabolome, proliferome, plurome, secretome, SSTRome) represent 29 genes. The NETest is an accurate diagnostic (>90%) test, but its prognostic utility has not been assessed. In this study, we describe the expansion of the NETest omic cluster components and demonstrate that integration amplifies NETest prognostic accuracy. METHODS Group 1: n = 222; including stable disease (SD, n = 146), progressive disease (PD, n = 76), and controls (n = 139). Group 2: NET Registry NCT02270567; n = 88; prospective samples (SD, n = 54; PD, n = 34) with up to 24 months follow-up. We used PubMed literature review, interactomic analysis, nonparametric testing, Kaplan-Meier survival curves, and χ2 analyses to inform and define the prognostic significance of NET genomic "hallmarks." RESULTS 2020 analyses: In-depth analyses of 47 -NETest genes identified a further six omes: fibrosome, inflammasome, metastasome, NEDome, neurome, and TFome. Group 1 analysis: Twelve omes, excluding the inflammasome and apoptome, were significantly (p < 0.05, 2.1- to 8.2-fold) elevated compared to controls. In the PD group, seven omes (proliferome, NEDome, epigenome, SSTRome, neurome, metastasome, and fibrosome) were elevated (both expression levels and fold change >2) versus SD. Group 2 analysis: All these seven omes were upregulated. In PD, they were significantly more elevated (p < 0.02) than in SD. The septet omic expression exhibited a 69% prognostic accuracy. The NETest alone was 70.5% accurate. A low NETest (≤40) integrated with epigenome/metastasome levels was an accurate prognostic for PD (90%). A high NETest (>40) including the fibrosome/NEDome predicted PD development within 3 months (100%). Using decision tree analysis to integrate the four omes (epigenome, metastasome, fibrosome, and NEDome) with the NETest score generated an overall prognostic accuracy of 93%. CONCLUSIONS Examination of NETest omic gene cluster analysis identified five additional clinically relevant cancer hallmarks. Identification of seven omic clusters (septet) provides a molecular pathological signature of disease progression. The integration of the quartet (epigenome, fibrosome, metastasome, NEDome) and the NETest score yielded a 93% accuracy in the prediction of future disease status.
Collapse
Affiliation(s)
- Mark Kidd
- Wren Laboratories, Branford, Connecticut, USA
| | | | | | - Irvin Modlin
- Yale University School of Medicine, New Haven, Connecticut, USA,
| |
Collapse
|
|
6
|
Abstract
Neuroendocrine neoplasms (NENs) of the gastrointestinal (GI) tract and pancreas are a rare and heterogeneous group of neoplasms characterized by common cellular features as well as unique site-specific traits. GI and pancreatic NENs are much rarer than the more common adenocarcinomas arising at these sites. However, the incidences of GI and pancreatic NENs have increased significantly, particularly in the stomach and common site, followed by rectum, appendix, colon, and stomach. Pancreatic NENs are also uncommon, with fewer than 1 per 100,000, accounting for 1% to 2% of all pancreatic neoplasms.
Collapse
|
|
7
|
Desai GS, Pande P, Chhabra V, Shah RC, Jagannath P. Multimodality management, recurrence patterns, and long-term outcome of gastroenteropancreatic neuroendocrine neoplasms: Progress over 17 years. Indian J Gastroenterol 2019; 38:399-410. [PMID: 31802438 DOI: 10.1007/s12664-019-00957-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 04/14/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Many advances in the management of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) happened in the last two decades. This study highlights the progress in its management over 17 years, outcomes, recurrence patterns, and follow up protocols. METHODS This retrospective analysis of prospectively maintained database at a single tertiary center included GEP-NEN patients from January 2001 to August 2017. Management protocols were based on European Neuroendocrine Tumor Society guidelines. Recurrences were categorized as follows: localized nodal, regional, distant hepatic, or combined. Patients were divided into cohorts: cohort 1 (2001-2006), cohort 2 (2007-2011), and cohort 3 (2012-2017). Survival patterns were analyzed. RESULTS One hundred and ninety-two patients were included with 98 (51.04%) grade (G) 1, 64 (33.34%) G2, and 30 (15.63%) G3. One hundred and four (54.16%) underwent curative surgery (58 G1, 27 G2, and 19 G3). Overall follow up ranged from 3 to 276 months; 39 were lost to follow up. Ninety-six patients had recurrences: 44 regional + distant and 40 liver-limited recurrences. One-, 3-, and 5-year survivals show significant differences among different treatment groups (p < 0.05). Significant increase in curative resections, chemotherapy utilization, and reduced recurrences were noted in cohort 3. Curative (R0) resection offered 1- and 3-year overall survival of 93.3% and 66.7% in cohort 1; 95.8% and 83.1% in cohort 2; and 100% and 92.9% in cohort 3. CONCLUSION Curative resection is the most significant factor for improved survival. Debulking surgerical procedure have a role whereas upfront peptide receptor radionuclide therapy is questionable. Chemotherapy improves overall survival in inoperable/metastatic setting. Recurrence patterns indicate that a long-term follow up greater than 10 years is necessary.
Collapse
Affiliation(s)
- Gunjan S Desai
- Department of Gastrointestinal Surgery, Lilavati Hospital and Research Center, Mumbai, 400 050, India. .,Department of Gastrointestinal Surgery, MPCT Hospital, C 7, Budhyadev Mandir Marg, Sector 4, Sanpada, Navi Mumbai, 400 705, India.
| | - Prasad Pande
- Department of Gastrointestinal Surgery, Lilavati Hospital and Research Center, Mumbai, 400 050, India
| | | | - Rajiv C Shah
- Department of Surgical Oncology, Lilavati Hospital and Research Centre, Mumbai, 400 050, India
| | - Palepu Jagannath
- Department of Surgical Oncology, Lilavati Hospital and Research Centre, Mumbai, 400 050, India
| |
Collapse
|
|
8
|
Pelosi G, Bianchi F, Hofman P, Pattini L, Ströbel P, Calabrese F, Naheed S, Holden C, Cave J, Bohnenberger H, Dinter H, Harari S, Albini A, Sonzogni A, Papotti M, Volante M, Ottensmeier CH. Recent advances in the molecular landscape of lung neuroendocrine tumors. Expert Rev Mol Diagn 2019; 19:281-297. [PMID: 30900485 DOI: 10.1080/14737159.2019.1595593] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 03/12/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Neuroendocrine tumors of the lung (Lung-NETs) make up a heterogenous family of neoplasms showing neuroendocrine differentiation and encompass carcinoids and neuroendocrine carcinomas. On molecular grounds, they considered two completely distinct and separate tumor groups with no overlap of molecular alterations nor common developmental mechanisms. Areas covered: Two perspectives were evaluated based on an extensive review and rethinking of literature: (1) the current classification as an instrument to obtaining clinical and molecular insights into the context of Lung-NETs; and (2) an alternative and innovative interpretation of these tumors, proposing a tripartite separation into early aggressive primary high-grade neuroendocrine tumors (HGNET), differentiating or secondary HGNET, and indolent NET. Expert opinion: We herein provide an alternative outlook on Lung-NETs, which is a paradigm shift to current pathogenesis models and expands the understanding of these tumors.
Collapse
Affiliation(s)
- Giuseppe Pelosi
- a Department of Oncology and Hemato-Oncology , University or Milan , Milan , Italy
- b Inter-hospital Pathology Division , Institute for Research and Care-IRCCS MultiMedica , Milan , Italy
| | - Fabrizio Bianchi
- c Cancer Biomarkers Unit, Foundation for Research and Care-IRCCS "Casa Sollievo della Sofferenza" , Foggia , Italy
| | - Paul Hofman
- d Laboratory of Clinical and Experimental Pathology , FHU OncoAge, Nice Hospital, Biobank BB-0033-00025, IRCAN, Inserm U1081 CNRS 7284, University Côte d'Azur , Nice , France
| | - Linda Pattini
- e Department of Electronics , Information and Bioengineering, Polytechnic of Milan , Milan , Italy
| | - Philipp Ströbel
- f Institute of Pathology , University Medical Center Göttingen , Göttingen , Germany
| | - Fiorella Calabrese
- g Department of Cardiac, Thoracic and Vascular Sciences , University of Padua , Padua , Italy
| | - Salma Naheed
- h Cancer Sciences Unit, Faculty of Medicine , University of Southampton , Southampton , UK
| | - Chloe Holden
- i Department of Medical Oncology , Royal Bournemouth and Christchurch Hospitals NHS Trust , Bournemouth , UK
| | - Judith Cave
- j Department of Medical Oncology , University Hospital Southampton NHS FT , Southampton , UK
| | - Hanibal Bohnenberger
- f Institute of Pathology , University Medical Center Göttingen , Göttingen , Germany
| | - Helen Dinter
- f Institute of Pathology , University Medical Center Göttingen , Göttingen , Germany
| | - Sergio Harari
- k Department of Medical Sciences and Division of Pneumology, San Giuseppe Hospital , Institute for Research and Care-IRCCS MultiMedica , Milan , Italy
| | - Adriana Albini
- l Laboratory of Vascular Biology and Angiogenesis , Institute for Research and Care-IRCCS MultiMedica , Milan , Italy
| | - Angelica Sonzogni
- m Department of Pathology and Laboratory Medicine , Foundation for Research and Care-IRCCS National Cancer Institute , Milan , Italy
| | - Mauro Papotti
- n Department of Oncology , University of Turin , Turin , Italy
| | - Marco Volante
- o Department of Oncology , University of Turin and Pathology Unit San Luigi Hospital , Turin , Italy
| | - Christian H Ottensmeier
- p Christian CRUK and NIHR Southamtpon Experimental Cancer Medicine Centre, Faculty of Medicine , University of Southampton , Southampton , UK
| |
Collapse
|
|
9
|
Shi H, Zhang Q, Han C, Zhen D, Lin R. Variability of the Ki-67 proliferation index in gastroenteropancreatic neuroendocrine neoplasms - a single-center retrospective study. BMC Endocr Disord 2018; 18:51. [PMID: 30055596 PMCID: PMC6064167 DOI: 10.1186/s12902-018-0274-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 06/27/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The Ki-67 index in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) may change throughout the disease course. However, the definitive effect of Ki-67 variability on GEP-NENs remains unknown. The aims of this study were to evaluate changes in Ki-67 levels throughout the disease course and investigate the role of Ki-67 index variability in GEP-NENs. METHODS Specimens with multiple pathologies were evaluated from 30 patients who were selected from 514 patients with GEP-NENs, being treated at Wuhan Union Hospital from July 2009 to February 2018. The Ki-67 index was evaluated among multiple specimens over the disease course. Univariable and multivariable Cox proportional hazards regression analyses were performed to assess the prognostic significance of various clinical and histopathologic features. RESULTS Among the 514 patients with GEP-NENs, metastases were seen in 182 (35.41%). Among the 30 patients from whom specimens with multiple pathologies were obtained, 24 were both primary and metastatic specimens and six were specimens collected over the course of the disease. Changes in Ki-67 levels were detected in 53.3% of the patients, of whom 40% had up-regulated Ki-67 levels, and 13.3% had down-regulated Ki-67 levels. Kaplan-Meier survival analysis showed that the group with Ki-67 variability had a shorter overall survival (p = 0.0297). The Cox regression analysis indicated that Ki-67 variability (p = 0.038) was the only independent prognostic factor for overall survival. CONCLUSIONS Our data suggest that patients with GEP-NENs and Ki-67 variability had a poorer prognosis. The re-assessment of Ki-67 at sites of metastasis or during the disease course might play a role in predicting the prognosis of patients with GEP-NENs. This finding could have implications for how GEP-NENs are monitored and treated.
Collapse
Affiliation(s)
- Huiying Shi
- 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
| | - Chaoqun Han
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ding Zhen
- 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
| |
Collapse
|
|
10
|
Pelosi G, Bianchi F, Dama E, Simbolo M, Mafficini A, Sonzogni A, Pilotto S, Harari S, Papotti M, Volante M, Fontanini G, Mastracci L, Albini A, Bria E, Calabrese F, Scarpa A. Most high-grade neuroendocrine tumours of the lung are likely to secondarily develop from pre-existing carcinoids: innovative findings skipping the current pathogenesis paradigm. Virchows Arch 2018; 472:567-577. [PMID: 29388013 DOI: 10.1007/s00428-018-2307-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 12/30/2017] [Accepted: 01/21/2018] [Indexed: 12/16/2022]
Abstract
Among lung neuroendocrine tumours (Lung-NETs), typical carcinoid (TC) and atypical carcinoid (AC) are considered separate entities as opposed to large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). By means of two-way clustering analysis of previously reported next-generation sequencing data on 148 surgically resected Lung-NETs, six histology-independent clusters (C1 → C6) accounting for 68% of tumours were identified. Low-grade Lung-NETs were likely to evolve into high-grade tumours following two smoke-related paths. Tumour composition of the first path (C5 → C1 → C6) was coherent with the hypothesis of an evolution of TC to LCNEC, even with a conversion of SCLC-featuring tumours to LCNEC. The second path (C4 → C2-C3) had a tumour composition supporting the evolution of AC to SCLC-featuring tumours. The relevant Ki-67 labelling index varied accordingly, with median values being 5%, 9% and 50% in the cluster sequence C5 → C1 → C6, 12% in cluster C4 and 50-60% in cluster C2-C3. This proof-of-concept study suggests an innovative view on the progression of pre-existing TC or AC to high-grade NE carcinomas in most Lung-NET instances.
Collapse
Affiliation(s)
- Giuseppe Pelosi
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.
- Inter-Hospital Pathology Division, Science & Technology Park, IRCCS MultiMedica, Milan, Italy.
- Servizio Interaziendale di Anatomia Patologica, Polo Scientifico e Tecnologico, IRCCS MultiMedica, Via Gaudenzio Fantoli 16/15, 20138, Milan, Italy.
| | - Fabrizio Bianchi
- ISBREMIT, Regenerative Medicine and Innovative Therapies, IRCCS Casa Sollievo della Sofferenza, Institute for Stem-Cell Biology, San Giovanni Rotondo, FG, Italy
| | - Elisa Dama
- ISBREMIT, Regenerative Medicine and Innovative Therapies, IRCCS Casa Sollievo della Sofferenza, Institute for Stem-Cell Biology, San Giovanni Rotondo, FG, Italy
| | - Michele Simbolo
- ARC-NET Research Centre and Section of Pathology of the Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Mafficini
- ARC-NET Research Centre and Section of Pathology of the Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Angelica Sonzogni
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Sara Pilotto
- Department of Medicine, Section of Medical Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Sergio Harari
- Department of Medical Sciences and Division of Pneumology, San Giuseppe Hospital, IRCCS MultiMedica, Milan, Italy
| | - Mauro Papotti
- Department of Oncology, City of Health and Science, University of Turin and Pathology Unit Molinette Hospital, Turin, Italy
| | - Marco Volante
- Department of Oncology, University of Turin and Pathology Unit San Luigi Hospital, Orbassano, Turin, Italy
| | - Gabriella Fontanini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
| | - Luca Mastracci
- Department of Surgical and Diagnostic Sciences (DISC), University of Genova and IRCCS San Martino-IST University Hospital, Genoa, Italy
| | - Adriana Albini
- Laboratory of Vascular Biology and Angiogenesis, Science & Technology Park, IRCCS MultiMedica, Milan, Italy
| | - Emilio Bria
- Department of Medicine, Section of Medical Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Fiorella Calabrese
- Department of Cardiothoracic and Vascular Sciences, Pathological Anatomy Section, University of Padua Medical School, Padua, Italy
| | - Aldo Scarpa
- ARC-NET Research Centre and Section of Pathology of the Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| |
Collapse
|
|
11
|
PRRT genomic signature in blood for prediction of 177Lu-octreotate efficacy. Eur J Nucl Med Mol Imaging 2018; 45:1155-1169. [PMID: 29484451 DOI: 10.1007/s00259-018-3967-6] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Accepted: 01/31/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT "responders" from "non-responders". This study clinically validates the utility of the PPQ in NETs. METHODS The development and validation of the PPQ was undertaken in three independent 177Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n = 44), and Erasmus Medical Center, Rotterdam, Netherlands (n = 42). Each cohort included predominantly well differentiated, low grade (86-95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: "predicted responder" (PPQ+); "predicted non-responder" (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses. RESULTS In the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64-79%), the PPQ was 95% accurate (Bad Berka: PPQ + =97%, PPQ- = 93%; Rotterdam: PPQ + =94%, PPQ- = 100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10-14 months; HR: 18-77, p < 0.0001). In the comparator cohorts, the predictor (PPQ) was 47-50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10-12 months vs. PPQ-: 9-15 months). CONCLUSION The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.
Collapse
|
|
12
|
Classification of Abdominal Neuroendocrine Tumors. Updates Surg 2018. [DOI: 10.1007/978-88-470-3955-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
13
|
Pelosi G, Sonzogni A, Harari S, Albini A, Bresaola E, Marchiò C, Massa F, Righi L, Gatti G, Papanikolaou N, Vijayvergia N, Calabrese F, Papotti M. Classification of pulmonary neuroendocrine tumors: new insights. Transl Lung Cancer Res 2017; 6:513-529. [PMID: 29114468 PMCID: PMC5653522 DOI: 10.21037/tlcr.2017.09.04] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 09/12/2017] [Indexed: 12/11/2022]
Abstract
Neuroendocrine tumors of the lung (Lu-NETs) embrace a heterogeneous family of neoplasms classified into four histological variants, namely typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). Defining criteria on resection specimens include mitotic count in 2 mm2 and the presence or absence of necrosis, alongside a constellation of cytological and histological traits including cell size and shape, nuclear features and overall architecture. Clinically, TC are low-grade malignant tumors, AC intermediate-grade malignant tumors and SCLC/LCNEC high-grade malignant full-blown carcinomas with no significant differences in survival between them. Homologous tumors arise in the thymus that occasionally have some difficulties in differentiating from the lung counterparts when presented with large unresectable or metastatic lesions. Immunohistochemistry (IHC) helps refine NE diagnosis at various anatomical sites, particularly on small-sized tissue material, in which only TC and small cell carcinoma categories can be recognized easily on hematoxylin & eosin stain, while AC and LCNEC can only be suggested on such material. The Ki-67 labeling index effectively separates carcinoids from small cell carcinoma and may prove useful for the clinical management of a metastatic disease to help the therapeutic decision-making process. Although carcinoids and high-grade neuroendocrine carcinomas in the lung and elsewhere make up separate tumor categories on molecular grounds, emerging data supports the concept of secondary high-grade NETs arising in the preexisting carcinoids, whose clinical and biological relevance will have to be placed into the proper context for the optimal management of these patients. In this review, we will discuss the selected, recent literature with a focus on current issues regarding Lu-NET nosology, i.e., classification, derivation and tumor evolution.
Collapse
Affiliation(s)
- Giuseppe Pelosi
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
- Inter-hospital Pathology Division, Science & Technology Park, IRCCS MultiMedica Group, Milan, Italy
| | - Angelica Sonzogni
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Sergio Harari
- Department of Medical Sciences and Division of Pneumology, San Giuseppe Hospital, Science & Technology Park, IRCCS MultiMedica Group, Milan, Italy
| | - Adriana Albini
- Laboratory of Vascular Biology and Angiogenesis, Science & Technology Park, IRCCS MultiMedica Group, Milan, Italy
| | - Enrica Bresaola
- Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy
| | - Caterina Marchiò
- Department of Medical Sciences, University of Turin, and Pathology Division, AOU Città della Salute e della Scienza, Turin, Italy
| | - Federica Massa
- Department of Oncology, University of Turin, and Pathology Division, AOU Città della Salute e della Scienza, Turin, Italy
| | - Luisella Righi
- Department of Oncology, University of Turin, Pathology Division, San Luigi Hospital, University of Turin, Turin, Italy
| | - Gaia Gatti
- Department of Oncology, University of Turin, Pathology Division, San Luigi Hospital, University of Turin, Turin, Italy
| | - Nikolaos Papanikolaou
- Inter-hospital Pathology Division, Science & Technology Park, IRCCS MultiMedica Group, Milan, Italy
| | - Namrata Vijayvergia
- Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Fiorella Calabrese
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padova, Italy
| | - Mauro Papotti
- Department of Oncology, University of Turin, and Pathology Division, AOU Città della Salute e della Scienza, Turin, Italy
| |
Collapse
|
|
14
|
Immunohistochemical Characterization of the Origins of Metastatic Well-differentiated Neuroendocrine Tumors to the Liver. Am J Surg Pathol 2017; 41:915-922. [PMID: 28498280 DOI: 10.1097/pas.0000000000000876] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metastatic neoplasms of unknown primary site pose a major challenge to patient management. As targeted therapies are now being tailored to neuroendocrine tumors (NETs) of different primary sites, identifying the origin of metastatic NETs has become increasingly important. Compared with more extensive efforts on metastatic adenocarcinomas of unknown primary, the literature on metastatic NETs (often to the liver) is relatively sparse and most studies are based on primary tumors. We sought to study metastatic well-differentiated NETs to the liver to identify markers that predict the site of origin. Eighty-five metastatic NETs to the liver were retrieved from the pathology archive. The primary sites were determined based on either pathologic review of the primary tumors (in most cases) or radiologic/clinical findings. Immunohistochemical labeling for TTF1, CDX2, ISL1, NKX2.2, and PDX1 was performed on either tissue microarrays or whole sections. The primary sites of the NETs in the study cohort included: pancreas (35%), small intestine (32%), rectum (8%), stomach (2%), bile duct (1%), lung (9%), and unknown primary (12%). We found predominant expression of TTF1 in lung carcinoid (63%), CDX2 in small intestinal (89%) and ISL1 in pancreatic NETs (77%), respectively. NKX2.2 was mainly expressed in NETs of the digestive organs. PDX1 was detected in a small percentage of pancreatic, small intestinal and the single bile duct NET. There was no statistically significant association between tumor grade (World Health Organization G1 vs. G2) and the expression of any of the above markers. The 3-marker panel (TTF1, CDX2, and ISL1) had sensitivities of 81%, 89%, and 63%, specificities of 100%, 94%, and 100%, positive predictive values of 100%, 89%, and 100%, and negative predictive values of 84%, 94%, and 96% in separating metastatic NETs into 3 major primary sites: pancreas/rectum, small intestine, and lung, respectively, with an overall accuracy of 82%. Furthermore, this panel predicted a primary site for 6 of the 10 NETs of unknown primary, which reduced the NETs of unknown primary from 12% to 5%. Thus, through immunohistochemical study of a large series of metastatic NETs to the liver, we have demonstrated the utility of a 3-marker panel for the identification of one or more potential primary sites of most metastatic NETs, which could provide practical guidance in patient management.
Collapse
|
|
15
|
Tracht J, Zhang K, Peker D. Grading and Prognostication of Neuroendocrine Tumors of the Pancreas: A Comparison Study of Ki67 and PHH3. J Histochem Cytochem 2017. [PMID: 28651471 DOI: 10.1369/0022155417708186] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Grading of pancreatic neuroendocrine tumors (pNETs) is currently based on mitotic rate and Ki67 proliferation index. Phosphohistone-H3 (PHH3) is an effective marker for mitosis that has been proposed to use in grading various NETs. It remains unclear which method more accurately predicts grade and clinical outcome. Cases of pNET were evaluated using immunohistochemical stains for Ki67 and PHH3. In addition, each case was evaluated for necrosis, lymphovascular invasion, and perineural invasion and compared with stage. R project statistical analysis was used for comparisons. Sixty-three cases were included in the study including 29 males and 34 females (M:F 0.9) with a median age of 59 years (ranging 34-84). There was not a significant discrepancy in the stratification of tumor grades for Ki67 and PHH3. PHH3 significantly predicted lymph node metastasis ( p=0.041). Necrosis correlated with overall survival ( p=0.017). The results suggest that PHH3 is an effective marker for determining mitotic activity and can be used alternative to Ki67. In addition, necrosis may be included in the reporting of pNET as it may play a prognostic role. Larger scale studies are warranted to understand the biology and behavior of these tumors.
Collapse
Affiliation(s)
- Jessica Tracht
- Department of Pathology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (JT, DP)
| | - Kui Zhang
- Department of Biostatistics, The University of Alabama at Birmingham School of Public Health, Birmingham, Alabama (KZ)
| | - Deniz Peker
- Department of Pathology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (JT, DP)
| |
Collapse
|
|
16
|
Sakai Y, Hong SM, An S, Kim JY, Corbeil D, Karbanová J, Otani K, Fujikura K, Song KB, Kim SC, Akita M, Nanno Y, Toyama H, Fukumoto T, Ku Y, Hirose T, Itoh T, Zen Y. CD133 expression in well-differentiated pancreatic neuroendocrine tumors: a potential predictor of progressive clinical courses. Hum Pathol 2017; 61:148-157. [PMID: 27864124 DOI: 10.1016/j.humpath.2016.10.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/18/2016] [Accepted: 10/28/2016] [Indexed: 01/11/2023]
Abstract
The present study aimed to elucidate whether the stemness molecule, CD133, is expressed in well-differentiated pancreatic neuroendocrine tumors (PanNETs; World Health Organization grades 1 and 2) and establish its clinical relevance using 2 separate cohorts. In the first series (n = 178) in which tissue microarrays were available, immunohistochemistry revealed that CD133 was expressed in 14 cases (8%). CD133+ PanNETs had higher TNM stages (P < .01), more frequent lymphovascular invasion (P = .01), and higher recurrence rates (P = .01). In the second cohort (n = 56), the expression of CD133 and CK19 was examined in whole tissue sections. CD133 and CK19 were positive in 10 (18%) and 36 (64%) cases, respectively. CD133 expression correlated with higher pT scores (P < .01), the presence of microscopic venous infiltration (P = .03), and shorter disease-free periods (P < .01). When cases were divided into grade 1 and 2 neoplasms, patients with CD133+ PanNET continued to have shorter disease-free periods than did those with CD133- tumors in both groups (P < .01 and P = .02, respectively). Although CK19+ cases had shorter disease-free periods than did CK19- cases in the whole cohort (P = .02), this difference was less apparent in subanalyses of grade 1 and 2 cases. CD133 expression also appeared to be an independent predictive factor for tumor recurrence in a multivariate analysis (P = .018). The CD133 phenotype was identical between primary and metastatic foci in 17 of 18 cases from which tissues of metastatic deposits were available. In conclusion, the combination of CD133 phenotyping and World Health Organization grading may assist in stratifying patients in terms of the risk of progressive clinical courses.
Collapse
Affiliation(s)
- Yasuhiro Sakai
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Soyeon An
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Joo Young Kim
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea.
| | - Denis Corbeil
- Tissue Engineering Laboratories (BIOTEC), Technische Universität Dresden, Dresden 01307, Germany.
| | - Jana Karbanová
- Tissue Engineering Laboratories (BIOTEC), Technische Universität Dresden, Dresden 01307, Germany.
| | - Kyoko Otani
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Kohei Fujikura
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Ki-Byung Song
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Song Cheol Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Masayuki Akita
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Yoshihide Nanno
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Hirochika Toyama
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Takumi Fukumoto
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Yonson Ku
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Takanori Hirose
- Department of Pathology, Hyogo Cancer Center, Akashi 673-8558, Japan.
| | - Tomoo Itoh
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Yoh Zen
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| |
Collapse
|
|
17
|
Singhi AD, Liu TC, Roncaioli JL, Cao D, Zeh HJ, Zureikat AH, Tsung A, Marsh JW, Lee KK, Hogg ME, Bahary N, Brand RE, McGrath KM, Slivka A, Cressman KL, Fuhrer K, O'Sullivan RJ. Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors. Clin Cancer Res 2017; 23:600-609. [PMID: 27407094 PMCID: PMC6560642 DOI: 10.1158/1078-0432.ccr-16-1113] [Citation(s) in RCA: 182] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 06/29/2016] [Accepted: 07/04/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE Pancreatic neuroendocrine tumors (PanNET) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing has identified recurrent mutations in the genes DAXX and ATRX, which correlate with loss of protein expression and alternative lengthening of telomeres (ALT). Both ALT and DAXX/ATRX loss were initially reported to be associated with a favorable prognosis; however, recent studies suggest the contrary. Our aims were to assess the prevalence and prognostic significance of ALT and DAXX/ATRX in both primary and metastatic PanNETs. EXPERIMENTAL DESIGN Telomere-specific FISH and DAXX/ATRX IHC was performed on a multi-institutional cohort of 321 patients with resected PanNET and 191 distant metastases from 52 patients. These results were correlated with clinicopathologic features, including disease-free survival (DFS) and disease-specific survival (DSS). RESULTS The prevalence of ALT and DAXX/ATRX loss in resected PanNETs was 31% and 26%, respectively, and associated with larger tumor size, higher WHO grade, lymph node metastasis, and distant metastasis (P < 0.001). The 5-year DFS and 10-year DSS of patients with ALT-positive and DAXX/ATRX-negative PanNETs were 40% and 50%, respectively, as compared with 96% and 89%, respectively, for wild-type PanNETs. Among distant metastases, ALT and DAXX/ATRX loss was 67% and 52%, respectively, and only occurred in the setting of an ALT-positive and DAXX/ATRX-negative primary PanNET. By multivariate analysis, both ALT and DAXX/ATRX loss were negative, independent prognostic factors for DFS. CONCLUSIONS ALT and DAXX/ATRX loss in PanNETs was associated with shorter DFS and DSS and likely plays a significant role in driving metastatic disease. Clin Cancer Res; 23(2); 600-9. ©2016 AACR.
Collapse
Affiliation(s)
- Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
| | - Ta-Chiang Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Justin L Roncaioli
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Dengfeng Cao
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Amer H Zureikat
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - J Wallis Marsh
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kenneth K Lee
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Melissa E Hogg
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Nathan Bahary
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Randall E Brand
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kevin M McGrath
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Adam Slivka
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kristi L Cressman
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kimberly Fuhrer
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Roderick J O'Sullivan
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| |
Collapse
|
|
18
|
Fabbri A, Cossa M, Sonzogni A, Papotti M, Righi L, Gatti G, Maisonneuve P, Valeri B, Pastorino U, Pelosi G. Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied. Virchows Arch 2017; 470:153-164. [PMID: 28054150 DOI: 10.1007/s00428-016-2062-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 11/10/2016] [Accepted: 12/21/2016] [Indexed: 02/07/2023]
Abstract
Optimal histopathological analysis of biopsies from metastases of neuroendocrine tumor (NET) of the lung requires more than morphology only. Additional parameters such as Ki-67 labeling index are required for adequate diagnosis, but few studies have compared reproducibility of different counting protocols and modalities of reporting on biopsies of lung NET. We compared the results of four different manual counting techniques to establish Ki-67 LI. On 47 paired biopsies and surgical specimens from 22 typical carcinoids (TCs), 14 atypical carcinoids (ACs), six large cell neuroendocrine carcinomas (LCNECs), and five small cell carcinomas (SCCs) immunohistochemical staining of Ki-67 antigen was performed. We counted, in regions of highest nuclear staining (HSR), a full ×40-high-power field (diameter = 0.55 mm), 500 or 2000 cells, or 2 mm2 surface area, including the HSR or the entire biopsy fragment(s). Mitoses and necrosis were evaluated in an area of 2 mm2 or the entire biopsy fragment(s). Between the four counting methods, no differences in Ki-67 LI were observed. However, a Ki-67 LI higher than 5% was found in only four cases when in an HSR, 500 cells were counted (18%), five (23%) when in an HSR 2000 cells were counted, four (18%) when 2 mm2 were counted, and one (5%) TC case when the entire biopsy was counted. A 20% cutoff distinguished TC and AC from LCNEC and SCC with 100% specificity and sensitivity, while mitoses and necrosis failed to a large extent. Ki-67 LI in biopsy samples was concordant with that in resection specimens when 2000 cells, 2 mm2, or the entire biopsy fragment(s) were counted. Our results are important for clinical management of patients with metastases of a lung NET.
Collapse
Affiliation(s)
- Alessandra Fabbri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Mara Cossa
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Angelica Sonzogni
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy
| | - Luisella Righi
- Department of Oncology, University of Turin, Turin, Italy
| | - Gaia Gatti
- Department of Oncology, University of Turin, Turin, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Barbara Valeri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Ugo Pastorino
- Division of Thoracic Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Giuseppe Pelosi
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
- Department of Oncology and Hemato-oncology, Università degli Studi, Milan, Italy.
- Dipartimento di Oncologia ed Emato-oncologia, Via Festa del Perdono, 7, I-20122, Milan, Italy.
| |
Collapse
|
|
19
|
Burad DK, Kodiatte TA, Rajeeb SM, Goel A, Eapen CE, Ramakrishna B. Neuroendocrine neoplasms of liver - A 5-year retrospective clinico-pathological study applying World Health Organization 2010 classification. World J Gastroenterol 2016; 22:8956-8966. [PMID: 27833387 PMCID: PMC5083801 DOI: 10.3748/wjg.v22.i40.8956] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 07/29/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To study the clinicopathological characteristics of neuroendocrine neoplasms (NEN) on liver samples and apply World Health Organization (WHO) 2010 grading of gastroenteropancreatic (GEP) NEN.
METHODS Clinicopathological features of 79 cases of NEN of the liver diagnosed between January 2011 to December 2015 were analyzed. WHO 2010 classification of GEP NEN was applied and the tumors were graded as G1, G2 or G3. Two more categories, D1/2 (discordant 1/2) and D2/3 (discordant 2/3) were also applied. The D1/2 grade tumors had a mitotic count of G1 and Ki-67 index of G2. The D2/3 tumors had a mitotic count of G2 and Ki-67 index of G3. The follow up details which were available till the end of the study period (December 2015) were collected.
RESULTS Of the 79 tumors, 16 each were G1 and G2, and 18 were G3 tumors. Of the remaining 29 tumors, 13 were assigned to D1/2 and 16 were D2/3 grade. Male preponderance was noted in all tumors except for G2 neoplasms, which showed a slight female predilection. The median age at presentation was 47 years (range 10-82 years). The most common presentation was abdominal pain (81%). Pancreas (49%) was the most common site of primary followed by gastrointestinal tract (24.4%) and lungs (18%). Radiologically, 87% of the patients had multiple liver lesions. Histopathologically, necrosis was seen in only D2/3 and G3 tumors. Microvascular invasion was seen in all grades. Metastasis occurred in all grades of primary NEN and the grades of the metastatic tumors and their corresponding primary tumors were similar in 67% of the cases. Of the 79 patients, 36 had at least one follow up visit with a median duration of follow up of 8.5 mo (range: 1-50 mo). This study did not show any impact of the grade of tumor on the short term clinical outcome of these patients.
CONCLUSION Liver biopsy is an important tool for clinicopathological characterization and grading of NEN, especially when the primary is not identified. Eighty-seven percent of the patients had multifocal liver lesions irrespective of the WHO grade, indicating a higher stage of disease at presentation. Follow up duration was inadequate to derive any meaningful conclusion on long term outcome in our study patients.
Collapse
|
|
20
|
Tang C, Gong L, Zou W, Zhang J, Zhou Y, Wu X, Lu F, Ouyang C, Liu X. Multivariate analysis of metastasis‑related risk factors for patients with gastroenteropancreatic neuroendocrine tumors based on clinicopathological and endoscopic features. Oncol Rep 2016; 36:3343-3352. [PMID: 27748940 DOI: 10.3892/or.2016.5170] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 07/13/2016] [Indexed: 11/06/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP‑NETs) are relatively uncommon. Unfortunately, epidemiological studies on the incidence of GEP‑NETs worldwide have reported a marked increase in the detection of these tumors. Although they often exhibit relatively indolent clinical courses, GEP‑NETs have the potential for lethal progression, especially in patients who present with advanced disease. Early detection and surgical removal is currently the only reliable curative treatment for GEP‑NET patients. The objective of this study was to analyze the clinicopathological characteristics of GEP‑NETs and explore the metastasis‑related risk factors of patients with GEP‑NETs. One hundred and forty‑six patients diagnosed pathologically with GEP‑NETs from January 2001 to January 2015 at the Second Xiangya Hospital of Central South University were retrospectively evaluated. We retrieved and analyzed information concerning clinical characteristics and metastasis‑related risk factors, and used Chi‑square test and logistic regression analysis to analyze the clinicopathological characteristics of GEP‑NETs and explore the association between tumor metastasis and possible related risk factors. The results revealed that the most common clinical manifestations were abdominal pain (n=88), alteration in the character of stool (n=58) and melaena (n=33). Rectum (91/146, 62.3%) and stomach (19/146, 13.0%) were the main sites of metastasis. Both Chi‑square test and logistic regression analysis showed that tumor size (P<0.05), tumor type (P=0.008) and peritumoral lymphatic vessel density (LVD) (P=0.004) were significantly correlated with tumor metastasis. Neither Chi‑square test nor logistic regression analysis indicated that gender (P>0.05), age (P>0.05), tumor location (P>0.05), tumor number (P>0.05), chromaffin granule protein A [chromogranin A (CgA), P>0.05], synaptophysin (Syn, P>0.05) or intratumoral LVD (P>0.05) had a significant correlation with tumor metastasis. Chi‑square test revealed that tumor grade was significantly correlated with tumor metastasis. In conclusion, GEP‑NETs may occur in multiple sites of the digestive system and lack specific clinical manifestations. Tumor size, tumor type, peritumoral LVD, total LVD and tumor grade are metastasis‑related risk factors for GEP‑NET patients.
Collapse
Affiliation(s)
- Caiyun Tang
- Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| | - Lingqi Gong
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Wenli Zou
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Jie Zhang
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Yuqian Zhou
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Xiaoping Wu
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Fanggen Lu
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Chunhui Ouyang
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| |
Collapse
|
|
21
|
Lee HE, Mounajjed T, Erickson LA, Wu TT. Sporadic Gastric Well-Differentiated Neuroendocrine Tumors Have a Higher Ki-67 Proliferative Index. Endocr Pathol 2016; 27:259-67. [PMID: 27306997 DOI: 10.1007/s12022-016-9443-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Well-differentiated neuroendocrine tumor (WDNET) of the stomach can arise in three distinct clinical settings: (1) in association with autoimmune atrophic gastritis, (2) in association with multiple neuroendocrine neoplasia type I (MEN I) or Zollinger-Ellison syndrome (ZES), or (3) sporadic. The Ki-67 proliferative index (PI) in gastric WDNETs in these three distinct clinical settings has not been evaluated in detail. Forty-five gastric WNETs underwent polypectomy (n = 4), endoscopic mucosal resection (n = 12), and surgical resection (n = 29) between 1994 and 2015 were included. H&E slides from each case were reviewed, and Ki-67 immunostain was performed on one representative tumor block. Ki-67 PI was determined by quantitative Aperio image analysis software in areas of strongest nuclear labeling ("hot spots"), and correlated with underlying clinical and pathological features. Twenty-one patients were male and 24 female with a median age of 57 years (range, 30-80 years). Tumors were classified as type I (n = 17), type II (n = 6), and type III (n = 22) WDNETs. Types II and III showed more advanced TNM stage compared to type I (p = 0.02, overall). WHO grade based on Ki-67 PI was higher in type III WDNETs [grade 1 (G1), n = 3; grade 2 (G2), n = 15; and grade 3 (G3), n = 4] than in type I WDNETs [G1, n = 5; G2, n = 12] and in type II WDNETs [G1, n = 2; G2, n = 4] (p = 0.050, overall). Ki-67 PI was significantly higher in type III WDNETs (mean ± SD = 13.0 ± 13.3 %) than in non-sporadic (type I and II) WDNETs (mean ± SD = 5.3 ± 3.3 %; p = 0.015). There was no difference in Ki-67 PI between type I WDNETs (mean ± SD = 5.2 ± 3.5 %) and type II WDNETs (mean ± SD = 5.6 ± 3.1%; p = 0.817). Higher Ki-67 PI was associated with higher tumor T stage (p = 0.003) and also tended to be associated with lymph node metastasis (p = 0.071). In the Kaplan-Meier survival analysis, type I was associated with a significantly longer disease-free survival (DFS) time compared to type II (p = 0.018) or III (0.010). Also, the WHO G3 group had a significantly shorter DFS time than the WHO G1 (p = 0.020) or G2 (p = 0.007) group. Gastric WDNET is a heterogeneous disease entity encompassing three clinical subtypes-type I, type II, and type III-having their own distinct clinicopathologic characteristics and prognosis. Our results showed that sporadic (type III) WDNET had a significantly higher Ki-67 PI than non-sporadic cases (type I or II); increased PI was associated with higher tumor stage. We also described four type III cases of morphologically WD gastric NET with WHO grade 3 on the basis of Ki-67 PI.
Collapse
Affiliation(s)
- Hee Eun Lee
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Taofic Mounajjed
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Lori A Erickson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Tsung-Teh Wu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
22
|
Ozturk Sari S, Taskin OC, Gundogdu G, Yegen G, Onder S, Keskin M, Saglam S, Ozluk Y, Gulluoglu M, Mete O. The Impact of Phosphohistone-H3-Assisted Mitotic Count and Ki67 Score in the Determination of Tumor Grade and Prediction of Distant Metastasis in Well-Differentiated Pancreatic Neuroendocrine Tumors. Endocr Pathol 2016; 27:162-170. [PMID: 26936845 DOI: 10.1007/s12022-016-9424-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
This study investigated the impact of phosphohistone-H3 (PHH3)-assisted mitotic count by comparing its performance with conventional mitotic count and Ki67 score as well as the status of distant metastasis. A total of 43 surgically resected pancreatic neuroendocrine tumors (panNET) with complete follow-up information has been subjected to a standardized assessment with respect to mitotic count (both conventional and PHH3-assisted) and Ki67 score. Five participants assessed mitotic count and the time spent was recorded in both methods. All tumors were assigned to a G1 category of mitotic rate on conventional mitotic count that failed to identify three tumors with a G2 category of mitotic rate on PHH3. Near-perfect and fair agreements were achieved among observers when using PHH3 and conventional method, respectively. The mean time spent to determine mitotic count on PHH3-stained slides was significantly shorter (p < 0.001). The performance of PHH3-assisted mitotic grade category was significant as the three cases with a G2 mitotic category were associated with distant metastasis (p = 0.01). Despite its performance, the PHH3-assisted mitotic count downgraded 17 cases that were classified as G2 based on Ki67 scores in this series. The Ki67 grade category was either the same or higher than the mitotic grade category. Ten patients developed distant metastasis. Eleven tumors exhibited vascular invasion characterized by intravascular tumor cells admixed with thrombus. Our results indicate that PHH3-assisted mitotic count facilitates an accurate mitotic count with a perfect agreement among observers. The small size of this cohort is an important limitation of the current study, a G2 mitotic grade category based on PHH3 immunohistochemistry was one of the correlates of panNETs with distant metastasis. While the prognostic impact of PHH3-assisted mitotic count needs to be clarified in larger cohorts, Ki67 scores designated higher grade category in all cases; thus, it was the best determinant of the tumor grade. More importantly, the presence of vascular invasion along with the Ki67 grade category was found to be independent predictors of distant metastasis.
Collapse
Affiliation(s)
- Sule Ozturk Sari
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
| | - Orhun Cig Taskin
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Gokcen Gundogdu
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Gulcin Yegen
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Semen Onder
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Metin Keskin
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Sezer Saglam
- Department of Medical Oncology, University of Bilim, Istanbul, Turkey
| | - Yasemin Ozluk
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mine Gulluoglu
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ozgur Mete
- Department of Pathology, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
23
|
Singh S, Asa SL, Dey C, Kennecke H, Laidley D, Law C, Asmis T, Chan D, Ezzat S, Goodwin R, Mete O, Pasieka J, Rivera J, Wong R, Segelov E, Rayson D. Diagnosis and management of gastrointestinal neuroendocrine tumors: An evidence-based Canadian consensus. Cancer Treat Rev 2016; 47:32-45. [PMID: 27236421 DOI: 10.1016/j.ctrv.2016.05.003] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 05/07/2016] [Indexed: 02/07/2023]
Abstract
The majority of neuroendocrine tumors originate in the digestive system and incidence is increasing within Canada and globally. Due to rapidly evolving evidence related to diagnosis and clinical management, updated guidance on the diagnosis and treatment of gastrointestinal neuroendocrine tumors (GI-NETs) are of clinical importance. Well-differentiated GI-NETs may exhibit indolent clinical behavior and are often metastatic at diagnosis. Some NET patients will develop secretory disease requiring symptom control to optimize quality of life and clinical outcomes. Optimal management of GI-NETs is in a multidisciplinary environment and is multimodal, requiring collaboration between medical, surgical, imaging and pathology specialties. Clinical application of advances in pathological classification and diagnostic technologies, along with evolving surgical, radiotherapeutic and medical therapies are critical to the advancement of patient care. We performed a systematic literature search to update our last set of published guidelines (2010) and identified new level 1 evidence for novel therapies, including telotristat etiprate (TELESTAR), lanreotide (CLARINET), everolimus (RADIANT-2; RADIANT-4) and peptide receptor radionuclide therapy (PRRT; NETTER-1). Integrating these data with the clinical knowledge of 16 multi-disciplinary experts, we devised consensus recommendations to guide state of the art clinical management of GI-NETs.
Collapse
Affiliation(s)
- Simron Singh
- Sunnybrook Health Sciences Centre, Department of Medicine, University of Toronto, 2075 Bayview Ave. Room T2-047, Toronto, Ontario M4N 3M5, Canada.
| | - Sylvia L Asa
- University Health Network, Department of Pathology, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
| | - Chris Dey
- Sunnybrook Health Sciences Centre, Department of Medical Imaging, University of Toronto, 2075 Bayview Ave. Room MG-182, Toronto, Ontario M4N 3M5, Canada.
| | - Hagen Kennecke
- BC Cancer Agency, Division of Medical Oncology, University of British Columbia, 600 West 10th Avenue, Vancouver, BC V5Z 4E1, Canada.
| | - David Laidley
- St. Joseph's Health Care London, Division of Nuclear Medicine, University of Western Ontario, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada.
| | - Calvin Law
- Sunnybrook Health Sciences Centre, Department of Surgery, University of Toronto, 2075 Bayview Ave. Room T2-001, Toronto, Ontario M4N 3M5, Canada.
| | - Timothy Asmis
- The Ottawa Hospital Cancer Centre, Division of Medical Oncology, University of Ottawa, 501 Smyth Road, Ottawa, Ontario K1H8L6, Canada.
| | - David Chan
- Sunnybrook Health Sciences Centre, Department of Medicine, University of Toronto, 2075 Bayview Ave. Room T2-047, Toronto, Ontario M4N 3M5, Canada.
| | - Shereen Ezzat
- Princess Margaret Cancer Centre, Departments of Medicine & Oncology, University of Toronto, 610 University Ave. Room 7-327, Toronto, Ontario M5G 2N2, Canada.
| | - Rachel Goodwin
- The Ottawa Hospital Research Institute, Department of Medical Oncology, University of Ottawa, 501 Smyth Road, Ottawa, Ontario K1H8L6, Canada.
| | - Ozgur Mete
- University Health Network, Department of Pathology, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
| | - Janice Pasieka
- Tom Baker Cancer Center and Foothills Medical Centre, Departments of Surgery & Oncology, University of Calgary, 1403 29th Street NW, North Tower Floor 10, Calgary, Alberta T2N 2T9, Canada.
| | - Juan Rivera
- McGill University Health Centre - Glen Campus, Bloc C - C04.5190, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada.
| | - Ralph Wong
- CancerCare Manitoba, St Boniface General Hospital, 407 Tache Avenue, Winnipeg, Manitoba R2H 2A6, Canada.
| | - Eva Segelov
- St Vincent's Clinical School, University of New South Wales, 438 Victoria St, Darlinghurst, NSW 2010, Australia.
| | - Daniel Rayson
- QEII Health Sciences Centre, Division of Medical Oncology, Dalhousie University, Suite 457A Bethune Building, 1276 South Park Street, Halifax, NS B3H 2Y9, Canada.
| |
Collapse
|
|
24
|
Smith JD, Nandakumar G. Hindgut Neuroendocrine Neoplasia. Indian J Surg Oncol 2016; 7:73-8. [PMID: 27065686 DOI: 10.1007/s13193-015-0477-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 10/13/2015] [Indexed: 12/17/2022] Open
Abstract
Neuroendocrine neoplasias (NENs) consist of a spectrum of tumors which can originate throughout the body, behave in a variety of different ways but are characterized by a similar histological appearance. This article reviews the classification, staging, diagnosis and treatment of Hindgut Neuroendocrine Neoplasias.
Collapse
Affiliation(s)
- James D Smith
- Surgery Weill Cornell Medical College, 525 East 68th Street, New York, NY 10021 USA
| | - Govind Nandakumar
- Courtesy Faculty at Weill Cornell Medical College, 20 Ali Asker Road, 560052 Bangalore, India
| |
Collapse
|
|
25
|
Villani V, Mahadevan KK, Ligorio M, Fernández-Del Castillo C, Ting DT, Sabbatino F, Zhang I, Vangel M, Ferrone S, Warshaw AL, Lillemoe KD, Wargo J, Deshpande V, Ferrone CR. Phosphorylated Histone H3 (PHH3) Is a Superior Proliferation Marker for Prognosis of Pancreatic Neuroendocrine Tumors. Ann Surg Oncol 2016; 23:609-617. [PMID: 27020585 DOI: 10.1245/s10434-016-5171-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Indexed: 11/18/2022]
Abstract
BACKGROUND The staging of pancreatic neuroendocrine tumors (PNETs) is continuously evolving. Mitotic count, as measured by hematoxylin and eosin (H&E) or Ki67 labeling index (Ki67LI), is the best predictor of disease biology. However, both of these methods have several limitations. Phosphorylated histone H3 (PHH3), a novel mitotic marker, is potentially more accurate and easier to evaluate. This study aimed to evaluate the prognostic impact of PHH3 on patients with PNETs. METHODS Clinicopathologic data and paraffin-embedded tissue were evaluated for 100 of the 247 PNET patients whose tumors were resected between 1998 and 2010. Mitotic counts were analyzed on H&E-, Ki67-, and PHH3-stained slides by two independent pathologists. Kaplan-Meier curves, log-rank tests, Cox regression models, and time-dependent receiver operative characteristics (ROC) curves were used to evaluate the prognostic power of these markers. An internal data cross-validation was performed to select the best cutoff. RESULTS Of the 100 PNET patients resected, 53 were men. The median age of the patients was 59 years (range 19-96 years). The median follow-up period was 68 months (range 3-186 months). The median time for evaluation of an H&E- or PHH3-stained slide was 3 min, relative to 15 min for Ki67. The findings showed H&E, Ki67, and PHH3 all to be excellent predictors of disease-specific survival (DSS). However, PHH3 was superior to H&E and Ki67 in predicting both disease-free survival (DFS) (p = 0.006) and DSS (p = 0.001). Evaluation of the PHH3 mitotic count showed 7 mitoses per 10 high-power fields (HPFs) to be the optimal cutoff for differentiating between low- and high-risk PNET patients. CONCLUSIONS PHH3 is a better predictor of both DFS and DSS than H&E or Ki67 in PNET. In addition, PHH3 appears to be both easier to interpret and more accurate when compared to current prognostic markers.
Collapse
Affiliation(s)
- Vincenzo Villani
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Krishnan K Mahadevan
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Matteo Ligorio
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - David T Ting
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Francesco Sabbatino
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Medicine and Surgery, University of Salerno, Salerno, Italy
| | - Irene Zhang
- Doctor of Medicine Program, Harvard Medical School, Boston, MA, USA
| | - Mark Vangel
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Andrew L Warshaw
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Keith D Lillemoe
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jennifer Wargo
- Department of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
26
|
Asa SL, Ezzat S. Aggressive Pituitary Tumors or Localized Pituitary Carcinomas: Defining Pituitary Tumors. Expert Rev Endocrinol Metab 2016; 11:149-162. [PMID: 30058871 DOI: 10.1586/17446651.2016.1153422] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Pituitary tumors are common and exhibit a wide spectrum of hormonal, proliferative and invasive behaviors. Traditional classifications consider them malignant only when they exhibit metastasis. Patients who suffer morbidity and mortality from aggressive tumors classified as "adenomas" are denied support provided to patients with "cancers" and in many jurisdictions, these tumors are considered curiosities that do not warrant reporting in health registries. We propose use of the term "tumor" rather than "adenoma" to align with other neuroendocrine tumors. The features that can serve as diagnostic, prognostic and predictive markers are reviewed. Clinico-pathological and radiographic classifications provide important information and to date, no single biomarker has been able to offer valuable insight to guide the management of patients with pituitary tumors.
Collapse
Affiliation(s)
- Sylvia L Asa
- a Department of Pathology , University Health Network, University of Toronto , Toronto , Canada
- b Department of Laboratory Medicine and Pathobiology , University of Toronto , Toronto , Canada
| | - Shereen Ezzat
- c Department of Medicine , University Health Network, University of Toronto , Toronto , Canada
| |
Collapse
|
|
27
|
Klimstra DS, Beltran H, Lilenbaum R, Bergsland E. The spectrum of neuroendocrine tumors: histologic classification, unique features and areas of overlap. Am Soc Clin Oncol Educ Book 2016:92-103. [PMID: 25993147 DOI: 10.14694/edbook_am.2015.35.92] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neuroendocrine neoplasms are diverse in terms of sites of origin, functional status, and degrees of aggressiveness. This review will introduce some of the common features of neuroendocrine neoplasms and will explore the differences in pathology, classification, biology, and clinical management between tumors of different anatomic sites, specifically, the lung, pancreas, and prostate. Despite sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype in most organs, well-differentiated neuroendocrine tumors (WD-NETs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) are two very different families of neoplasms. WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades), closely resemble non-neoplastic neuroendocrine cells, and demonstrate production of neurosecretory proteins, such as chromogranin A. They arise in the lungs and throughout the gastrointestinal tract and pancreas, but WD-NETs of the prostate gland are uncommon. Surgical resection is the mainstay of therapy, but treatment of unresectable disease depends on the site of origin. In contrast, PD-NECs (grade 3, small cell or large cell) of all sites often demonstrate alterations in P53 and Rb, exhibit an aggressive clinical course, and are treated with platinum-based chemotherapy. Only WD-NETs arise in patients with inherited neuroendocrine neoplasia syndromes (e.g., multiple endocrine neoplasia type 1), and some common genetic alterations are site-specific (e.g., TMPRSS2-ERG gene rearrangement in PD-NECs arising in the prostate gland). Advances in our understanding of the molecular basis of NETs should lead to new diagnostic and therapeutic strategies and is an area of active investigation.
Collapse
Affiliation(s)
- David S Klimstra
- From the Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY; Yale Cancer Center, New Haven, CT; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
| | - Himisha Beltran
- From the Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY; Yale Cancer Center, New Haven, CT; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
| | - Rogerio Lilenbaum
- From the Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY; Yale Cancer Center, New Haven, CT; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
| | - Emily Bergsland
- From the Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY; Yale Cancer Center, New Haven, CT; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
| |
Collapse
|
|
28
|
Haugvik SP, Janson ET, Österlund P, Langer SW, Falk RS, Labori KJ, Vestermark LW, Grønbæk H, Gladhaug IP, Sorbye H. Surgical Treatment as a Principle for Patients with High-Grade Pancreatic Neuroendocrine Carcinoma: A Nordic Multicenter Comparative Study. Ann Surg Oncol 2015; 23:1721-8. [PMID: 26678407 DOI: 10.1245/s10434-015-5013-2] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Indexed: 12/29/2022]
Abstract
BACKGROUND This study aimed to evaluate the role of surgery for patients with high-grade pancreatic neuroendocrine carcinoma (hgPNEC) in a large Nordic multicenter cohort study. Prior studies evaluating the role of surgery for patients with hgPNEC are limited, and the benefit of the surgery is uncertain. METHODS Data from patients with a diagnosis of hgPNEC determined between 1998 and 2012 were retrospectively registered at 10 Nordic university hospitals. Kaplan-Meier curves were used to compare the overall survival of different treatment groups, and Cox-regression analysis was used to evaluate factors potentially influencing survival. RESULTS The study registered 119 patients. The median survival period from the time of metastasis was 23 months for patients undergoing initial resection of localized nonmetastatic disease and chemotherapy at the time of recurrence (n = 14), 29 months for patients undergoing resection of the primary tumor and resection/radiofrequency ablation of synchronous metastatic liver disease (n = 12), and 13 months for patients with synchronous metastatic disease given systemic chemotherapy alone (n = 78). The 3-year survival rate after surgery of the primary tumor and metastatic disease was 69 %. Resection of the primary tumor was an independent factor for improved survival after occurrence of metastatic disease. CONCLUSIONS Patients with resected localized nonmetastatic hgPNEC and later metastatic disease seemed to benefit from initial resection of the primary tumor. Patients selected for resection of the primary tumor and synchronous liver metastases had a high 3-year survival rate. Selected patients with both localized hgPNEC and metastatic hgPNEC should be considered for radical surgical treatment.
Collapse
Affiliation(s)
- Sven-Petter Haugvik
- Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | | | - Pia Österlund
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
| | - Seppo W Langer
- Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ragnhild Sørum Falk
- Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
| | - Knut Jørgen Labori
- Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Oslo, Norway
| | | | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Ivar Prydz Gladhaug
- Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| |
Collapse
|
|
29
|
Abstract
The pathologic classification of neuroendocrine neoplasms has evolved over the past decades, as new understanding of the biological behavior, histologic characteristics, and genetic features have emerged. Nonetheless, many aspects of the classification systems remain confusing or controversial. Despite these difficulties, much progress has been made in determining the features predicting behavior. Genetic findings have helped establish relationships among different types of neuroendocrine neoplasms and revealed potential therapeutic targets. This review summarizes the current approach to the diagnosis, classification, grading, and therapeutic stratification of neuroendocrine neoplasms, with a focus on those arising in the lung and thymus, pancreas, and intestines.
Collapse
Affiliation(s)
- David S Klimstra
- Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| |
Collapse
|
|
30
|
Pelosi G, Fabbri A, Cossa M, Sonzogni A, Valeri B, Righi L, Papotti M. What clinicians are asking pathologists when dealing with lung neuroendocrine neoplasms? Semin Diagn Pathol 2015; 32:469-79. [PMID: 26561395 DOI: 10.1053/j.semdp.2015.10.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Lung neuroendocrine tumors (NET) are currently classified in resection specimens according to four histological categories, namely typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCC). Diagnostic criteria have remained unchanged in the 2015 WHO classification, which has ratified the wide acceptance and popularity of such terminology in the pathologists׳ and clinicians׳ community. A unifying umbrella of NE morphology and differentiation has been recognized in lung NET, which has pushed to enter an unique box of invasive tumors along with diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) as a pre-invasive lesion with a potential toward the development of carcinoids. However, uncertainties remain in the terminology of lung NET upon small samples, where Ki-67 antigen could play some role to avoid misdiagnosing carcinoids as high-grade NE tumors. Epidemiologic, clinical and genetic traits support a biological three-tier over a pathology four-tier model, according to which TC are low malignancy tumors, AC intermediate malignancy tumors and LCNEC/SCC high malignancy tumors with no significant differences in survival among them. Inconsistencies in diagnostic reproducibility, troubles in the therapy of AC and LCNEC, and limitations to histology within the same tumor category argue in favor of a global re-thinking of lung NET where a grading system could play a role. This review outlines three main key questions in the field of lung NET: (A) unbiased diagnoses, (B) the role of Ki-67 and tumor grading, and (C) management of predictive markers. Answers are still inconclusive, thus additional research is required to improve our understanding on lung NET.
Collapse
Affiliation(s)
- Giuseppe Pelosi
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli Studi, Milan, Italy.
| | - Alessandra Fabbri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy
| | - Mara Cossa
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy
| | - Angelica Sonzogni
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy
| | - Barbara Valeri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy
| | - Luisella Righi
- Department of Pathology, University of Torino, Torino, Italy
| | - Mauro Papotti
- Department of Pathology, University of Torino, Torino, Italy
| |
Collapse
|
|
31
|
Kuriry H, Swied AM. Large-Cell Neuroendocrine Carcinoma of the Esophagus: A Case from Saudi Arabia. Case Rep Gastroenterol 2015; 9:327-34. [PMID: 26600769 PMCID: PMC4649715 DOI: 10.1159/000441381] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Neuroendocrine carcinomas of the esophagus are very rare, and the majority are high grade (poorly differentiated). They occur most frequently in males in their sixth and seventh decades of life. There have been no concrete data published on clinical features or on prognosis. We report a case of large-cell neuroendocrine carcinoma of the esophagus in a 66-year-old Saudi female with progressive dysphagia and weight loss. Upper endoscopy revealed an esophageal ulcerated mass.
Collapse
Affiliation(s)
- Hadi Kuriry
- King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Abdul Monem Swied
- King Saud bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia
| |
Collapse
|
|
32
|
Gene transcript analysis blood values correlate with 68Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status. Eur J Nucl Med Mol Imaging 2015; 42:1341-52. [DOI: 10.1007/s00259-015-3075-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 04/21/2015] [Indexed: 01/18/2023]
|
|
33
|
Chen ZE, Lin F. Application of immunohistochemistry in gastrointestinal and liver neoplasms: new markers and evolving practice. Arch Pathol Lab Med 2015; 139:14-23. [PMID: 25549141 DOI: 10.5858/arpa.2014-0153-ra] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Diagnosis of primary gastrointestinal and liver neoplasms is usually straightforward. Immunohistochemistry is most helpful to differentiate metastatic carcinomas with morphologic similarity and to resolve tumors of unknown origin. Recently, several new markers highly sensitive and specific for primary liver and gastrointestinal tumors have been discovered. Their potential diagnostic application has not been widely appreciated by general practicing pathologists. In addition, a new trend in immunohistochemistry application has started, focusing on assessing predictive markers (such as human epidermal growth factor receptor 2) and mutation-specific markers (v-raf murine sarcoma viral oncogene homolog B V600E) to directly guide clinical management. Practicing pathologists need to be aware of and prepared for this evolving trend. OBJECTIVES To summarize the usefulness of several recently discovered immunohistochemical markers in the study of gastrointestinal and liver tumors; to suggest the most current and effective immunohistochemical panels addressing common diagnostic challenges for these tumors; to share practical experience and useful tips for human epidermal growth factor receptor 2 testing in gastric and gastroesophageal junction adenocarcinoma and v-raf murine sarcoma viral oncogene homolog B V600E immunohistochemistry in colorectal carcinoma. DATA SOURCES Sources include literature review, and authors' research data and practice experience. The cases illustrated are selected from the pathology archives of the Geisinger Medical Center (Danville, Pennsylvania). CONCLUSIONS Application of immunohistochemistry in gastrointestinal and liver tumors continues to evolve. New tumor-specific markers constantly emerge and help pathologists to further improve diagnostic accuracy. Assessment of predictive and prognostic markers by immunohistochemistry in routine pathologic diagnosis is a new trend and will greatly facilitate the advancement of personalized cancer therapy.
Collapse
Affiliation(s)
- Zongming Eric Chen
- From the Department of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania
| | | |
Collapse
|
|
34
|
Mitotic count by phosphohistone H3 immunohistochemical staining predicts survival and improves interobserver reproducibility in well-differentiated neuroendocrine tumors of the pancreas. Am J Surg Pathol 2015; 39:13-24. [PMID: 25353284 DOI: 10.1097/pas.0000000000000341] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Well-differentiated neuroendocrine tumors (WDNETs) of the pancreas are graded on the basis of mitotic count or Ki67 index. Mitotic count has a narrow cutoff; its assessment is time consuming and carries poor interobserver reproducibility. Phosphohistone H3 (PHH3) is a mitosis-specific marker whose value has been validated in several tumor types. We sought to assess the utility of PHH3 in histologic grading of pancreatic WDNETs. Sixty-three cases of surgically resected primary pancreatic WDNETs were retrieved, and immunohistochemical analysis for PHH3 and Ki67 was performed. Mitotic rate was independently assessed by 4 pathologists on hematoxylin and eosin (HE; in 50 high-power fields [HPFs], expressed as mitoses/10 HPF) and PHH3 stains (in 50 HPFs, one 10×, and one 20× hotspot). PHH3 and Ki67 labeling indices were determined on a single 20× hotspot and expressed as the percentage of positive cells to total cells. We found that mitotic counts by various methods significantly correlated with each other and also with PHH3 and Ki67 indices, with the best correlation seen within the 3 different PHH3 counts (in 50 HPFs, one 10× and one 20× hotspot). Moreover, mitotic count on PHH3 was less time consuming than that on HE (1.68 vs. 3.67 min for 50 HPFs, P<0.0001). Histologic grade determined by PHH3 significantly correlated with disease-specific and disease-free survivals, with the best cutoffs of ≥4 mitoses/10 HPF (2 mm), ≥7 mitoses/10× hotspot, ≥5 mitoses/20× hotspot (log rank test, P<0.0001), and ≥0.16% for PHH3 labeling index (log rank test, P<0.0006). Tumor grades based on PHH3 stain also showed significant correlation with patient survivals in multivariate Cox proportional hazards models (P<0.05). Histologic grades by mitotic counts on PHH3 demonstrated high concordance and κ agreement with grades determined by mitotic count on HE. PHH3 stain also showed improved interobserver agreement in both original mitotic count (intraclass correlation 0.98 vs. 0.79) and final grade assignment (Fleiss κ 0.69 vs. 0.46) as compared with HE. Thus, our data confirmed that histologic grading by PHH3 stain has practical and prognostic values and offers reduced time and improved interobserver reproducibility in mitotic rate assessment and grade assignment. Although larger series are needed for validation, mitotic rate can potentially be determined by counting 1 hotspot, which will greatly facilitate the assessment of histologic grade in pancreatic WDNETs.
Collapse
|
|
35
|
Smith A, Thornton PS, Galliani CA, Miller JP, Dykes J, Leung-Pineda V. A 14-year old girl with reversible hypoglycemic episodes: the role of ASVS. Pediatr Dev Pathol 2015; 18:80-3. [PMID: 25437309 DOI: 10.2350/14-08-1537-cr.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
We present the case of a 14-year-old female who experienced several episodes of reversible altered mental status triggered by hypoglycemia. Following endocrine investigation, she was diagnosed with insulinoma. Insulinoma, a rare, differentiated, and functioning neuroendocrine tumor of the pancreas overproduces insulin, thus leading to hypoglycemic episodes. Conventional imaging failed to detect the lesion; therefore, arterial calcium stimulation with venous sampling (ASVS) was used for preoperative localization. The patient recovered without complications after surgical enucleation of the tumor. The ASVS is a useful method for localizing insulinomas when conventional imaging techniques fail, and can help reduce morbidities associated with surgical excision.
Collapse
Affiliation(s)
- Alisha Smith
- 1 Department of Pathology and Laboratory, Cook Children's Medical Center, Fort Worth, Texas 76104, USA
| | | | | | | | | | | |
Collapse
|
|
36
|
Pelosi G, Hiroshima K, Mino-Kenudson M. Controversial issues and new discoveries in lung neuroendocrine tumors. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.mpdhp.2014.09.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
|
37
|
Pelosi G, Papotti M, Rindi G, Scarpa A. Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. Endocr Pathol 2014; 25:151-64. [PMID: 24771462 DOI: 10.1007/s12022-014-9320-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Currently, grading in lung neuroendocrine tumors (NETs) is inherently defined by the histological classification based on cell features, mitosis count, and necrosis, for which typical carcinoids (TC) are low-grade malignant tumors with long life expectation, atypical carcinoids (AC) intermediate-grade malignant tumors with more aggressive clinical behavior, and large cell NE carcinomas (LCNEC) and small cell lung carcinomas (SCLC) high-grade malignant tumors with dismal prognosis. While Ki-67 antigen labeling index, highlighting the proportion of proliferating tumor cells, has largely been used in digestive NETs for assessing prognosis and assisting therapy decisions, the same marker does not play an established role in the diagnosis, grading, and prognosis of lung NETs. Next generation sequencing techniques (NGS), thanks to their astonishing ability to process in a shorter timeframe up to billions of DNA strands, are radically revolutionizing our approach to diagnosis and therapy of tumors, including lung cancer. When applied to single genes, panels of genes, exome, or the whole genome by using either frozen or paraffin tissues, NGS techniques increase our understanding of cancer, thus realizing the bases of precision medicine. Data are emerging that TC and AC are mainly altered in chromatin remodeling genes, whereas LCNEC and SCLC are also mutated in cell cycle checkpoint and cell differentiation regulators. A common denominator to all lung NETs is a deregulation of cell proliferation, which represents a biological rationale for morphologic (mitoses and necrosis) and molecular (Ki-67 antigen) parameters to successfully serve as predictors of tumor behavior (i.e., identification of pathological entities with clinical correlation). It is envisaged that a novel grading system in lung NETs based on the combined assessment of mitoses, necrosis, and Ki-67 LI may offer a better stratification of prognostic classes, realizing a bridge between molecular alterations, morphological features, and clinical behavior.
Collapse
Affiliation(s)
- Giuseppe Pelosi
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,
| | | | | | | |
Collapse
|
|
38
|
Basturk O, Tang L, Hruban RH, Adsay NV, Yang Z, Krasinskas AM, Vakiani E, La Rosa S, Jang KT, Frankel WL, Liu X, Zhang L, Giordano TJ, Bellizzi AM, Chen JH, Shi C, Allen P, Reidy DL, Wolfgang CL, Saka B, Rezaee N, Deshpande V, Klimstra DS. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol 2014; 38:437-47. [PMID: 24503751 PMCID: PMC3977000 DOI: 10.1097/pas.0000000000000169] [Citation(s) in RCA: 186] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited. DESIGN A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed. RESULTS The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively. CONCLUSIONS Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.
Collapse
Affiliation(s)
- Olca Basturk
- Departments of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Laura Tang
- Departments of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Ralph H. Hruban
- Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | | | - Zhaohai Yang
- Departments of Pathology, Penn State Hershey MC, Hershey, PA
| | | | - Efsevia Vakiani
- Departments of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Stefano La Rosa
- Departments of Pathology, Ospedale di Circolo, Varese, Italy
| | - Kee-Taek Jang
- Departments of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - Xiuli Liu
- Departments of Pathology, Cleveland Clinic, Cleveland, OH
| | - Lizhi Zhang
- Departments of Pathology, Mayo Clinic, Rochester, MN
| | | | - Andrew M. Bellizzi
- Departments of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA
| | - Jey-Hsin Chen
- Departments of Pathology, Indiana University, Indianapolis, IN
| | - Chanjuan Shi
- Departments of Pathology, Vanderbilt University, Nashville, TN
| | - Peter Allen
- Departments of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Diane L. Reidy
- Department of Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Christopher L. Wolfgang
- Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
- Departments of Surgery, The Johns Hopkins University, Baltimore, MD
| | - Burcu Saka
- Departments of Pathology, Emory University, Atlanta, GA
| | - Neda Rezaee
- Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
- Departments of Surgery, The Johns Hopkins University, Baltimore, MD
| | - Vikram Deshpande
- Departments of Pathology, Massachusetts General Hospital, Boston, MA
| | - David S. Klimstra
- Departments of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY
| |
Collapse
|