Transcriptomic data helps refining classification of pulmonary carcinoid tumors with increased mitotic counts

Published on Apr 14, 2020in Modern Pathology7.842
· DOI :10.1038/S41379-020-0538-8
Olga V. Sazonova10
Estimated H-index: 10
,
Venkata S. K. Manem9
Estimated H-index: 9
+ 5 AuthorsPhilippe Joubert15
Estimated H-index: 15
(Laval University)
Sources
Abstract
Pulmonary neuroendocrine neoplasms are classified by WHO as either typical or atypical carcinoids, large cell (LCNEC) or small cell (SCLC) neuroendocrine carcinoma based on mitotic count, morphology, and necrosis assessment. LCNEC with low mitotic count and sharing morphologic features with carcinoids are in a gray zone for classification and their rare prevalence and the paucity of studies precludes proper validation of the current grading system. In this study, we aim to investigate their clinicopathological and transcriptomic profiles. Lung resection specimens obtained from 18 patients diagnosed with carcinoids or LCNEC were selected. Four of them were characterized as borderline tumors based on a mitotic rate ranging between 10 and 30 mitoses per 2 mm(2). Comprehensive morphological and immunohistochemical (IHC) evaluation was performed and tumor-based transcriptomic profiles were analyzed through unsupervised clustering. Clustering analysis revealed two distinct molecular groups characterized by low (C1) and high (C2) proliferation. C1 was comprised of seven carcinoids and three borderline tumors, while C2 was comprised of seven LCNEC and one borderline tumor. Furthermore, patients in cluster C1 had a better recurrence-free survival compared with patients in cluster C2 (20% vs 75%). Histological features, IHC profile, and molecular analysis showed that three out of four borderline tumors showed features consistent with carcinoids. Therefore, our findings convey that the current diagnostic guidelines are suboptimal for classification of pulmonary neuroendocrine tumors with increased proliferative index and carcinoid-like morphology. These results support the emerging concept that neuroendocrine tumors with carcinoid-like features and mitotic count of <20 mitoses per 2 mm(2) should be regarded as pulmonary carcinoids instead of LCNEC.
📖 Papers frequently viewed together
References34
Newest
#1Michele SimboloH-Index: 22
#2Stefano BarbiH-Index: 23
Last. Aldo ScarpaH-Index: 100
view all 20 authors...
Abstract Introduction DNA mutational profiling showed that atypical carcinoids (ACs) share alterations with large cell neuroendocrine carcinomas (LCNECs). Transcriptomic studies suggested that LCNECs are composed of two subtypes, one of which shares molecular anomalies with SCLC. The missing piece of information is the transcriptomic relationship between ACs and LCNECs, as a direct comparison is lacking in the literature. Methods Transcriptomic and genomic alterations were investigated by next-g...
Source
#1Saurabh V. Laddha (RU: Rutgers University)H-Index: 14
#2Edaise M da Silva (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 12
Last. Chang S. Chan (RU: Rutgers University)H-Index: 21
view all 10 authors...
Lung carcinoids (LCs) are rare and slow growing primary lung neuroendocrine tumors. We performed targeted exome sequencing, mRNA sequencing and DNA methylation array analysis on macro-dissected lung carcinoids. Recurrent mutations were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C and KMT2A) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profile...
Source
#1Nicolas Alcala (IARC: International Agency for Research on Cancer)H-Index: 11
#2Noémie Leblay (IARC: International Agency for Research on Cancer)H-Index: 6
Last. Akram Ghantous (IARC: International Agency for Research on Cancer)H-Index: 23
view all 70 authors...
The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups wit...
Source
Abstract Introduction The WHO classification of pulmonary neuroendocrine tumors (PNETs) is also used to classify thymic NETs (TNETs) into typical and atypical carcinoid (TC and AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), but little is known about the usability of alternative classification systems. Methods One hundred seven TNET (22 TC, 51 AC, 28 LCNEC, and 6 SCC) from 103 patients were classified according to the WHO, the European Neuroendocrine Tumor Socie...
Source
#1Deena M.A. Gendoo (University of Birmingham)H-Index: 13
#2Michael Zon (McMaster University)H-Index: 2
Last. Benjamin Haibe-KainsH-Index: 72
view all 8 authors...
A wealth of transcriptomic and clinical data on solid tumours are under-utilized due to unharmonized data storage and format. We have developed the MetaGxData package compendium, which includes manually-curated and standardized clinical, pathological, survival, and treatment metadata across breast, ovarian, and pancreatic cancer data. MetaGxData is the largest compendium of curated transcriptomic data for these cancer types to date, spanning 86 datasets and encompassing 15,249 samples. Open acce...
Source
The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the standard upper proliferative criteria—as defined largely based on early-stage carcinoids—in metastatic setting. Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n = 132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopatho...
Source
#1Atsuko Kasajima (TUM: Technische Universität München)H-Index: 19
#2Björn Konukiewitz (TUM: Technische Universität München)H-Index: 22
Last. Günter Klöppel (TUM: Technische Universität München)H-Index: 54
view all 11 authors...
: The clinicopathological features of lung neuroendocrine neoplasms (NEN) with a high proliferative index at the border area between atypical carcinoid and neuroendocrine carcinoma have not been investigated so far. The aim of this study was, therefore, to search for lung NENs which are well differentiated but show Ki67 values that overlap with those of poorly differentiated (PD)-NENs. Resected lung NENs from 244 Japanese patients were reviewed, and Ki67 indices were assessed in all tumors. The ...
Source
#1Guido Rindi (UCSC: Catholic University of the Sacred Heart)H-Index: 87
#2David S. Klimstra (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 147
Last. Ian A. Cree (IARC: International Agency for Research on Cancer)H-Index: 60
view all 26 authors...
The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tum...
Source
#1Jules L. Derks (Maastricht University Medical Centre)H-Index: 11
#2Noémie Leblay (IARC: International Agency for Research on Cancer)H-Index: 6
Last. Lynnette Fernandez-Cuesta (IARC: International Agency for Research on Cancer)H-Index: 25
view all 6 authors...
Abstract Carcinoids and large cell neuroendocrine carcinomas (LCNECs) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g., menin 1 gene [ MEN1 ]), and few affect genes of the phosphoinositide 3-kinase ( PI3K ) -AKT...
Source
#1Julie George (University of Cologne)H-Index: 18
#2Vonn Walter (Penn State Milton S. Hershey Medical Center)H-Index: 25
Last. Roman K. Thomas (DKFZ: German Cancer Research Center)H-Index: 78
view all 62 authors...
Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas a...
Source
Cited By5
Newest
#1Jules L. Derks (Maastricht University Medical Centre)H-Index: 11
#2N. Rijnsburger (Erasmus University Medical Center)H-Index: 1
Last. Anne Marie C. Dingemans (Erasmus University Medical Center)H-Index: 4
view all 10 authors...
Abstract null null Diagnosing a pulmonary neuroendocrine neoplasm (NEN) may be difficult, challenging clinical decision making. In this review key clinical and pathological issues and informative molecular markers are being discussed: 1) What is the preferred outcome parameter for curatively resected low grade NENs (carcinoid) e.g., overall survival or recurrence free interval? 2) Does the World Health Organization (WHO) classification combined with a Ki-67 proliferation index and molecular mark...
Source
#1Marco Volante (UNITO: University of Turin)H-Index: 72
#2Ozgur Mete (U of T: University of Toronto)H-Index: 37
Last. Silvia Uccella (University of Insubria)H-Index: 25
view all 6 authors...
Thoracic (pulmonary and thymic) neuroendocrine tumors are well-differentiated epithelial neuroendocrine neoplasms that are classified into typical and atypical carcinoid tumors based on mitotic index cut offs and presence or absence of necrosis. This classification scheme is of great prognostic value but designed for surgical specimens, only. Deep molecular characterization of thoracic neuroendocrine tumors highlighted their difference with neuroendocrine carcinomas. Neuroendocrine tumors of the...
Source
#2Olga V. SazonovaH-Index: 10
Last. Philippe Joubert (Laval University)H-Index: 15
view all 8 authors...
Pulmonary neuroendocrine tumors (NETs) are a heterogeneous family of malignancies whose classification relies on morphology and mitotic rate, unlike extrapulmonary neuroendocrine tumors that require both mitotic rate and Ki-67. As mitotic count is proportional to Ki-67, it is crucial to understand if Ki-67 can complement the existing diagnostic guidelines, as well as discover the benefit of these two markers to unravel the biological heterogeneity. In this study, we investigated the association ...
Source
#1B.C.M. Hermans (Maastricht University Medical Centre)H-Index: 4
#2Jules L. Derks (Maastricht University Medical Centre)H-Index: 11
Last. A-M.C. Dingemans (EUR: Erasmus University Rotterdam)H-Index: 12
view all 8 authors...
Abstract Objectives Pulmonary neuroendocrine neoplasms (NENs) are subdivided in carcinoids and neuroendocrine carcinomas (small cell lung carcinoma and large cell neuroendocrine carcinoma (LCNEC)), based on the presence of necrosis and mitotic index (MI). However, it is unclear if tumors with well differentiated morphology but high proliferation rate should be regarded as LCNEC or as high grade carcinoids. In previous case series, a longer overall survival then expected in LCNEC has been suggest...
Source
#1Giovanni CentonzeH-Index: 12
#2Davide BiganzoliH-Index: 1
Last. Massimo MilioneH-Index: 33
view all 14 authors...
Lung neuroendocrine neoplasms (LNENs) represent a rare and heterogeneous population of lung tumors. LNENs incidence rate has increased dramatically over the past 30 years. The current World Health Organization LNENs classification (WHO 2015), distinguished four LNENs prognostic categories, according to their morphology, necrosis amount and mitotic count: typical carcinoid (TC), atypical-carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC). At present, due...
Source
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.