PMID- 22579738
OWN - NLM
STAT- MEDLINE
DCOM- 20130110
LR  - 20220321
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1826
IP  - 2
DP  - 2012 Dec
TI  - Molecular and cellular biology of neuroendocrine lung tumors: evidence for 
      separate biological entities.
PG  - 255-71
LID - S0304-419X(12)00035-2 [pii]
LID - 10.1016/j.bbcan.2012.05.001 [doi]
AB  - Pulmonary neuroendocrine tumors (NETs) are traditionally described as comprising 
      a spectrum of neoplasms, ranging from low grade typical carcinoids (TCs) via the 
      intermediate grade atypical carcinoids (ACs) to the highly malignant small cell 
      lung cancers (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). Recent 
      data, however, suggests that two categories can be distinguished on basis of 
      molecular and clinical data, i.e. the high grade neuroendocrine (NE) carcinomas 
      and the carcinoid tumors. Bronchial carcinoids and SCLCs may originate from the 
      same pulmonary NE precursor cells, but a precursor lesion has only been observed 
      in association with carcinoids, termed diffuse idiopathic pulmonary 
      neuroendocrine cell hyperplasia. The occurrence of mixed tumors exclusively 
      comprising high grade NE carcinomas also supports a different carcinogenesis for 
      these two groups. Histopathologically, high grade NE lung tumors are 
      characterized by high mitotic and proliferative indices, while carcinoids are 
      defined by maximally 10 mitoses per 2mm(2) (10 high-power fields) and rarely have 
      Ki67-proliferative indices over 10%. High grade NE carcinomas are chemosensitive 
      tumors, although they usually relapse. Surgery is often not an option due to 
      extensive disease at presentation and early metastasis, especially in SCLC. 
      Conversely, carcinoids are often insensitive to chemo- and radiation therapy, but 
      cure can usually be achieved by surgery. A meta-analysis of comparative genomic 
      hybridization studies performed for this review, as well as gene expression 
      profiling data indicates separate clustering of carcinoids and carcinomas. 
      Chromosomal aberrations are much more frequent in carcinomas, except for deletion 
      of 11q, which is involved in the whole spectrum of NE lung tumors. Deletions of 
      chromosome 3p are rare in carcinoids but are a hallmark of the high grade 
      pulmonary NE carcinomas. On the contrary, mutations of the multiple endocrine 
      neoplasia type 1 (MEN1) gene are restricted to carcinoid tumors. Many of the 
      differences between carcinoids and high grade lung NETs can be ascribed to 
      tobacco consumption, which is strongly linked to the occurrence of high grade NE 
      carcinomas. Smoking causes p53 mutations, very frequently present in SCLCs and 
      LCNECs, but rarely in carcinoids. It further results in other early genetic 
      events in SCLCs and LCNECs, such as 3p and 17p deletions. Smoking induces 
      downregulation of E-cadherin and associated epithelial to mesenchymal transition. 
      Also, high grade lung NETs display higher frequencies of aberrations of the Rb 
      pathway, and of the intrinsic and extrinsic apoptotic routes. Carcinoid biology 
      on the other hand is not depending on cigarette smoke intake but rather 
      characterized by aberrations of other specific genetic events, probably including 
      Menin or its targets and interaction partners. This results in a gradual 
      evolution, most likely from proliferating pulmonary NE cells via hyperplasia and 
      tumorlets towards classical carcinoid tumors. We conclude that carcinoids and 
      high grade NE lung carcinomas are separate biological entities and do not 
      comprise one spectrum of pulmonary NETs. This implies the need to reconsider both 
      diagnostic as well as therapeutic approaches for these different groups of 
      malignancies.
CI  - Copyright (c) 2012 Elsevier B.V. All rights reserved.
FAU - Swarts, Dorian R A
AU  - Swarts DR
AD  - Department of Molecular Cell Biology, Maastricht University Medical Center, 
      Maastricht, The Netherlands. d.swarts@maastrichtuniversity.nl
FAU - Ramaekers, Frans C S
AU  - Ramaekers FC
FAU - Speel, Ernst-Jan M
AU  - Speel EJ
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20120510
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
SB  - IM
MH  - Animals
MH  - Carcinoid Tumor/etiology/genetics/pathology
MH  - Carcinoma, Small Cell/etiology/genetics/pathology
MH  - Cell Transformation, Neoplastic
MH  - Chromosome Deletion
MH  - Gene Expression Profiling
MH  - Genes, Tumor Suppressor
MH  - Humans
MH  - Lung Neoplasms/etiology/*genetics/pathology
MH  - Neuroendocrine Tumors/etiology/*genetics/pathology
MH  - Oncogenes
EDAT- 2012/05/15 06:00
MHDA- 2013/01/11 06:00
CRDT- 2012/05/15 06:00
PHST- 2012/03/13 00:00 [received]
PHST- 2012/05/04 00:00 [accepted]
PHST- 2012/05/15 06:00 [entrez]
PHST- 2012/05/15 06:00 [pubmed]
PHST- 2013/01/11 06:00 [medline]
AID - S0304-419X(12)00035-2 [pii]
AID - 10.1016/j.bbcan.2012.05.001 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2012 Dec;1826(2):255-71. doi: 10.1016/j.bbcan.2012.05.001. 
      Epub 2012 May 10.