MTP22-01: Neuroendocrine tumors

Abstract

Neuroendocrine lung tumors comprise 4 categories of tumors described in the WHO 1999 (1Histological Typing of Lung and Pleural Tumors.in: Travis W.D. Colby T.V. Corrin B. Shimosato Y. Brambilla E. In Collaboration with L.H. Sobin and Pathologists from 14 Countries. World Health Organization. International Histological Classification of Tumors. Third Edition. Springer, 1999Google Scholar) and 2004 classification (2Travis WD Brambilla E Muller-Hemerlink HK Harris CC World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon2004Google Scholar) along with 3 different grades: small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are 2 high grade lung tumors. Carcinoids have 2 subtypes: the typical carcinoids a low grade tumor and atypical carcinoids an intermediate grade tumor. This subset of tumors shares morphological, ultrastructural, immunohistochemical and molecular characteristics but probably derive from 2 different stem cells. Although it appears as a spectrum of high grade less differentiated to well differentiated neuroendocrine tumors, it has been shown for long that they likely belong to 2 categories with 2 different stem cells and it is also believed that they originate from 2 different stem cells. SCLC and LCNEC display neuroendocrine features have a high rate of proliferation, high clinical agressivity and metastatic potential. They are probably derived of a common lung cancer stem cells. There is no preinvasive lesion identified for the high grade neuroendocrine tumors SCLC and LCNEC. In contrast, carcinoids typical and atypical, have an indolent or intermediate clinical course and likely derive from each others, atypical showing nests of proliferation inside an otherwise wide typical carcinoid, it is likely that atypical carcinoids derive from progression of typical carcinoids. A precursor lesion identified for carcinoids is the diffuse idiopathic pulmonary neuroendocrine hyperplasia (DIPNECH) which is not a preneoplastic lesion. SCLC is the most frequent neuroendocrine tumor accounting for 20-25 % of lung cancer, but all others are rare not exceeding 7 % all together. These phenotypic traits constitute immunohistochemical features that allow positive and differential diagnosis of SCLC and other neuroendocrine tumors. A common signature between all these is the expression of specific neuroendocrine markers. To this level since all 4 entities disclose neuroendocrine markers at about the same level, these could not be considered as a grading of differentiation but as a constant trait linking them. Chromogranin, synaptophysin, CD56/NCAM are the 3 specific neuroendocrine markers allowing their recognition from NSCLC, but not from each other. SCLC has a high rate of mitosis and proliferation with 20 to 100 mitosis for 10 high power field and a Ki-67 proliferative index exceeding 50 % of positive tumor cells. In the same way, LCNEC has high rate of proliferation and both have large areas of necrosis. Their apoptotic levels are as high as expected from high proliferation rate and high cell turnover. In contrast, carcinoid tumors are characterized by organoid growth pattern dysplaying more achieved neuroendocrine differentiation than SCLC, the same level of differentiation than LCNEC but are characterized by a lower mitotic rate (3Travis WD Rush W Flieder DB Falk R Fleming MV Gal AA Koss MN Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid.Am. J. Surg. Pathol. 1998; 22: 934-944Crossref PubMed Scopus (661) Google Scholar). TTF-1 is only expressed in the 2 high grade neuroendocrine proliferations in 85 % of SCLC and 50 % of LCNEC but usually not in carcinoids (a few atypical carcinoids has been reported for TTF-1 expression). This difference otherwise reflects the two different stem cell for high grade neuroendocrine tumor arising from a typical lung stem cell and the carcinoids (a predestined neuroendocrine cell) (4Sturm N Rossi G Lantuejoul S et al.Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids.Hum Pathol. 2002; 33: 175-182Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). The molecular genetic alteration reflecting proliferation and progression, chromosomal imbalances, P53 pathway alterations, Rb inactivation (5Gouyer V Gazzeri S Bolon I et al.Mechanism of retinoblastoma gene inactivation in the spectrum of neuroendocrine lung tumors.Am J Respir Cell Mol Biol. 1998; 18: 188-196Crossref PubMed Scopus (57) Google Scholar) and a Fas and FasL deregulation are characteristic of high grade neuroendocrine tumors, SCLC and LCNEC. Alteration of upstream regulators of P53, P14ARF and Mdm2 are frequent in SCLC and LCNEC but rare in carcinoids. E2F1 overexpression (6Eymin B Gazzeri S Brambilla C et al.Distinct pattern of E2F1 expression in human lung tumors: E2F1 is upregulated in small cell lung carcinoma.Oncogene. 2001; 20: 1678-1687Crossref PubMed Scopus (103) Google Scholar), a high frequency of P53 mutation and overexpression (80 % and 70 % respectively), the deregulation of Bcl2:Bax ratio in favor of Bcl2 (7Brambilla E Negoescu A Gazzeri S et al.Apoptosis-related factors P53, Bcl2, and Bax in neuroendocrine lung tumors.Am J Pathol. 1996; 149: 1941-1952PubMed Google Scholar), a downregulation of Fas with upregulation of its ligand FasL (8Viard-Leveugle I Veyrenc S French LE et al.Frequent loss of Fas expression and function in human lung tumors with overexpression of FasL in small cell lung carcinoma.J Pathol. 2003; 2: 268-277Crossref Scopus (71) Google Scholar) and 95 % frequency of Rb inactivation (9Beasley MB Lantuejoul S Abbondanzo S et al.The p16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung.Hum Pathol. 2003; 34: 136-142Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar) are characteristics of high grade neuroendocrine tumors. Upstream regulator of P53, P14ARF, and one of its inducing factor E2F1are characteristically lost or gained respectively in high grade neuroendocrine tumors with 50 % los of P14ARF (10Gazzeri S Della Valle V Chaussade L et al.The human p19ARF protein encoded by the α transcript of the p16INK4 gene is frequently lost in small cell lung tumors.Cancer Res. 1998; 58: 3926-3931PubMed Google Scholar) and 90 % overexpression of E2F1 (6Eymin B Gazzeri S Brambilla C et al.Distinct pattern of E2F1 expression in human lung tumors: E2F1 is upregulated in small cell lung carcinoma.Oncogene. 2001; 20: 1678-1687Crossref PubMed Scopus (103) Google Scholar) are characteristic of SCLC and LCNEC. In contrast, a common frequency of 30 % of Mdm2 overexpression is observed in all neuroendocrine tumors and NSCLC. P14ARF plays independent role of P53 in G2 arrest and apoptosis, in response to both oncogenic stimuli and DNA damage (11Eymin B Leduc C Coll JL et al.P14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumors established in nude mice.Oncogene. 2003; 22: 1822-1835Crossref PubMed Scopus (102) Google Scholar, 12Eymin B Claverie P Salon C et al.p14ARF activates a Tip60-dependent ATM/ATR/CHK pathway in response to genotoxic stresses.Mol Cell Biol. 2006; 26: 4339-4350Crossref PubMed Scopus (81) Google Scholar, 13Eymin B Claverie P Salon C et al.P14ARF triggers G2 arrest through ERK-mediated Cdc25C phosphorylation, ubiquitination and proteasomal degradation.Cell Cycle. 2006; 5: 759-765Crossref PubMed Scopus (37) Google Scholar). Cell immortalization by telomerase is an almost constant features in SCLC and LCNEC and unconspicuous in carcinoids. In regard with the E-cadherin intercellular adhesion membrane, E-catenin complex protein, E-cadherin and β-catenin loss or impaired expression (cytoplasmic versus membranar) was observed with a higher frequency in high grade neuroendocrine tumors (90 %) than in NSCLC and in carcinoids, 30 % of which have loss or cytoplasmic delocalization of E-cadherin or β-catenin. E-cadherin impairment expression was correlated with extensive disease in typical and atypical carcinoids (14Salon C Moro D Lantuejoul S Brichon PY Drabkin H Brambilla C Brambilla E The E-cadherin / α-catenin Adhesion Complex in Neuroendocrine Tumors of the Lung: a suggested role upon local invasion and metastasis.Human Pathol. 2004; 35/9: 1148-1155Abstract Full Text Full Text PDF Scopus (29) Google Scholar). The Sonic Hedge-hog pathway (SHh) with its receptor Patch is characteristic of neuroendocrine differentiation but is strongly activated in SCLC and involved in the maintenance of its malignant phenotype. There was no study of SHh pathway in carcinoid tumors. Human Acute Homolog 1 (ASH1) a transcription factor known to play a crucial role in neuronal endocrine determination and differentiation is expressed at high level and uniformly in classic SCLC and in NSCLC with neuroendocrine features. It has been shown to be absent in differentiated typical carcinoids, although it was expressed in atypical carcinoids, LCNEC and SCLC, such imitating its early and transient expression pattern during development but not being necessary for the maintenance of neuroendocrine phenotype as it is absent typical carcinoids. The tyrosine-kinase growth factors and receptors are involved in the oncogenesis of SCLC where kit receptor encoded by the c-kit gene (homologous with PDGF) is overexpressed in about 50 % of SCLC. It is also overexpressed in 63 % of LCNEC as was PDGRa. Met the product of the proto-oncogene c-met is aberrantly overexpressed in high grade neuroendocrine tumors, SCLC and LCNEC. Aberrant met activations through binding to its high affinity ligands HGF (scatter factor) provokes activation of multiple signal transductors of the tyrosine-kinase pathway. Interestingly Met was the only prognostic factor in LCNEC with Met expression and was significantly correlated with overall survival (p=0.03) (15Rossi G Cavazza A MarchioniI A Longo L Migaldi M Sartori G Bigiani N Schirosi L Casali C Morandi U Facciolongo N Maiorana A Bavieri M Fabbri L Brambilla E Role of the chemotherapy and the receptor tyrosine kinases KIT, PDGFRa, PDGFRα and Met in large-cell neuroendocrine carcinoma of the lung.J Clin Oncol. 2005; 23: 8774-8785Crossref PubMed Scopus (201) Google Scholar). Although no mutation was observed in Met or RTK in positive LCNEC, Met mutation have been found in SCLC prompting clinical investigation for the therapeutic effect of RTK inhibitors targeting c-met in SCLC.