Alteration of the E-cadherin/beta-catenin cell adhesion system is common in pulmonary neuroendocrine tumors and is an independent predictor of lymph node metastasis in atypical carcinoids.
BACKGROUND
To the authors' knowledge, little is known regarding the role of E-cadherin/beta-catenin system dysregulation in pulmonary neuroendocrine tumors.


METHODS
E-cadherin and beta-catenin immunoreactivity was evaluated in 10 hyperplastic neuroendocrine tumorlets and 210 neuroendocrine tumors, including 96 typical carcinoids (CTs), 35 atypical carcinoids (ACTs), 49 large cell neuroendocrine carcinomas (LCNECs), and 30 small cell lung carcinomas (SCLCs).


RESULTS
Normal and hyperplastic bronchial neuroendocrine cells expressed E-cadherin/beta-catenin with an orderly distribution along the cell membrane. Neuroendocrine tumors retained beta-catenin expression in all tumors and E-cadherin in most tumors, with the exception of 2% of LCNECs, 3% of SCLCs and 9% of ACTs. E-cadherin showed a prevalent membrane-associated, linear immunoreactivity in CTs, whereas membrane-disarrayed and cytoplasmic staining was seen in most ACTs, LCNECs, and SCLCs (P < 0.001). beta-Catenin exhibited similar immunoreactivity patterns according to tumor type and a close association with E-cadherin subcellular distribution (P < 0.001). Nuclear accumulation of beta-catenin was found only in seven LCNECs and in two SCLCs. In ACTs, disarrayed immunoreactivity for E-cadherin and/or beta-catenin was associated with a nontrabecular growth pattern, altered expression of the cell-motility marker fascin, and lymph node metastases. Furthermore, a disarrayed E-cadherin distribution pattern was associated with the pathologic lymph node classification and the number of involved lymph nodes. Multivariate analysis confirmed that a disarrayed E-cadherin or beta-catenin pattern was an independent predictor of lymph node metastases in patients with ACT.


CONCLUSIONS
The subcellular compartmentalization of the E-cadherin/beta-catenin complex was altered in pulmonary neuroendocrine tumors. This likely affects the tumor growth pattern and cell motility of ACT and was correlated with the occurrence of lymph node metastases.
Pelosi
Giuseppe
G
Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan School of Medicine, Milan, Italy. giuseppe.pelosi@ieo.it
Scarpa
Aldo
A
Puppa
Giacomo
G
Veronesi
Giulia
G
Spaggiari
Lorenzo
L
Pasini
Felice
F
Maisonneuve
Patrick
P
Iannucci
Antonio
A
Arrigoni
Gianluigi
G
Viale
Giuseppe
G
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis; D001707:Biopsy, Needle; D015820:Cadherins / Q000032:analysis / Q000378:metabolism*; D002276:Carcinoid Tumor / Q000378:metabolism / Q000401:mortality / Q000556:secondary* / Q000628:therapy; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000556:secondary; D002448:Cell Adhesion; D002465:Cell Movement; D016009:Chi-Square Distribution; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011237:Predictive Value of Tests; D011379:Prognosis; D018570:Risk Assessment; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*; D051176:beta Catenin
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin