Increased Claudin 4 Expression Is Associated with Aggressiveness of Pulmonary Neuroendocrine Tumors
Jianhong Li, Shaolei Lu, Shamlal Mangray, Bassam Aswad, Renee Monahan, Lelia Noble, Murray Resnick, Evgeny Yakirevich. Alpert Medical School of Brown University, Providence, RI
Background: Claudins are members of a large family of tight junction proteins, which regulate cellular adhesion, polarity, and glandular differentiation. Dysregulation of claudin protein expression has been described in a number of malignancies, including lung carcinomas; however, expression of claudins in pulmonary neuroendocrine tumors (PNT) has not been addressed. Our goal was to investigate the protein expression patterns of claudins 1,3,4,7and 8 in PNTs.
Design: Sixty seven cases of PNTs were retrieved from the archives of Rhode Island Hospital including 38 typical carcinoids (TC), 11 atypical carcinoids (AC), 9 small cell carcinomas (SCC), 4 large cell neuroendocrine carcinomas (LCNEC), and 5 combined small cell/large cell neuroendocrine carcinomas (CSLNEC). Paraffin embedded tissue microarrays were analyzed for IHC expression of claudins 1,3,4,7, and 8. The immunoreactivity was assessed based on a combined score of the extent and intensity on a scale of 0-3+.
Results: In the normal lung tissue bronchial epithelial cells exhibited membranous claudin staining for all of the claudins studied. Alveolar cells demonstrated diffuse membranous immunoreactivity for claudins 7 and 8, focal staining for claudins 3 and 4, and were negative for claudin 1. In PNTs all claudins exhibited membranous staining pattern. A relatively low frequency of moderate to strong claudin expression (2-3+) varying from 2.6 to 36.3% was observed for claudins 1,3, and 7 in TC, AC, and SCC. Claudin 8 was weakly expressed in TC and AC, and was negative in all SCC cases. In contrast to other claudins, claudin 4 exhibited significantly higher expression in the more aggressive tumor subtypes as opposed to TC (p<0.001). Moderate to strong (2-3+) claudin 4 expression was detected in 2.6% of TC, 18.2 % of AC, 55.6% of SCC, 75% of LCNEC, and 80% of CSLNEC. Interestingly, while the majority of LCNEC were positive for claudin 4, none were positive for claudins 1,3, and 7 and only one case was positive for claudin 8.
|TC (n=38)||AC (n=11)||SCC (n=9)||LCNEC (n=4)||CSLNEC (n=5)|
|Claudin 1||5.3 %||27.3 %||11.1 %||0.0 %||0.0 %|
|Claudin 3||10.5 %||18.2 %||22.2 %||0.0 %||20.0 %|
|Claudin 4 *||2.6 %||18.2 %||55.6 %||75.0 %||80.0 %|
|Claudin 7||21.6 %||36.3 %||33.3 %||0.0 %||20.0 %|
|Claudin 8||16.2 %||27.3 %||0.0 %||25.0 %||60.0 %|