Claudin Proteins Are Differentially Expressed in Gastrointestinal and Pulmonary Neuroendocrine Tumors
Rashna Clubwala, Jianhong Li, Shaolei Lu, Mangray Shamlal, Monahan Renee, Noble Lelia, Resnick Murray, Yakirevich Evgeny. Rhode Island Hospita/Warren 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 and gastrointestinal carcinomas; however, expression of claudins in neuroendocrine tumors (NET) has not been addressed. Our goal was to investigate the protein expression patterns of claudins 1,3,4,7, 8 in neuroendocrine tumors from the GI tract and lung.
Design: One hundred and eight cases of low-to-intermediate grade NETs were retrieved from the archives of Rhode Island Hospital, including 70 of the GI tract (41 ileal (IC), 17 appendiceal (AC), and 12 rectal (RC)) and 38 typical pulmonary carcinoids (TPC). 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: Normal intestinal and bronchial epithelium showed positive membranous staining for all claudins studied. In addition, alveolar cells showed immunoreactivity for claudins 3,4,7, and 8. In NETs, all claudins exhibited a membranous staining pattern independent of location. GI NETs demonstrated significantly higher frequencies of moderate to strong (2-3+) staining for all claudins as opposed to TPC (p<0.002). The differences between GI and pulmonary NET were most striking in claudin 8 with moderate to strong expression (2-3+) between IC and TPC (78.3% vs 16.2%, p<0.0001) and claudin 4 with moderate to strong expression (2-3+) among all GI NETs as compared to TPC (56.3-60.9% vs 2.6%, p<0.0001). In addition, within the GI NET group, claudin 8 expression was significantly more frequent in IC as opposed to AC (78.3% vs 50.0%, p=0.03). Claudin 3 expression was significantly higher in RC as compared to IC (69.2% vs 26.1%, p=0.0082).
|Ileal NET (n=41)||Appendiceal NET (n=17)||Rectal NET (n=12)||Typical Pulmonary Carcinoids (n=38)|