Background: Among neuroendocrine tumours (NET) of the lung, typical (TC) and atypical (AC) carcinoids represent the low, small cell lung carcinomas (SCLC) and large cell neuroendocrine carcinomas (LCNEC) the high grade spectrum. The N-glycoprotein periostin (POSTN) was recently found to be upregulated in both tumour cell cytoplasm and peritumoural stroma of non-small cell lung carcinomas (NSCLC) in the context of epithelialmesenchymal transition (EMT). This study aimed at investigating periostin protein expression in NET in these respective compartments. Patients and Methods: Between 1993 and 2007, a retrospective multicenter cohort of 192 patients with surgically resected NET or diagnosed as such at autopsy was investigated on a tissue microarray (TMA) by immunohistochemistry (IHC). Periostin immunoreactivity was semi-quantitatively scored in the cytoplasm of tumour epithelia and in the peritumoural stroma. Data was correlated with neuroendocrine (NE) categories, markers of neuroendocrine (synaptophysin, chromogranin A) or lung (TTF-1) differentiation, and the tumour proliferation rate Mib-1. Results: The cohort consisted of 58 TC, 42 AC, 32 LCNEC and 60 SCLC. Concerning neuroendocrine differentiation, chromogranin A was less tightly associated with it than synaptophysin. Cytosolic periostin expression was higher in carcinoids than in SCLC or LCNEC (p < 0.001). There was no significant difference between POSTN expression in tumour cells and overall survival rate (p = 0.139). No (grade 0) or weak (grade 1-2) stromal staining with POSTN was detected in more than half of typical (70.7 %) and atypical carcinoids (54.8 %), whereas strong (grade 5-6) staining was observed in LCNEC (56.3 %) and SCLC (46.7 %). Thus high stromal expression of periostin was associated with higher tumour grade and the SCLC and LCNEC categories, respectively, as well as higher pTNM and therefore correlated with a decreased survival rate (p-values <0.05). Furthermore, besides proliferation, a
correlation between high TTF-1 expression and worse prognosis was seen in high-grade NET. Conclusion: Aggressive clinical behaviour of SCLC and LCNEC corresponds not only with high proliferation rate and high expression of TTF-1 but also with the formation of a prominent desmoplastic stroma containing the EMT protein periostin.