The World Health Organization's classification of lung tumors separately categorizes neuroendocrine (NE) lung tumors, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC) as high-grade NE malignancies and carcinoids (typical, [TC] and atypical [AC]) as low- and intermediate-grade malignancies. Although these NE tumors are considered with NE hyperplasia (NEH) and tumorlets as part of a spectrum of NE proliferations, their derivation from a common progenitor cell has not received full agreement. With the aim of refining their differential diagnosis and extending our understanding of their histogenesis, we studied the expression of thyroid transcription factor-1 (TTF-1), a transcription factor that regulates lung morphogenesis and differentiation, along the spectrum of NE lung tumors. Two hundred and twenty- seven NE proliferations and tumors were immunostained with TTF-1 antibody. Positive immunostaining for TTF-1 was detected in 47 of 55 (85.5%) pure SCLCs, in 31 of 64 (49%) pure LCNECs, but in none of 15 NEHs, 23 tumorlets, or 50 carcinoid tumors (27 TCs and 23 ACs). In 19 of 20 (95%) combined SCLCs and LCNECs, TTF-1 expression was identical in both NE and non-NE components. These results show that TTF-1 is not expressed in normal and hyperplastic NE cells or in carcinoids, but is expressed in high-grade NE proliferations and in lung adenocarcinomas. This challenges the concept of a spectrum of NE proliferations and tumors and lends credence to the alternative hypothesis of a common derivation for SCLC and non-SCLC including LCNEC, with carcinoids deriving from a different stem cell.
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