Lung Carcinoids with Sustentacular Cells and Low Keratin Expression: A Common yet Underrecognized Phenomenon with...

Sustentacular cell presence and the absence of keratin expression represent diagnostic hallmarks for distinguishing paragangliomas from neuroendocrine tumors/carcinoids. However, based on the literature and our practice, pulmonary carcinoids can exhibit both features. Here, we examined the prevalence and biological correlates of this phenomenon. Lung carcinoids (N = 109) were analyzed with several common keratins, including AE1/AE3, sustentacular cell markers (S100 and SOX10), nuclear markers of lung carcinoids (OTP, TTF1, and ASCL1) and paragangliomas (GATA3 and PHOX2B), and 505-gene next-generation sequencing. AE1/AE3 was strikingly variable (mean H score, 127 of 300; SD, 80), with 18 cases (17%) exhibiting low labeling (H score, <50), including 3 AE1/AE3-negative cases. CAM5.2 was similarly variable (mean H score, 105; SD, 94) and was low/negative in 16 of 18 AE1/AE3-low cases. Conversely, pan-keratin OSCAR and CK18 were higher overall (mean H scores, 253 and 264, respectively) and showed unequivocal positivity in all AE1/AE3-low/negative cases. Sustentacular cells were present diffusely in 35% of carcinoids, with 15 of 18 AE1/AE3-low carcinoids containing sustentacular cells. Overall, 15 of 109 lung carcinoids (14%) were AE1/AE3 low and sustentacular cell positive. In contrast, such features were seen in only 4 of 188 enteropancreatic neuroendocrine tumors (2%). All AE1/AE3-low lung carcinoids were GATA3 and PHOX2B negative, while TTF1, OTP, and/or ASCL1 positive. By next-generation sequencing, all cases lacked mutations typical of paragangliomas, and many harbored alterations typical of lung carcinoids. Notably, lower AE1/AE3 was associated with the presence of sustentacular cells (S100: P = .003; SOX10: P = .005), spindle morphology, peripheral location, and ASCL1+/TTF1+/OTP+/HNF4A- immunophenotype-the constellation reflecting the emerging concept of "proneuronal" carcinoids. We conclude that lung carcinoids are not keratin negative but instead keratin variable, and some may appear as negative in an antibody-dependent manner. Together with the common presence of sustentacular cells, this may yield a profile overlapping with paragangliomas. We suggest using additional keratins and tumor-specific transcription factors (eg, OTP and GATA3) as the updated approach for this differential diagnosis. Potential biological implications of paraganglioma-like features in lung carcinoids are discussed.