Lung carcinoids with sustentacular cells and low keratin expression: A common yet under-recognized phenomenon with diagnostic and biological implications.

Abstract

Sustentacular cell presence and the absence of keratin expression represent diagnostic hallmarks for distinguishing paragangliomas from neuroendocrine tumors (NET)/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, SOX10), nuclear markers of lung carcinoids (OTP, TTF1, ASCL1) and paragangliomas (GATA3, PHOX2B), and 505-gene next-generation sequencing (NGS). AE1/AE3 was strikingly variable (mean H-score 127; 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 16/18 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 15/18 AE1/AE3-low carcinoids containing sustentacular cells. Overall, 15/109 (14%) lung carcinoids were AE1/AE3-low and sustentacular cell-positive. In contrast, such features were seen in only 4/188 (2%) entero-pancreatic NETs. All AE1/AE3-low carcinoids were GATA3 and PHOX2B-negative while TTF1, OTP, and/or ASCL1-positive. By NGS, 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=0.003, SOX10: p=0.005), 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 (e.g. OTP, GATA3) as the updated approach for this differential diagnosis. Potential biological implications of paraganglioma-like features in lung carcinoids are discussed.