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

Authors

Jonathan Willner, Rania G Aly, Prithviraj Solanki, Irfan Khan, Christina E Wilson, Francis Bodd, Irina Linkov, Olca Basturk, Laura H Tang, Amitabh Srivastava, Anuradha Gopalan, Jason Chang, Marina K Baine, William D Travis, Jake June-Koo Lee, Charles M Rudin, Natasha Rekhtman

Published in

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. Pages 101037. Jul 04, 2026. Epub Jul 04, 2026.

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.

PMID:
42401207
Bibliographic data and abstract were imported from PubMed on 05 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.