Analysis of ASCL1/NEUROD1/POU2F3/YAP1 yields novel insights for the diagnosis of olfactory neuroblastoma and identifies sinonasal tuft cell–like carcinoma Journal Article


Authors: Febres-Aldana, C. A.; Elsayad, M. M.; Saliba, M.; Bhanot, U.; Ntiamoah, P.; Takeyama, A.; Purgina, B. M.; Rodriguez-Urrego, P. A.; Marusic, Z.; Jakovcevic, A.; Chute, D. J.; Dunn, L. A.; Ganly, I.; Cohen, M. A.; Pfister, D. G.; Ghossein, R. A.; Baine, M. K.; Rekhtman, N.; Dogan, S.
Article Title: Analysis of ASCL1/NEUROD1/POU2F3/YAP1 yields novel insights for the diagnosis of olfactory neuroblastoma and identifies sinonasal tuft cell–like carcinoma
Abstract: The diagnosis and treatment of sinonasal small round epithelial/neuroepithelial malignancies depend on the expression of conventional neuroendocrine markers (NEMs), such as synaptophysin, chromogranin A, INSM1, and CD56/NCAM1. However, these tumors remain diagnostically challenging because of overlapping histologic and immunohistochemical features. The transcriptional regulators ASCL1, NEUROD1, POU2F3, and YAP1 are novel NEM (nNEM) used for the subtyping of small-cell lung cancer (SCLC). Here, we assessed the immunoexpression of nNEM in 76 sinonasal malignancies, including 27 olfactory neuroblastomas (ONB), 14 small-cell neuroendocrine carcinomas (SCNEC), 2 large-cell neuroendocrine carcinomas, 12 sinonasal undifferentiated carcinomas (SNUC), 7 olfactory carcinomas (OC), 11 SWI/SNF-deficient carcinomas, and 3 neuroendocrine tumors. We correlated nNEM expression with the extent of neuroendocrine (NE) differentiation, as defined by averaged conventional NEM expression (NE-high: H-score, ≥150; NE-low: H-score, <150). Dominant NE subtypes were defined by the nNEM with the highest H-score. Coexpression of 2 nNEM with <100 H-score difference defined a codominant NE subtype. NE differentiation positively correlated with NEUROD1 and negatively with YAP1 expression (P < .0001). ONB were NE-high (96%), and all were NEUROD1-dominant/POU2F3-negative/ASCL1-negative (low)/YAP1-negative (low). In contrast to ONB, all OC were NE-low, mostly (71%) codominant subtypes, NEUROD1-low (negative) (100%, P = .0001), and YAP1 high (71%; P = .0001). Most notably, all SNUC were POU2F3-(co)dominant/NEUROD1-negative irrespective of the IDH2 mutations. Sinonasal tumors with high POU2F3 expression showed enrichment for “tuft cell carcinoma” and tuft cell signatures (P = .009). Similar to SCLC, SCNEC was heterogeneous in terms of nNEM expression comprising several molecular subtypes, including ASCL1-(co)dominant (43%) cases. All SWI/SNF-deficient carcinomas were consistently ASCL1/NEUROD1/POU2F3-negative and YAP1-positive. ASCL1/NEUROD1/POU2F3/YAP1 are useful markers in the differential diagnosis of ONB, SNUC, OC, and SWI/SNF-deficient carcinomas. Subsets of SNUC and large-cell neuroendocrine carcinomas may represent tuft cell–like carcinomas, suggesting that the tuft cell could be explored as the cell of origin for these tumors. The therapeutic vulnerabilities associated with POU2F3 expression in SCLC suggest that a similar approach might be considered for POU2F3-positive carcinomas of the sinonasal tract. Given their diagnostic and possible therapeutic relevance, nNEM have the potential to transform the way we approach the diagnosis and management of sinonasal small round epithelial/neuroepithelial malignancies. © 2024 United States & Canadian Academy of Pathology
Keywords: immunohistochemistry; adolescent; adult; controlled study; human tissue; protein expression; aged; major clinical study; cancer diagnosis; phenotype; cell structure; gene expression; differential diagnosis; cohort analysis; cell differentiation; immunofluorescence; immunoreactivity; basal cell; nerve cell adhesion molecule; transcription factor yap1; esthesioneuroblastoma; genetic heterogeneity; histogram; small cell lung cancer; synaptophysin; respiratory epithelium; large cell neuroendocrine carcinoma; chromogranin a; antibody labeling; cd56 antigen; olfactory neuroblastoma; sinonasal undifferentiated carcinoma; transcription factor mash1; treatment protocol; human; male; female; article; differential gene expression; neurogenic differentiation factor; codominance; protein expression level; pou2f3; neurogenic differentiation factor 1; olfactory carcinoma; tuft cell–like carcinoma; tuft cell
Journal Title: Modern Pathology
Volume: 38
Issue: 3
ISSN: 0893-3952
Publisher: Nature Research  
Date Published: 2025-03-01
Start Page: 100674
Language: English
DOI: 10.1016/j.modpat.2024.100674
PUBMED: 39613231
PROVIDER: scopus
PMCID: PMC11928266
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Snjezana Dogan -- Source: Scopus
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MSK Authors
  1. Natasha Rekhtman
    434 Rekhtman
  2. Ronald A Ghossein
    488 Ghossein
  3. David G Pfister
    389 Pfister
  4. Snjezana Dogan
    190 Dogan
  5. Ian Ganly
    432 Ganly
  6. Umeshkumar Kapaldev Bhanot
    93 Bhanot
  7. Lara   Dunn
    141 Dunn
  8. Marc A Cohen
    139 Cohen
  9. Marina K Baine
    58 Baine
  10. Anjanie Khimraj
    13 Khimraj
  11. Maelle Fouad Saliba
    24 Saliba