TY - JOUR
T1 - Transcriptionally Active HPV and Targetable EGFR Mutations in Sinonasal Inverted Papilloma
T2 - An Association between Low-risk HPV, Condylomatous Morphology, and Cancer Risk?
AU - Mehrad, Mitra
AU - Stelow, Edward B.
AU - Bishop, Justin A.
AU - Wang, Xiaowei
AU - Haynes, Wesley
AU - Oliver, Dwight
AU - Chernock, Rebecca D.
AU - Lewis, James S.
N1 - Funding Information:
The authors acknowledge the Translational Pathology Shared Resource (TPSR) at Vanderbilt University Medical Center which is supported by NCI/NIH Cancer Center Support Grant 5P30 CA68485-19, the Vanderbilt Mouse Metabolic Phenotyping Center Grant 2 U24 DK059637-16, and the Shared Instrumentation Grant S10 OD023475-01A1 for the Leica Bond RX instrument. The work was also supported by NIH grant R01DE026471. They also personally thank Cindy Lowe from TPSR for her technical assistance with block retrieval, sectioning, and immunohistochemistry. Finally, EGFR sequencing was funded by the Jane B. and Edwin P. Jenevein M.D Endowment for Pathology at UT Southwestern Medical Center.
Publisher Copyright:
© 2019 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Sinonasal inverted papillomas (IPs) commonly recur, and transform to malignancy in 5% to 10% of patients. It has long been debated whether IPs are caused by high-risk or low-risk (lr) human papillomavirus (HPV) and whether the HPV is transcriptionally active. EGFR mutations have also been recently implicated in the pathogenesis of IP with an unclear relationship to HPV status. IP cases over a 10-year period were tested for p16 by immunohistochemistry and for transcriptionally active hrHPV and lrHPV by reverse-transcriptase real-time polymerase chain reaction and RNA in situ hybridization, respectively. EGFR tyrosine kinase domain Sanger sequencing was performed on all lrHPV RNA positive and 15 randomly selected lrHPV RNA negative IPs. Seven sinonasal nonkeratinizing squamous cell carcinomas (SCCs) without associated IP were included as controls. Of the 44 IPs, 5 (11.4%) were associated with SCC, all keratinizing type. All IPs and associated SCCs were negative for p16 and hrHPV. lrHPV RNA was detected in 5/42 (12%) cases, including 3/5 (60%) with associated SCC (P=0.009). All 5 lrHPV RNA positive IPs involved the nasal cavity, had a distinct, condylomatous morphology, and were EGFR wild-type. In contrast, 11/15 (73.3%) lrHPV RNA negative IPs that were sequenced had EGFR exon 19 or 20 mutations. All control nonkeratinizing SCCs were lrHPV RNA negative, but 5/7 (71.4%) were p16 and high-risk HPV RNA positive. This study shows that a subset of IPs involving the nasal cavity have transcriptionally active lrHPV, condylomatous morphology, and possibly increased risk of malignancy. Furthermore, lrHPV positivity is mutually exclusive with EGFR mutations, which suggests alternate mechanisms of pathogenesis.
AB - Sinonasal inverted papillomas (IPs) commonly recur, and transform to malignancy in 5% to 10% of patients. It has long been debated whether IPs are caused by high-risk or low-risk (lr) human papillomavirus (HPV) and whether the HPV is transcriptionally active. EGFR mutations have also been recently implicated in the pathogenesis of IP with an unclear relationship to HPV status. IP cases over a 10-year period were tested for p16 by immunohistochemistry and for transcriptionally active hrHPV and lrHPV by reverse-transcriptase real-time polymerase chain reaction and RNA in situ hybridization, respectively. EGFR tyrosine kinase domain Sanger sequencing was performed on all lrHPV RNA positive and 15 randomly selected lrHPV RNA negative IPs. Seven sinonasal nonkeratinizing squamous cell carcinomas (SCCs) without associated IP were included as controls. Of the 44 IPs, 5 (11.4%) were associated with SCC, all keratinizing type. All IPs and associated SCCs were negative for p16 and hrHPV. lrHPV RNA was detected in 5/42 (12%) cases, including 3/5 (60%) with associated SCC (P=0.009). All 5 lrHPV RNA positive IPs involved the nasal cavity, had a distinct, condylomatous morphology, and were EGFR wild-type. In contrast, 11/15 (73.3%) lrHPV RNA negative IPs that were sequenced had EGFR exon 19 or 20 mutations. All control nonkeratinizing SCCs were lrHPV RNA negative, but 5/7 (71.4%) were p16 and high-risk HPV RNA positive. This study shows that a subset of IPs involving the nasal cavity have transcriptionally active lrHPV, condylomatous morphology, and possibly increased risk of malignancy. Furthermore, lrHPV positivity is mutually exclusive with EGFR mutations, which suggests alternate mechanisms of pathogenesis.
KW - EGFR
KW - human papillomavirus
KW - inverted papilloma
KW - sinonasal tract
KW - squamous cell carcinoma
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U2 - 10.1097/PAS.0000000000001411
DO - 10.1097/PAS.0000000000001411
M3 - Article
C2 - 31743131
AN - SCOPUS:85075305146
VL - 44
SP - 340
EP - 346
JO - American Journal of Surgical Pathology
JF - American Journal of Surgical Pathology
SN - 0147-5185
IS - 3
ER -