PMID- 38084005 OWN - NLM STAT- MEDLINE DCOM- 20240220 LR - 20240507 IS - 1532-0979 (Electronic) IS - 0147-5185 (Linking) VI - 48 IP - 3 DP - 2024 Mar 1 TI - Keratocystoma: A Distinctive Salivary Gland Neoplasm Characterized by RUNX2 Rearrangements. PG - 317-328 LID - 10.1097/PAS.0000000000002169 [doi] AB - Keratocystoma is a rare salivary gland lesion that has been reported primarily in children and young adults. Because of a scarcity of reported cases, very little is known about it, including its molecular underpinnings, biological potential, and histologic spectrum. Purported to be a benign neoplasm, keratocystoma bears a striking histologic resemblance to benign lesions like metaplastic Warthin tumor on one end of the spectrum and squamous cell carcinoma on the other end. This overlap can cause diagnostic confusion, and it raises questions about the boundaries and definition of keratocystoma as an entity. This study seeks to utilize molecular tools to evaluate the pathogenesis of keratocystoma as well as its relationship with its histologic mimics. On the basis of targeted RNA sequencing (RNA-seq) results on a sentinel case, RUNX2 break-apart fluorescence in situ hybridization (FISH) was successfully performed on 4 cases diagnosed as keratocystoma, as well as 13 cases originally diagnosed as tumors that morphologically resemble keratocystoma: 6 primary squamous cell carcinomas, 3 metaplastic/dysplastic Warthin tumors, 2 atypical squamous cysts, 1 proliferating trichilemmal tumor, and 1 cystadenoma. RNA-seq and/or reverse transcriptase-PCR were attempted on all FISH-positive cases. Seven cases were positive for RUNX2 rearrangement, including 3 of 4 tumors originally called keratocystoma, 2 of 2 called atypical squamous cyst, 1 of 1 called proliferating trichilemmal tumor, and 1 of 6 called squamous cell carcinoma. RNA-seq and/or reverse transcriptase-PCR identified IRF2BP2::RUNX2 in 6 of 7 cases; for the remaining case, the partner remains unknown. The cases positive for RUNX2 rearrangement arose in the parotid glands of 4 females and 3 males, ranging from 8 to 63 years old (mean, 25.4 years; median, 15 years). The RUNX2 -rearranged cases had a consistent histologic appearance: variably sized cysts lined by keratinizing squamous epithelium, plus scattered irregular squamous nests, with essentially no cellular atypia or mitotic activity. The background was fibrotic, often with patchy chronic inflammation and/or giant cell reaction. One case originally called squamous cell carcinoma was virtually identical to the other cases, except for a single focus of small nerve invasion. The FISH-negative case that was originally called keratocystoma had focal cuboidal and mucinous epithelium, which was not found in any FISH-positive cases. The tumors with RUNX2 rearrangement were all treated with surgery only, and for the 5 patients with follow-up, there were no recurrences or metastases (1 to 120 months), even for the case with perineural invasion. Our findings solidify that keratocystoma is a cystic neoplastic entity, one which appears to consistently harbor RUNX2 rearrangements, particularly IRF2BP2::RUNX2 . Having a diagnostic genetic marker now allows for a complete understanding of this rare tumor. They arise in the parotid gland and affect a wide age range. Keratocystoma has a consistent morphologic appearance, which includes large squamous-lined cysts that mimic benign processes like metaplastic Warthin tumor and also small, irregular nests that mimic squamous cell carcinoma. Indeed, RUNX2 analysis has considerable promise for resolving these differential diagnoses. Given that one RUNX2 -rearranged tumor had focal perineural invasion, it is unclear whether that finding is within the spectrum of keratocystoma or whether it could represent malignant transformation. Most important, all RUNX2 -rearranged cases behaved in a benign manner. CI - Copyright (c) 2023 Wolters Kluwer Health, Inc. All rights reserved. FAU - Bishop, Justin A AU - Bishop JA AD - Department of Pathology, UT Southwestern Medical Center. FAU - Nakaguro, Masato AU - Nakaguro M AD - Departments of Pathology and Laboratory Medicine, Nagoya University Hospital. FAU - Urano, Makoto AU - Urano M AD - Department of Diagnostic Pathology, Bantane Hospital, Fujita Health University School of Medicine, Nagoya. FAU - Yamamoto, Yoshinari AU - Yamamoto Y AD - Department of Anatomic Pathology, Tokyo Medical University. FAU - Utsumi, Yoshitaka AU - Utsumi Y AD - Department of Anatomic Pathology, Tokyo Medical University. FAU - Li, Rong AU - Li R AD - Department of Pathology and Laboratory Medicine, Children's of Alabama, Birmingham, AL. FAU - Weinreb, Ilan AU - Weinreb I AD - Department of Pathology, University Health Network and the University of Toronto, Toronto, ON, Canada. FAU - Nagashima, Yoji AU - Nagashima Y AD - Department of Surgical Pathology, Tokyo Women's Medical University Hospital, Tokyo. FAU - Gangahar, Chiraag AU - Gangahar C AD - Department of Pathology, Texas Health Presbyterian Hospital. FAU - Yamashiro, Katsushige AU - Yamashiro K AD - Department of Diagnostic Pathology, Nikko Memorial Hospital, Muroran. FAU - Hashimoto, Kimio AU - Hashimoto K AD - Department of Pathology, Nishi-Kobe Medical Center, Kobe, Japan. FAU - Rooper, Lisa M AU - Rooper LM AD - Departments of Pathology and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD. FAU - Carlile, Brian AU - Carlile B AD - Department of Pathology, Baylor Scott and White Health, All Saints Medical Center, Fort Worth, TX. FAU - Wang, Richard C AU - Wang RC AD - Department of Dermatology, UT Southwestern Medical Center, Dallas. FAU - Gagan, Jeffrey AU - Gagan J AD - Department of Pathology, UT Southwestern Medical Center. FAU - Nagao, Toshitaka AU - Nagao T AD - Department of Anatomic Pathology, Tokyo Medical University. LA - eng PT - Journal Article DEP - 20231212 PL - United States TA - Am J Surg Pathol JT - The American journal of surgical pathology JID - 7707904 RN - 0 (Core Binding Factor Alpha 1 Subunit) RN - EC 2.7.7.49 (RNA-Directed DNA Polymerase) RN - 0 (Biomarkers, Tumor) RN - 0 (RUNX2 protein, human) SB - IM MH - Male MH - Female MH - Young Adult MH - Child MH - Humans MH - Adolescent MH - Adult MH - Middle Aged MH - *Adenolymphoma/pathology MH - In Situ Hybridization, Fluorescence MH - Core Binding Factor Alpha 1 Subunit/genetics MH - *Salivary Gland Neoplasms/pathology MH - *Carcinoma, Squamous Cell/pathology MH - *Cysts MH - RNA-Directed DNA Polymerase/genetics MH - Biomarkers, Tumor/genetics/analysis COIS- Conflicts of Interest and Source of Funding: Supported by Jane B. and Edwin P. Jenevein M.D Endowment for Pathology at UT Southwestern Medical Center. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. EDAT- 2023/12/12 06:42 MHDA- 2024/02/20 11:50 CRDT- 2023/12/12 02:37 PHST- 2024/02/20 11:50 [medline] PHST- 2023/12/12 06:42 [pubmed] PHST- 2023/12/12 02:37 [entrez] AID - 00000478-990000000-00275 [pii] AID - 10.1097/PAS.0000000000002169 [doi] PST - ppublish SO - Am J Surg Pathol. 2024 Mar 1;48(3):317-328. doi: 10.1097/PAS.0000000000002169. Epub 2023 Dec 12.