Novel RUNX1/2 fusions in unclassified cystic squamous salivary gland tumors: Possible expansion of the keratocystoma family.

Keratocystoma is a rare salivary gland tumor described in 2002. Recently our group identified IRF2BP2::RUNX2 as a consistent genetic feature which may define keratocystoma. On the other hand, rare keratocystoma-like tumors were negative for this fusion, including two cases from our previous study. Herein we describe 3 cystic squamous salivary gland tumors harboring novel RUNX1 or RUNX2 fusions. Cases were identified from our practices. RNA-sequencing was performed for fusion identification, while reverse-transcriptase polymerase chain reaction (RT-PCR) and RUNX1 or RUNX2 break apart fluorescence in situ hybridization (FISH) were performed to confirm the identified fusions. Three tumors were identified, each with a unique fusion: RUNX1::IKZF3, RUNX1::VGLL4, and RUNX2::CDK2AP1, respectively. All fusions were confirmed by FISH and RT-PCR. Two had been diagnosed as keratocystoma and 1 as low-grade cystadenocarcinoma. All 3 arose in parotid glands of men, aged 48, 52, and 61 years. The tumors diagnosed as keratocystoma had features reminiscent of that tumor, except for a well-developed granular cell layer in one case, and foci of mucinous/glandular epithelium in the other. The third case was also cystic but only focally lined by mature keratinized squamous epithelium; the remaining epithelium was transitional and micropapillary. Cellular atypia and mitotic activity was minimal in all cases. All tumors were treated with surgery only; two patients had no recurrences (after 5 and 24 months), while follow-up was unavailable in the third case. Instead of keratocystoma being defined narrowly by IRF2BP2::RUNX2 fusions, there may exist a broader spectrum of RUNX1/2-rearranged cystic, squamous salivary gland tumors. More cases will be needed to further define this emerging family of neoplasms.