Abstract：
Calcifying odontogenic cyst (COC), once called calcifying cystic odontogenic tumor, is classified under the category of odontogenic cysts. However, the proliferative capacity of the lesional epithelium and consistent nuclear β-catenin expression raise questions about its current classification. This study aimed to determine whether COC would be better classified as a neoplasm in the histologic and molecular context. Eleven odontogenic lesions diagnosed as COC or calcifying cystic odontogenic tumor were included in this study. The growth patterns of the lesional epithelium were analyzed histologically in all cases. β-catenin immunohistochemistry and molecular profiling using Sanger sequencing and whole-exome sequencing were performed in 10 cases. Of the 11 cases studied, histologic features reminiscent of so-called adenoid ameloblastoma were observed in 72.7% (8/11), and small islands of clear cells extended into the wall in 36.4% (4/11). Intraluminal and/or mural epithelial proliferation was found in 72.7% of the cases (8/11). Nuclear β-catenin expression was observed focally in all 10 cases studied, mainly highlighting epithelial cells forming morules and adjacent to dentinoid. CTNNB1 hotspot mutations were detected in 60.0% of the cases (6/10). All the remaining cases had frameshift mutations in tumor-suppressor genes involved in the WNT pathway, including APC and NEDD4L. Recurrent WNT pathway mutations leading to nuclear translocation of β-catenin and distinct epithelial growth patterns found in COC are the neoplastic features shared by its solid counterpart, dentinogenic ghost cell tumor, supporting its classification as a tumor rather than a cyst.
摘要：
钙化性牙源性囊肿（COC），曾经被称为钙化性囊性牙源性肿瘤（CCOT），被归类为牙源性囊肿。然而,病变上皮的增殖能力和一致的核β-catenin表达引起了对其当前分类的质疑。这项研究旨在确定COC在组织学和分子背景下是否会更好地归类为肿瘤。本研究包括11个诊断为COC或CCOT的牙源性病变。在所有情况下，对病变上皮的生长方式进行了组织学分析。10例患者采用Sanger测序和全外显子组测序进行β-catenin免疫组织化学和分子谱分析。在研究的11个案例中，在72.7%（8/11）观察到类似腺样体成釉细胞瘤的组织学特征，36.4％（4/11）的透明细胞小岛延伸到壁中。在72.7％的病例中发现腔内和/或壁上皮增殖（8/11）。在所有研究的10例病例中，均在局灶性观察到核β-catenin表达，主要突出上皮细胞形成的磨牙和邻近牙质。60.0%(6/10)的病例检测到CTNNB1热点突变。其余病例均有参与WNT通路的抑癌基因移码突变,包括APC和NEDD4L。在COC中发现的导致β-catenin核易位的反复WNT途径突变和不同的上皮生长模式是其固体对应物共有的肿瘤特征。牙本质鬼细胞瘤，支持将其分类为肿瘤而不是囊肿。
