Sakyo Airi, Ryo Eijitsu, Nishino Shogo, Kobayashi Kenya, Yoshimoto Seiichi, Omura Go, Fushimi Chihiro, Sakai Toshihiko, Sakai Azusa, Eguchi Kohtaro, Takahashi Hideaki, Yokoyama Kazuki, Honma Yoshitaka, Mori Akiko, Kato Hiroko, Hatano Toshiyuki, Yoshida Akihiko, Matsumoto Fumihiko, Yatabe Yasushi, Mori Taisuke
Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan; Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan; Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, Tokyo, Japan.
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
Lab Invest. 2025 Mar;105(3):102205. doi: 10.1016/j.labinv.2024.102205. Epub 2024 Nov 29.
Hyalinized clear cell carcinoma (HCCC) is a rare tumor of the minor salivary gland, characterized by pale cytoplasm and EWSR1::ATF1 fusion. Recently, new fusions, such as EWSR1::LARP4 and SMARCA2::CREM, have also been identified. Histologically, HCCC closely resembles other salivary gland tumors like mucoepidermoid carcinoma and myoepithelial carcinoma, and there are no specific immunohistological markers for its identification. In this study, we investigated potential markers for HCCC based on the characteristics of minor salivary gland acini, from which these tumors may originate. SOX10 is a known marker for serous gland clusters and NKX3.1 for mucus gland clusters. Fluorescence intensity analysis of double staining, objectively evaluated by artificial intelligence, revealed variations in the positive intensity of cells single positive for NKX3.1 and SOX10, as well as cells positive for both markers, which are commonly observed in normal minor salivary glands. We evaluated NKX3.1 expression by immunohistochemistry in 12 HCCC cases (including 9 EWSR1::ATF1, 1 EWSR1::LARP4, and 1 SMARCA2::CREM), 12 myoepithelial carcinoma cases, and tissue microarray containing 88 cases of multiple salivary gland tumors using immunohistochemistry. NKX3.1 was expressed in all 12 HCCC cases (100%), with NKX3.1-positive cells ≧90% in 3 cases, ≧60% 1 case, ≧30% 4 cases, and <30% 4 cases, respectively. SOX10 was negative in 10 cases and weakly positive in 2 cases. This finding mimics the pattern of expression in minor salivary glands and may explain the occurrence of weak NKX3.1 staining and SOX10-positive cases in HCCC. Additionally, in the tissue microarray analysis, NKX3.1 staining was observed in only 1 HCCC case. These findings indicate that NKX3.1 is a useful marker for distinguishing HCCC from other clear cell salivary gland neoplasms. This study suggests that NKX3.1, along with SOX10 and CK7, can be utilized to improve the accuracy of HCCC diagnosis.
透明化透明细胞癌（HCCC）是一种罕见的小唾液腺肿瘤，其特征为细胞质淡染以及EWSR1::ATF1融合。最近，还发现了新的融合基因，如EWSR1::LARP4和SMARCA2::CREM。在组织学上，HCCC与其他唾液腺肿瘤如黏液表皮样癌和肌上皮癌极为相似，且尚无用于鉴别诊断的特异性免疫组化标志物。在本研究中，我们基于这些肿瘤可能起源的小唾液腺腺泡的特征，探究了HCCC的潜在标志物。SOX10是浆液性腺泡簇的已知标志物，NKX3.1是黏液性腺泡簇的标志物。通过人工智能客观评估的双重染色荧光强度分析显示，NKX3.1和SOX10单阳性细胞以及两种标志物均阳性的细胞的阳性强度存在差异，这在正常小唾液腺中较为常见。我们采用免疫组化方法评估了12例HCCC病例（包括9例EWSR1::ATF1、1例EWSR1::LARP4和1例SMARCA2::CREM）、12例肌上皮癌病例以及包含88例多种唾液腺肿瘤的组织芯片中NKX3.1的表达情况。12例HCCC病例均表达NKX3.1（100%），其中3例NKX3.1阳性细胞≥9例，1例≥60%，4例≥30%，4例＜30%。SOX10在10例中呈阴性，2例呈弱阳性。这一发现与小唾液腺中的表达模式相似，可能解释了HCCC中NKX3.1染色弱阳性和SOX10阳性病例的出现。此外，在组织芯片分析中，仅1例HCCC病例观察到NKX3.1染色。这些发现表明，NKX3.1是区分HCCC与其他透明细胞唾液腺肿瘤的有用标志物。本研究提示，NKX3.1与SOX10和CK7一起可用于提高HCCC诊断的准确性。
