Iwamura Ryuji, Komatsu Kazuki, Kusano Midori, Kubo Chisachi, Inaba Yuna, Shiba Eisuke, Nawata Aya, Tajiri Ryosuke, Matsuyama Atsuji, Matoba Hisanori, Koga Kaori, Takeda Maiko, Itami Hiroe, Hisaoka Masanori
Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Mod Pathol. 2023 Mar;36(3):100070. doi: 10.1016/j.modpat.2022.100070. Epub 2023 Jan 10.
Pericytic tumors are subclassified as myopericytomas, myofibromas, angioleiomyomas, and glomus tumors according to the current World Health Organization classification. These pericytic tumors form a continuous morphologic spectrum, including those with combined morphology. However, to our knowledge, no widely accepted criteria for classifying tumors with combined morphology are available. Recent studies have identified platelet-derived growth factor receptor-beta (PDGFRB) gene mutations in a subset of myofibromas, myopericytomas, and myopericytomatoses but not in angioleiomyomas. NOTCH receptor 3 (NOTCH3) mutations have been reported in a subset of infantile myofibromatosis. To assess their potential role in classifying pericytic tumors, we investigated PDGFRB and NOTCH3 mutations in 41 pericytic tumors of variable morphology, including some combined forms. Our results show these mutations to be present in a variety of pericytic tumors, such as myopericytomas (PDGFRB, 3/11; NOTCH3, 4/11), myopericytomatoses (1/2; 1/2), myofibromas (3/6; 0/6), angioleiomyomas (2/13; 3/13), and glomus tumors (5/9; 1/9). Point mutations were identified in 3 tumors in PDGFRB exon 12 (Y562C, S574F, and G576S), 12 tumors in PDGFRB exon 14 (M655I, H657L, and N666K), and 9 tumors in NOTCH3 exon 25 (A1480S/T, D1481N, G1482S, T1490A, E1491K, G1494S, and V1512A). All PDGFRB mutations and NOTCH3 G1482S, T1490A, and G1494S mutations were classified as "deleterious/damaging" by ≥4 of 6 pathogenicity prediction tools in silico. Five-mutation-positive tumors, including 1 myopericytoma-angioleiomyoma, 2 myopericytomatoses-myofibroma, 1 myofibroma-myopericytoma and 1 angioleiomyoma-myopericytoma, were of combined morphology. Therefore, we found PDGFRB and NOTCH3 mutations to be detectable in a much wider variety of pericytic tumors than previously reported and confirmed myopericytomas, myofibromas, angioleiomyomas, and glomus tumors as members harboring PDGFRB or NOTCH3 mutations. Our results thus suggest that PDGFRB or NOTCH3 mutations are not useful for subclassifying members of the pericytic tumor family.
根据世界卫生组织的现行分类，周细胞瘤可细分为肌周细胞瘤、肌纤维瘤、血管平滑肌瘤和球瘤。这些周细胞瘤形成了一个连续的形态学谱系，包括那些具有混合形态的肿瘤。然而，据我们所知，目前尚无广泛接受的用于对具有混合形态的肿瘤进行分类的标准。最近的研究在一部分肌纤维瘤、肌周细胞瘤和肌周细胞瘤病中发现了血小板衍生生长因子受体β（PDGFRB）基因突变，但在血管平滑肌瘤中未发现。在一部分婴儿型肌纤维瘤病中报告了NOTCH受体3（NOTCH3）突变。为了评估它们在周细胞瘤分类中的潜在作用，我们研究了41例形态各异的周细胞瘤中的PDGFRB和NOTCH3突变，其中包括一些混合形式。我们的结果显示，这些突变存在于多种周细胞瘤中，如肌周细胞瘤（PDGFRB，3/11；NOTCH3，4/11）、肌周细胞瘤病（1/2；1/2）、肌纤维瘤（3/6；0/6）、血管平滑肌瘤（2/13；3/13）和球瘤（5/9；1/9）。在PDGFRB外显子12的3个肿瘤中鉴定出点突变（Y562C、S574F和G576S），在PDGFRB外显子14的12个肿瘤中鉴定出点突变（M655I、H657L和N666K），在NOTCH3外显子25的9个肿瘤中鉴定出点突变（A1480S/T、D1481N、G1482S、T1490A、E1491K、G1494S和V1512A）。所有PDGFRB突变以及NOTCH3的G1482S、T1490A和G1494S突变在6种致病性预测工具中的至少4种工具预测下被分类为“有害/损伤性”。5个突变阳性肿瘤，包括1例肌周细胞瘤 - 血管平滑肌瘤、2例肌周细胞瘤病 - 肌纤维瘤、1例肌纤维瘤 - 肌周细胞瘤和1例血管平滑肌瘤 - 肌周细胞瘤，具有混合形态。因此，我们发现PDGFRB和NOTCH3突变在比先前报道的更广泛的周细胞瘤类型中均可检测到，并证实肌周细胞瘤、肌纤维瘤、血管平滑肌瘤和球瘤是携带PDGFRB或NOTCH3突变的成员。因此，我们的结果表明，PDGFRB或NOTCH3突变对于周细胞瘤家族成员的亚分类并无用处。
