PMID- 34785767 OWN - NLM STAT- MEDLINE DCOM- 20220428 LR - 20230210 IS - 1530-0285 (Electronic) IS - 0893-3952 (Linking) VI - 35 IP - 5 DP - 2022 May TI - Histological and immunohistochemical features and genetic alterations in the malignant progression of giant cell tumor of bone: a possible association with TP53 mutation and loss of H3K27 trimethylation. PG - 640-648 LID - 10.1038/s41379-021-00972-x [doi] AB - In rare cases, giant cell tumor of bone (GCTB) can undergo primary or secondary malignant transformation to malignant giant cell tumor of bone (MGCTB), but the details of the molecular alterations are still unclear. The present study aimed to elucidate the clinicopathologic and molecular features of MGCTBs based on immunohistochemistry, fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) of nine MGCTBs (five primary and four secondary). Seven (78%) of 9 MGCTBs were immunohistochemically positive for H3.3 G34W. In two (22%) patients, although GCTB components were focally or diffusely positive for H3.3 G34W, their malignant components were entirely negative for H3.3 G34W, which was associated with heterozygous loss of H3F3A by FISH. NGS on four MGCTBs revealed pathogenic mutations in TP53 (n = 3), EZH2 (n = 1) and several other genes. Immunohistochemical analysis of the nine MGCTBs confirmed the p53 nuclear accumulation (n = 5) and loss of H3K27me3 expression (n = 3) and showed that they were mutually exclusive. In addition, four (80%) of five cases of pleomorphic or epithelioid cell-predominant MGCTBs were positive for p53, while three (75%) of four cases of spindle cell-predominant MGCTBs were negative for trimethylation at lysine 27 of histone 3 (H3K27me3). The results suggested that p53 alteration and dysfunction of histone methylation as evidenced by H3K27me3 loss may play an important role in the malignant progression of GCTB, and might contribute to the phenotype-genotype correlation in MGCTB. The combined histologic, immunohistochemical and molecular information may be helpful in part for the diagnosis of challenging cases. CI - (c) 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology. FAU - Ishihara, Shin AU - Ishihara S AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Yamamoto, Hidetaka AU - Yamamoto H AUID- ORCID: 0000-0001-9148-6445 AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Iwasaki, Takeshi AU - Iwasaki T AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Toda, Yu AU - Toda Y AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Yamamoto, Takeo AU - Yamamoto T AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Yoshimoto, Masato AU - Yoshimoto M AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Ito, Yoshihiro AU - Ito Y AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Susuki, Yousuke AU - Susuki Y AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Kawaguchi, Kengo AU - Kawaguchi K AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Kinoshita, Izumi AU - Kinoshita I AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Yamada, Yuichi AU - Yamada Y AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Kohashi, Kenichi AU - Kohashi K AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Fujiwara, Toshifumi AU - Fujiwara T AD - Department of Orthopaedic surgery, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Setsu, Nokitaka AU - Setsu N AD - Department of Orthopaedic surgery, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Endo, Makoto AU - Endo M AD - Department of Orthopaedic surgery, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Matsumoto, Yoshihiro AU - Matsumoto Y AD - Department of Orthopaedic surgery, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Kakuda, Yuko AU - Kakuda Y AD - Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, 411-8777, Japan. FAU - Nakashima, Yasuharu AU - Nakashima Y AD - Department of Orthopaedic surgery, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Oda, Yoshinao AU - Oda Y AD - Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. oda.yoshinao.389@m.kyushu-u.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211116 PL - United States TA - Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JID - 8806605 RN - 0 (Histones) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) SB - IM MH - *Bone Neoplasms/diagnosis/genetics MH - *Giant Cell Tumor of Bone/diagnosis/genetics MH - *Histones/genetics/metabolism MH - Humans MH - In Situ Hybridization, Fluorescence MH - Methylation MH - Mutation MH - *Sarcoma/diagnosis/genetics MH - *Tumor Suppressor Protein p53/genetics EDAT- 2021/11/18 06:00 MHDA- 2022/04/29 06:00 CRDT- 2021/11/17 06:47 PHST- 2021/04/24 00:00 [received] PHST- 2021/11/02 00:00 [accepted] PHST- 2021/11/02 00:00 [revised] PHST- 2021/11/18 06:00 [pubmed] PHST- 2022/04/29 06:00 [medline] PHST- 2021/11/17 06:47 [entrez] AID - S0893-3952(22)00116-8 [pii] AID - 10.1038/s41379-021-00972-x [doi] PST - ppublish SO - Mod Pathol. 2022 May;35(5):640-648. doi: 10.1038/s41379-021-00972-x. Epub 2021 Nov 16.