Immunohistochemical and biogenetic features of diffuse-type tenosynovial giant cell tumors: the potential roles of cyclin A, P53, and deletion of 15q in sarcomatous transformation.
OBJECTIVE
Diffuse-type tenosynovial giant cell tumor (D-TSGCT) is an aggressive proliferation of synovial-like mononuclear cells with inflammatory infiltrates. Despite the COL6A3-CSF1 gene fusion discovered in benign lesions, molecular aberrations of malignant D-TSGCTs remain unidentified.


METHODS
We used fluorescent in situ hybridization and in situ hybridization to evaluate CSF1 translocation and mRNA expression in six malignant D-TSGCTs, which were further immunohistochemically compared with 24 benign cases for cell cycle regulators involving G(1) phase and G(1)-S transition. Comparative genomic hybridization, real-time reverse transcription-PCR, and a combination of laser microdissection and sequencing were adopted to assess chromosomal imbalances, cyclin A expression, and TP53 gene, respectively.


RESULTS
Five of six malignant D-TSGCTs displayed CSF1 mRNA expression by in situ hybridization, despite only one having CSF1 translocation. Cyclin A (P = 0.008) and P53 (P < 0.001) could distinguish malignant from benign lesions without overlaps in labeling indices. Cyclin A transcripts were more abundant in malignant D-TSGCTs (P < 0.001). All malignant cases revealed a wild-type TP53 gene, which was validated by an antibody specifically against wild-type P53 protein. Chromosomal imbalances were only detected in malignant D-TSGCTs, with DNA losses predominating over gains. Notably, -15q was recurrently identified in five malignant D-TSGCTs, four of which showed a minimal overlapping deletion at 15q22-24.


CONCLUSIONS
Deregulated CFS1 overexpression is frequent in malignant D-TSGCTs. The sarcomatous transformation involves aberrations of cyclin A, P53, and chromosome arm 15q. Cyclin A mRNA is up-regulated in malignant D-TSGCTs. Non-random losses at 15q22-24 suggest candidate tumor suppressor gene(s) in this region. However, P53 overexpression is likely caused by alternative mechanisms rather than mutations in hotspot exons.
Huang
Hsuan-Ying
HY
Department of Pathology and Orthopedic Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
West
Robert B
RB
Tzeng
Ching-Cherng
CC
van de Rijn
Matt
M
Wang
Jun-Wen
JW
Chou
Shih-Cheng
SC
Huang
Wen-Wei
WW
Eng
Hock-Liew
HL
Lin
Ching-Nan
CN
Yu
Shih-Chen
SC
Wu
Jing-Mei
JM
Lu
Chiu-Chin
CC
Li
Chien-Feng
CF
D000328:Adult; D000368:Aged; D002471:Cell Transformation, Neoplastic; D002884:Chromosomes, Human, Pair 15 / Q000648:ultrastructure*; D019925:Cyclin A / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005870:Giant Cell Tumors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D019925:Cyclin A; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016173:Macrophage Colony-Stimulating Factor