TGFBR3 and MGEA5 rearrangements in pleomorphic hyalinizing angiectatic tumors and the spectrum of related neoplasms.
Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare, locally aggressive tumor of the distal extremities with a proclivity for local recurrence. PHATs contain characteristic ectatic, thin-walled vessels, lined by fibrin, and are surrounded by groups of variably pleomorphic spindled to epithelioid neoplastic cells. The putative precursor lesion of PHAT, originally termed "early PHAT" shares many clinicopathologic features with hemosiderotic fibrolipomatous tumor (HFLT). HFLT, myxoinflammatory fibroblastic sarcoma (MIFS), and tumors showing hybrid features of HFLT and MIFS often show TGFBR3 and MGEA5 gene rearrangements. To date, only a small number of PHATs has been tested for either rearrangement; all have been negative. We hypothesized that PHATs contain TGFBR3 and/or MGEA5 rearrangements. Cases of PHAT (all containing areas of HFLT) (N=10), HFLT (N=7), MIFS (N=6), hybrid HFLT/MIFS (N=3), and PHAT-like undifferentiated pleomorphic sarcomas (N=7) were retrieved from our institutional and consultation archives and analyzed for TGFBR3 and MGEA5 rearrangements using a break-apart probe strategy for FISH. Six of 10 PHATs harbored TGFBR3 and/or MGEA5 gene rearrangements: 4 cases had both TGFBR3 and MGEA5 rearrangements, and 2 cases contained MGEA5 rearrangements. Two of 7 HFLTs were positive: 1 case had a TGFBR3 rearrangement, and 1 case had an MGEA5 rearrangement. One of 6 MIFSs had an MGEA5 rearrangement. All 3 hybrid HFLT/MIFS cases were positive: 2 cases had both TGFBR3 and MGEA5 rearrangements, and 1 case had a TGFBR3 rearrangement. All PHAT-like undifferentiated pleomorphic sarcomas were negative. We report, for the first time, the presence of TGFBR3 and/or MGEA5 rearrangements in tumors showing mixed features of HFLT and PHAT. The presence of such rearrangements strongly suggests that HFLT is related to both PHAT and MIFS and that the latter 2 tumors may represent morphologic variants of a single, genetically defined entity in which only MIFS has acquired the capacity to metastasize.
*Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN †Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD ‡Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH.
Jodi M
JM
Carter
William R
WR
Sukov
Elizabeth
E
Montgomery
John R
JR
Goldblum
Steven D
SD
Billings
Karen J
KJ
Fritchie
Andrew L
AL
Folpe
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001706:Biopsy; D002454:Cell Differentiation; D002648:Child; D005260:Female; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D051548:Histone Acetyltransferases / Q000235:genetics*; D006801:Humans; D006818:Hyalin / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D011509:Proteoglycans / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000473:pathology; D009626:Terminology as Topic; D014481:United States; D055815:Young Adult
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan; D051548:Histone Acetyltransferases; C115866:OGA protein, human; D006821:Hyaluronoglucosaminidase