Immunoexpression of Ultraviolet Photoproducts and p53 Mutation Analysis in Atypical Fibroxanthoma and Superficial Malignant Fibrous Histiocytoma

Abstract

p53 mutation is one of the major results of ultraviolet (UV) radiation. UV photoproducts of cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (64PPs) also play an important role in skin cancer development. Atypical fibroxanthoma (AFX), which mimics malignant fibrous histiocytoma (MFH) histologically, occurs in the sun-exposed skin of the elderly, and therefore, an association with UV has long been suspected. Eighteen fibrohistiocytic skin lesions comprising AFX (n = 7), storiform-pleomorphic type MFH centered in the subcutis (superficial MFH; S-MFH; n = 4) and benign fibrous histiocytoma (BFH; n = 7) were used for immunohistochemical and molecular analysis. Eight cases of deep MFH (D-MFH) were also analyzed for UV photoproduct expression for the purposes of comparison. Immunohistochemically, the CPD scores of AFX (3.6 +/- 0.4) were significantly higher than those of S-MFH (1.3 +/- 0.8), D-MFH (0.8 +/- 0.5), or BHF (1.4 +/- 0.7); however, the 64PP scores were extremely low in all these tumors (AFX, 0.1 +/- 0.1; S-MFH, 0.0 +/- 0.0; D-MFH, 0.0 +/- 0.0; and BHF, 0.0 +/- 0.0). AFX, S-MFH, and BFH showed immunoexpression for p53 (2/7, 2/4, and 0/7), respectively. p53 mutations were detected in AFX (4/6; 67%) and S-MFH (1/4; 25%), but not in BFH (0/5; 0%) using polymerase chain reaction-single-strand conformation polymorphism, and all of the mutations in AFX were either C-T transitions or at dipyrimidine sites. In conclusion, AFX and S-MFH are both similar fibrohistocytic lesions; however, AFX has high immunoreactivity for CPDs compared with S-MFH, D-MFH, or BFH. These data suggest that CPDs may play an important role in the pathogenesis of AFX.

TERT promoter mutations are frequent in atypical fibroxanthomas and pleomorphic dermal sarcomas

“…1,[20][21][22][23][24][25][26] UV exposure is considered to be a major risk factor for atypical fibroxanthoma, but its link to pleomorphic dermal sarcoma is less clear. 9,[12][13][14] In our cohort, the clinical presentation of both tumors was very similar, with tumors arising in elderly patients, on heavily sun-exposed areas (primarily head), with a strong male predominance (less hair protection), all of which support a role for UV exposure. The identification of TP53 mutations with a UV signature is supportive of a pathogenetic role of UV exposure.…”

“…The identification of TP53 mutations with a UV signature is supportive of a pathogenetic role of UV exposure. 12,13 All mutations identified in our study had a UV signature (C4T or CC4TT). However, both 228C4T and 250C4T mutations have also been found in tumor types for which a UV exposure link is unlikely, such as hepatocellular carcinoma and gliomas.…”

“…To date, only TP53 mutations in 67-70% 12,13 of atypical fibroxanthomas and 25% of pleomorphic dermal sarcomas (diagnosed as superficial malignant fibrous histiocytomas 13 ) and RAS mutations in 25% of pleomorphic dermal sarcomas (diagnosed as malignant fibrous histiocytoma 14 ) have been described. The mutations in the TERT promoter described in the present study constitute the most prevalent mutation identified to date in both tumors.…”

“…12) and 4/6 (ref. 13) cases) and pleomorphic dermal sarcomas (1/4 cases, diagnosed as 'malignant fibrous histiocytomas' 13 ), as well as one HRAS mutation and one KRAS mutation in eight pleomorphic dermal sarcomas (diagnosed as 'malignant fibrous histiocytomas') analyzed. 14 In another study, pleomorphic dermal sarcomas (diagnosed as 'undifferentiated pleomorphic sarcomas') were found to harbor more frequent DNA copy number alterations than atypical fibroxanthomas.…”

Atypical Fibroxanthoma

“…3,4 For example, most lesions are found in the head and neck region, where exposure to sunlight is the highest. Ultraviolet p53 mutations at dipyrimidine sites, often encountered in other skin tumors, have also been found in AFX, further supporting this theory.…”