Estudo clínico-patológico, imuno-histoquímico e molecular (amplificação do gene MYC) em angiossarcomas e lesões vasculares atípicas da mama

Abstract

Introduction: Angiosarcomas (AS) of the breast, primary (PAS) or secondary (SAS) to radiotherapy, are rare and aggressive, with significant risk of morbidity and mortality. Atypical vascular lesions (AVL) are vascular proliferations that develop within previously irradiated skin usually with a benign clinical course. Low-grade AS and AVL share morphological similarities, and, to date, there are no specific criteria to distinguish them. Recently, MYC amplification and overexpression have been pointed as an important diagnostic tool to distinguish post-radiation cutaneous vascular lesions of the breast. Purpose: We evaluated clinicopathological, immunohistochemical, and evolutive characteristics of a series of AVL of the breast. We also investigated and further compared the presence of MYC amplification and overexpression in a series of AVL, PAS and SAS to verify whether MYC is a useful diagnostic tool, and if it is implicated in the pathogenesis and prognosis of radiation-induced vascular proliferations. Methods: We selected 30 cases of AVL and 49 cases of AS of the breast diagnosed between 1999 and 2014. Immunohistochemical study for CD31, D2-40, CD105, and Ki-67 was performed in all AVL cases. AVL were classified based on D2-40 expression: lymphatic type, LT-AVL, (D2-40 positive) or vascular type, VT-AVL (D2-40 negative). We analyzed MYC amplification and protein expression by fluorescent in situ hybridization (FISH) and IHC in AVL, PAS and SAS. Follow-up data were collected, and survival analyses were performed, comparing them with MYC amplification. Results: Twenty-two AVL were classified as LT, six cases were classified as VT, and D2-40 was not tested in 2 cases. In three cases when margin was compromised, the patients presented with unfavorable outcomes: one patient had local recurrence of AVL 32 months after the diagnosis of AVL, and the other two cases progressed to high-grade AS 19 and 89 months later: one case was LT-AVL, and the other was VT-AVL, respectively. Of the 49 patients diagnosed with breast AS, thirty-seven patients had SAS, and twelve patients had PAS. Between 37 patients with SAS, twenty cases showed high-level MYC amplification and protein overexpression (54%). None of PAS or AVL cases showed MYC amplification or protein expression. Concordance between MYC amplification (FISH) and protein expression (IHC) was 100% in AVL, PAS, and SAS. Survival analysis of the SAS patients demonstrates that cases with MYC amplification had a significantly worse overall survival compared with cases without MYC amplification (P=0.035). There was a non-significant trend toward a poor disease-free survival between cases with and without MYC amplification (P=0,155) Conclusions: Our study could not identify a specific immunohistochemical marker to distinguish AVL from low-grade AS. We cast doubt on the importance of classifying AVL according to D2-40 expression, since we found the same risk for malignant progression on both types of AVL. Since compromised surgical margins were associated with unfavorable outcomes in AVL, we recommend complete excision and close follow-up of patients until the natural history of the AVL is better explained. MYC amplification is a highly specific but poorly sensitive marker for SAS, and was associated with adverse prognosis. The genetic and molecular aberrations involved in AS and AVL tumorigenesis remain poorly understood, and further studies are necessary to better understand the pathogenesis and progression of these lesions.