Postradiation Cutaneous Angiosarcoma After Treatment of Breast Carcinoma is Characterized by MYC Amplification in Contrast to Atypical Vascular Lesions After Radiotherapy and Control Cases

Clinicopathological, Immunohistochemical and Molecular Analysis of 66 Cases

T Mentzel; H U Schildhaus; G Palmedo; R Büttner; H Kutzner

Disclosures

Mod Pathol. 2012;25(1):75-85. 

In This Article

Discussion

Breast-conserving surgery for the treatment of early-stage breast cancer and in situ lesions is usually combined with adjuvant radiation therapy. It has been shown that radiogenic lymphangiogenesis of the affected skin occurs during the first year after therapy, and that an increased number of podoplanin-positive lymphatic vessels and of CD68-positive histiocytes showing expression of vascular endothelial growth factors can be found.[7] An important complication of radiotherapy after breast-conserving surgery represents the development of atypical and malignant vascular neoplasms of the skin, and although the exact incidence is unknown, it seems that there has been an increase of postradiation vascular neoplasms. In addition to obvious postradiation cutaneous angiosarcomas, characterized by a significant morbidity and mortality, atypical vascular lesions after radiotherapy for breast cancer have been described under various designations, including atypical vascular proliferation, benign lymphangiomatous papule, acquired (progressive) lymphangioma, acquired lymphangiectasis, and lymphangioma circumscriptum.[4] Clinically, postradiation atypical vascular lesions tend to occur in slightly younger patients and after a shorter time interval after radiation in comparison to postradiation angiosarcomas and typically present as small solitary papules or nodules. However, in about 20–50% these lesions present as multiple synchronous or metachronous lesions or even as large plaques, and may recur locally.[8]

Recently, a larger series of 56 radiation-induced vascular lesions arising in 36 patients has been reported.[9] The vascular neoplasms have been described as relatively well-circumscribed, mainly intradermal lesions with micropapillary tufts and architectural and/or cytologic atypia in 10 cases. Of the patients with follow-up information, five patients developed new vascular lesions in the same area, and of the 10 patients with lesions showing atypical histological features two developed local recurrences. None of the patients showed progression to cutaneous angiosarcoma, and the authors concluded, that postradiation atypical vascular lesions are characterized by a benign clinical course. In contrast, other authors reported that cases of postradiation atypical vascular lesions may show progression to cutaneous angiosarcoma in some cases of subsequent local recurrences, and emphasized that atypical vascular lesions rather represent true precursor lesions.[10,11] In one of these studies, a broader morphological spectrum of postradiation vascular lesions had been reported, and it had been shown that the risk of tumor progression is associated with the morphological features. Atypical vascular lesions that are composed of small, irregularly dispersed capillary-sized vascular structures, and represent complex vascular neoplasms with involvement of deeper dermal structures, have a higher risk than superficially located, lymphangioma-like lesions composed of dilated, thin-walled lymphatic vessels.[11] Given the significant clinical, histological, and immunohistochemical overlap between atypical and obvious malignant postradiation vascular lesions, it seems very problematic to classify reliably individual cases.

The MYC oncogene is a basic helix-loop-helix and leucine zipper transcription factor that is well known for its role in cell proliferation, cellular differentiation, and apoptosis. Importantly, MYC is also known to stimulate angiogenesis and may promote invasion and metastasis.[12]MYC deregulation by amplification has been noted in many solid tumors, and recent work emphasizes its role as an important anticancer target.[13] In regard to soft tissue sarcomas, MYC overexpression and increased MYC copy numbers are frequent in high-grade chondrosarcomas,[14] epithelioid sarcomas of the proximal type,[15] in higher-grade myxoid liposarcomas,[16] and have an adverse prognostic impact in leiomyosarcomas of soft tissues.[17]

A recent study reported MYC high-level gene amplification in postradiation cutaneous angiosarcomas and in chronic lymphedema-associated cutaneous angiosarcomas (so-called secondary angiosarcomas), whereas so-called primary angiosarcomas of skin, soft tissues, bone, and visceral organs were negative.[6] Interestingly, high-level amplification of MYC was found in 55% of secondary angiosarcomas in this study and was not associated with tumor grade and clinical prognosis. Although primary and secondary angiosarcomas are indistinguishable on morphological ground, they represent genetically different neoplasms. Most recently, a consistent MYC amplification has been reported in radiation-associated cutaneous angiosarcomas, but not in atypical vascular lesions after radiotherapy for breast cancer.[18] In this study, the authors reported high-level MYC amplification at 8q24 region in 100% of secondary angiosarcomas, and found a gene amplification of FLT4 in 25% of cases analyzed. The latter result is of therapeutic interest, and in some patients, in this study showing an amplification of MYC and FLT4, a complete or partial response to sorafenib has been reported.

Our results confirm these previous findings in a large case series. We found amplification of MYC by FISH analysis in all 25 cases of postradiation cutaneous angiosarcomas, whereas no amplification was detected in atypical vascular lesions following radiotherapy of breast cancer, in so-called primary angiosarcomas of skin and soft tissues, and in control cases. In seven atypical vascular proliferations worrisome morphological features were seen; however, in none of these cases an expression or an amplification of MYC was present, and none of these cases showed a progression to an angiosarcoma. In all, except one case, immunohistochemical stainings for MYC reflected the presence or absence of MYC amplification, emphasizing the use of immunohistochemical stainings in questionable cases. In addition, it has been shown in selected cases that small newly formed vessels in the vicinity of obvious angiosarcomatous areas that were lined by atypical endothelial cells showed an expression for MYC as well. In contrast, no MYC amplification has been found by FISH analysis in small newly formed vessels in the periphery of the specimens that were lined by cytologically uniform endothelial cells. These findings suggest that immunohistochemical stainings for MYC are very helpful for mapping of these lesions and for exact control of tumor-free margins. The homeobox gene Prox-1 has an important role in the differentiation of lymphatic vessels[19] and represents a master control gene that is involved in re-programming of blood vascular to lymphatic endothelial cells.[20] Considering the increase of lymphatic vessels shortly after radiotherapy,[7] it is not surprising that the endothelial cells of most cases of analyzed postradiation cutaneous angiosarcomas and of many atypical vascular lesions after radiotherapy stained positively for prox-1, as it has been shown in our study. The lack of prox-1 expression in reactive lesions remains unclear.

Although the presence or absence of MYC amplification as well as the immunohistochemical expression of MYC clearly separated malignant and atypical postradiation cutaneous vascular neoplasm in our and in previous studies,[18] and are of considerable diagnostic importance, the pathogenesis of these neoplasms and their relationship are still unclear. Given the lack of MYC amplification in postradiation atypical vascular lesions, their role as true precursor lesions for postradiation cutaneous angiosarcomas could be questioned, and it could be speculated that atypical vascular lesions have a distinct pathogenesis.[18] However, it has been shown convincingly that patients with postradiation atypical vascular lesions may develop further lesions, and that these lesions may recur and may even rarely progress to frank cutaneous angiosarcoma.[10,11] It would be interesting to investigate these rare cases of atypical vascular proliferation showing progression to angiosarcoma in regard to the expression and amplification of MYC, as we assume that MYC amplification is the molecular event in this progression. For practical purposes, complete excision of postradiation atypical vascular lesions and close follow-up of affected patients are mandatory. Postradiation cutaneous angiosarcomas have to be treated aggressively, and recent knowledge about molecular changes may provide the basis for an additional target therapy of advanced neoplasms.

In summary, we have shown that postradiation cutaneous angiosarcomas are characterized by expression and amplification of MYC, whereas reactive and atypical vascular lesions after radiotherapy do not show these findings. In addition, immunohistochemical stainings for MYC are not only helpful in daily diagnostic work but are also of additional help in mapping of these neoplasms and of careful control of tumor-free margins. Further studies are necessary to clarify the exact relationship of atypical and malignant cutaneous vascular lesions after radiotherapy of breast cancer, to control the predictive value of MYC stainings in preneoplastic and precursor lesions, and to examine the exact response of advanced neoplasms to targeting therapy. Although the exact incidence is unknown, it seems that the change of therapy of early forms of breast cancer increases the incidence of atypical and malignant cutaneous vascular lesions, and that these therapeutic options have to be discussed critically in some instances.

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