Potential risks and benefits of radiation therapy as adjuvant treatment in patients with low-risk carcinoma of the mammary gland: taking cutaneous postradiation angiosarcoma as an opportunity for a critical appraisal of postoperative radiotherapy.

In this issue of Annals of Oncology, M. Moe and G. Bertelli [1] propose, in a Letter to the Editor’, a number of interesting considerations on the clinical pattern and treatment of breast angiosarcoma, with emphasis on a woman presenting this disease after breast-conserving surgery (BCS) and radiotherapy, with a short latent period following her first-line treatment. Their letter first calls for a number of comments on a typical example of radio-induced late effects, the occurrence of which always represents a source of profound frustration both for the patient and her radiation oncologist. As an aggressive tumor of endothelial origin, angiosarcoma of the breast (AS) is occurring as idiopathic, lymphedemaassociated, postirradiation, soft tissue, and various other clinical settings [1, 2]. Among these settings, iatrogenic AS, also known as Stewart–Treves syndrome is usually attributed to chronic lymphedema, which can occur in a number of patients treated with BCS. Later on, with emphasis on breast-conservingtherapy combined with adjuvant radiation, a form of cutaneous postradiation angiosarcoma of the breast (CPRASB) emerged from histopathologic reviews [3]. Characterized by a lack of association with lymphedema, CPRASB is frequently multifocal at presentation, most tumors have a vasoformative, sieve-like pattern of growth, and high-grade nuclear features. Can we quantify the risk to develop a secondary angiosarcoma, following conventional, postoperative radiation doses? In 2001, a retrospective study conducted by Huang and Mackillop [4] on 194 798 breast cancer patients treated between 1973 and 1995, provides useful clues regarding this relative risk; in this cohort of patients, the age standardized incidence ratios for AS was 26.2 and 2.1 in the radiotherapy (RT) and non-RT cohort, respectively. Two other studies, published in 2005 and 2006, indicate that breast AS has a prevalence ranging between 0.002% and 0.005% per year [5], while the estimated overall incidence of breast angiosarcoma after breast-conserving therapy is low (0.14%), most of AS developing in cutaneous areas [6]. Actually is the prevalence of secondary AS higher than that of angiosarcomas in radiotherapy-naive breasts in all retrospective studies? It does not seem to be the case. From a survey conducted in 11 French Cancer Centers [7], an AS prevalence of five cases per 10 000 was observed among 18 115 patients a majority of whom were T1N0M0 and node negative, which is the same prevalence for primary breast angiosarcomas occurring in healthy breasts. Irradiated patients present with small, reddish, intradermal nodules over the treated area, which can also reveal hyperpigmentation, retraction, or discolored skin thickening. In some cases the clinical aspect can be mimicked by postirradiation morphea [8]; in case of AS the histologic pattern shows malignant cells with an endothelial immunophenotype in the cell block [9]. CPRASB is more often found in breasts developing postoperative and postirradiation edema and fibrosis [2]. It mainly affects women >60 and prevails in those who underwent axillary lymphadenectomy. Analyzing one of the largest cohorts of patients with AS, Vorburger SA et al. [10] also showed that the cases who had received prior radiation therapy were on average 30 years older than those presenting with radiation-naive angiosarcoma. Latent periods between the treatment of the breast cancer and the diagnosis of AS markedly vary across the retrospective studies, ranging from 5 to 26 years [5, 11, 12] with an average 14 years according to Kirova et al. [12]. Interestingly enough, secondary angiosarcomas can appear in the breast much earlier, e.g. as soon as a few months after lympectomy and postoperative radiotherapy, as recently reported by Deutsch and Safyan [13] and by Moe and Bertelli, in this issue [1]. Traditionally, secondary AS is treated with mastectomy, and in some cases with postoperative chemotherapy. This disease has a dismal prognosis, especially in the presence of multiple skin lesions. Median survival rates are usually low, ranging from 12 to 33.5 months [11, 12]. Likewise, from a review by Rao et al. [14], the estimated 3-year overall survival for 58 patients was only 20%. The causes of failure are both local and systemic; reviewing the treatment outcome in 100 cases, Monroe et al. [15] showed that surgical excision is associated with very high rates of disease recurrence (55/75 patients, 73%). Distant metastases were also shown to develop simultaneously or shortly after local recurrences (LRs). In the French study mentioned above, Marchal et al. [7] report a median survival of 15.5 months. Interestingly enough, in the study by Vorburger et al. [10] mentioned above, the Kaplan–Meier curves were not statistically different between patients with radiation therapy-associated disease and radiation therapy-naive patients. Despite the fact AS developing in the wake of a radiation therapy are found quite infrequently, their occurrence in the follow-up of breast irradiation is an issue which should not be e d it o ri a l