Radiation-induced cutaneous vasculopathy of the breast: a rare case report

Vasculopathy is a general term used to describe any condition that affects blood vessels. Purpura and ecchymoses are caused by extravasation of blood from the vasculature into the skin. The differential diagnosis can be divided into platelet disorders, vascular factor deficiencies and coagulation factor deficiencies. Disorders can be congenital. They can be associated with vasculitis or can be caused by trauma, medications, infections, or malignancy.

Radiation-induced vascular disease after RT to the heart, neck or brain is well known because of its serious, possibly fatal consequences. The clinical manifestations vary from coronary insults and myocardial infarction to heart failure and stroke. Pathology of these manifestations progresses slowly, and the duration from RT to clinical manifestations can exceed 10 years [4‐6]. The cause of radiotherapy-induced coronary heart disease is suggested to be the induction or acceleration of atherosclerosis in conduit arteries located in the irradiated field [7]. The incidence is greater in patients with ‘classical’ risk factors, such as smoking, hypertension and obesity [8]. After RT of the neck, Silverberg et al. described in 1978 a pattern of atherosclerotic changes on angiography of the carotid arteries, even in areas unusual for the natural occurrence of arterial disease. Patients showing radiation-induced atherosclerosis were significantly younger and had significantly fewer generalized lesions than patients showing carotid vascular disease without associated RT [9]. In the brain, vasculopathic changes are thought to be a central diagnostic feature of late radiation injury. Wang et al. found 77 cases of delayed radiation-induced cerebrovasculopathy after pediatric intracranial irradiation [10]. There was a statistically significant correlation between increasing doses of radiation and earlier presentation.

The mechanism of radiation injury is similar in all blood vessels and has been linked mainly to endothelial dysfunction [11, 12]. Initial endothelial loss is followed by and partially overlapped by thrombi formation and hemorrhage. Long-term morphological changes include endothelial proliferation, basement membrane thickening, adventitial fibrosis, and vessel dilatation [13]. Among all blood vessels, capillaries are the most radiosensitive because they have only a single layer of endothelium. Well-differentiated endothelial cells, as found in dermal capillaries, undergo cellular senescence similar to aging and premature atherosclerosis. Senescence induced by DNA damage from irradiation could lead to slower growth and perhaps increased vascular permeability [14].

Microvascular dysfunction has been demonstrated [15]. This could be explained by the fact that irradiated tissues suffer from chronic oxidative stress accompanied by increased production of reactive oxygen species [16]. Overproduction of reactive oxygen species is also regarded as an integral part of atherosclerosis [17]. In vitro studies have suggested that radiation induces endothelial activation characterized by activation of the transcription factor nuclear factor kappa beta (NF-κB), resulting in alterations in vascular adhesion molecule expression and chemokine and cytokine production [18‐21]. The activated endothelium is prothrombotic as a result of leucocyte-endothelial cell or platelet-endothelial cell adherence, leucocyte infiltration into tissue and thrombus formation [22‐24]. By comparing irradiated arteries with nonirradiated arteries from the same patient, it has been possible to confirm NF-κB activation by RT in humans [25]. Activation of NF-κB is regarded as one of the most important and early events in endothelial activation [26]. Leukocyte adhesion to endothelial cells and thrombi can block the vascular lumen, as can the growth of endothelial cell colonies during vascular regeneration [27‐29]. These alterations cause chronic injury to endothelial cells, which can lead to visible changes over months to years. Fajardo described the morphologic patterns of the effect of radiation on mammalian tissues [30]. Radiation does not produce pathognomonic morphologic features. However, a consistent feature is the lack or paucity of a cellular inflammatory response. The most radiosensitive blood capillaries and sinusoids can exhibit irregular cytoplasm with the formation of pseudopodia, swelling of ‘blebs’ in the cytoplasm, detachment of endothelial cells from the basal lamina, cell pyknosis, rupture of the plasma membrane, thrombosis, and rupture of the capillary wall.

The risk and severity of late reactions depend on several factors. Radiation-related treatment factors included the total dose, the dose per fraction, and the schedule of treatment. Late effects are generally more sensitive to changes in fraction size and less sensitive to changes in overall treatment time [31, 32]. When a relatively large dose of radiation is administered, blood vessels tend to develop edema, thrombosis, and hemorrhage. In contrast, when a lower dose of radiation is given, vascular injury is not initially evident but rather manifests as delayed telangiectasia formation and hemorrhagic infarcts until 1–2 years after the completion of radiation exposure [30, 33].

Patient-related factors include age at the time of RT, trauma, or surgery at an irradiated site and comorbidities, particularly those involving impaired vascularity, such as diabetes and hypertension [34, 35]. Patients with scleroderma and systemic lupus erythematosus are at increased risk of severe toxicity [36].

Several factors could have triggered this incident. She had developed widespread telangiectasia, a sign of radiation-induced injury to the vessels of the irradiated breast. Blood analysis revealed an elevated level of serum lipids even though she was taking atorvastatin. Tamoxifen, which is known to be thrombotic, was used as part of her treatment. She had a history of smoking, although she had stopped smoking more than two decades ago. There was a history of skin sarcoidosis. She had undergone multiple surgical interventions in the treated breast.

The possible presence of a platelet disorder, a vascular factor, or a coagulation factor deficiency was ruled out as a precipitating comorbidity by history, clinical examination, and blood analysis. She did not have any congenital disorders that could be associated with vasculitis. No recent trauma or infection had occurred. Tumor relapse was not observed via magnetic resonance imaging of the breast.

However, which factor caused the sudden unset of this vasculopathic reaction is unclear. Most likely, this incident was multifactorial.

Treatment of radiation-induced vasculopathy depends on the severity of the condition. For nonlife-threatening patients, treatment usually focuses on using medication to relax blood vessels and allow better blood flow. Medication can be prescribed to help prevent blood clots from forming. Radiation-induced atherosclerosis and stenosis of large vessels are treated as nonradiation-induced lesions without increased mortality [9].