Diffuse Dermal Angiomatosis of the Breasts: A Case Series of 8 Patients

Diffuse dermal angiomatosis (DDA) is a rare, benign, acquired reactive vascular disorder of the skin first described in 1994 most commonly affecting middle-aged females. As of early 2016, only 73 patients with DDA had been reported to date. Most case reports and series describe an association with hypoxic conditions such as vascular disease, calciphylaxis, and smoking, as well as other comorbid conditions including obesity and diabetes. DDA can present as early as three years after significant weight gain. The condition has also been reported as more common in females with large pendulous breasts. DDA typically presents with multiple erythematous to violaceous purpuric patches and plaques that may progress to necrosis and painful ulceration. Although breast involvement was once considered rare in DDA, recent studies suggest that the ABSTRACT


INTRODUCTION
breasts may be the most common site. 3,4,7,8 Histology is typically characterized by extensive proliferation of CD31 and CD34 positive endothelial cell proliferation around collagen bundles. 2,3,[5][6][7]9,10 Although there is currently no standard of care, improvement in comorbidities including smoking cessation (if applicable), medical therapy (including corticosteroids, isotretinoin, aspirin, and pentoxifylline), and reduction mammaplasty have all been reported to be effective. [1][2][3][4]7,8,10 A 49-year-old female with a one pack-year history of smoking and obesity (body mass index 45) presented to clinic with a 10month history of painful plaques on bilateral breasts refractory to oral antibiotics. Recent mammogram was normal. Physical exam revealed large pendulous breasts, with prominent small telangiectasias and crusted ulcerations at the inferior aspects and an active ulcer on the left medial breast and scars from prior ulcers ( Figure 1). The patient reported allergy to aspirin, but was counseled on smoking cessation, referred for reduction mammaplasty, and started on pentoxifylline. At follow up three months later, her pain was drastically improved, all prior ulcers were healed, and she had no new ulcers. She had maintained abstinence from smoking but had only taken the pentoxifylline for two months due to cost. The patient eventually underwent bilateral reduction mammaplasty nine months later with full recovery and has not had any recurrence of her symptoms.
After obtaining IRB approval, we performed a retrospective chart review of all patients with DDA seen at our institution between 2010 and 2020. We obtained a list of patients from the MC Research Analytics team, who did an electronic medical record (EPIC) search of "diffuse dermal angiomatosis." We compiled data on demographics, clinical presentation, relevant co-morbidities including body mass index (BMI), smoking history, biopsy and lab results, and any treatments used with described outcomes. Basic statistical analyses, including t-tests of unequal variance, were performed to further describe clinical characteristics including BMI and age.
Our initial review identified 17 patients with potential DDA. Nine patients were excluded due to a more likely alternative diagnosis or incomplete medical record. Of the eight patients determined to have DDA (Table 1), all were female and five were symptomatic. All eight of the patients had DDA of the breasts without involvement of any other location. The mean age was 49.5 years.  The symptomatic cohort consisted of three white and two black females with a mean age of 46.6 years (SD=14.6). Of these five patients, all had histories of obesity (BMI: M=48.3, SD=13.9), macromastia, and smoking. Other common co-morbidities included hypertension (3 patients), hyperlipidemia (2 patients), fibromyalgia (2 patients), and hypothyroidism (2 patients). Histologic specimens obtained from three symptomatic patients were consistent with DDA with proliferation of superficial dermal vessels ( Figure 2). All patients saw improvement in their symptoms with reduction mammaplasty (1 patient), aspirin (1 patient), pentoxifylline (3 patients), smoking cessation (2 patients), and/or weight loss (1 patient). By last follow up, two of the four patients who were smoking at initial presentation had quit and had seen improvement in symptoms.

RESULTS
In the asymptomatic group, all three were white females and the mean age was similar to that in the symptomatic group (54.3 ± 17.7, t4=-0.63, p=0.56). None of the patients had a history of smoking and BMI was lower than in the symptomatic group (BMI: M=32.2, SD=5.9, t6=2.27, p=0.06). Patient 6 had undergone reduction mammaplasty years prior to being seen by dermatology; macromastia was not noted on dermatologic evaluation. Biopsy was deferred in all asymptomatic cases and the diagnoses were made on clinical grounds alone. The patients remained clinically stable at last follow up.
Our series of eight patients represents the second largest cohort of patients with DDA of the breasts, and third largest cohort of DDA overall. The case series of 22 patients with DDA of the breasts by Reusche et al. is the largest to date. 4 Ten of their patients were diagnosed with DDA clinically while twelve were confirmed with biopsy. Other notable case series include: nine patients with concomitant calciphylaxis and DDA but only one with involvement of the breasts 5 , seven patients with DDA found in a case series of patients with calciphylaxis but none involving the breasts 6 , and five patients with DDA of the breasts 7 .
Our case series confirmed many recognized characteristics and co-morbidities of DDA. Five of the eight (62.5%) patients experienced moderate-to-severe mastalgia. However, three patients (37.5%) were asymptomatic and not treated. In their series, Reusche et al. similarly reported that 50% (11/22) had no documentation of treatment, including three patients with biopsy-confirmed DDA. 4 We also found high prevalence of comorbidities reported to be associated with DDA including obesity (7/8), hypertension (4/8), and hyperlipidemia (3/8), very similar to prior reports. The difference in BMI between the symptomatic and asymptomatic groups was on the threshold of significance, likely affected by small sample size (n=8). All of the symptomatic patients in our series had a history of smoking, consistent with the reported association between DDA and smoking. Reusche et al. reported that 50% (11/22) patients identified as former or current smokers, with 58.3% (7/12) of patients with biopsy-confirmed DDA having a smoking history. Interestingly, all 3 asymptomatic patients were non-smokers. Our confirmation of this association is notable as other series have contested the link between smoking and DDA. 4 Prior to our series only a single patient with concomitant DDA and fibromyalgia (FM) had been reported. 1 Our series of DDA patients includes three patients diagnosed with FM DISCUSSION (38%). The prevalence of FM in the United States is approximately 2%, thus it would not be unreasonable that this observation represents mere coincidence. However, the two disease processes may be linked by a common association, specifically obesity. 11 Alternatively, there may be an under recognition of DDA as a diagnosis and significant cause of pain, which may be misattributed to FM by non-dermatologists.
Diffuse dermal angiomatosis occurring after reduction mammaplasty has been reported in five patients. 2,4,7 Reusche et al. reported one patient in their series with recurrence of macromastia and DDA following breast reduction 30 years prior. 4 Adams et al. reported one case of DDA in a female who had undergone reduction mammaplasty over 20 years prior. 2 Tollefson et al. reported three of five patients in their series had undergone breast reduction mammaplasty six weeks to 30 years prior to presenting with DDA. 7 In our series, two patients had undergone reduction mammaplasty years prior to developing DDA. Despite positive outcomes reported after reduction mammaplasty for patients with DDA of the breasts, these reports of DDA in patients with previous reduction mammaplasty suggest that the surgery is not curative since macromastia may still recur with time. The above literature provides support for the proposed causative association between macromastia and DDA. Macromastia is believed to result in tissue hypoxemia due to subclinical torsion, compression, and increased venous hydrostatic pressure. 8 Mastectomy may lead to full resolution 4,9 but should be considered only after exhausting all more conservative approaches.
We report the first case of DDA that improved with weight loss as the primary intervention (Patient 3, BMI decreased from 70.4 to 55.9). In the literature one patient with DDA was reported to improve with the combination of weight loss and smoking cessation 10 , however another patient did not see substantial improvement despite reducing smoking and losing weight. 8 Furthermore, there are reports of DDA presenting after or worsening with weight gain. 1,3,4,8 In the series, we saw a trend of greater BMI among symptomatic patients compared to asymptomatic patients. Higher BMI would likely result in larger pendulous breasts, a risk factor for DDA of breasts. Our observation of DDA improving with weight loss as the sole intervention provides further evidence that obesity may be a primary etiologic factor in this rare disease.
In summary, our series confirms many of the previously reported associations with DDA including obesity, smoking, and large pendulous breasts. Our series identified a novel potential association between DDA and fibromyalgia which warrants further investigation. Finally, we report the first known case of improvement of DDA with weight loss as a sole intervention and recommend weight reduction be considered alongside other first line interventions for this rare disease.