Breast calcifications due to Ehlers-Danlos syndrome: A rarely reported finding

A 47-year-old woman, asymptomatic, presented for a first screening mammogram. As a personal history, the patient mentioned Ehlers-Danlos syndrome genetically confirmed, which manifests by skin hyperextensibility and joint hypermobility. The patient denied a history of bruising or temporary palpable breast masses. Clinical examination of the breast and axilla was normal, and there was no family history of breast cancer or Ehlers-Danlos syndrome.

The screening mammography shows bilateral pleomorphic microcalcifications with a diffuse distribution involving much of the parenchyma, although without unambiguously symmetrical involvement (Fig. 1). The breast ultrasound didn’t reveal abnormalities.

Given the mammographic findings, a bilateral mammography-guided stereotactic breast core biopsy (Fig. 2) was performed. The histological study revealed stromal fibrosis with numerous coarse, rounded, and elongated microcalcifications, without evidence of malignancy. As the multidisciplinary team considered there could be radiological-pathological disagreement, a bilateral surgical biopsy was performed, whose histology only added the presence of scarce areas of adenosis (the remaining findings were superimposed).

The integration of mammographic and histological findings, clinical evaluation, and long-term follow-up allowed the calcifications to be attributed to Ehlers-Danlos syndrome.

The patient remains under routine mammographic surveillance. Over ten years, new calcifications gradually emerged (Fig. 3), namely in the right breast, where liponecrotic calcifications and a coarse calcification at the 9 o’clock position (probably a fibroadenoma).

Breast microcalcifications are frequent mammographic findings, most often benign aetiology, although they are present in 30-50% of non-palpable tumours and most cases of ductal carcinoma in situ [1,2]. Breast calcifications can arise in the ductal system, acini, stroma, or blood vessels [3].

The classification of calcifications according to the Breast Imaging Reporting and Data System (BI-RADS) is essential in screening diagnostic mammograms. The 5th edition of the BI-RADS divides calcifications into typically benign or suspicious morphology, being it is essential to evaluate its morphology and distribution to establish this distinction [4].

Pleomorphic calcifications (variable in size and shape) have a positive predictive value of 29% for malignancy, fall into BI-RADS category 4B and require biopsy. These calcifications develop in DCIS, invasive ductal cancer, atypical breast lesions, and rarely in lobular carcinoma [5].

Faced with findings that do not strictly meet the criteria for benign or probably benign lesions, it is essential to obtain histopathological confirmation to avoid diagnostic errors [6]. Although bilateral diffuse calcifications are typically associated with a low risk of malignancy, in the case presented, its pleomorphic morphology and the not clearly symmetrical distribution led to a biopsy to exclude an occult neoplasm, namely an invasive carcinoma.

Although mammography is mainly used to detect breast cancer, it can occasionally reveal breast abnormalities secondary to systemic diseases. Some connective tissue diseases, such as systemic lupus erythematosus, dermatomyositis, and scleroderma, may be associated with stromal breast calcifications [7].

Ehlers-Danlos syndromes (EDS) is a group of hereditary connective tissue disorders that primarily manifest with joint hypermobility, cutaneous hyperextensibility, and tissue fragility [8,9]. The age of presentation is variable, with heterogeneous clinical manifestations, and transmission can be autosomal dominant or recessive. Currently, 13 subtypes are recognized, with classic and hypermobile EDS being the most frequent subtypes. Considering all subtypes, EDS occurs in approximately 1:5000 births [8].

The stromal breast calcifications in EDS are rare, with few cases described, and the pathophysiology is still not well determined. Villan et al. argue that the appearance of calcifications may result from quotidian microtraumas that trigger cytosteatonecrosis lesions that progress to hyalinization and calcification [10-12]. This hypothesis is congruent with the predominance of microcalcifications in the superficial areas of the upper quadrants of the breasts in the published cases, which are the sites most susceptible to trauma [11].

In conclusion, several systemic diseases may involve the breast, so the radiologist must know their possible mammographic findings.

Written informed patient consent for publication has been obtained.