Granulomatous mastitis (GM) is a rare, benign, chronic inflammatory breast disease (1). It is characterized histologically by lymphocytes, plasma cells, epithelioid histiocytes, and multinucleated giant cells, with the formation of non-caseating granulomas and abscesses (2,3). Its incidence is estimated at 2.4 cases per 100,000 females in the USA. GM is most commonly observed in premenopausal women during or after pregnancy, though it can also occur in nulliparous women. Reported cases span a wide age range, from as young as 11 years to patients in their 60s, 70s and even 80s (2,4,5).

GM is generally divided into two etiological types: Idiopathic and secondary. Idiopathic GM has no clearly identified cause, although an autoimmune mechanism is strongly suggested, given its favorable response to corticosteroids and its links with other autoimmune conditions. Secondary GM, on the other hand, arises from specific underlying factors, including infectious agents, such as Mycobacterium tuberculosis, fungi, parasites, or bacteria, as well as systemic illnesses such as sarcoidosis and granulomatosis with polyangiitis (6,7).

The clinical diagnosis of GM requires careful evaluation, as it can be easily mistaken for other conditions, such as non-puerperal mastitis, breast abscess, or, more commonly, carcinoma (8). GM may also be associated with systemic manifestations, including erythema nodosum (EN), which is the most common form of panniculitis, an inflammatory disorder of the subcutaneous fat characterized by erythematous, tender nodules that typically appear on the anterior aspect of the lower extremities. It has been linked to autoimmune conditions, such as sarcoidosis and inflammatory bowel disease (9,10). However, the coexistence of GM and EN is exceedingly rare, with only limited documentation in the literature regarding clinical features and therapeutic approaches (11). Given this rarity, the present case report aimed to add to the available evidence by describing a patient with concurrent GM and EN. The present case report follows the CaReL guidelines, and all cited references were reviewed for eligibility and relevance (12,13).

In 1972, Kessler and Wolloch (14) described the first case of GM, emphasizing that its clinical features can closely resemble those of breast cancer. Such features include palpable masses, breast pain, swelling, skin alterations, abscess formation, ulceration, sinus tract or fistula development in advanced or chronic cases, and, at times, accompanying axillary lymphadenopathy (2,14). GM is considered to develop following injury to the breast ductal epithelium. Such damage permits luminal secretions to leak into the surrounding lobular connective tissue, initiating a localized inflammatory reaction. This process attracts lymphocytes and macrophages to the site, ultimately leading to a granulomatous inflammatory response (6).

The exact etiology of GM remains unclear; however, multiple mechanisms have been proposed, suggesting a multifactorial origin. Autoimmunity is considered the most accepted hypothesis, supported by the favorable response to corticosteroids and other immunosuppressive therapies, as well as the frequent association with systemic manifestations such as EN and arthritis (15). Hormonal influences appear significant, as GM occurs predominantly in women of reproductive age, particularly during the postpartum period, and has been linked to factors, such as pregnancy, breastfeeding, oral contraceptive use and hyperprolactinemia. A potential genetic predisposition has also been suggested, with certain human leukocyte antigen (HLA) types, including HLA-A*10, HLA-A*2403, HLA-B*18 and HLA-DR*17, found more commonly in affected individuals (15). Environmental and infectious triggers, including Corynebacterium species and other microbiological agents, have also been implicated. Overall, GM appears to result from a complex interaction of autoimmune, hormonal, genetic and environmental factors rather than a single underlying cause (15).

EN is a frequently encountered condition in rheumatology, characterized as an inflammatory process of the subcutaneous tissue. It typically presents with the acute onset of tender, erythematous nodules or plaques ranging from 1 to 6 cm in diameter (16). The lesions most often appear in a bilateral and symmetrical distribution, predominantly involving the pretibial regions of the lower extremities, though they may also extend to the ankles, thighs and forearms (17). In line with these observations, both the present case report and the study by Alungal et al (18) documented painful cutaneous lesions confined to the lower limbs.

In the present study, a literature review was also conducted to identify studies reporting GM associated with EN. The search was performed using Google Scholar with the key words ‘granulomatous mastitis’ and ‘erythema nodosum’, yielding six relevant reports (Table II) (1,16-20). The association between GM and EN was first described in 1987(19). The documented patients ranged in age from 16 to 42 years, all of whom were female. Among the 6 cases, 3 cases involved lesions in the right breast.

Adams et al (19) described the case of a 24-year-old postpartum female patient presenting with a painful left breast mass, florid EN on both legs and periarthritis. The initial clinical impression suggested carcinoma due to the breast mass and nipple retraction; however, the prominent cutaneous lesions and joint involvement indicated an inflammatory rather than malignant etiology (19). Similarly, Salesi et al (1) reported the case of a 23-year-old pregnant female who developed painful right breast swelling, arthritis and EN on both tibiae. Their case highlighted that systemic manifestations, such as arthritis and panniculitis, may precede or occur concurrently with breast symptoms, supporting a potential autoimmune or hypersensitivity component in idiopathic GM (1).

Other reports support this pattern. Alungal et al (18) described the case of a 25-year-old female patient presenting with a breast mass, polyarthritis and EN, with nodules distributed on the shins and forearms. Bes et al (16) documented the cases of 2 female patients, aged 27 and 34 years, both of whom developed breast masses clinically suggestive of carcinoma, followed by EN on the lower legs. In these cases, EN developed either concurrently with or shortly after the breast lesion (16), as was also observed in the present case. Laor et al (20) extended the phenotype to a 16-year-old adolescent who presented with breast swelling, polyarthritis, and EN on the shins and thighs, highlighting that the same constellation can occur even in younger age groups. Recently, Pesce et al (17) reported the case of a 42-year-old female patient whose presentation was initially indistinguishable from breast cancer. However, the incidental finding of bilateral EN on her legs shifted diagnostic suspicion toward idiopathic GM (17).

The diagnosis of GM is often challenging due to imaging modalities, such as US, mammography and magnetic resonance imaging, which typically yield non-specific findings, usually demonstrating only a mass, parenchymal distortion, or multifocal lesions. Consequently, HPE remains the definitive diagnostic method, and the biopsy of any suspicious area is essential. Characteristic features of GM include chronic granulomatous inflammation with giant cells, leukocytes, epithelioid cells, and macrophages (21).

In the case presented herein, the diagnosis was established through a combination of histopathology and systematic exclusion of infectious and systemic causes, consistent with approaches reported in the literature. Clinical suspicion was raised by a unilateral painful breast mass accompanied by EN. A laboratory evaluation revealed leukocytosis and anemia, whereas ASO titers, chest radiography and IGRA were negative. The US identified a mass, prompting a core biopsy. Histopathological analysis demonstrated non-caseating granulomas composed of epithelioid histiocytes and multinucleated giant cells, without evidence of caseous necrosis or microorganisms, confirming idiopathic GM as the underlying process. The diagnosis was further supported by the resolution of EN following immunomodulatory therapy.

In the case described in the study by Alungal et al (18), fine-needle aspiration cytology demonstrated epithelioid cells, multinucleated giant cells and non-caseating granulomas. Specific stains for bacteria, fungi and acid-fast bacilli were negative, and autoimmune serological analyses did not yield any notable findings, supporting a diagnosis of idiopathic GM (18). Bes et al (16) emphasized the pitfalls of misdiagnosis: Of note, 1 patient was initially treated as having tuberculosis due to a misinterpreted histological analysis exhibiting necrosis. Upon reevaluation, the cultures were negative, and the presence of EN guided the recognition of idiopathic GM (16). Laor et al (20) performed a broader pediatric workup, including autoimmune serologies and ophthalmological examination for sarcoidosis, all of which yielded negative results. A histological analysis confirmed lobulocentric granulomas with microabscesses, establishing idiopathic GM in an adolescent (20). Pesce et al (17) highlighted the cancer-mimicking nature of idiopathic GM on imaging, ultimately reaching the diagnosis through core biopsy demonstrating lobulocentric granulomatous inflammation, after cultures and stains excluded infection.

The management of GM remains a subject of debate, perhaps attributed to its infrequent occurrence and the limited comprehension of its pathophysiology, as well as its prevalence among economically disadvantaged patients. Several therapy approaches have been documented, although their effectiveness has varied. The alternatives include careful waiting, surgical intervention, systemic corticosteroids and chemotherapeutic medicines. Corticosteroid administration has emerged as the most consistently effective intervention across published series. Alungal et al (18) reported the rapid remission of both breast and systemic manifestations following glucocorticoid therapy, while Bes et al (16) described the cases of 2 female patients with idiopathic GM-associated EN who exhibited a marked improvement on corticosteroids after the misdiagnosis of tuberculosis was excluded. By contrast, Adams et al (19) observed spontaneous regression with symptomatic management, and Pesce et al (17) described the case of a patient managed conservatively without corticosteroids in whom EN resolved spontaneously, suggesting a variable natural course. In the case in the present study, oral prednisolone combined with colchicine resulted in the complete resolution of both cutaneous and breast manifestations. The addition of colchicine, although less frequently reported in the literature, may be particularly rational given its efficacy in neutrophilic dermatoses, such as EN, as demonstrated by Salesi et al (1), who employed colchicine alongside steroids and azathioprine with favorable outcomes.

A limitation of the present case report is the unavailability of breast US images. Although the US was performed and its findings described, the absence of imaging documentation may limit the clarity and illustrative value of the case.

In conclusion, the accurate diagnosis of GM is essential to prevent unnecessary interventions. Management with corticosteroids can lead to favorable outcomes. Understanding systemic associations, such as EN, is vital for comprehensive patient care.