Abstract
Granulomatous mastitis (GM) is a long-term inflammatory disease of the breast that usually occurs in women of reproductive age. Autoimmune mastitis is one of the most common pathological breast conditions necessitating tailored treatment. However, GM as a first clinical manifestation of sarcoidosis is uncommon. Simultaneous occurrence of GM, erythema nodosum (EN), and arthritis, termed "GMENA" syndrome, is a rare clinical entity associated with autoimmune rheumatic diseases. Herein, we report the case of a 31-year-old female patient with GMENA syndrome, who presented with a painful nodule of the left breast. Initial treatment entailed antibiotics under the presumption of a breast abscess, yielding negligible improvement. During this period, the patient developed polyarthritis and bilateral EN on the lower extremities. Histopathologic examination of the breast tissue exhibited noncaseating granulomas. The patient responded positively to prednisolone and methotrexate treatment. Literature review revealed a coherent pattern across GMENA cases. Our findings suggest that the "GMENA" syndrome represents a unique acute manifestation of sarcoidosis and highlight the necessity for heightened awareness, accurate diagnosis, and tailored therapeutic approaches for GMENA syndrome. Further research is warranted to elucidate its cause and optimize patient management. This case highlights the importance of identifying and effectively managing such interrelated clinical presentations.
Introduction
Granulomatous mastitis (GM) is a rare long-term inflammatory disease affecting the breast. It is characterized by the formation of noncaseating granulomas, which can lead to symptoms such as unilateral or bilateral breast pain, palpable masses, abscesses, erythema, induration, or swelling. Although the exact cause of GM remains uncertain, it is hypothesized that a localized autoimmune inflammatory response to milk within the breast ducts may play a role in its pathogenesis.1,2
On the contrary, erythema nodosum (EN) represents a reactive inflammatory condition of the subcutaneous adipose tissue provoked by a range of antigenic stimuli. 3 Although a considerable portion of EN cases lack a defined cause, it can serve as an early indicator of an underlying systemic process, such as sarcoidosis, tuberculosis, infections, or drug-related reactions. 3 Clinically, it manifests as tender erythematous nodules with a soft texture, predominantly appearing on the extensor surfaces of the lower legs. 3
Numerous documented reports in the literature have outlined the simultaneous presence of GM, EN, and arthritis. 1 These clinical manifestations have been correlated with various autoimmune rheumatic diseases, suggesting that GM might involve a common immune-mediated mechanism that could possibly signify a distinct clinical entity. 1 Herein, we describe a patient who developed GM accompanied by EN and polyarthritis.
Case Presentation
A 31-year-old female patient presented to the rheumatology clinic complaining of a painful, hard, erythematous nodule in her left breast, which had persisted for 1e month. She initially sought medical evaluation in the surgical clinic upon the initial appearance of the nodule. Subsequent to being diagnosed with a breast abscess, a 2-week regimen of antibiotics was prescribed. However, the patient’s condition failed to improve following the administration of antibiotic treatment.
Subsequently, the patient was referred to the hospital, where a biopsy was taken from the nodule. The biopsy results indicated characteristics consistent with an abscess, ruling out any signs of malignancy. As a result, antibiotic therapy was continued, and the abscess was drained surgically. However, there was no improvement in her symptoms. In addition, she described painful, reddish nodules on her legs and forearms, along with severe pain and swelling in both knees, ankles, and wrists, as well as bilateral ankle joint swelling.
The patient also mentioned light sensitivity, excessive tearing, headache, a feverish sensation, night sweats, fatigue, unintentional weight loss of 2 kg within a week, and shortness of breath. These symptoms heightened the suspicion of a systemic inflammatory disorder, prompting further evaluation. The patient’s medical history was unremarkable, and there were no pertinent factors in the family history.
Vital signs were within the normal range. Physical examination of the breasts was notable for a solid mass measuring approximately 5 × 10 cm in the upper outer quadrant of the left breast. The skin overlying the mass appeared fixed and erythematous. Palpable lymph nodes were evident in the left axillary region. Further examination revealed tender, erythematous nodules distributed across both legs and forearms. Notably, a right knee effusion was observed, accompanied by bilateral ankle swelling and tenderness.
Laboratory investigations revealed an elevated C-reactive protein level of 150.2 g/l, an erythrocyte sedimentation rate level of 60 mm/hr, and a white blood cell count of 13 000, primarily consisting of neutrophils. Notably, both the rheumatoid factor and purified protein derivative (PPD) test results were negative. Breast ultrasound findings depicted well-defined, heterogeneous lesions with lobulated margins, measuring around 2 × 1 cm within the left breast. Moreover, a sizable, infiltrative heterogeneous region was observed encompassing the upper and lower inner quadrants of the left breast. Computed tomography (CT) scan showed an enlarged heterogeneous left breast primarily in the retro-areolar region, accompanied by skin thickening suggestive of an inflammatory process. A large lobulated heterogeneous lesion, measuring 2.4 × 1.2 cm and featuring tiny calcifications, was also identified in the lower left breast. Multiple enlarged axillary lymph nodes were likewise detected (Figure 1).
Chest CT scan in the coronal plane showing an enlarged heterogeneous left breast, particularly notable in the retro-areolar region, accompanied by skin thickening indicative of an inflammatory process (red arrow).
Consequently, a repeat breast biopsy was performed, revealing characteristics indicative of GM with abscess formation. Histological examination also disclosed the presence of a few noncaseating granulomas and giant cells (Figure 2). This constellation of findings led to the diagnosis of GM, EN, and arthritis syndrome (GMENA). Treatment commenced with a daily oral prednisolone dose of 20 mg (tapering regimen) and a weekly intake of methotrexate at 20 mg. Over the course of 6 months, the patient displayed significant improvement, marked by the complete resolution of the EN, breast mass, and arthritis. During this period, the patient continued on a weekly dosage of methotrexate with gradual discontinuation of steroids.
Histological patterns of granulomatous mastitis: (A) section shows small cystic spaces lined by neutrophils (microabscesses); overlapping features with cystic neutrophilic granulomatous mastitis (H&E, 40×). (B) Lobulocentric inflammation (H&E, 10×); (C) section shows multinucleated giant cells (blue arrow); nonnecrotizing granulomas (black arrow) (H&E, 20×).
Discussion
This study describes the case of a patient who presented with GMENA syndrome. During our search on PubMed from December 2020 to July 2022, we came across three previously documented cases.2,4,5 Interestingly, one of the articles we encountered conducted a literature review up until December 2020 and identified a total of eight cases focusing on GMENA syndrome. Notably, all patients had normal chest radiographs and negative tissue cultures. Symptom improvement was achieved through the administration of glucocorticoids, while surgical intervention was pursued for GM management in two patients. 1
A coherent pattern surfaced across the three documented cases, revealing a simultaneous occurrence of GM, EN, and arthritis. The ages of the respective patients were 16, 24, and 27. Notably, two cases experienced favorable therapeutic outcomes through prednisolone treatment, while surgical intervention was deemed appropriate for the pregnant patient. Our research involved a thorough and comprehensive literature review, accompanied by a summary of the clinical characteristics displayed by sarcoidosis patients who present with the GMENA syndrome, as summarized in Table 1.
Literature Review and Summary of Clinical Characteristics in Sarcoidosis Patients Presenting with GMENA Syndrome.
Abbreviations: GM, granulomatous mastitis; EN, erythema nodosum; CR, complete resolution; NR, not reported; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
Duration between granulomatous mastitis and erythema nodosum.
Criteria for the diagnosis of sarcoid arthritis.
A review of the existing literature revealed that most cases of GEMNA syndrome exhibited arthritis affecting both ankles.1,2 Remarkably, a substantial percentage, ranging between 77% and 100% of individuals with sarcoidosis-related acute arthritis displayed ankle involvement. Furthermore, sarcoidosis was independently associated with bilateral ankle disease. When other autoimmune diseases are excluded, unilateral ankle involvement was found to be linked with sarcoidosis.4,5,12,13
Visser and colleagues proposed a set of criteria for the diagnosis of sarcoid arthritis that have high sensitivity and specificity. Those include the presence of EN, symptom duration lesser than 2 months, age less than 40, and symmetrical ankle arthritis. At least 3 of the 4 characteristics should be present for the diagnosis. 12 We identified 12 cases of GMENA syndrome, most of which have fulfilled the proposed diagnostic criteria (Table 1).1,2,4-11
While many clinicians will readily diagnose sarcoidosis when the lungs show clear signs through either a lung biopsy or chest radiograph, the absence of lung involvement does not necessarily rule out the possibility of sarcoidosis. 14 Moreover, the term "isolated extrapulmonary sarcoidosis" is frequently used in instances where individuals are diagnosed with sarcoidosis without any lung involvement, such as in cases of hepatosplenic or gastrointestinal sarcoidosis. Although this condition is uncommon, it has been reported, with an incidence rate of approximately 2%. 15
Furthermore, all patients listed in the table met the diagnostic criteria for sarcoidosis, which require the involvement of at least 2 organ systems, the presence of noncaseating granulomas in histopathological examination, and the exclusion of other potential diseases.14,15
However, when only a single organ exhibits noncaseating granulomas, the diagnosis of sarcoidosis cannot be established because sarcoidosis is characterized as a multisystemic disease, typically involving more than 2 organs. In addition, there are reports of idiopathic granulomatous diseases affecting individual organs, although these instances are rare and not necessarily indicative of sarcoidosis. For instance, conditions like idiopathic granulomatous hepatitis and idiopathic panuveitis present with noncaseating granulomas solely in one organ. 14 Similarly, suspicion of idiopathic GM can arise when sarcoidosis affects the breast without involving any other organ.
Granulomatous mastitis treatment is widely variable depending on multiple factors and includes corticosteroids, surgery, methotrexate, and other immunosuppressive regimens. 16 A high success rate of remission has been demonstrated with the use of high-dose steroids. However, the undesirable side effects have limited its use. 16 Conversely, studies have reported plausible outcomes and a lower recurrence rate of GM with the use of methotrexate as a single-drug regimen or in addition to low-dose corticosteroids.
Conclusion
In conclusion, the GMENA syndrome, which comprises the unique triad of GM, EN, and arthritis, represents a rare clinical entity resulting from complex interactions of immune processes in disease pathogenesis. The reported case underscores the need for heightened awareness among health care professionals to recognize and appropriately diagnose this syndrome, given its overlapping symptoms with other conditions. While the precise underlying pathophysiology remains uncertain, the positive treatment response to immunosuppressive and immunomodulatory medications supports the involvement of abnormal immunoinflammatory processes. Based on our findings, it can be suggested that GMENA may be characterized as its own distinct clinical entity or potentially a unique presentation of sarcoidosis. Further research is warranted to uncover the syndrome’s underlying cause, enhance diagnostic criteria, and develop targeted treatment strategies that can lead to improved patient outcomes.
Footnotes
Acknowledgements
The authors express their gratitude to the patient and their family for their great contribution.
Author Contributions
AA, MA, and MAy, contributed to the design of the study, data collection, data interpretation, and drafting of the manuscript. AM and ONM contributed to the design of the study, and drafting of the manuscript. LA and MAy contributed to the design of the study, data interpretation, drafting of the manuscript, and supervision of the work. All authors have read and approved the final manuscript. Each author has participated sufficiently in the work to take public responsibility for the content.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent
Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
