Aseptic breast abscess syndrome as an example of neutrophilic dermatosis. Can an immune defect be the reason of a disease?

Introduction

Aseptic abscess syndrome (AAS) belongs to neutrophilic dermatoses. It is a group of rare idiopathic diseases in which neutrophilic infiltrative lesions occur in different layers of the skin [1]. Local and generalized clinical manifestations are identical to those of bacterial infections, but the pathogen within the observed lesions is never identified [2, 3]. It is assumed that an unknown defect activates neutrophils leading to their proliferation and migration with formation of collections forming microabscesses and abscesses. Recurrent episodes of inflammation in the absence of infection or allergy are a characteristic feature [4]. Features of autoimmunity (autoantibodies or autoreactive T cells) are also absent. Antibiotic therapy, aseptic medications and surgical debridement are unsuccessful. However, immunosuppressive drugs are effective: oral glucocorticosteroids (GCS) and, in severe cases, tumor necrosis factor-a (TNF-a) inhibitors [2].

Objective

The study presents the diagnostic challenge of aseptic abscesses syndrome, a disease that exhibits some features of autoinflammatory disorders and focuses on investigating humoral and cellular immunity, with a specific emphasis on potential neutrophil defects. The objective is to comprehensively examine the function of the immune system in AAS as there is currently no other publication so thoroughly presenting the function of the immune system.

Case report

A 45-year-old female patient referred to a gynecologist with a non-painful, palpable nodule in her left breast and accompanying malaise. Ultrasound of the breast revealed a tumor in the left one, and after a few days another tumor-like lesion of a purulent nature was found in the left breast. The surgical treatment applied several times as well as broad-spectrum antibiotic therapy did not bring a lasting therapeutic effect. Due to its ineffectiveness, the diagnosis was expanded in the direction of breast cancer, which was excluded. In several biopsies, the histopathological result was most consistent with abscess nature of the lesions. Extensive differential diagnosis with positive inflammatory indices, repeatedly negative bacteriological, mycological cultures confirmed AAS. An evaluation of humoral and cellular immunity made it possible to rule out known immune defects as a potential cause of the lesions. The use of prednisone gave rapid clinical improvement, complete healing of the lesions and maintenance of remission for months, despite the reduction of the drug dose from 30 mg/day to 2.5 mg/day. The patient has remained in 30-month remission since starting treatment with GCS. No complications of this therapy were observed in the patient. On physical examination, deformity of the breast and scarring from abscesses and their surgical treatment are evident.
Laboratory tests showed an elevation of inflammatory markers throughout the observation period, such as erythrocyte sedimentation rate (ESR), C-reative protein (CRP) (multiple measurements with values ranging from 9.6 mg/l to 178.1 mg/l). There was leukocytosis (14.32 thousand/µl [norm: 4.00–10.00]), neutrophilia (12.29 × 10³/μl [norm: 1.79–6.04]) and decreased lymphocytes (0.99 × 10³/μl [norm: 1.3–3.40]) correlated with active disease severity.
Performed tests for Lyme disease and tuberculosis (QuantiFERON-TB Gold) were negative. Cultures by Ziehl-Neelsen method did not reveal acid-fast mycobacteria. Bacteriological and mycological cultures were negative on several occasions.
Laboratory examination of tumor antigen levels showed an elevation of CA 125 (45.30 IU/ml with a normal of up to 35), while no significant deviations were found for CA 15-3, CA 19-9, CEA. Humoral immunity (levels of IgA, IgG, IgM immunoglobulins and IgG subclasses) was assessed, with no abnormalities found. Granulocyte oxygen burst activity by flow cytometry in whole peripheral blood (Phagoburst test) was performed, with no abnormalities in reactive oxygen intermediates (ROIs) production and chemiluminescence, in which there was a normal response to latex stimulation. A lymphocyte subpopulation study was performed (table 1). The lymphocyte response to stimulation with mitogens and anti-CD3 antibody was evaluated (table 2). The stimulation index was normal. Myeloperoxidase was present. Adhesion defect was excluded in terms of CD11/CD18 molecules. The levels of complement components C3 and C4 and CH50 were normal. Nuclear antibodies ANA and ANCA were negative.

Imaging and histopathological studies

Numerous ultrasound examinations of the breast described abnormalities located in the left breast, in the nature of hypoechoic lesions, heterogeneous, non-vascular structures of 5–32 mm in size. Labeled white blood cell scintigraphy (WBCS) showed pathological accumulation of leukocytes of the left breast with a tendency to increase over time. Mammographic examinations described the absence of changes in the skin and subcutaneous tissue of the breast with a mixed fat-glandular structure. In the upper-external quadrant of the left breast, about 7 cm from the nipple, an area of disturbed architecture measuring 29 × 32 × 23 mm was visualized.
Core-needle biopsies were performed on multiple hypoechoic areas located peripherally in the left breast. Microscopically an extensive inflammatory infiltrate composed mainly of neutrophils, eosinophils, macrophages and lymphocytes was detected. Immunohistochemical stains for CK7 and CK AE1/AE3 were negative. Histopathological diagnosis of a breast abscess was established (figs. 1, 2).
Magnetic resonance imaging showed enlargement of the left breast, with features of swelling and thickening of the skin and prominent areas of fluid. PET-CT of the left breast in the outer quadrants revealed irregular tissue changes with heterogeneously elevated glucose metabolism. A review examination revealed no focal lesions.
The patient reported no gastrointestinal complaints but, due to connection of AAS with inflammatory bowel diseases (IBD) an abdominal ultrasound, gastroscopy and colonoscopy were performed, which showed no abnormalities. Due to elevation of Ca 125, complete gynecological checkup has been done (transvaginal ultrasonography, cytology, ROMA panel).
Differentiation was performed for other neutrophilic dermatoses, including Sweet’s syndrome, pyoderma gangrenosum, neutrophilic dermatitis, and neutrophilic rheumatoid dermatitis [5]. Idiopathic granulomatous mastoiditis, characterized by a lack of significant response to corticosteroid treatment and a specific histopathological picture, was also excluded in the patient [6].
Based on the patient’s clinical data, laboratory diagnosis and histopathological results, the diagnosis of aseptic breast abscess syndrome was established.

Discussion

An issue regarding the cause of neutrophilic abscesses stays unsolved. The study of humoral immunity, cellular immunity, complement function and neutrophils activation seems to be a natural target for investigators, but so far has not been analyzed in detail. Our patient’s immunological findings were within normal range.
No features of agitation suggestive of autoinflammation and autoimmunity were observed despite the inflammation present. No immune defect was found, which could indirectly indicate a latent atypical infection. The available works have focused on differential diagnosis to exclude possible infectious disease (bacterial, fungal, mixed), manifestation of autoimmune diseases including IBD [2–10], while no investigator has published such a broad diagnosis of the immune system, which makes it impossible to compare the results obtained by the authors with other data.
The determination of C11, C18 adhesion molecules was particularly valuable, but they were normal. Undoubtedly, the disease has features of an autoimmune or autoinflammatory syndrome, but its pathomechanism is unknown. Oral GCS remain the most effective therapeutic option. It is known that neutrophils are the main cells responsible for clinical symptoms, and normalization of their numbers allows to achieve remission and resolution of inflammatory indicators. There might be a defect in leukocyte migration, activation of adhesion molecules (selectins and integrins), but studies of their function are unavailable in our laboratory.
Aseptic abscess syndrome is one of the rare diseases whose incidence correlates with autoimmune diseases. The 2022 Trefond’s cohort study found a 42% coexistence of AAS with IBD [4]. In the case of the patient described here, IBD was ruled out by endoscopic examination. The lesions characteristic for aseptic abscess syndrome are located in specific organs and areas of the patients’ bodies. Abscesses in AAS are most commonly located in the spleen, lymph nodes, skin, liver and lungs [4, 7, 9]. The mammary glands are one of the rarer locations, along with the brain, genitals, kidneys, and muscles [9].

Conclusions

Although the patient was documented to have increased inflammatory markers and leukocytosis with a predominance of neutrophils, no immunodeficiency could be identified to explain the mechanism of nuclear cell activation. However, their role is paramount, suggesting the use of immunosuppressive treatment ex juvantibus. Oral GCS remain the most effective therapeutic option. The efficacy of TNF-a inhibitors or anakinra in patients with contraindications to or ineffectiveness of GCS, as described in publications, confirming the predominant role of pro-inflammatory cytokines [11]. However, TNF and other inflammatory mediators do not specify the source of the disease. It is well known that neutrophils are the main cells responsible for clinical symptoms, and normalization of their number leads to remission and resolution of inflammatory indicators.

Acknowledgments

Przemysław Borowy, Alicja Kamińska, Katarzyna Gołojuch have contributed equally to this work and share first authorship.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References