Key Points

• Cystic neutrophilic granulomatous mastitis (CNGM) has an identical clinical presentation to idiopathic granulomatous mastitis (IGM)

• IGM and CNGM are managed surgically and/or with antibiotics, steroids, and steroid-sparing immunosuppressives

• Tumor necrosis factor alpha (TNF-α) inhibitors are considered safe and effective as long-term treatment for chronic autoimmune granulomatous diseases, such as inflammatory bowel disease and sarcoidosis

• TNF-α inhibitors may be a potential non-steroidal, non-anti-microbial and non-surgical treatment alternative for refractory IGM and CNGM

Introduction

Idiopathic granulomatous mastitis (IGM) is a rare, benign, inflammatory breast disease, the etiology and management of which are poorly defined in the literature. Patients classically present with a painful, unilateral inflammatory breast mass. Cystic neutrophilic granulomatous mastitis (CNGM) presents identically to IGM. Although no treatment consensus exists, IGM and CNGM may be managed surgically with wide local excision or mastectomy or medically with antibiotics, intralesional or systemic steroids, or other immunosuppressive therapies, such as methotrexate (1, 2, 3, 4). Adalimumab is a humanized monoclonal antibody to tumor necrosis factor alpha (TNF-α) that is used to treat a variety of autoimmune conditions, including plaque psoriasis. We describe a case of CNGM that responded to adalimumab prescribed for the patient’s comorbid plaque psoriasis. Adalimumab has not previously been reported as a treatment option for CNGM.

Case Presentation

A 30-year-old Hispanic woman presented with a one-week history of a firm, tender mass under the left nipple. She was a gravida 1 para 1, who delivered at age 25 and did not breastfeed. Her medical history was significant for poorly controlled psoriasis, treated latent tuberculosis infection, and a prolactinoma.

Physical examination of the left breast revealed a firm, subcutaneous mass measuring 2.5 centimeters at the 9 o’clock position under and medial to the nipple, centered at 1 cm from the nipple. There were no overlying skin changes, although there were psoriatic plaques affecting the skin on both breasts and over 10% of her body surface area. No other masses or nipple discharge were observed.

Ultrasound revealed a heterogeneous, hypoechoic, irregular mass with extension to the skin/nipple (Figure 1a).

A round, isoechoic and hypervascular lesion, less than 1 cm in diameter, was also found within the mass, correlating with the physical exam finding. Given the appearance of an abscess, the patient was started on a course of trimethoprim/sulfamethoxazole.

Aspirate fluid from the mass was sent for culture and revealed moderate Corynebacterium tuberculostearicum. However, as the patient felt well after her antibiotic course, she opted for observation only.

About one month later, her symptoms persisted, and the mass had slightly enlarged. Ultrasound-guided vacuum-assisted core needle biopsy revealed sheets of histiocytes and mixed acute and chronic inflammation with granulation tissue formation in a background of a few benign breast lobules. Interspersed granulomas with central neutrophilic abscess formation or large “punched out” spaces were present. The gram stain highlighted gram-positive bacilli within the cystic spaces. In the absence of features suggestive of a more specific etiology, these findings were most consistent with IGM. Specifically, the neutrophilic micro-abscesses within granulomas, in association with punched-out spaces and gram-positive bacilli, were morphologically consistent with CNGM (Figure 2a, b, c, d).

 The patient elected to try co-managing her psoriasis and CNGM with adalimumab. She injected herself with 40 mg/0.8 mL of adalimumab subcutaneously every 14 days. After one month of treatment, the patient reported her breast pain had resolved, and repeat ultrasound revealed decreased size of the mass (Figure 1b). Her skin significantly improved after treatment with adalimumab, with her psoriasis affecting only about 1% of her body surface area.

During a temporary discontinuation of adalimumab two months later, her breast symptoms recurred. One week after resuming treatment, the breast mass again decreased in size and induration, and her pain and swelling again resolved.

Discussion and Conclusion

Adalimumab and other TNF-α inhibitors are considered safe and effective as long-term treatment for other chronic autoimmune granulomatous diseases, such as inflammatory bowel disease and sarcoidosis (5). Only one previously published case described successful treatment of IGM with a TNF-α inhibitor (etanercept), in combination with methotrexate (6). The immunological etiopathogenesis of IGM is poorly understood. Investigations are limited to a single study, which found serum levels of proinflammatory cytokines, such as interleukin-8 (IL-8) and interleukin-17 (IL-17), were elevated in cases of IGM compared with controls (7). While TNF-α levels have not been reported to be significantly higher in patients with IGM or CNGM, other T helper 17/IL-17- driven diseases, such as psoriasis, and diseases exhibiting elevated IL-8 levels, such as rheumatoid arthritis, respond to TNF-α blockade (8). Notably, treatment with adalimumab resolved the CNGM symptoms in our patient without requiring prolonged antibiotic therapy or surgical management, which is associated with high morbidity and recurrence rates (9, 10). TNF-α inhibitors are widely viewed as having a more favorable safety profile than systemic steroids, which are associated with potentially serious sequelae, including weight gain, osteoporosis, hypertension, glucose intolerance, and risk for opportunistic infection. Though further study is needed to determine the efficacy of TNF-a inhibitors in CNGM, their therapeutic potential for this challenging condition is evident.

While the clinical presentations of IGM and CNGM are indistinguishable, CNGM has been described as a histologically distinct entity characterized by clear spaces/vacuoles rimmed by neutrophils and cuffs of epithelioid histiocytes/granulomas in the background of a mixed inflammatory infiltrate comprised of lymphocytes, giant cells and neutrophils (11). Distinguishing features of CNGM and IGM are summarized in Table 1. CNGM has been reported to be often, but inconsistently, associated with various Corynebacterium species (3, 6, 12) with gram-positive rods localized in the clear cystic spaces, which are absent in the non-cystic neutrophilic presentation of IGM (13). Non-diphtheriae Corynebacterium species have not been reported to cause adverse systemic sequelae in the setting of TNF blockade.

A summary of published cases describing CNGM is presented in Table 2. Many cases of both IGM and CNGM are treated with variable, serial combinations of surgery, antibiotics, and/or immunosuppression, such as intralesional or systemic steroids or methotrexate (1, 2, 3, 4) with one study reporting the protracted clinical course of both to range from 6 to 50 months (3). Some authors have suggested CNGM should be treated with long-term lipophilic antibiotics targeted at Corynebacterium spp. (6, 12, 14). However, of 328 cases previously described in the literature, only one report of three patients (12) clearly describes improvement after four weeks or less of tetracycline antibiotics as monotherapy. A recently published report describes 18 patients who improved after an average of seven months on antibiotic monotherapy, the majority of whom received a course of clarithromycin (5). The remaining cases report varying clinical outcomes, from recurrence of mastitis in the contralateral breast (14), to persistent symptoms after antibiotic and surgical management (2, 3, 15), to eventual resolution after combination therapy with empirical antibiotics, immunosuppression, and/or multiple procedures including incision and drainage, lumpectomy, and/or mastectomy (2, 3, 4). Many cases of IGM spontaneously resolve without intervention (15). We believe that there are insufficient data to clearly conclude that antibiotics lead to improved outcomes for CNGM compared with other forms of IGM.

Our patient’s swift response to adalimumab provides supporting evidence that patients with CNGM may respond to immunosuppression alone, and the distinction between IGM and CNGM may be histopathologic rather than clinical. Our case illustrates the near-immediate improvement of symptoms, compared with an average of 6–8 months reported for improvement of CNGM with antibiotic therapy in some reports (2, 13). The patient’s symptoms recurred after a brief interruption of her adalimumab, then rapidly (one week) improved again with reintroduction of the drug, indicating that the adalimumab was controlling her symptoms, rather than representing a case of spontaneous resolution that happened to coincide with introduction of therapy. This robust response to adalimumab suggests that TNF-α inhibitors should be further explored as a potential non-steroidal, non-antimicrobial and non-surgical, well-tolerated treatment alternative for IGM and CNGM to alleviate symptoms until spontaneous resolution occurs.

The treatment of CNGM remains therapeutically challenging, given the absence of consistent response to surgical or medical treatment. Adalimumab or other TNF-α inhibitors may provide a novel therapeutic approach for refractory IGM or CNGM.

Informed Consent: It was obtained from the patient.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and/or Medical Practices: L.C., K.G., P.V., E.A.; Concept: E.A.; Design: E.A.; Data Collection and/or Processing: L.C., K.G., P.V., E.A.; Analysis and/or Interpretation: L.C., E.A.; Literature Search: L.C., K.G., P.V., E.A.; Writing: L.C., K.G., P.V., E.A.

Conflict of Interest: No conflict of interest declared by the authors.

Financial Disclosure: The authors declare that this study received no financial disclosure.