Idiopathic granulomatous mastitis

Introduction

Idiopathic granulomatous mastitis (IGM) is a benign inflammatory breast condition first described in the literature in 1972 (1). Also referred to as idiopathic granulomatous lobular mastitis, it is a rare and chronic condition characterized by relapsing sterile, draining breast abscesses. IGM is challenging clinically, as it mimics the presentation of a bacterial abscess or breast cancer. Often, the diagnosis of IGM is given when all other differential diagnoses are excluded. IGM usually presents in premenopausal women who were recently pregnant or lactating (2-4). It can occur in any race but does have a higher incidence in Hispanics (3,5-7) and people of Mediterranean descent (8).

Despite being present in the literature for the last fifty years, many things are still unknown about this complex, inflammatory disease. First, the etiology remains unclear despite many research studies investigating this disease. Many hypotheses exist for the exact mechanism of action, but an amplified autoimmune response is considered one of the top theories (1,9). Second, the gold-standard treatment modality for this disease remains highly debated within the literature with no clear consensus on the recommended treatment. The recommended treatments range from observation, steroids, methotrexate, surgical excision, and unique combinations of these treatment approaches (10). In this review, we aim to provide a clear overview of IGM as well as analyze the common treatment modalities highlighted in the literature.

Methods

A PubMed search was used to identify all articles regarding the diagnosis and treatment of IGM. A total of 616 articles from the time frame of 1972 to June 2020 were identified utilizing the search term of “granulomatous mastitis”. Each article was analyzed for the main finding of the study as well as the recurrence rate. Few articles were prospective randomized trials and many were retrospective analyses or case studies identifying the success of various treatment regimens. All pertinent articles are included online: https://cdn.amegroups.cn/static/public/ABS-2020-BBD-03-supplementary.xlsx. Institutional review board approval was not obtained since only published studies were analyzed for this review article.

A summarized version of the appendix is included in this paper (Table 1) which highlights the type of study performed, number of subjects included, which treatment modalities were compared, recurrence rates as well as findings and recommendations. Table 1 was created from the appendix by first identifying the different treatment modalities and then identifying how many published articles, in the conclusion of the manuscript, supported that treatment modality. Manuscripts supporting the various treatments were grouped together. Treatment groups that contained less than ten publications had every article included in the table. If a treatment group had more than ten published studies, then the articles were selectively chosen to be added to Table 1 if they (I) had a sample size larger than 20 subjects and (II) contributed to the field through multiple citations, robust data, supported conclusions and low recurrence rates. With the presented conflicting arguments of each treatment modality highlighted, this review will give treatment guidelines for clinicians as well as a simplified management algorithm.

Review results

Diagnosis

Presentation

IGM presents clinically as a palpable breast lesion(s) (Figure 1) that vary in size from 1–5 cm, with an array of other symptoms such as tenderness, overlying skin induration, erythema, sinus tract formation, or breast edema which can clinically mimic a breast abscess or breast cancer on various imaging modalities (1,3,30-32,54-56). IGM commonly presents unilaterally (3) in the upper outer quadrant of the breast (3,4,31), but can be found in any quadrant as well as in both breasts concurrently (27). The palpable, erythematous breast lesion(s) are sterile abscesses often accompanied by the development of spontaneous fistulae or sinus formation.

Figure 1 Clinical presentation of IGM in two separate patients.

Inflammation of Cooper’s ligaments can occur, causing nipple inversion or retraction (9). In 13% to 40% of women, enlarged, palpable reactive lymph nodes are noted on exam (3,4,56). Systemic symptoms, such as a fever, are generally absent from the objective findings (8). An essential component of this challenging disease is recognizing the complex presentation to avoid unnecessary surgical interventions and excessive antibiotics. Clinicians diagnose IGM when all other differential diagnoses are excluded, and specific pathologic findings on core needle biopsy are present.

Imaging

In addition to the clinical symptoms mimicking other diseases, the imaging can also present ambiguously. Mammography findings can include an ill-defined density with speculated margins along with associated overlying skin thickening (Figure 2) (56,57). On ultrasound, IGM displays abscess formation with tubular extensions or hypoechoic mass (Figure 3A), with or without enlarged lymph nodes (Figure 3B) with mild concentric cortical thickening (3,56,57). Magnetic Resonance Imaging (MRI) shows IGM as one or many masses with a ring or nodular enhancement (Figure 4) (57). Since IGM is a chronic disease that needs monitoring for a significant amount of time, MRI’s can help evaluate the extent of the disease at presentation as well as monitor progression following the reduction and resolution of lesions with time (9).

Figure 2 Mammography imaging demonstrates asymmetric densities mimicking breast carcinoma and enlarged lymph node.

Figure 3 Ultrasound images of IGM. (A) Ultrasound findings of breast parenchyma with ill-defined abscess cavities and (B) ultrasound findings of IGM showcase enlarged axillary lymph node with eccentric cortical thickening.

Figure 4 MRI with nodular ring enhancement of the IGM areas in the left breast.

Biopsies

IGM is confirmed with specific histopathological findings obtained from a core needle biopsy of the abscess wall. The hallmark pathological finding of IGM is the presence of multinucleated giant cells, plasma cells, polymorphonuclear leukocytes, lymphocytes, and occasionally sterile microabscesses (Figure 5) (3,4,31,56,58). A core needle biopsy is preferred over an excisional biopsy or fine-needle aspiration (FNA) because it completely characterizes the lesion, is less disfiguring and rules out malignancy (31). If an abscess is present, drainage should occur by FNA and cultures should be obtained to rule out any infectious etiology such as aerobes, anaerobes, fungal infection (periodic acid-Schiff), as well as microorganisms such as Corynebacterium (Gram stain), or acid-fast bacilli (Zeihl-Neelsen) (3,59). Other plausible pathogens should be ruled out at this time including mycobacterial, parasitic, or mycotic origins (1,9,27). Tuberculosis mastitis should also be eliminated from the differential diagnosis through a purified protein derivative (PPD) serum test, skin test, or chest x-ray in addition to the tissue staining for the acid-fast bacilli. Autoimmune etiologies like sarcoidosis or foreign material should be excluded through blood work examining antinuclear antibody (ANA), rheumatoid factor, C-reactive protein, and alpha-I-antitrypsin (1,9,27).

Figure 5 Photomicrograph of tissue specimen shows granulomatous inflammation with non-caseating granulomas and multinucleated giant cells (H and E, ×20).

Etiology

The etiology of IGM remains unclear, although a correlation is well documented with recently pregnant or lactating women (51). Many studies support the hypothesis of an autoimmune component (1,9). Other theories suggest an association of hormonal imbalance, oral contraceptives (31), smoking (60), corynebacterium (28), unknown microbiological agents (8), and α1-antitrypsin deficiency (8) whereas other studies have refuted these associations (8,30). It is speculated that the pathology is from local trauma or changes to the ductal epithelium allowing for luminal secretions to be present in the lobular connective tissue, therefore causing lymphocyte and macrophage migration, triggering a granulomatous response within the breast (9). Further research is needed to isolate the exact mechanism of IGM, which would allow for a more personalized treatment approach.

Treatment

Currently, no standardized treatment for IGM exists. Treatments are decided through analyzing each patient’s presentation, the severity of the symptoms, the size of the lesions, the overall health of the patient as well as the surgeon’s preferred treatment method. Many treatment algorithms are present throughout the literature, but none have been widely accepted (3,4,27,31,54,55,61). Although a benign disease, effective treatment is necessary to manage the symptoms and prevent the recurrence of the disease. Recurrence and relapse rates for IGM have varied from 20–50% (3,57,62) causing stress for the patient and the treating physician. Importantly and reassuringly, IGM is a self-limiting disease resolving within 2 to 24 months of onset, regardless of the treatment modality used (4,57). A variety of treatment methods have been utilized to relieve the patient’s chief complaints such as observation, various forms of steroids, immune modulators and surgical excision. This review will outline each treatment method and give an algorithm up-to-date with the current research. An extensive literature review of IGM treatment modalities is presented (Table 1).

Antibiotics and pain management

Since IGM is a disease of exclusion, it is essential upon presentation to rule out any infectious agents while beginning a workup, as bacterial abscesses are more common. Therefore, a bacterial etiology must be before diagnosing IGM. All abscesses should be aspirated or drained followed by broad-spectrum antibiotics during the period of diagnostic evaluation. Acceptable antibiotics include sulfamethoxazole and trimethoprim, amoxicillin/clavulanate (4), doxycycline (48) as well as metronidazole.

For symptomatic pain relief, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil) and celecoxib (Celebrex) are the drugs of choice to help with the inflammatory pain that corresponds to the IGM masses (3). Opiates are rarely required for this level of pain management (3).

Observation

IGM is known to be self-limiting; therefore a more conservative treatment method used is observation of the abscesses with regular clinic examinations (14). Many patients present with an array of symptoms and abscess sizes, but if the symptoms are mild to painless along with small lesions, observation may be the first line of treatment, as it will self-resolve (5,11-13,15). Patients need to be reassured that IGM does resolve, but the time to resolution can average 5 months (15). Once the diagnosis of IGM is confirmed, and infections etiology including Corynebacterium is ruled out, patients do not necessarily need to maintain on long-term antibiotics. However, physicians also need to follow patients during observation to ensure no signs of other opportunistic bacterial infection occur due to the open skin areas.

Surgical treatment

Surgical treatment methods vary from abscess drainage, wide surgical excision, and mastectomy. Although the literature has demonstrated that wide surgical excision has been successful (4,14,16,17,20,30,31,53,63), recurrence rates range from 0% to 50% (16,30,64). When completing a wide excision, the goal is a complete removal of the questionable area including fistula tract, affected skin, with a lesion free margin ranging from 5 to 10 mm (3,30).

Much debate still exists about the benefits of surgical excision. Since newer treatment methods have evolved within the last ten years, the utilization of surgical intervention as a first-line therapy has reduced (5,13,28,29). If the patient has a single small lesion, surgical excision could be considered but high recurrence rates are likely. Additionally, there are side effects to surgical excision such as poor cosmetic results, extensive scarring, as well as delays in both would healing and fistula formation (28,32,33). Although mastectomy in severe cases has been described, so has recurrence after mastectomy, so this approach is not optimal.

Steroids

The utilization of steroids for IGM was first published in 1980 (65) and remains today the first-line treatment. Steroids are administered in three different ways: oral, topical, or injections.

Oral steroids are still commonly used and have documented success rates up to 80% (22), but still have the chance for relapse. The prescribed range for IGM is 10–60 mg/day of prednisone or 30–60 mg/day of prednisolone (27) with a gradual taper over the following weeks to months (30). Additional treatment options include 16 mg prednisolone twice a day for two weeks (36) or 1 mg/kg of prednisolone for three weeks (3). Unfortunately, the high rates of IGM resolution with use of oral steroids come at a price: systemic side effects. The side effects range from glucose intolerance and insomnia to cushingoid features. In addition, patients can potentially relapse when discontinuing treatment a few months later (3), however an extra course of steroids can be prescribed when that occurs.

Clinicians prescribe topical steroids as a popular alternative to oral steroids due to having less systemic side effects. Case reports all show positive results and endorse the usage of topical steroids (23,36-38). The pharmacological agent of choice is prednisolone ointment (0.125%) twice a day for 1–3 months (23,36). The recurrence rates for topical steroid use range from 10–18% (23,36-38). In a study published by Cetin et al., the steroid administration routes of topical, systemic, and topical plus systemic steroids were examined and topical steroids had the best results with the lowest recurrence rate of 14.7% (23).

Steroid injections directly into the IGM lesions are the newest advancements in the treatment of IGM and given the reported effectiveness and decreased recurrence rates (39-42), should be considered as the first-line therapy for any newly presenting IGM patient. Steroid injections are based on the well-established techniques for treating arthritic diseases. Steroid injections for IGM were first described in 2012 with a small sample size, but a very low recurrence rate (42). Many newer studies have reported no recurrences with steroid injections along with a faster resolution time compared to other treatment modalities (39-42). The prescribed dose is Kenalog-40 (triamcinolone 40 mg/mL) ranging in volume from 2–4 mL (80–160 mg) mixed with lidocaine as a local anesthetic (39). The injection into the IGM lesion(s) is completed under ultrasound guidance and repeated every 1–2 weeks until resolution. A potential complication of this treatment modality is skin atrophy (39), but otherwise it holds a great deal of promise as a minimally invasive first-line treatment approach.

Immune modulators

Methotrexate (MTX), an immunosuppressive agent, has also been successful in the treatment of IGM. This method is an alternate therapeutic option for any patient who is unresponsive to steroid therapy (3,49). MTX can be given with other treatment modalities such as steroids (25), but a recent study has shown promising effects of this treatment modality on its own demonstrating that by 15 months of treatment, 94% of patients had disease improvement along with 75% achieving remission (50). The pharmacological dosing for MTX is 10–15 mg/week and increasing to 20–25 mg/week given either orally or subcutaneously based on clinical response (50). Reported adverse effects range from elevated liver enzymes and hair loss to more mild symptoms such as nausea, decreased appetite, and mild headaches (41,50).

In the situation where the IGM lesions are not responding (or progressing) and MTX is being considered, consultation to rheumatology and infectious disease is recommended.

Studies comparing different treatment modalities

A comprehensive search was conducted over all the published literature for IGM examining the many detailed treatment studies. A comprehensive table (Table 1) is provided of the most significant treatment studies along with all comparative studies to date (full review: https://cdn.amegroups.cn/static/public/ABS-2020-BBD-03-supplementary.xlsx). Based on review of these comparisons, a flow sheet reviewing work-up and management options has been complied as a reference (Figure 6).

Figure 6 Diagnosis and treatment algorithm for idiopathic granulomatous mastitis.

Discussion

Many significant advancements in the treatment modalities for IGM have occurred within the last ten years. Still, randomized controlled trials are needed to determine which treatment modality is superior. Promising studies exist for each treatment modality, but an accurate conclusion about the best treatment modality cannot be drawn without a randomized control trial. As highlighted in the spreadsheet of treatment studies (Table 1), the recurrence rates for steroid injections into the abscess cavity are remarkably low in the published literature. Due to these low rates, steroid injections hold great promise and; therefore, we recommend it as the preferred treatment modality due to the high success, minimal systemic side effects and low recurrence rates.

Our comprehensive treatment algorithm (Figure 6) serves to provide a road map for any clinician to diagnose and treat IGM successfully. A thorough workup is critical to exclude all other differential diagnoses to detect IGM accurately. From our literature review, a comprehensive treatment plan is presented to help guide any clinician who encounters IGM in their clinic. Patients presenting with a mass suspicious for IGM should have diagnostic imaging. If an abscess is present, aspiration should be performed, sent for cultures and prophylactic antibiotics initiated. If the abscess cultures are sterile or there is a mass on imaging, a core biopsy should be performed to obtain a tissue diagnosis to confirm IGM. Based on the literature review, the authors recommend observation as the first line treatment with attention to symptom management. This includes non-steroidal anti-inflammatory medication for the pain and topic steroids to the affected area. If the symptoms worsen, use of injectable steroids into the abscess cavity can facility resolution of the breast abscesses. If no improvement or a large area of the breast is involved, oral steroids can be utilized. In refractory cases, methotrexate can be used. Surgical excision should be used sparingly, with mastectomy as a very last resort.

Acknowledgments

Pathology photo Figure 5 courtesy of Dr. J. Jordi Rowe, Department of Pathology, Cleveland Clinic.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Katharine Yao) for the series “A Practical Guide to Management of Benign Breast Disease” published Annals of Breast Surgery. The article has undergone external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form, available at: http://dx.doi.org/10.21037/abs-20-89. The series “A Practical Guide to Management of Benign Breast Disease” was commissioned by the editorial office without any funding or sponsorship. Both authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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