SUBMITTED 29 DEC 21 1 REVISION REQ. 15 FEB 22; REVISIONS RECD. 27 FEB 22 2 ACCEPTED 23 MAR 22 3 ONLINE-FIRST: APRIL 2022 4 DOI: https://doi.org/10.18295/squmj.4.2022.030 5 6 Idiopathic Granulomatous Mastitis 7 A six-years’ experience and the current evidence in literature 8 *Mahmood M. Al Awfi1 and Salim K. Al Rahbi2 9 10 1Department of General Surgery, Oman Medical Specialty Board, Muscat, Oman; 2Department 11 of Surgery, The Royal Hospital, Muscat, Oman 12 *Corresponding Author’s e-mail: mahmood.alawfi@gmail.com 13 14 15 Abstract 16 Objective: This study aims to retrospectively describe the clinicopathological pattern and 17 management experience of idiopathic granulomatous mastitis in women attending care at royal 18 hospital, a tertiary care center at sultanate of Oman. Then to compare our experience with the 19 current literature trends. Methods: The data of patient were retrospective reviewed from 1st of 20 January 2012 to 31st of December 2017, after receiving ethical approval from the center of studies 21 and research. Results: Sixty-four patients were conformed to have idiopathic granulomatous 22 mastitis. All of our patients were in the premenopausal phase with only one being nulliparous. 23 Mastitis was the most common clinical diagnosis and half of them had a palpable mass. Most of 24 our patient had received antibiotics during their treatment span. Drainage procedure was done in 25 73% of the patient, whereas excisional procedure was done for 38.7%. Only 52.4% of our patient 26 were able to achieve complete clinical resolution within 6 months of follow-up. Conclusion: There 27 is no standardized management algorithm, due to the paucity of high-level evidence comparing 28 different modalities. However, Steroids, Methotrexate and surgery are all considered to be 29 effective and acceptable treatments. Moreover, current literature tends towards multi-modality 30 treatments planned tailed case-to-case based on the clinical context and patient’s preference. 31 Keywords: Granulomatous; Mastitis; Chronic breast infection. 32 33 Advancement in knowledge 34 The clinicopathological characteristics of Omani women’s care similar to the international 35 community. 36 Multi-modality management of idiopathic granulomatous mastitis tend to have the best 37 clinical outcome. 38 Application to Patient Care 39 Immunosuppressive therapy is important to ensure low-rate reoccurrence. 40 Management plan should be tailored case-by-case, given the pros and cons of each 41 treatment modality, according to patients’ need and expectations. 42 43 Introduction 44 Granulomatous mastitis is a relatively uncommon category of inflammatory breast conditions. 45 Granuloma based inflammation is the defining character of this inflammatory process. This entity 46 can be further classified as specific or idiopathic (1). Specific granulomatous mastitis is 47 subcategorized as per the causative process to the granulomatous inflammatory reaction, which 48 could be Infections, autoimmunity or duct ectasis (2). Whereas, if no cause was identified, then it 49 is considered as idiopathic granulomatous mastitis (IGM). 50 51 Kessler and Wolloch were the first to set the bases of this diagnostic entity in 1972 through 52 reporting a series of five cases (3). This condition tends to mimic inflammatory breast cancer and 53 infectious breast conditions in the clinical presentation. Hence, IGM is a diagnosis of exclusion 54 and histopathology examination is the gold standard to conform the diagnosis. IGM represent 1.8% 55 of all benign breast conditions biopsied (4). This condition was found to predominantly occur in 56 childbearing age women. Pregnancy and lactation history were noted in majority to proceed the 57 occurrence of IGM (5). 58 59 Idiopathic granulomatous mastitis is an evolved term to declare the enigma behind its real etiology. 60 However, there have been some cases reported IGM patients with common autoimmune clinical 61 manifestation such as erythema nodosum and arthritis (6). However, Altintoprak F and colleagues 62 observed no association between IGM patients and autoantibodies (7). Accordingly, those reported 63 autoimmune related clinical manifestation could be attributed to another undiagnosed condition. 64 Otherwise, the granulomatous mastitis is just the first manifestation of autoimmune condition yet 65 to flare completely (8). 66 67 Etiology guided management is the standard of treatment for specific type granulomatous mastitis. 68 Whereas, the idiopathic type treatment is controversial. However, immunosuppressive treatment 69 has lately merged to be the mainstay of treatment. The role of surgical management is debatable. 70 Yet, it is a vital option as solo or combination therapy tailored to case base (9). 71 72 The aim of this study is to retrospectively describe the clinicopathological pattern and management 73 experience of idiopathic granulomatous mastitis in women attending care at royal hospital, a 74 tertiary care center at sultanate of Oman. 75 76 Methods 77 Patient records were retrospectively reviewed from 1st of January 2012 to 31st of December 2017, 78 after receiving ethical approval from the center of studies and research. Data collected included, 79 demographic data, past medical history, obstetric and gynecological history, clinical manifestation 80 history, radiological findings, microbiological findings, medical and surgical treatment along with 81 the treatment outcome. 82 83 Data were obtained from patient medical records system, plus from phone calls to complete 84 missing history related information. EpiData software v4.4.2.1 was used for data entry and SPSS 85 statistics software v25 used for statistical analysis. Categorical variables were expressed in 86 percentages whereas, continuous variables were expressed in mean with its’ standard deviation. 87 88 Results 89 Our search reviled a total of 65 patients with histopathological diagnosis of granulomatous 90 mastitis. One case was excluded from the analysis as granulomatous mastitis was due to 91 mycobacterium tuberculosis infection. The remaining 64 patients were conformed to be idiopathic 92 granulomatous mastitis by exclusion. 96.8% of the woman responded to the phone calls inquiry 93 form. The mean age of our population was 35.56 ± 6.75 years old. 95.3% of patients were Omani’s. 94 The regional distribution of our patients was as follow, Al Bitanah 40.6%, Muscat 28.1%, Al 95 Sharqiyah & Al Dakhilia 10.9%, Al Dhahirah 6.3%, Al Buraimi & Dhofar 1.6%. 96 97 None of our patients had previous history of tuberculosis infection. Only one patient had a resolved 98 past diagnosis of autoimmune condition, which was reactive arthritis. Diabetes mellites was found 99 in 10.9% of the patients. There was no history of smoking among our patients but 22% gave history 100 of 2nd hand smoking. All of the woman was premenopausal, 10.9% were pregnant and 31.3% were 101 lactating at time of presentation. Only one woman was nulliparous. The median number of parities 102 was four. History of abortion was present in 45.2% and still birth in 6.5%. Seventy six percent 103 have breastfed their children. Hormonal contraceptive was used by 51.7% of woman (Table 1). 104 105 The mean time to diagnosis was 11.44±22.99 weeks. The most common clinical presentation was 106 mastitis. All of our patient had a single breast affected and almost equally distributed between each 107 side. Half of our patients had a mass clinically and radiologically (Table 2). About two thirds had 108 a surgical biopsy during a surgical intervention. Bacteriology testing done and only 10.9% had a 109 concomitated bacterial infection. Methicillin-sensitive Staphylococcus aureus was the most 110 common isolated organism. Gram-negative organisms were isolated in two cases only which were 111 klebsiella pneumoniae and proteus mirabilis. Antibiotics were used in 93.8% of our patients, 112 whereas only 15.6% were treated with steroids. Severe inflammation was treated with 60 113 milligrams once per day of prednisolone for a week then gradually tapered as per patient response 114 and tolerance. It would be stopped once patient reach clinical resolution or could not tolerate the 115 treatment. While, mild to moderate inflammation the starting dose was 20 milligram once per day 116 of prednisolone. Severity assessment was subjective to the treating surgeon. Drainage was done to 117 73% patients. One third of patients had an excisional procedure (Table 3). 118 119 Twenty-two patients have lost follow up during the first 6 months. Out of 42 patients, 52.4% 120 showed complete resolution, 23.8 % had partial resolution and 23.8% had persistence of disease. 121 122 Discussion 123 Granulomatous mastitis is an infrequent diagnosis reached by exclusion of other more common 124 breast condition with similar clinical manifestation. To diagnose a patient with idiopathic 125 granulomatous mastitis, every effort should be made to exclude known cause of granulomatous 126 infection, as treatment will depend on it. Moreover, till date the trigger of this granulomatous 127 inflammation in this subset of patient population is unknown. 128 129 Granulomatous inflammation is a chronic inflammatory process due to ongoing cellular injury 130 from a trigger, leading to granuloma formation with macrophages and multinucleated giant cells 131 being the predominant inflammatory cells (10). This pathohistological features explain the natural 132 presentation of the disease as chronic, recurrent and remittent infection. Plus, they tend to present 133 with breast inflammation or mass or the combination of both. 134 135 IGM affects the premenopausal childbearing woman. This was noticed in almost all studies as well 136 in our cohort. The reason behind it is not clear yet, but those women breast features and cyclic 137 changes are unique and defiantly has a vital environmental role for disease onset. Furthermore, it 138 rarely affects the nulliparous woman. Most studies reported the disease inception was few years 139 after pregnancy, but there were few cases where disease onset was during pregnancy or lactation 140 period (4-5). There were few reported cases where non-gestational/non-lactational related 141 hyperprolactinemia were responsible for the IGM which have resolved after normalization of 142 prolactin level (11). This all suggest that a full mature breast is the best medium of disease onset 143 and elevation of prolactin level have a triggering role. 144 145 Diabetes mellitus have not been reported to have any association between it and the occurrence of 146 IGM. Instead, the presence of diabetes should stimulate the physician to rule out diabetic 147 mastopathy, which is an important differential diagnosis of specific granulomatous mastitis to 148 exclude (12). Autoimmunity features and Autoantibodies are found is some patients with IGM 149 occasionally as stated earlier, therefore excluding autoimmune disease is essential (6-8). 150 Additionally, autoimmune disease is known to occur more in childbearing age women and that 151 abortions and still births are known to be of frequent occurrence in them (13). Furthermore, we 152 found in our IGM cohort to have a significate percentage of overall fetal loss reaching to 51.6%. 153 Looking at the similarities between IGM patient and autoimmune disease patient, give the 154 indication that IGM probably is a disease under the same umbrella that is yet not well understood. 155 156 There is no known association between breastfeeding, oral contraceptive use, smoking and IGM. 157 Our cohort similar rate of breastfeeding compared to other studies but a higher percentage of oral 158 contraceptive than other studies, which could be due to culture different preference only (4-5, 7). 159 Most patients tend to present with mastitis with or without abscess as seen in our cohort. Moreover, 160 they are diagnosed late because of significant overlap with acute bacterial mastitis. 161 162 The radiological findings of IGM patient are non-specific with wide range of findings. On 163 ultrasonography, the breast tends to have an altered echotexture with the presence of a single or 164 multiple hypoechoic mass with single or multiple collections. In our cohort abscess was found 165 more commonly than a mass. In mammography, abnormal asymmetrical density is the most 166 common finding (14). 167 168 The usual microbiological work-up for granulomatous mastitis is to rule out fungal infection and 169 tuberculosis infection, because those are the most common infections causing granulomatous 170 reaction. Recent data is recommending routine testing to rule out Corynebacterium infections as 171 well due its association with special type of recurrent granulomatous mastitis called, cystic 172 neutrophilic granulomatous mastitis (CNGM). This recommendation was based on the fact that, 173 those types of infections require special antibiotics ragmen for longer duration. This type of 174 organisms is difficult to be detect, whoever new technology made it easy, using 16S RNA 175 sequencing and matrix-assisted laser desorption ionization–time of flight mass spectrometry 176 (MALDI-TOF MS) (15). Once those cultures came to be negative then IGM diagnosis can be 177 established, however it’s not uncommon to have a secondary bacterial infection (5). We have also 178 demonstrated secondary bacterial infection and it was noted to be more common during the follow 179 up period. For that reason, bacterial cultures are needed on first encounter at every relapse as well, 180 in order to treat as well. 181 182 IGM diagnosis is a difficult to reach, as a result most of patient on their first encounter are treated 183 with antibiotics plus aspiration or surgical drainage. Only when the patient does not respond to 184 treatment or has reoccurrence, this diagnostic entity is thought off. This is clearly noted in our 185 cohort, as 93.8% received antibiotic and 73% had drainage procedure. 186 187 However, the current literature is supporting the use of immunosuppression for the treatment of 188 IGM, such as corticosteroid or other immunomodulatory such as methotrexate (16-17). Pandey et 189 al (16), have reported 80% of patients had complete resolution on systemic steroids only. 190 Additionally, Montazer et al (18), have reported in a small randomized clinical trial that high dose 191 steroids have achieved 93.3% remission rate with 0% reoccurrence within 12 months follow-up 192 period. Interestingly, Tang et al (19) have also reported the effectiveness of Intralesional steroid 193 injection. Steroid’s effectiveness was also demonstrated in another randomized clinical trial by 194 Çetin et al (20) to be above 80% with reoccurrence rate of near 20%. They have demonstrated in 195 their trial that topical steroids are as effective as systemic steroids in terms of response rate, but 196 with prolonged recovery period and lesser side effect profile. 197 198 Non-steroidal immunosuppressive/steroid-sparing therapy have emerged to overcome the 199 systemic steroids side-effect from prolonged use. Of those group, methotrexate so far have proven 200 efficacy as monotherapy and as combination therapy. As monotherapy, Papila Kundaktepe et al 201 (17), reported a complete recovery rate of 81.25%, which similar to the reported rates of steroidal 202 treatment, with low acceptable side-effect profile compared to steroid. Furthermore, Kehribar et 203 al (21), have demonstrated a remission rate of 87.9% with combination therapy of steroids and 204 methotrexate with zero relapse during 24-months follow-up period. Unfortunately, in our cohort 205 the use of immunosuppressive medications was decimal because it was only recently introduced 206 to the unit and this could explain the poor remission rates. 207 208 On the other hand, surgical treatment is also an effective method to reach remission. Zhou et al 209 (22), have demonstrated in their systematic review of 10 studies (1101 patients), that there is no 210 significant difference between non-surgical (includes; oral steroids, MTX, antibiotics, and 211 observation and surgical (includes; excisional and drainage procedures) when comparing 212 remission and relapse rates. Nevertheless, Lei et al (23), reported in their meta-analysis of 15 213 studies that surgical treatment (excisional & drainage) had the highest complete remission rate and 214 the lowest reoccurrence rate. Ma et al (24), is another recent systematic review and meta-analysis 215 of 21 publications, that reported surgical treatment is superior to non-surgical management. 216 Though, to reach to this high remission rate with low reoccurrence rate in surgical management, 217 the patient would have to go for an excisional procedure with negative surgical margin for active 218 disease (25). This will lead to large breast tissue volume loss with large surgical scar, which would 219 be considered disfiguring in some cases. Thus, excisional procedures should be left for cases failed 220 medical management, not willing for medical management or patients asking for a quick fix. In 221 our cohort, 38.7% had excisional procedure. 222 223 Fascinatingly, there are studies that have demonstrated that IGM is self-limiting and can be 224 observed only without treatment. Bouton et al (26), have reported the largest cohort of patients 225 subjected to observation only, where 72% of patients achieved remission during an average time 226 of 7.4 months, with 11% reoccurrence rate. Those outcomes are comparable to some studies 227 outcome from the use of steroids. 228 229 Those are the reasons why the treatment is still not standardized. Therefore, patient is best treated 230 with multimodality treatment and those treatments are selected patient-to-patient base (27). For 231 this reasons, latest publications have looked into multi-modality treatments. For example, Wang 232 J., and colleagues have reported best clinical outcome in patients treated with surgery after steroid 233 therapy (28). Akcan et al (29), is another example, where they have reported superiority of wide 234 local excision after steroidal therapy when compared to surgery alone. Likewise, Godazandeh G, 235 and colleagues have reported in their recent systematic review and meta-analysis, that steroids with 236 surgery is superior to steroids alone (30). The combination therapy dose not only improve the 237 remission rate and reduce the reoccurrence rate, but they also reduce the breast tissue volume loss 238 and the surgical scar. 239 240 Conclusion 241 Triple breast assessment is a necessity in all patients with breast complain in order not to miss or 242 delay a diagnosis of cancer or a chronic breast inflammatory disorder. Moreover, recurrent breast 243 inflammation with or without mass should raise the suspicion of granulomatous mastitis and 244 comprehensive work-up is essential. Once the diagnosis of idiopathic granulomatous mastitis has 245 been established and other differential diagnoses were ruled out, an agreed multi-modality 246 treatment plan should be commenced according to patient needs and preference. 247 248 Authors’ Contribution 249 MMA and SKR conceptualized and designed the study. MMA collected the data and drafted the 250 manuscript. MMA and SKR edited and revised the manuscript. Both authors approved the final 251 version of the manuscript. 252 253 Conflict of Interest 254 The authors declare no conflicts of interest. 255 256 Funding 257 No funding was received for this study. 258 259 Reference 260 1. Binesh F, Kargar S, Zahir ST, Behniafard N, Navabi H, et al. (2014) Idiopathic 261 Granulomatous Mastitis, a Clinicopathological Review of 22 Cases. J Clin Exp Pathol 4: 262 157. 263 2. Altintoprak F, Kivilcim T, Ozkan OV. Aetiology of idiopathic granulomatous mastitis. 264 World J Clin Cases. 2014 Dec 16; 2(12):852-8. 265 3. 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Surg Today. 2021 Feb 15. 341 342 Table 1: Demographic and baseline characteristics of our IGM patients 343 Patient’s characteristics n (%) or Mean ± SD Age at diagnosis in years 35.56 ± 6.75 Omani nationality 61 (95.3%) Diabetes mellitus 7 (10.9%) Autoimmune disease 1 (1.6%) History of tuberculosis 0 (0%) History of 1st hand smoking 0 (0%) History of 2nd had smoking 13 (22%) History of abortion 28 (45.2%) History of stillbirth 4 (6.5%) Use of hormonal contraceptive 31 (51.7%) Hormonal treatment 3 (5.1%) Breastfeeding 48 (76.2%) Infertility treatment 7 (11.9%) Premenopausal 64 (100%) Time to diagnosis in weeks 11.44 ± 22.99 Pregnancy at presentation 7 (10.9%) Lactate at presentation 20 (31.3%) 344 Table 2: Clinical and radiological characteristics of our IGM patients 345 Patient’s characteristics n (%) or Mean ± SD Breast affected Left breast 31 (48.4%) Right breast 33 (51.6%) Clinical examination Mastitis 46 (71.9%) Abscess 29 (45.3%) Mass 44 (68.8%) Ultrasonography* Mastitis 42 (85.7%) Abscess 31 (63.3%) Mass 28 (56.0%) *14 patients had missing data 346 347 Table 3: Diagnostic work-up and management of our IGM patients 348 Patient’s characteristics n (%) or Mean ± SD Type of biopsy Core needle 25 (39.1%) Surgical 39 (60.9%) Positive bacterial Culture* First culture 5 (10.9%) During follow-up 11 (23.4%) Medical Management Antibiotics 60 (93.8%) Steroids 10 (15.6%) Surgical Management Drainage** 46 (73.0%) Excision*** 24 (38.7%) *18 patients had missing data; **1 patient had missing data; ***2 patients had missing data 349