As we known, Corynebacterium kroppenstedtii was an unusual member of the genus Corynebacterium first described in 1998 as it lacks the characteristic mycolic acids in the cell envelope [18,30-32]. The C. kroppenstedtii type strain has revealed a lipophilic (lipid-requiring) lifestyle and a remarkable repertoire of carbohydrate uptake and utilization systems [3,18,30,33]. Breasts are made of fat and glands, and full of lipid. Sue Paviour et al found that Corynebacteria were isolated from breast tissue, pus, or deep wound swabs of 24 women; the most common species isolated was the newly described Corynebacterium kroppenstedtii [12]. The rich lipid environment of the breast is conducive to the growth and reproduction of C. kroppenstedtii [34-36]. Thus, the breast is a favourable condition for the development of lipophilic corynebacterial. Moreover, P. Kieffer et al thought that mammary areas rich in lipids or malformations such as ductal ectasia can be a factor favoring the development of GM [15]. Therefore, lipid-rich breast tissue provides the perfect habitat for C. kroppenstedtii to reside and form granulomas and abscesses [37]. According to recent studies, more and more evidences have confirmed that GM is closely related to C. kroppenstedtii. Yu HJ et al confirmed that the predominance of Corynebacterium kroppenstedtii infection in GM patients (11 of 19 patients, 57.9%) with Sanger sequencing and the qPCR assay [13]. Tariq et al found that C kroppenstedtii 16S rRNA real-time polymerase chain reaction was positive on formalin-fixed, paraffin-embedded tissues from 46 of 67 (68.7%) GM cases [38]. Li XQ et al achieved a detection rate of C. kroppenstedtii up to 56% in nanopore sequencing method [39]. And in our study, using MALDI-TOF MS, Corynebacterium kroppenstedtii was confirmed in more than 50% of patients as well.
From our study, 61.7% patients in CK group form sinus, compared to negative group, patients in CK group seems to be more likely to form sinus, which means that sinus formation is more common in granulomatous mastitis with Corynebacterium kroppenstedtii in our study than those with no evidence of bacteria. Taylor et al conducted a research on the case group (34 patients with Corynebacterium spp.) versus the control group (28 patients with no evidence of Corynebacteria) and found that the formation of draining sinuses was the statistically significant differences between the two group and was more frequent in the case group [1]. Bi JX et al found 16 of 25 (64.00%) patients diagnosed as GM in their study were accompanied by skin ulceration and pus, and 9 of them (56.25%) accompanied by skin ulceration had the pathogen of C. kroppenstedtii [34]. Corynebacterium kroppenstedtii preferred to grow and proliferate in lipid-rich areas of breast including the subcutaneous, firstly forming small and scattered localized abscesses, then gradually expanding and infiltrating the subcutaneous and forming sinuses. Thus, it is much easier to form sinus for GM with Corynebacterium kroppenstedtii infection.
Except for sinus formation, we also found that recurrence may be associated with Corynebacterium kroppenstedtii. In our study, a total of 52 patients (25.9%) suffered from recurrence, and among them, 35 patients were found to be positive with Corynebacterium kroppenstedtii. In the literature, there is a recurrence rate of about 24.8% for GM whether Corynebacterium kroppenstedtii infection or not, as well [40]. Some studies also reported that presence of C. kroppenstedtii was significant prognosticators for recurrence [5,41]. Azizi A et al found that breast skin lesions were associated with a significantly higher odds of recurrence, but unfortunately, there was no further explore with Corynebacterium kroppenstedtii [40]. In conclusion, granulomatous mastitis accompanied by Corynebacterium kroppenstedtii is much easier to recur. Given the high rate of recurrence, close long-term follow-up must be emphasized [42].
According to the literature, the most common treatments used in C. kroppenstedtii breast infections are surgery, steroids, and antibiotics, but their individual and combined impact is unclear [2,37,43]. Besides, close observation might be the optional management for GM [43-45]. Godazandeh carried out a meta-analysis and reported that the combination of steroids and surgery was more effective than steroids only [46]. Additionally, most of Chinese experts agreed that corticosteroid combined surgery was used as the primary treatment for GM [47,48]. Methotrexate is a treatment option for patients who have relapsed or who do not tolerate high-dose corticosteroid therapy [29,49]. Surgery was performed depending on the individual clinical efficacy and the choice of surgical technique varied from wide excision to mastectomy even with TRAM flap in literature [29,42,50]. Hazel C. Dobinson et al considered that if granulomatous disease is present, it seems prudent to choose agents that are both active against Corynebacterium spp. and have physicochemical properties that would promote activity within the lipid-filled spaces. Preferred choices would include clarithromycin and rifampicin, which are also active in other granulomatous infections such as mycobacteria [2]. In our study, we tried multiple treatment strategies including surgery combined with antibiotics and immunosuppressants, surgery combined with immunosuppressants, surgery combined with antibiotics, immunosuppressants combined with antibiotics, immunosuppressants alone, antibiotics alone according to the individual clinical appraisal. Most of them underwent surgery combined with immunosuppressants, 30/107(28.0%) patients who accepted this treatment regimen suffered relapses, and patients with Corynebacterium kroppenstedtii had the higher rate of recurrence of 45%, but the rate of recurrence in those patients with Corynebacterium kroppenstedtii who treated with lipophilic antibiotics combined or alone was only 22% (11/50). Thus, lipophilic antibiotics may be essential for GM with Corynebacterium kroppenstedtii infection when formulating treatment protocol, but more evidences and prospective studies are needed.
Davis et al reported the average time to resolution was 5 months (range 0-20) on their 120 patients identified with GM [44]. And in our study, the median time to complete remission was 5.0 months as well, ranged from 1.0 to 24.0 months, and patients in CK group needed more time to achieve cure at their first treatment periods than those in negative group. But, as reported in the literature, surgery which could easily change the time of achieving cure at their first treatment periods was performed not only depending on clinicians’ judgements but also taking into account of patients’ wish [29]. And in our study, nearly 70% patients underwent surgery. Therefore, though the time to complete remission in our study made a difference, we still needed to be cautious. So as to the result of the diameter of mass on the first medical consultation in our study, because as we known, the mass of GM grew and spread rapidly [51], and the time of their first medical consultation after the initial presentation of the mass was not completely consistent as well.
As far as we know, this is the largest study in the literature discussing about the clinical characteristics and therapeutic strategy of granulomatous mastitis with Corynebacterium kroppenstedtii infection. However, we still have some limitations of the current study, first was its retrospective nature, and missing some data of partial patients about the lactating time. Second, except for surgery combined with immunosuppressants, patients treated with other protocols were too few, respectively. In brief, our findings should be interpreted prudently and validated in the future study.