Clinical characteristics and therapeutic strategy of Granulomatous mastitis accompanied by Corynebacterium kroppenstedtii —— a retrospective cohort study

DOI: https://doi.org/10.21203/rs.3.rs-2120478/v1

Abstract

Background: More and more evidences have suggested that Corynebacterium kroppenstedtii is associated with some cases of granulomatous mastitis, mostly based on pathology or microbiology. We aimed to find the clinical characteristics and treatment regimens for granulomatous mastitis with Corynebacterium kroppenstedtii infection. Understanding these clinical features is essential for patient care.

Methods: We retrospectively collected 201 patients who were diagnosed as granulomatous mastitis pathologically and had microbiological results either Corynebacterium kroppenstedtii or no bacterial growth, recorded and analyzed their demographics and clinical characteristics, clinical outcome.

Results: There were 107 patients in CK group, 94 patients in negative group. Sinus formation (x2=13.028, p=0.000), time to complete remission at the first treatment periods (Z=-3.027, p=0.002), diameter of breast mass at first-time medical consultancy (Z=-2.539, p=0.011) and recurrence (x2=4.953, p=0.026) were statistically significant. Age (Z=-1.046, p=0.295), laterality (x2=4.217, p=0.121), delivery way (x2=0.098, p=0.755), time to presentation since last delivery (x2=0.028, p=0.868), BMI (Z=-0.947, p=0.344), lactating time (Z=-1.378, p=0.168), parity (x2=1.799, p=0.180), gravida (Z=-0.144, p=0.885), history of lactational mastitis or abscess (x2=0.115, p=0.734), local trauma (x2=0.982, p=0.322), hyperprolactinemia (x2=0.706, p=0.401), erythema nodosum (x2=0.292, p=0.589), nipple discharge (x2=0.281, p=0.596) did not demonstrate a statistically significance. As to recurrence related to therapeutic strategy, except for surgery combined with immunosuppressants (x2=9.110, p=0.003) was statistically significant, none of the other treatment regimens reached statistical significance. Recurrence rate of patients in CK group using rifampicin in their treatment course was 22.0% (x2=4.892, p=0.027).

Conclusions: Granulomatous mastitis accompanied by Corynebacterium kroppenstedtii is easier to form sinus and has higher recurrence rate. Both of the clinical characteristics may prove Corynebacterium kroppenstedtii plays an important role in the development and progression of granulomatous mastitis. Lipophilic antibiotics may be essential for GM with Corynebacterium kroppenstedtii infection.

Background

Granulomatous mastitis (GM) is a rare inflammatory disease of the post-lactation breast, clinically mimicking breast cancer [15]. Recently, granulomatous mastitis is more and more popular in China [6]. Its clinical presentation can be variable, ranging from acute infective episodes such as abscess or mastitis to breast lump resembling malignancy [5, 7, 8]. Sometimes, erythema nodosum and arthritis occur as extramammary presentations of GM [9]. The etiology of GM is still unknown, and may be hormonal imbalance such as hyperprolactinemia, autoimmunity, microbiological agents, smoking, oral contraceptive pills, ethnicity, and α1-antitrypsin deficiency [7, 10, 11].

Recent studies have found that particular corynebacterium may be involved in the pathogenesis of some cases of GM [12]. Corynebacterium kroppenstedtii is a lipophilic Corynebacterium first described in 1998 after isolation from a sputum specimen [13]. In 2002, Corynebacterium kroppenstedtii (C. kroppenstedtii, CK) was first described in a retrospective case series of histologically proven granulomatous lobar mastitis in predominantly young Polynesian women, and accounted for 40% of isolates recovered from these patients [12]. Since then, Corynebacterium kroppenstedtii has been reported in multiple case reports and case series associating with granulomatous mastitis [1517], typically in young parous women [1820]. CK can be recognized by whole genome sequence, matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS), and 16S rRNA sequencing. And MALDI-TOF MS has largely supplanted gene sequencing due to the higher cost, greater technical complexity, and prolonged turnaround time associated with gene sequencing [21, 22]. Recently, there is increasing evidence of an association between corynebacteria infection and a distinct pattern termed cystic neutrophilic granulomatous mastitis, characterized by lipogranulomas consisting of clear spaces rimmed by neutrophils and surrounding granulomatous inflammation [2329]. But nearly all of these researches focused on pathological microorganisms, few studies analyzed the clinical features and the best treatment methods of granulomatous mastitis infected with Corynebacterium kroppenstedtii. So here, we retrospectively collected all patients who were pathologically diagnosed as granulomatous mastitis for the first time in our hospital from 2018 to 2021 and had microbiological results, in addition completed treatment plans and achieved cure which was defined as breast lesions completely disappeared with surgery or drugs at least one time. And their clinical signs, managements, clinical course, and clinical outcomes had been collected and analyzed.

Our study attempted to find out the clinical characteristics and the better therapeutic strategy of granulomatous mastitis with Corynebacterium kroppenstedtii infection, not only in order to deepen and complete the understanding of the clinical features of granulomatous mastitis with Corynebacterium kroppenstedtii infection in the literature, but also trying to provide direct and objective evidence of Corynebacterium kroppenstedtii in the development and progression of granulomatous mastitis.

Methods

Ethical approval

The Institutional Review Board of Chengdu Women's and Children's Central Hospital approved this study (reference number 2022(96)). The requirement for patient consent to participate in this study was waived because of the retrospective nature of the study. Information was gathered from electrical medical systems in an anonymous manner, where all authors could ensure the confidentiality of patient data. The study followed the latest version of the Helsinki Declaration.

Study subjects

Our study was on the patients who were treated in the Breast Department of Chengdu Women's and Children's Central Hospital between January 2018 and June 2021. The follow-up time ranged from 13 to 42 months. Eligibility criteria:a) diagnosed as GM pathologically which means the histopathologic features are noncaseating granulomas centered on lobules, with or without associated microabscesses,b) accompanied by abscess formation throughout the course of the disease, c), did bacterial culture of pus routinely and used MALDI-TOF MS to identify if the bacteria was Corynebacterium kroppenstedtii, d) achieve cure at least one time. Excluded criteria: a) evidence of other bacteria, b) in pregnancy, c) suffered from psychiatric illness. 

Study data

The patients’ medical records were retrieved from not only outpatient but also inpatient department, we recorded their age, laterality, gravida times, parity, BMI, mental illness, time to presentation since last delivery and breast feeding, way of last delivery, history of lactational mastitis or abscess, local trauma, bacterial results, serum prolactin levels and clinical findings including diameter of breast mass at first-time medical consultancy, sinus formation, erythema nodosum, nipple discharge, management protocols including immunosuppressants such as steroid and methotrexate, surgery, and antibiotics (antituberculosis drugs rifampicin), time to complete remission at the first treatment periods, recurrence. All patients were assessed by physical examination, laboratory tests and USG on follow-up period. At the same time, we designed a questionnaire for more information of interest such as lactating time and recurrence. The data were analyzed retrospectively.

Statistical analysis

Data are presented as median and range for quantitative variables and as number or percentage for qualitative variables. Quantitative data between the groups were firstly tested the normality and compared using Mann–Whitney U test. The chi-square test, Fisher’s exact test and Mann–Whitney U test was used to compare qualitative data. A p value of < 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS statistical software package version 23.0.

Results

In total, there were 201 patients enrolled in our study, they were all Chinese parous women, aged from 23 to 52, and 107 patients in CK group (defined as a group with Corynebacterium kroppenstedtii infection), 94 patients in negative group (defined as a group with no evidence of bacteria). Most patients had normal BMI and their baby was 5 years old or younger when they were diagnosed as GM. The majority of enrolled patients had only one child and nearly half of them lasted their lactation time for 7-12 months. The details of demographics and clinical characteristics including recurrence were presented in Table 1, but some data of lactating time was missing for 18 patients in CK group and 16 in negative group. Recurrence related to treatment methods was presented in Table 2 and Table 3.

Table 1 provides that the median age of total patients was 31 years, and 31 years in CK group and 32 years in negative group (Z=-1.046, p=0.295). 11(5.5%) patients had bilateral lesions, others were all unilateral (x2=4.217, p=0.121). The median diameter of mass on the first medical consultation in our study was 5.5cm, 6.0cm in CK group and 5.0cm in negative group (Z=-2.539, p=0.011). Sinus formation (x2=13.028, p=0.000) and recurrence (x2=4.953, p=0.026) were statistically significant, and both were more frequent in CK group. However, delivery way (x2=0.098, p=0.755), time to presentation since last delivery (x2=0.028, p=0.868), BMI (Z=-0.947, p=0.344), lactating time (Z=-1.378, p=0.168), parity (x2=1.799, p=0.180), gravida (Z=-0.144, p=0.885), history of lactational mastitis or abscess (x2=0.115, p=0.734), local trauma (x2=0.982, p=0.322), hyperprolactinemia (x2=0.706, p=0.401), erythema nodosum (x2=0.292, p=0.589), nipple discharge (x2=0.281, p=0.596) did not demonstrate a statistically significance. The median time to complete remission at the first treatment periods in our study was 5.0 months, ranged from 1.0 to 24.0 months, and 6.0 months in CK group, 4.0 months in negative group (Z=-3.027, p=0.002). 

Table 2 shows that 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 in our study, more than 50% (107) of the patients underwent surgery combined with immunosuppressants and 30(28.0%) patients suffered from recurrence, and 18 (45.0%) in CK group, 12 (17.9%) in negative group (x2=9.110, p=0.003). None of the patients who received antibiotics alone suffered from recurrence. But surgery combined with antibiotics and immunosuppressants (Fisher’s exact test, p=0.270), surgery combined with antibiotics (Fisher’s exact test, p=0.167), immunosuppressants combined with antibiotics (Fisher’s exact test, p=0.545), immunosuppressants alone (Fisher’s exact test, p=1.000) were not statistically significant. 

Patients in CK group were divided into groups A and B according to whether using rifampicin or not in their treatment course, and group A was defined as management protocols which included rifampicin, group B was defined as management protocols which did not include rifampicin. Recurrence rate was 22.0% in group A and 42.1% in group B (x2=4.892, p=0.027) (Table 3).

Discussion

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. 

Conclusion

Sinus formation and higher recurrence rate is intimately related to Corynebacterium kroppenstedtii infection, and both of them may prove the possible important role of Corynebacterium kroppenstedtii in the development and progression of granulomatous mastitis. Although, the time to complete remission at the first treatment periods and the diameter of mass on the first medical consultation made statistically differences in our study, we still need to be cautious. Besides, lipophilic antibiotics may should be considered using for GM with Corynebacterium kroppenstedtii infection when developing the treatment plans.

Abbreviations

GM:Granulomatous mastitis; CK:Corynebacterium kroppenstedtii;  MALDI-TOF MS:matrix-assisted laser desorption ionization-time-of-flight mass spectrometry; USG: ultrasonography; TRAM: transverse rectus abdominis musculocutaneous.

Declarations

Ethics approval and consent to participate

The Institutional Review Board of Chengdu Women's and Children's Central Hospital approved this study (reference number 2022(96)). Informed consent was waived by the local Ethics Committee of Chengdu Women's and Children's Central Hospital in view of the retrospective nature of the study and that all the procedures being performed were part of the routine medical care.

Consent to publish

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article/as supplementary information files.

Competing interests

ShunBo Li, Qian Huang, PeiPei Song, XiaoRong Han, ZeYu Liu, Lin Zhou, Ping Ning declare they have no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' Contributions

Shun-Bo Li and Ping Ning conceived and designed the study and wrote the first draft of the manuscript. Shun-Bo Li, Qian Huang, PeiPei Song, ZeYu Liu, and Lin Zhou collected and cleaned the clinical data. Shun-Bo Li, Qian Huang, and Xiao-Rong Han analyzed the data, interpreted the results. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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Tables

Table 1 Demographics and clinical characteristics 

Characteristics

Total N=201

CK 

(n=107)

N

(n=94)

P

Age in year

31(23-52)

31(23-48)

32(23-52)

0.295

Laterality

 

 

 

0.121

Left

105(52.2%)

52(48.6%)

53(56.4%)

 

Right

85(42.3%)

46(43.0%)

39(41.5%)

Bilateral

11(5.5%)

9(8.4%)

2(2.1%)

Diameter(cm)

5.5(2.0-17.0)

6.0(2.0-17.0)

5.0(2.0-17.0)

0.011

BMI (kg/m2)

 

 

 

0.344

<18.5

14(7.0%)

7(6.5%)

7(7.4%)

 

18.6-24.9

144(71.6%)

74(69.2%)

70(74.5%)

 

25-29.9

35(17.4)

22(20.6%)

13(13.8%)

 

≥30

8(4.0%)

4(3.7%)

4(4.3%)

 

Delivery way

 

 

 

0.755

Eutocia

96(47.8%)

50(46.7%)

46(48.9%)

 

Cesarean

105(52.2%)

57(53.3%)

48(51.1%)

Time to presentation since last delivery(year)

 

 

 

0.868

≤5

181(90.0%)

96(89.7%)

85(90.4%)

 

>5

20(10.0%)

11(10.3%)

9(9.6%)

 

Lactating time(month)*

 

 

 

0.168

0

11(6.6%)

6(6.7%)

5(6.4%)

 

1-6

45(26.9%)

19(21.3%)

26(33.3%)

 

7-12

80(47.9%)

46(51.7%)

34(43.6%)

 

13-18

23(13.8%)

12(13.5%)

11(14.1%)

 

19-24

6(3.6%)

5(5.6%)

1(1.3%)

 

>24

2(1.2%)

1(1.1%)

1(1.3%)

 

missing

34(16.9%)

18(16.8%)

16(17.0%)

 

Parity times

 

 

 

0.180

1

156(77.6%)

87(81.3%)

69(73.4%)

 

>1

45(22.4%)

20(18.7%)

25(26.6%)

Gravida times

 

 

 

0.855

1

66(32.8%)

37(34.6%)

29(30.9%)

 

2

73(36.3%)

36(33.6%)

37(39.4%)

 

3

35(17.4%)

19(17.8%)

16(17.0%)

 

≥4

27(13.4%)

15(14.0%)

12(12.8%)

 

Lactational mastitis

34(16.9%)

19(17.8%)

15(16.0%)

0.734

Local trauma

17(8.5%)

11(10.3%)

6(6.4%)

0.322

Hyperprolactinemia

37(18.4%)

22(20.6%)

15(16.0%)

0.401

Erythema nodosum

9(4.5%)

4(3.7%)

5(5.3%)

0.589

Sinus formation

100(49.8%)

66(61.7%)

34(36.2%)

0.000

Nipple discharge

15(7.5%)

7(6.5%)

8(8.5%)

0.596

Time to complete remission (month)

5.0(1.0-24.0)

6.0(1.0-24.0)

4.0(1.0-24.0)

0.002

Recurrence

52(25.9%)

35(32.7%)

17(18.1%)

0.018

*Data were missing for some patients  

CK: Corynebacterium kroppenstedtii group  

N: negative group

BMI: body mass index

Table 2 Recurrence related to treatment methods 

Treatment

Patients

Recurrence

CK 

N

P

IM+antibiotics+surgery

23(11.4%)

6(26.1%)

4/19(21.1%)

2/4(50.0%)

0.270

IM+surgery

107(53.2%)

30(28.0%)

18/40(45.0%)

12/67(17.9%)

0.003

antibiotics+surgery

9(4.5%)

3 (33.3%)

3/5(60.0%)

0/4(0.0%)

0.167

IM

26(13.0%)

9(34.6%)

6/17(35.3%)

3/9(33.3%)

1.000

antibiotics

9(4.5%)

0(0.0%)

0/5(0.0%)

0/4(0.0%)

-

IM+antibiotics

27(13.4%)

4(14.8%)

4/21(19.0%)

0/6(0.0%)

0.545

IM: immunosuppressants  

CK: Corynebacterium kroppenstedtii group  

N: negative group

Table 3 Recurrence related to antibiotics (rifampicin) in CK group

Group

Patients

Recurrence

No recurrence

P

A

50

11(22.0%)

39(78.0%)

0.027

b

57

24(42.1%)

33(57.9%)

CK: Corynebacterium kroppenstedtii   

A: management protocols which included rifampicin   

B: management protocols which did not include rifampicin