Treatment of Granulomatous Mastitis with steroids: Should the decision to end the treatment be made radiologically?

doi:10.21203/rs.3.rs-2248579/v1

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Treatment of Granulomatous Mastitis with steroids: Should the decision to end the treatment be made radiologically?

https://doi.org/10.21203/rs.3.rs-2248579/v1

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Purpose: Idiopathic granulomatous mastitis (IGM) is a benign inflammatory breast disease of unknown etiology that affects women in their reproductive ages. The most preferred option as first-line treatment is steroids, but the lack of standard treatment protocol and high recurrence rate after treatment constitutes a recurring challenge during its management. This study aimed to find an answer to the question of whether the decision to end the treatment should be made radiologically or clinically.

Methods: This retrospective cohort study included IGM patients who had complete clinical recovery with steroids and were followed for a minimum of 30 months. Patients’ demographics, disease severity and findings, treatment regimens and duration, and MRI findings at clinical recovery were assessed for their relation to recurrence.

Results: Eighty-nine patients who were clinically completely healed after steroids were included in the study. At the time of clinical healing, 51(57.3%) patients had a complete radiological response and 38(42.7%) had a partial radiological response (PRR) on MRI. Overall, recurrence developed in 22(27.4%) patients after a median 38.6-month follow-up. Patients who experienced recurrence were significantly older and had PRR when their treatment was stopped upon clinical healing.

Conclusions: During the process of clinical healing, the imaging findings revealed that the remained disease seems to be a significant predictor for recurrence in IGM patients. In patients with partial radiological response, extending the treatment with either prolonged steroid therapy or by surgical excision of the occult residual disease may prevent recurrences in IGM patients.

Granulomatous mastitis

steroid treatment

recurrence

MRI

Idiopathic granulomatous mastitis (IGM) is a benign inflammatory breast disease of unknown etiology that affects women of reproductive age. The lack of a standard protocol for its treatment, high anxiety among patients due to its mimicking malignancy with clinical and radiological findings, and the high recurrence rate after treatment are the challenges to managing the disease. Although it has endemic proclivity regarding Middle Eastern - Asian countries mainly, these challenges also constitute a problem for western clinicians due to immigration. In general, diagnosis is not difficult for physicians in endemic areas. Although physicians can diagnose the IGM easily, they deal with challenges when managing the disease owing to its presentation as well as after recurrence.

The surgery was the primary treatment for many years, even after the effectiveness of steroids was reported and proven in 1980.¹ However, steroids' clinical efficacy as a first-line treatment, rising to 90%, was subdued due to the recurrence rates of up to 46% following the treatment discontinuation.² Also, the side effects during the long-term treatment reduce compliance with the treatment for the patients.³ Considering these reasons, surgery has been the preferred first-line treatment again, recently.^4-6 However, reported recurrence rates of surgical excisions are similar to steroid therapy, therefore limiting its feasibility.^7,8 Moreover, either repetitive interventions or wide surgical excisions may be required to achieve remission, which leads to poor cosmetic results. The complexity of the management considering these reasons urged the physicians who are dealing with IGM to investigate the factors associated with disease recurrence.

Although there were many studies considering the dosage, time, and methods to apply steroids, there was no study regarding the end-point to discontinue the treatment up to date. Complete clinical response (CCR) was the criterion to discontinue the treatment in the search for the effectiveness of steroid treatment, in accordance with the studies to date.⁹ However, there is no standardized and objective definition of CCR. In addition, we know about the residual findings of the disease which could be determined with only imaging were present in up to 50% of the patients with CCR.³

The imaging modalities such as ultrasound (US) and contrast‐enhanced MRI are used routinely in the diagnosis of IGM.¹⁰ US possesses the distinct advantages of high sensitivity, noninvasiveness, and valuable in screening patients in cases of mild disease. On the other hand, MRI is a useful imaging modality for the differential diagnosis of breast cancer and it also could be more useful to indicate active lesions and locate the extent of the lesions.¹¹ Therefore, it was used in the evaluation of the response to steroid treatment.^3,11

This study aimed to find an answer to the question of whether the decision to end the treatment should be made radiologically or clinically and to assess the factors which may have an impact on recurrence in patients with IGM after steroid treatment. We tested this hypothesis on a cohort of patients treated with steroids and had a long-term follow-up.

Study design

The study was planned as a retrospective cohort design and conducted at a tertiary breast care unit. The study protocol was approved by the institutional ethics committee. Patients with IGM diagnosis who were treated with steroids as first-line treatment and had CCR were included in the study. IGM patients who did not receive their steroid treatment according to the planned regimen or did not have a satisfactory response to the treatment or had a follow-up less than 30 months after clinical recovery or did not have an MRI exam at the time of clinical recovery were excluded from the study (Fig. 1). On our database, we determined 30 months as the minimum follow-up time since the latest recurrence was seen at 30th month after full clinical recovery among all IGM patients who only received steroid therapy.

Study groups

Following the CCR, the reappearance of clinical symptoms and/or findings such as palpable mass, erythema, fistula-formation, skin ulceration, and abscess formation suggesting IGM at the same breast was regarded as recurrence.

The patients were grouped according to their radiological findings at the termination of steroid therapy when patients turned symptom-free. The patients who had the findings suggesting a remaining disease on MRI (abscess formation, heterogeneous mass, skin thickening, unresolved fistula tracks, contrast-enhanced appearances) were grouped as Group PRR (Partially Radiological Response), whereas those with no such radiological findings were grouped as Group CRR (Complete Radiological Response).

Study outcomes

The primary outcome is to assess the impact of MRI findings at CCR on predicting the recurrence in IGM patients who only received steroids as their treatment. Therefore, the rate of recurrence in both study groups was compared. As the secondary outcome, demographic and clinical variables related to IGM which may have an independent impact on the recurrence were also analyzed.

Variables

Patients’ features and demographics, clinical findings and extension of the disease, treatment history including the type of agents and their duration, and MRI findings at the end of the treatment were collected from patient files for univariate and multivariate analysis.

Steroid treatment protocol

Patients in the study cohort received three different regimens of steroids. Some patients received only topical, some others received only oral steroids and the rest received both. The choice of the treatment regimen was at the physician’s discretion.

Topical steroid administration: Prednasinolone 0.125% pomade (Prednol pomad; Mustafa Nevzat Pharmaceuticals, Istanbul, Turkey) was applied topically by the patients to the affected breast, twice a day on the weekdays with breaks during weekends (1-week cycle).

Treatment with oral steroid: Postprandial 0.8 mg/kg oral methylprednisolone (Prednol tablet, Mustafa Nevzat Pharmaceuticals, Istanbul, Turkey) was given once daily.

Combined steroid therapy: Postprandial 0.4 mg/kg oral methylprednisolone was given once daily and Prednasinolone 0.125% pomade – with the same pharmaceutical agent - was applied topically to the diseased breast as it is described in the topical steroid administration protocol.

Steroid treatment according to the unit protocol was continued until the first signs of disease amelioration were observed. Then the treatment was tapered in patients who received oral methylprednisolone. Topical treatment cycles were ended when CCR was obtained.

Decision for completion of steroid treatment

Following tissue diagnosis, before starting steroid treatment all patients underwent MRI in order to assess the extent of the disease within the breast. Thereafter, the response to treatment was assessed by physical examination and breast US.

The decision to stop steroid treatment was given according to the clinical responses. The lack of palpable mass and erythema on physical examination, and healing of the skin with the closure of ulceration, and fistula were considered CCR. Patients were also assessed by breast MRI at the end of steroid treatment when CCR is achieved. The lack of image findings indicative of the remaining IGM on MRI was regarded as CRR. Any remaining image findings suggesting IGM such as heterogeneous mass, skin thickening, unresolved fistula tracks, and contrast-enhanced appearances were regarded as PRR (Fig. 2).

Follow-up

During the treatment course, patients were checked for the disease's findings. After the termination of treatment, patients were followed on the first, third, and sixth months, and every six months thereafter. At each visit, a physical examination and breast US were performed to assess the patient for recurrence.

Statistics and data analysis

Data were analyzed with Statistical Package for Social Sciences software (SPSS ver. 24.0, IBM Co., Armonk, NY, USA). Pearson’s chi-square test and Fisher’s exact test were used to compare qualitative data. Normality for the distribution of quantitative variables was analyzed with the Kolmogorov Smirnov and Shapiro-Wilk tests. The student t-test was used to compare the normally distributed data. Mann-Whitney-U test was used to compare the variables without normal distribution. Multivariate logistic regression analysis was performed to assess variables that may be associated with recurrence. Based on the result of the analysis, p < 0.05 was considered to be statistically significant.

Study Cohort

The study included 222 patients who were diagnosed with IGM between September 2014 and October 2019 at the Breast Unit in Dr. Lütfi Kırdar Training and Research Hospital in Kartal, İstanbul, Turkey.

Among those, surgical treatment was done as first-line treatment in 24 patients, and the remaining 198 patients received steroid therapy. 89 patients who fulfilled the inclusion criteria remained in the cohort of the current study (Fig. 1). Some of the patients in the current cohort were also included in our previous trials with different outcomes and the results were published elsewhere.^3,12

The mean age of the cohort was 33.2±6.4, and 87(97.8%) patients were of reproductive age. The most common finding was palpable mass (n:85, 95.5%), followed by erythematous appearance (n:72, 80.9%).

MRI findings at clinical recovery

When CCR is achieved and steroid treatment is stopped, 51(57.3%) patients had CRR and 38(42.7%) had PRR in MRI.

Recurrence rate and associated factors

Recurrence was observed in 22(27.4%) patients after a mean follow-up of 42±10.3 months. Patients who had recurrence were significantly older than those who did not (35.8±6.8 vs. 32.4±6, p = 0.03). Most recurrences were seen in Group PRR [Group PRR; n:19(86.4%) vs. Group CRR; n:3(13.6%), (p < 0.001)] (Table1).

The multivariate analysis revealed that each one-year increase in age significantly increased the probability of recurrence by around 1.1 times more [OR (95%CI):1.11(1.01, 1.22), p:0.029]. Also, PRR at the end of treatment increased the probability of recurrence nearly 18 times more [OR (95%CI):18.25(4.48, 74.34), p < 0.001] (Table 2).

For the whole cohort, recurrences were observed in the median of 3.5 months after stopping the treatment. Recurrences developed significantly earlier in those patients who had PRR [median: 3 months (range:1-30)] than in those who had CRR [median: 15 months (range:15-20), p:0.03].

A 27.4% recurrence rate was observed in our IGM cohort, which comprised patients with long-term follow-up, where steroids were used as first-line treatment, and treatment was discontinued based on clinical responses. Radiological residual disease at the time of discontinuation and age was an independent risk factor for recurrence, considering univariate and multivariate analysis. Each one-year increase in age significantly increased the probability of recurrence by around 1.1, and PRR at the end of treatment increased the probability of recurrence by nearly 18 times more. Also, we found recurrences developed significantly earlier in those patients who had PRR than in those who had CRR.

To the best of our knowledge, the decision to discontinue medical treatment has been made clinically in all studies up to date.⁹ However, there was no standard definition of complete remission in the treatment of IGM. Complete remission was defined as the absence of pain, swelling, erythema, tenderness, and lump after treatment^13-15, but the radiological responses were never addressed in the decision to finalize the treatment. This is the first study investigating the relationship between the radiological responses and recurrences while the decision of treatment discontinuation was done. The long-term follow-up of our series is longer than the ones in the literature and thus has strengthened the results of our study.

Retrospective design and use of different treatment modalities with different time periods—even though all cases were treated with steroids successfully—were the most important limitations of our study. Moreover, recurrence was not found to be related to different treatment modalities and different periods in our series. Another limitation of our study was the use of MRI instead of the US, which is more sophisticated and expensive in comparison to the US. MRI is useful for evaluating possible residual disease after treatment or for monitoring the disease in patients who underwent conservative treatment.^16,17

A recurrence rate of 27.4% in total was eligible with the literature; besides, it was 5.9% (3/51) in the CRR group and 50% (19/38) in the PRR group. Wang et al. reported a lower recurrence rate in the group with surgical excision following systemic steroid treatment than the group with only systemic steroid treatment (5.1% vs. 22.7%).⁵ The high total recurrence rate could be explained by long follow-up intervals and different treatment protocols of ours. The patients who received wide surgical excision following systemic steroids in the study of Wang et al. have shown similar characteristics to the CRR group in our series in terms of the recurrence rate. Gürleyik et al. reported a similar recurrence rate of 5.3% in 19 patients with local excision following 8 weeks of oral methylprednisolone treatment, in a retrospective cohort.¹⁸ Additionally, Lei et al. reported the method of surgery following treatment with steroids as the lowest recurrent modality (4%) in a meta-analysis.⁹ On the other hand, recurrence rates were low and similar regarding the patients with CRR in our series. In our opinion, the similarity of the lower recurrence rate is related to the removal of residual disease following steroid treatment.

To the best of our knowledge, there are two studies in the literature investigating the relationship between age and recurrence in IGM.^19,20 Although Yılmaz et al. reported higher mean age of patients with recurrence (40.1 vs. 38.4 years), there was no correlation between age and recurrence in both studies. Contrary to these studies, we found a statistically significant relationship between age and recurrence.

In recent years, the factors affecting the recurrence following the treatment of IGM have been examined in retrospective studies, in the literature.^19-22 Demographics, the number of births, breastfeeding period, smoking, use of oral contraceptives, and the type of pharmaceutical course on the breast were evaluated, and different findings for recurrence were reported in these studies. Uysal et al. have found that pregnancy, breastfeeding, previous mastitis, and smoking are related to recurrence in a multicenter retrospective study.¹⁹ Also, Yılmaz et al. have found high BMI, the number of births, breastfeeding period, luminal inflammation, fistula, and abscess to be closely related to recurrence, in contrast, smoking is not related to, as per a study with a lower recurrence rate (8/63, 12.7%).²⁰ Even though the treatment modalities were different, all patients received steroids in our study. The number of births, breastfeeding period, smoking, and oral contraceptives were not found to be related to recurrence in our study. Tan et al. have reported a recurrence rate of 17.7%.²² Moreover, different treatment modalities (antibiotics, steroids, and surgery) have been applied in the study. Even though it was not statistically significant, inflammatory findings and the symptoms on the breast, and previous treatment with antibiotics, were mentioned to be higher in recurrent cases. Findings on the breast and previous treatment with antibiotics were not related to recurrence in our series.

We suggest evaluating radiological responses besides the clinical responses for discontinuing the treatment of the patients receiving steroids as first-line treatment. Prolonging the steroid therapy until the achievement of complete radiological response for the disease, or excision -without damaging breasts’ completeness- for the radiologically detected residual disease could lower the recurrence. Excision of radiologically marked disease could be a reasonable approach.

Ethical approval:

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol was approved by Dr. Lütfi Kırdar Research and Training Hospital in affiliation with University of Health Sciences’ ethics committee (reg. 2020/514/177/43).

Informed consent:

Informed consent was taken from patients to collect and use data.

Conflict of interest:

The authors report there are no competing interests to declare.

Funding:

This study did not receive any funding.

Author Contributions:

Concept- K.Ç., H.E.S., G.R..; Design – K.Ç., B.M.G., G.R.; Supervision- K.Ç., H.E.S.; Materials- K.Ç., H.E.S., B.T., F.F.; Data Collection and/or Processing – K.Ç., F.F., G.R.; Analysis and Interpretation- K.Ç., F.F., G.R.; Literature Review – K.Ç., H.E.S., G.R.; Writing Manuscript – K.Ç., B.M.G., F.F.; Critical Reviews –B.M.G.

DeHertogh DA, Rossof AH, Harris AA, et al. Prednisone management of granulomatous mastitis. N Engl J Med. 1980;303(14):799-800. doi:10.1056/NEJM198010023031406.
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Table 1: Patients’ variables and their associations with recurrence

	Study cohort, n: 89	Recurrence		P value
	Study cohort, n: 89	No, n: 67	Yes, n: 22	P value

Age; mean year ± sd.	33.2 ± 6.4	32.4 ± 6	35.8 ± 6,8	0.03
Smoking; n (%)	18 (20.2)	13 (19.4)	5 (22.7)	0.8
Oral contraceptive use; n (%)	18 (20.2)	14 (20.9)	4 (18.2)	0.8
Number of live births; median (range)	2 (0-7)	2 (0-7)	2 (1-5)	0.3
Total breastfeeding time *	36 (0-120)	36 (0-120)	36 (9-120)	0.7

Affected side; n (%)				0.61
Right	48 (53.9)	37 (55.2)	11 (50)
Left	39 (43.8)	28 (41.8)	11 (50)
Bilateral	2 (2.2)	2 (3)	0 (0)

Previous treatments; n (%)
Antibiotics ± abscess drainage	54 (60.7)	43 (64.2)	11 (50)	0.24
Steroids	13 (14.6)	10 (14.9)	3 (13.6)	0.88

Presence of breast mass; n (%)	85 (95.5)	65 (97)	20 (90.9)	0.25
Presence of skin fistula; n (%)	45 (50.6)	32 (47.8)	12 (54.5)	0.6
Presence of skin ulceration; n (%)	15 (16.8)	12 (17.9)	3 (13.6)	0.75
Presence of abscess; n (%)	56 (62.9)	42 (62.7)	14 (63.6)	0.94

Extent of breast involvement; n (%)				0.8
Single quadrant	53 (59.5)	39 (58.2)	14 (63.6)
Two or more quadrants	36 (40.4)	28 (41.8)	8 (36.4)

Co-occurrence of EN; n (%)	7 (7.9)	4 (6)	3 (13.6)	0.25

Steroid treatment protocol				0.3
Topical	35 (39.3)	29 (43.3)	6 (27.3)
Systemic	26 (29.2)	17 (25.4)	9 (40.9)
Combined	28 (31.5)	21 (31.3)	7 (31.8)

Duration of treatment *	5 (1-10)	4 (1-10)	5 (2-9)	0.25

Radiological response; n (%)				<0.001
CRR	51 (57.3)	48 (71.6)	3 (13.6)
PRR	38 (42.7)	19 (28.4)	19 (86.4)

Follow-up time *	38.6 (30-66)	38.1 (30-66)	43.7 (30-62)	0.14

* median month (range)

Student t, Mann–Whitney U, and Chi-square tests were used

EN erythema nodosum, PRR partial radiological response, CRR complete radiological response

Table 2: The multivariate analysis of the factors associated with recurrences

Variables	Multivariate analysis

	Odds Ratio	CI %95	P-value

Age	1.11	1.01 – 1.22	0.029

Radiological response
PRR vs. CRR	18.25	4.48 – 74.34	<0.001

Binary Logistic Regression was used

OR odds ratio, CI, confidence interval, PRR partial radiological response, CRR complete radiological response

No competing interests reported.

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Treatment of Granulomatous Mastitis with steroids: Should the decision to end the treatment be made radiologically?

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Abstract

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