Pregnancy Associated Granulomatous Mastitis: Clinical Characteristics,Management,and Outcome

Introduction

Idiopathic granulomatous mastitis (IGM) is known as a rare benign chronic inflammatory disorder of the breast, first described by Kessler and Wolloch in 1972, ¹ and further elaborated by Cohen in 1977, ² typically presenting as a breast lump in parous women of childbearing age within 5 years of childbirth. ³ The histopathologic features of IGM are noncaseating granulomas centered on lobules, with or without associated microabscesses. ⁴ Although the novel biopsy techniques that can be used for the diagnosis of IGM of the breast are fine-needle aspiration biopsy, ⁵ core needle biopsy (CNB), or surgical biopsy (excisional or incisional), ⁶ CNB in conjunction with high diagnostic accuracy has a significant role in distinctive diagnosis of IGM and, hence, is useful for treatment planning. ⁷ The clinical manifestations usually are pain, redness, thickening of the breast skin, and a poorly defined hard mass. They can be of various sizes (1–20 cm) and are mostly unilateral. IGM can be seen with equal frequency in both breasts. The upper outer quadrant can be the most commonly involved site. Peau d'orange appearance of the skin and nipple retraction may also be seen. ⁸ It can also present with abscesses and draining tracts or fistulae. Extra-mammary presentations of IGM include axillary lymphadenopathy, erythema nodosum (EN), episcleritis, and arthritis. ⁹ The clinical presentation frequently mimics breast abscess, infective mastitis, and breast cancer. ¹⁰ However, IGM is not a cause of malignancy. Etiology of granulomatous mastitis has not been fully elucidated and may be hormonal imbalance such as hyperprolactinemia, autoimmunity, unknown microbiological agents, smoking, oral contraceptive pills, ethnicity, and α 1-antitrypsin deficiency. ¹¹ At present, there is still no universally accepted management strategy for IGM. The therapy regimens consist of antibiotics, steroids, immunosuppressants, surgery, and expectant treatment, with varying degrees of success. ³

In recent years, the prevalence of IGM has increased significantly. Although IGM reportedly affects pregnant women as well, ¹² there's still little literature to discuss about pregnancy associated granulomatous mastitis (PAGM). So, in our study we talk about PAGM by collecting and describing the clinical signs, managements, clinical course, and clinical outcomes after treatment of PAGM in our hospital. To our knowledge, this is the largest PAGM study. We believe that the study will contribute to the literature.

Methods

Our study is on 15 female patients diagnosed with PAGM between December 2018 and December 2020 and treated in our hospital, and the pathological criteria for diagnosis of PAGM were presence of the histopathological features of noncaseous granulomatous inflammation on breast lobule infiltrated by lymphocytes, plasma cells, and neutrophils microscopically during pregnancy. IGM associated with Corynebacterium kroppenstedtii is an increasingly recognized situation, so we did bacterial culture when abscess existed. The patients' medical records were retrieved from outpatient and inpatient department, and we also designed a questionnaire for more information of interest. The data were analyzed retrospectively.

We recorded their age, gravida times, parturition, and gestational age, BMI during pregnancy, comorbidities, time to presentation since last delivery and breast feeding, way of last delivery, history of lactational mastitis or abscess, weight of the newborn, growth and development of the newborn, etiologic factors such as smoking, use of oral contraceptives, local trauma, bacterial culture, nipple retraction, family history of breast cancer, initial presenting symptoms, clinical findings, including size and localization of the lesion, and the presence of abscess or sinus formation, management protocols, including steroid, surgery, conservative treatment, time to complete remission, recurrence, and follow-up time. We also looked for any history of autoimmune disease; antinuclear antibody spectrum, humoral immunity, and rheumatoid factor were detected in some patients. Some of the patients were tested for serum prolactin levels as well.

All patients underwent breast and axillary ultrasonography (USG) examination when consulting in our outpatient clinic. All patients were assessed by physical examination and USG on follow-up period.

Results

In total, 15 pregnant patients diagnosed with PAGM were identified between December 2018 and December 2020. All patients were performed tissue diagnosis by CNB. Owing to the particularity of pregnancy and patients' worries, some of our patients got through CNB immediately after delivery. Patients' basic data, including their age at diagnosis, gravida, para, and gestational age, BMI during pregnancy, comorbidities, time to presentation since last delivery and breastfeeding, way of last delivery, history of lactational mastitis, or abscess are shown in Table 1. The mean age of the patients at diagnosis was 30.5 (range 24–35) years. All patients had one birth before, and had at least two gravida times, 6 of them (40%) had three gravida times, and only one of them had four gravida times at diagnosis. The mean weeks of gestational age were 23.7 (range 4–37) weeks, only 2 patients were diagnosed in the first trimester, 7 of them were diagnosed in the second trimester, and 6 of them were diagnosed in the third trimester. Most patients had normal BMI; just two patients' BMI were greater than 30, which were considered obese. All patients had no comorbidities except one patient who had gestational diabetes mellitus. The mean time to presentation since last delivery was 38.4 (range 19–78) months; all patients were diagnosed within 5 years of last childbirth except that one patient was 78 months after her last delivery. We can see from Table 1 that all patients had a history of breastfeeding; the average breastfeeding time was 12.97 months, more than 1 year, and the shortest time was 5.5 months, nearly half a year. Just 2 of them were diagnosed with lactational mastitis before; others had neither lactational mastitis nor lactational abscess.

Only 7% of our patients were associated with an oral contraceptive pill or smoking, 20% of them had nipple retraction, 27% of them had breast trauma recently, and 33% of them had positive bacterial culture of pyogenic fluids; interestingly the bacteria of these five patients were the same called Corynebacterium kroppenstedtii. During pregnancy, 40% of our patients had abnormal humoral immunity, shown as elevated C3 or C4, and 13% of them had elevated serum prolactin. The data are presented in Table 2.

Clinical presentations, treatments, outcome, and follow-up of 15 patients diagnosed with PAGM are shown in Table 3. All patients presented as mass with pain, most of them had abscess (87%), redness (93%), and fistula (73%) in the course of the disease, and only two of them had EN and oligoarthritis. Nearly all patients had unilateral lesion. The mean follow-up was 11 (range 1–24) months, except that one patient was still in pregnancy, one had an abortion, others all gave birth to a healthy baby, and at the end of the study period all babies had a healthy growth and development, although almost all patients chose observation during pregnancy. Nine of them demonstrated complete remission, about half (5) of them underwent surgery after steroids and/or antibiotics, one patient had observation alone, two chose postpartum steroids alone, and the last one chose postpartum antibiotics alone. The average time to complete remission was 11.2 (range 7–18) months.

Discussion

From our study, we found that PAGM patients were all parous women and generally within 5 years of their last pregnancy as well, the same as other IGM patients described in most literature. Bilal Al-Khaffaf et al. also showed IGM typically presented in parous women of childbearing age within 5 years of childbirth. ³ The mean age of our patients at diagnosis was 30.5 (range 24–35) years; Chirappapha et al. found that the average of IGM patient age was 38 years old, ¹³ slightly higher than our mean age, maybe because our patients were all in childbearing age.

In our study, only 2 patients were diagnosed in the first trimester, 7 of them were diagnosed in the second trimester, and 6 of them were diagnosed in the third trimester. To our knowledge, among those case reports about PAGM, only Juan A Garcia-Rodiguez1 and Andrew Pattullo reported a patient who was diagnosed in the first trimester (11 weeks pregnant), her other characteristics were 30 years old, South American, and with an apparent infectious mastitis. She presented with progressive worsening of her breast symptoms and multiple negative laboratory tests. She suffered different side effects from several prescribed treatments and endured a prolonged recovery. ¹⁰ Other reported cases were all in the second trimester and the third trimester. Goldberg et al. reported a 25-year-old black gravida 4 para 2 at 17 weeks' gestation woman diagnosed with Granulomatous mastitis in 2000, treated with steroids initially, recurred after delivery, still treated with steroids alone, and the outcome was complete remission with no palpable mass or drainage. They thought that postpartum recurrence might require further steroid treatment. ¹⁴ Olfatbakhsh et al. described a case of IGM with EN and arthritis in a young pregnant woman in 2008. The patient was a 30-year-old pregnant woman in the 32nd week of pregnancy. ¹⁵ Poniecka et al. reported a 27-year-old, 7-month-pregnant woman presented with a hard nodule in her right breast diagnosed with IGM. ¹⁶ Lucas et al. showed a 25-year-old Hispanic G2P1 at 17 weeks gestation diagnosed with IGM. ¹⁷

As we know, the mechanism of development of IGM is believed to involve the following sequence: ductal epithelial damage, transition of luminal secretions to the lobular connective tissue, local inflammation in connective tissue, macrophage and lymphocyte migration to the region, and local granulomatosis inflammatory response. However, the trigger factor in the development of epithelial damage has not been clarified. Four of our patients had breast trauma recently before onset, this may explain why ductal epithelial damage occurred; however, the exact triggers of this epithelial destruction in the absence of physical trauma remain unknown. ¹⁸ All patients in our study had a history of breastfeeding, and the average breastfeeding time was 12.97 months, more than 1 year, so we supposed if long term breastfeeding may provide a pathogenic microenvironment, but it deserved further research.

High levels of estrogen and/or progesterone (either through pregnancy or exogenous use) and elevated prolactin have been postulated in the pathogenesis of IGM.^19,20 It has been postulated that IGM results from a localized autoimmune response to the retained or extravasated fat- or protein-rich secretion in the breast ducts during childbearing age due to a previous hyperprolactinemia in women. ²¹ It seemed to support the point of the secretion theory. The secretion theory has an important place in the pathophysiology of IGM. A process starting with nonpuerperal secretion has been proposed as the most rational theory for the pathogenesis of IGM. A hormonal imbalance due to a deviation in the estrogen-progesterone ratio or hyperprolactinemia is believed to cause this secretion and inflammation. Ductal ectasia occurs due to the intraductal accumulation of a protein-rich secretion. Permanent inflammation occurs following perforation of the ducts and contact between the secretion and stromal cells. The accumulation of secretion, ductal ectasia, galactophoritis (intraductal inflammation), and chronic IGM are steps in the pathophysiological process. Autoimmunity against a secretion that is extravasated from the lobules is also considered to cause this event. ¹¹ Unfortunately, in our retrospective study, we missed most of the test data at diagnosis; only 2 patients had exactly elevated serum prolactin at diagnosis.

In recent study, Davis et al. found that factors that may affect the natural history and therefore the time to resolution of IGM include the size of mass, the age of patient, and hormonal influences, such as pregnancy, breastfeeding or lactation, and prolactin. ²² So, all patients were given bromocriptine after delivery to stop breastfeeding.

Generally, IGM is unilateral, but it occasionally occurs in both breasts. ²³ In our study, 14 patients had unilateral lesion, and only 1 patient had bilateral lesions. Five patients had positive bacterial culture of pyogenic fluids in our study, and all were the same bacteria called Corynebacterium kroppenstedtii. As we know, granulomatous mastitis due to Corynebacterium kroppenstedtii is an increasingly recognized cause of an indolent and distressing mastitis in nonlactating females^24,25; it seems to be suitable for pregnant women as well.

The combination of limited surgical treatment and systemic prednisolone given for 6 months effectively controls the disease, as well as prevents recurrence. ²⁶ Two other studies have reported improved outcomes when using a combination of corticosteroids and surgery. ²⁷ In our study, 9 patients reached complete remission and till the end of the study there's no recurrence; 5 of them underwent surgery after steroids, proving the effectiveness of the operation combined with steroids for PAGM too.

Zhou et al. suggested that the observational management is acceptable for IGM, and literature reports that IGM can be self-limiting with 6–12 months natural course to stable no matter what treatment had been taken, and more than half of IGM patients who do not receive any treatment revealed complete remission.^22,28 Mahlab-Guri et al. suggested that the therapeutic approach includes observation alone in severe cases. ²⁹ In our study, almost all PAGM patients had abscess (87%), redness (93%), and fistula (73%) in the course of the disease, the clinical presentation was so poor, and even though they were treated with different ways, including observation, steroids, antibiotics, and surgery, the average time to complete remission was 11.2 months, supporting the viewpoint that IGM can be self-limiting with 6–12 months natural course whatever treatment had been taken, and it seemed to apply to PAGM as well. But it deserves to be mentioned that only one patient in our study achieved complete remission by observation alone.

Owing to the particularity of pregnancy, the management plans were discussed with the patients to involve close observation with patient education except for one patient with steroids in the period of pregnancy and one patient chose interruption of pregnancy of her own free will. At the end of our study, 13 patients had their delivery as expected, 12 of them chose observation during pregnancy, except that one patient chose steroids, 9 of them had met complete remission, and their average time to complete remission was almost consistent with literature reports, their babies all had a healthy growth and development till the end of our study; this may prove the reliability of observational therapy during pregnancy for PAGM. There are some studies showing that immunosuppressive therapy with low-dose prednisone was relatively safe to treat or prevent a variety of conditions during pregnancy, such as autoimmune disease, asthma, solid organ transplant rejection, and others^30–32 ; however, slight intrauterine growth retardation of both the infant and the placenta had been recorded. ³³ Hence the needs of the mother must be carefully weighed against the possible harms to the fetus when glucocorticoids are prescribed. ³⁴ Surgery may be performed in all trimesters, ³⁵ but 16%–50% recurrence rate was reported after surgical treatment, ²⁸ and it may be not essential for this disease during pregnancy. Thus, we think that surgery should be avoided during pregnancy for IGM.

To conclude, PAGM is a much rare disorder which has onset during pregnancy and mainly happens in the second trimester and the third trimester. PAGM occurs in parous women and generally within 5 years of their last pregnancy, also with uncertain etiology and pathogenesis. Observational therapy during pregnancy for PAGM is a reliable and feasible alternative.

Ethics Approval

Not applicable since the study was not a RCT.