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Home , Granulomatous mastitis, Mastitis

CASE REPORT

Idiopathic Granulomatous

Karyn Haitz, MD; Amy Ly, MD; Gideon Smith, MD, PhD

that hyperprolactinemia2 or an immune response to local PRACTICE POINTS lobular secretions might play a role in pathogenesis. Early • Idiopathic (IGM) is a painful misdiagnosis as bacterial mastitis is common, prompting and scarring rare granulomatous disorder that multiple regimens. When fail, patients can have a prolonged time to diagnosis that delays are worked up for inflammatory breast , given the proper treatment. nonhealing breast nodules. , ultrasonog- • The pathogenesis of IGM remains poorly understood. raphy, and fine-needle aspiration often are unable to rule The temporal association of the disorder with breast- out carcinoma, warranting excisional biopsies of nodules. feeding suggests that hyperprolactinemia or an immune The patient is then referred to rheumatology for potential response to local lobular secretions might play a role. or to dermatology for IGM. In either case, the • Although many cases of IGM resolve without treat- workup should be similar, but additional history focused ment, more severe cases can persist for a long on behavior and medications is essential in suspected IGM, period before adequate symptomatic treatment is copy given the association with hyperprolactinemia. provided with methotrexate, , or surgi- Because IGM is rare, there are no randomized, cal excision. placebo-controlled trials of treatment efficacy. In many • Before any of these therapies are applied, however, contributing factors, such as long-term cases,not patients undergo complete mastectomy, which and drugs that induce hyperprolactinemia, should be is curative but may be psychologically and physically identified and withdrawn. impactful in young women. In some cases, high-dose cor- ticosteroids have been successful; however, because the IGM process can last longer than 2 years, patients treated Doin this manner are exposed to steroid morbidities.1 Idiopathic granulomatous mastitis (IGM) is a rare, poorly understood We report 3 cases of IGM that add to the literature condition that presents as inflammatory nodules of the breast. It is on possible contributing factors, clinical presentations, often initially misdiagnosed as furunculosis or cellulitis. Despite the and treatments for this disease. We also demonstrate painful, scarring, and debilitating nature of the disease, patients often have a delay in accurate diagnosis and treatment. Even when IGM is that appropriate trigger identification and steroid-sparing considered as a diagnosis, it is one of exclusion, with the differential agents, specifically methotrexate, can be breast-saving as diagnosis including serious conditions such as , sar- they can alleviate this debilitating condition, obviating the coidosis, and cutaneous . Therefore, appropriate workup need for radical surgical intervention. is important. Given that IGM is a diseaseCUTIS of the , it is important for dermatologists to be familiar with its presentation. We describe CASE REPORTS 3 cases of young women with this condition and demonstrate that identification of triggers or methotrexate treatment is highly success- Patient 1 ful in sparing patients the drastic surgical alternative of mastectomy. A 40-year-old woman with a 4-year history of breastfeed- Cutis. 2019;103:38-42. ing noted a grape-sized nodule on the left breast that grew to the size of a grapefruit after 2 weeks. Ulceration and drainage periodically occurred, forming pink plaques diopathic granulomatous mastitis (IGM) is rare during along the lateral aspects of the breast after healing. Her ; it typically is seen in women of childbearing primary care provider suspected infectious mastitis; she Ipotential from 6 months to 6 years postpartum.1 Because was given an oral antibiotic (cephalexin) and intravenous of a temporal association with breastfeeding, it is believed antibiotics without improvement.

Dr. Haitz is from the Department of Dermatology and Cutaneous Surgery, University of Miami, Florida. Drs. Ly and Smith are from Massachusetts General Hospital, Boston. Dr. Ly is from the Department of Pathology, and Dr. Smith is from the Department of Dermatology. The authors report no conflict of interest. The eTable is available in the Appendix online at www.mdedge.com/cutis. Correspondence: Karyn Haitz, MD, University of Miami, Department of Dermatology and Cutaneous Surgery, 1600 NW 10th Ave, RMSB 2023A, Miami, FL 33136 ([email protected]).

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Imaging—Subsequent magnetic resonance imaging peau d’orange change to the epidermis (Figure 2A). Based revealed a large, irregular, enhancing mass within the on pathologic analysis, she was worked up for a possible outer left breast (6.5 cm at greatest dimension) with granulomatous etiology. Negative purified protein deriva- additional surrounding amorphous enhancement highly tive (tuberculin)(PPD) and a normal chest radiograph suspicious for malignancy. There also were multiple ruled out tuberculosis. Normal chest radiography, serum prominent left axillary lymph nodes, with the largest Ca2+ and angiotensin-converting enzyme (ACE) levels, demonstrating a cortical thickness of 8 mm. and ophthalmology examination ruled out sarcoidosis. Biopsy—Core showed benign tissue The patient reported she continued breastfeeding her with . Fine-needle aspiration revealed few 4-year-old son. Additionally, she had been started on benign ductal cells and rare histiocytes; because these trazadone and buspirone for alcohol abuse recovery, then findings were nondiagnostic and cancer was still a con- switched to and maintained on fluoxetine 1 year before sideration, the patient underwent excisional biopsy. developing these symptoms. Histologic sections of breast tissue showed exten- Buspirone, fluoxetine, and prolonged breastfeeding sive lobulocentric comprising histiocytes all contribute to hyperprolactinemia, a possible trigger of and lymphocytes, with neutrophils admixed and forming IGM. The patient was therefore advised to stop breast- microabscesses (Figure 1A). Multinucleated giant cells and feeding and to be switched from fluoxetine to a medica- single-cell necrosis were seen, but true caseous necro- tion that would not increase the level. She did sis was absent (Figure 1B). Duct spaces often contained not require methotrexate treatment because her condi- inflammatory cells or secretions. Special stains for fungal tion resolved rapidly after breastfeeding and fluoxetine and acid-fast bacterial microorganisms were negative. were discontinued (Figure 2B). Referral to Dermatology—Granulomatous lobular mas- titis was diagnosed, and the patient was referred to der- Patient 2 matology. On presentation to dermatology, the left breast A 40-year-old womancopy with no history of breastfeeding showed a 6-cm area of firm induration and overlying who gave birth 4.5 years prior presented to her primary care provider with a painful breast lump and rash on the right breast of 2 months’ duration. Infectious mastitis was not Do

A

CUTIS A

B B FIGURE 1. A, Histopathology showed breast tissue with inflamma- tion in a lobulocentric distribution (H&E, original magnification ×40). FIGURE 2. A, Firm induration and overlying peau d’orange change B, Neutrophilic microabscess (left side) and multinucleated cells also to the epidermis at presentation to the dermatology department. were seen (H&E, original magnification ×400). B, Resolution after discontinuation of breastfeeding and fluoxetine.

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suspected; she was given cephalexin and clindamycin 8 months compared to prior unremitting and drain- without improvement of symptoms. age. She was then tapered from methotrexate over Imaging—Mammography and ultrasonography 6 weeks without additional flares. were nondiagnostic. Biopsy—Breast biopsy showed tissue with large Patient 3 expanses of histiocytes, neutrophils, lymphocytes, plasma A 27-year-old woman who gave birth 2 years prior and cells, and multinucleated giant cells (Figure 3A). Many discontinued breastfeeding 6 weeks after delivery noted discrete granulomas were seen against this mixed inflam- bilateral breast rashes for several months. The lesions matory background, associated with focal fat necrosis were growing in size, tender, and draining. Her primary (Figure 3B). Special stains were negative for microorgan- care provider suspected infectious mastitis and prescribed isms. Histologic findings were consistent with granulo- antibiotics, which were ineffective. matous mastitis. Biopsy—Breast core biopsy showed histologic findings Referral to Dermatology—On presentation to dermatol- similar to patients 1 and 2, including lobulocentric mixed ogy, the patient was worked up for a possible granuloma- inflammation, neutrophilic microabscesses, and scattered tous etiology, which included a negative PPD, as well as a discrete granulomas. Microorganisms were not found normal chest radiograph, serum Ca2+ and ACE levels, and using special stains. Breast cancer was ruled out, and ophthalmology examination. Review of symptoms (ROS), granulomatous mastitis was diagnosed. medical history, and medication review were unremarkable. Referral to Dermatology—Two years earlier, the patient By exclusion, the patient was given a diagnosis tested positive for latent tuberculosis and was prescribed of IGM and started on methotrexate (15 mg weekly) a 9-month regimen of isoniazid. At the current presenta- with folic acid (1 mg daily). The condition of the right tion, she did not have symptoms of active tuberculosis breast improved within 4 weeks of starting metho- on ROS (ie, no cough, hemoptysis, weight loss, night trexate; however, methotrexate was increased to 30 sweats); a chestcopy radiograph was normal. Additionally, mg weekly because of occasional flares. The patient serum Ca2+ and ACE levels as well as an ophthalmology remained on methotrexate without further IGM flares for examination were normal, and she was not taking any medications known to increase the prolactin level. The patient was started on methotrexate (12.5 mg weekly) andnot folic acid (1 mg daily). She had 1 IGM flare and was given a tapering regimen of prednisone. She received methotrexate for 14 months, tapered during the final 3 months. She has been off methotrexate for 3 years without DoIGM flares and appears to be in complete remission.

COMMENT We report 3 cases of IGM, which contribute to the litera- ture on possible presentations, causes, and conservative treatment of this rare connective-tissue disorder. A CUTIS The time between recognition of symptoms and diagnosis and treatment of IGM often is prolonged because IGM can present similarly to other disorders, such as infection, breast cancer, tuberculosis, and sarcoidosis. Idiopathic granulomatous mastitis is a diagnosis of exclusion, made after obtaining evidence of granulomatous inflammation on breast biopsy and ruling out other granulomatous disorders, such as tuberculosis and sarcoidosis (Table 1).3,4 Tuberculosis—A full ROS and a PPD test or T-SPOT.TB test can be helpful in ruling out tuberculosis; because anergy occurs in some patients, tuberculosis should be B evaluated in the context of known immunosuppression or human immunodeficiency virus status, or in the case FIGURE 3. A, Large expanses of histiocytes, neutrophils, lymphocytes, of miliary tuberculosis. plasma cells, and multinucleated giant cells were seen (H&E, original Chest radiography findings classically showing magnification ×20). B, Two granulomas were seen in a mixed inflam- matory background; the granuloma on the right side contained a neu- upper lobe infiltrates with cavities in active tuberculosis 3 trophilic microabscess (H&E, original magnification ×400). also should be sought. Ziehl-Neelsen staining of 2 spu- tum specimens, assessed by conventional light microscopy

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at the time of tissue biopsy has 64% sensitivity and cause oligomenorrhea or amenorrhea and 98% specificity for detecting tuberculo- in 90% and 80% of premenopausal women, respectively, sis; auramine O staining, examined with light-emitting as well as erectile dysfunction and decreased libido in diode fluorescence microscopy, has 73% sensitivity and men. Infertility, headache, and visual impairment may be 93% specificity.5 experienced in both sexes.4 Sarcoidosis—Because more than 90% of sarcoid A normal prolactin level is less than 25 μg/L; more patients have lung disease, a chest radiograph is used to than 25 μg/L but less than 100 μg/L usually is due to screen for hilar lymphadenopathy.3 An elevated serum certain drugs (eTable),6-11 estrogen, or idiopathic reasons; ACE level also can be helpful in diagnosis, but patients do and more than 150 μg/L usually is due to prolactinoma.5 not always have increased ACE, which can occur in other In many cases, removal of hyperprolactinemia-precipitating diseases, such as hyperthyroidism and miliary tuberculosis. factors can resolve disease, as in patient 1. If symp- Sarcoid granulomas can increase active vitamin D produc- toms continue or precipitating factors are absent, IGM tion, which in turn increases serum Ca2+ in 10% of sarcoid symptom-based treatment should be administered. patients. Last, an ophthalmology evaluation should be obtained to rule out anterior or posterior uveitis that can Course and Management occur in sarcoidosis and initially remain asymptomatic.3 Idiopathic granulomatous mastitis is self-limited and usu- Once these other causes of granulomatous inflammation ally resolves within 2 years. Therefore, the goal of treatment have been ruled out, a diagnosis of IGM can be made. is to suppress associated pain and drainage until the active Prolactinoma—Prolactinoma is an important cause of inflammatory phase of IGM self-resolves. An established hyperprolactinemia that can be screened for based on protocol for treating IGM does not exist, but common treat- ROS and the serum prolactin level. Prolactinoma can ments include corticosteroids, methotrexate, and limited or copy TABLE 1. Workup of Granulomatous Breast Disease3 Diagnosis Tests not Behaviors associated with IGM Long-term breastfeeding

Medications associated with IGM See eTable

Prolactinoma4 MRI evidenceDo of pituitary adenoma, serum prolactin level (>150 μg/L)

Sarcoidosis ACE, chest radiograph, ophthalmology examination (for uveitis), serum Ca2+

Triggering infection (Corynebacterium, Tissue culture for bacteria, fungi, atypical mycobacteria Histoplasma, mycoses)

Tuberculosis PPD, T-SPOT.TB test, tissue staining Abbreviations: IGM, idiopathic granulomatousCUTIS mastitis; MRI, magnetic resonance imaging; ACE, angiotensin-converting enzyme; PPD, purified protein derivative (tuberculin).

TABLE 2. Treatment Options for Idiopathic Granulomatous Mastitis12-16

Treatment Symptom Resolution Recurrence Side Effects Level of Evidence

Corticosteroids 80% 23% Cushing syndrome, gastritis, glucose Prospective intolerance, osteoporosis, weight gain observational studies

Methotrexate 83% 17% Birth defects,a stomatitis Case reports (with folic acid) Surgical excision 100% 5%–50% , chronic pyogenic Prospective and secretions, disfigurement, fistula retrospective observational studies

aWhen taken during pregnancy.

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wide surgical excision (Table 2).12-16 Before beginning any of Surgical excision can be performed in cases refractory these treatments, IGM triggers, such as breastfeeding and to all systemic therapies. drugs that induce hyperprolactinemia, should be removed. It is important to consider which treatment option is CONCLUSION best for limiting disease recurrence and adverse effects Idiopathic granulomatous mastitis is a rare granulomatous (AEs). Keep in mind that the available data are limited, as breast disorder that can have a prolonged time to diagno- there are no randomized controlled trials looking at these sis, delaying proper treatment. Many cases self-resolve, treatments. Nevertheless, we recommend methotrexate but more severe cases can persist for a long period before as first line because it resolves granulomatous inflamma- adequate symptomatic treatment is achieved by metho- tion symptoms without invasive surgery, while limiting trexate, corticosteroids, or surgical excision. Before using AEs.12 these therapies, it is important to identify and remove With or without concurrent use of corticosteroids, contributing factors, such as long-term breastfeeding and surgical excision typically is the mainstay of treatment. drugs that induce hyperprolactinemia. Improving the rate However, surgical excision of IGM lesions can be compli- of IGM diagnosis and treatment would greatly benefit cated by abscess formation, fistula, and chronic pyogenic these patients. We report 1 case in which removal of pos- secretions, in addition to a 5% to 50% rate of recurrence sible precipitating IGM factors led to symptom resolution of disease.12-14 Limited excision often is insufficient; and 2 cases in which methotrexate was an effective IGM therefore, wide local excision, in which negative margins treatment that limited the need for invasive procedures around granulomatous inflammation are obtained, is the and corticosteroid AEs. surgical modality of choice.14 Wide local excision can be disfiguring to the breast in young women affected by REFERENCES IGM, making it an undesirable treatment option. 1. Patel RA, Strickland P, Sankara IR, et al. Idiopathic granulomatous Corticosteroids often have been used to treat IGM, but mastitis: case reportscopy and review of literature. J Gen Intern Med. 2010;25:270-273. their efficacy is variable, symptoms can recur upon drug 2. Bellavia M, Damiano G, Palumbo VD, et al. Granulomatous mastitis removal, and remarkable AEs can result from long-term during chronic antidepressant therapy: is it possible a conservative thera- use.12 Additionally, corticosteroid therapy often is used in peutic approach? J Breast Cancer. 2012;15:371-372. combination with excision, making it difficult to deter- 3. Longo D, Fauci A, Kasper D, et al. Harrison’s Principles of Internal Medicine. mine the extent to which corticosteroids or excision are not18th ed. New York, NY: McGraw-Hill; 2012. 4. Davis JL, Cattamanchi A, Cuevas LE, et al. Diagnostic accuracy of same- more beneficial. In a prospective observational study, cor- day microscopy versus standard microscopy for pulmonary tuberculosis: ticosteroid therapy alone resolved 80% of IGM symptoms a systematic review and meta-analysis. Lancet Infect Dis. 2013;13:147-154. after 159 days on average. After complete symptom reso- 5. Casanueva FF, Molitch ME, Schlechte JA, et al. Guidelines of the lution, 23% of patients had disease recurrence.9 ObservedDo Pituitary Society for the diagnosis and management of prolactinomas. AEs included gastritis, weight gain, osteoporosis, glucose Clin Endocrinol (Oxf). 2006;65:265-273. 12,15 6. Akbulut S, Arikanoglu Z, Senol A, et al. Is methotrexate an acceptable intolerance, and Cushing syndrome. treatment in the management of idiopathic granulomatous mastitis? Methotrexate for IGM has not been reviewed in a Arch Gynecol Obstet. 2011;284:1189-1195. randomized controlled trial; case reports have shown 7. Bani-Hani KE, Yaghan RJ, Matalka II, et al. Idiopathic granulomatous mas- 83% symptom resolution, with 17% recurrence and titis: time to avoid unnecessary mastectomies. Breast J. 2004;10:318-322. limited long-term AEs.12 Because the active phase of 8. Asoglu O, Ozmen V, Karanlik H, et al. Feasibility of surgical management in patients with granulomatous mastitis. Breast J. 2005;11:108-114. IGM can persist for 2 years, immunosuppressive therapy CUTIS 9. Pandey TS, Mackinnon JC, Bressler L, et al. Idiopathic granulomatous with limited AEs is necessary. Many AEs can occur when mastitis—a prospective study of 49 women and treatment outcomes with high-dose methotrexate is given for cancer treatment. steroid therapy. Breast J. 2014;20:258-266. Low-dose methotrexate has been extensively studied 10. Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic in long-term treatment of rheumatoid arthritis. Adverse acid for reducing side effects in patients receiving methotrexate for rheu- matoid arthritis. Cochrane Database Syst Rev. 2013;5:CD000951. effects may include gastrointestinal tract upset and hepatic 11. Molitch ME. Drugs and prolactin. Pituitary. 2008;11:209-218. dysfunction, which are limited when given with folic acid. 12. Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly Regardless of folic acid cotreatment, stomatitis may approved antipsychotics on serum prolactin levels: a comprehensive occur. Women should use an effective method of birth review. CNS Drugs. 2014;28:421-453. control because severe birth defects may occur on even 13. Kondo T, Otani K, Ishida M, et al. Adverse effects of zotepine and their 16 relationship to serum concentrations of the drug and prolactin. Ther Drug low-dose methotrexate. Monit. 1994;16:120-124. Compared to corticosteroid or surgical treatment, we 14. Sharpe M, Clements A, Hawton K, et al. Increased prolactin response to recommend low-dose methotrexate therapy based on its buspirone in chronic syndrome. J Affect Disord. 1996;41:71-76. high efficacy with limited AEs. An occasional mild flare 15. Risch SC, Janowsky DS, Siever LJ, et al. Correlated cholinomimetic- of IGM symptoms with methotrexate is not unusual. If stimulated beta-endorphin and prolactin release in humans. Peptides. 1982;3:319-322. it occurs, corticosteroids can be added and tapered for 16. Pedrini JL, Francalacci Savaris R, Casales Schorr M, et al. The effect of as long as 2 weeks to speed up resolution of flares while neoadjuvant chemotherapy on hormone receptor status, HER2/neu and reducing long-term AEs of corticosteroids. prolactin in breast cancer. Tumori. 2011;97:704-710.

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APPENDIX

eTABLE. Drugs That Induce Sustained Hyperprolactinemia6,7

Class Medications

Antihypertensives Labetalol, methyldopa, reserpine, verapamil

Antipsychotics Typical: butyrophenones (eg, haloperidol), phenothiazines (eg, chlorpromazine, thioridazine), thioxanthines; atypical: asenapine, benzamides (eg, amisulpride), clozapine, iloperidone, lurasidone, molindone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, zotepine8 Hormone-based preparations Antiandrogens, estrogens, oral contraceptives

Monoamine oxidase inhibitor antidepressants Clorgyline, pargyline, tranylcypromine

Opiates and cocaine Cocaine, methadone, morphine

Selective serotonin-reuptake Citalopram, fluoxetine, fluvoxamine, paroxetine inhibitor antidepressants

Tricyclic antidepressants Amitriptyline, amoxapine, clomipramine, desipramine, imipramine, maprotiline

Other psychotropics Alprazolam, buspirone9

Others Alcohol, chemotherapeutic agents,11copy fenfluramine, physostigmine10 not Do

CUTIS

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