GRANULOMATOUS MASTITIS: AN AUTOIMMUNE PROCESS OR IDIOPATHIC? A CASE SERIES STUDY AMINA LODHI, PGY 3 MICHAEL GRISANTI, MD JOSEPH GRISANTI, MD BUFFALO RHEUMATOLOGY

GRANULOMA The term granuloma refers to a nodular organized aggregation of mononuclear inflammatory cells or collection of modified macrophages referred to as epithelioid cells, usually surrounded by a rim of lymphocytes and often containing multinucleated giant cells. Some granulomas may also contain eosinophils and plasma cells.

ETIOLOGY OF GRANULOMATOUS INFLAMMATION INFECTIOUS CAUSES 1.BACTERIAL TUBERCULOSIS LEPROSY CAT SCRATCH DISEASE 2. FUNGAL HISTOPLASMOSIS CRYPROCOCCOSIS 3.PROTOZOAL SHISTOSOMIASIS AUTOIMMUNE CAUSES 1.CROHN’S DISEASE 2.SARCOIDOSIS 3.VASCULITIS GRANULOMATOSIS WITH POLYANGIITIS (WEGNER’S GRANULOMATOSIS) GIANT CELL ARTERITIS TAKAYASU’S ATERITIS CHURG-STRAUSS SYNDROME INERT MATERIALS 1.SILICON 2.BERYLLIUM IDIOPATHIC

PATHOGENESIS OF GRANULOMA FORMATION Events that give rise to the formation of granuloma and role of cytokines in the pathogenesis of granuloma (courtesy Robins Pathologic Basis of Disease, Chapter 5- Diseases of the immune system)

GRANULOMATOUS MASTITIS Granulomatous mastitis also called granulomatous lobular mastitisis is a benign chronic inflammatory condition of breast which is diagnosed histologically by the presence of granulomas. Its clinical presentation is very vague, mimicking breast abscesses, breast mass and inflammatory carcinoma of breast. It has chronic course with frequent recurrences.

GRANULOMATOUS MASTITIS ETIOLOGY: – Lactation – Trauma – Largely been considered idiopathic TREATMENT – SURGERY : As primary treatment modality. Wide local excision as well as radical mastectomy Outcomes of surgery_ recurrence, Failure to induce full remission, local scarring – MEDICAL TREATMENT: Prednisone and Methotrexate

GRANULOMATOUS MASTITIS LITERATURE REVIEW – Most of the studies are either individual case reports or a series of case reports – Most of them come from Surgery, Dermatology, Radiology or Pathology – It has not been studied enough by the non- surgical subspecialties – The countries in which it is studied mostly include Italy, Turkey, India, Pakistan

Largest that has been done so far Granulomatous Lobular Mastitis: Imaging, Diagnosis andTreatment Linda J. Hovanessian Larsen, Banafsheh Peyvandi, Nancy Klipfel Edward Grant and Geeta Iyengar American Journal of Roentgenology : Department of Radiology, University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, 1441 Eastlake Ave., Ste. 2315, Los Angeles, CA 90033

METHODS PATIENTS To investigate the association between granulomatous mastitis and autoimmunity we conducted a case series study of seven patients with histologically proven granulomatous mastitis who were being treated at Buffalo Rheumatology between 2010 and 2013.

METHODS OBSERVED PARAMETERS : We measured different parameters in the patients history; age, race, history of rheumatic autoimmune disease and history of non-rheumatic autoimmune disease, personal or family history of breast cancer, history ofpregnacy and lactation and history of smoking. Then we focused on the clinical presentation of the disease and looked if the disease was unilateral or bilateral, the presence or absence of nipple discharge, other nipple changes, ulcers, palpable masses, draining sinuses, lymphadenopathy, presence or absence of constitutional symptoms, associated articular manifestations, extra-articular manifestations.

METHODS OBSERVED PARAMETERS: Also reviewed were the investigations to reach diagnosis including inflammatory and autoimmune markers, angiotensin converting enzyme levels as sarcoidosis is an important differential diagnosis to consider, ultrasound and mammographic description of the lesions and the histologic appearance of the lesions. Attention was also paid to the workup that was done to exclude infectious causes of granulomatous mastitis including gram stain, AFB stain, fungal and bacterial cultures.

METHODS OBSERVED PARAMETERS: Finally we evaluated the treatment outcomes in these patients. We evaluated their response to 1.Immunosuppressive therapy which was measured as complete remission, near complete remission and partial remission 2.The role of antibiotics, 3.The surgical treatments

RESULTS

STATISTICAL ANALYSIS OF THE AGE OF PATIENTS Mean Median42 Variance Standard Deviation

Granulomatous inflammation with foreign body giant cells, ductal ectasia with eosinophillic cellular material, focal areas of fat necrosis

Multiple vaguely nodular areas of neutrophils, mature lymphocytes, macrophages and plasma cells consistent with granulomas with necrosis, areas of fat necrosis

Acute purulent mastitis with areas of fibrin-o-purulent material consisting of neutrophils and areas of granulomatous lobular mastitis

Acute mastitis with abscess formation and granulomatous lobular mastitis with areas necrosis and multinucleated giant cells surrounding ducts. Diffuse fibrin-o-purulent material.

Abscess formation with areas of granulomatous inflammation with foreign body giant cells and granulation tissue, Areas of fat necrosis.

Areas of fat necrosis, blood vessels with lymphocytes within the smooth muscle walls-lymphocytic vasculitis of breast with areas of granulomatous inflammation

Negative History No Autoimmune Markers Granulomatous mastitis ? History of bilateral breast implants, Psoriasis Granulomatous mastitis Elevated ESR, Elevated IgE levels ? Negative history No Autoimmune markers Granulomatous mastitis, Sjogren syndrome, ESR, CRP, Positive Anti SSA ? History of Rheumatoid Arthritis Ani CCP Positive Granulomatous mastitis ? History of hypothyroidism Granulomatous mastitis ANA Positive 1:320,speckled ? Negative history No Autoimmune Markers Granulomatous mastitis No Autoimmune Markers ? History of Hashimoto thyroiditis, breast cancer,Treated with lumpectomy/radiation and chemotherapy Granulomatous mastitis in association with Lymphocytic vasculitis of breast,Positive ANA pANCA ?

CONCLUSION __ ________ __ _______ __ __________ ________ ___ ___ _______ __ ____________ __ __ ________ ___ ____ ________________ ____ __________ ___ ____________ ___ ____ __ ______ _________ _____ ____ __ _____ __ ____ __ ____________ __ __ ________ ___ __ __________ _______ ________ __ _______ __ ___ __________ ________ _____ _______ _____ ______ __ _____________ __ ___ __ ____ _______ _____ ___ ________ __ ___ __________ ________ __ ___________ ____ ________ __________ _______ __ ________ __________ _______ _ ___ __ _ _______ ________ __ _ _________ ________ __ ___________ ____ _____ __________ ________ The presence of history of autoimmune diseases and the markers of autoimmunity in 71% of patients and that immunomodulation with prednisone and methotrexate was able to induce remission shows that it there is role of autoimmunity in it. 29 % patients had no autoimmune markers positive, no history of any autoimmune disorder which demands close follow up prospectively to see if they develop signs and symptoms of any autoimmune disorder or seroconvert from negative autoimmune markers to positive autoimmune markers. It can be a primary disorder or a secondary disorder in association with other autoimmune diseases.

CONCLUSION Granulomatous mastitis is a medically manageable disease with the mainstay of treatment being immunosupressive therapy Failure to induce remission and recurrence is not uncommon with primary immunomodulating agents Considering important role of TNF in the pathogenesis of formation as well as maintenance of granuloma, there can be a potential role of anti TNF therapy in such patients who fail to respond to first line immunosuppressive agents. Role of surgery is only limited to the incision and drainage in case of signs and symptoms of concurrent infection, biopsy and excision for the purpose of diagnosis

CONCLUSION More studies are needed to be done, retrospectively as well as prospectively 1.To find the association between granulomatous mastitis and autoimmune disorders and different autoimmune markers. 2.To find if there are any markers which are unknown to us at this time which are either specifically associated with granulomatous mastitis or are common between granulomatous mastitis and other autoimmune disorders 3.To identify the environmental, clinical as well as biological factors that play a role in the pathogenesis of granulomatous mastitis 4.To formulate reasonable treatment algoriths to treat it with success

CONCLUSION There is a need to spread awareness of this disease among the PCP as well as specialists, so that these patients who present with recurrent breast abscesses with failure to respond to antibiotics and multiple incision and drainage with little or no success can be identified, worked up for this diagnosis and managed appropriately.