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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
AUTOIMMUNE CAUSES1.CROHN’S DISEASE 2.SARCOIDOSIS3.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 Roentgenology2009193:2 574-581 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 to1. Immunosuppressive therapy which was measured as complete
remission, near complete remission and partial remission2. The role of antibiotics, 3. The surgical treatments
RESULTS
PARAMETERS OBSERVED IN HISTORY
Mean age at presentation 42.83 years
Race Caucasian Asian
5/7(71.42 %) 2/7(28.4%)
History of Autoimmune disease
5/7 ((71.42 %).
Rheumatic Autoimmune disease Non Rheumatic Autoimmune disease
3/5 (60%) 3/5 (42.8%)Sjogren’s Syndrome
Rheumatoid Arthritis
Vasculitis Hypothyrioidism Psoriasis without joint involvement
1 1 1 2 1
Personal history of breast cancer
1/7( 14.3%)
Family history of Breast Cancer
1/7 (14.3%)
History of Breast Implant 1/7 (14.3%)
Smoking history 2/7 (28.6 %)
Pregnancy within the last two years
2/7 (28.6 %)
Breast feeding within the last two years
1/7 (14.3 %)
STATISTICAL ANALYSIS OF THE AGE OF PATIENTS
Mean 46.42857143
Median 42
Variance 206.6190476
Standard Deviation 14.37424946
PARAMETERS OBSERVED ON PHYSICAL EXAMINATION
Constitutional symptoms Fatigue (most common 83%), Fever, Night sweats, Weakness
Articular manifestations Arthralgia
Arthritis Chronic Neck and Back pain
3/7 1/7 (in association with Rheumatoid arthritis)
1/7
Extra-articular manifestations
3/7
Erythema Nodosum 1
Dry mouth and dry eyes
1
Psoriatic skin rash 1
laterality Unilateral Bilateral
5/7 (71.4%)
Right Left 1/7 (14.3%)
1/7 (14.3 %)
4/7(57.1%)
Nipple discharge 1/7 (14.3%)
Draining sinuses 4/7 (57.1%)
Abscesses and Ulcers 7/7 (100%)
Lymph nodes palpable or detected on imaging
Palpable as well as on imaging
On imaging alone
1/7 (14.3%) 3/7 (42.8 %)
71%
29%
Articular manifestations
With Articular manifestations Without Articular manifestations
60%20%
20%
Articular Manifestations:Detailed Analysis
Arthritis arthralgia chronic neck and back pain
34%
33%
33%
Extra-articular manifestations:Detailed Analysis
Erythema nodosum Dy mouth and dry eyes Psoriatic skin rash
IMAGING STUDIES AND HISTOPATHOLOGY
Ultrasound dilated ducts to complex cystic structures consistent with abscesses, dense parenchymal
lobules, increased thickness of skin and subcutaneous nodules.
Mammogram Mammographic changes reported were nodularity with internal echoes, hyper dense
parenchymal changes, changes consistent with abscesses and enlarged lymph nodes.
Histopathology All seven patients had histologically proven granulomatous mastitis. Other findings
reported on histopathology included foreign body giant cells, acute mastitis, abscesses, and
fat necrosis and duct ectasias. Most interesting association was with
lymphocytic infiltration within in smooth muscles of walls of blood vessels of breast in one patient consistent with lymphocytic
vasculitis of the breast
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
INFECTIOUS DISEASE WORKUP AND ANGIOTENSIN CONVERTING ENZYME
Gram stain Negative
AFB Negative
Bacterial Cultures Negative
Fungal Cultures Negative
Angiotensin Converting Enzyme Negative
MARKERS OF AUTOIMMUNITY
Patient 1 Negative
Patient 2 ANA 1:132, speckled pattern
Patient 3 Elevated ESR,CRP,Positive Anti SSB, reduced C3
Patient 4 Negative
Patient 5 Elevated ESR, IgE level very high
Patient 6 Anti CCP Positive
Patient 7 ANA positive, pANCA Positive
TREATMENTS AND OUTCOMES OF TREATMENT
Patient 1 2 3 4 5 6 7
Incision and
Drainage
Yes Yes Yes Yes Yes yes yes
Excision No No No No Yes, localexcision
no no
Antibiotics Multiple Courses
Multiple Course
Multiple Courses
Multiple Courses
Multiple Courses
Multiple Courses
Multiple Courses
Prednisone
Yes Yes Yes Yes Yes Yes Yes
Methotrexate
yes Yes Yes Yes Yes Yes Yes
Treatment outcomes
Full Remission
Full remission
Full Remission
Full Remission
Partial remission
Near Complete remission
Near complete remission
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 mastitisNo 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.