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 HISTORYMean age at presentation 42.83 years

Race Caucasian Asian5/7(71.42 %) 2/7(28.4%)

History of Autoimmune disease

5/7 ((71.42 %). Rheumatic Autoimmune disease Non Rheumatic Autoimmune

disease3/5 (60%) 3/5 (42.8%)

Sjogren’s Syndrome 

Rheumatoid Arthritis

Vasculitis Hypothyrioidism Psoriasis without joint involvement

1 1 1 2 1Personal history of breast

cancer1/7( 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 PATIENTSMean  46.42857143Median  42Variance 206.6190476Standard Deviation 14.37424946

PARAMETERS OBSERVED ON PHYSICAL EXAMINATIONConstitutional symptoms Fatigue (most common 83%), Fever, Night sweats,

WeaknessArticular manifestations

Arthralgia

Arthritis Chronic Neck and Back pain

3/7 1/7 (in association with Rheumatoid arthritis)

1/7

Extra-articular manifestations

3/7Erythema Nodosum

1Dry mouth and dry

eyes 1

Psoriatic skin rash 1

laterality Unilateral Bilateral5/7 (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 imagingPalpable as well as on

imagingOn imaging alone

1/7 (14.3%) 3/7 (42.8 %)

71%

29%

Articular manifestationsWith 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 AnalysisErythema nodosum Dy mouth and dry eyes Psoriatic skin rash

IMAGING STUDIES AND HISTOPATHOLOGYUltrasound 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 AUTOIMMUNITYPatient 1 NegativePatient 2 ANA 1:132, speckled patternPatient 3 Elevated ESR,CRP,

Positive Anti SSB, reduced C3Patient 4 NegativePatient 5 Elevated ESR,

IgE level very highPatient 6 Anti CCP Positive

Patient 7 ANA positive, pANCA Positive

TREATMENTS AND OUTCOMES OF TREATMENTPatient 1 2 3 4 5 6 7Incision

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

MarkersGranulomatous

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 

CONCLUSIONMore studies are needed to be done, retrospectively as well as 

prospectively1. 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.