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 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 5Diseases 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
PATIENTS
METHODS
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
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
Articular manifestations
Fatigue (most common 83%), Fever, Night sweats, Weakness
Arthralgia
Arthritis
3/7
Chronic Neck
and Back pain
1/7 (in association with
1/7
Rheumatoid arthritis)
Extra-articular manifestations
3/7
Erythema Nodosum
1
laterality
Dry mouth and dry eyes
1
Unilateral
Psoriatic skin rash
1
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
1/7 (14.3%)
On imaging alone
3/7 (42.8 %)
Articular manifestations
With Articular manifestations
Without Articular manifestations
29%
71%
Articular Manifestations:Detailed Analysis
Arthritis
arthralgia
chronic neck and back pain
Extra-articular manifestations:Detailed Analysis
Erythema nodosum
Dy mouth and dry eyes
Psoriatic skin rash
20%
33%
20%
34%
60%
33%
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, local
excision
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
Methotrexat
e
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
Granulomatous mastitis
No Autoimmune Markers
No Autoimmune Markers
?
Granulomatous mastitis
History of hypothyroidism
Negative history
No Autoimmune markers
Negative History
No Autoimmune Markers
History of bilateral breast
implants, Psoriasis
History of Rheumatoid
Arthritis Ani CCP Positive
ANA Positive
1:320,speckled
?
Granulomatous
mastitis, Sjogren
syndrome, ESR, CRP,
Positive Anti SSA
?
Granulomatous
mastitis
?
Granulomatous
mastitis
Elevated ESR,
Elevated IgE levels
Granulomatous
mastitis
History of Hashimoto thyroiditis, Granulomatous mastitis in
breast cancer,Treated with
association with Lymphocytic
vasculitis of breast,Positive
lumpectomy/radiation and
ANA pANCA
chemotherapy
?
?
?
markers of autoimmunity in 71% of patients and that
•
CONCLUSION
__ ________ __ _______ __ __________ ________ ___ ___ _______ __
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,
history
___ __
__________
_______ ________
_______ __no
___
__________ ________ _____ _______ _____ ______ __ _____________ __ ___
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
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.