A Retrospective / Prospective Cohort Study to Evaluate the Incidence, Diagnostic Features, Clinical Course and Treatment Strategies in Histologically Confirmed Idiopathic Granulomatous Mastitis
Conditions: Idiopathic Granulomatous Mastitis, Granulomatous Mastitis
Sponsor: European Breast Cancer Research Association of Surgical Trialists

 
 
 
 
 
 
 
 
GRAnulomatous MAstitis REGistry study 
 
(EUBREAST-15) 
 
 
A retrospective / prospective Cohort Study to evaluate the Incidence, 
Diagnostic Features, Clinical Course and Treatment Strategies in 
histologically confirmed  
Idiopathic Granulomatous Mastitis  
 
 
 
 
Study Protocol 
 
 
 
 
 
Version 1.4 
 
01.07.2025 
 
 
 

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Table of Contents 
 
 
1. 
Study administration ................................................................................................................. 3 
2. 
Glossary and Abbreviations .................................................................................................... 7 
3. 
Rationale ....................................................................................................................................... 8 
4. 
Methods ...................................................................................................................................... 10 
4.1. 
Study design ...................................................................................................................... 10 
4.2. 
Aims and objectives ........................................................................................................ 10 
4.3. 
Inclusion and exclusion criteria ................................................................................... 10 
4.4. 
Registration ........................................................................................................................ 11 
4.5. 
Target accrual .................................................................................................................... 11 
4.6. 
Study duration ................................................................................................................... 12 
5. 
Data management..................................................................................................................... 13 
5.1. 
Data Purpose ..................................................................................................................... 14 
5.2. 
Data Ownership................................................................................................................. 14 
6. 
Publication and authorship policy ....................................................................................... 15 
6.1. 
Named authors .................................................................................................................. 15 
6.2. 
Acknowledged collaborators ........................................................................................ 15 
7. 
Statistical considerations ....................................................................................................... 16 
8. 
Safety ........................................................................................................................................... 16 
9. 
Funding ....................................................................................................................................... 16 
10. References ................................................................................................................................. 17 
11. Protocol Change Log ............................................................................................................... 18 
 
 
 
 
 
 

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1. Study administration 
 
 
Principal Investigators 
Prof. Dr. med. Maggie Banys-Paluchowski 
Vice-Chair of EUBREAST e.V. 
Head of Breast Cancer Center 
Head of Center for Familial Breast and Ovarian Cancer 
Department of Gynecology and Obstetrics 
University Hospital Schleswig-Holstein 
Campus Lübeck 
Lübeck, Germany 
 
Priv.-Doz. Dr. med. Natalia Krawczyk 
Leading Senior Physician  
Department of Gynecology and Obstetrics 
University Hospital Düsseldorf 
Düsseldorf, Germany  
Steering Board 
Dr. Sadaf Alipour 
Professor of Oncologic Surgery 
Breast Surgeon- Arash Women’s Hospital 
Deputy of Research- Breast Disease Research Center 
Tehran University of Medical Sciences 
Tehran, Iran 
Prof. Dr. med. Vesna Bjelic-Radisic 
Head of the Breast Center and the Department of Senology 
Helios University Hospital Wuppertal  
Wuppertal, Germany  
Prof. Dr. Jana de Boniface 
Associate Professor at the Department of Molecular Medicine and Surgery 
Karolinska Institutet 
Department of Surgery, Breast Centre 
Capio St. Göran's Hospital 
Stockholm, Sweden 
Prof. Dr. med. Nina Ditsch 

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Treasurer of EUBREAST e.V.  
Head of Breast Cancer Center 
University Hospital Augsburg 
Augsburg, Germany 
Prof. Maria Luisa Gasparri 
Treasurer of EUBREAST Italy 
Department of Gynecology and Obstetrics 
Ospedale Regionale di Lugano EOC  
Centro di Senologia della Svizzera Italiana (CSSI), Ente Ospedaliero Cantonale 
Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI) 
Lugano, Switzerland 
Prof. Oreste Gentilini 
Chairman of EUBREAST Italy 
Head of Department of Breast Surgery 
Ospedale San Raffaele 
Milan, Italy 
Prof. Dr. med. Markus Hahn 
President of German Society of Ultrasound in Medicine (DEGUM) 
Head of Experimental Senology 
Department of Women’s Health 
University Hospital Tübingen 
Eberhard Karls University of Tübingen 
Tübingen, Germany 
Priv.-Doz. Dr. med. Steffi Hartmann 
Senior physician  
Department of Gynecology and Obstetrics 
University Hospital Rostock 
Rostock, Germany 
Prof. Dr. med. Güldeniz Karadeniz Çakmak 
Professor of Surgery 
Director of Breast and Endocrine Unit 
Zonguldak BEUN The School of Medicine 
Kozlu/Zonguldak, Turkey 
Prof. Cliona Kirwan 
Professor of Surgery 
Clinician Scientist in Surgical Oncology and Consultant Oncoplastic Breast Surgeon 

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Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and 
Health, University of Manchester 
Manchester, United Kingdom  
Prof. Dr. med. Thorsten Kühn 
Chairman of EUBREAST e.V. 
Department of Gynecology and Obstetrics 
University of Ulm  
Ulm, Germany 
Dr. Yazan Masannat 
Consultant Oncoplastic Breast Surgeon 
Broomfield Hospital, Mid & South Essex NHS Trust, Chelmsford, Essex, England, UK 
Visiting Associate Professor 
Anglia Ruskin University, Cambridge, England, United Kingdom  
Dr. Rosa Di Micco 
Vice-Chair of EUBREAST Italy  
Breast Surgery Unit 
Ospedale San Raffaele  
Milan, Italy  
Prof. Dr. med. Annette Lebeau  
Senior physician 
Institute of Pathology  
University Medical Center Hamburg-Eppendorf | UKE 
Hamburg, Germany 
Group Praxis for Pathology 
Lübeck, Germany  
International Steering Committee – GRAMAREG-sono 
Prof. Dr. med. Nina Ditsch 
Treasurer of EUBREAST e.V.  
Head of Breast Cancer Center 
University Hospital Augsburg 
Augsburg, Germany 
Prof. Dr. med. Markus Hahn 
President of German Society of Ultrasound in Medicine (DEGUM) 
Head of Experimental Senology 
Department of Women’s Health 
University Hospital Tübingen 

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Eberhard Karls University of Tübingen 
Tübingen, Germany 
Priv.-Doz. Dr. med. Steffi Hartmann 
Senior physician  
Department of Gynecology and Obstetrics 
University Hospital Rostock 
Rostock, Germany 
Prof. Dr. med. Thorsten Kühn 
Chairman of EUBREAST e.V. 
Department of Gynecology and Obstetrics 
University of Ulm  
Ulm, Germany 
Dr. Rosa Di Micco 
Vice-Chair of EUBREAST Italy  
Breast Surgery Unit 
Ospedale San Raffaele  
Milan, Italy 
 
Data management 
EUBREAST (European Breast Cancer Research Association of Surgical Trialists) e.V. 
Chairman: Prof. Dr. med. Thorsten Kühn 
Esslingen, Germany  
 
 
 

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2. Glossary and Abbreviations 
 
IGM 
 
Idiopathic Granulomatous mastitis 
MRI 
 
Magnetic resonance imaging 
CNGM  
Cystic neutrophilic granulomatous mastitis 
 
 
 
 
 

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3. Rationale 
 
Idiopathic granulomatous mastitis (IGM) is a benign inflammatory condition of the breast first 
described by Kessler and Wolloch in 1972 [1]. The etiology of IGM is largely unknown due to 
its rare occurrence with an estimated prevalence of 2.4 per 100,000 women aged 20-40 years 
[2, 3]. Valid data on the prevalence of IGM in Europe are lacking. However, the incidence in 
the low-income countries appears to be higher compared to western Europe [4], [5], [6]. Since 
only case reports and small case series of IGM have been so far reported in the literature, our 
knowledge on risk factors, clinical course of disease, therapeutic management, and clinical 
outcomes is very limited. Based on the published cases, IGM is considered to predominantly 
occur in women of childbearing age, mostly parous and more frequently of non-white ethnicity 
[2, 7-10].  
 
The local symptoms of IGM are mostly severe, lasting up to many weeks or months, causing 
strong pain and often mimicking inflammatory breast cancer (Fig 1). Diagnosis can be 
confirmed only by histological evaluation, usually using core needle biopsy. The patients 
commonly develop recurrent breast abscesses, which do not improve on antibacterial 
medication and often require repeat incisions or drainages. The degree of suffering of IGM 
patients is therefore very high.  
 
IGM needs to be differentiated from granulomatous inflammation of the breast that can appear 
in duct ectasia, as a reaction to foreign material, or in association with specific infections (e.g., 
mycobacteria, fungi, parasites) as well as in the course of systemic granulomatous diseases 
such as sarcoidosis. Further, cystic neutrophilic granulomatous mastitis (CNGM) was recently 
described as a specific form of granulomatous inflammation of the breast linked to infection 
with Corynebacterium species. However, it has not be fully clarified whether CNGM represents 
a distinct entity or rather a subtype of IGM [11].  

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Figure 1. Clinical examples of idiopathic granulomatous mastitis.  
 
 
Treatments 
strategies 
including 
high-dose 
steroids, 
immunosuppressive 
agents, 
bromocriptine, antibiotics, and surgical resection or even mastectomy have been described in 
the published cases [10, 12-14]. However, no evidence-based treatment recommendations 
are available to date.  
 
GRAMAREG will be the first registry for patients with histologically confirmed idiopathic 
granulomatous mastitis in Europe with an aim to systematically evaluate this uncommon 
disease and its management as well patient outcomes (duration of symptoms and recurrence 
rate). 
  
 
 
 

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4. Methods 
 
4.1. 
Study design 
 
Investigator-initiated non-interventional observational international prospective / retrospective 
cohort study 
 
4.2. 
Aims and objectives 
 
Primary outcomes: 
• 
Proportion of patients presenting with specific symptoms (e.g., pain, redness, 
palpable mass) 
• 
Duration of symptoms depending on treatment strategy 
 
Secondary outcomes: 
• 
Type and duration of systemic treatment  
• 
Number of surgeries, if performed  
• 
Recurrence rate 
• 
Risk factors associated with recurrence  
• 
Time between first symptoms occurring and first histological confirmation  
• 
Presentation on breast imaging (mammography, sonography, MRI, if performed) 
 
The analysis of outcomes regarding diagnostics and ultrasound will be performed by the 
International Steering Committee GRAMAREG-sono. 
 
4.3. 
Inclusion and exclusion criteria 
 
Inclusion criteria 
• 
Histologically confirmed idiopathic granulomatous mastitis or cystic neutrophilic 
granulomatous mastitis by the local pathology (minimally invasive biopsy or 
histological confirmation on surgical specimen) after 01.01.2015  
• 
Female / male patients ≥ 18 years old 
• 
Signed informed consent form for all patients that are included in the prospective 
part of the study (presentation with idiopathic granulomatous mastitis after 
activation of the study at study site) 
 
Exclusion criteria 

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• 
Patients with suspicion of idiopathic granulomatous mastitis but without histological 
confirmation 
• 
Suspicion of or confirmed secondary granulomatous mastitis due to e.g., 
tuberculosis, sarcoidosis, fungal and parasitic infection, foreign body 
 
4.4. 
Registration  
 
This study is based on a database with both retrospective and prospective character.  
 
Retrospective data collection:  
Collection and analysis are performed via an anonymized electronic database maintained by 
EUBREAST e.V. The participating Study Sites commit themselves to identification and 
documentation of patients with histologically confirmed idiopathic granulomatous mastitis 
treated during the investigational period at their institution (i.e., between 1st January 2015 and 
activation of Study Site). No patient identifying information will be disclosed or documented. 
Data collected during the retrospective phase of the study will be fully anonymous. The 
retrospective data will not include prospective follow up.  
 
Prospective data collection:  
All patients with histologically confirmed idiopathic granulomatous mastitis presenting at the 
Study Site after activation of the study will be informed about the possible participation in the 
GRAMAREG registry. The inclusion and exclusion criteria are verified by the investigator and 
written informed consent is obtained from the patient.  
 
Diagnostic management and treatment should be conducted according to institutional 
standards. Since the GRAMAREG study in a non-interventional trial, the Study Sites do not 
deviate from their own institutional protocol at any timepoint. 
 
The follow up on patient status is conducted 1, 3 and 5 years after the first diagnosis. In order 
to collect follow up data the patients will be contacted directly by the study site to evaluate 
current symptoms (follow up after 1 year) and to document a potential recurrence of IGM 
(follow up 1, 3 and 5 years after the first diagnosis).  
 
4.5. 
Target accrual 
 
Unlimited  
 

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4.6. 
Study duration 
 
Open registry due to the rarity of the disease 
 
 
 
 

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5. Data management  
 
This part of the Protocol will discuss the Data Sharing and Data Management policy between 
two parties: The Provider & The Recipient. The Provider as per this agreement will be the 
Study Site supplying the dataset in accordance with the Protocol of the study. The Recipient 
will be EUBREAST e.V. who will collect the data in accordance with the Data Protection policy 
as set out in this agreement. Study data will be collected and managed using REDCap 
(Research Electronic Data Capture) electronic data capture tools hosted at the server 
belonging to and managed by EUBREAST. 
To register for the study, Study Sites (Providers) will contact the Head of their National Steering 
Committee to request participation in the Study and access to the online database. Each Study 
Site will then be designated a Site ID in format: Two-letter Country Code – Site number (e.g., 
DE-001 for the first German Study Site), which will be used as a prefix for the Patient ID (e.g., 
DE-001-001 for the first patient recruited at Study Site DE-001). All patients who consent to 
participation in the Study are recorded in the Subject Identification Log that remains at the 
study site. This document is the only record containing patient personal data and the 
corresponding Patient ID. EUBREAST does not have access to the Subject Identification Log 
at any time. No personal data will be disclosed under the Data Sharing Agreement. No patient 
identifiable data will be recorded for the purpose of the Study. 
For further analysis data are filled in the REDCap-based eCRF by the Study Site. The printed 
version of CRF (PDF file) is also available. Its use is optional. All data are checked for 
plausibility through remote monitoring. The Monitors do not have access to patient data and 
do not visit Study Sites. Are the data insufficient for evaluation of predefined study aims, the 
Monitor will generate a query and Study Site will be requested to clarify.  
REDCap has been disseminated for local use by more than 1,005 academic/non-profit 
consortium partners in 79 countries. Vanderbilt leads the REDCap Consortium, which currently 
supports more than 99,000 projects and 128,000 users. More information about the consortium 
and system security can be found at http://www.projectredcap.org/. REDCap is a secure, web-
based application designed to support data capture for research studies, providing 1) an 
intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and 
export procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages; and 4) procedures for importing data from external sources.  

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REDCap is created by Vanderbilt University, with the server hosted by the EUBREAST. 
REDCap was developed specifically around HIPAA-Security guidelines. Web browser 
communication to the server is SSL-encrypted by default. All other ports are firewall protected. 
Data is stored in MySQL databases on a separate server. This server is behind a firewall and 
can only be accessed from the IP address of the web server. An SSL-tunnel encrypts 
communication between the web and databases servers. File upload is secured between 
servers using theWebDAV protocol with SSL. “At rest” encryption is in place on the database 
server (aes-xts-plain64:sha256 with 512-bit keys). Daily back-ups are made of both servers 
and stored for two weeks prior to being deleted. Operating security updates are installed 
automatically. Antivirus software runs to a scheduled protocol on the web server. User 
passwords are managed directly. Accounts are disabled after 5 failed login attempts. Users 
are auto logged out after 30 mins of no activity. Daily audit tracking of users is in place with 
removal of unused user accounts.  
5.1. 
Data Purpose 
The Recipient will have access to the Data Set to the extent necessary for the purpose of the 
Study. The pseudonymized Data Set shall be made available only to the Party responsible for 
Statistical Analysis. The Data Set will not be disclosed, transferred, or made available to any 
other third party. Summary Safety data may be transferred to the Manufacturers; however, this 
will NOT include any personal patient data. The Data Set will be kept confidential, and all 
reasonable steps will be taken to protect it against accidental or unlawful loss, modification or 
destruction, or unauthorized access, disclosure, copying, use, misappropriation, or 
modification. Following study closure, datasets cannot be transferred to any third party without 
the permission of the Recipient. 
The results will be published in an academic publication. The Study Sites will be informed 
about the publication, and the publications will be uploaded to the EUBREAST website, the 
link to this publication will be sent to Study Sites. In accordance with customary scientific 
practice, any publications or presentations made in relation to the results, whether in oral, 
visual, or written form, the Study Site will be acknowledged as the source of the Data Set (see 
section “Publication and authorship policy”).  
5.2. 
Data Ownership 
The data is submitted by the Provider with the intention of contributing to a combined dataset. 
Providers can access their Study Site’s complete dataset at any point within the study 
recruitment period.  

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6. Publication and authorship policy 
All presentations and publications will be made on behalf of the EUBREAST Study Group. Two 
levels of authorship are proposed based on degree of study participation: 
6.1. 
Named authors 
Named authors will be required to meet the International Committee of Medical Journal Editors 
(ICMJE) criteria (www.icmje.org) for authorship. These will include: 
• 
Principal Investigator and Deputy Principal Investigator  
• 
Members of the Steering Board  
• 
Heads of National Steering Committees representing countries with top recruiter status 
• 
Main statistician 
6.2. 
Acknowledged collaborators  
Collaborators will have made a considerable contribution to the study but will not have met the 
ICMJE criteria for authorship (non-author contributors). These will include: 
• 
Heads of National Steering Committees representing countries without top recruiter 
status 
• 
Members of National Steering Committees 
• 
Local Pis of active Study Sites who have recruited at least one study participant. 
Recruitment in this context includes submission of a completed data set. In case a 
Study Site enrolled more than ten patients, an additional member of the Study Site will 
act as acknowledged collaborator. In case a Study Site enrolled more than fifty patients, 
two additional members of the Study Site will act as acknowledged collaborators. 
All acknowledged collaborators will be listed as GRAMAREG Study Group. 
 
 
 

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7. Statistical considerations 
 
Data analysis will be descriptive only. 
 
 
8. Safety 
 
GRAMAREG is a non-interventional study. All diagnostic and therapeutic procedures will be 
conducted according to institutional standards in the clinical routine.  
 
 
9. Funding 
 
Study support is currently applied for. 
 
 
 
 
 

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10. References 
 
1. 
Kessler E, Wolloch Y: Granulomatous mastitis: a lesion clinically simulating carcinoma. Am J 
Clin Pathol 1972, 58(6):642-646. 
2. 
Idiopathic granulomatous mastitis in Hispanic women - Indiana, 2006-2008. MMWR Morb 
Mortal Wkly Rep 2009, 58(47):1317-1321. 
3. 
Krawczyk N, Kuhn T, Ditsch N, Hartmann S, Gentilini OD, Lebeau A, de Boniface J, Hahn M, 
Cakmak GK, Alipour S et al: Idiopathic Granulomatous Mastitis as a Benign Condition 
Mimicking Inflammatory Breast Cancer: Current Status, Knowledge Gaps and Rationale for 
the GRAMAREG Study (EUBREAST-15). Cancers (Basel) 2024, 16(19). 
4. 
Llancari PA, Ortiz A, Becerra J, Munoz R, Valeriano C, Novoa RH: Treatment and Management 
Experience of Idiopathic Granulomatous Mastitis in a Low-income Country. Rev Bras Ginecol 
Obstet 2023, 45(6):319-324. 
5. 
Al Awfi MM, Al Rahbi SK: Idiopathic Granulomatous Mastitis: Six years of experience and the 
current evidence in literature. Sultan Qaboos Univ Med J 2023, 23(1):36-41. 
6. 
Akbari M, Negahi A, Dabbagh N, Salimi Kordasiabi AH, Zarean Shahraki S, Akbari ME: Idiopathic 
Granulomatous Mastitis (IGM): Clinical Features and Non-Surgical Management. Int J Cancer 
Manag 2023, 16(1):e119945. 
7. 
Sheybani F, Sarvghad M, Naderi H, Gharib M: Treatment for and clinical characteristics of 
granulomatous mastitis. Obstet Gynecol 2015, 125(4):801-807. 
8. 
Aghajanzadeh M, Hassanzadeh R, Alizadeh Sefat S, Alavi A, Hemmati H, Esmaeili Delshad MS, 
Emir Alavi C, Rimaz S, Geranmayeh S, Najafi Ashtiani M et al: Granulomatous mastitis: 
Presentations, diagnosis, treatment and outcome in 206 patients from the north of Iran. 
Breast 2015, 24(4):456-460. 
9. 
Patel RA, Strickland P, Sankara IR, Pinkston G, Many W, Jr., Rodriguez M: Idiopathic 
granulomatous mastitis: case reports and review of literature. J Gen Intern Med 2010, 
25(3):270-273. 
10. 
Freeman CM, Xia BT, Wilson GC, Lewis JD, Khan S, Lee SJ, Lower EE, Edwards MJ, Shaughnessy 
EA: Idiopathic granulomatous mastitis: A diagnostic and therapeutic challenge. Am J Surg 
2017, 214(4):701-706. 
11. 
Renshaw AA, Derhagopian RP, Gould EW: Cystic neutrophilic granulomatous mastitis: an 
underappreciated pattern strongly associated with gram-positive bacilli. Am J Clin Pathol 
2011, 136(3):424-427. 
12. 
Elzahaby IA, Khater A, Fathi A, Hany I, Abdelkhalek M, Gaballah K, Elalfy A, Hamdy O: Etiologic 
revelation and outcome of the surgical management of idiopathic granulomatous mastitis; 
An Egyptian centre experience. Breast Dis 2016, 36(4):115-122. 
13. 
Bashir MU, Ramcharan A, Alothman S, Beaugris S, Khan SA, Sbeih MA, Engdahl R: The enigma 
of granulomatous mastitis: A series. Breast Dis 2017, 37(1):17-20. 
14. 
Yu H, Wang Q: Severe idiopathic granulomatous mastitis treated with systemic medication; 
A case report. Journal of International Medical Research 2020, 48(1):0300060519895685. 
 
 
 
 

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11. Protocol Change Log 
 
 
Version 
Changes 
1.4  
Members of the Steering Board updated (Prof. Maria Luisa Gasparri, 
Dr. Rosa Di Micco, Prof. Cliona Kirwan and Dr. Yazan Masannat 
added) 
International Steering Committee GRAMAREG-sono added 
Corrected scientific title of Prof. Gentilini  
Literature updated (Krawczyk et al. Cancers 2024) 
1.3 
Addition of "diagnostic features" to the study tittle 
Rationale for inclusion of cystic neutrophilic granulomatous mastitis 
(CNGM) specified 
Inclusion criteria expanded to include CNGM 
Study flow chart corrected 
1.2 
Members of the Steering Board updated (Prof. Dr. Bjelic-Radisic 
added) 
Protocol change log added 
1.1 
Follow up described in more detail