Idiopathic granulomatous mastitis joins the pantheon of erythema nodosum-associated disorders

By Warren R. Heymann, MD, FAAD
Dec. 11, 2024
Vol. 6, No. 49

Patients often ask me, “Doctor, is my disease rare?” I’m never quite sure how to respond — while most patients are relieved to know that they are not alone (“misery loves company”), some relish the experience of being unique. By my definition, at this point in my career, if it’s the first time I’m seeing a disorder, perhaps it is unusual. If I have encountered it several times, probably not. In the literature, idiopathic granulomatous dermatitis (IGM) is considered a rare disease. I have diagnosed IGM at least a few times. By my imprecise definition, IGM may be uncommon but not rare.

IGM is a chronic inflammatory disease characterized by unilateral or bilateral tender, erythematous, painful, indurated breast masses associated with edema, erythema, drainage, and scarring. IGM is typically observed in women of reproductive age. (1,2) IGM mostly affects Hispanic, Middle Eastern, Black, and Asian women. (3,4)

Ringsted and Friedman eloquently state, “IGM is an enigmatic orphaned disease. Patients diagnosed with this condition often suffer through cancer-scares, numerous biopsies, and multiple rounds of unsuccessful treatments. Once they are finally diagnosed, these patients are faced with a frustrating paucity of high-quality data to guide their management, and a lack of certainty who should be treating them.” (5)

This commentary will focus on newer literature associating IGM with extramammary manifestations, notably erythema nodosum (EN).

The reasons for a delayed diagnosis include a lack of awareness of the entity and that IGM mimics other entities. Clinical features such as nipple retraction, a peau d’orange appearance, and axillary adenopathy could be mistaken for breast cancer. Draining nodules could be misdiagnosed as non-puerperal mastitis or a breast abscess. (6) Imaging of IGM is neither distinctive nor pathognomonic; ultrasound images appear heterogeneous, while magnetic resonance imaging can present as focal or diffuse nonmass enhancements. (7) The diagnosis of IGM relies on histologic confirmation demonstrating non-caseating granulomas with multinucleated giant cells and may contain microabscesses. (5) An appropriate work-up should rule out infectious disorders such as tuberculosis, atypical mycobacterial infections, and fungal infections by using appropriate tissue stains, cultures, as well as TB testing such as QuantiFERON-TB-Gold. (8) Primary sarcoidosis of the breast is rare, involving less than 1% of sarcoidosis patients. (9) A chest X-ray and angiotensin-converting enzyme may help differentiate IGM from sarcoidosis. (8) Granulomatosis with polyangiitis (GPA) of the breast may rarely present with breast lesions mimicking IGM; the presence of antiproteinase 3-antineutrophil cytoplasmic antibodies would confirm the diagnosis of GPA. (10)

Adams et al. were the first to report a patient developing EN, accompanied by arthralgias, following the diagnosis of IGM. Their patient was a 24-year-old woman with IGM (manifesting as a painful “left breast lump”), appearing four months after the birth of her second child. (11) Subsequently, there has been a burgeoning literature about extramammary features of IGM, manifesting as fever, arthralgia, episcleritis, and EN. (3) EN usually follows about a month after the diagnosis of IGM, but both may present concurrently. (7)

Velidedeoğlu et al. evaluated 43 women with IGM coexisting with EN compared to 43 women with a diagnosis of IGM only. The authors demonstrated that the association of IGM with EN has a more aggressive disease course. White blood cells, erythrocyte sedimentation rate, and C-reactive protein were significantly higher in the EN-positive group (P < .05). Arthralgia, breastfeeding, fistula distribution, and recurrence distributions were significantly higher in the EN-positive group (P < .05). (9) Dermatologists are intimately familiar with EN-associated conditions including pregnancy, infections (streptococcal, tuberculosis, deep fungal, viral, others), inflammatory bowel disease (Crohn disease, ulcerative colitis), Behcet’s disease, sarcoidosis (Lofgren syndrome), drugs (oral contraceptives, iodides, sulfonamides, TNF-alpha inhibitors, others), and malignancies (notably leukemia, lymphoma). (12) As Velidedeoğlu et al. aptly state, “All physicians should not neglect questioning breast complaints in patients with EN since EN may be associated with IGM.” (9)

The etiology of IGM is unknown. Risk factors include genetic predisposition, trauma, hormones (pregnancy, oral contraceptives), lactation, elevated prolactin levels, autoimmunity, and infections (especially Corynebacterium). (5) In a series of 26 IGM patients tested by culture/smear of breast fluid, 9 were positive for Corynebacterium. (4)

---

Although IGM may resolve spontaneously, most patients will require therapy. (3) Controversies about therapy for IGM abound in the literature but include corticosteroids [also for extramammary features of IGM], immunosuppressive agents (methotrexate, azathioprine), antibiotics (doxycycline), and surgery. (1,8) The duration of therapy required to achieve full remission ranges from 3 to 18 months. (13)

In conclusion, IGM is an enigmatic, underrecognized disorder with potential extramammary manifestations, such as EN. The diagnosis is based on ruling out other mimickers of breast inflammation, including breast cancer. Most patients will improve with therapy, although it would be ideal to have prospective, comparative trials — an unlikely event.

Point to Remember: Idiopathic granulomatous mastitis (IGM) should be considered in inflammatory dermatoses of the breast in women of reproductive age. The diagnosis is confirmed by ruling out inflammatory, infectious, and malignant conditions that clinically mimic the disease. There are an increasing number of reports of IGM accompanied by extramammary manifestations, notably erythema nodosum.

Our expert’s viewpoint

Alisa Femia, MD, FAAD
Associate Professor
Director of Inpatient Dermatology
Director of Autoimmune Conective Tissue Disease
Director of Faculty Development
The Ronald O. Perelman Dept. of Dermatology
NYU Grossman School of Medicine

My introduction to idiopathic granulomatous mastitis was not via the textbooks nor my medical training. Rather, it began when a breast surgeon approached our complex medical dermatology clinic to request assistance with a group of patients. These patients shared a similar presentation, including development of erythematous nodules on the breast, oftentimes associated with drainage and substantial pain. At times nipple retraction, ulceration, and a peau d’orange appearance were present. Breast imaging studies led to biopsies, which often demonstrated cystic neutrophilic and sometimes granulomatous abscesses. With this collaboration with our colleagues in breast surgery, we soon found ourselves streamlining a pathway to open urgent slots to accommodate patients with IGM.

As with many conditions in complex medical dermatology, the patients we met had often experienced alternative diagnoses prior to identification of their condition. A varied clinical presentation including draining nodules mimicking abscesses and firm nodules mimicking malignancy were likely in part to blame for delays in diagnosis. Pain, fistula formation, and scarring were often present, and some patients experienced nipple retraction with the potential to impact breastfeeding. The potential severity of this seemingly not-so-rare condition motivated our group to pursue systematic evaluation and analysis. All patients were seen in conjunction with a breast service and were recommended breast imaging, chest X-ray, a biopsy, tissue cultures for bacteria, mycobacteria and fungi, and laboratory studies such as prolactin levels and QuantiFERON gold testing. No patient was found to have a positive fungal or mycobacterial culture. Interestingly, biopsy sites were observed to be prone to persistent inflammation, perhaps invoking similarities to sarcoidosis pathophysiology in which honing towards scars occurs. Most patients had a history of breastfeeding and prolactin levels were elevated in several patients. With therapy, patients improved, but scarring often occurred.

Co-occurrence of IGM with erythema nodosum has been described and observed in our department’s cohort. This invites the question of whether there is shared pathogenesis or common underlying associations between these two conditions. An association of IGM with recent pregnancy, lactation and elevated prolactin levels, and of EN with oral contraceptive use and pregnancy suggest a role of hormonal regulation in both disorders; however, there is currently a lack of known association of IGM with common EN triggers such as inflammatory bowel disease. Despite a lack of clear shared pathogenesis, the association between IGM and EN reminds us to examine the breast in patients with panniculitides. For example, lupus mastitis, another condition that may mimic breast malignancy, is a likely under-recognized component of lupus panniculitis, yet the association is logical given the relatively high proportion of fatty tissue within the breast. Perhaps it is not surprising to see an association between a granulomatous inflammatory condition within the breast and a panniculitis with similar histopathology elsewhere on the body.

There is much room for further investigation into the realm of IGM. For example, it remains unclear why some patients with IGM develop more systemic inflammation such as EN and arthritis. Is there potential in very rare cases for internal organ involvement as seen in other granulomatous disorders? There is also a lack of clarity regarding potential pathogenesis. Inflammatory granulomatous conditions such as sarcoidosis are thought to develop in response to a variety of potential antigenic stimuli such as medications, infections, and environmental factors. Hereditary predispositions such as HLA types may also play a role.

In IGM, a predisposition in certain ethnicities, in particular patients of Hispanic background, has been reported. Local trauma or damage to the ductal epithelium related to breastfeeding or milk status has also been postulated to play a role. Smoking, medications that increase prolactin levels, and co-existent autoimmune disorders may also increase the risk of IGM. Similar to other granulomatous conditions, activation of the Th1 immune response with upregulation of IFN and upregulation of Th17-mediated cytokines may also serve as contributing factors, but much remains unknown regarding the pathogenesis of IGM.

Finally, many patients with IGM have likely suffered as a result of not knowing which specialist to see or lack of ability to find a physician familiar with this condition. Dermatologists should have a role in the diagnosis and management of IGM, especially given its linkage with EN and its resemblance to other disorders within the realm of dermatology such as hidradenitis suppurativa. Overall, I would be mindful that IGM is a condition that may follow the expression — you may not have seen it, but most likely, it has seen you.

1. Fruchter R, Castilla C, Ng E, Pomeranz MK, Femia AN. Erythema nodosum in association with idiopathic granulomatous mastitis: a case series and review of the literature. J Eur Acad Dermatol Venereol. 2017 Sep;31(9):e391-e393. doi: 10.1111/jdv.14194. Epub 2017 Apr 5. PMID: 28271562.

2. Ufkes N, Bertoch S. A case of idiopathic granulomatous mastitis associated with erythema nodosum. Int J Womens Dermatol. 2024 Feb 22;10(1):e136. doi: 10.1097/JW9.0000000000000136. PMID: 38389951; PMCID: PMC10883621.

3. Hamsho S, Alaswad M, Alsmodi H, Sleiay M, Hoha G, Alcheikh S. Idiopathic granulomatous mastitis with extramammary manifestations: a case report. Ann Med Surg (Lond). 2023 Oct 12;85(12):6192-6195. doi: 10.1097/MS9.0000000000001397. PMID: 38098607; PMCID: PMC10718323.

4. Otto TS, Argobi Y, Lerwill MJ, Smith GP, Fedeles F. A retrospective study of idiopathic granulomatous mastitis diagnosis and clinical presentation. J Am Acad Dermatol. 2022 Feb;86(2):467-469. doi: 10.1016/j.jaad.2021.09.055. Epub 2021 Oct 2. PMID: 34610382.

5. Ringsted S, Friedman M. A rheumatologic approach to granulomatous mastitis: A case series and review of the literature. Int J Rheum Dis. 2021 Apr;24(4):526-532. doi: 10.1111/1756-185X.14065. Epub 2021 Feb 1. PMID: 33523600; PMCID: PMC8152827.

6. Salesi M, Karimifar M, Salimi F, Mahzouni P. A case of granulomatous mastitis with erythema nodosum and arthritis. Rheumatol Int. 2011 Aug;31(8):1093-5. doi: 10.1007/s00296-009-1273-0. Epub 2009 Dec 11. PMID: 20012050.

7. Pesce KA, Caro Peralta KL, Chico MJ, Wernicke A, Binder F. Granulomatous mastitis with erythema nodosum: A breast cancer mimicking entity. Radiol Case Rep. 2023 Aug 24;18(11):3809-3814. doi: 10.1016/j.radcr.2023.08.016. PMID: 37663565; PMCID: PMC10474357.

8. Steuer AB, Stern MJ, Cobos G, Castilla C, Joseph KA, Pomeranz MK, Femia AN. Clinical Characteristics and Medical Management of Idiopathic Granulomatous Mastitis. JAMA Dermatol. 2020 Apr 1;156(4):460-464. doi: 10.1001/jamadermatol.2019.4516. PMID: 31968055; PMCID: PMC6990845.

9. Panzacchi R, Gallo C, Fois F, Dalpiaz G, Cucchi MC, Degli Esposti R, Foschini MP. Primary sarcoidosis of the breast: case description and review of the literature. Pathologica. 2010 Jun;102(3):104-7. PMID: 21171514.

10. Kawataka M, Kido T, Tsuda R, Onose T, Asano R, Yamazaki M, Sugishita N, Hounoki H, Kakiuchi T, Shinoda K, Tobe K. A Case of Granulomatosis with Polyangiitis with Various Breast Lesions as the Initial Symptoms: A Case-Based Review. Case Rep Rheumatol. 2021 Aug 20;2021:4416072. doi: 10.1155/2021/4416072. PMID: 34545315; PMCID: PMC8448995.

11. Velidedeoğlu M, Papila Kundaktepe B, Mete B, Uğurlu S. Idiopathic granulomatous mastitis associated with erythema nodosum may indicate a worse prognosis. Int J Rheum Dis. 2021 Nov;24(11):1370-1377. doi: 10.1111/1756-185X.14218. Epub 2021 Sep 12. PMID: 34514701.

12. Hafsi W, Badri T. Erythema Nodosum. 2022 Nov 28. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 29262192.

13. Zabetian S, Friedman BJ, McHargue C. A case of idiopathic granulomatous mastitis associated with erythema nodosum, arthritis, and reactive cough. JAAD Case Rep. 2016 Mar 5;2(2):125-7. doi: 10.1016/j.jdcr.2016.01.011. PMID: 27051851; PMCID: PMC4810290

---