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Gadolinium-Naive Nephrogenic Systemic Fibrosis of Breast Mimicking Inflammatory Breast Carcinoma

Halteh, Pierre; Huang, Jing MD; Wildman, Horatio F. MD; Magro, Cynthia M. MD

The American Journal of Dermatopathology: April 2017 - Volume 39 - Issue 4 - p 322–324
doi: 10.1097/DAD.0000000000000772
Letters to the Editor

*Department of Dermatology, Weill Cornell Medicine, New York, NY

Division of Dermatopathology, Department of Pathology, Weill Cornell Medicine, New York, NY

The authors declare no conflicts of interest.

To the Editor:

We encountered a case of a 54-year-old woman with end-stage renal disease (ESRD) of unknown etiology on hemodialysis evaluated for pruritic breast swelling and redness of the right breast for more than 2 months. On physical examination, significant edema and slight erythema of the right breast was notable, demonstrating a peau d'orange appearance, including thickening of the periareolar skin, with an unremarkable left breast (Figs. 1A, B). Mammography of the breast did not reveal any masses or microcalcifications in the breast parenchyma.



The excisional biopsy specimen of the right breast was generous measuring 2.2 cm in greatest dimension. On microscopic examination, the biopsy showed a very striking sclerosing reaction involving the deeper dermis and subcutis, associated with significant interstitial hypercellularity and unaccompanied by the typical adnexal atrophy seen in morphea (Figs. 2A, B). The stromal cells had an activated appearance, staining positively CD34 but as well the spindled cells exhibited additional positivity to suggest a dendritic monocyte lineage, including CD68, CD163, HLADR, CD11c, and CD14 (Figs. 3A–D). Despite the unusual location and lack of confirmatory history regarding gadolinium exposure, we felt very strongly that the findings were diagnostic of nephrogenic systemic fibrosis (NSF) at least according to the accepted histopathological criteria for that entity as outlined by Girardi et al.1 The authors emphasize the salient findings in NSF from a histomorphologic perspective. In this grading scheme, the presence of increased dermal cellularity, thick and thin collagen fibers, septal involvement, and CD34+ infiltration each count for 1 point, whereas the presence of osseous metaplasia automatically receives a +3 score. Our patient exhibited morphologic features that would qualify the biopsy as having a score of at least +3, which is “consistent with NSF.”1





Of course, when one considers the conventional findings in NSF, they are invariably in the context of woody indurated papules and plaques of the trunk and extremities solely in patients with ESRD, where emphasis is always placed on gadolinium exposure. However, NSF can rarely affect sites outside its classic anatomic distribution, including the breast. There is one previously reported case of NSF affecting the breast in isolation with its occurrence in a 61-year-old woman with ESRD on hemodialysis. Her clinical presentation was very similar to ours whereby she presented with tense swelling and dimpling of both breasts (Table 1). As with our case, her clinical presentation was thought to be suspicious for inflammatory breast carcinoma.2



The presence of the extensive peau d'orange alteration of the skin along with the histomorphologic findings raises diagnostic consideration regarding scleromyxedema. Indeed, before the recognition of NSF as a distinct clinical pathological entity, such cases that would now be labeled as NSF were invariably diagnosed as scleromyxedema. Scleromyxedema in adults is almost invariably associated with an underlying paraproteinemia, whereas one of the constant clinical finding in the setting of NSF is renal failure.3 Although an increase in hyaluronic acid is a characteristic finding in scleromyxedema, not all cases of NSF demonstrate a significant increase in mesenchymal mucin deposition. Indeed, in our cases, there was only a modest increase in interstitial mucin, mirroring the changes found in a subset of cases of NSF encountered by Deng et al,4 who reported considerable variation in mucin deposition in biopsies of NSF including cases where it was scant.4

The unique monocytic profile demonstrated by the CD34+ fibrocytes sheds further light on the pathogenic basis of NSF. In our case and other cases we have examined, many of the cells have a dendritic monocytic phenotype as revealed by the extent of staining for CD11c and CD14, hence providing an in vivo proof regarding earlier espousals suggesting the myeloid monocytic marrow derived origin of the NSF-associated fibrocyte.5,6 CD14-positive monocyte-derived cells with myofibroblastic differentiation are well defined in the literature and play a critical role in the matrix deposition responsible for accelerated atherosclerosis in the setting of lupus erythematosus and scleroderma, the arteriopathy of Degos disease, and transplant arteriopathy. Monocytes have tremendous morphologic and functional plasticity, including their ability to differentiate into spindled cells with collagen- and matrix-producing properties.5

Although we could not establish gadolinium as an inciting trigger, we still cannot rule out an occult exposure to the agent. Gadolinium stimulates peripheral blood monocytes to express profibrotic cytokines, especially type 1 interferon, and other growth hormones, through Toll-like receptors (TLR) 4 and 7 signaling. If one is to assume that our case truly arose in the absence of gadolinium, this case would hardly be the first one reporting NSF without gadolinium exposure. There is a growing body of literature regarding the development of classic NSF without gadolinium exposure defining the entity of so-called gadolinium-naive NSF.7,8 Our case and other reported cases emphasize that no single toxic, pharmacological, or infective etiology is causative of this disease process.

This case of NSF emphasizes the need for high clinical suspicion in patients with ESRD exhibiting an inflammatory breast carcinoma-like presentation. In addition, a novel theory regarding monocyte myofibroblastic differentiation in the dermis is substantiated with CD14 staining, with interferon I, TLR I, and TLR IV playing significant roles. A careful investigation into gadolinium exposure is integral, as multiple theories exist suggesting strong association between onset of NSF and exposure. Early recognition of lesions and aggressive treatment to revere renal dysfunction is essential to clinical management. Biologic targeting of pathways involved in promoting the dedifferentiation of the monocyte-derived fibrocyte, and inflammasome inhibitors, such as caspase inhibitors, could define the future cornerstone of effective therapy.

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