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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4. Deng A, Martin DB, Spillane A, et al. Nephrogenic systemic fibrosis with a spectrum of clinical and histopathological presentation: a disorder of aberrant dermal remodeling. J Cutan Pathol. 2010;37:204–210.
5. Binai N, O'Reilly S, Griffiths B, et al. Differentiation potential of CD14+ monocytes into myofibroblasts in patients with systemic sclerosis. PLoS One. 2012;7:1–7.
6. Swaminathan S, Arbiser JL, Hiatt KM, et al. Rapid improvement of nephrogenic systemic fibrosis with rapamycin therapy: possible role of phospho-70-ribosomal-S6 kinase. J Am Acad Dermatol. 2010;62:343–345.
7. Zou Z, Zhang HL, Roditi GH, et al. Nephrogenic systemic fibrosisReview of 370 biopsy-confirmed cases. JACC Cardiovasc Imaging. 2011;4:1206–1216.
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8. Anavekar NS, Chong AH, Norris R, et al. Nephrogenic systemic fibrosis in a gadolinium-naive renal transplant recipient. Australas J Dermatol. 2008;49:44–47.