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Case Report

Nephrogenic Systemic Fibrosis Mimicking Inflammatory Breast Carcinoma
Garron J. Solomon, MD; Elizabeth Wu, MD; Paul Peter Rosen, MD

● Nephrogenic systemic fibrosis, previously known as nephrogenic fibrosing dermopathy, is a newly recognized systemic fibrosing disorder primarily affecting patients with chronic renal failure. Patients with skin involvement often develop papules and plaques with peau d’orange surface changes. The lower extremities and trunk are most commonly affected. The most important histologic differential diagnosis is with scleromyxedema. To our knowledge, we report the first case of nephrogenic systemic fibrosis involving the breasts of a 61-year-old woman with end-stage renal disease, clinically mimicking inflammatory breast carcinoma. We propose that nephrogenic systemic fibrosis be considered in the differential diagnosis as a rare possibility when cutaneous changes in the breast suggest inflammatory breast carcinoma in a patient with renal failure. (Arch Pathol Lab Med. 2007;131:145–148)

agulability, with a recent thrombectomy performed for a left arm thrombosis involving her arteriovenous shunt. The patient was taking many medications including epoetin alfa. The patient’s only significant laboratory findings were an elevated creatinine (10.2 mg/dL), a mild normocytic normochromic anemia (hemoglobin, 11.0 g/dL), and mild thrombocytopenia (platelet count, 140 103/ L). She had no palpable breast mass on physical examination. The clinical impression was inflammatory breast carcinoma, for which a biopsy was performed. The referring pathologist noted ‘‘an infiltrating pattern of fibroblastic cells’’ and submitted the slides for consultation to rule out fibromatosis.

MATERIALS AND METHODS
Clinical information was obtained from patient records. The diagnosis was based on examination of histologic sections stained with hematoxylin-eosin. Stromal mucin was demonstrated with the Alcian blue histochemical procedure, and CD68-reactive and CD34-reactive cells were identified by immunohistochemistry using a standard avidin-biotin method.

N

ephrogenic systemic fibrosis (NSF) is a recently described systemic fibrosing disorder primarily affecting patients with chronic renal insufficiency. Although the exact cause is unknown, bone marrow–derived circulating fibrocytes are suspected to be involved in the pathogenesis of this rare condition. Skin involvement in NSF frequently presents on the extremities as erythematous papules or plaques, often with peau d’orange surface changes and woody induration. Truncal involvement is less common, and breast involvement has not previously been reported. We report here a case of a woman with advanced renal disease who presented with bilateral breast swelling leading to the clinical impression of inflammatory breast carcinoma. Biopsy of one of the breasts revealed NSF. REPORT OF A CASE

PATHOLOGIC FINDINGS The excisional biopsy specimen of the left breast measured 5.0 4.0 1.0 cm with an attached skin ellipse measuring 5.0 1.0 cm. The microscopic sections showed marked thickening of the dermis with accumulation of thick collagen bundles separated by clefts in the papillary and reticular dermis (Figures 1 and 2). There was focal extension into the subcutaneous tissue along thickened fibrous septae. Within the dermis there was a laminar proliferation of small blood vessels surrounded by a predominantly plasmacytic infiltrate (Figure 3). Higher magnification of the collagenous stroma revealed an increased number of spindled cells resembling fibroblasts and increased stromal mucin (Figures 4 and 5). The stromal spindle cells were largely CD68-positive and CD34-positive (Figure 6, a and b). COMMENT Nephrogenic systemic fibrosis is an emerging disease principally affecting individuals with advanced chronic renal disease.1 It has also been associated with chronic hepatic disease and the hepatorenal syndrome.2 The scleroderma-like cutaneous manifestations of this clinicopathologic entity were first recognized in 1997 in a cohort of renal dialysis patients and reported by Cowper and colleagues3 in 2000. The term nephrogenic fibrosing dermopathy (NFD) was introduced in 2001.4 Subsequently, an autopsy performed on an individual diagnosed with NFD revealed fibrosis of the diaphragm, psoas muscle, renal tubules, and rete testis, suggesting that the fibrosing disorder was not limited exclusively to the integument.5 AdNephrogenic Systemic Fibrosis—Solomon et al 145

The patient is a 61-year-old woman with end-stage renal disease on hemodialysis who presented with tense swelling and ‘‘dimpling’’ of both breasts. The patient’s medical history also included diabetes mellitus, hypertension, asthma, and hypercoAccepted for publication September 7, 2006. From the Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York (Drs Solomon and Rosen); and the Department of Pathology, New York Methodist Hospital, Brooklyn, NY (Dr Wu). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Garron J. Solomon, MD, Resident in Pathology, New YorkPresbyterian Hospital, Weill Cornell Medical College, 525 E 68 St, Starr 10, New York, NY 10021 (e-mail: gas9012@nyp.org). Arch Pathol Lab Med—Vol 131, January 2007

Figure 1. Low-power image showing fibrocollagenous thickening of the dermis (hematoxylin-eosin, original magnification 20). Figure 2. Medium-power image showing the accumulation of thick collagen bundles separated by clefts in the reticular dermis (hematoxylin-eosin, original magnification 40). Figure 3. High-power image showing a perivascular, predominantly plasmacytic infiltrate in the dermis (hematoxylin-eosin, original magnification 400).

ditional reports demonstrated that the lungs, heart, and skeletal muscle can also be affected,6,7 and as a consequence, the preferred terminology is now NSF/NFD. Currently, 175 cases have been reported to the International Center for Nephrogenic Fibrosing Dermopathy
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Research.8 Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy is not restricted to patients undergoing dialysis for chronic renal insufficiency, and the terminology proposed by Jimenez and coworkers,6 ‘‘dialysisassociated systemic sclerosis,’’ is no longer recommended. Clinical improvement in NSF/NFD may occur in cases where the renal dysfunction is successfully reversed— usually early in the course of the disease before contracture development. Therefore, it is important for physicians to be aware of this disease since early diagnosis may lead to beneficial intervention. Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy affects male and female patients equally, has no apparent racial predilection, and has been documented in patients from 8 to 86 years of age.1 Most of the case reports so far have been from the United States, but other cases have been documented in Europe, Asia, India, and the Middle East.9 Renal insufficiency is universal in NSF/ NFD patients and may be acute or chronic. Importantly, 10% of patients with NSF/NFD have never been dialyzed.10 The causes of the underlying renal disease in NSF/NFD patients are variable. The onset of NSF/NFD may be tied to other clinical events. For example, many patients developing NSF/NFD report a recent thrombotic event in the preceding 2 weeks.1 A small subset of these patients have anticardiolipin antibodies.11 Also, an inciting role for surgery has been postulated because many patients with NSF/NFD (up to 48%) have had surgical procedures, often in the 2 weeks prior to the onset of NSF/ NFD.1 An elevated erythrocyte sedimentation rate or Creactive protein was found in 9 of 12 patients in one study.12 Although the pathogenesis of NSF/NFD is incompletely understood, it is thought that bone marrow–derived circulating fibrocytes are aberrantly recruited to skin and other target tissues, where they engage in dysregulated matrix production and remodeling.1 Several authors have concluded that TGF-B1 is the cytokine responsible for the fibrotic process.1,12 It has been noted that no cases of NSF/ NFD were identified prior to 1997. Cowper and colleagues13 suspect deposition of a recently introduced material, such as a contrast agent, medication, or other allergen in peripheral tissues as the inciting event. Patients with NSF/NFD present with painful or pruritic, symmetric, skin-colored to erythematous papules coalescing into brawny plaques—usually on the extremities and trunk. Ankles, shins, and lower thighs are the most commonly affected sites.12 The skin lesions often take on a peau d’orange appearance, and patients are often mistakenly diagnosed as having cellulitis. The clinical differential diagnosis also includes scleroderma, eosinophilic fasciitis, eosinophilia-myalgia syndrome, and scleromyxedema. Many patients with NSF/NFD are found to have ocular lesions described as yellow scleral plaques.14 A small percentage ( 5%) of NSF patients have a fulminant course characterized by a rapid loss of mobility and severe pain.1 The occurrence of peau d’orange surface changes on the breasts of the female patient in this report led to the clinical impression of inflammatory breast carcinoma. To our knowledge, this is the first case of NSF/NFD presenting in this manner. Skin biopsy is considered the gold standard in the diagnosis of NSF/NFD. Histopathologic findings include a markedly thickened reticular dermis with a disorderly arrangement of collagen fibers and surrounding clefts. The
Nephrogenic Systemic Fibrosis—Solomon et al

Figure 4. High-power image of the dermis showing spindled cells resembling fibroblasts (hematoxylin-eosin, original magnification Figure 5. Increased stromal mucin is seen in the dermis (Alcian blue, original magnification 400).

400).

Figure 6. Immunostains for CD68 (a) and CD34 (b). Many of the spindled cells were positive for CD68 and CD34 (immunoperoxidase, original magnification 200).

process often extends into the subcutaneous tissue and/ or muscle along fibrous septae. There may be increased stromal mucin and neovascularization in the dermis. A mild perivascular lymphoplasmacytic infiltrate is not uncommon. Immunohistochemistry reveals increased numbers of CD34-positive, procollagen-producing fibroblasts and CD68-positive cells. The skin biopsy findings most closely resemble scleromyxedema; however, this condition can be ruled out on clinical grounds since the latter is not typically associated with renal disease, is most common on the face and neck, and occurs in patients with an underlying paraproteinemia (usually immunoglobulin G).15 The treatment for NSF/NFD is variable and includes renal transplantation, extracorporeal photopheresis, plasmapheresis, and corticosteroids, among others. LeBoit16 suggested reducing the dose of erythropoietin in patients with renal dysfunction since recombinant erythropoietin has potential fibrogenic properties. The optimal management is not known since treatment data are available for only a small number of cases. Furthermore, it is difficult to assess clinical improvement, as no standard for staging the disease exists. ‘‘Improvement’’ generally implies reduction of induration, reduction of contractures, or imArch Pathol Lab Med—Vol 131, January 2007

proved mobility.1 Follow-up skin biopsy after treatment is seldom undertaken. The term inflammatory breast carcinoma was proposed in 1924 to describe the clinical appearance of patients with this condition.17 Inflammatory carcinoma is characterized by erythema of the mammary skin with thickening, especially at the edge of the erysipeloid area.18 The skin may show peau d’orange changes, which are often most pronounced in the dependent portions of the breast. In advanced cases these cutaneous manifestations may extend to the chest wall. Typically, the breast is either diffusely indurated or a mass can be palpated.19 The differential diagnosis of the clinical presentation of inflammatory breast carcinoma includes many nonneoplastic conditions such as cellulitis, deep venous thrombosis, radiation dermatitis, postsurgical dermal lymphedema,20 mastitis due to various causes, scleroderma, and panniculitis. Lymphomatous and leukemic infiltration may also mimic inflammatory carcinoma. In patients with renal failure, NSF/ NFD should be considered as a rare possibility when cutaneous changes in the breast suggest inflammatory breast carcinoma. An appropriate surgical biopsy of the skin and underlying breast is necessary to distinguish NSF/NFD from inflammatory carcinoma.
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We thank N. Scott McNutt, MD, for confirming our diagnostic impression.
References
1. Cowper SE, Boyer PJ. Nephrogenic systemic fibrosis: an update. Curr Rheumatol Rep. 2006;8:151–157. 2. Baron PW, Cantos K, Hillebrand DJ, et al. Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol. 2003;25:204–209. 3. Cowper SE, Robin HS, Steinberg SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2000;356:1000–1001. 4. Cowper SE, Su LD, Bhawan J, et al. Nephrogenic fibrosing dermopathy. Am J Dermatopathol. 2001;23:383–393. 5. Ting WW, Stone MS, Madison KC, et al. Nephrogenic fibrosing dermopathy with systemic involvement. Archiv Dermatol. 2003;139:903–906. 6. Jimenez SA, Artlett CM, Sandorfi N, et al. Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin. Arthritis Rheum. 2004; 50:2660–2666. 7. Levine JM, Taylor RA, Elman LB, et al. Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy). Muscle Nerve. 2004;30:569–577. 8. Cowper SE. Nephrogenic fibrosing dermopathy [NFD/NSF Web site]. 2001– 2006. Available at: http://www.icnfdr.org. Accessed June 4, 2006. 9. Panda S, Bandyopadhyay D, Tarafder A. Nephrogenic fibrosing dermopathy: a series in a non-Western population. J Am Acad Dermatol. 2006;54:155–159. 10. Cowper SE. Nephrogenic systemic fibrosis: the nosological and conceptual

evolution of nephrogenic fibrosing dermopathy. Am J Kidney Dis. 2005;46:763– 765. 11. Mackay-Wiggan JM, Cohen DJ, Hardy MA, et al. Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol. 2003;48:55–60. 12. Mendoza FA, Artlett CM, Sandorfi N, et al. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum. 2006;35:238–249. 13. Cowper SE, Bucala R, LeBoit PE. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis—setting the record straight. Semin Arthritis Rheum. 2006;35:208–210. 14. Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol. 2003;15:785–790. 15. Kucher C, Xu X, Pasha T, et al. Histopathologic comparison of nephrogenic fibrosing dermopathy and scleromyxedema. J Cutan Pathol. 2005;32:484–490. 16. LeBoit PE. What nephrogenic fibrosing dermopathy might be. Arch Dermatol. 2003;139:928–930. 17. Lee BJ, Tannenbaum E. Inflammatory carcinoma of the breast: a report of twenty-eight cases from the breast clinic of the Memorial Hospital. Surg Gynecol Obstet. 1924;39:580–595. 18. Rosen PP. Unusual clinical presentations of carcinoma. In: Rosen’s Breast Pathology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:653– 687. 19. Nussbaum H, Kagan AR, Gilbert H, et al. Management of inflammatory breast carcinoma. Breast. 1977;3:25–28. 20. King R, Duncan L, Shupp DL, et al. Postsurgical dermal lymphedema clinically mimicking inflammatory breast carcinoma. Arch Dermatol. 2001;137:969– 970.

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