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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.

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.


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: Arch Pathol Lab Med—Vol 131, January 2007

175 cases have been reported to the International Center for Nephrogenic Fibrosing Dermopathy 146 Arch Pathol Lab Med—Vol 131. and has been documented in patients from 8 to 86 years of age.6. an inciting role for surgery has been postulated because many patients with NSF/NFD (up to 48%) have had surgical procedures. skin-colored to erythematous papules coalescing into brawny plaques—usually on the extremities and trunk. Patients with NSF/NFD present with painful or pruritic. it is important for physicians to be aware of this disease since early diagnosis may lead to beneficial intervention.1 Several authors have concluded that TGF-B1 is the cytokine responsible for the fibrotic process. Cowper and colleagues13 suspect deposition of a recently introduced material. Ankles. has no apparent racial predilection. symmetric.8 Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy is not restricted to patients undergoing dialysis for chronic renal insufficiency.12 The skin lesions often take on a peau d’orange appearance. India. and lower thighs are the most commonly affected sites.9 Renal insufficiency is universal in NSF/ NFD patients and may be acute or chronic. or other allergen in peripheral tissues as the inciting event. Skin biopsy is considered the gold standard in the diagnosis of NSF/NFD. and patients are often mistakenly diagnosed as having cellulitis.Figure 1. High-power image showing a perivascular. original magnification 40).1 A small subset of these patients have anticardiolipin antibodies.1. To our knowledge. Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy affects male and female patients equally. eosinophilic fasciitis. eosinophilia-myalgia syndrome.11 Also. Figure 3. Medium-power image showing the accumulation of thick collagen bundles separated by clefts in the reticular dermis (hematoxylin-eosin. Figure 2. and scleromyxedema. this is the first case of NSF/NFD presenting in this manner. shins.6 ‘‘dialysisassociated systemic sclerosis. original magnification 20).1 Most of the case reports so far have been from the United States. it is thought that bone marrow–derived circulating fibrocytes are aberrantly recruited to skin and other target tissues. Therefore. predominantly plasmacytic infiltrate in the dermis (hematoxylin-eosin. but other cases have been documented in Europe. Currently. The clinical differential diagnosis also includes scleroderma. often in the 2 weeks prior to the onset of NSF/ NFD. ditional reports demonstrated that the lungs. the preferred terminology is now NSF/NFD. such as a contrast agent. January 2007 Research. many patients developing NSF/NFD report a recent thrombotic event in the preceding 2 weeks. medication. heart. Histopathologic findings include a markedly thickened reticular dermis with a disorderly arrangement of collagen fibers and surrounding clefts.’’ is no longer recommended. and skeletal muscle can also be affected. Low-power image showing fibrocollagenous thickening of the dermis (hematoxylin-eosin. The Nephrogenic Systemic Fibrosis—Solomon et al .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. and the terminology proposed by Jimenez and coworkers.12 It has been noted that no cases of NSF/ NFD were identified prior to 1997.12 Although the pathogenesis of NSF/NFD is incompletely understood. 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. and the Middle East. For example.7 and as a consequence.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. 10% of patients with NSF/NFD have never been dialyzed.1 An elevated erythrocyte sedimentation rate or Creactive protein was found in 9 of 12 patients in one study. original magnification 400). where they engage in dysregulated matrix production and remodeling. Asia. Importantly. 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.

radiation dermatitis. or imArch Pathol Lab Med—Vol 131. Furthermore. deep venous thrombosis. original magnification 200).19 The differential diagnosis of the clinical presentation of inflammatory breast carcinoma includes many nonneoplastic conditions such as cellulitis. procollagen-producing fibroblasts and CD68-positive cells. 400). plasmapheresis.Figure 4. original magnification 400). Many of the spindled cells were positive for CD68 and CD34 (immunoperoxidase. Figure 6. In advanced cases these cutaneous manifestations may extend to the chest wall. however. reduction of contractures. Lymphomatous and leukemic infiltration may also mimic inflammatory carcinoma. There may be increased stromal mucin and neovascularization in the dermis. ‘‘Improvement’’ generally implies reduction of induration. Typically. especially at the edge of the erysipeloid area.18 The skin may show peau d’orange changes. and occurs in patients with an underlying paraproteinemia (usually immunoglobulin G). The optimal management is not known since treatment data are available for only a small number of cases. In patients with renal failure. The term inflammatory breast carcinoma was proposed in 1924 to describe the clinical appearance of patients with this condition. which are often most pronounced in the dependent portions of the breast. Nephrogenic Systemic Fibrosis—Solomon et al 147 . as no standard for staging the disease exists. it is difficult to assess clinical improvement. among others. is most common on the face and neck. NSF/ NFD should be considered as a rare possibility when cutaneous changes in the breast suggest inflammatory breast carcinoma. Increased stromal mucin is seen in the dermis (Alcian blue.20 mastitis due to various causes. The skin biopsy findings most closely resemble scleromyxedema. January 2007 proved mobility. High-power image of the dermis showing spindled cells resembling fibroblasts (hematoxylin-eosin. Immunohistochemistry reveals increased numbers of CD34-positive. this condition can be ruled out on clinical grounds since the latter is not typically associated with renal disease. A mild perivascular lymphoplasmacytic infiltrate is not uncommon. scleroderma. An appropriate surgical biopsy of the skin and underlying breast is necessary to distinguish NSF/NFD from inflammatory carcinoma.1 Follow-up skin biopsy after treatment is seldom undertaken. original magnification Figure 5. and panniculitis. Immunostains for CD68 (a) and CD34 (b). process often extends into the subcutaneous tissue and/ or muscle along fibrous septae. the breast is either diffusely indurated or a mass can be palpated.17 Inflammatory carcinoma is characterized by erythema of the mammary skin with thickening. and corticosteroids. extracorporeal photopheresis.15 The treatment for NSF/NFD is variable and includes renal transplantation. LeBoit16 suggested reducing the dose of erythropoietin in patients with renal dysfunction since recombinant erythropoietin has potential fibrogenic properties. postsurgical dermal lymphedema.

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