G a s t r o i n t e s t i n a l I m a g i n g P i c t o r i a l E s s ay

Morris et al. Imaging Features of NSF Gastrointestinal Imaging Pictorial Essay

FOCUS ON:

Features of Nephrogenic Systemic Fibrosis on Radiology Examinations

OBJECTIVE. The objective of this article is to illustrate the spectrum of imaging findings with photographic and histopathologic correlation in patients with biopsy-proven nephrogenic systemic fibrosis (NSF). CONCLUSION. Features of NSF may be evident on the patients skin as well as on routine imaging studies, although these imaging findings are nonspecific and are more likely to occur with other diseases. ephrogenic systemic fibrosis (NSF) is a rare disease seen in patients with severe renal impairment that has garnered increased interest among radiologists because of reports of its association with gadolinium-based contrast agents (GBCAs) [120]. Many case series have reported that high doses of GBCA and possibly of linear nonionic GBCA contribute to an increased risk of NSF [16, 17, 2125]. These findings have led to recommendations for radiologists to avoid the use of GBCA or reduce the dose of GBCA in patients with an estimated glomerular filtration rate (GFR) of less than 30 mL/ min [26]. It is also recommended that dialysis patients undergo dialysis immediately after GBCA injection to further minimize the risk of NSF when GBCA is essential [27]. NSF was originally reported by Cowper et al. [28] to have first occurred in 1997. NSF affects male and female patients equally and has been reported to occur in patients of all ages including children as young as 8 years old [29]. Although the cause of NSF remains unknown, most patients have a history of gadolinium exposure and gadolinium has been detected in NSF skin lesions, as reported by several authors [9, 30]. Cowper [31] has established the following diagnostic criteria for NSF: large areas of hardened skin with slightly raised plaques, papules, or confluent papules; with or without pigmentary alteration and/or with biopsies showing increased numbers of fibroblasts, alteration of the normal pattern of colla-

Michael F. Morris1 Yang Zhang Honglei Zhang Joan C. Prowda David N. Silvers Rashid A. Fawwaz Martin R. Prince
Morris MF, Zhang Y, Zhang H, et al.

gen bundles seen in the dermis, and often increased dermal deposits of mucin. These criteria have been expanded in a recent review [32]. Because NSF primarily involves the skin, little attention has been paid to its imaging characteristics [33]. We have seen the imaging studies of 26 biopsy-confirmed cases of NSF at our institution. This article illustrates the spectrum of imaging findings in these NSF patients with photographic and histopathologic correlation. Histopathology Deep punch biopsy specimens of NSF lesions show, in varying proportions, spindle cell proliferation, thickened collagen bundles, and mucin deposition (Fig. 1) in a process believed to be mediated by circulating fibrocytes inappropriately stimulated by gadolinium [34]. Although NSF primarily affects the skin, involvement of skeletal muscle, heart, and lungs has also been reported [23, 32, 35]. The histologic features of NSF can be very similar in appearance to other dermatologic conditions, including scleromyxedema, scleroderma and deep morphea, lipodermatosclerosis, eosinophilic fasciitis (Shulman syndrome), and chronic graft-versus-host disease [32]. Thus, diagnosing NSF requires a combination of characteristic histologic and clinical findings. Clinical Manifestations All NSF patients have significant renal impairment, with an estimated GFR of < 30

Keywords: CT, gadolinium, mammography, MRI, nephrogenic systemic fibrosis, PET, scintigraphy, ultrasound DOI:10.2214/AJR.08.1352 Received June 5, 2008; accepted after revision December 25, 2008. M. R. Prince has patent agreements with the following companies, which manufacture gadolinium-based contrast agents: GE Healthcare, Bayer HealthCare, Mallinckrodt Imaging, Bracco Laboratories, and Epix.
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All authors: Department of Radiology and Department of Dermatology and Dermatopathology at Columbia and Cornell Universities, 416 E 55th St., New York, NY 10022. Address correspondence to M. R. Prince (map2008@med.cornell.edu).

AJR 2009; 193:6169 0361803X/09/193161 American Roentgen Ray Society

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Morris et al. mL/min (stage IV or V kidney disease), dialysis-dependent end-stage renal disease, or acute renal failure. Patients often initially present with nonspecific complaintsincluding joint pain, extremity swelling, and stiffnessthat in turn may lead to multiple imaging procedures. On physical examination, the cutaneous manifestations of NSF commonly involve the extremities and trunk beginning distally and spreading proximally while sparing the face. Patients with mild disease can present with a variety of nonspecific findings ranging from erythema, papules, and plaques (Fig. 2) to skin dimpling and peau dorange (Fig. 3). Patients may develop contractures that reduce mobility (Fig. 4). Although most cases of NSF are self-limiting and some regress spontaneously, an estimated 5% have a rapidly progressive fulminate course [23]. Unlike allergic reactions that happen within minutes of injection and are independent of contrast agent dose, the skin changes of NSF typically are delayed, occurring from 2 weeks to 2 months after high-dose GBCA injection. NSF is rare with standard 0.1 mmol/ kg doses of gadolinium [27]. There may be an initial prodrome of muscle pain, fever, weakness, swelling, redness, pruritus, or pain in the limbs sometimes with muscle weakness, edema, or erythema and occasionally with palpable warmth of the involved extremities; there may be florid scleral telangiectasia resembling conjunctivitis [36]. Clinical severity is related to both the extent of the fibrosing dermopathy and the degree of systemic involvement. Muscle involvement tends to be underlying the cutaneous lesions with fibrotic bands in the subcutaneous tissues tethering the skin to the underlying fascia. In some patients the NSF lesions resolve with restoration of normal renal function after renal transplantation or resolution of acute renal failure. In many cases the lesions persist, although a recent report shows promising results for treating patients with NSF using imatinib mesylate [37]. Radiography The conventional radiographic findings of NSF are nonspecific, and abnormalities on radiographs are rare and usually are secondary to the sequelae of joint contracture and immobility. Flexion deformities and disuse osteopenia from contractures occur most commonly in the feet (Fig. 4), knees, hands, and elbows. In 140 NSF patients described in detail in case reports, limited range of motion or joint contractions were noted clinically in 106 (58%) [38]. We saw joint contractures on radiographs in two of our 26 patients, but the contractures in one patient were due to juvenile rheumatoid arthritis and had been present before NSF developed. Note that the differential diagnosis for joint contractures includes arthritides and immobilization (e.g., due to trauma, burns, nerve injury, or stroke); the likelihood that a joint contracture signifies NSF is negligible. Although microscopic dermal calcifications are common in NSF specimens and Cowper and colleagues have described skin calcifications on radiographs, these calcifications are rare in NSF cases [39]. We found cutaneous calcifications on an imaging study in only one of our 26 biopsy-positive NSF patients. In that patient, skin calcifications on abdominopelvic CT were thought to be more likely related to the patients other diseases including juvenile rheumatoid arthritis, dialysis-dependent end-stage renal failure, and systemic lupus erythematosus. Vascular calcifications visible on radiographs are usually related to diabetes or renal failure. Mammography Three of the six female NSF patients who underwent mammography at our hospital had skin thickening and increased subcutaneous linear markings (Fig. 5) corresponding to NSF lesions. Although the breast skin thickening in these patients was readily identified as part of the NSF process occurring over the legs, arms, and chest, skin thickening on mammography is much more likely to be related to inflammatory breast cancer, cellulitis, scarring, or venous or lymphatic obstruction. Ultrasound Duplex ultrasound may be performed to assess for extremity deep venous thrombosis (DVT) in patients with NSF because of the common complaints of extremity pain and swelling. Breast ultrasound may be performed in female patients with NSF who have mammographic abnormalities, and it may show skin thickening and subcutaneous edemalike inflammatory changes. Note that these findings are nonspecific; are much more likely to result from DVT, inflammation, or cellulitis; and would not be expected to elicit the diagnosis of NSF. CT The most common CT study performed in patients with NSF is of the abdomen and pelvis; however, occasionally CT of an extremity is performed during a workup for extremity pain. Depending on the severity of disease, CT may show varying degrees of skin thickening and infiltration of the subcutaneous and soft tissues (Figs. 6 and 7). Reformations in coronal and sagittal planes and along the axis of the bones may facilitate assessment of dermal infiltration. In particular, bands of collagen in the subcutaneous fat tether the skin to underlying soft tissues [40]. Systemic involvement of the internal organs is difficult to identify on CT and thus has been reported only at autopsy or on surgical and biopsy specimens. The differential diagnosis for skin thickening and infiltration of the subcutaneous fat on CT includes edema, cellulitis, fascitis and panniculitis, scleroderma and sclerodermalike conditions (e.g., morphea), cutaneous T-cell lymphoma, and Merkel cell carcinoma. MRI The spectrum of abnormal MRI findings in patients with NSF can be similar to that seen on CT. Subtle areas of edema are seen on STIR or T2-weighted fat-saturated images in patients with mild clinical manifestations of NSF, whereas patients with more severe involvement show skin thickening and diffuse inflammatory changes throughout the soft tissues (Figs. 810). Although gadolinium is contraindicated in patients with severe renal impairment, enhancement of the subcutaneous tissues and skeletal muscle may be seen on T1-weighted fat-saturated images when GBCA is administered [24]. These nonspecific findings are seen in many inflammatory, neoplastic, and traumatic conditions and should not raise suspicion for NSF. Nuclear Medicine Extraosseous accumulation of 99mTc-hydroxydiphosphonate (HDP) can be seen in NSF patients undergoing bone scintigraphy (Fig. 11) and was previously reported [32, 41, 42]. The differential diagnosis for diffuse extremity soft-tissue uptake on bone scans includes myositis ossificans and heterotopic calcifications; dermatomyositis; rhabdomyolysis; polymyositis; metastatic calcifications; and technical factors, including contamination and tourniquet effects. There is a case report describing FDG uptake in NSF [41]. We found only one NSF patient with FDG uptake on PET and that patient had cutaneous T-cell lymphoma, which was more likely to be the reason for FDG activity in the skin.

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Imaging Features of NSF Conclusion NSF has a variable appearance on routine imaging studies. Often there are no abnormal imaging findings. However, conventional radiographs can show joint contractures, skin thickening, and possibly cutaneous calcinosis; ultrasound may show thickening and edema of the cutis, particularly in the breast; CT may show skin thickening and infiltration of subcutaneous tissues; MRI may show increased signal on fluid-sensitive sequences in the skin, subcutaneous tissues, and extremity musculature; and bone scintigraphy may show diffuse soft-tissue uptake in the extremities. Studies of the head and anterior neck fail to show changes related to NSF because the disease spares that region. All these imaging findings are nonspecific and cannot be used to diagnose NSF using the currently accepted diagnostic criteria. References
1. Karlik SJ. Gadodiamide-associated nephrogenic systemic fibrosis. (letter) AJR 2007; 188:W584; author reply, W585 2. Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR 2007; 188:586592 3. Grobner T, Prischl FC. Gadolinium and nephrogenic systemic fibrosis. Kidney Int 2007; 72:260 264 4. High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007; 56:2126 5. Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007; 56:2730 6. High WA, Ayers RA, Cowper SE. Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007; 56:710712 7. Grobner T. Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006; 21:11041108 [Erratum in Nephrol Dial Transplant 2006; 21:1745] 8. Ng YY, Lee RC, Shen SH, Kirk G. Gadoliniumassociated nephrogenic systemic fibrosis: double dose, not single dose. (letter) AJR 2007; 188:W582; author reply, W583 9. Wiginton CD, Kelly B, Oto A, et al. Gadoliniumbased contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. AJR 2008; 190:10601068 10. Chewning RH, Murphy KJ. Gadolinium-based contrast media and the development of nephrogenic systemic fibrosis in patients with renal insufficiency. J Vasc Interv Radiol 2007; 18:331333 11. Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE. Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology 2007; 242: 647649 12. Perazella MA, Rodby RA. Gadolinium-induced nephrogenic systemic fibrosis in patients with kidney disease. Am J Med 2007; 120:561562 13. Collidge TA, Thomson PC, Mark PB, et al. Gadolinium-enhanced MR imaging and nephrogenic systemic fibrosis: retrospective study of a renal replacement therapy cohort. Radiology 2007; 245:168175 14. Rosenkranz AR, Grobner T, Mayer GJ. Conventional or gadolinium containing contrast media: the choice between acute renal failure or nephrogenic systemic fibrosis? Wien Klin Wochenschr 2007; 119:271275 15. Thomsen HS, Marckmann P, Logager VB. Enhanced computed tomography or magnetic resonance imaging: a choice between contrast mediuminduced nephropathy and nephrogenic systemic fibrosis? Acta Radiol 2007; 48:593596 16. Rydahl C, Thomsen HS, Marckmann P. High prevalence of nephrogenic systemic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent. Invest Radiol 2008; 43:141144 17. Thomsen HS, Morcos SK, Dawson P. Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? Clin Radiol 2006; 61:905906 18. Hedley AJ, Molan MP, Hare DL, Anavekar NS, Ierino FL. Nephrogenic systemic fibrosis associated with gadolinium-containing contrast media administration in patients with reduced glomerular filtration rate. Nephrology (Carlton) 2007; 12: 111 19. Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006; 17:23592362 20. Marckmann P, Skov L, Rossen K, Heaf JG, Thomsen HS. Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant 2007; 22:31743178 21. Introcaso CE, Hivnor C, Cowper S, Werth VP. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: a case series of nine patients and review of the literature. Int J Dermatol 2007; 46: 447452 22. Deo A, Fogel M, Cowper SE. Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol 2007; 2:264267 23. Cowper SE, Boyer PJ. Nephrogenic systemic fibrosis: an update. Curr Rheumatol Rep 2006; 8: 151157 24. Sadowski EA, Bennett LK, Chan MR, et al. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology 2007; 243:148157 25. Peak AS, Sheller A. Risk factors for developing gadolinium-induced nephrogenic systemic fibrosis. Ann Pharmacother 2007; 41:14811485 26. U.S. Food and Drug Administration Website. Important drug warning for gadolinium-based contrast agents. www.fda.gov/medwatch/safety/2007/ gadolinium_DHCP.pdf. Published September 12, 2007; accessed March 23, 2009 27. Prince MR, Zhang H, Morris M, et al. Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology 2008; 248:807816 28. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000; 356:10001001 29. Mendichovszky IA, Marks SD, Simcock CM, Olsen OE. Gadolinium and nephrogenic systemic fibrosis: time to tighten practice. Pediatr Radiol 2008; 38:489496 30. Khurana A, Greene JFJ, High WA. Quantification of gadolinium in nephrogenic systemic fibrosis: re-examination of a reported cohort with analysis of clinical factors. J Am Acad Dermatol 2008; 59:218224 31. Cowper SE. Nephrogenic fibrosing dermopathy. NFD/NSF Website 20012009. www.icnfdr.org. Accessed August 24, 2008 32. Cowper SE, Rabach M, Girardi M. Clinical and histological findings in nephrogenic systemic fibrosis. Eur J Radiol 2008; 66:191199 33. Weigle JP, Broome DR. Nephrogenic systemic fibrosis: chronic imaging findings and review of the medical literature. Skeletal Radiol 2008; 37:457 464 34. Quan TE, Cowper SE, Bucala R. The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep 2006; 8:145150 35. Marckmann P, Skov L, Rossen K, Thomsen HS. Clinical manifestation of gadodiamide-related nephrogenic systemic fibrosis. Clin Nephrol 2008; 69:161168 36. Knopp EA, Cowper SE. Nephrogenic systemic fibrosis: early recognition and treatment. Semin Dial 2008; 21:123128 37. Kay J, High WA. Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum 2008; 58:25432548 38. Prince MR, Zhang H, Roditi GH. Risk factors for NSF: a literature review. J Magn Reson 2009 (in press) 39. Ting WW, Stone MS, Madison KC, Kurtz K. Nephrogenic fibrosing dermopathy with systemic

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involvement. Arch Dermatol 2003; 139:903906 40. Levine JM, Taylor RA, Elman LB, et al. Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy). Muscle Nerve 2004; 30:569577 41. Evenepoel P, Zeegers M, Segaert S, et al. Nephrogenic fibrosing dermopathy: a novel, disabling disorder in patients with renal failure. Nephrol Dial Transplant 2004; 19:469473 42. Gremmels JM, Kirk GA. Two patients with abnormal skeletal muscle uptake of Tc-99m hydroxymethylene diphosphonate following liver transplant: nephrogenic fibrosing dermopathy and graft vs host disease. Clin Nucl Med 2004; 29: 694697

Fig. 1Photomicrographs of H and Estained skin punch biopsy in 56-year-old woman show interstitial spindle cell proliferation at all levels of dermis typical of nephrogenic systemic fibrosis. A and B, Low power (A, 4) and higher power (B, 20).

A
Fig. 268-year-old man with nephrogenic systemic fibrosis. Note multiple erythematous papules (arrows) on leg similar to classic scleromyxedema. Fig. 356-year-old woman with nephrogenic systemic fibrosis (NSF). A and B, Note skin dimpling in lower extremities (A) and peau dorange appearance of woody and indurated skin in upper extremities (B). Biopsy of right thigh showed proliferation of spindle cells with abundant interstitial dermal mucin consistent with NSF.

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Imaging Features of NSF

Fig. 436-year-old woman with nephrogenic systemic fibrosis (NSF) involving chest, back, and both lower extremities. Left leg biopsy showed proliferation of spindle cells and thick collagen bundles consistent with NSF. A and B, Lateral ankle radiographs show flexion contractures with moderately severe osteopenia bilaterally, likely from disuse. These radiographic findings are not specific for NSF.

Fig. 551-year-old woman with nephrogenic systemic fibrosis (NSF) on chest, back, arms, and buttocks. Chest skin biopsy showed slight dermal fibrosis consistent with spectrum of histologic findings in NSF. A, Mammogram shows skin thickening (arrows), increased breast density, and infiltration of subcutaneous tissues. B, Breast ultrasound image shows skin thickening, edema (white arrows), and increased tissue echogenicity with large collateral vessels (black arrow). These findings are not specific for NSF.

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Fig. 657-year-old woman with nephrogenic systemic fibrosis (NSF) involving bilateral thighs. Skin biopsy of right thigh showed thickening of dermal collagen and fibrous septa between fat lobules. A and B, Coronal (A) and axial (B) reformatted lower extremity CT images show nonspecific findings for NSF including diffuse infiltration of subcutaneous tissues of thighs with variable degrees of skin thickening (arrowheads, A). C and D, T1-weighted (C) and STIR (D) images show dermal thickening (arrowhead, C) and bands within subcutaneous fat (arrow, D); these MRI findings are similar to those seen on CT. E, On conventional radiograph, skin thickening is difficult to see and changes in subcutaneous fat are subtle.

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A
Fig. 771-year-old woman with nephrogenic systemic fibrosis (NSF) involving left arm and forearm. Left forearm biopsy showed sun-damaged skin with edema and dermal mucin typical of NSF. Oblique reformatted upper extremity CT scan shows diffuse infiltration of subcutaneous tissues (arrows) and variable degrees of skin thickening. These CT findings are not specific for NSF.

Fig. 856-year-old woman with nephrogenic systemic fibrosis (NSF) involving thighs and calves bilaterally. Biopsies of right thigh and calf showed proliferation of spindle cells, thick collagen bundles, and abundant interstitial mucin in dermis typical of NSF. A and B, Unenhanced sagittal STIR images of right calf show skin thickening (arrows), predominantly anteriorly, in patient with only mild NSF. These findings are not specific for NSF.

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Fig. 954-year-old woman with nephrogenic systemic fibrosis (NSF) involving both lower extremities and left upper extremity. Biopsy of right thigh showed granulomatous septa in panniculus that was not thought to represent NSF, but Shawn E. Cowper [31] reviewed histologic sections and interpreted changes as consistent with NSF. A and B, Coronal STIR images of thigh (A) and calf (B) show increased signal throughout subcutaneous tissues and muscles of legs bilaterally. These findings are not specific for NSF.

Fig. 1060-year-old man with nephrogenic systemic fibrosis (NSF) involving legs and back and neck. Biopsies of right leg and upper back showed dermal fibrosis with small amount of mucin consistent with NSF. Axial T2-weighted MR image with fat saturation shows dermal thickening (arrowheads) with changes in subcutaneous fat resembling edema and inflammatory changes in underlying skeletal muscles of anterior thighs (arrows). These MR findings are not specific for NSF.

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Fig. 1150-year-old man with nephrogenic systemic fibrosis (NSF) primarily involving legs and left forearm. Biopsies of right thigh and left arm show spindle cell proliferation consistent with NSF. A and B, Bone scintigraphy images show diffuse increased 99mTc-hydroxydiphosphonate activity in skin and subcutaneous tissues on bone scan that corresponds to distribution of skin rash. These findings are not specific for NSF.

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