Nektarios I. Lountzis, MD

Nephrogenic systemic fibrosis (NSF) is a rare debilitating disorder characterized by dermal plaques, joint contractures, and fibrosis of the skin with possible involvement of muscles and internal organs.^1-3 Originally identified in 1997 as nephrogenic fibrosing dermopathy to describe its characteristic cutaneous thickening and hardening, the name was changed to NSF to more accurately reflect the noncutaneous manifestations present in other organ tissues.^2,4,5 Nephrogenic systemic fibrosis occurs in patients with a history of renal insufficiency and exposure to gadolinium-based contrast agents (GBCAs) used in magnetic resonance angiography and magnetic resonance imaging. There is no predilection for age, sex, or ethnicity.

Nephrogenic systemic fibrosis may develop over a period of days to several weeks. However, there have been cases of NSF developing 10 years after gadolinium exposure.² In most cases, patients have a history of severe chronic renal disease requiring hemodialysis. There have been a few reported cases of NSF occurring in patients with resolved acute kidney injury or resolved acute on chronic renal disease.^1,6-10 We present a case of NSF occurring in a patient with resolved transient renal insufficiency and no history of chronic renal disease.

Case Report

A 68-year-old woman presented with new dark, painless, pink plaques on the right thigh and calf. The patient stated the condition started and got worse after she was hospitalized 12 years prior for lower extremity cellulitis, sepsis, and acute renal failure. The patient developed complications during that hospital stay and underwent a renal biopsy and renal artery embolization requiring use of a GBCA. After the procedure, she noticed skin hardening in the extremities and decreased mobility in both legs while she was still in the hospital. It was thought that the lower leg changes were due to cellulitis. Therefore, when the renal issues resolved, she was discharged. Her skin and joint changes remained stable until 6 years later when she noticed new pink plaques appearing. Her medical history was positive for breast cancer, which was surgically and medically treated 16 years prior to presentation.

On presentation, physical examination revealed dark pink, hyperpigmented plaques on the right leg and a firm hypopigmented broad linear plaque on the right forearm. Palpation of the legs revealed thickened sclerotic plaques from the thighs down to the ankles (Figure 1). The plaques were not tender to palpation. She did have a decreased range of motion with eversion and inversion of the feet and ankles.

Biopsies from the right medial leg and right volar forearm showed increased bland dermal spindle cellularity associated with numerous round to ovoid osteoid aggregates encircling elastic fibers and surrounded by osteoblasts (Figure 2). CD34 immunohistochemistry showed general retention of staining within the dermal fibroblast population, and elastin stain showed general retention of elastic fiber bundles and thickening.

Laboratory workup included a complete blood cell count, comprehensive metabolic panel, thyroid-stimulating hormone level, and serum protein electrophoresis; results were all within reference range. The patient also had a urine element profile from an outside provider 1 month after presenting to our office that showed an elevated urine gadolinium level of 4.146 μg/g (reference range, 0–0.019 μg/g). The patient’s skin lesions have remained stable, and she is now working with physical therapy to help with her range of motion.

Comment

Gadolinium Causing Fibrosis—The incidence of NSF varies according to the severity of renal impairment, dosage level of GBCA used, and the history of GBCA use. In patients with normal renal function, gadolinium is excreted within 90 minutes. In patients with severe renal disease, the half-life can increase to up to 34.3 hours.¹¹ Reduced renal clearance and increased half-life of gadolinium lead to prolonged excretion, causing the GBCA to become unstable and dissociate into its constituents, leading to tissue deposition of Gd³⁺ cations. This dissociation is thought to be due to differences in the stability of the various chelation complexes among the different formulations of GBCAs.¹² The mechanism by which the dissociated gadolinium causes the fibrosis in the skin or other organs of the body is still unknown. Furthermore, even patients with normal renal function who undergo repeated administration of GBCA have been found to have higher levels of Gd³⁺ in their tissues, even in the absence of symptoms.¹³

Diagnosing NSF—In 2011, Girardi et al¹⁴ created a clinical and histopathological scoring system to help diagnose NSF. Clinical findings can be broken down into major criteria and minor criteria. Major criteria consist of patterned plaques, joint contractures, cobblestoning, marked induration, or peau d’orange change. Minor criteria consist of puckering, linear banding, superficial plaques or patches, dermal papules, and scleral plaques. Histopathologic findings include increased dermal cellularity (score +1), CD34⁺ cells with tram tracking (score +1), thickened or thin collagen bundles (score +1), preserved elastic fibers (score −1), septal involvement (score +1), and osseous metaplasia (score +3)(eTable).¹⁴

Differential Diagnosis—The differential diagnosis of NSF includes scleromyxedema, scleroderma, eosinophilic fasciitis, eosinophilia-myalgia syndrome, lipodermatosclerosis, morphea, and chronic graft-vs-host disease. Histopathologic examination of scleromyxedema can look identical to NSF. Therefore, a review of the patient’s medical history, prior hospitalizations, and prior gadolinium exposure is important. Appropriate laboratory workups should be ordered to rule out the other differential diagnoses.

NSF and Kidney Injury—A PubMed search of articles indexed for MEDLINE using the terms NSF with kidney injury revealed 7 cases of NSF occurring in patients who either had resolved acute kidney injury or resolved acute on chronic kidney disease.^1,6-10 Of those cases, 3 reported NSF occurring in patients with completely resolved acute kidney injury.^6,7,10 One of those cases involved a 65-year-old man who developed acute renal failure due to acute tubular necrosis.⁷ He had no history of renal disease prior to hospitalization. His skin lesions continued to improve as his renal function normalized back to baseline after discharge.⁷ The second case involved a 42-year-old man who had repeated exposure to GBCAs during a brief period of acute kidney injury.⁶ Nephrogenic systemic fibrosis developed after his renal function normalized. The authors did not mention if there was clinical improvement.⁶ The third case involved a 22-year-old man who developed acute renal failure after ingestion of hair dye. He did not have a history of chronic renal disease, and as he recovered from the acute kidney injury, almost all of the skin lesions cleared after 1 year.¹⁰

Our patient did not have a history of chronic renal disease when she presented to the hospital for sepsis and acute tubular necrosis. Unlike 2 of the prior cases, she did not notice improvement of the skin lesions as the renal function returned to baseline. She continued to experience changes in the skin, even up to 5 years after, and then stabilized. Throughout that time, her renal function was normal. Interestingly, despite having a normal creatinine level, the patient had an elevated gadolinium level on the urine gadolinium test, which typically is not a standard test for NSF. However, the elevated value does shed light on the persistence of gadolinium in the patient despite her exposure having been more than 10 years earlier.

Treatment of NSF—There is no gold standard treatment of NSF, and reversing the fibrosis has proven to be difficult. Avoidance of GBCAs in acute kidney injury or chronic severe renal disease, as recommended by the US Food and Drug Administration, is key to preventing this debilitating disease.¹⁵ Restoration of renal function is essential for excreting the gadolinium and improvement in NSF.¹² Physical and occupational therapy can improve joint mobility. Therapies such as extracorporeal photopheresis, sodium thiosulfate, pentoxifylline, glucocorticoids, plasmapheresis, intravenous immunoglobulin, cyclophosphamide, imatinib mesylate, intralesional interferon alfa, topical calcipotriene, corticosteroids, and UVA1 light therapy have been used with varying results.¹² It has been suggested that renal transplantation can stop the progression of NSF. However, in the cases we reviewed, renal transplantation would not have benefited those patients because their renal function normalized.^6,7,10 Additionally, even though our patient’s renal function normalized after discharge from the hospital, she continued to see more skin lesions developing, likely due to the accumulated gadolinium that was already in her tissue. The possibility of chelation therapy to remove the gadolinium has been proposed. In 1 case study involving deferoxamine injected intramuscularly in a patient with NSF, the urine excretion of gadolinium increased almost 2-fold, but there was no change in the serum concentration level of gadolinium or improvement in the patient’s clinical symptoms.¹⁶ We anticipate that our patient’s symptoms will slowly improve, as her body is still excreting the gadolinium. Our patient also was added to the International NSF Registry that was created by Dr. Shawn E. Cowper at the Yale School of Medicine (New Haven, Connecticut).

Conclusion

We report a rare case of NSF occurring in a patient with resolved acute kidney injury and no history of chronic renal disease. Our patient initially did not improve after her renal function normalized, as she continued to develop lesions 10 years after the exposure. Her elevated urine gadolinium excretion level also sheds light on the persistence of gadolinium in her body despite her normal renal function 10 years after her exposure. Although her clinical symptoms have stabilized, our case reiterates the complex pathology of this entity and challenge regarding treatment options. Physicians should be aware that NSF can still occur in healthy patients with no chronic renal disease who have had an episode of acute renal insufficiency along with exposure to a GBCA.

Nephrogenic systemic fibrosis (NSF) is a rare debilitating disorder characterized by dermal plaques, joint contractures, and fibrosis of the skin with possible involvement of muscles and internal organs.^1-3 Originally identified in 1997 as nephrogenic fibrosing dermopathy to describe its characteristic cutaneous thickening and hardening, the name was changed to NSF to more accurately reflect the noncutaneous manifestations present in other organ tissues.^2,4,5 Nephrogenic systemic fibrosis occurs in patients with a history of renal insufficiency and exposure to gadolinium-based contrast agents (GBCAs) used in magnetic resonance angiography and magnetic resonance imaging. There is no predilection for age, sex, or ethnicity.

Nephrogenic systemic fibrosis may develop over a period of days to several weeks. However, there have been cases of NSF developing 10 years after gadolinium exposure.² In most cases, patients have a history of severe chronic renal disease requiring hemodialysis. There have been a few reported cases of NSF occurring in patients with resolved acute kidney injury or resolved acute on chronic renal disease.^1,6-10 We present a case of NSF occurring in a patient with resolved transient renal insufficiency and no history of chronic renal disease.

Case Report

A 68-year-old woman presented with new dark, painless, pink plaques on the right thigh and calf. The patient stated the condition started and got worse after she was hospitalized 12 years prior for lower extremity cellulitis, sepsis, and acute renal failure. The patient developed complications during that hospital stay and underwent a renal biopsy and renal artery embolization requiring use of a GBCA. After the procedure, she noticed skin hardening in the extremities and decreased mobility in both legs while she was still in the hospital. It was thought that the lower leg changes were due to cellulitis. Therefore, when the renal issues resolved, she was discharged. Her skin and joint changes remained stable until 6 years later when she noticed new pink plaques appearing. Her medical history was positive for breast cancer, which was surgically and medically treated 16 years prior to presentation.

On presentation, physical examination revealed dark pink, hyperpigmented plaques on the right leg and a firm hypopigmented broad linear plaque on the right forearm. Palpation of the legs revealed thickened sclerotic plaques from the thighs down to the ankles (Figure 1). The plaques were not tender to palpation. She did have a decreased range of motion with eversion and inversion of the feet and ankles.

Biopsies from the right medial leg and right volar forearm showed increased bland dermal spindle cellularity associated with numerous round to ovoid osteoid aggregates encircling elastic fibers and surrounded by osteoblasts (Figure 2). CD34 immunohistochemistry showed general retention of staining within the dermal fibroblast population, and elastin stain showed general retention of elastic fiber bundles and thickening.

Laboratory workup included a complete blood cell count, comprehensive metabolic panel, thyroid-stimulating hormone level, and serum protein electrophoresis; results were all within reference range. The patient also had a urine element profile from an outside provider 1 month after presenting to our office that showed an elevated urine gadolinium level of 4.146 μg/g (reference range, 0–0.019 μg/g). The patient’s skin lesions have remained stable, and she is now working with physical therapy to help with her range of motion.

Comment

Gadolinium Causing Fibrosis—The incidence of NSF varies according to the severity of renal impairment, dosage level of GBCA used, and the history of GBCA use. In patients with normal renal function, gadolinium is excreted within 90 minutes. In patients with severe renal disease, the half-life can increase to up to 34.3 hours.¹¹ Reduced renal clearance and increased half-life of gadolinium lead to prolonged excretion, causing the GBCA to become unstable and dissociate into its constituents, leading to tissue deposition of Gd³⁺ cations. This dissociation is thought to be due to differences in the stability of the various chelation complexes among the different formulations of GBCAs.¹² The mechanism by which the dissociated gadolinium causes the fibrosis in the skin or other organs of the body is still unknown. Furthermore, even patients with normal renal function who undergo repeated administration of GBCA have been found to have higher levels of Gd³⁺ in their tissues, even in the absence of symptoms.¹³

Diagnosing NSF—In 2011, Girardi et al¹⁴ created a clinical and histopathological scoring system to help diagnose NSF. Clinical findings can be broken down into major criteria and minor criteria. Major criteria consist of patterned plaques, joint contractures, cobblestoning, marked induration, or peau d’orange change. Minor criteria consist of puckering, linear banding, superficial plaques or patches, dermal papules, and scleral plaques. Histopathologic findings include increased dermal cellularity (score +1), CD34⁺ cells with tram tracking (score +1), thickened or thin collagen bundles (score +1), preserved elastic fibers (score −1), septal involvement (score +1), and osseous metaplasia (score +3)(eTable).¹⁴

Differential Diagnosis—The differential diagnosis of NSF includes scleromyxedema, scleroderma, eosinophilic fasciitis, eosinophilia-myalgia syndrome, lipodermatosclerosis, morphea, and chronic graft-vs-host disease. Histopathologic examination of scleromyxedema can look identical to NSF. Therefore, a review of the patient’s medical history, prior hospitalizations, and prior gadolinium exposure is important. Appropriate laboratory workups should be ordered to rule out the other differential diagnoses.

NSF and Kidney Injury—A PubMed search of articles indexed for MEDLINE using the terms NSF with kidney injury revealed 7 cases of NSF occurring in patients who either had resolved acute kidney injury or resolved acute on chronic kidney disease.^1,6-10 Of those cases, 3 reported NSF occurring in patients with completely resolved acute kidney injury.^6,7,10 One of those cases involved a 65-year-old man who developed acute renal failure due to acute tubular necrosis.⁷ He had no history of renal disease prior to hospitalization. His skin lesions continued to improve as his renal function normalized back to baseline after discharge.⁷ The second case involved a 42-year-old man who had repeated exposure to GBCAs during a brief period of acute kidney injury.⁶ Nephrogenic systemic fibrosis developed after his renal function normalized. The authors did not mention if there was clinical improvement.⁶ The third case involved a 22-year-old man who developed acute renal failure after ingestion of hair dye. He did not have a history of chronic renal disease, and as he recovered from the acute kidney injury, almost all of the skin lesions cleared after 1 year.¹⁰

Our patient did not have a history of chronic renal disease when she presented to the hospital for sepsis and acute tubular necrosis. Unlike 2 of the prior cases, she did not notice improvement of the skin lesions as the renal function returned to baseline. She continued to experience changes in the skin, even up to 5 years after, and then stabilized. Throughout that time, her renal function was normal. Interestingly, despite having a normal creatinine level, the patient had an elevated gadolinium level on the urine gadolinium test, which typically is not a standard test for NSF. However, the elevated value does shed light on the persistence of gadolinium in the patient despite her exposure having been more than 10 years earlier.

Treatment of NSF—There is no gold standard treatment of NSF, and reversing the fibrosis has proven to be difficult. Avoidance of GBCAs in acute kidney injury or chronic severe renal disease, as recommended by the US Food and Drug Administration, is key to preventing this debilitating disease.¹⁵ Restoration of renal function is essential for excreting the gadolinium and improvement in NSF.¹² Physical and occupational therapy can improve joint mobility. Therapies such as extracorporeal photopheresis, sodium thiosulfate, pentoxifylline, glucocorticoids, plasmapheresis, intravenous immunoglobulin, cyclophosphamide, imatinib mesylate, intralesional interferon alfa, topical calcipotriene, corticosteroids, and UVA1 light therapy have been used with varying results.¹² It has been suggested that renal transplantation can stop the progression of NSF. However, in the cases we reviewed, renal transplantation would not have benefited those patients because their renal function normalized.^6,7,10 Additionally, even though our patient’s renal function normalized after discharge from the hospital, she continued to see more skin lesions developing, likely due to the accumulated gadolinium that was already in her tissue. The possibility of chelation therapy to remove the gadolinium has been proposed. In 1 case study involving deferoxamine injected intramuscularly in a patient with NSF, the urine excretion of gadolinium increased almost 2-fold, but there was no change in the serum concentration level of gadolinium or improvement in the patient’s clinical symptoms.¹⁶ We anticipate that our patient’s symptoms will slowly improve, as her body is still excreting the gadolinium. Our patient also was added to the International NSF Registry that was created by Dr. Shawn E. Cowper at the Yale School of Medicine (New Haven, Connecticut).

Conclusion

We report a rare case of NSF occurring in a patient with resolved acute kidney injury and no history of chronic renal disease. Our patient initially did not improve after her renal function normalized, as she continued to develop lesions 10 years after the exposure. Her elevated urine gadolinium excretion level also sheds light on the persistence of gadolinium in her body despite her normal renal function 10 years after her exposure. Although her clinical symptoms have stabilized, our case reiterates the complex pathology of this entity and challenge regarding treatment options. Physicians should be aware that NSF can still occur in healthy patients with no chronic renal disease who have had an episode of acute renal insufficiency along with exposure to a GBCA.

Nephrogenic systemic fibrosis (NSF) is a rare debilitating disorder characterized by dermal plaques, joint contractures, and fibrosis of the skin with possible involvement of muscles and internal organs.^1-3 Originally identified in 1997 as nephrogenic fibrosing dermopathy to describe its characteristic cutaneous thickening and hardening, the name was changed to NSF to more accurately reflect the noncutaneous manifestations present in other organ tissues.^2,4,5 Nephrogenic systemic fibrosis occurs in patients with a history of renal insufficiency and exposure to gadolinium-based contrast agents (GBCAs) used in magnetic resonance angiography and magnetic resonance imaging. There is no predilection for age, sex, or ethnicity.

Nephrogenic systemic fibrosis may develop over a period of days to several weeks. However, there have been cases of NSF developing 10 years after gadolinium exposure.² In most cases, patients have a history of severe chronic renal disease requiring hemodialysis. There have been a few reported cases of NSF occurring in patients with resolved acute kidney injury or resolved acute on chronic renal disease.^1,6-10 We present a case of NSF occurring in a patient with resolved transient renal insufficiency and no history of chronic renal disease.

Case Report

A 68-year-old woman presented with new dark, painless, pink plaques on the right thigh and calf. The patient stated the condition started and got worse after she was hospitalized 12 years prior for lower extremity cellulitis, sepsis, and acute renal failure. The patient developed complications during that hospital stay and underwent a renal biopsy and renal artery embolization requiring use of a GBCA. After the procedure, she noticed skin hardening in the extremities and decreased mobility in both legs while she was still in the hospital. It was thought that the lower leg changes were due to cellulitis. Therefore, when the renal issues resolved, she was discharged. Her skin and joint changes remained stable until 6 years later when she noticed new pink plaques appearing. Her medical history was positive for breast cancer, which was surgically and medically treated 16 years prior to presentation.

On presentation, physical examination revealed dark pink, hyperpigmented plaques on the right leg and a firm hypopigmented broad linear plaque on the right forearm. Palpation of the legs revealed thickened sclerotic plaques from the thighs down to the ankles (Figure 1). The plaques were not tender to palpation. She did have a decreased range of motion with eversion and inversion of the feet and ankles.

Biopsies from the right medial leg and right volar forearm showed increased bland dermal spindle cellularity associated with numerous round to ovoid osteoid aggregates encircling elastic fibers and surrounded by osteoblasts (Figure 2). CD34 immunohistochemistry showed general retention of staining within the dermal fibroblast population, and elastin stain showed general retention of elastic fiber bundles and thickening.

Laboratory workup included a complete blood cell count, comprehensive metabolic panel, thyroid-stimulating hormone level, and serum protein electrophoresis; results were all within reference range. The patient also had a urine element profile from an outside provider 1 month after presenting to our office that showed an elevated urine gadolinium level of 4.146 μg/g (reference range, 0–0.019 μg/g). The patient’s skin lesions have remained stable, and she is now working with physical therapy to help with her range of motion.

Comment

Gadolinium Causing Fibrosis—The incidence of NSF varies according to the severity of renal impairment, dosage level of GBCA used, and the history of GBCA use. In patients with normal renal function, gadolinium is excreted within 90 minutes. In patients with severe renal disease, the half-life can increase to up to 34.3 hours.¹¹ Reduced renal clearance and increased half-life of gadolinium lead to prolonged excretion, causing the GBCA to become unstable and dissociate into its constituents, leading to tissue deposition of Gd³⁺ cations. This dissociation is thought to be due to differences in the stability of the various chelation complexes among the different formulations of GBCAs.¹² The mechanism by which the dissociated gadolinium causes the fibrosis in the skin or other organs of the body is still unknown. Furthermore, even patients with normal renal function who undergo repeated administration of GBCA have been found to have higher levels of Gd³⁺ in their tissues, even in the absence of symptoms.¹³

Diagnosing NSF—In 2011, Girardi et al¹⁴ created a clinical and histopathological scoring system to help diagnose NSF. Clinical findings can be broken down into major criteria and minor criteria. Major criteria consist of patterned plaques, joint contractures, cobblestoning, marked induration, or peau d’orange change. Minor criteria consist of puckering, linear banding, superficial plaques or patches, dermal papules, and scleral plaques. Histopathologic findings include increased dermal cellularity (score +1), CD34⁺ cells with tram tracking (score +1), thickened or thin collagen bundles (score +1), preserved elastic fibers (score −1), septal involvement (score +1), and osseous metaplasia (score +3)(eTable).¹⁴

Differential Diagnosis—The differential diagnosis of NSF includes scleromyxedema, scleroderma, eosinophilic fasciitis, eosinophilia-myalgia syndrome, lipodermatosclerosis, morphea, and chronic graft-vs-host disease. Histopathologic examination of scleromyxedema can look identical to NSF. Therefore, a review of the patient’s medical history, prior hospitalizations, and prior gadolinium exposure is important. Appropriate laboratory workups should be ordered to rule out the other differential diagnoses.

NSF and Kidney Injury—A PubMed search of articles indexed for MEDLINE using the terms NSF with kidney injury revealed 7 cases of NSF occurring in patients who either had resolved acute kidney injury or resolved acute on chronic kidney disease.^1,6-10 Of those cases, 3 reported NSF occurring in patients with completely resolved acute kidney injury.^6,7,10 One of those cases involved a 65-year-old man who developed acute renal failure due to acute tubular necrosis.⁷ He had no history of renal disease prior to hospitalization. His skin lesions continued to improve as his renal function normalized back to baseline after discharge.⁷ The second case involved a 42-year-old man who had repeated exposure to GBCAs during a brief period of acute kidney injury.⁶ Nephrogenic systemic fibrosis developed after his renal function normalized. The authors did not mention if there was clinical improvement.⁶ The third case involved a 22-year-old man who developed acute renal failure after ingestion of hair dye. He did not have a history of chronic renal disease, and as he recovered from the acute kidney injury, almost all of the skin lesions cleared after 1 year.¹⁰

Our patient did not have a history of chronic renal disease when she presented to the hospital for sepsis and acute tubular necrosis. Unlike 2 of the prior cases, she did not notice improvement of the skin lesions as the renal function returned to baseline. She continued to experience changes in the skin, even up to 5 years after, and then stabilized. Throughout that time, her renal function was normal. Interestingly, despite having a normal creatinine level, the patient had an elevated gadolinium level on the urine gadolinium test, which typically is not a standard test for NSF. However, the elevated value does shed light on the persistence of gadolinium in the patient despite her exposure having been more than 10 years earlier.

Treatment of NSF—There is no gold standard treatment of NSF, and reversing the fibrosis has proven to be difficult. Avoidance of GBCAs in acute kidney injury or chronic severe renal disease, as recommended by the US Food and Drug Administration, is key to preventing this debilitating disease.¹⁵ Restoration of renal function is essential for excreting the gadolinium and improvement in NSF.¹² Physical and occupational therapy can improve joint mobility. Therapies such as extracorporeal photopheresis, sodium thiosulfate, pentoxifylline, glucocorticoids, plasmapheresis, intravenous immunoglobulin, cyclophosphamide, imatinib mesylate, intralesional interferon alfa, topical calcipotriene, corticosteroids, and UVA1 light therapy have been used with varying results.¹² It has been suggested that renal transplantation can stop the progression of NSF. However, in the cases we reviewed, renal transplantation would not have benefited those patients because their renal function normalized.^6,7,10 Additionally, even though our patient’s renal function normalized after discharge from the hospital, she continued to see more skin lesions developing, likely due to the accumulated gadolinium that was already in her tissue. The possibility of chelation therapy to remove the gadolinium has been proposed. In 1 case study involving deferoxamine injected intramuscularly in a patient with NSF, the urine excretion of gadolinium increased almost 2-fold, but there was no change in the serum concentration level of gadolinium or improvement in the patient’s clinical symptoms.¹⁶ We anticipate that our patient’s symptoms will slowly improve, as her body is still excreting the gadolinium. Our patient also was added to the International NSF Registry that was created by Dr. Shawn E. Cowper at the Yale School of Medicine (New Haven, Connecticut).

Conclusion

We report a rare case of NSF occurring in a patient with resolved acute kidney injury and no history of chronic renal disease. Our patient initially did not improve after her renal function normalized, as she continued to develop lesions 10 years after the exposure. Her elevated urine gadolinium excretion level also sheds light on the persistence of gadolinium in her body despite her normal renal function 10 years after her exposure. Although her clinical symptoms have stabilized, our case reiterates the complex pathology of this entity and challenge regarding treatment options. Physicians should be aware that NSF can still occur in healthy patients with no chronic renal disease who have had an episode of acute renal insufficiency along with exposure to a GBCA.

To the Editor:

Erlotinib is a small-molecule selective tyrosine kinase inhibitor that functions by blocking the intracellular portion of the epidermal growth factor receptor (EGFR)^1,2; EGFR normally is expressed in the basal layer of the epidermis, sweat glands, and hair follicles, and is overexpressed in some cancers.^1,3 Normal activation of EGFR leads to signal transduction through the mitogen-activated protein kinase (MAPK) signaling pathway, which stimulates cell survival and proliferation.^4,5 Erlotinib-induced inhibition of EGFR prevents tyrosine kinase phosphorylation and aims to decrease cell proliferation in these tumors.

Erlotinib is indicated as once-daily oral monotherapy for the treatment of advanced-stage non–small cell lung cancer (NSCLCA) and in combination with gemcitabine for treatment of advanced-stage pancreatic cancer.¹ A number of cutaneous side effects have been reported, including acneform eruption, xerosis, paronychia, and pruritus.⁶ Other tyrosine kinase inhibitors, which also decrease signal transduction through the MAPK pathway, have some overlapping side effects; among these are vemurafenib, a selective BRAF inhibitor, and sorafenib, a multikinase inhibitor.^7,8

A 70-year-old man with NSCLCA presented with eruptive nevi and darkening of existing nevi 3 months after starting monotherapy with erlotinib. Physical examination demonstrated the simultaneous appearance of scattered acneform papules and pustules; diffuse xerosis; and numerous dark brown to black nevi on the trunk, arms, and legs. Compared to prior clinical photographs taken in our office, darkening of existing medium brown nevi was noted, and new nevi developed in areas where no prior nevi had been visible (Figure 1).

A review of the patient’s treatment timeline revealed that all other chemotherapeutic medications had been discontinued a minimum of 5 weeks before starting erlotinib. A complete cutaneous examination performed in our office after completion of these chemotherapeutic agents and prior to initiation of erlotinib was unremarkable for abnormally dark or eruptive nevi.

Since starting erlotinib treatment, the patient underwent 10 biopsies of clinically suspicious dark nevi performed by a dermatologist in our office. Two of these were diagnosed as melanoma in situ and one as an atypical nevus. A temporal association of the darkening and eruptive nevi with erlotinib treatment was established; however, because erlotinib was essential to his NSCLCA treatment, he continued erlotinib with frequent complete cutaneous examinations.

A number of cutaneous side effects have been described during treatment with erlotinib, the most common being acneform eruption.⁶ The incidence and severity of acneform eruptions have been positively correlated to survival in patients with NSCLCA.^3,5,6 Other common side effects include xerosis, paronychia, and pruritus.^1,5,6 Less common side effects include periungual pyogenic granulomas and hair growth abnormalities.¹

Eruptive nevi previously were reported in a patient who was treated with erlotinib.¹ Other tyrosine kinase inhibitors that also decrease signal transduction through the MAPK pathway, including sorafenib and vemurafenib, have been reported to cause eruptive nevi. There are 7 reports of eruptive nevi with sorafenib and 5 reports with vemurafenib.^7-9 Development of nevi were noted within a few months of initiating treatment with these medications.⁷

A PubMed search of articles indexed for MEDLINE using the terms erlotinib and melanoma and erlotinib and nevi yielded no prior reports of darkening of existing nevi or the development of melanoma during treatment with erlotinib. However, vemurafenib has been reported to cause dysplastic nevi, melanomas, and darkening of existing nevi, in addition to eruptive nevi.^8-10 The side effects of vemurafenib have been ascribed to a paradoxical upregulation of MAPK in BRAF wild-type cells. This effect has been well documented and demonstrated in vivo.^8,10 Perhaps erlotinib has a similar potential to paradoxically upregulate the MAPK pathway, thus stimulating cellular proliferation and survival.

Another tyrosine kinase receptor, c-KIT, is found on the cell membrane of melanocytes along with EGFR.^11,12 The c-KIT receptor also activates the MAPK pathway and is critical to the development, migration, and survival of melanocytes.^11,13 Stimulation of the c-KIT tyrosine kinase receptor also can induce melanocyte proliferation and melanogenesis.¹¹ The c-KIT receptor is encoded by the KIT gene (KIT proto-oncogene receptor tyrosine kinase). Mutations in this gene are associated with melanocytic disorders. Inherited KIT mutation leading to c-KIT receptor deficiency is associated with piebaldism. Acquired activating KIT mutations increasing c-KIT expression are associated with acral and mucosal melanomas as well as melanomas in chronically sun-damaged skin.¹³

We hypothesized that erlotinib-induced inhibition of the MAPK pathway could lead to a reactive increase in expression of c-KIT and thus stimulate melanocyte proliferation and pigment production. Similar feedback upregulation of an MAPK pathway stimulating receptor during downstream MAPK inhibition has been demonstrated in colon adenocarcinoma; in this setting, BRAF inhibitors blocking the MAPK pathway leads to upregulation of EGFR.­¹⁴ In our patient, c-KIT immunostaining revealed a mild to moderate increase in intensity (ie, the darkness of the staining) in nevi and melanomas during treatment with erlotinib compared to nevi biopsied before erlotinib treatment (Figure 2). The increased intensity of c-KIT immunostaining was further confirmed via semiquantitative digital image analysis. Using this method, a darkened nevus biopsied during treatment with erlotinib demonstrated 43.16% of cells (N=31,451) had very strong c-KIT staining, while a nevus biopsied before treatment with erlotinib demonstrated only 3.32% of cells (N=7507) with very strong c-KIT staining. Increased expression of c-KIT, possibly reactive to downstream inhibition the MAPK pathway from erlotinib, could be implicated in our case of eruptive nevi. 

To the Editor:

Erlotinib is a small-molecule selective tyrosine kinase inhibitor that functions by blocking the intracellular portion of the epidermal growth factor receptor (EGFR)^1,2; EGFR normally is expressed in the basal layer of the epidermis, sweat glands, and hair follicles, and is overexpressed in some cancers.^1,3 Normal activation of EGFR leads to signal transduction through the mitogen-activated protein kinase (MAPK) signaling pathway, which stimulates cell survival and proliferation.^4,5 Erlotinib-induced inhibition of EGFR prevents tyrosine kinase phosphorylation and aims to decrease cell proliferation in these tumors.

Erlotinib is indicated as once-daily oral monotherapy for the treatment of advanced-stage non–small cell lung cancer (NSCLCA) and in combination with gemcitabine for treatment of advanced-stage pancreatic cancer.¹ A number of cutaneous side effects have been reported, including acneform eruption, xerosis, paronychia, and pruritus.⁶ Other tyrosine kinase inhibitors, which also decrease signal transduction through the MAPK pathway, have some overlapping side effects; among these are vemurafenib, a selective BRAF inhibitor, and sorafenib, a multikinase inhibitor.^7,8

A 70-year-old man with NSCLCA presented with eruptive nevi and darkening of existing nevi 3 months after starting monotherapy with erlotinib. Physical examination demonstrated the simultaneous appearance of scattered acneform papules and pustules; diffuse xerosis; and numerous dark brown to black nevi on the trunk, arms, and legs. Compared to prior clinical photographs taken in our office, darkening of existing medium brown nevi was noted, and new nevi developed in areas where no prior nevi had been visible (Figure 1).

A review of the patient’s treatment timeline revealed that all other chemotherapeutic medications had been discontinued a minimum of 5 weeks before starting erlotinib. A complete cutaneous examination performed in our office after completion of these chemotherapeutic agents and prior to initiation of erlotinib was unremarkable for abnormally dark or eruptive nevi.

Since starting erlotinib treatment, the patient underwent 10 biopsies of clinically suspicious dark nevi performed by a dermatologist in our office. Two of these were diagnosed as melanoma in situ and one as an atypical nevus. A temporal association of the darkening and eruptive nevi with erlotinib treatment was established; however, because erlotinib was essential to his NSCLCA treatment, he continued erlotinib with frequent complete cutaneous examinations.

A number of cutaneous side effects have been described during treatment with erlotinib, the most common being acneform eruption.⁶ The incidence and severity of acneform eruptions have been positively correlated to survival in patients with NSCLCA.^3,5,6 Other common side effects include xerosis, paronychia, and pruritus.^1,5,6 Less common side effects include periungual pyogenic granulomas and hair growth abnormalities.¹

Eruptive nevi previously were reported in a patient who was treated with erlotinib.¹ Other tyrosine kinase inhibitors that also decrease signal transduction through the MAPK pathway, including sorafenib and vemurafenib, have been reported to cause eruptive nevi. There are 7 reports of eruptive nevi with sorafenib and 5 reports with vemurafenib.^7-9 Development of nevi were noted within a few months of initiating treatment with these medications.⁷

A PubMed search of articles indexed for MEDLINE using the terms erlotinib and melanoma and erlotinib and nevi yielded no prior reports of darkening of existing nevi or the development of melanoma during treatment with erlotinib. However, vemurafenib has been reported to cause dysplastic nevi, melanomas, and darkening of existing nevi, in addition to eruptive nevi.^8-10 The side effects of vemurafenib have been ascribed to a paradoxical upregulation of MAPK in BRAF wild-type cells. This effect has been well documented and demonstrated in vivo.^8,10 Perhaps erlotinib has a similar potential to paradoxically upregulate the MAPK pathway, thus stimulating cellular proliferation and survival.

Another tyrosine kinase receptor, c-KIT, is found on the cell membrane of melanocytes along with EGFR.^11,12 The c-KIT receptor also activates the MAPK pathway and is critical to the development, migration, and survival of melanocytes.^11,13 Stimulation of the c-KIT tyrosine kinase receptor also can induce melanocyte proliferation and melanogenesis.¹¹ The c-KIT receptor is encoded by the KIT gene (KIT proto-oncogene receptor tyrosine kinase). Mutations in this gene are associated with melanocytic disorders. Inherited KIT mutation leading to c-KIT receptor deficiency is associated with piebaldism. Acquired activating KIT mutations increasing c-KIT expression are associated with acral and mucosal melanomas as well as melanomas in chronically sun-damaged skin.¹³

We hypothesized that erlotinib-induced inhibition of the MAPK pathway could lead to a reactive increase in expression of c-KIT and thus stimulate melanocyte proliferation and pigment production. Similar feedback upregulation of an MAPK pathway stimulating receptor during downstream MAPK inhibition has been demonstrated in colon adenocarcinoma; in this setting, BRAF inhibitors blocking the MAPK pathway leads to upregulation of EGFR.­¹⁴ In our patient, c-KIT immunostaining revealed a mild to moderate increase in intensity (ie, the darkness of the staining) in nevi and melanomas during treatment with erlotinib compared to nevi biopsied before erlotinib treatment (Figure 2). The increased intensity of c-KIT immunostaining was further confirmed via semiquantitative digital image analysis. Using this method, a darkened nevus biopsied during treatment with erlotinib demonstrated 43.16% of cells (N=31,451) had very strong c-KIT staining, while a nevus biopsied before treatment with erlotinib demonstrated only 3.32% of cells (N=7507) with very strong c-KIT staining. Increased expression of c-KIT, possibly reactive to downstream inhibition the MAPK pathway from erlotinib, could be implicated in our case of eruptive nevi. 

To the Editor:

Erlotinib is a small-molecule selective tyrosine kinase inhibitor that functions by blocking the intracellular portion of the epidermal growth factor receptor (EGFR)^1,2; EGFR normally is expressed in the basal layer of the epidermis, sweat glands, and hair follicles, and is overexpressed in some cancers.^1,3 Normal activation of EGFR leads to signal transduction through the mitogen-activated protein kinase (MAPK) signaling pathway, which stimulates cell survival and proliferation.^4,5 Erlotinib-induced inhibition of EGFR prevents tyrosine kinase phosphorylation and aims to decrease cell proliferation in these tumors.

Erlotinib is indicated as once-daily oral monotherapy for the treatment of advanced-stage non–small cell lung cancer (NSCLCA) and in combination with gemcitabine for treatment of advanced-stage pancreatic cancer.¹ A number of cutaneous side effects have been reported, including acneform eruption, xerosis, paronychia, and pruritus.⁶ Other tyrosine kinase inhibitors, which also decrease signal transduction through the MAPK pathway, have some overlapping side effects; among these are vemurafenib, a selective BRAF inhibitor, and sorafenib, a multikinase inhibitor.^7,8

A 70-year-old man with NSCLCA presented with eruptive nevi and darkening of existing nevi 3 months after starting monotherapy with erlotinib. Physical examination demonstrated the simultaneous appearance of scattered acneform papules and pustules; diffuse xerosis; and numerous dark brown to black nevi on the trunk, arms, and legs. Compared to prior clinical photographs taken in our office, darkening of existing medium brown nevi was noted, and new nevi developed in areas where no prior nevi had been visible (Figure 1).

A review of the patient’s treatment timeline revealed that all other chemotherapeutic medications had been discontinued a minimum of 5 weeks before starting erlotinib. A complete cutaneous examination performed in our office after completion of these chemotherapeutic agents and prior to initiation of erlotinib was unremarkable for abnormally dark or eruptive nevi.

Since starting erlotinib treatment, the patient underwent 10 biopsies of clinically suspicious dark nevi performed by a dermatologist in our office. Two of these were diagnosed as melanoma in situ and one as an atypical nevus. A temporal association of the darkening and eruptive nevi with erlotinib treatment was established; however, because erlotinib was essential to his NSCLCA treatment, he continued erlotinib with frequent complete cutaneous examinations.

A number of cutaneous side effects have been described during treatment with erlotinib, the most common being acneform eruption.⁶ The incidence and severity of acneform eruptions have been positively correlated to survival in patients with NSCLCA.^3,5,6 Other common side effects include xerosis, paronychia, and pruritus.^1,5,6 Less common side effects include periungual pyogenic granulomas and hair growth abnormalities.¹

Eruptive nevi previously were reported in a patient who was treated with erlotinib.¹ Other tyrosine kinase inhibitors that also decrease signal transduction through the MAPK pathway, including sorafenib and vemurafenib, have been reported to cause eruptive nevi. There are 7 reports of eruptive nevi with sorafenib and 5 reports with vemurafenib.^7-9 Development of nevi were noted within a few months of initiating treatment with these medications.⁷

A PubMed search of articles indexed for MEDLINE using the terms erlotinib and melanoma and erlotinib and nevi yielded no prior reports of darkening of existing nevi or the development of melanoma during treatment with erlotinib. However, vemurafenib has been reported to cause dysplastic nevi, melanomas, and darkening of existing nevi, in addition to eruptive nevi.^8-10 The side effects of vemurafenib have been ascribed to a paradoxical upregulation of MAPK in BRAF wild-type cells. This effect has been well documented and demonstrated in vivo.^8,10 Perhaps erlotinib has a similar potential to paradoxically upregulate the MAPK pathway, thus stimulating cellular proliferation and survival.

Another tyrosine kinase receptor, c-KIT, is found on the cell membrane of melanocytes along with EGFR.^11,12 The c-KIT receptor also activates the MAPK pathway and is critical to the development, migration, and survival of melanocytes.^11,13 Stimulation of the c-KIT tyrosine kinase receptor also can induce melanocyte proliferation and melanogenesis.¹¹ The c-KIT receptor is encoded by the KIT gene (KIT proto-oncogene receptor tyrosine kinase). Mutations in this gene are associated with melanocytic disorders. Inherited KIT mutation leading to c-KIT receptor deficiency is associated with piebaldism. Acquired activating KIT mutations increasing c-KIT expression are associated with acral and mucosal melanomas as well as melanomas in chronically sun-damaged skin.¹³

We hypothesized that erlotinib-induced inhibition of the MAPK pathway could lead to a reactive increase in expression of c-KIT and thus stimulate melanocyte proliferation and pigment production. Similar feedback upregulation of an MAPK pathway stimulating receptor during downstream MAPK inhibition has been demonstrated in colon adenocarcinoma; in this setting, BRAF inhibitors blocking the MAPK pathway leads to upregulation of EGFR.­¹⁴ In our patient, c-KIT immunostaining revealed a mild to moderate increase in intensity (ie, the darkness of the staining) in nevi and melanomas during treatment with erlotinib compared to nevi biopsied before erlotinib treatment (Figure 2). The increased intensity of c-KIT immunostaining was further confirmed via semiquantitative digital image analysis. Using this method, a darkened nevus biopsied during treatment with erlotinib demonstrated 43.16% of cells (N=31,451) had very strong c-KIT staining, while a nevus biopsied before treatment with erlotinib demonstrated only 3.32% of cells (N=7507) with very strong c-KIT staining. Increased expression of c-KIT, possibly reactive to downstream inhibition the MAPK pathway from erlotinib, could be implicated in our case of eruptive nevi. 

Case Report

A 26-year-old woman with a medical history of newly diagnosed diabetes mellitus (DM), obesity, and asthma was evaluated as a hospital consultation with a vegetative plaque on the left lateral ankle of 13 months’ duration. The lesion first appeared as a red scaly rash that became purulent. The lesion had been treated with multiple rounds of topical antibiotics, oral antibiotics, topical antifungals, and corticosteroids without resolution. The patient denied pain or any decrease in ankle mobility. Review of systems was otherwise negative.

On physical examination, 3 large, pink, scaly, crusted plaques with surrounding erythema were observed (Figure 1A). On palpation, purulent drainage with a foul odor was noted in the area underlying the lesion. Initial punch biopsy demonstrated epidermal hyperplasia with neutrophil-rich sinus tracts consistent with pyoderma vegetans (PV)(Figure 2A). Tissue culture was positive for Staphylococcus aureus and Streptococcus anginosus. Cultures for both fungi and acid-fast bacilli were negative for growth.

The patient was treated with mupirocin ointment 2% and 3 months of cephalexin 250 mg twice daily, which cleared the purulent crust; however, serous drainage, ulceration, and erythema persisted. The patient needed an extended course of antibiotics, which had not been previously administered to clear the purulence. During this treatment regimen, the patient’s DM remained uncontrolled.

A second deeper punch biopsy revealed a layered granulomatous infiltrate with sclerosis throughout the dermis most consistent with necrobiosis lipoidica (NL)(Figure 2B). Direct immunofluorescence biopsy was negative. Once the PV was clear, betamethasone dipropionate ointment 0.05% was initiated to address the residual lesions (Figure 1B).

Physical examination combined with histopathologic findings and staphylococcal- and streptococcal-positive tissue cultures supported a diagnosis of NL with superimposed PV.

Comment

Necrobiosis lipoidica is a chronic granulomatous disease characterized by collagen degeneration, granulomatous formation, and endothelial wall thickening.¹ The condition is most commonly seen in association with insulin-dependent DM, though it also has been described in other inflammatory conditions. A case of NL in monozygotic twins has been reported, suggesting a genetic component in nondiabetic patients with NL.² Necrobiosis lipoidica affects females more often than males.

The pathogenesis of NL is not well understood but likely involves secondary microangiopathy because of glycoprotein deposition in vessel walls, leading to vascular thickening. Histopathology reveals palisading and necrobiotic granulomas comprising large confluent areas of necrobiosis throughout the dermis, giving a layered appearance.³

Clinically, NL presents with asymptomatic, well-circumscribed, violaceous papules and nodules that coalesce into plaques on the lower extremities, face, or trunk. The plaques have a central red-brown hue that progressively becomes more yellow and atrophic. The lesions can become eroded and ulcerated if left untreated.¹

Clinical diagnosis of NL can be challenging due to the similar clinical findings of other granulomatous lesions, such as granuloma annulare and cutaneous sarcoidosis. As reported by Pellicano and colleagues,⁴ dermoscopy has proved to be an excellent tool for differentiating these granulomatous skin lesions. Necrobiosis lipoidica demonstrates elongated serpentine telangiectases overlying a white structureless background, whereas granuloma annulare reveals orange-red structureless peripheral borders.⁵

Treatment of NL is difficult; patients often are refractory. Tight control of blood glucose alone has not been proven to cure NL. The mainstay of treatment is topical and intralesional corticosteroids at the active borders of the lesions. Tumor necrosis factor α inhibitors have shown some success, though recurrence has been reported.⁶ Other treatments, such as topical tretinoin and topical tacrolimus, may be of some benefit for atrophic NL lesions. Studies also have shown that skin grafting can be of surgical benefit in ulcerative NL with a low rate of recurrence.⁶ Control and management of DM plus lifestyle modifications may play a role in decreasing the severity of NL.⁷ Topical psoralen plus UVA light therapy and other experimental treatments, such as antiplatelet medications,⁸ also have been utilized.

The case of NL presented here was complicated by a superimposed suppurative infection consistent with PV, a rare chronic bacterial infection of the skin that presents with vegetative plaques. Pyoderma vegetans is most commonly observed in patients with underlying immunosuppression, likely secondary to DM in this case. Pyoderma vegetans is most often caused by S aureus and β-hemolytic streptococci. The clinical presentation of PV reveals verrucous vegetative plaques with pustules and abscesses. The borders of the lesions may be elevated and have a granulomatous appearance, thus complicating clinical diagnosis. There often is foul-smelling, purulent discharge within the plaques.⁹

Histopathology reveals pseudoepitheliomatous hyperplasia with abscesses and sinus tracts. An acute or chronic granulomatous inflammatory infiltrate may be observed. Basophilic fungus like granules are not seen within specimens of PV, which helps differentiate the disease from botryomycosis.¹⁰

There is no standardized treatment of PV; topical and systemic antibiotics are mainstays.¹⁰ One reported case of PV responded well to acitretin.⁹ Our patient responded well to 3 months of oral antibiotic therapy, followed by topical corticosteroids.

Case Report

A 26-year-old woman with a medical history of newly diagnosed diabetes mellitus (DM), obesity, and asthma was evaluated as a hospital consultation with a vegetative plaque on the left lateral ankle of 13 months’ duration. The lesion first appeared as a red scaly rash that became purulent. The lesion had been treated with multiple rounds of topical antibiotics, oral antibiotics, topical antifungals, and corticosteroids without resolution. The patient denied pain or any decrease in ankle mobility. Review of systems was otherwise negative.

On physical examination, 3 large, pink, scaly, crusted plaques with surrounding erythema were observed (Figure 1A). On palpation, purulent drainage with a foul odor was noted in the area underlying the lesion. Initial punch biopsy demonstrated epidermal hyperplasia with neutrophil-rich sinus tracts consistent with pyoderma vegetans (PV)(Figure 2A). Tissue culture was positive for Staphylococcus aureus and Streptococcus anginosus. Cultures for both fungi and acid-fast bacilli were negative for growth.

The patient was treated with mupirocin ointment 2% and 3 months of cephalexin 250 mg twice daily, which cleared the purulent crust; however, serous drainage, ulceration, and erythema persisted. The patient needed an extended course of antibiotics, which had not been previously administered to clear the purulence. During this treatment regimen, the patient’s DM remained uncontrolled.

A second deeper punch biopsy revealed a layered granulomatous infiltrate with sclerosis throughout the dermis most consistent with necrobiosis lipoidica (NL)(Figure 2B). Direct immunofluorescence biopsy was negative. Once the PV was clear, betamethasone dipropionate ointment 0.05% was initiated to address the residual lesions (Figure 1B).

Physical examination combined with histopathologic findings and staphylococcal- and streptococcal-positive tissue cultures supported a diagnosis of NL with superimposed PV.

Comment

Necrobiosis lipoidica is a chronic granulomatous disease characterized by collagen degeneration, granulomatous formation, and endothelial wall thickening.¹ The condition is most commonly seen in association with insulin-dependent DM, though it also has been described in other inflammatory conditions. A case of NL in monozygotic twins has been reported, suggesting a genetic component in nondiabetic patients with NL.² Necrobiosis lipoidica affects females more often than males.

The pathogenesis of NL is not well understood but likely involves secondary microangiopathy because of glycoprotein deposition in vessel walls, leading to vascular thickening. Histopathology reveals palisading and necrobiotic granulomas comprising large confluent areas of necrobiosis throughout the dermis, giving a layered appearance.³

Clinically, NL presents with asymptomatic, well-circumscribed, violaceous papules and nodules that coalesce into plaques on the lower extremities, face, or trunk. The plaques have a central red-brown hue that progressively becomes more yellow and atrophic. The lesions can become eroded and ulcerated if left untreated.¹

Clinical diagnosis of NL can be challenging due to the similar clinical findings of other granulomatous lesions, such as granuloma annulare and cutaneous sarcoidosis. As reported by Pellicano and colleagues,⁴ dermoscopy has proved to be an excellent tool for differentiating these granulomatous skin lesions. Necrobiosis lipoidica demonstrates elongated serpentine telangiectases overlying a white structureless background, whereas granuloma annulare reveals orange-red structureless peripheral borders.⁵

Treatment of NL is difficult; patients often are refractory. Tight control of blood glucose alone has not been proven to cure NL. The mainstay of treatment is topical and intralesional corticosteroids at the active borders of the lesions. Tumor necrosis factor α inhibitors have shown some success, though recurrence has been reported.⁶ Other treatments, such as topical tretinoin and topical tacrolimus, may be of some benefit for atrophic NL lesions. Studies also have shown that skin grafting can be of surgical benefit in ulcerative NL with a low rate of recurrence.⁶ Control and management of DM plus lifestyle modifications may play a role in decreasing the severity of NL.⁷ Topical psoralen plus UVA light therapy and other experimental treatments, such as antiplatelet medications,⁸ also have been utilized.

The case of NL presented here was complicated by a superimposed suppurative infection consistent with PV, a rare chronic bacterial infection of the skin that presents with vegetative plaques. Pyoderma vegetans is most commonly observed in patients with underlying immunosuppression, likely secondary to DM in this case. Pyoderma vegetans is most often caused by S aureus and β-hemolytic streptococci. The clinical presentation of PV reveals verrucous vegetative plaques with pustules and abscesses. The borders of the lesions may be elevated and have a granulomatous appearance, thus complicating clinical diagnosis. There often is foul-smelling, purulent discharge within the plaques.⁹

Histopathology reveals pseudoepitheliomatous hyperplasia with abscesses and sinus tracts. An acute or chronic granulomatous inflammatory infiltrate may be observed. Basophilic fungus like granules are not seen within specimens of PV, which helps differentiate the disease from botryomycosis.¹⁰

There is no standardized treatment of PV; topical and systemic antibiotics are mainstays.¹⁰ One reported case of PV responded well to acitretin.⁹ Our patient responded well to 3 months of oral antibiotic therapy, followed by topical corticosteroids.

Case Report

A 26-year-old woman with a medical history of newly diagnosed diabetes mellitus (DM), obesity, and asthma was evaluated as a hospital consultation with a vegetative plaque on the left lateral ankle of 13 months’ duration. The lesion first appeared as a red scaly rash that became purulent. The lesion had been treated with multiple rounds of topical antibiotics, oral antibiotics, topical antifungals, and corticosteroids without resolution. The patient denied pain or any decrease in ankle mobility. Review of systems was otherwise negative.

On physical examination, 3 large, pink, scaly, crusted plaques with surrounding erythema were observed (Figure 1A). On palpation, purulent drainage with a foul odor was noted in the area underlying the lesion. Initial punch biopsy demonstrated epidermal hyperplasia with neutrophil-rich sinus tracts consistent with pyoderma vegetans (PV)(Figure 2A). Tissue culture was positive for Staphylococcus aureus and Streptococcus anginosus. Cultures for both fungi and acid-fast bacilli were negative for growth.

The patient was treated with mupirocin ointment 2% and 3 months of cephalexin 250 mg twice daily, which cleared the purulent crust; however, serous drainage, ulceration, and erythema persisted. The patient needed an extended course of antibiotics, which had not been previously administered to clear the purulence. During this treatment regimen, the patient’s DM remained uncontrolled.

A second deeper punch biopsy revealed a layered granulomatous infiltrate with sclerosis throughout the dermis most consistent with necrobiosis lipoidica (NL)(Figure 2B). Direct immunofluorescence biopsy was negative. Once the PV was clear, betamethasone dipropionate ointment 0.05% was initiated to address the residual lesions (Figure 1B).

Physical examination combined with histopathologic findings and staphylococcal- and streptococcal-positive tissue cultures supported a diagnosis of NL with superimposed PV.

Comment

Necrobiosis lipoidica is a chronic granulomatous disease characterized by collagen degeneration, granulomatous formation, and endothelial wall thickening.¹ The condition is most commonly seen in association with insulin-dependent DM, though it also has been described in other inflammatory conditions. A case of NL in monozygotic twins has been reported, suggesting a genetic component in nondiabetic patients with NL.² Necrobiosis lipoidica affects females more often than males.

The pathogenesis of NL is not well understood but likely involves secondary microangiopathy because of glycoprotein deposition in vessel walls, leading to vascular thickening. Histopathology reveals palisading and necrobiotic granulomas comprising large confluent areas of necrobiosis throughout the dermis, giving a layered appearance.³

Clinically, NL presents with asymptomatic, well-circumscribed, violaceous papules and nodules that coalesce into plaques on the lower extremities, face, or trunk. The plaques have a central red-brown hue that progressively becomes more yellow and atrophic. The lesions can become eroded and ulcerated if left untreated.¹

Clinical diagnosis of NL can be challenging due to the similar clinical findings of other granulomatous lesions, such as granuloma annulare and cutaneous sarcoidosis. As reported by Pellicano and colleagues,⁴ dermoscopy has proved to be an excellent tool for differentiating these granulomatous skin lesions. Necrobiosis lipoidica demonstrates elongated serpentine telangiectases overlying a white structureless background, whereas granuloma annulare reveals orange-red structureless peripheral borders.⁵

Treatment of NL is difficult; patients often are refractory. Tight control of blood glucose alone has not been proven to cure NL. The mainstay of treatment is topical and intralesional corticosteroids at the active borders of the lesions. Tumor necrosis factor α inhibitors have shown some success, though recurrence has been reported.⁶ Other treatments, such as topical tretinoin and topical tacrolimus, may be of some benefit for atrophic NL lesions. Studies also have shown that skin grafting can be of surgical benefit in ulcerative NL with a low rate of recurrence.⁶ Control and management of DM plus lifestyle modifications may play a role in decreasing the severity of NL.⁷ Topical psoralen plus UVA light therapy and other experimental treatments, such as antiplatelet medications,⁸ also have been utilized.

The case of NL presented here was complicated by a superimposed suppurative infection consistent with PV, a rare chronic bacterial infection of the skin that presents with vegetative plaques. Pyoderma vegetans is most commonly observed in patients with underlying immunosuppression, likely secondary to DM in this case. Pyoderma vegetans is most often caused by S aureus and β-hemolytic streptococci. The clinical presentation of PV reveals verrucous vegetative plaques with pustules and abscesses. The borders of the lesions may be elevated and have a granulomatous appearance, thus complicating clinical diagnosis. There often is foul-smelling, purulent discharge within the plaques.⁹

Histopathology reveals pseudoepitheliomatous hyperplasia with abscesses and sinus tracts. An acute or chronic granulomatous inflammatory infiltrate may be observed. Basophilic fungus like granules are not seen within specimens of PV, which helps differentiate the disease from botryomycosis.¹⁰

There is no standardized treatment of PV; topical and systemic antibiotics are mainstays.¹⁰ One reported case of PV responded well to acitretin.⁹ Our patient responded well to 3 months of oral antibiotic therapy, followed by topical corticosteroids.