Photo by Rhoda Baer

VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.

The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.

These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.

The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).

“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.

“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”

Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.

The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.

CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.

Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.

Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).

Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).

The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).

Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.

Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).

“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.

“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”

“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”

Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.

He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.

“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”

“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.” 

Photo by Rhoda Baer

VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.

The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.

These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.

The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).

“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.

“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”

Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.

The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.

CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.

Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.

Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).

Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).

The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).

Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.

Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).

“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.

“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”

“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”

Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.

He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.

“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”

“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.” 

Photo by Rhoda Baer

VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.

The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.

These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.

The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).

“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.

“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”

Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.

The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.

CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.

Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.

Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).

Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).

The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).

Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.

Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).

“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.

“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”

“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”

Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.

He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.

“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”

“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.” 

Lab mouse

A new compound has shown promise for treating multiple myeloma (MM) by inhibiting the oncogenic MYC-driven translation program supporting the disease, according to researchers.

The compound is CMLD01059, a derivative of natural products called rocaglates that are known to interfere with translation.

CMLD010509 induced apoptosis in MM cells in culture and exhibited anti-myeloma activity in 3 different mouse models.

In addition, the compound was well-tolerated by the mice and spared normal cells in culture.

Salomon Manier, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Science Translational Medicine.

The researchers found that CMLD01059 treatment significantly reduced the levels of 54 proteins in MM cell lines, including 5 known drivers of tumor progression—MYC, MDM2, CCND1, MAF, and MCL-1.

Further investigation confirmed that CMLD010509 inhibits the translation of oncoproteins that support the proliferation and survival of MM cells.

The researchers also found that CMLD010509 triggered a “strong” and “rapid” apoptotic response in MM cells (NCI-H929 and MM1S).

So the team tested the anti-myeloma activity of CMLD010509 in mouse models.

In one model (mice injected with MM1S cells), CMLD010509 “caused a marked reduction in tumor burden,” according to the researchers.

The median survival was 47 days in CMLD010509-treated mice, compared to 35 days in control mice (P<0.001).

The researchers also noted that 4 weeks of CMLD010509 treatment was well-tolerated in the mice, who maintained their weight and normal complete blood counts.

In another MM model (mice injected with KMS-11 cells), the mice received CMLD010509 or vehicle control twice a week for 4 weeks and were sacrificed at the end of treatment.

Immunohistochemistry studies conducted on bone marrow samples revealed a decrease in CD138+ plasma cells, depletion of MYC, and inhibition of proliferation in the CMLD010509-treated mice.

For the last model, the researchers injected transplantable mouse MM cells into C57BL/6 mice. The team noted that these cells are driven by plasma cell-specific MYC overexpression (Vk*Myc cells).

The mice received CMLD010509 or vehicle control twice a week starting 1 week after cell inoculation.

The researchers said CMLD010509 was well-tolerated, and they observed a “robust” decrease of M-spike in the treated mice that was associated with a significant improvement in survival.

The median survival was 39 days in the control mice, but it had not been reached by 90 days in the treated mice (P=0.0019).

The researchers said these results support targeting translation with rocaglates to treat MM. 

Lab mouse

A new compound has shown promise for treating multiple myeloma (MM) by inhibiting the oncogenic MYC-driven translation program supporting the disease, according to researchers.

The compound is CMLD01059, a derivative of natural products called rocaglates that are known to interfere with translation.

CMLD010509 induced apoptosis in MM cells in culture and exhibited anti-myeloma activity in 3 different mouse models.

In addition, the compound was well-tolerated by the mice and spared normal cells in culture.

Salomon Manier, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Science Translational Medicine.

The researchers found that CMLD01059 treatment significantly reduced the levels of 54 proteins in MM cell lines, including 5 known drivers of tumor progression—MYC, MDM2, CCND1, MAF, and MCL-1.

Further investigation confirmed that CMLD010509 inhibits the translation of oncoproteins that support the proliferation and survival of MM cells.

The researchers also found that CMLD010509 triggered a “strong” and “rapid” apoptotic response in MM cells (NCI-H929 and MM1S).

So the team tested the anti-myeloma activity of CMLD010509 in mouse models.

In one model (mice injected with MM1S cells), CMLD010509 “caused a marked reduction in tumor burden,” according to the researchers.

The median survival was 47 days in CMLD010509-treated mice, compared to 35 days in control mice (P<0.001).

The researchers also noted that 4 weeks of CMLD010509 treatment was well-tolerated in the mice, who maintained their weight and normal complete blood counts.

In another MM model (mice injected with KMS-11 cells), the mice received CMLD010509 or vehicle control twice a week for 4 weeks and were sacrificed at the end of treatment.

Immunohistochemistry studies conducted on bone marrow samples revealed a decrease in CD138+ plasma cells, depletion of MYC, and inhibition of proliferation in the CMLD010509-treated mice.

For the last model, the researchers injected transplantable mouse MM cells into C57BL/6 mice. The team noted that these cells are driven by plasma cell-specific MYC overexpression (Vk*Myc cells).

The mice received CMLD010509 or vehicle control twice a week starting 1 week after cell inoculation.

The researchers said CMLD010509 was well-tolerated, and they observed a “robust” decrease of M-spike in the treated mice that was associated with a significant improvement in survival.

The median survival was 39 days in the control mice, but it had not been reached by 90 days in the treated mice (P=0.0019).

The researchers said these results support targeting translation with rocaglates to treat MM. 

Lab mouse

A new compound has shown promise for treating multiple myeloma (MM) by inhibiting the oncogenic MYC-driven translation program supporting the disease, according to researchers.

The compound is CMLD01059, a derivative of natural products called rocaglates that are known to interfere with translation.

CMLD010509 induced apoptosis in MM cells in culture and exhibited anti-myeloma activity in 3 different mouse models.

In addition, the compound was well-tolerated by the mice and spared normal cells in culture.

Salomon Manier, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Science Translational Medicine.

The researchers found that CMLD01059 treatment significantly reduced the levels of 54 proteins in MM cell lines, including 5 known drivers of tumor progression—MYC, MDM2, CCND1, MAF, and MCL-1.

Further investigation confirmed that CMLD010509 inhibits the translation of oncoproteins that support the proliferation and survival of MM cells.

The researchers also found that CMLD010509 triggered a “strong” and “rapid” apoptotic response in MM cells (NCI-H929 and MM1S).

So the team tested the anti-myeloma activity of CMLD010509 in mouse models.

In one model (mice injected with MM1S cells), CMLD010509 “caused a marked reduction in tumor burden,” according to the researchers.

The median survival was 47 days in CMLD010509-treated mice, compared to 35 days in control mice (P<0.001).

The researchers also noted that 4 weeks of CMLD010509 treatment was well-tolerated in the mice, who maintained their weight and normal complete blood counts.

In another MM model (mice injected with KMS-11 cells), the mice received CMLD010509 or vehicle control twice a week for 4 weeks and were sacrificed at the end of treatment.

Immunohistochemistry studies conducted on bone marrow samples revealed a decrease in CD138+ plasma cells, depletion of MYC, and inhibition of proliferation in the CMLD010509-treated mice.

For the last model, the researchers injected transplantable mouse MM cells into C57BL/6 mice. The team noted that these cells are driven by plasma cell-specific MYC overexpression (Vk*Myc cells).

The mice received CMLD010509 or vehicle control twice a week starting 1 week after cell inoculation.

The researchers said CMLD010509 was well-tolerated, and they observed a “robust” decrease of M-spike in the treated mice that was associated with a significant improvement in survival.

The median survival was 39 days in the control mice, but it had not been reached by 90 days in the treated mice (P=0.0019).

The researchers said these results support targeting translation with rocaglates to treat MM. 

Red blood cells

The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).

This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.

APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).

Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.

In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.

In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days. 

Red blood cells

The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).

This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.

APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).

Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.

In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.

In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days. 

Red blood cells

The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).

This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.

APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).

Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.

In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.

In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days. 

The FP made the presumptive diagnosis of nummular eczema, but recognized that a fungal infection and psoriasis were part of the differential diagnosis. He performed a potassium hydroxide (KOH) preparation, which was negative for hyphae and fungal elements. (See a video on how to perform a KOH preparation here: http://www.mdedge.com/jfponline/article/100603/dermatology/koh-preparation.) In order to explore whether this might be a case of guttate psoriasis, the FP asked about any preceding strep pharyngitis or other respiratory infections. The patient, however, had not had any preceding infections. The FP also checked her nails, scalp, and umbilicus for other signs of psoriasis, but found none. The FP was now confident in making a clinical diagnosis of nummular eczema (also known as nummular dermatitis).

Nummular eczema is a type of eczema characterized by circular or oval-shaped scaling plaques with well-defined borders. (“Nummus” is Latin for “coin.”) Nummular eczema produces multiple lesions that are most commonly found on the dorsa of the hands, arms, and legs.

Patients who have a history of atopic dermatitis are more likely to get nummular eczema even after they outgrow the atopic dermatitis. The 2 conditions involve problems with the barrier function of the skin, and emollients are helpful for the prevention and treatment of both.

In this case, the FP prescribed 0.1% triamcinolone ointment to be applied twice daily until the lesions resolved. At a one-month follow-up appointment, the patient indicated that her legs were now smooth and she was happy that she could shave them again. The FP told her that it would be a good idea to use emollients after bathing to keep the skin moist in order to prevent future episodes of nummular eczema.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Wah Y, Usatine R. Eczema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP made the presumptive diagnosis of nummular eczema, but recognized that a fungal infection and psoriasis were part of the differential diagnosis. He performed a potassium hydroxide (KOH) preparation, which was negative for hyphae and fungal elements. (See a video on how to perform a KOH preparation here: http://www.mdedge.com/jfponline/article/100603/dermatology/koh-preparation.) In order to explore whether this might be a case of guttate psoriasis, the FP asked about any preceding strep pharyngitis or other respiratory infections. The patient, however, had not had any preceding infections. The FP also checked her nails, scalp, and umbilicus for other signs of psoriasis, but found none. The FP was now confident in making a clinical diagnosis of nummular eczema (also known as nummular dermatitis).

Nummular eczema is a type of eczema characterized by circular or oval-shaped scaling plaques with well-defined borders. (“Nummus” is Latin for “coin.”) Nummular eczema produces multiple lesions that are most commonly found on the dorsa of the hands, arms, and legs.

Patients who have a history of atopic dermatitis are more likely to get nummular eczema even after they outgrow the atopic dermatitis. The 2 conditions involve problems with the barrier function of the skin, and emollients are helpful for the prevention and treatment of both.

In this case, the FP prescribed 0.1% triamcinolone ointment to be applied twice daily until the lesions resolved. At a one-month follow-up appointment, the patient indicated that her legs were now smooth and she was happy that she could shave them again. The FP told her that it would be a good idea to use emollients after bathing to keep the skin moist in order to prevent future episodes of nummular eczema.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Wah Y, Usatine R. Eczema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP made the presumptive diagnosis of nummular eczema, but recognized that a fungal infection and psoriasis were part of the differential diagnosis. He performed a potassium hydroxide (KOH) preparation, which was negative for hyphae and fungal elements. (See a video on how to perform a KOH preparation here: http://www.mdedge.com/jfponline/article/100603/dermatology/koh-preparation.) In order to explore whether this might be a case of guttate psoriasis, the FP asked about any preceding strep pharyngitis or other respiratory infections. The patient, however, had not had any preceding infections. The FP also checked her nails, scalp, and umbilicus for other signs of psoriasis, but found none. The FP was now confident in making a clinical diagnosis of nummular eczema (also known as nummular dermatitis).

Nummular eczema is a type of eczema characterized by circular or oval-shaped scaling plaques with well-defined borders. (“Nummus” is Latin for “coin.”) Nummular eczema produces multiple lesions that are most commonly found on the dorsa of the hands, arms, and legs.

Patients who have a history of atopic dermatitis are more likely to get nummular eczema even after they outgrow the atopic dermatitis. The 2 conditions involve problems with the barrier function of the skin, and emollients are helpful for the prevention and treatment of both.

In this case, the FP prescribed 0.1% triamcinolone ointment to be applied twice daily until the lesions resolved. At a one-month follow-up appointment, the patient indicated that her legs were now smooth and she was happy that she could shave them again. The FP told her that it would be a good idea to use emollients after bathing to keep the skin moist in order to prevent future episodes of nummular eczema.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Wah Y, Usatine R. Eczema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

ANSWER

The correct answer is Becker nevus (BN; choice “c”).

Because the lesion was not congenital, a number of possibilities, including congenital melanocytic nevus (choice “a”), were ruled out. Another differential item that was eliminated was nevus spilus (choice “b”), a tan congenital nevus covered with darker, punctate macules that usually manifest on extremities. These have little, if any, malignant potential.

And while BN is not associated with malignancy, it is possible for it to co-exist with melanoma (choice “d”). Therefore, atypical BN cases may need to be followed or serially biopsied.

DISCUSSION

BN is unusual but not rare. Also referred to as Becker melanosis, the condition affects approximately 0.5% of the population. It primarily manifests in young men during early puberty, although women can develop BN.

Histologic signs of BN include epidermal thickening, elongation of rete ridges, and increased bundles of smooth muscle in the dermis.

Androgen causation is strongly indicated by the condition’s predominance in males and onset at puberty, as well as its associated hypertrichosis and increased density of androgen receptors in affected areas. Variations of the condition can involve the legs, arms, or face. It is possible for BN to manifest without additional hair growth. Hypoplasia of ipsilateral pectoral structures (or the ipsilateral breast in women) has also been reported.

Several types of lasers can be used to lighten the hyperpigmentation and remove hairs. This treatment modality yields variable results.

ANSWER

The correct answer is Becker nevus (BN; choice “c”).

Because the lesion was not congenital, a number of possibilities, including congenital melanocytic nevus (choice “a”), were ruled out. Another differential item that was eliminated was nevus spilus (choice “b”), a tan congenital nevus covered with darker, punctate macules that usually manifest on extremities. These have little, if any, malignant potential.

And while BN is not associated with malignancy, it is possible for it to co-exist with melanoma (choice “d”). Therefore, atypical BN cases may need to be followed or serially biopsied.

DISCUSSION

BN is unusual but not rare. Also referred to as Becker melanosis, the condition affects approximately 0.5% of the population. It primarily manifests in young men during early puberty, although women can develop BN.

Histologic signs of BN include epidermal thickening, elongation of rete ridges, and increased bundles of smooth muscle in the dermis.

Androgen causation is strongly indicated by the condition’s predominance in males and onset at puberty, as well as its associated hypertrichosis and increased density of androgen receptors in affected areas. Variations of the condition can involve the legs, arms, or face. It is possible for BN to manifest without additional hair growth. Hypoplasia of ipsilateral pectoral structures (or the ipsilateral breast in women) has also been reported.

Several types of lasers can be used to lighten the hyperpigmentation and remove hairs. This treatment modality yields variable results.

ANSWER

The correct answer is Becker nevus (BN; choice “c”).

Because the lesion was not congenital, a number of possibilities, including congenital melanocytic nevus (choice “a”), were ruled out. Another differential item that was eliminated was nevus spilus (choice “b”), a tan congenital nevus covered with darker, punctate macules that usually manifest on extremities. These have little, if any, malignant potential.

And while BN is not associated with malignancy, it is possible for it to co-exist with melanoma (choice “d”). Therefore, atypical BN cases may need to be followed or serially biopsied.

DISCUSSION

BN is unusual but not rare. Also referred to as Becker melanosis, the condition affects approximately 0.5% of the population. It primarily manifests in young men during early puberty, although women can develop BN.

Histologic signs of BN include epidermal thickening, elongation of rete ridges, and increased bundles of smooth muscle in the dermis.

Androgen causation is strongly indicated by the condition’s predominance in males and onset at puberty, as well as its associated hypertrichosis and increased density of androgen receptors in affected areas. Variations of the condition can involve the legs, arms, or face. It is possible for BN to manifest without additional hair growth. Hypoplasia of ipsilateral pectoral structures (or the ipsilateral breast in women) has also been reported.

Several types of lasers can be used to lighten the hyperpigmentation and remove hairs. This treatment modality yields variable results.

CLINICAL QUESTION: Are alpha blockers efficacious in patients with ureteric stones?

CLINICAL QUESTION: Are alpha blockers efficacious in patients with ureteric stones?

CLINICAL QUESTION: Are alpha blockers efficacious in patients with ureteric stones?

CLINICAL QUESTION: How efficacious are interventions to reduce burnout in physicians?

BACKGROUND: Burnout is characterized by emotional exhaustion, depersonalization, and a diminished sense of personal accomplishment. It is driven by workplace stressors and affects nearly half of physicians practicing in the U.S.

Dr. Ecker is the assistant director of education, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

CLINICAL QUESTION: How efficacious are interventions to reduce burnout in physicians?

BACKGROUND: Burnout is characterized by emotional exhaustion, depersonalization, and a diminished sense of personal accomplishment. It is driven by workplace stressors and affects nearly half of physicians practicing in the U.S.

Dr. Ecker is the assistant director of education, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

CLINICAL QUESTION: How efficacious are interventions to reduce burnout in physicians?

BACKGROUND: Burnout is characterized by emotional exhaustion, depersonalization, and a diminished sense of personal accomplishment. It is driven by workplace stressors and affects nearly half of physicians practicing in the U.S.

Dr. Ecker is the assistant director of education, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

Deep infiltrating endometriosis lesions were found to harbor several genetic mutations, including well-known cancer-driver mutations in the ARID1A, PIK3CA, KRAS, and PPP2R1A genes, investigators reported in the May 11 issue of the New England Journal of Medicine.

This finding was possible only through the use of a combination of next-generation sequencing tools, together with highly sensitive digital genomic assays. A finding of cancer-related mutations in noncancerous lesions – and, “in particular, in nonovarian deep infiltrating lesions that rarely (if ever) transform into cancer” – was very “surprising” and raises new questions about the pathobiology of endometriosis, said Michael S. Anglesio, PhD, of the University of British Columbia, Vancouver, and his associates.

©designer491/Thinkstock

Deep infiltrating endometriosis lesions were found to harbor several genetic mutations, including well-known cancer-driver mutations in the ARID1A, PIK3CA, KRAS, and PPP2R1A genes, investigators reported in the May 11 issue of the New England Journal of Medicine.

This finding was possible only through the use of a combination of next-generation sequencing tools, together with highly sensitive digital genomic assays. A finding of cancer-related mutations in noncancerous lesions – and, “in particular, in nonovarian deep infiltrating lesions that rarely (if ever) transform into cancer” – was very “surprising” and raises new questions about the pathobiology of endometriosis, said Michael S. Anglesio, PhD, of the University of British Columbia, Vancouver, and his associates.

©designer491/Thinkstock

Deep infiltrating endometriosis lesions were found to harbor several genetic mutations, including well-known cancer-driver mutations in the ARID1A, PIK3CA, KRAS, and PPP2R1A genes, investigators reported in the May 11 issue of the New England Journal of Medicine.

This finding was possible only through the use of a combination of next-generation sequencing tools, together with highly sensitive digital genomic assays. A finding of cancer-related mutations in noncancerous lesions – and, “in particular, in nonovarian deep infiltrating lesions that rarely (if ever) transform into cancer” – was very “surprising” and raises new questions about the pathobiology of endometriosis, said Michael S. Anglesio, PhD, of the University of British Columbia, Vancouver, and his associates.

©designer491/Thinkstock

Antibodies against measles, mumps, and rubella persisted for up to 2 years after vaccination of children 12-15 months with the MMR vaccine approved in the United States and a similar one approved in Europe, both of which are manufactured without human serum albumin, Andrea A. Berry, MD, at the University of Maryland, Baltimore, and her associates said.

In 752 children aged a mean 12 months who received either the United States MMR vaccine and the European one, seropositivity for measles, mumps, and rubella persisted for up to 2 years with both vaccines. Both vaccines also were well tolerated.

copyright luiscar/Thinkstock

Antibodies against measles, mumps, and rubella persisted for up to 2 years after vaccination of children 12-15 months with the MMR vaccine approved in the United States and a similar one approved in Europe, both of which are manufactured without human serum albumin, Andrea A. Berry, MD, at the University of Maryland, Baltimore, and her associates said.

In 752 children aged a mean 12 months who received either the United States MMR vaccine and the European one, seropositivity for measles, mumps, and rubella persisted for up to 2 years with both vaccines. Both vaccines also were well tolerated.

copyright luiscar/Thinkstock

Antibodies against measles, mumps, and rubella persisted for up to 2 years after vaccination of children 12-15 months with the MMR vaccine approved in the United States and a similar one approved in Europe, both of which are manufactured without human serum albumin, Andrea A. Berry, MD, at the University of Maryland, Baltimore, and her associates said.

In 752 children aged a mean 12 months who received either the United States MMR vaccine and the European one, seropositivity for measles, mumps, and rubella persisted for up to 2 years with both vaccines. Both vaccines also were well tolerated.

copyright luiscar/Thinkstock

Acquired epidermodysplasia verruciformis (EDV) is a rare disorder occurring in patients with depressed cellular immunity, particularly individuals with human immunodeficiency virus (HIV). Rare cases of acquired EDV have been reported in stem cell or solid organ transplant recipients. Weakened cellular immunity predisposes the patient to human papillomavirus (HPV) infections, with 92% of renal transplant recipients developing warts within 5 years posttransplantation.¹ Specific EDV-HPV subtypes have been isolated from lesions in several immunosuppressed individuals, with HPV-5 and HPV-8 being the most commonly isolated subtypes.^2,3 Herein, we present the clinical findings of a renal transplant recipient who presented for evaluation of multiple skin lesions characteristic of EDV 5 years following transplantation and initiation of immunosuppressive therapy. Additionally, we review the current diagnostic findings, management, and treatment of acquired EDV.

A 44-year-old white woman presented for evaluation of several pruritic cutaneous lesions that had developed on the chest and neck of 1 month’s duration. The patient had been on the immunosuppressant medications cyclosporine and mycophenolate mofetil for more than 5 years following renal transplantation 7 years prior to the current presentation. She also was on low-dose prednisone for chronic systemic lupus erythematosus. Her family history was negative for any pertinent skin conditions.

On physical examination the patient exhibited several grouped 0.5-cm, shiny, pink lichenoid macules located on the upper mid chest, anterior neck, and left leg clinically resembling the lesions of pityriasis versicolor (Figure 1). A shave biopsy was taken from one of the newest lesions on the left leg. Histopathology revealed viral epidermal cytopathic changes, blue cytoplasm, and coarse hypergranulosis characteristic of EDV (Figure 2). A diagnosis of acquired EDV was made based on the clinical and histopathologic findings.

The patient’s skin lesions became more widespread despite several different treatment regimens, including cryosurgery; tazarotene cream 0.05% nightly; imiquimod cream 5% once weekly; and intermittent short courses of 5-fluorouracil cream 5%, which provided the best response. At her most recent clinic visit 8 years after initial presentation, she continued to have more widespread lesions on the trunk, arms, and legs, but no evidence of malignant transformation.

Comment

Epidermodysplasia verruciformis was first recognized as an inherited condition, most commonly inherited in an autosomal-dominant fashion; however, X-linked recessive cases have been reported.^4,5 Patients with the inherited forms of this condition are prone to recurrent HPV infections secondary to a missense mutation in the epidermodysplasia verruciformis 1 and 2 genes, EVER1 and EVER2, on the EV1 locus located on chromosome 17q25.⁶ Because of this mutation, the patient’s cellular immunity becomes weakened. Cellular presentation of the EDV-HPV antigen to T lymphocytes becomes impaired, thereby inhibiting the body’s ability to successfully clear itself of the virus.^5,6 The most commonly isolated EDV-HPV subtypes are HPV-5 and HPV-8, but HPV types 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, and 50 also have been associated with EDV.^1,3,7

Patients who have suppressed cellular immunity, such as transplant recipients on long-term immunosuppressant medications and individuals with HIV, graft-vs-host disease, systemic lupus erythematosus, and hematologic malignancies, are susceptible to EDV, as well as patients with atopic dermatitis being treated with topical calcineurin inhibitors.^2,3,8-15 These patients acquire depressed cellular immunity and become increasingly susceptible to infections with the EDV-HPV subtypes. When clinical and histopathologic findings are consistent with EDV, a diagnosis of acquired EDV is given, which was further confirmed in a study conducted by Harwood et al.¹⁶ They found immunocompromised patients carry more EDV-HPV subtypes in skin lesions analyzed by polymerase chain reaction than immunocompetent individuals.¹⁶ Additionally, there is a positive correlation between the length of immunosuppression and the development of HPV lesions, with a majority of patients developing lesions within 5 years following initial immunosuppression.^1,7,10,17

Epidermodysplasia verruciformis commonly presents with multiple hypopigmented to red macules that may coalesce into patches with a fine scale, clinically resembling the lesions of pityriasis versicolor.^2,3,8-15 Epidermodysplasia verruciformis also may present as multiple flesh-colored, flat-topped, verrucous papules that clinically resemble the lesions of verruca plana on sun-exposed areas such as the face, arms, and legs.⁹ The characteristic histopathologic findings are enlarged keratinocytes with perinuclear halos and blue-gray cytoplasm as well as hypergranulosis.¹⁸ Immunocompromised hosts infected with EDV-HPV histologically tend to display more severe dysplasia than immunocompetent individuals.¹⁹ The differential diagnosis includes pityriasis versicolor, squamous cell carcinoma (SCC), and verruca plana. Tissue cultures and potassium hydroxide scrapings for microorganisms should be negative.

The specific EDV-HPV strains 5, 8, and 41 carry the highest oncogenic potential, with more than 60% of inherited EDV patients developing SCC by the fourth and fifth decades of life.¹⁶ Unlike inherited EDV, the clinical course of acquired EDV is less well known; however, UV light is thought to act synergistically with the EDV-HPV in oncogenic transformation of the lesions, as most of the SCCs develop on sun-exposed areas, and darker-skinned patients seem to have a decreased risk for malignant transformation of EDV lesions.^4,9,20,21 Preventative measures such as strict sun protection and annual surveillance of lesions can help to prevent oncogenic progression of the lesions; however, several single- and multiple-agent regimens have been used in the treatment of EDV with variable results. Topical imiquimod, 5-fluorouracil, tretinoin, and tazarotene have been used with variable success. Acitretin alone and in combination with interferon alfa-2a also has been used.^22,23 Highly active antiretroviral therapy in patients with HIV has effectively decreased the number of lesions in a subset of patients.²⁴ We (anecdotal) and others²⁵ also have had success using photodynamic therapy. Squamous cell carcinoma arising in patients with EDV can be managed by excision or by Mohs micrographic surgery.

Conclusion

We report a rare case of acquired EDV in a solid organ transplant recipient. Epidermodysplasia verruciformis can be acquired in immunosuppressed patients such as ours, and these patients should be followed closely due to the potential for malignant transformation. More studies regarding the anticipated clinical course of skin lesions in patients with acquired EDV are needed to better predict the time frame for malignant transformation.

Acquired epidermodysplasia verruciformis (EDV) is a rare disorder occurring in patients with depressed cellular immunity, particularly individuals with human immunodeficiency virus (HIV). Rare cases of acquired EDV have been reported in stem cell or solid organ transplant recipients. Weakened cellular immunity predisposes the patient to human papillomavirus (HPV) infections, with 92% of renal transplant recipients developing warts within 5 years posttransplantation.¹ Specific EDV-HPV subtypes have been isolated from lesions in several immunosuppressed individuals, with HPV-5 and HPV-8 being the most commonly isolated subtypes.^2,3 Herein, we present the clinical findings of a renal transplant recipient who presented for evaluation of multiple skin lesions characteristic of EDV 5 years following transplantation and initiation of immunosuppressive therapy. Additionally, we review the current diagnostic findings, management, and treatment of acquired EDV.

A 44-year-old white woman presented for evaluation of several pruritic cutaneous lesions that had developed on the chest and neck of 1 month’s duration. The patient had been on the immunosuppressant medications cyclosporine and mycophenolate mofetil for more than 5 years following renal transplantation 7 years prior to the current presentation. She also was on low-dose prednisone for chronic systemic lupus erythematosus. Her family history was negative for any pertinent skin conditions.

On physical examination the patient exhibited several grouped 0.5-cm, shiny, pink lichenoid macules located on the upper mid chest, anterior neck, and left leg clinically resembling the lesions of pityriasis versicolor (Figure 1). A shave biopsy was taken from one of the newest lesions on the left leg. Histopathology revealed viral epidermal cytopathic changes, blue cytoplasm, and coarse hypergranulosis characteristic of EDV (Figure 2). A diagnosis of acquired EDV was made based on the clinical and histopathologic findings.

The patient’s skin lesions became more widespread despite several different treatment regimens, including cryosurgery; tazarotene cream 0.05% nightly; imiquimod cream 5% once weekly; and intermittent short courses of 5-fluorouracil cream 5%, which provided the best response. At her most recent clinic visit 8 years after initial presentation, she continued to have more widespread lesions on the trunk, arms, and legs, but no evidence of malignant transformation.

Comment

Epidermodysplasia verruciformis was first recognized as an inherited condition, most commonly inherited in an autosomal-dominant fashion; however, X-linked recessive cases have been reported.^4,5 Patients with the inherited forms of this condition are prone to recurrent HPV infections secondary to a missense mutation in the epidermodysplasia verruciformis 1 and 2 genes, EVER1 and EVER2, on the EV1 locus located on chromosome 17q25.⁶ Because of this mutation, the patient’s cellular immunity becomes weakened. Cellular presentation of the EDV-HPV antigen to T lymphocytes becomes impaired, thereby inhibiting the body’s ability to successfully clear itself of the virus.^5,6 The most commonly isolated EDV-HPV subtypes are HPV-5 and HPV-8, but HPV types 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, and 50 also have been associated with EDV.^1,3,7

Patients who have suppressed cellular immunity, such as transplant recipients on long-term immunosuppressant medications and individuals with HIV, graft-vs-host disease, systemic lupus erythematosus, and hematologic malignancies, are susceptible to EDV, as well as patients with atopic dermatitis being treated with topical calcineurin inhibitors.^2,3,8-15 These patients acquire depressed cellular immunity and become increasingly susceptible to infections with the EDV-HPV subtypes. When clinical and histopathologic findings are consistent with EDV, a diagnosis of acquired EDV is given, which was further confirmed in a study conducted by Harwood et al.¹⁶ They found immunocompromised patients carry more EDV-HPV subtypes in skin lesions analyzed by polymerase chain reaction than immunocompetent individuals.¹⁶ Additionally, there is a positive correlation between the length of immunosuppression and the development of HPV lesions, with a majority of patients developing lesions within 5 years following initial immunosuppression.^1,7,10,17

Epidermodysplasia verruciformis commonly presents with multiple hypopigmented to red macules that may coalesce into patches with a fine scale, clinically resembling the lesions of pityriasis versicolor.^2,3,8-15 Epidermodysplasia verruciformis also may present as multiple flesh-colored, flat-topped, verrucous papules that clinically resemble the lesions of verruca plana on sun-exposed areas such as the face, arms, and legs.⁹ The characteristic histopathologic findings are enlarged keratinocytes with perinuclear halos and blue-gray cytoplasm as well as hypergranulosis.¹⁸ Immunocompromised hosts infected with EDV-HPV histologically tend to display more severe dysplasia than immunocompetent individuals.¹⁹ The differential diagnosis includes pityriasis versicolor, squamous cell carcinoma (SCC), and verruca plana. Tissue cultures and potassium hydroxide scrapings for microorganisms should be negative.

The specific EDV-HPV strains 5, 8, and 41 carry the highest oncogenic potential, with more than 60% of inherited EDV patients developing SCC by the fourth and fifth decades of life.¹⁶ Unlike inherited EDV, the clinical course of acquired EDV is less well known; however, UV light is thought to act synergistically with the EDV-HPV in oncogenic transformation of the lesions, as most of the SCCs develop on sun-exposed areas, and darker-skinned patients seem to have a decreased risk for malignant transformation of EDV lesions.^4,9,20,21 Preventative measures such as strict sun protection and annual surveillance of lesions can help to prevent oncogenic progression of the lesions; however, several single- and multiple-agent regimens have been used in the treatment of EDV with variable results. Topical imiquimod, 5-fluorouracil, tretinoin, and tazarotene have been used with variable success. Acitretin alone and in combination with interferon alfa-2a also has been used.^22,23 Highly active antiretroviral therapy in patients with HIV has effectively decreased the number of lesions in a subset of patients.²⁴ We (anecdotal) and others²⁵ also have had success using photodynamic therapy. Squamous cell carcinoma arising in patients with EDV can be managed by excision or by Mohs micrographic surgery.

Conclusion

We report a rare case of acquired EDV in a solid organ transplant recipient. Epidermodysplasia verruciformis can be acquired in immunosuppressed patients such as ours, and these patients should be followed closely due to the potential for malignant transformation. More studies regarding the anticipated clinical course of skin lesions in patients with acquired EDV are needed to better predict the time frame for malignant transformation.

Acquired epidermodysplasia verruciformis (EDV) is a rare disorder occurring in patients with depressed cellular immunity, particularly individuals with human immunodeficiency virus (HIV). Rare cases of acquired EDV have been reported in stem cell or solid organ transplant recipients. Weakened cellular immunity predisposes the patient to human papillomavirus (HPV) infections, with 92% of renal transplant recipients developing warts within 5 years posttransplantation.¹ Specific EDV-HPV subtypes have been isolated from lesions in several immunosuppressed individuals, with HPV-5 and HPV-8 being the most commonly isolated subtypes.^2,3 Herein, we present the clinical findings of a renal transplant recipient who presented for evaluation of multiple skin lesions characteristic of EDV 5 years following transplantation and initiation of immunosuppressive therapy. Additionally, we review the current diagnostic findings, management, and treatment of acquired EDV.

A 44-year-old white woman presented for evaluation of several pruritic cutaneous lesions that had developed on the chest and neck of 1 month’s duration. The patient had been on the immunosuppressant medications cyclosporine and mycophenolate mofetil for more than 5 years following renal transplantation 7 years prior to the current presentation. She also was on low-dose prednisone for chronic systemic lupus erythematosus. Her family history was negative for any pertinent skin conditions.

On physical examination the patient exhibited several grouped 0.5-cm, shiny, pink lichenoid macules located on the upper mid chest, anterior neck, and left leg clinically resembling the lesions of pityriasis versicolor (Figure 1). A shave biopsy was taken from one of the newest lesions on the left leg. Histopathology revealed viral epidermal cytopathic changes, blue cytoplasm, and coarse hypergranulosis characteristic of EDV (Figure 2). A diagnosis of acquired EDV was made based on the clinical and histopathologic findings.

The patient’s skin lesions became more widespread despite several different treatment regimens, including cryosurgery; tazarotene cream 0.05% nightly; imiquimod cream 5% once weekly; and intermittent short courses of 5-fluorouracil cream 5%, which provided the best response. At her most recent clinic visit 8 years after initial presentation, she continued to have more widespread lesions on the trunk, arms, and legs, but no evidence of malignant transformation.

Comment

Epidermodysplasia verruciformis was first recognized as an inherited condition, most commonly inherited in an autosomal-dominant fashion; however, X-linked recessive cases have been reported.^4,5 Patients with the inherited forms of this condition are prone to recurrent HPV infections secondary to a missense mutation in the epidermodysplasia verruciformis 1 and 2 genes, EVER1 and EVER2, on the EV1 locus located on chromosome 17q25.⁶ Because of this mutation, the patient’s cellular immunity becomes weakened. Cellular presentation of the EDV-HPV antigen to T lymphocytes becomes impaired, thereby inhibiting the body’s ability to successfully clear itself of the virus.^5,6 The most commonly isolated EDV-HPV subtypes are HPV-5 and HPV-8, but HPV types 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, and 50 also have been associated with EDV.^1,3,7

Patients who have suppressed cellular immunity, such as transplant recipients on long-term immunosuppressant medications and individuals with HIV, graft-vs-host disease, systemic lupus erythematosus, and hematologic malignancies, are susceptible to EDV, as well as patients with atopic dermatitis being treated with topical calcineurin inhibitors.^2,3,8-15 These patients acquire depressed cellular immunity and become increasingly susceptible to infections with the EDV-HPV subtypes. When clinical and histopathologic findings are consistent with EDV, a diagnosis of acquired EDV is given, which was further confirmed in a study conducted by Harwood et al.¹⁶ They found immunocompromised patients carry more EDV-HPV subtypes in skin lesions analyzed by polymerase chain reaction than immunocompetent individuals.¹⁶ Additionally, there is a positive correlation between the length of immunosuppression and the development of HPV lesions, with a majority of patients developing lesions within 5 years following initial immunosuppression.^1,7,10,17

Epidermodysplasia verruciformis commonly presents with multiple hypopigmented to red macules that may coalesce into patches with a fine scale, clinically resembling the lesions of pityriasis versicolor.^2,3,8-15 Epidermodysplasia verruciformis also may present as multiple flesh-colored, flat-topped, verrucous papules that clinically resemble the lesions of verruca plana on sun-exposed areas such as the face, arms, and legs.⁹ The characteristic histopathologic findings are enlarged keratinocytes with perinuclear halos and blue-gray cytoplasm as well as hypergranulosis.¹⁸ Immunocompromised hosts infected with EDV-HPV histologically tend to display more severe dysplasia than immunocompetent individuals.¹⁹ The differential diagnosis includes pityriasis versicolor, squamous cell carcinoma (SCC), and verruca plana. Tissue cultures and potassium hydroxide scrapings for microorganisms should be negative.

The specific EDV-HPV strains 5, 8, and 41 carry the highest oncogenic potential, with more than 60% of inherited EDV patients developing SCC by the fourth and fifth decades of life.¹⁶ Unlike inherited EDV, the clinical course of acquired EDV is less well known; however, UV light is thought to act synergistically with the EDV-HPV in oncogenic transformation of the lesions, as most of the SCCs develop on sun-exposed areas, and darker-skinned patients seem to have a decreased risk for malignant transformation of EDV lesions.^4,9,20,21 Preventative measures such as strict sun protection and annual surveillance of lesions can help to prevent oncogenic progression of the lesions; however, several single- and multiple-agent regimens have been used in the treatment of EDV with variable results. Topical imiquimod, 5-fluorouracil, tretinoin, and tazarotene have been used with variable success. Acitretin alone and in combination with interferon alfa-2a also has been used.^22,23 Highly active antiretroviral therapy in patients with HIV has effectively decreased the number of lesions in a subset of patients.²⁴ We (anecdotal) and others²⁵ also have had success using photodynamic therapy. Squamous cell carcinoma arising in patients with EDV can be managed by excision or by Mohs micrographic surgery.

Conclusion

We report a rare case of acquired EDV in a solid organ transplant recipient. Epidermodysplasia verruciformis can be acquired in immunosuppressed patients such as ours, and these patients should be followed closely due to the potential for malignant transformation. More studies regarding the anticipated clinical course of skin lesions in patients with acquired EDV are needed to better predict the time frame for malignant transformation.