About 11.8 million Americans selected or were automatically reenrolled in plans on the health insurance exchanges during the 2018 open enrollment, the Centers for Medicare & Medicaid Services reported.

That’s a drop of 3.3%, compared with the 12.2 million enrollees for 2017, and a drop of 7.1% from the peak year of 2016, according to the 2018 open enrollment final report.

The total for 2018 includes 8.7 million consumers in the 39 states that use the HealthCare.gov platform and about 3 million consumers in the 11 states and the District of Columbia that operate their own marketplaces. Of those 11.8 million consumers, about 27% were new enrollees, 47% were active reenrollees, and 24% were automatic reenrollees, according to CMS.

For 2018, the average premium before application of the premium tax credit was $621 in the HealthCare.gov states, which is an increase of 30% from the $476 average for 2017. After the tax credit, the average premium for 2018 was $153.

“Our primary goal this year was to ensure that Americans who wanted coverage through the exchange had a seamless experience,” CMS Administrator Seema Verma said in a statement. “We are pleased that consumer satisfaction was the highest it’s ever been during the 2018 open enrollment period.”

 

About 11.8 million Americans selected or were automatically reenrolled in plans on the health insurance exchanges during the 2018 open enrollment, the Centers for Medicare & Medicaid Services reported.

That’s a drop of 3.3%, compared with the 12.2 million enrollees for 2017, and a drop of 7.1% from the peak year of 2016, according to the 2018 open enrollment final report.

The total for 2018 includes 8.7 million consumers in the 39 states that use the HealthCare.gov platform and about 3 million consumers in the 11 states and the District of Columbia that operate their own marketplaces. Of those 11.8 million consumers, about 27% were new enrollees, 47% were active reenrollees, and 24% were automatic reenrollees, according to CMS.

For 2018, the average premium before application of the premium tax credit was $621 in the HealthCare.gov states, which is an increase of 30% from the $476 average for 2017. After the tax credit, the average premium for 2018 was $153.

“Our primary goal this year was to ensure that Americans who wanted coverage through the exchange had a seamless experience,” CMS Administrator Seema Verma said in a statement. “We are pleased that consumer satisfaction was the highest it’s ever been during the 2018 open enrollment period.”

 

About 11.8 million Americans selected or were automatically reenrolled in plans on the health insurance exchanges during the 2018 open enrollment, the Centers for Medicare & Medicaid Services reported.

That’s a drop of 3.3%, compared with the 12.2 million enrollees for 2017, and a drop of 7.1% from the peak year of 2016, according to the 2018 open enrollment final report.

The total for 2018 includes 8.7 million consumers in the 39 states that use the HealthCare.gov platform and about 3 million consumers in the 11 states and the District of Columbia that operate their own marketplaces. Of those 11.8 million consumers, about 27% were new enrollees, 47% were active reenrollees, and 24% were automatic reenrollees, according to CMS.

For 2018, the average premium before application of the premium tax credit was $621 in the HealthCare.gov states, which is an increase of 30% from the $476 average for 2017. After the tax credit, the average premium for 2018 was $153.

“Our primary goal this year was to ensure that Americans who wanted coverage through the exchange had a seamless experience,” CMS Administrator Seema Verma said in a statement. “We are pleased that consumer satisfaction was the highest it’s ever been during the 2018 open enrollment period.”

 

LOS ANGELES – Results from recent trials suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease urinary albumin-to-creatinine ratio in type 2 diabetes, independent of hemoglobin A¹c lowering.

“Despite optimal care around blood pressure control, glycemic control, and control of other risk factors, our patients still have a significant risk of both cardiovascular disease progression and renal disease progression,” David Cherney, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “In fact, when we have a narrow focus on glycemia, there is a lot of additional residual risk, and that A¹c lowering by itself does not negate that risk and in fact has very little effect on clinical outcomes. That brings us to the newer hyperglycemic therapies, including the SGLT2 inhibitors. While these agents do indeed block the reabsorption of glucose in the kidney, they also have an effect on other nonglycemic risk factors.”

Dr. Cherney, director of the renal physiology laboratory at the University Health Network, Toronto, noted that both animal and human studies have shown that SGLT2 inhibitors feature several mechanisms for renal protection, including glycemic control, improved insulin levels, increased insulin sensitivity, and positive effects on blood pressure and uric acid levels.

“Inside the kidney, there are direct effects on reducing intraglomerular hypertension, leading to reductions in proteinuria,” he said. “These agents are interesting because of the way that they influence how the kidney handles sodium. As a consequence, they impact on glomerular hypertension.”

Under normal physiological conditions, humans who become volume depleted or hypotensive experience a reduction in sodium delivery to the kidney by the afferent arteriole, he explained. If less sodium is delivered to the afferent arteriole, less is filtered and delivered to the macula densa, which is the sodium-sensing area of the kidney.

“If less sodium is delivered to the macula densa, less sodium will be reabsorbed, which is an energy-requiring process that leads to the breakdown of ATP [adenosine triphosphate],” Dr. Cherney said. “If less ATP is broken down to adenosine, then less adenosine is produced. Adenosine is a vasoconstrictor in this area. So, under conditions of hypervolemia or hypotension, that’s great, because we want to maintain blood flow to the kidney; that’s a protective autoregulatory response that all of us have called tubular glomerular feedback. It’s through sodium delivery to the macula densa.”

He went on to note that hyperglycemic patients who are not taking an SGLT2 inhibitor experience an increase in sodium absorption proximally, which decreases sodium delivery to the macula densa. As a result, this causes afferent dilation, which leads to a rise in glomerular pressure, glomerular hypertension, hyperfiltration, and an increased risk of renal disease progression.

“This leads to all the effects that we see clinically, including the GFR [glomerular filtration rate] dip and the reduction in proteinuria that these agents cause either when used alone or with an ACE or ARB [angiotensin II receptor blocker],” Dr. Cherney said. “SGLT2s constrict the afferent arterial and reduce glomerular hypertension and proteinuria, whereas ACE inhibitors dilate the efferent arterial, which also reduces glomerular hypertension and proteinuria.”

An analysis of renal data from the multicenter EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) found that the use of empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events, including a 40%-50% reduction in microalbuminuria in patients with micro- or macroalbuminuria (N Engl J Med. 2016 Jul 28;375:323-34).

In a recent study of EMPA-REG OUTCOME patients, Dr. Cherney and his associates examined the effects of empagliflozin on the urinary albumin to creatinine ratio in patients with type 2 diabetes and established cardiovascular disease (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). They found that even in patients with normal albuminuria at baseline, by the end of the trial at about 3 years there was a modest but statistically significant 15% reduction in urinary albumin secretion. “That reduction was greater in patients with microalbuminuria at baseline,” Dr. Cherney said. “There was a more than 40% reduction in microalbuminuric patients, and almost a 50% in patients who had macroalbuminuria at baseline, suggesting that the effect is greater in patients with higher levels of albuminuria.”

Meanwhile, results from the CANVAS program, which integrated data from two trials of more than 10,000 patients with type 2 diabetes and high cardiovascular disease risk, showed that those who received canagliflozin had a 14% reduced risk of 3-point major adverse cardiovascular events (3P-MACE), compared with those who received placebo. (N Engl J Med. 2017 Aug;377:644-57). “There was a curious increased risk of amputation and fracture in the canagliflozin group, which has not been seen in other trials,” Dr. Cherney said. “That certainly merits further thought and investigation, to better understand how significant this risk is.”

 

Upcoming trials of renal endpoints to look out for, he said, include the CREDENCE study (results expected in 2019), DAPA-CKD, which is in the recruitment stage, and a new outcome study to evaluate the effect of empagliflozin for the treatment of people with chronic kidney disease. “This is an expanding area in the renal and cardiovascular world that we will hear a lot more about in the next 3-5 years,” he said.

Dr. Cherney reported consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe, and Sanofi.

dbrunk@frontlinemedcom.com

 

LOS ANGELES – Results from recent trials suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease urinary albumin-to-creatinine ratio in type 2 diabetes, independent of hemoglobin A¹c lowering.

“Despite optimal care around blood pressure control, glycemic control, and control of other risk factors, our patients still have a significant risk of both cardiovascular disease progression and renal disease progression,” David Cherney, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “In fact, when we have a narrow focus on glycemia, there is a lot of additional residual risk, and that A¹c lowering by itself does not negate that risk and in fact has very little effect on clinical outcomes. That brings us to the newer hyperglycemic therapies, including the SGLT2 inhibitors. While these agents do indeed block the reabsorption of glucose in the kidney, they also have an effect on other nonglycemic risk factors.”

Dr. Cherney, director of the renal physiology laboratory at the University Health Network, Toronto, noted that both animal and human studies have shown that SGLT2 inhibitors feature several mechanisms for renal protection, including glycemic control, improved insulin levels, increased insulin sensitivity, and positive effects on blood pressure and uric acid levels.

“Inside the kidney, there are direct effects on reducing intraglomerular hypertension, leading to reductions in proteinuria,” he said. “These agents are interesting because of the way that they influence how the kidney handles sodium. As a consequence, they impact on glomerular hypertension.”

Under normal physiological conditions, humans who become volume depleted or hypotensive experience a reduction in sodium delivery to the kidney by the afferent arteriole, he explained. If less sodium is delivered to the afferent arteriole, less is filtered and delivered to the macula densa, which is the sodium-sensing area of the kidney.

“If less sodium is delivered to the macula densa, less sodium will be reabsorbed, which is an energy-requiring process that leads to the breakdown of ATP [adenosine triphosphate],” Dr. Cherney said. “If less ATP is broken down to adenosine, then less adenosine is produced. Adenosine is a vasoconstrictor in this area. So, under conditions of hypervolemia or hypotension, that’s great, because we want to maintain blood flow to the kidney; that’s a protective autoregulatory response that all of us have called tubular glomerular feedback. It’s through sodium delivery to the macula densa.”

He went on to note that hyperglycemic patients who are not taking an SGLT2 inhibitor experience an increase in sodium absorption proximally, which decreases sodium delivery to the macula densa. As a result, this causes afferent dilation, which leads to a rise in glomerular pressure, glomerular hypertension, hyperfiltration, and an increased risk of renal disease progression.

“This leads to all the effects that we see clinically, including the GFR [glomerular filtration rate] dip and the reduction in proteinuria that these agents cause either when used alone or with an ACE or ARB [angiotensin II receptor blocker],” Dr. Cherney said. “SGLT2s constrict the afferent arterial and reduce glomerular hypertension and proteinuria, whereas ACE inhibitors dilate the efferent arterial, which also reduces glomerular hypertension and proteinuria.”

An analysis of renal data from the multicenter EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) found that the use of empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events, including a 40%-50% reduction in microalbuminuria in patients with micro- or macroalbuminuria (N Engl J Med. 2016 Jul 28;375:323-34).

In a recent study of EMPA-REG OUTCOME patients, Dr. Cherney and his associates examined the effects of empagliflozin on the urinary albumin to creatinine ratio in patients with type 2 diabetes and established cardiovascular disease (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). They found that even in patients with normal albuminuria at baseline, by the end of the trial at about 3 years there was a modest but statistically significant 15% reduction in urinary albumin secretion. “That reduction was greater in patients with microalbuminuria at baseline,” Dr. Cherney said. “There was a more than 40% reduction in microalbuminuric patients, and almost a 50% in patients who had macroalbuminuria at baseline, suggesting that the effect is greater in patients with higher levels of albuminuria.”

Meanwhile, results from the CANVAS program, which integrated data from two trials of more than 10,000 patients with type 2 diabetes and high cardiovascular disease risk, showed that those who received canagliflozin had a 14% reduced risk of 3-point major adverse cardiovascular events (3P-MACE), compared with those who received placebo. (N Engl J Med. 2017 Aug;377:644-57). “There was a curious increased risk of amputation and fracture in the canagliflozin group, which has not been seen in other trials,” Dr. Cherney said. “That certainly merits further thought and investigation, to better understand how significant this risk is.”

 

Upcoming trials of renal endpoints to look out for, he said, include the CREDENCE study (results expected in 2019), DAPA-CKD, which is in the recruitment stage, and a new outcome study to evaluate the effect of empagliflozin for the treatment of people with chronic kidney disease. “This is an expanding area in the renal and cardiovascular world that we will hear a lot more about in the next 3-5 years,” he said.

Dr. Cherney reported consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe, and Sanofi.

dbrunk@frontlinemedcom.com

 

LOS ANGELES – Results from recent trials suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease urinary albumin-to-creatinine ratio in type 2 diabetes, independent of hemoglobin A¹c lowering.

“Despite optimal care around blood pressure control, glycemic control, and control of other risk factors, our patients still have a significant risk of both cardiovascular disease progression and renal disease progression,” David Cherney, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “In fact, when we have a narrow focus on glycemia, there is a lot of additional residual risk, and that A¹c lowering by itself does not negate that risk and in fact has very little effect on clinical outcomes. That brings us to the newer hyperglycemic therapies, including the SGLT2 inhibitors. While these agents do indeed block the reabsorption of glucose in the kidney, they also have an effect on other nonglycemic risk factors.”

Dr. Cherney, director of the renal physiology laboratory at the University Health Network, Toronto, noted that both animal and human studies have shown that SGLT2 inhibitors feature several mechanisms for renal protection, including glycemic control, improved insulin levels, increased insulin sensitivity, and positive effects on blood pressure and uric acid levels.

“Inside the kidney, there are direct effects on reducing intraglomerular hypertension, leading to reductions in proteinuria,” he said. “These agents are interesting because of the way that they influence how the kidney handles sodium. As a consequence, they impact on glomerular hypertension.”

Under normal physiological conditions, humans who become volume depleted or hypotensive experience a reduction in sodium delivery to the kidney by the afferent arteriole, he explained. If less sodium is delivered to the afferent arteriole, less is filtered and delivered to the macula densa, which is the sodium-sensing area of the kidney.

“If less sodium is delivered to the macula densa, less sodium will be reabsorbed, which is an energy-requiring process that leads to the breakdown of ATP [adenosine triphosphate],” Dr. Cherney said. “If less ATP is broken down to adenosine, then less adenosine is produced. Adenosine is a vasoconstrictor in this area. So, under conditions of hypervolemia or hypotension, that’s great, because we want to maintain blood flow to the kidney; that’s a protective autoregulatory response that all of us have called tubular glomerular feedback. It’s through sodium delivery to the macula densa.”

He went on to note that hyperglycemic patients who are not taking an SGLT2 inhibitor experience an increase in sodium absorption proximally, which decreases sodium delivery to the macula densa. As a result, this causes afferent dilation, which leads to a rise in glomerular pressure, glomerular hypertension, hyperfiltration, and an increased risk of renal disease progression.

“This leads to all the effects that we see clinically, including the GFR [glomerular filtration rate] dip and the reduction in proteinuria that these agents cause either when used alone or with an ACE or ARB [angiotensin II receptor blocker],” Dr. Cherney said. “SGLT2s constrict the afferent arterial and reduce glomerular hypertension and proteinuria, whereas ACE inhibitors dilate the efferent arterial, which also reduces glomerular hypertension and proteinuria.”

An analysis of renal data from the multicenter EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) found that the use of empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events, including a 40%-50% reduction in microalbuminuria in patients with micro- or macroalbuminuria (N Engl J Med. 2016 Jul 28;375:323-34).

In a recent study of EMPA-REG OUTCOME patients, Dr. Cherney and his associates examined the effects of empagliflozin on the urinary albumin to creatinine ratio in patients with type 2 diabetes and established cardiovascular disease (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). They found that even in patients with normal albuminuria at baseline, by the end of the trial at about 3 years there was a modest but statistically significant 15% reduction in urinary albumin secretion. “That reduction was greater in patients with microalbuminuria at baseline,” Dr. Cherney said. “There was a more than 40% reduction in microalbuminuric patients, and almost a 50% in patients who had macroalbuminuria at baseline, suggesting that the effect is greater in patients with higher levels of albuminuria.”

Meanwhile, results from the CANVAS program, which integrated data from two trials of more than 10,000 patients with type 2 diabetes and high cardiovascular disease risk, showed that those who received canagliflozin had a 14% reduced risk of 3-point major adverse cardiovascular events (3P-MACE), compared with those who received placebo. (N Engl J Med. 2017 Aug;377:644-57). “There was a curious increased risk of amputation and fracture in the canagliflozin group, which has not been seen in other trials,” Dr. Cherney said. “That certainly merits further thought and investigation, to better understand how significant this risk is.”

 

Upcoming trials of renal endpoints to look out for, he said, include the CREDENCE study (results expected in 2019), DAPA-CKD, which is in the recruitment stage, and a new outcome study to evaluate the effect of empagliflozin for the treatment of people with chronic kidney disease. “This is an expanding area in the renal and cardiovascular world that we will hear a lot more about in the next 3-5 years,” he said.

Dr. Cherney reported consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe, and Sanofi.

dbrunk@frontlinemedcom.com

 

ORLANDO – A fast-track approach to urinary catheter management after benign gynecologic surgery reduced catheter dwell time, but did not significantly improve outcomes or patient satisfaction in a prospective, randomized trial.

Catheter dwell times in 200 women randomized 1:1 to receive either fast-track catheter management with planned catheter removal at 4 hours after surgery, or conventional catheter management with planned catheter removal 1 day after surgery, were 650 minutes versus 1,196 minutes in the groups, respectively, Patrick Lang, MD, reported at the annual scientific meeting of the Society of Gynecologic Surgeons.

Overall, 93% of patients had a successful voiding trial for catheter removal, but failures occurred more often in the fast-track management group than in the conventional management group (12% vs. 2%), said Dr. Lang, a fellow at the Christ Hospital Health Network, Cincinnati.

Furthermore, the reduction in Urogenital Distress Inventory short form scores after surgery was significant overall but did not differ significantly in the fast-track and conventional management groups, and there was a trend toward less of a reduction in Urogenital Distress Inventory scores among those who failed the voiding trial versus those who passed, he noted.

Follow-up patient surveys at 2-3 weeks after surgery showed no significant difference between the groups in the rates of reported urinary tract infections (13% and 19% with fast-track and conventional management, respectively) and antibiotic exposure, or in lower urinary tract symptoms (P = .24 and .92), he said.

Patients also had a positive overall impression of their catheter management, with no significant difference between the groups in the percentage of patients who strongly agreed that their catheter was well managed (80% and 87%, respectively).

 

In women undergoing gynecologic surgery, indwelling urinary catheters often are used for an extended period as postoperative voiding dysfunction is presumed, Dr. Lang noted.

For the current single-center study, women undergoing any benign gynecologic surgery with an anticipated hospital stay of at least 1 night were enrolled and randomized to fast-track or conventional catheter management. All underwent hysterectomy, and the approaches, including robotic in 42%, traditional laparoscopic in 33%, vaginal in 14.3%, and abdominal in 10.3%, did not differ among the groups. Neither the rates of voiding trial success nor catheter dwell time differed, based on hysterectomy approach, he said.

“Catheter dwell time is reduced with a fast-track approach, but dwell time does not appear to influence patient satisfaction or urinary tract symptomatology, urinary tract infection, or antibiotic exposure in the 2-3 weeks following benign gynecologic surgery,” he concluded.

Dr. Lang reported having no disclosures.

sworcester@mdedge.com

SOURCE: Lang P et al. SGS 2018, Oral Poster 20.

 

ORLANDO – A fast-track approach to urinary catheter management after benign gynecologic surgery reduced catheter dwell time, but did not significantly improve outcomes or patient satisfaction in a prospective, randomized trial.

Catheter dwell times in 200 women randomized 1:1 to receive either fast-track catheter management with planned catheter removal at 4 hours after surgery, or conventional catheter management with planned catheter removal 1 day after surgery, were 650 minutes versus 1,196 minutes in the groups, respectively, Patrick Lang, MD, reported at the annual scientific meeting of the Society of Gynecologic Surgeons.

Overall, 93% of patients had a successful voiding trial for catheter removal, but failures occurred more often in the fast-track management group than in the conventional management group (12% vs. 2%), said Dr. Lang, a fellow at the Christ Hospital Health Network, Cincinnati.

Furthermore, the reduction in Urogenital Distress Inventory short form scores after surgery was significant overall but did not differ significantly in the fast-track and conventional management groups, and there was a trend toward less of a reduction in Urogenital Distress Inventory scores among those who failed the voiding trial versus those who passed, he noted.

Follow-up patient surveys at 2-3 weeks after surgery showed no significant difference between the groups in the rates of reported urinary tract infections (13% and 19% with fast-track and conventional management, respectively) and antibiotic exposure, or in lower urinary tract symptoms (P = .24 and .92), he said.

Patients also had a positive overall impression of their catheter management, with no significant difference between the groups in the percentage of patients who strongly agreed that their catheter was well managed (80% and 87%, respectively).

 

In women undergoing gynecologic surgery, indwelling urinary catheters often are used for an extended period as postoperative voiding dysfunction is presumed, Dr. Lang noted.

For the current single-center study, women undergoing any benign gynecologic surgery with an anticipated hospital stay of at least 1 night were enrolled and randomized to fast-track or conventional catheter management. All underwent hysterectomy, and the approaches, including robotic in 42%, traditional laparoscopic in 33%, vaginal in 14.3%, and abdominal in 10.3%, did not differ among the groups. Neither the rates of voiding trial success nor catheter dwell time differed, based on hysterectomy approach, he said.

“Catheter dwell time is reduced with a fast-track approach, but dwell time does not appear to influence patient satisfaction or urinary tract symptomatology, urinary tract infection, or antibiotic exposure in the 2-3 weeks following benign gynecologic surgery,” he concluded.

Dr. Lang reported having no disclosures.

sworcester@mdedge.com

SOURCE: Lang P et al. SGS 2018, Oral Poster 20.

 

ORLANDO – A fast-track approach to urinary catheter management after benign gynecologic surgery reduced catheter dwell time, but did not significantly improve outcomes or patient satisfaction in a prospective, randomized trial.

Catheter dwell times in 200 women randomized 1:1 to receive either fast-track catheter management with planned catheter removal at 4 hours after surgery, or conventional catheter management with planned catheter removal 1 day after surgery, were 650 minutes versus 1,196 minutes in the groups, respectively, Patrick Lang, MD, reported at the annual scientific meeting of the Society of Gynecologic Surgeons.

Overall, 93% of patients had a successful voiding trial for catheter removal, but failures occurred more often in the fast-track management group than in the conventional management group (12% vs. 2%), said Dr. Lang, a fellow at the Christ Hospital Health Network, Cincinnati.

Furthermore, the reduction in Urogenital Distress Inventory short form scores after surgery was significant overall but did not differ significantly in the fast-track and conventional management groups, and there was a trend toward less of a reduction in Urogenital Distress Inventory scores among those who failed the voiding trial versus those who passed, he noted.

Follow-up patient surveys at 2-3 weeks after surgery showed no significant difference between the groups in the rates of reported urinary tract infections (13% and 19% with fast-track and conventional management, respectively) and antibiotic exposure, or in lower urinary tract symptoms (P = .24 and .92), he said.

Patients also had a positive overall impression of their catheter management, with no significant difference between the groups in the percentage of patients who strongly agreed that their catheter was well managed (80% and 87%, respectively).

 

In women undergoing gynecologic surgery, indwelling urinary catheters often are used for an extended period as postoperative voiding dysfunction is presumed, Dr. Lang noted.

For the current single-center study, women undergoing any benign gynecologic surgery with an anticipated hospital stay of at least 1 night were enrolled and randomized to fast-track or conventional catheter management. All underwent hysterectomy, and the approaches, including robotic in 42%, traditional laparoscopic in 33%, vaginal in 14.3%, and abdominal in 10.3%, did not differ among the groups. Neither the rates of voiding trial success nor catheter dwell time differed, based on hysterectomy approach, he said.

“Catheter dwell time is reduced with a fast-track approach, but dwell time does not appear to influence patient satisfaction or urinary tract symptomatology, urinary tract infection, or antibiotic exposure in the 2-3 weeks following benign gynecologic surgery,” he concluded.

Dr. Lang reported having no disclosures.

sworcester@mdedge.com

SOURCE: Lang P et al. SGS 2018, Oral Poster 20.

Clinical question: Does PCI provide symptom relief in patients with stable angina?

Background: More than 500,000 PCIs are done yearly worldwide in patients with stable angina. Meta-­analyses have demonstrated no impact of PCI on rates of death and myocardial infarction in patients with stable angina. Rather, relief of angina is the main reason for performance of PCI in patients with stable coronary artery disease, and this effect is frequently noted. However, there have been no data from double-blind, randomized, controlled trials to confirm the efficacy of PCI in relieving anginal pain.
Study design: Multicenter, double-blind, randomized, controlled trial.

Setting: Five sites in the United Kingdom.

Synopsis: The Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial was designed to evaluate the effect of PCI, compared with placebo, on exercise time in patients with stable angina. The 230 patients who were enrolled in ORBITA had severe (70% or more), single-vessel stenosis. After enrolling, patients’ medication regimens were optimized so that almost all were taking aspirin, a second antiplatelet drug, and a statin. Beta-blockers and calcium channel blockers also were widely used by trial participants. Two hundred patients were randomized to either PCI (105 patients) or placebo procedure (95 patients). The primary endpoint was exercise time, and no difference was observed between the two groups. ORBITA’s results apply to patients with stable angina but not to those who undergo PCI for acute coronary syndrome (which includes ST-elevation MI); in the latter population, PCI has been demonstrated to reduce morbidity and mortality.

Bottom line: In patients with stable angina, PCI does not increase exercise time.

Citation: Al-Lamee R et al. Percutaneous coronary intervention in stable angina (ORBITA): A double-­blind, randomised controlled trial. Lancet. 2018 Jan;391(10115);31-40.

 

 

Dr. Clarke is assistant professor of medicine in the division of hospital medicine, Emory University, Atlanta.

 

Clinical question: Does PCI provide symptom relief in patients with stable angina?

Background: More than 500,000 PCIs are done yearly worldwide in patients with stable angina. Meta-­analyses have demonstrated no impact of PCI on rates of death and myocardial infarction in patients with stable angina. Rather, relief of angina is the main reason for performance of PCI in patients with stable coronary artery disease, and this effect is frequently noted. However, there have been no data from double-blind, randomized, controlled trials to confirm the efficacy of PCI in relieving anginal pain.
Study design: Multicenter, double-blind, randomized, controlled trial.

Setting: Five sites in the United Kingdom.

Synopsis: The Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial was designed to evaluate the effect of PCI, compared with placebo, on exercise time in patients with stable angina. The 230 patients who were enrolled in ORBITA had severe (70% or more), single-vessel stenosis. After enrolling, patients’ medication regimens were optimized so that almost all were taking aspirin, a second antiplatelet drug, and a statin. Beta-blockers and calcium channel blockers also were widely used by trial participants. Two hundred patients were randomized to either PCI (105 patients) or placebo procedure (95 patients). The primary endpoint was exercise time, and no difference was observed between the two groups. ORBITA’s results apply to patients with stable angina but not to those who undergo PCI for acute coronary syndrome (which includes ST-elevation MI); in the latter population, PCI has been demonstrated to reduce morbidity and mortality.

Bottom line: In patients with stable angina, PCI does not increase exercise time.

Citation: Al-Lamee R et al. Percutaneous coronary intervention in stable angina (ORBITA): A double-­blind, randomised controlled trial. Lancet. 2018 Jan;391(10115);31-40.

 

 

Dr. Clarke is assistant professor of medicine in the division of hospital medicine, Emory University, Atlanta.

 

Clinical question: Does PCI provide symptom relief in patients with stable angina?

Background: More than 500,000 PCIs are done yearly worldwide in patients with stable angina. Meta-­analyses have demonstrated no impact of PCI on rates of death and myocardial infarction in patients with stable angina. Rather, relief of angina is the main reason for performance of PCI in patients with stable coronary artery disease, and this effect is frequently noted. However, there have been no data from double-blind, randomized, controlled trials to confirm the efficacy of PCI in relieving anginal pain.
Study design: Multicenter, double-blind, randomized, controlled trial.

Setting: Five sites in the United Kingdom.

Synopsis: The Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial was designed to evaluate the effect of PCI, compared with placebo, on exercise time in patients with stable angina. The 230 patients who were enrolled in ORBITA had severe (70% or more), single-vessel stenosis. After enrolling, patients’ medication regimens were optimized so that almost all were taking aspirin, a second antiplatelet drug, and a statin. Beta-blockers and calcium channel blockers also were widely used by trial participants. Two hundred patients were randomized to either PCI (105 patients) or placebo procedure (95 patients). The primary endpoint was exercise time, and no difference was observed between the two groups. ORBITA’s results apply to patients with stable angina but not to those who undergo PCI for acute coronary syndrome (which includes ST-elevation MI); in the latter population, PCI has been demonstrated to reduce morbidity and mortality.

Bottom line: In patients with stable angina, PCI does not increase exercise time.

Citation: Al-Lamee R et al. Percutaneous coronary intervention in stable angina (ORBITA): A double-­blind, randomised controlled trial. Lancet. 2018 Jan;391(10115);31-40.

 

 

Dr. Clarke is assistant professor of medicine in the division of hospital medicine, Emory University, Atlanta.

 

 

CHICAGO – One quarter of men with low sperm counts met criteria for metabolic syndrome in a large prospective cohort study of couples with infertility. Low testosterone levels alone didn’t account for the finding, said Alberto Ferlin, MD, PhD, professor of reproductive endocrinology at the University of Brescia, Italy.

“So at the end, we showed that, independent of testosterone, low sperm count could be a marker of general male health, in particular for cardiovascular risk factors or metabolic derangement,” said Dr. Ferlin in an interview following a press conference at the annual meeting of the Endocrine Society.

The Italian study, which Dr. Ferlin said was the largest of its kind to date, studied 5,177 males who were part of an infertile couple, comparing men with low sperm count (less than 39 million sperm per ejaculate) with those with normal sperm count (at least 39 million sperm per ejaculate). In all, 2,583 of the participants had low sperm counts.

“Our main aim was to understand if semen analysis and, in general, the reproductive function of a man, could be a marker of his general cardiovascular and metabolic health,” said Dr. Ferlin.

Only men with a comprehensive work-up were included, so all participants had a medical history and physical exam, and semen analysis and culture. Additional components of the evaluation included blood lipid and glucose metabolism testing, reproductive hormone levels, ultrasound of the testes and, for men diagnosed with hypogonadism, bone densitometry.

The study, said Dr. Ferlin, found that among men with a low total sperm count, there was a high prevalence of hypogonadism, defined as both low testosterone and elevated levels of luteinizing hormone. Additionally, these men had a high prevalence of elevated luteinizing hormones with normal testosterone – “so-called subclinical hypogonadism,” said Dr. Ferlin.

In men with a low sperm count – defined as fewer than 39 million sperm per ejaculate – the prevalence of biochemical hypogonadism was about 45%, compared with just 6% in men with normal sperm counts, said Dr. Ferlin. Men with infertility had an odds ratio for hypogonadism of 12.2, said Dr. Ferlin (95% confidence interval, 10.2-14.6).

 

Additionally, Dr. Ferlin reported that 35% of men with hypogonadism had osteopenia, and 17% met criteria for osteoporosis. The numbers surprised the investigators. “These are very young men – about 30 years old,” said Dr. Ferlin.

Dr. Ferlin and his collaborators also looked at the subset of eugonadal men in the study, comparing those with normal sperm counts (n = 2,431) to those who had low sperm counts, (n = 1,423). They found that men with low sperm counts had significantly higher body mass index, waist circumference, systolic blood pressure, hemoglobin A1c, and homeostatic model assessment of insulin resistance (HOMA-IR) levels (P less than .001 for all).

High density lipoprotein (HDL) cholesterol, testosterone, and follicle stimulating hormone levels were also significantly lower for men with low sperm count. “Men with oligozoospermia … have an increased risk of metabolic derangement – so, altered lipid profile with higher LDL cholesterol and lower HDL [cholesterol], higher triglycerides, higher insulin resistance,” said Dr. Ferlin.

The findings have implications for reproductive endocrinologists caring for couples with infertility, said Dr. Ferlin. “Infertile men should be studied comprehensively, and the diagnosis cannot be limited to just one semen analysis,” given the study’s findings, he said. “All these men should be counseled, should be treated … for worsening of these cardiovascular and metabolic risk factors that are present in such frequency in oligozoospermic men.”

Dr. Ferlin reported no conflicts of interest.

koakes@mdedge.com

 

CHICAGO – One quarter of men with low sperm counts met criteria for metabolic syndrome in a large prospective cohort study of couples with infertility. Low testosterone levels alone didn’t account for the finding, said Alberto Ferlin, MD, PhD, professor of reproductive endocrinology at the University of Brescia, Italy.

“So at the end, we showed that, independent of testosterone, low sperm count could be a marker of general male health, in particular for cardiovascular risk factors or metabolic derangement,” said Dr. Ferlin in an interview following a press conference at the annual meeting of the Endocrine Society.

The Italian study, which Dr. Ferlin said was the largest of its kind to date, studied 5,177 males who were part of an infertile couple, comparing men with low sperm count (less than 39 million sperm per ejaculate) with those with normal sperm count (at least 39 million sperm per ejaculate). In all, 2,583 of the participants had low sperm counts.

“Our main aim was to understand if semen analysis and, in general, the reproductive function of a man, could be a marker of his general cardiovascular and metabolic health,” said Dr. Ferlin.

Only men with a comprehensive work-up were included, so all participants had a medical history and physical exam, and semen analysis and culture. Additional components of the evaluation included blood lipid and glucose metabolism testing, reproductive hormone levels, ultrasound of the testes and, for men diagnosed with hypogonadism, bone densitometry.

The study, said Dr. Ferlin, found that among men with a low total sperm count, there was a high prevalence of hypogonadism, defined as both low testosterone and elevated levels of luteinizing hormone. Additionally, these men had a high prevalence of elevated luteinizing hormones with normal testosterone – “so-called subclinical hypogonadism,” said Dr. Ferlin.

In men with a low sperm count – defined as fewer than 39 million sperm per ejaculate – the prevalence of biochemical hypogonadism was about 45%, compared with just 6% in men with normal sperm counts, said Dr. Ferlin. Men with infertility had an odds ratio for hypogonadism of 12.2, said Dr. Ferlin (95% confidence interval, 10.2-14.6).

 

Additionally, Dr. Ferlin reported that 35% of men with hypogonadism had osteopenia, and 17% met criteria for osteoporosis. The numbers surprised the investigators. “These are very young men – about 30 years old,” said Dr. Ferlin.

Dr. Ferlin and his collaborators also looked at the subset of eugonadal men in the study, comparing those with normal sperm counts (n = 2,431) to those who had low sperm counts, (n = 1,423). They found that men with low sperm counts had significantly higher body mass index, waist circumference, systolic blood pressure, hemoglobin A1c, and homeostatic model assessment of insulin resistance (HOMA-IR) levels (P less than .001 for all).

High density lipoprotein (HDL) cholesterol, testosterone, and follicle stimulating hormone levels were also significantly lower for men with low sperm count. “Men with oligozoospermia … have an increased risk of metabolic derangement – so, altered lipid profile with higher LDL cholesterol and lower HDL [cholesterol], higher triglycerides, higher insulin resistance,” said Dr. Ferlin.

The findings have implications for reproductive endocrinologists caring for couples with infertility, said Dr. Ferlin. “Infertile men should be studied comprehensively, and the diagnosis cannot be limited to just one semen analysis,” given the study’s findings, he said. “All these men should be counseled, should be treated … for worsening of these cardiovascular and metabolic risk factors that are present in such frequency in oligozoospermic men.”

Dr. Ferlin reported no conflicts of interest.

koakes@mdedge.com

 

CHICAGO – One quarter of men with low sperm counts met criteria for metabolic syndrome in a large prospective cohort study of couples with infertility. Low testosterone levels alone didn’t account for the finding, said Alberto Ferlin, MD, PhD, professor of reproductive endocrinology at the University of Brescia, Italy.

“So at the end, we showed that, independent of testosterone, low sperm count could be a marker of general male health, in particular for cardiovascular risk factors or metabolic derangement,” said Dr. Ferlin in an interview following a press conference at the annual meeting of the Endocrine Society.

The Italian study, which Dr. Ferlin said was the largest of its kind to date, studied 5,177 males who were part of an infertile couple, comparing men with low sperm count (less than 39 million sperm per ejaculate) with those with normal sperm count (at least 39 million sperm per ejaculate). In all, 2,583 of the participants had low sperm counts.

“Our main aim was to understand if semen analysis and, in general, the reproductive function of a man, could be a marker of his general cardiovascular and metabolic health,” said Dr. Ferlin.

Only men with a comprehensive work-up were included, so all participants had a medical history and physical exam, and semen analysis and culture. Additional components of the evaluation included blood lipid and glucose metabolism testing, reproductive hormone levels, ultrasound of the testes and, for men diagnosed with hypogonadism, bone densitometry.

The study, said Dr. Ferlin, found that among men with a low total sperm count, there was a high prevalence of hypogonadism, defined as both low testosterone and elevated levels of luteinizing hormone. Additionally, these men had a high prevalence of elevated luteinizing hormones with normal testosterone – “so-called subclinical hypogonadism,” said Dr. Ferlin.

In men with a low sperm count – defined as fewer than 39 million sperm per ejaculate – the prevalence of biochemical hypogonadism was about 45%, compared with just 6% in men with normal sperm counts, said Dr. Ferlin. Men with infertility had an odds ratio for hypogonadism of 12.2, said Dr. Ferlin (95% confidence interval, 10.2-14.6).

 

Additionally, Dr. Ferlin reported that 35% of men with hypogonadism had osteopenia, and 17% met criteria for osteoporosis. The numbers surprised the investigators. “These are very young men – about 30 years old,” said Dr. Ferlin.

Dr. Ferlin and his collaborators also looked at the subset of eugonadal men in the study, comparing those with normal sperm counts (n = 2,431) to those who had low sperm counts, (n = 1,423). They found that men with low sperm counts had significantly higher body mass index, waist circumference, systolic blood pressure, hemoglobin A1c, and homeostatic model assessment of insulin resistance (HOMA-IR) levels (P less than .001 for all).

High density lipoprotein (HDL) cholesterol, testosterone, and follicle stimulating hormone levels were also significantly lower for men with low sperm count. “Men with oligozoospermia … have an increased risk of metabolic derangement – so, altered lipid profile with higher LDL cholesterol and lower HDL [cholesterol], higher triglycerides, higher insulin resistance,” said Dr. Ferlin.

The findings have implications for reproductive endocrinologists caring for couples with infertility, said Dr. Ferlin. “Infertile men should be studied comprehensively, and the diagnosis cannot be limited to just one semen analysis,” given the study’s findings, he said. “All these men should be counseled, should be treated … for worsening of these cardiovascular and metabolic risk factors that are present in such frequency in oligozoospermic men.”

Dr. Ferlin reported no conflicts of interest.

koakes@mdedge.com

Merkel cell carcinoma (MCC) is a rare, rapidly growing, aggressive neoplasm with a generally poor prognosis. The cells of origin are highly anaplastic and share structural and immunohistochemical features with various neuroectodermally derived cells. Although Merkel cells, which are slow-acting cutaneous mechanoreceptors located in the basal layer of the epidermis, and MCC share immunohistochemical and ultrastructural features, there is limited evidence of a direct histogenetic relationship between the two.^1,2 Additionally, some extracutaneous neuroendocrine tumors have features similar to MCC; therefore, although it may be more accurate and perhaps more practical to describe these lesions as primary neuroendocrine carcinomas of the skin, the term MCC is more commonly used both in the literature and in clinical practice.^1,2

Merkel cell carcinoma typically presents in the head and neck region in white patients older than 70 years of age and in the immunocompromised population.^3-6 The mean age of diagnosis is 76 years for women and 74 years for men.⁷ The incidence of MCC in the United States tripled over a 15-year period, and there are approximately 1500 new cases of MCC diagnosed each year, making it about 40 times less common than melanoma.⁸ The 5-year survival rate for patients without lymph node involvement is 75%, whereas the 5-year survival rate for patients with distant metastases is 25%.⁹

Merkel cell carcinoma is thought to develop through 1 of 2 distinct pathways. In a virally mediated pathway, which represents at least 80% of cases, the Merkel cell polyomavirus (MCV) monoclonally integrates into the host genome and promotes oncogenesis via altered p53 and retinoblastoma protein expression.^10-12 The remainder of cases are believed to develop via a nonvirally mediated pathway in which genetic anomalies, immune status, and environmental factors influence oncogenesis.^10-13

Due to the similarity between MCC and metastatic neuroendocrine neoplasms, especially small-cell lung carcinomas, immunohistochemistry is important in making the diagnosis. Cytokeratin 20 and neuron-specific enolase positivity and thyroid transcription factor 1 negativity are the most useful markers in identifying MCC.

Regression of MCC is a very rare and poorly understood event. A 2010 review of the literature described 22 cases of spontaneous regression.¹⁴ We report a rare case of rapid and complete regression of MCC following punch biopsy in a 96-year-old woman.

Case Report

A 96-year-old woman presented with a rapidly enlarging lesion overlying the suprasternal notch of 8 weeks’ duration (Figure 1). The lesion consisted of a 5.0×4.5-cm, friable, erythematous, flesh-colored nodule with ulceration and heavy crusting. Surrounding the nodule was an erythematous to violaceous patch extending to the anterior chest and bilateral supraclavicular area. No cervical or clavicular lymphadenopathy was observed. According to the patient’s caregiver, the lesion originated as a small, erythematous, scaly macule that rapidly increased in size over an 8-week period to a maximum of 5.0×4.5 cm at presentation. The lesion bled on 2 or 3 occasions during the 8-week period and was controlled with a warm compress. The patient’s caregiver had treated the lesion with topical tea tree oil (for malodor) and antibiotic ointment as needed. The clinical differential diagnosis included squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, cutaneous metastasis of a primary visceral malignancy, basal cell carcinoma, and MCC. Biopsy of the lesion was recommended at this time but the patient’s family declined.

A 4-mm punch biopsy was obtained at a follow-up visit 4 weeks later (12 weeks after the reported onset of the lesion). Hematoxylin and eosin staining showed a small-cell neoplasm with stippled nuclei and scant cytoplasm forming a nested and somewhat trabecular pattern. Mitotic activity, apoptosis, and nuclear molding also were present (Figure 2). The tumor cells were positive for cytokeratin 20 with a dotlike, paranuclear pattern (Figure 3). Staining for CAM 5.2 also was positive. Cytokeratin 5/6, human melanoma black 45, and leukocyte common antigen were negative. The immunophenotyping of the lymphocytic response to the tumor showed that the majority of intratumoral lymphocytes were CD8 positive (Figure 4). CD4-positive lymphocytes were predominantly seen at the periphery of the tumor nests without tumor infiltration (Figure 5). Based on these findings, a diagnosis of MCC was made. The patient’s family declined treatment based on her advanced age and current health status, which included advanced dementia.

Two weeks after the punch biopsy, the lesion had noticeably decreased in size and lost its dome-shaped appearance. Within 8 weeks after biopsy (20 weeks since the lesion first appeared), the lesion had completely resolved (Figure 6). The patient was lost to follow-up months later, but no recurrence of the lesion was reported.

 

Comment

Spontaneous regression is not unique to MCC, as this phenomenon also has been reported in keratoacanthoma, lymphoma, basal cell carcinoma, and melanoma.¹⁵ Complete spontaneous regression is defined as occurring in the absence of therapy that is intended to have a treatment effect.^15,16 Spontaneous regression is estimated to occur in malignant neoplasms at a rate of 1 case per 60,000 to 100,000 (approximately 0.0013% of all malignant neoplasms).¹⁷ Considering the reported prevalence of MCC and the number of cases that have been known to regress, the estimated incidence of complete spontaneous regression may be as high as 1.5%.¹⁴ Though spontaneous regression of MCC is more prevalent than expected, it still is considered a rare phenomenon. A 2010 review of the literature yielded 22 cases of complete spontaneous regression of MCC.¹⁴ No recurrences have been observed; however, follow-up was relatively short in some cases.

In a unique report by Bertolotti et al,¹⁸ a patient with MCC on the nasal tip presented 4 weeks after biopsy with complete spontaneous regression of the tumor, which was associated with bilateral cervical lymph node involvement as noted by hypermetabolic uptake on positron emission tomography scanning. The patient underwent radiation therapy and was disease free at 12 months’ follow-up.¹⁸

Complete spontaneous regression has been described in MCC patients with local disease, regional recurrences, and metastatic disease.¹⁹ In all reviewed cases, the regression is a fairly quick phenomenon occurring over the course of 1 to 5 months.^16,19,20,21 Our patient presented with advanced age and a tumor location characteristic of MCC. In our search of PubMed articles indexed for MEDLINE using the terms MCC, Merkel cell carcinoma, regression, and spontaneous regression, all but 1 case of MCC regression involved tumors that were located on the head.¹⁴

The histopathologic features observed in our case, specifically intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells, were similar to the findings in other reported cases. In one series of 2 cases, the one case showed scar tissue with a moderate, predominantly T-lymphocytic infiltrate and no tumor cells, and the second showed cellular proliferation in the deep dermis with dense lymphocytic infiltrates primarily composed of CD3-positive T cells.¹⁴ Other studies of regression of both localized and metastatic MCC demonstrated infiltration by CD4-positive, CD8-positive, and CD3-positive lymphocytes and foamy macrophages.^21-23

The discovery of the MCV was one of the most important advances in elucidating the pathogenesis of MCC.^10,24-26 Merkel cell polyomavirus DNA has been detected in a majority of MCC cases.^25,27 Viral integration has been shown to take place early, prior to tumor clonal expansion.¹⁰ Importantly, not all cases of MCC show MCV infection, and MCV infection is not exclusive to MCC.²⁸ Merkel cell polyomavirus is considered to be part of the normal human flora, and asymptomatic infection is quite common.²⁹ It has been identified in 80% of adults older than 50 years of age and, interestingly, in 35% of children by 13 years of age or younger.^30,31 It remains unclear what role the presence of MCV plays in determining MCC prognosis. Several reports have demonstrated lower disease-specific mortality associated with MCV-positive MCC.^32-35 In contrast, Schrama et al³⁶ correlated the MCV status of 174 MCC tumors and found no difference in clinical behavior or prognosis between MCV-positive and MCV-negative MCCs.

Immunosuppression also may play a role in the development of MCC.^5,25 There is increased prevalence of MCC in the human immunodeficiency virus–positive population, as well as in organ-transplant recipients and patients with leukemia. Chronic lymphocytic leukemia seems to be the most frequent neoplasia associated with development of MCC.³⁷

The mechanism of MCC regression remains unclear, but many investigators emphasize the importance of T-cell–mediated immunity.^{16,21-23,38,39} Apoptosis also has been shown to play an important role.⁴⁰ Our case showed tumor-infiltrating CD8-positive lymphocytes and CD4-positive lymphocytes present predominantly at the periphery of the tumor, with close proximity to the tumor nests but with no tumor infiltration (Figure 3). This distribution was consistently present in multiple sections of the tumor. These findings are consistent with prior reports of both CD4-positive and CD8-positive T lymphocytes associated with MCC regression. Our findings confirm that immune response may play an important role in spontaneous regression of MCC.

There is much speculation regarding the initial biopsy of an MCC lesion (or other traumatic event) and its role in tumor regression. Koba et al⁴¹ examined the effect of biopsy on CD8-positive lymphocytic infiltration of MCC tumor cells and found that biopsy does not commonly alter intratumoral CD8-positive infiltration. These findings suggest trauma does not directly induce immunologic recognition of this cancer.

Conclusion

We report a case of complete spontaneous regression of a localized MCC following a punch biopsy. The histopathology showed a brisk T-lymphocyte response with intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells. The age and clinical profile of our patient as well as the clinicopathologic characteristics of the tumor regression are similar to other reported cases. Further research is needed to elucidate the mechanism of MCC regression, and a better understanding of this fascinating phenomenon could help in development of new immunotherapeutic approaches.

Merkel cell carcinoma (MCC) is a rare, rapidly growing, aggressive neoplasm with a generally poor prognosis. The cells of origin are highly anaplastic and share structural and immunohistochemical features with various neuroectodermally derived cells. Although Merkel cells, which are slow-acting cutaneous mechanoreceptors located in the basal layer of the epidermis, and MCC share immunohistochemical and ultrastructural features, there is limited evidence of a direct histogenetic relationship between the two.^1,2 Additionally, some extracutaneous neuroendocrine tumors have features similar to MCC; therefore, although it may be more accurate and perhaps more practical to describe these lesions as primary neuroendocrine carcinomas of the skin, the term MCC is more commonly used both in the literature and in clinical practice.^1,2

Merkel cell carcinoma typically presents in the head and neck region in white patients older than 70 years of age and in the immunocompromised population.^3-6 The mean age of diagnosis is 76 years for women and 74 years for men.⁷ The incidence of MCC in the United States tripled over a 15-year period, and there are approximately 1500 new cases of MCC diagnosed each year, making it about 40 times less common than melanoma.⁸ The 5-year survival rate for patients without lymph node involvement is 75%, whereas the 5-year survival rate for patients with distant metastases is 25%.⁹

Merkel cell carcinoma is thought to develop through 1 of 2 distinct pathways. In a virally mediated pathway, which represents at least 80% of cases, the Merkel cell polyomavirus (MCV) monoclonally integrates into the host genome and promotes oncogenesis via altered p53 and retinoblastoma protein expression.^10-12 The remainder of cases are believed to develop via a nonvirally mediated pathway in which genetic anomalies, immune status, and environmental factors influence oncogenesis.^10-13

Due to the similarity between MCC and metastatic neuroendocrine neoplasms, especially small-cell lung carcinomas, immunohistochemistry is important in making the diagnosis. Cytokeratin 20 and neuron-specific enolase positivity and thyroid transcription factor 1 negativity are the most useful markers in identifying MCC.

Regression of MCC is a very rare and poorly understood event. A 2010 review of the literature described 22 cases of spontaneous regression.¹⁴ We report a rare case of rapid and complete regression of MCC following punch biopsy in a 96-year-old woman.

Case Report

A 96-year-old woman presented with a rapidly enlarging lesion overlying the suprasternal notch of 8 weeks’ duration (Figure 1). The lesion consisted of a 5.0×4.5-cm, friable, erythematous, flesh-colored nodule with ulceration and heavy crusting. Surrounding the nodule was an erythematous to violaceous patch extending to the anterior chest and bilateral supraclavicular area. No cervical or clavicular lymphadenopathy was observed. According to the patient’s caregiver, the lesion originated as a small, erythematous, scaly macule that rapidly increased in size over an 8-week period to a maximum of 5.0×4.5 cm at presentation. The lesion bled on 2 or 3 occasions during the 8-week period and was controlled with a warm compress. The patient’s caregiver had treated the lesion with topical tea tree oil (for malodor) and antibiotic ointment as needed. The clinical differential diagnosis included squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, cutaneous metastasis of a primary visceral malignancy, basal cell carcinoma, and MCC. Biopsy of the lesion was recommended at this time but the patient’s family declined.

A 4-mm punch biopsy was obtained at a follow-up visit 4 weeks later (12 weeks after the reported onset of the lesion). Hematoxylin and eosin staining showed a small-cell neoplasm with stippled nuclei and scant cytoplasm forming a nested and somewhat trabecular pattern. Mitotic activity, apoptosis, and nuclear molding also were present (Figure 2). The tumor cells were positive for cytokeratin 20 with a dotlike, paranuclear pattern (Figure 3). Staining for CAM 5.2 also was positive. Cytokeratin 5/6, human melanoma black 45, and leukocyte common antigen were negative. The immunophenotyping of the lymphocytic response to the tumor showed that the majority of intratumoral lymphocytes were CD8 positive (Figure 4). CD4-positive lymphocytes were predominantly seen at the periphery of the tumor nests without tumor infiltration (Figure 5). Based on these findings, a diagnosis of MCC was made. The patient’s family declined treatment based on her advanced age and current health status, which included advanced dementia.

Two weeks after the punch biopsy, the lesion had noticeably decreased in size and lost its dome-shaped appearance. Within 8 weeks after biopsy (20 weeks since the lesion first appeared), the lesion had completely resolved (Figure 6). The patient was lost to follow-up months later, but no recurrence of the lesion was reported.

 

Comment

Spontaneous regression is not unique to MCC, as this phenomenon also has been reported in keratoacanthoma, lymphoma, basal cell carcinoma, and melanoma.¹⁵ Complete spontaneous regression is defined as occurring in the absence of therapy that is intended to have a treatment effect.^15,16 Spontaneous regression is estimated to occur in malignant neoplasms at a rate of 1 case per 60,000 to 100,000 (approximately 0.0013% of all malignant neoplasms).¹⁷ Considering the reported prevalence of MCC and the number of cases that have been known to regress, the estimated incidence of complete spontaneous regression may be as high as 1.5%.¹⁴ Though spontaneous regression of MCC is more prevalent than expected, it still is considered a rare phenomenon. A 2010 review of the literature yielded 22 cases of complete spontaneous regression of MCC.¹⁴ No recurrences have been observed; however, follow-up was relatively short in some cases.

In a unique report by Bertolotti et al,¹⁸ a patient with MCC on the nasal tip presented 4 weeks after biopsy with complete spontaneous regression of the tumor, which was associated with bilateral cervical lymph node involvement as noted by hypermetabolic uptake on positron emission tomography scanning. The patient underwent radiation therapy and was disease free at 12 months’ follow-up.¹⁸

Complete spontaneous regression has been described in MCC patients with local disease, regional recurrences, and metastatic disease.¹⁹ In all reviewed cases, the regression is a fairly quick phenomenon occurring over the course of 1 to 5 months.^16,19,20,21 Our patient presented with advanced age and a tumor location characteristic of MCC. In our search of PubMed articles indexed for MEDLINE using the terms MCC, Merkel cell carcinoma, regression, and spontaneous regression, all but 1 case of MCC regression involved tumors that were located on the head.¹⁴

The histopathologic features observed in our case, specifically intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells, were similar to the findings in other reported cases. In one series of 2 cases, the one case showed scar tissue with a moderate, predominantly T-lymphocytic infiltrate and no tumor cells, and the second showed cellular proliferation in the deep dermis with dense lymphocytic infiltrates primarily composed of CD3-positive T cells.¹⁴ Other studies of regression of both localized and metastatic MCC demonstrated infiltration by CD4-positive, CD8-positive, and CD3-positive lymphocytes and foamy macrophages.^21-23

The discovery of the MCV was one of the most important advances in elucidating the pathogenesis of MCC.^10,24-26 Merkel cell polyomavirus DNA has been detected in a majority of MCC cases.^25,27 Viral integration has been shown to take place early, prior to tumor clonal expansion.¹⁰ Importantly, not all cases of MCC show MCV infection, and MCV infection is not exclusive to MCC.²⁸ Merkel cell polyomavirus is considered to be part of the normal human flora, and asymptomatic infection is quite common.²⁹ It has been identified in 80% of adults older than 50 years of age and, interestingly, in 35% of children by 13 years of age or younger.^30,31 It remains unclear what role the presence of MCV plays in determining MCC prognosis. Several reports have demonstrated lower disease-specific mortality associated with MCV-positive MCC.^32-35 In contrast, Schrama et al³⁶ correlated the MCV status of 174 MCC tumors and found no difference in clinical behavior or prognosis between MCV-positive and MCV-negative MCCs.

Immunosuppression also may play a role in the development of MCC.^5,25 There is increased prevalence of MCC in the human immunodeficiency virus–positive population, as well as in organ-transplant recipients and patients with leukemia. Chronic lymphocytic leukemia seems to be the most frequent neoplasia associated with development of MCC.³⁷

The mechanism of MCC regression remains unclear, but many investigators emphasize the importance of T-cell–mediated immunity.^{16,21-23,38,39} Apoptosis also has been shown to play an important role.⁴⁰ Our case showed tumor-infiltrating CD8-positive lymphocytes and CD4-positive lymphocytes present predominantly at the periphery of the tumor, with close proximity to the tumor nests but with no tumor infiltration (Figure 3). This distribution was consistently present in multiple sections of the tumor. These findings are consistent with prior reports of both CD4-positive and CD8-positive T lymphocytes associated with MCC regression. Our findings confirm that immune response may play an important role in spontaneous regression of MCC.

There is much speculation regarding the initial biopsy of an MCC lesion (or other traumatic event) and its role in tumor regression. Koba et al⁴¹ examined the effect of biopsy on CD8-positive lymphocytic infiltration of MCC tumor cells and found that biopsy does not commonly alter intratumoral CD8-positive infiltration. These findings suggest trauma does not directly induce immunologic recognition of this cancer.

Conclusion

We report a case of complete spontaneous regression of a localized MCC following a punch biopsy. The histopathology showed a brisk T-lymphocyte response with intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells. The age and clinical profile of our patient as well as the clinicopathologic characteristics of the tumor regression are similar to other reported cases. Further research is needed to elucidate the mechanism of MCC regression, and a better understanding of this fascinating phenomenon could help in development of new immunotherapeutic approaches.

Merkel cell carcinoma (MCC) is a rare, rapidly growing, aggressive neoplasm with a generally poor prognosis. The cells of origin are highly anaplastic and share structural and immunohistochemical features with various neuroectodermally derived cells. Although Merkel cells, which are slow-acting cutaneous mechanoreceptors located in the basal layer of the epidermis, and MCC share immunohistochemical and ultrastructural features, there is limited evidence of a direct histogenetic relationship between the two.^1,2 Additionally, some extracutaneous neuroendocrine tumors have features similar to MCC; therefore, although it may be more accurate and perhaps more practical to describe these lesions as primary neuroendocrine carcinomas of the skin, the term MCC is more commonly used both in the literature and in clinical practice.^1,2

Merkel cell carcinoma typically presents in the head and neck region in white patients older than 70 years of age and in the immunocompromised population.^3-6 The mean age of diagnosis is 76 years for women and 74 years for men.⁷ The incidence of MCC in the United States tripled over a 15-year period, and there are approximately 1500 new cases of MCC diagnosed each year, making it about 40 times less common than melanoma.⁸ The 5-year survival rate for patients without lymph node involvement is 75%, whereas the 5-year survival rate for patients with distant metastases is 25%.⁹

Merkel cell carcinoma is thought to develop through 1 of 2 distinct pathways. In a virally mediated pathway, which represents at least 80% of cases, the Merkel cell polyomavirus (MCV) monoclonally integrates into the host genome and promotes oncogenesis via altered p53 and retinoblastoma protein expression.^10-12 The remainder of cases are believed to develop via a nonvirally mediated pathway in which genetic anomalies, immune status, and environmental factors influence oncogenesis.^10-13

Due to the similarity between MCC and metastatic neuroendocrine neoplasms, especially small-cell lung carcinomas, immunohistochemistry is important in making the diagnosis. Cytokeratin 20 and neuron-specific enolase positivity and thyroid transcription factor 1 negativity are the most useful markers in identifying MCC.

Regression of MCC is a very rare and poorly understood event. A 2010 review of the literature described 22 cases of spontaneous regression.¹⁴ We report a rare case of rapid and complete regression of MCC following punch biopsy in a 96-year-old woman.

Case Report

A 96-year-old woman presented with a rapidly enlarging lesion overlying the suprasternal notch of 8 weeks’ duration (Figure 1). The lesion consisted of a 5.0×4.5-cm, friable, erythematous, flesh-colored nodule with ulceration and heavy crusting. Surrounding the nodule was an erythematous to violaceous patch extending to the anterior chest and bilateral supraclavicular area. No cervical or clavicular lymphadenopathy was observed. According to the patient’s caregiver, the lesion originated as a small, erythematous, scaly macule that rapidly increased in size over an 8-week period to a maximum of 5.0×4.5 cm at presentation. The lesion bled on 2 or 3 occasions during the 8-week period and was controlled with a warm compress. The patient’s caregiver had treated the lesion with topical tea tree oil (for malodor) and antibiotic ointment as needed. The clinical differential diagnosis included squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, cutaneous metastasis of a primary visceral malignancy, basal cell carcinoma, and MCC. Biopsy of the lesion was recommended at this time but the patient’s family declined.

A 4-mm punch biopsy was obtained at a follow-up visit 4 weeks later (12 weeks after the reported onset of the lesion). Hematoxylin and eosin staining showed a small-cell neoplasm with stippled nuclei and scant cytoplasm forming a nested and somewhat trabecular pattern. Mitotic activity, apoptosis, and nuclear molding also were present (Figure 2). The tumor cells were positive for cytokeratin 20 with a dotlike, paranuclear pattern (Figure 3). Staining for CAM 5.2 also was positive. Cytokeratin 5/6, human melanoma black 45, and leukocyte common antigen were negative. The immunophenotyping of the lymphocytic response to the tumor showed that the majority of intratumoral lymphocytes were CD8 positive (Figure 4). CD4-positive lymphocytes were predominantly seen at the periphery of the tumor nests without tumor infiltration (Figure 5). Based on these findings, a diagnosis of MCC was made. The patient’s family declined treatment based on her advanced age and current health status, which included advanced dementia.

Two weeks after the punch biopsy, the lesion had noticeably decreased in size and lost its dome-shaped appearance. Within 8 weeks after biopsy (20 weeks since the lesion first appeared), the lesion had completely resolved (Figure 6). The patient was lost to follow-up months later, but no recurrence of the lesion was reported.

 

Comment

Spontaneous regression is not unique to MCC, as this phenomenon also has been reported in keratoacanthoma, lymphoma, basal cell carcinoma, and melanoma.¹⁵ Complete spontaneous regression is defined as occurring in the absence of therapy that is intended to have a treatment effect.^15,16 Spontaneous regression is estimated to occur in malignant neoplasms at a rate of 1 case per 60,000 to 100,000 (approximately 0.0013% of all malignant neoplasms).¹⁷ Considering the reported prevalence of MCC and the number of cases that have been known to regress, the estimated incidence of complete spontaneous regression may be as high as 1.5%.¹⁴ Though spontaneous regression of MCC is more prevalent than expected, it still is considered a rare phenomenon. A 2010 review of the literature yielded 22 cases of complete spontaneous regression of MCC.¹⁴ No recurrences have been observed; however, follow-up was relatively short in some cases.

In a unique report by Bertolotti et al,¹⁸ a patient with MCC on the nasal tip presented 4 weeks after biopsy with complete spontaneous regression of the tumor, which was associated with bilateral cervical lymph node involvement as noted by hypermetabolic uptake on positron emission tomography scanning. The patient underwent radiation therapy and was disease free at 12 months’ follow-up.¹⁸

Complete spontaneous regression has been described in MCC patients with local disease, regional recurrences, and metastatic disease.¹⁹ In all reviewed cases, the regression is a fairly quick phenomenon occurring over the course of 1 to 5 months.^16,19,20,21 Our patient presented with advanced age and a tumor location characteristic of MCC. In our search of PubMed articles indexed for MEDLINE using the terms MCC, Merkel cell carcinoma, regression, and spontaneous regression, all but 1 case of MCC regression involved tumors that were located on the head.¹⁴

The histopathologic features observed in our case, specifically intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells, were similar to the findings in other reported cases. In one series of 2 cases, the one case showed scar tissue with a moderate, predominantly T-lymphocytic infiltrate and no tumor cells, and the second showed cellular proliferation in the deep dermis with dense lymphocytic infiltrates primarily composed of CD3-positive T cells.¹⁴ Other studies of regression of both localized and metastatic MCC demonstrated infiltration by CD4-positive, CD8-positive, and CD3-positive lymphocytes and foamy macrophages.^21-23

The discovery of the MCV was one of the most important advances in elucidating the pathogenesis of MCC.^10,24-26 Merkel cell polyomavirus DNA has been detected in a majority of MCC cases.^25,27 Viral integration has been shown to take place early, prior to tumor clonal expansion.¹⁰ Importantly, not all cases of MCC show MCV infection, and MCV infection is not exclusive to MCC.²⁸ Merkel cell polyomavirus is considered to be part of the normal human flora, and asymptomatic infection is quite common.²⁹ It has been identified in 80% of adults older than 50 years of age and, interestingly, in 35% of children by 13 years of age or younger.^30,31 It remains unclear what role the presence of MCV plays in determining MCC prognosis. Several reports have demonstrated lower disease-specific mortality associated with MCV-positive MCC.^32-35 In contrast, Schrama et al³⁶ correlated the MCV status of 174 MCC tumors and found no difference in clinical behavior or prognosis between MCV-positive and MCV-negative MCCs.

Immunosuppression also may play a role in the development of MCC.^5,25 There is increased prevalence of MCC in the human immunodeficiency virus–positive population, as well as in organ-transplant recipients and patients with leukemia. Chronic lymphocytic leukemia seems to be the most frequent neoplasia associated with development of MCC.³⁷

The mechanism of MCC regression remains unclear, but many investigators emphasize the importance of T-cell–mediated immunity.^{16,21-23,38,39} Apoptosis also has been shown to play an important role.⁴⁰ Our case showed tumor-infiltrating CD8-positive lymphocytes and CD4-positive lymphocytes present predominantly at the periphery of the tumor, with close proximity to the tumor nests but with no tumor infiltration (Figure 3). This distribution was consistently present in multiple sections of the tumor. These findings are consistent with prior reports of both CD4-positive and CD8-positive T lymphocytes associated with MCC regression. Our findings confirm that immune response may play an important role in spontaneous regression of MCC.

There is much speculation regarding the initial biopsy of an MCC lesion (or other traumatic event) and its role in tumor regression. Koba et al⁴¹ examined the effect of biopsy on CD8-positive lymphocytic infiltration of MCC tumor cells and found that biopsy does not commonly alter intratumoral CD8-positive infiltration. These findings suggest trauma does not directly induce immunologic recognition of this cancer.

Conclusion

We report a case of complete spontaneous regression of a localized MCC following a punch biopsy. The histopathology showed a brisk T-lymphocyte response with intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells. The age and clinical profile of our patient as well as the clinicopathologic characteristics of the tumor regression are similar to other reported cases. Further research is needed to elucidate the mechanism of MCC regression, and a better understanding of this fascinating phenomenon could help in development of new immunotherapeutic approaches.

Progressive macular hypomelanosis (PMH) is a noninflammatory skin disorder characterized by ill-defined, nummular, hypopigmented, and nonscaly macules. Historically, various names have been used to describe this entity. Several of these terms, including cutis trunci variata and nummular and confluent hypomelanosis of the trunk, reflected its predominantly truncal distribution.^1,2 Less frequently, involvement on the neck, buttocks, and arms and legs has been noted.^1,2 A lack of facial involvement previously has been highlighted as a key clinical feature of PMH.³

Progressive macular hypomelanosis is a diagnosis of exclusion. Hypopigmented diseases commonly considered in the differential include those caused by fungi and yeasts (eg, tinea versicolor, seborrheic dermatitis), inflammatory skin disorders (eg, pityriasis alba, postinflammatory dyschromia), and mycosis fungoides (MF) as well as leprosy.

The hypopigmented macules of PMH have nonspecific histopathologic findings; lesional skin often shows minimal alterations as compared to normal skin. A sparse perivascular lymphocytic infiltrate often is observed,^4,5 and at times, a decrease in epidermal melanin content can be detected.^1-3,6,7

We report 4 cases with considerable facial involvement of hypopigmented macules that were determined to be consistent with PMH. We propose that characteristic macules that are not clinically or histopathologically consistent with other disease entities are compatible with a diagnosis of PMH, regardless of the distribution. A diagnosis of PMH should be considered in the differential when there are suggestive facial lesions in addition to truncal lesions.

Case Reports

Patient 1
A 40-year-old man presented with hypopigmented macules on the face (Figure 1), trunk, chest, arms, and legs of 2 years’ duration. The lesions were asymptomatic and had started on the forehead as hypopigmented macules, then progressed to the trunk, arms, and legs. The patient denied any prior rash, injury, or hyperpigmentation associated with the distribution of the lesions.

A rapid plasma reagin (RPR) test was conducted to rule out secondary syphilis and was nonreactive. During a series of clinical encounters over several months, a total of 5 biopsies of lesions on the face and back were performed. All specimens contained mild mononuclear perivascular inflammation (Figure 2). In some foci, staining for Melan-A revealed a decrease in epidermal melanocytes (Figure 3). Periodic acid–Schiff staining performed on one section revealed a few pityriasis spores but no hyphal elements, suggesting colonization rather than infection.

The patient initially was started on tacrolimus ointment 0.1% once daily and narrowband UVB phototherapy twice weekly for 3 months without benefit. A diagnosis of tinea versicolor was revisited and the patient was switched to ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing, and ketoconazole cream 2% was applied twice daily to the affected areas for 2 months without notable improvement. Once-weekly 150-mg pulse doses of oral fluconazole for 8 weeks were started but proved equally ineffective. Antibiotic therapy aimed at eradicating Propionibacterium acnes was considered following a provisional diagnosis of PMH after the patient failed 5 months of therapy for tinea versicolor.

Patient 2
A 54-year-old man presented with hypopigmented to depigmented nonscaly macules on the face, trunk, chest, and arms of several months’ duration. The patient initially noted hypopigmentation on the face that gradually spread to the rest of the body. The patient denied any prior rash or hyperpigmentation in the affected areas. At the initial visit to our clinic, a potassium hydroxide (KOH) preparation of the face and back was positive for tinea versicolor. The patient was treated with ketoconazole shampoo 1% two to 3 times weekly for several weeks on the scalp, face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and 2 total doses of oral fluconazole 150 mg taken 1 week apart.

Three months later the patient returned with no improvement of the existing lesions and with progression of the disease to previously uninvolved areas of the trunk, arms, and legs. Biopsy of a facial lesion was performed, and laboratory studies including RPR, thyroid-stimulating hormone, and antinuclear antibody tests were conducted to screen for possible systemic disease. Microscopic analysis of the biopsied facial lesion revealed a sparse perivascular infiltrate of lymphocytes and plasma cells but no evidence of yeast or hyphal elements. Melan-A staining did not reveal a decreased number of epidermal melanocytes. All laboratory studies were negative or within normal limits. Desonide ointment 0.05% was prescribed to relieve the patient’s occasional pruritus. Although the patient’s symptoms resolved, the hypopigmented macules continued to progress, making a diagnosis of PMH more likely given the lack of improvement on treatment for tinea versicolor. Pimecrolimus cream 1% was started with discontinuation of desonide for steroid-sparing therapy.

Patient 3
A 63-year-old man presented with progressive nonscaly and asymptomatic hypopigmented macules on the face, trunk, abdomen, and back of 5 years’ duration. He first noted lesions on the abdomen and they subsequently spread to the rest of the body. The patient denied any prior rash, hyperpigmentation, or other lesions in the involved areas.

One year prior to the current presentation, KOH scrapings from the lesions performed by an outside physician were negative. During his initial visit to our clinic, an abdominal biopsy was performed, and histopathologic analysis showed postinflammatory pigmentary alteration; however, the patient denied any prior history of rash or injury in the distribution of the lesions that would correlate with the histopathologic findings of postinflammatory pigmentation. Because the histopathologic findings showed postinflammatory pigmentary alteration, additional stains including Melan-A were not performed.

The patient was provisionally treated with ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and ketoconazole cream 2% twice daily to the affected areas. After several months on this regimen, the patient did not report any improvement. An abdominal skin biopsy was again performed and revealed similar histopathology. Periodic acid–Schiff staining was negative for fungus. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin lotion.

Patient 4
A 45-year-old woman presented with hypopigmented, nonscaly macules on the face, neck, chest, trunk, and back. She first noted the lesions on the face and trunk more than 8 years prior, and they subsequently progressed. Potassium hydroxide scrapings performed on the lesions at the current presentation were negative, and a skin biopsy from the neck revealed postinflammatory pigmentary alteration, although the patient had no history of rash or injury in the areas in which the lesions were distributed.

Fontana-Masson and Melan-A staining of the skin biopsy of the neck revealed a normal distribution of melanocytes and pigment at the dermoepidermal junction. An RPR test was nonreactive. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin phosphate lotion 1%.

 

Comment

The 4 cases of PMH reported here showed extensive facial involvement in addition to the characteristic hypopigmented lesions on the trunk, arms, and legs. It is unclear why the lesions in these patients had a predominantly facial distribution. Involvement of the face in PMH has not been commonly reported in the literature. Martínez-Martínez et al³ reported 12 PMH patients with lesions only presenting in lumbar and abdominal distributions. Kim et al⁸ presented a series of 23 PMH patients treated with narrowband UVB in whom 56% (9/16) saw repigmentation in 90% of the lesions following treatment. The most commonly affected area was the lower back, followed by the abdomen, upper back, chest, sacral region, flank, and shoulders, respectively.⁸ In a review by Relyveld et al,¹ PMH is described as a predominantly truncal disease that can occasionally extend to the neck, face, and proximal arms and legs; however, no specific cases were reported.

Previous case series have reported PMH primarily in adolescents and young adults, with mean ages ranging from 26 to 30 years.^1,3 The 4 patients reported here were older, ranging in age from 40 to 65 years. This discrepancy in age may contribute to the facial distribution encountered in this patient population; however, given the small number of patients in our case series, such extrapolation is premature. Most recently, Westerhof et al⁶ demonstrated a relationship between the presence of P acnes, a common skin commensal of the face, and the hypopigmented macules of PMH. The investigators suggested that some strains of P acnes produce a factor that is yet to be identified that interferes with melanogenesis. The response of PMH lesions to topical treatments such as benzoyl peroxide, clindamycin, and phototherapy has lent credence to the potential etiologic role of P acnes in this condition.^9,10 The interplay between age, PMH distribution, and P acnes requires further investigation.

The biopsies in our 4 patients were consistent with the nonspecific histopathologic characteristics of PMH lesions. Biopsies in all 4 patients revealed a sparse perivascular lymphocytic infiltrate, and in 2 of the cases, postinflammatory pigmentary alteration was noted. Such changes often are described in PMH lesions.^4,5 In other cases detailed in the literature, lesional and nonlesional skin often are indistinguishable on hematoxylin and eosin staining.¹¹ In the 3 patients for whom we performed additional immunohistochemical studies, results were mixed: Melan-A staining revealed a decreased number of melanocytes in Patient 1 but not in Patients 2 or 4. Many reported cases in the literature have not demonstrated a decrease in melanocyte density but instead show a decrease in melanin content in lesional skin.^1-3,6,7 Although additional stains performed in Patient 4 revealed neither a decrease in the number of melanocytes nor a decrease in the melanin content, such histopathologic findings of PMH often are subtle. Additional stains were not performed in Patient 3. More studies are needed to characterize the immunohistochemical staining patterns of lesional skin in patients with PMH.

Tinea versicolor, pityriasis alba, mycosis fungoides, sarcoidosis, leprosy, and syphilis typically are included in the differential diagnosis for PMH. Tinea versicolor traditionally is diagnosed based on the combination of irregular hypopigmented or hyperpigmented scaly macules and a KOH preparation that is positive for hyphae and spores. Similar to PMH, tinea versicolor is most often found on the trunk, but unusual cases have been reported involving the face.¹²

Patient 2 reflected how it can be difficult diagnostically to distinguish between tinea versicolor and PMH. Although this patient initially had a KOH scraping suggestive for tinea versicolor, adequate treatment with oral fluconazole and ketoconazole shampoo did not result in improvement. The hypopigmented lesions in this patient continued to progress despite therapy. Additionally, his hypopigmented to depigmented nonscaly macules were more clinically consistent with the characteristic description of lesion configuration in PMH than with the irregular, more sharply defined, asymmetric, and scaly spots of tinea versicolor. Furthermore, the inflammatory findings on biopsy favored a diagnosis of PMH.

Pityriasis alba, most frequently presents on the face in the form of hypopigmented, sometimes slightly scaly macules but also can occur on the body. It usually occurs in younger patients who often have an atopic diathesis. Histologic findings generally are nonspecific, but discrete eczematous changes can sometimes be appreciated in the epidermis and dermis. None of our patients had histories suggestive of an atopic diathesis or lesion distributions typical of pityriasis alba. Histologic findings also were more consistent with PMH than pityriasis alba.

A diagnosis of patch-stage hypopigmented MF should also be entertained in patients with hypopigmented macules, as it can appear similar to the lesions of PMH. Hypopigmented MF often is associated with subtle atrophy, scaling, poikiloderma, and erythema. These features were not present in the 4 cases presented here. Histologically, atypical lymphocytes with prominent epidermotropism and tagging of the epidermis by large lymphocytic infiltrates are seen in cases of hypopigmented MF. These findings were not present in biopsies from our patients.

Hypopigmented sarcoidosis, leprosy, and syphilis are other systemic diseases associated with hypopigmented lesions. Histologically, noncaseasting granulomas in the dermis or subcutaneous tissue would favor a diagnosis of sarcoidosis over PMH. In patients who live in endemic areas, a diagnosis of leprosy for an anesthetic hypopigmented lesion would be higher in the differential. Finally, it is important to rule out secondary syphilis when diagnosing PMH. Known as the great imitator, secondary syphilis may present in a patient in the form of hypopigmented macules. Patients 1, 2, and 4 had nonreactive RPR tests; unfortunately, RPR was not checked in Patient 3. He denied all risk factors for syphilis.

Various topical and oral treatments were prescribed for each patient, but so far none have been unequivocally effective. In the literature, there are reports supporting the efficacy of topical antimicrobial agents targeting P acnes.^9,10 One case report noted improvement in a patient with PMH after isotretinoin use.¹³ Phototherapy also has been reported to improve PMH in several case reports^4-8; however, consistent response to these therapies has not been documented. Unfortunately for patients with a diagnosis of PMH, a lack of effective treatment options often exists.

This series of 4 cases highlights the importance of considering PMH in the differential of hypopigmented macules, even when they appear predominantly on the face.

Progressive macular hypomelanosis (PMH) is a noninflammatory skin disorder characterized by ill-defined, nummular, hypopigmented, and nonscaly macules. Historically, various names have been used to describe this entity. Several of these terms, including cutis trunci variata and nummular and confluent hypomelanosis of the trunk, reflected its predominantly truncal distribution.^1,2 Less frequently, involvement on the neck, buttocks, and arms and legs has been noted.^1,2 A lack of facial involvement previously has been highlighted as a key clinical feature of PMH.³

Progressive macular hypomelanosis is a diagnosis of exclusion. Hypopigmented diseases commonly considered in the differential include those caused by fungi and yeasts (eg, tinea versicolor, seborrheic dermatitis), inflammatory skin disorders (eg, pityriasis alba, postinflammatory dyschromia), and mycosis fungoides (MF) as well as leprosy.

The hypopigmented macules of PMH have nonspecific histopathologic findings; lesional skin often shows minimal alterations as compared to normal skin. A sparse perivascular lymphocytic infiltrate often is observed,^4,5 and at times, a decrease in epidermal melanin content can be detected.^1-3,6,7

We report 4 cases with considerable facial involvement of hypopigmented macules that were determined to be consistent with PMH. We propose that characteristic macules that are not clinically or histopathologically consistent with other disease entities are compatible with a diagnosis of PMH, regardless of the distribution. A diagnosis of PMH should be considered in the differential when there are suggestive facial lesions in addition to truncal lesions.

Case Reports

Patient 1
A 40-year-old man presented with hypopigmented macules on the face (Figure 1), trunk, chest, arms, and legs of 2 years’ duration. The lesions were asymptomatic and had started on the forehead as hypopigmented macules, then progressed to the trunk, arms, and legs. The patient denied any prior rash, injury, or hyperpigmentation associated with the distribution of the lesions.

A rapid plasma reagin (RPR) test was conducted to rule out secondary syphilis and was nonreactive. During a series of clinical encounters over several months, a total of 5 biopsies of lesions on the face and back were performed. All specimens contained mild mononuclear perivascular inflammation (Figure 2). In some foci, staining for Melan-A revealed a decrease in epidermal melanocytes (Figure 3). Periodic acid–Schiff staining performed on one section revealed a few pityriasis spores but no hyphal elements, suggesting colonization rather than infection.

The patient initially was started on tacrolimus ointment 0.1% once daily and narrowband UVB phototherapy twice weekly for 3 months without benefit. A diagnosis of tinea versicolor was revisited and the patient was switched to ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing, and ketoconazole cream 2% was applied twice daily to the affected areas for 2 months without notable improvement. Once-weekly 150-mg pulse doses of oral fluconazole for 8 weeks were started but proved equally ineffective. Antibiotic therapy aimed at eradicating Propionibacterium acnes was considered following a provisional diagnosis of PMH after the patient failed 5 months of therapy for tinea versicolor.

Patient 2
A 54-year-old man presented with hypopigmented to depigmented nonscaly macules on the face, trunk, chest, and arms of several months’ duration. The patient initially noted hypopigmentation on the face that gradually spread to the rest of the body. The patient denied any prior rash or hyperpigmentation in the affected areas. At the initial visit to our clinic, a potassium hydroxide (KOH) preparation of the face and back was positive for tinea versicolor. The patient was treated with ketoconazole shampoo 1% two to 3 times weekly for several weeks on the scalp, face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and 2 total doses of oral fluconazole 150 mg taken 1 week apart.

Three months later the patient returned with no improvement of the existing lesions and with progression of the disease to previously uninvolved areas of the trunk, arms, and legs. Biopsy of a facial lesion was performed, and laboratory studies including RPR, thyroid-stimulating hormone, and antinuclear antibody tests were conducted to screen for possible systemic disease. Microscopic analysis of the biopsied facial lesion revealed a sparse perivascular infiltrate of lymphocytes and plasma cells but no evidence of yeast or hyphal elements. Melan-A staining did not reveal a decreased number of epidermal melanocytes. All laboratory studies were negative or within normal limits. Desonide ointment 0.05% was prescribed to relieve the patient’s occasional pruritus. Although the patient’s symptoms resolved, the hypopigmented macules continued to progress, making a diagnosis of PMH more likely given the lack of improvement on treatment for tinea versicolor. Pimecrolimus cream 1% was started with discontinuation of desonide for steroid-sparing therapy.

Patient 3
A 63-year-old man presented with progressive nonscaly and asymptomatic hypopigmented macules on the face, trunk, abdomen, and back of 5 years’ duration. He first noted lesions on the abdomen and they subsequently spread to the rest of the body. The patient denied any prior rash, hyperpigmentation, or other lesions in the involved areas.

One year prior to the current presentation, KOH scrapings from the lesions performed by an outside physician were negative. During his initial visit to our clinic, an abdominal biopsy was performed, and histopathologic analysis showed postinflammatory pigmentary alteration; however, the patient denied any prior history of rash or injury in the distribution of the lesions that would correlate with the histopathologic findings of postinflammatory pigmentation. Because the histopathologic findings showed postinflammatory pigmentary alteration, additional stains including Melan-A were not performed.

The patient was provisionally treated with ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and ketoconazole cream 2% twice daily to the affected areas. After several months on this regimen, the patient did not report any improvement. An abdominal skin biopsy was again performed and revealed similar histopathology. Periodic acid–Schiff staining was negative for fungus. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin lotion.

Patient 4
A 45-year-old woman presented with hypopigmented, nonscaly macules on the face, neck, chest, trunk, and back. She first noted the lesions on the face and trunk more than 8 years prior, and they subsequently progressed. Potassium hydroxide scrapings performed on the lesions at the current presentation were negative, and a skin biopsy from the neck revealed postinflammatory pigmentary alteration, although the patient had no history of rash or injury in the areas in which the lesions were distributed.

Fontana-Masson and Melan-A staining of the skin biopsy of the neck revealed a normal distribution of melanocytes and pigment at the dermoepidermal junction. An RPR test was nonreactive. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin phosphate lotion 1%.

 

Comment

The 4 cases of PMH reported here showed extensive facial involvement in addition to the characteristic hypopigmented lesions on the trunk, arms, and legs. It is unclear why the lesions in these patients had a predominantly facial distribution. Involvement of the face in PMH has not been commonly reported in the literature. Martínez-Martínez et al³ reported 12 PMH patients with lesions only presenting in lumbar and abdominal distributions. Kim et al⁸ presented a series of 23 PMH patients treated with narrowband UVB in whom 56% (9/16) saw repigmentation in 90% of the lesions following treatment. The most commonly affected area was the lower back, followed by the abdomen, upper back, chest, sacral region, flank, and shoulders, respectively.⁸ In a review by Relyveld et al,¹ PMH is described as a predominantly truncal disease that can occasionally extend to the neck, face, and proximal arms and legs; however, no specific cases were reported.

Previous case series have reported PMH primarily in adolescents and young adults, with mean ages ranging from 26 to 30 years.^1,3 The 4 patients reported here were older, ranging in age from 40 to 65 years. This discrepancy in age may contribute to the facial distribution encountered in this patient population; however, given the small number of patients in our case series, such extrapolation is premature. Most recently, Westerhof et al⁶ demonstrated a relationship between the presence of P acnes, a common skin commensal of the face, and the hypopigmented macules of PMH. The investigators suggested that some strains of P acnes produce a factor that is yet to be identified that interferes with melanogenesis. The response of PMH lesions to topical treatments such as benzoyl peroxide, clindamycin, and phototherapy has lent credence to the potential etiologic role of P acnes in this condition.^9,10 The interplay between age, PMH distribution, and P acnes requires further investigation.

The biopsies in our 4 patients were consistent with the nonspecific histopathologic characteristics of PMH lesions. Biopsies in all 4 patients revealed a sparse perivascular lymphocytic infiltrate, and in 2 of the cases, postinflammatory pigmentary alteration was noted. Such changes often are described in PMH lesions.^4,5 In other cases detailed in the literature, lesional and nonlesional skin often are indistinguishable on hematoxylin and eosin staining.¹¹ In the 3 patients for whom we performed additional immunohistochemical studies, results were mixed: Melan-A staining revealed a decreased number of melanocytes in Patient 1 but not in Patients 2 or 4. Many reported cases in the literature have not demonstrated a decrease in melanocyte density but instead show a decrease in melanin content in lesional skin.^1-3,6,7 Although additional stains performed in Patient 4 revealed neither a decrease in the number of melanocytes nor a decrease in the melanin content, such histopathologic findings of PMH often are subtle. Additional stains were not performed in Patient 3. More studies are needed to characterize the immunohistochemical staining patterns of lesional skin in patients with PMH.

Tinea versicolor, pityriasis alba, mycosis fungoides, sarcoidosis, leprosy, and syphilis typically are included in the differential diagnosis for PMH. Tinea versicolor traditionally is diagnosed based on the combination of irregular hypopigmented or hyperpigmented scaly macules and a KOH preparation that is positive for hyphae and spores. Similar to PMH, tinea versicolor is most often found on the trunk, but unusual cases have been reported involving the face.¹²

Patient 2 reflected how it can be difficult diagnostically to distinguish between tinea versicolor and PMH. Although this patient initially had a KOH scraping suggestive for tinea versicolor, adequate treatment with oral fluconazole and ketoconazole shampoo did not result in improvement. The hypopigmented lesions in this patient continued to progress despite therapy. Additionally, his hypopigmented to depigmented nonscaly macules were more clinically consistent with the characteristic description of lesion configuration in PMH than with the irregular, more sharply defined, asymmetric, and scaly spots of tinea versicolor. Furthermore, the inflammatory findings on biopsy favored a diagnosis of PMH.

Pityriasis alba, most frequently presents on the face in the form of hypopigmented, sometimes slightly scaly macules but also can occur on the body. It usually occurs in younger patients who often have an atopic diathesis. Histologic findings generally are nonspecific, but discrete eczematous changes can sometimes be appreciated in the epidermis and dermis. None of our patients had histories suggestive of an atopic diathesis or lesion distributions typical of pityriasis alba. Histologic findings also were more consistent with PMH than pityriasis alba.

A diagnosis of patch-stage hypopigmented MF should also be entertained in patients with hypopigmented macules, as it can appear similar to the lesions of PMH. Hypopigmented MF often is associated with subtle atrophy, scaling, poikiloderma, and erythema. These features were not present in the 4 cases presented here. Histologically, atypical lymphocytes with prominent epidermotropism and tagging of the epidermis by large lymphocytic infiltrates are seen in cases of hypopigmented MF. These findings were not present in biopsies from our patients.

Hypopigmented sarcoidosis, leprosy, and syphilis are other systemic diseases associated with hypopigmented lesions. Histologically, noncaseasting granulomas in the dermis or subcutaneous tissue would favor a diagnosis of sarcoidosis over PMH. In patients who live in endemic areas, a diagnosis of leprosy for an anesthetic hypopigmented lesion would be higher in the differential. Finally, it is important to rule out secondary syphilis when diagnosing PMH. Known as the great imitator, secondary syphilis may present in a patient in the form of hypopigmented macules. Patients 1, 2, and 4 had nonreactive RPR tests; unfortunately, RPR was not checked in Patient 3. He denied all risk factors for syphilis.

Various topical and oral treatments were prescribed for each patient, but so far none have been unequivocally effective. In the literature, there are reports supporting the efficacy of topical antimicrobial agents targeting P acnes.^9,10 One case report noted improvement in a patient with PMH after isotretinoin use.¹³ Phototherapy also has been reported to improve PMH in several case reports^4-8; however, consistent response to these therapies has not been documented. Unfortunately for patients with a diagnosis of PMH, a lack of effective treatment options often exists.

This series of 4 cases highlights the importance of considering PMH in the differential of hypopigmented macules, even when they appear predominantly on the face.

Progressive macular hypomelanosis (PMH) is a noninflammatory skin disorder characterized by ill-defined, nummular, hypopigmented, and nonscaly macules. Historically, various names have been used to describe this entity. Several of these terms, including cutis trunci variata and nummular and confluent hypomelanosis of the trunk, reflected its predominantly truncal distribution.^1,2 Less frequently, involvement on the neck, buttocks, and arms and legs has been noted.^1,2 A lack of facial involvement previously has been highlighted as a key clinical feature of PMH.³

Progressive macular hypomelanosis is a diagnosis of exclusion. Hypopigmented diseases commonly considered in the differential include those caused by fungi and yeasts (eg, tinea versicolor, seborrheic dermatitis), inflammatory skin disorders (eg, pityriasis alba, postinflammatory dyschromia), and mycosis fungoides (MF) as well as leprosy.

The hypopigmented macules of PMH have nonspecific histopathologic findings; lesional skin often shows minimal alterations as compared to normal skin. A sparse perivascular lymphocytic infiltrate often is observed,^4,5 and at times, a decrease in epidermal melanin content can be detected.^1-3,6,7

We report 4 cases with considerable facial involvement of hypopigmented macules that were determined to be consistent with PMH. We propose that characteristic macules that are not clinically or histopathologically consistent with other disease entities are compatible with a diagnosis of PMH, regardless of the distribution. A diagnosis of PMH should be considered in the differential when there are suggestive facial lesions in addition to truncal lesions.

Case Reports

Patient 1
A 40-year-old man presented with hypopigmented macules on the face (Figure 1), trunk, chest, arms, and legs of 2 years’ duration. The lesions were asymptomatic and had started on the forehead as hypopigmented macules, then progressed to the trunk, arms, and legs. The patient denied any prior rash, injury, or hyperpigmentation associated with the distribution of the lesions.

A rapid plasma reagin (RPR) test was conducted to rule out secondary syphilis and was nonreactive. During a series of clinical encounters over several months, a total of 5 biopsies of lesions on the face and back were performed. All specimens contained mild mononuclear perivascular inflammation (Figure 2). In some foci, staining for Melan-A revealed a decrease in epidermal melanocytes (Figure 3). Periodic acid–Schiff staining performed on one section revealed a few pityriasis spores but no hyphal elements, suggesting colonization rather than infection.

The patient initially was started on tacrolimus ointment 0.1% once daily and narrowband UVB phototherapy twice weekly for 3 months without benefit. A diagnosis of tinea versicolor was revisited and the patient was switched to ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing, and ketoconazole cream 2% was applied twice daily to the affected areas for 2 months without notable improvement. Once-weekly 150-mg pulse doses of oral fluconazole for 8 weeks were started but proved equally ineffective. Antibiotic therapy aimed at eradicating Propionibacterium acnes was considered following a provisional diagnosis of PMH after the patient failed 5 months of therapy for tinea versicolor.

Patient 2
A 54-year-old man presented with hypopigmented to depigmented nonscaly macules on the face, trunk, chest, and arms of several months’ duration. The patient initially noted hypopigmentation on the face that gradually spread to the rest of the body. The patient denied any prior rash or hyperpigmentation in the affected areas. At the initial visit to our clinic, a potassium hydroxide (KOH) preparation of the face and back was positive for tinea versicolor. The patient was treated with ketoconazole shampoo 1% two to 3 times weekly for several weeks on the scalp, face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and 2 total doses of oral fluconazole 150 mg taken 1 week apart.

Three months later the patient returned with no improvement of the existing lesions and with progression of the disease to previously uninvolved areas of the trunk, arms, and legs. Biopsy of a facial lesion was performed, and laboratory studies including RPR, thyroid-stimulating hormone, and antinuclear antibody tests were conducted to screen for possible systemic disease. Microscopic analysis of the biopsied facial lesion revealed a sparse perivascular infiltrate of lymphocytes and plasma cells but no evidence of yeast or hyphal elements. Melan-A staining did not reveal a decreased number of epidermal melanocytes. All laboratory studies were negative or within normal limits. Desonide ointment 0.05% was prescribed to relieve the patient’s occasional pruritus. Although the patient’s symptoms resolved, the hypopigmented macules continued to progress, making a diagnosis of PMH more likely given the lack of improvement on treatment for tinea versicolor. Pimecrolimus cream 1% was started with discontinuation of desonide for steroid-sparing therapy.

Patient 3
A 63-year-old man presented with progressive nonscaly and asymptomatic hypopigmented macules on the face, trunk, abdomen, and back of 5 years’ duration. He first noted lesions on the abdomen and they subsequently spread to the rest of the body. The patient denied any prior rash, hyperpigmentation, or other lesions in the involved areas.

One year prior to the current presentation, KOH scrapings from the lesions performed by an outside physician were negative. During his initial visit to our clinic, an abdominal biopsy was performed, and histopathologic analysis showed postinflammatory pigmentary alteration; however, the patient denied any prior history of rash or injury in the distribution of the lesions that would correlate with the histopathologic findings of postinflammatory pigmentation. Because the histopathologic findings showed postinflammatory pigmentary alteration, additional stains including Melan-A were not performed.

The patient was provisionally treated with ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and ketoconazole cream 2% twice daily to the affected areas. After several months on this regimen, the patient did not report any improvement. An abdominal skin biopsy was again performed and revealed similar histopathology. Periodic acid–Schiff staining was negative for fungus. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin lotion.

Patient 4
A 45-year-old woman presented with hypopigmented, nonscaly macules on the face, neck, chest, trunk, and back. She first noted the lesions on the face and trunk more than 8 years prior, and they subsequently progressed. Potassium hydroxide scrapings performed on the lesions at the current presentation were negative, and a skin biopsy from the neck revealed postinflammatory pigmentary alteration, although the patient had no history of rash or injury in the areas in which the lesions were distributed.

Fontana-Masson and Melan-A staining of the skin biopsy of the neck revealed a normal distribution of melanocytes and pigment at the dermoepidermal junction. An RPR test was nonreactive. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin phosphate lotion 1%.

 

Comment

The 4 cases of PMH reported here showed extensive facial involvement in addition to the characteristic hypopigmented lesions on the trunk, arms, and legs. It is unclear why the lesions in these patients had a predominantly facial distribution. Involvement of the face in PMH has not been commonly reported in the literature. Martínez-Martínez et al³ reported 12 PMH patients with lesions only presenting in lumbar and abdominal distributions. Kim et al⁸ presented a series of 23 PMH patients treated with narrowband UVB in whom 56% (9/16) saw repigmentation in 90% of the lesions following treatment. The most commonly affected area was the lower back, followed by the abdomen, upper back, chest, sacral region, flank, and shoulders, respectively.⁸ In a review by Relyveld et al,¹ PMH is described as a predominantly truncal disease that can occasionally extend to the neck, face, and proximal arms and legs; however, no specific cases were reported.

Previous case series have reported PMH primarily in adolescents and young adults, with mean ages ranging from 26 to 30 years.^1,3 The 4 patients reported here were older, ranging in age from 40 to 65 years. This discrepancy in age may contribute to the facial distribution encountered in this patient population; however, given the small number of patients in our case series, such extrapolation is premature. Most recently, Westerhof et al⁶ demonstrated a relationship between the presence of P acnes, a common skin commensal of the face, and the hypopigmented macules of PMH. The investigators suggested that some strains of P acnes produce a factor that is yet to be identified that interferes with melanogenesis. The response of PMH lesions to topical treatments such as benzoyl peroxide, clindamycin, and phototherapy has lent credence to the potential etiologic role of P acnes in this condition.^9,10 The interplay between age, PMH distribution, and P acnes requires further investigation.

The biopsies in our 4 patients were consistent with the nonspecific histopathologic characteristics of PMH lesions. Biopsies in all 4 patients revealed a sparse perivascular lymphocytic infiltrate, and in 2 of the cases, postinflammatory pigmentary alteration was noted. Such changes often are described in PMH lesions.^4,5 In other cases detailed in the literature, lesional and nonlesional skin often are indistinguishable on hematoxylin and eosin staining.¹¹ In the 3 patients for whom we performed additional immunohistochemical studies, results were mixed: Melan-A staining revealed a decreased number of melanocytes in Patient 1 but not in Patients 2 or 4. Many reported cases in the literature have not demonstrated a decrease in melanocyte density but instead show a decrease in melanin content in lesional skin.^1-3,6,7 Although additional stains performed in Patient 4 revealed neither a decrease in the number of melanocytes nor a decrease in the melanin content, such histopathologic findings of PMH often are subtle. Additional stains were not performed in Patient 3. More studies are needed to characterize the immunohistochemical staining patterns of lesional skin in patients with PMH.

Tinea versicolor, pityriasis alba, mycosis fungoides, sarcoidosis, leprosy, and syphilis typically are included in the differential diagnosis for PMH. Tinea versicolor traditionally is diagnosed based on the combination of irregular hypopigmented or hyperpigmented scaly macules and a KOH preparation that is positive for hyphae and spores. Similar to PMH, tinea versicolor is most often found on the trunk, but unusual cases have been reported involving the face.¹²

Patient 2 reflected how it can be difficult diagnostically to distinguish between tinea versicolor and PMH. Although this patient initially had a KOH scraping suggestive for tinea versicolor, adequate treatment with oral fluconazole and ketoconazole shampoo did not result in improvement. The hypopigmented lesions in this patient continued to progress despite therapy. Additionally, his hypopigmented to depigmented nonscaly macules were more clinically consistent with the characteristic description of lesion configuration in PMH than with the irregular, more sharply defined, asymmetric, and scaly spots of tinea versicolor. Furthermore, the inflammatory findings on biopsy favored a diagnosis of PMH.

Pityriasis alba, most frequently presents on the face in the form of hypopigmented, sometimes slightly scaly macules but also can occur on the body. It usually occurs in younger patients who often have an atopic diathesis. Histologic findings generally are nonspecific, but discrete eczematous changes can sometimes be appreciated in the epidermis and dermis. None of our patients had histories suggestive of an atopic diathesis or lesion distributions typical of pityriasis alba. Histologic findings also were more consistent with PMH than pityriasis alba.

A diagnosis of patch-stage hypopigmented MF should also be entertained in patients with hypopigmented macules, as it can appear similar to the lesions of PMH. Hypopigmented MF often is associated with subtle atrophy, scaling, poikiloderma, and erythema. These features were not present in the 4 cases presented here. Histologically, atypical lymphocytes with prominent epidermotropism and tagging of the epidermis by large lymphocytic infiltrates are seen in cases of hypopigmented MF. These findings were not present in biopsies from our patients.

Hypopigmented sarcoidosis, leprosy, and syphilis are other systemic diseases associated with hypopigmented lesions. Histologically, noncaseasting granulomas in the dermis or subcutaneous tissue would favor a diagnosis of sarcoidosis over PMH. In patients who live in endemic areas, a diagnosis of leprosy for an anesthetic hypopigmented lesion would be higher in the differential. Finally, it is important to rule out secondary syphilis when diagnosing PMH. Known as the great imitator, secondary syphilis may present in a patient in the form of hypopigmented macules. Patients 1, 2, and 4 had nonreactive RPR tests; unfortunately, RPR was not checked in Patient 3. He denied all risk factors for syphilis.

Various topical and oral treatments were prescribed for each patient, but so far none have been unequivocally effective. In the literature, there are reports supporting the efficacy of topical antimicrobial agents targeting P acnes.^9,10 One case report noted improvement in a patient with PMH after isotretinoin use.¹³ Phototherapy also has been reported to improve PMH in several case reports^4-8; however, consistent response to these therapies has not been documented. Unfortunately for patients with a diagnosis of PMH, a lack of effective treatment options often exists.

This series of 4 cases highlights the importance of considering PMH in the differential of hypopigmented macules, even when they appear predominantly on the face.

Case Report

A 77-year-old man was admitted to the general medicine service at our institution for treatment of a diffuse macular eruption and hemorrhagic bullae 12 days after undergoing left-knee revision arthroplasty during which a cement spacer impregnated with vancomycin and tobramycin was placed. At the time of the surgery, the patient also received intravenous (IV) vancomycin and oral ciprofloxacin, which were continued postoperatively until his hospital presentation. The patient was recovering well until postoperative day 7, when he developed painful swelling and erythema surrounding the surgical wound on the left knee. Concerned that his symptoms indicated a flare of gout, he restarted a former allopurinol prescription from an outside physician after 2 years of nonuse. The skin changes progressed distally on the left leg over the next 48 hours. By postoperative day 10, he had developed serosanguinous blisters on the left knee (Figure 1A) and oral mucosa (Figure 1B), as well as erythematous nodules on the bilateral palms. He presented to our institution for emergent care on postoperative day 12 following progression of the eruption to the inguinal region (Figure 2A), buttocks (Figure 2B), and abdominal region.

Due to concerns about a potential drug reaction, the IV vancomycin, oral ciprofloxacin, and oral allopurinol were discontinued on hospital admission. A dermatology consultation (D.A.D., J.A.Z., E.T.) was obtained, and a punch biopsy from a lesion on the left thigh revealed a neutrophil-rich subepidermal bulla with scattered eosinophils (Figure 3A). Direct immunofluorescence demonstrated linear IgA (Figure 3B) and C3 deposition along the dermoepidermal junction, which confirmed a diagnosis of drug-induced linear IgA bullous dermatosis (LABD). Vancomycin was suspected as the causative agent.¹ An initial vancomycin trough level drawn 48 hours after discontinuation (postoperative day 13) was still therapeutic at 14 µg/mL (reference range, 10–20 µg/mL in adults). This was substantially higher than the predicted value of 3 µg/mL based on renal excretion. Similarly, 5 additional serum levels obtained during the patient’s hospital course were greater than those predicted, and follow-up trough levels remained detectable at 1 µg/mL 2 weeks after discontinuation.

Oral prednisone 60 mg once daily and oral dapsone 25 mg once daily were initiated on hospital days 4 and 6 (postoperative days 15 and 17), respectively. A 6-week course of oral ciprofloxacin 750 mg twice daily and daptomycin 8 mg/kg once daily was initiated for bacterial coverage on hospital day 5 (postoperative day 16). Topical triamcinolone and an anesthetic mouthwash also were used to treat the mucosal involvement. The lesions stabilized on the third day of steroid therapy, and the patient was discharged 7 days after hospital admission (postoperative day 18). Dapsone was rapidly increased to 100 mg once daily over the next week for Pneumocystis jirovecii pneumonia prophylaxis. An increase in prednisone to 80 mg once daily was required 3 days after the patient was discharged due to worsening oral lesions. Five days after discharge, the patient was readmitted to the hospital for 3 days due to acute kidney injury (AKI) in which his baseline creatinine level tripled. The cause of renal impairment was unknown, resulting in empiric discontinuation of dapsone on postoperative day 27. Prophylaxis for P jirovecii pneumonia was replaced with once-monthly inhaled pentamidine. Prednisone was tapered 20 days after the original presentation (postoperative day 32) following gradual improvement of both the skin and oral lesions. At dermatology follow-up 2 weeks later, doxycycline 100 mg twice daily was added for residual inflammation of the left leg. A deep vein thrombosis was discovered in the left leg 10 days later, and 3 months of anticoagulation therapy was initiated with discontinuation of the doxycycline. The patient continued to have renal insufficiency several weeks after dapsone discontinuation and developed prominent peripheral motor neuropathy with bilateral thenar atrophy. He did not experience any skin eruptions or relapses in the weeks following prednisone cessation and underwent successful removal of the cement spacer with full left-knee reconstruction 4 months after his initial presentation to our institution. At 9-month dermatology follow-up, the LABD remained in remission.

 

Comment

Linear IgA bullous dermatosis is a well-documented autoimmune mucocutaneous disorder characterized by linear IgA deposits at the dermoepidermal junction. The development of autoantibodies to antigens within the basement membrane zone leads to both cellular and humoral immune responses that facilitate the subepidermal blistering rash in LABD.^2,3 Linear IgA bullous dermatosis affects all ages and races with a bimodal epidemiology. The adult form typically appears after 60 years of age, whereas the childhood form (chronic bullous disease of childhood) appears between 6 months and 6 years of age.³ Medications—particularly vancomycin—are responsible for a substantial portion of cases.^1-4 In one review, vancomycin was implicated in almost half (22/52 [42.3%]) of drug-related cases of LABD.⁴ Other associated medications include captopril, trimethoprim-sulfamethoxazole, phenytoin, and diclo-fenac.^3,4 Vancomycin-associated LABD has a substantially shorter time to onset of symptoms, with a mean of 8.6 days compared to 63.8 days for other causative agents.⁴Resolution of symptoms also occurs more quickly, with remission occurring in 66.7% (16/24) of cases at a mean time of 13 days compared to a 39.2% (11/28) resolution rate with a mean time of 18.9 days following discontinuation of other implicated medications.⁴ While idiopathic LABD involves the mucous membranes in up to 80% of cases, drug-induced LABD is less commonly associated with mucosal lesions. In an earlier systematic review from 1966 to 2002, 32% (7/22) of reported cases of vancomycin-induced LABD were reported to have mucosal involvement.^5,6 In 2012, one group found that most published cases of drug-induced LABD do not use standardized algorithms, such as the Naranjo algorithm, to definitively tie LABD onset to medication use.⁴ The Naranjo algorithm, devised in 1981, consists of 10 questions that determine the probability of adverse drug reactions.⁷ In our case, a Naranjo score of 5 suggested a probable adverse drug reaction due to vancomycin use; however, we cannot completely exclude ciprofloxacin in our case in light of a case report of LABD in the setting of IV vancomycin and ciprofloxacin use.⁸ In our patient, ciprofloxacin had a Naranjo score of 2, which suggested a possible adverse drug reaction. Allopurinol, which does not have any published association with LABD, also had a Naranjo score of 2 in our patient.

The initial treatment of drug-induced LABD is immediate discontinuation of the suspected agent(s) and supportive care.⁹ Although future avoidance of vancomycin is recommended in patients with a history of LABD, there are reported cases of successful rechallenges.^4,10 The early removal of our patient’s cement spacer was discouraged by both the orthopedics and infectious disease consultation services due to potential complications as well as the patient’s gradual improvement during his hospital course.

Dapsone is considered the standard systemic treatment for LABD. Sulfapyridine is an alternative to dapsone, or a combination of these 2 drugs may be used. Corticosteroids can be added to each of these regimens to achieve remission, as in our case.² Although dapsone was discontinued in the setting of the patient’s AKI, the vancomycin in the dual-eluting spacer was more likely the culprit. A review of 544 postoperative outcomes following the use of an antibiotic-impregnated cement spacer (AICS) during 2-stage arthroplasty displayed an 8- to 10-fold increase in the development of AKIs compared to the rate of AKIs following primary joint arthroplasty.¹⁰ While our patient’s AKI was not attributed to dapsone, his prominent peripheral motor neuropathy with resultant bilateral thenar atrophy was a rare complication of dapsone use. While dapsone-associated neuropathy has been reported in daily dosages of as low as 75 mg, it typically is seen in doses of at least 300 mg per day and in larger cumulative dosages.¹¹

Despite having a well-characterized vancomycin-induced LABD in the setting of known vancomycin exposure, our patient’s case was particularly challenging given the continued presence of the vancomycin-impregnated cement spacer (VICS) in the left knee, resulting in vancomycin levels at admission and during subsequent measurements over 2 weeks that were all several-fold higher than the renal clearance predicted.

Vancomycin-associated LABD does not appear to be dose dependent and has been reported at both subtherapeutic^1-3 and supratherapeutic levels,^5-9 whereas toxicity reactions are more common at supratherapeutic levels.⁹ The literature on AICS use suggests that drug elution occurs at relatively unpredictable rates based on a variety of factors, including the type of cement used and the initial antibiotic concentration.^12,13 Furthermore, the addition of tobramycin to VICSs has been found to increase the rate of vancomycin delivery through a phenomenon known as passive opportunism.¹⁴

As AICS devices allow for the delivery of higher concentrations of antibiotics to a localized area, systemic complications are considered rare but have been reported.¹³ Our report describes a rare case of LABD in the setting of a VICS. One clinical aspect of our case that supports the implication of VICS as the cause of the patient’s LABD is the concentration of bullae overlying the incision site on the left knee. A case of a desquamating rash in a patient with an implanted VICS has been documented in which the early lesions were localized to the surgical leg, as in our case.¹⁵ Unlike our case, there was a history of Stevens-Johnson syndrome following previous vancomycin exposure. A case of a gentamicin-impregnated cement spacer causing allergic dermatitis that was most prominent in the surgical leg also has been reported.¹⁶ An isomorphic phenomenon (Köbner phenomenon) has been suggested in the setting of vancomycin-induced LABD lesions that intensified at a site of adhesive tape application,¹⁷ but the Köbner phenomenon did not appear to be a major factor in our patient. The removal of the patient’s cement spacer was performed to prevent development of a chronic autoimmune response or autoreactivity state against the skin basement membrane zone structural antigen.

Case Report

A 77-year-old man was admitted to the general medicine service at our institution for treatment of a diffuse macular eruption and hemorrhagic bullae 12 days after undergoing left-knee revision arthroplasty during which a cement spacer impregnated with vancomycin and tobramycin was placed. At the time of the surgery, the patient also received intravenous (IV) vancomycin and oral ciprofloxacin, which were continued postoperatively until his hospital presentation. The patient was recovering well until postoperative day 7, when he developed painful swelling and erythema surrounding the surgical wound on the left knee. Concerned that his symptoms indicated a flare of gout, he restarted a former allopurinol prescription from an outside physician after 2 years of nonuse. The skin changes progressed distally on the left leg over the next 48 hours. By postoperative day 10, he had developed serosanguinous blisters on the left knee (Figure 1A) and oral mucosa (Figure 1B), as well as erythematous nodules on the bilateral palms. He presented to our institution for emergent care on postoperative day 12 following progression of the eruption to the inguinal region (Figure 2A), buttocks (Figure 2B), and abdominal region.

Due to concerns about a potential drug reaction, the IV vancomycin, oral ciprofloxacin, and oral allopurinol were discontinued on hospital admission. A dermatology consultation (D.A.D., J.A.Z., E.T.) was obtained, and a punch biopsy from a lesion on the left thigh revealed a neutrophil-rich subepidermal bulla with scattered eosinophils (Figure 3A). Direct immunofluorescence demonstrated linear IgA (Figure 3B) and C3 deposition along the dermoepidermal junction, which confirmed a diagnosis of drug-induced linear IgA bullous dermatosis (LABD). Vancomycin was suspected as the causative agent.¹ An initial vancomycin trough level drawn 48 hours after discontinuation (postoperative day 13) was still therapeutic at 14 µg/mL (reference range, 10–20 µg/mL in adults). This was substantially higher than the predicted value of 3 µg/mL based on renal excretion. Similarly, 5 additional serum levels obtained during the patient’s hospital course were greater than those predicted, and follow-up trough levels remained detectable at 1 µg/mL 2 weeks after discontinuation.

Oral prednisone 60 mg once daily and oral dapsone 25 mg once daily were initiated on hospital days 4 and 6 (postoperative days 15 and 17), respectively. A 6-week course of oral ciprofloxacin 750 mg twice daily and daptomycin 8 mg/kg once daily was initiated for bacterial coverage on hospital day 5 (postoperative day 16). Topical triamcinolone and an anesthetic mouthwash also were used to treat the mucosal involvement. The lesions stabilized on the third day of steroid therapy, and the patient was discharged 7 days after hospital admission (postoperative day 18). Dapsone was rapidly increased to 100 mg once daily over the next week for Pneumocystis jirovecii pneumonia prophylaxis. An increase in prednisone to 80 mg once daily was required 3 days after the patient was discharged due to worsening oral lesions. Five days after discharge, the patient was readmitted to the hospital for 3 days due to acute kidney injury (AKI) in which his baseline creatinine level tripled. The cause of renal impairment was unknown, resulting in empiric discontinuation of dapsone on postoperative day 27. Prophylaxis for P jirovecii pneumonia was replaced with once-monthly inhaled pentamidine. Prednisone was tapered 20 days after the original presentation (postoperative day 32) following gradual improvement of both the skin and oral lesions. At dermatology follow-up 2 weeks later, doxycycline 100 mg twice daily was added for residual inflammation of the left leg. A deep vein thrombosis was discovered in the left leg 10 days later, and 3 months of anticoagulation therapy was initiated with discontinuation of the doxycycline. The patient continued to have renal insufficiency several weeks after dapsone discontinuation and developed prominent peripheral motor neuropathy with bilateral thenar atrophy. He did not experience any skin eruptions or relapses in the weeks following prednisone cessation and underwent successful removal of the cement spacer with full left-knee reconstruction 4 months after his initial presentation to our institution. At 9-month dermatology follow-up, the LABD remained in remission.

 

Comment

Linear IgA bullous dermatosis is a well-documented autoimmune mucocutaneous disorder characterized by linear IgA deposits at the dermoepidermal junction. The development of autoantibodies to antigens within the basement membrane zone leads to both cellular and humoral immune responses that facilitate the subepidermal blistering rash in LABD.^2,3 Linear IgA bullous dermatosis affects all ages and races with a bimodal epidemiology. The adult form typically appears after 60 years of age, whereas the childhood form (chronic bullous disease of childhood) appears between 6 months and 6 years of age.³ Medications—particularly vancomycin—are responsible for a substantial portion of cases.^1-4 In one review, vancomycin was implicated in almost half (22/52 [42.3%]) of drug-related cases of LABD.⁴ Other associated medications include captopril, trimethoprim-sulfamethoxazole, phenytoin, and diclo-fenac.^3,4 Vancomycin-associated LABD has a substantially shorter time to onset of symptoms, with a mean of 8.6 days compared to 63.8 days for other causative agents.⁴Resolution of symptoms also occurs more quickly, with remission occurring in 66.7% (16/24) of cases at a mean time of 13 days compared to a 39.2% (11/28) resolution rate with a mean time of 18.9 days following discontinuation of other implicated medications.⁴ While idiopathic LABD involves the mucous membranes in up to 80% of cases, drug-induced LABD is less commonly associated with mucosal lesions. In an earlier systematic review from 1966 to 2002, 32% (7/22) of reported cases of vancomycin-induced LABD were reported to have mucosal involvement.^5,6 In 2012, one group found that most published cases of drug-induced LABD do not use standardized algorithms, such as the Naranjo algorithm, to definitively tie LABD onset to medication use.⁴ The Naranjo algorithm, devised in 1981, consists of 10 questions that determine the probability of adverse drug reactions.⁷ In our case, a Naranjo score of 5 suggested a probable adverse drug reaction due to vancomycin use; however, we cannot completely exclude ciprofloxacin in our case in light of a case report of LABD in the setting of IV vancomycin and ciprofloxacin use.⁸ In our patient, ciprofloxacin had a Naranjo score of 2, which suggested a possible adverse drug reaction. Allopurinol, which does not have any published association with LABD, also had a Naranjo score of 2 in our patient.

The initial treatment of drug-induced LABD is immediate discontinuation of the suspected agent(s) and supportive care.⁹ Although future avoidance of vancomycin is recommended in patients with a history of LABD, there are reported cases of successful rechallenges.^4,10 The early removal of our patient’s cement spacer was discouraged by both the orthopedics and infectious disease consultation services due to potential complications as well as the patient’s gradual improvement during his hospital course.

Dapsone is considered the standard systemic treatment for LABD. Sulfapyridine is an alternative to dapsone, or a combination of these 2 drugs may be used. Corticosteroids can be added to each of these regimens to achieve remission, as in our case.² Although dapsone was discontinued in the setting of the patient’s AKI, the vancomycin in the dual-eluting spacer was more likely the culprit. A review of 544 postoperative outcomes following the use of an antibiotic-impregnated cement spacer (AICS) during 2-stage arthroplasty displayed an 8- to 10-fold increase in the development of AKIs compared to the rate of AKIs following primary joint arthroplasty.¹⁰ While our patient’s AKI was not attributed to dapsone, his prominent peripheral motor neuropathy with resultant bilateral thenar atrophy was a rare complication of dapsone use. While dapsone-associated neuropathy has been reported in daily dosages of as low as 75 mg, it typically is seen in doses of at least 300 mg per day and in larger cumulative dosages.¹¹

Despite having a well-characterized vancomycin-induced LABD in the setting of known vancomycin exposure, our patient’s case was particularly challenging given the continued presence of the vancomycin-impregnated cement spacer (VICS) in the left knee, resulting in vancomycin levels at admission and during subsequent measurements over 2 weeks that were all several-fold higher than the renal clearance predicted.

Vancomycin-associated LABD does not appear to be dose dependent and has been reported at both subtherapeutic^1-3 and supratherapeutic levels,^5-9 whereas toxicity reactions are more common at supratherapeutic levels.⁹ The literature on AICS use suggests that drug elution occurs at relatively unpredictable rates based on a variety of factors, including the type of cement used and the initial antibiotic concentration.^12,13 Furthermore, the addition of tobramycin to VICSs has been found to increase the rate of vancomycin delivery through a phenomenon known as passive opportunism.¹⁴

As AICS devices allow for the delivery of higher concentrations of antibiotics to a localized area, systemic complications are considered rare but have been reported.¹³ Our report describes a rare case of LABD in the setting of a VICS. One clinical aspect of our case that supports the implication of VICS as the cause of the patient’s LABD is the concentration of bullae overlying the incision site on the left knee. A case of a desquamating rash in a patient with an implanted VICS has been documented in which the early lesions were localized to the surgical leg, as in our case.¹⁵ Unlike our case, there was a history of Stevens-Johnson syndrome following previous vancomycin exposure. A case of a gentamicin-impregnated cement spacer causing allergic dermatitis that was most prominent in the surgical leg also has been reported.¹⁶ An isomorphic phenomenon (Köbner phenomenon) has been suggested in the setting of vancomycin-induced LABD lesions that intensified at a site of adhesive tape application,¹⁷ but the Köbner phenomenon did not appear to be a major factor in our patient. The removal of the patient’s cement spacer was performed to prevent development of a chronic autoimmune response or autoreactivity state against the skin basement membrane zone structural antigen.

Case Report

A 77-year-old man was admitted to the general medicine service at our institution for treatment of a diffuse macular eruption and hemorrhagic bullae 12 days after undergoing left-knee revision arthroplasty during which a cement spacer impregnated with vancomycin and tobramycin was placed. At the time of the surgery, the patient also received intravenous (IV) vancomycin and oral ciprofloxacin, which were continued postoperatively until his hospital presentation. The patient was recovering well until postoperative day 7, when he developed painful swelling and erythema surrounding the surgical wound on the left knee. Concerned that his symptoms indicated a flare of gout, he restarted a former allopurinol prescription from an outside physician after 2 years of nonuse. The skin changes progressed distally on the left leg over the next 48 hours. By postoperative day 10, he had developed serosanguinous blisters on the left knee (Figure 1A) and oral mucosa (Figure 1B), as well as erythematous nodules on the bilateral palms. He presented to our institution for emergent care on postoperative day 12 following progression of the eruption to the inguinal region (Figure 2A), buttocks (Figure 2B), and abdominal region.

Due to concerns about a potential drug reaction, the IV vancomycin, oral ciprofloxacin, and oral allopurinol were discontinued on hospital admission. A dermatology consultation (D.A.D., J.A.Z., E.T.) was obtained, and a punch biopsy from a lesion on the left thigh revealed a neutrophil-rich subepidermal bulla with scattered eosinophils (Figure 3A). Direct immunofluorescence demonstrated linear IgA (Figure 3B) and C3 deposition along the dermoepidermal junction, which confirmed a diagnosis of drug-induced linear IgA bullous dermatosis (LABD). Vancomycin was suspected as the causative agent.¹ An initial vancomycin trough level drawn 48 hours after discontinuation (postoperative day 13) was still therapeutic at 14 µg/mL (reference range, 10–20 µg/mL in adults). This was substantially higher than the predicted value of 3 µg/mL based on renal excretion. Similarly, 5 additional serum levels obtained during the patient’s hospital course were greater than those predicted, and follow-up trough levels remained detectable at 1 µg/mL 2 weeks after discontinuation.

Oral prednisone 60 mg once daily and oral dapsone 25 mg once daily were initiated on hospital days 4 and 6 (postoperative days 15 and 17), respectively. A 6-week course of oral ciprofloxacin 750 mg twice daily and daptomycin 8 mg/kg once daily was initiated for bacterial coverage on hospital day 5 (postoperative day 16). Topical triamcinolone and an anesthetic mouthwash also were used to treat the mucosal involvement. The lesions stabilized on the third day of steroid therapy, and the patient was discharged 7 days after hospital admission (postoperative day 18). Dapsone was rapidly increased to 100 mg once daily over the next week for Pneumocystis jirovecii pneumonia prophylaxis. An increase in prednisone to 80 mg once daily was required 3 days after the patient was discharged due to worsening oral lesions. Five days after discharge, the patient was readmitted to the hospital for 3 days due to acute kidney injury (AKI) in which his baseline creatinine level tripled. The cause of renal impairment was unknown, resulting in empiric discontinuation of dapsone on postoperative day 27. Prophylaxis for P jirovecii pneumonia was replaced with once-monthly inhaled pentamidine. Prednisone was tapered 20 days after the original presentation (postoperative day 32) following gradual improvement of both the skin and oral lesions. At dermatology follow-up 2 weeks later, doxycycline 100 mg twice daily was added for residual inflammation of the left leg. A deep vein thrombosis was discovered in the left leg 10 days later, and 3 months of anticoagulation therapy was initiated with discontinuation of the doxycycline. The patient continued to have renal insufficiency several weeks after dapsone discontinuation and developed prominent peripheral motor neuropathy with bilateral thenar atrophy. He did not experience any skin eruptions or relapses in the weeks following prednisone cessation and underwent successful removal of the cement spacer with full left-knee reconstruction 4 months after his initial presentation to our institution. At 9-month dermatology follow-up, the LABD remained in remission.

 

Comment

Linear IgA bullous dermatosis is a well-documented autoimmune mucocutaneous disorder characterized by linear IgA deposits at the dermoepidermal junction. The development of autoantibodies to antigens within the basement membrane zone leads to both cellular and humoral immune responses that facilitate the subepidermal blistering rash in LABD.^2,3 Linear IgA bullous dermatosis affects all ages and races with a bimodal epidemiology. The adult form typically appears after 60 years of age, whereas the childhood form (chronic bullous disease of childhood) appears between 6 months and 6 years of age.³ Medications—particularly vancomycin—are responsible for a substantial portion of cases.^1-4 In one review, vancomycin was implicated in almost half (22/52 [42.3%]) of drug-related cases of LABD.⁴ Other associated medications include captopril, trimethoprim-sulfamethoxazole, phenytoin, and diclo-fenac.^3,4 Vancomycin-associated LABD has a substantially shorter time to onset of symptoms, with a mean of 8.6 days compared to 63.8 days for other causative agents.⁴Resolution of symptoms also occurs more quickly, with remission occurring in 66.7% (16/24) of cases at a mean time of 13 days compared to a 39.2% (11/28) resolution rate with a mean time of 18.9 days following discontinuation of other implicated medications.⁴ While idiopathic LABD involves the mucous membranes in up to 80% of cases, drug-induced LABD is less commonly associated with mucosal lesions. In an earlier systematic review from 1966 to 2002, 32% (7/22) of reported cases of vancomycin-induced LABD were reported to have mucosal involvement.^5,6 In 2012, one group found that most published cases of drug-induced LABD do not use standardized algorithms, such as the Naranjo algorithm, to definitively tie LABD onset to medication use.⁴ The Naranjo algorithm, devised in 1981, consists of 10 questions that determine the probability of adverse drug reactions.⁷ In our case, a Naranjo score of 5 suggested a probable adverse drug reaction due to vancomycin use; however, we cannot completely exclude ciprofloxacin in our case in light of a case report of LABD in the setting of IV vancomycin and ciprofloxacin use.⁸ In our patient, ciprofloxacin had a Naranjo score of 2, which suggested a possible adverse drug reaction. Allopurinol, which does not have any published association with LABD, also had a Naranjo score of 2 in our patient.

The initial treatment of drug-induced LABD is immediate discontinuation of the suspected agent(s) and supportive care.⁹ Although future avoidance of vancomycin is recommended in patients with a history of LABD, there are reported cases of successful rechallenges.^4,10 The early removal of our patient’s cement spacer was discouraged by both the orthopedics and infectious disease consultation services due to potential complications as well as the patient’s gradual improvement during his hospital course.

Dapsone is considered the standard systemic treatment for LABD. Sulfapyridine is an alternative to dapsone, or a combination of these 2 drugs may be used. Corticosteroids can be added to each of these regimens to achieve remission, as in our case.² Although dapsone was discontinued in the setting of the patient’s AKI, the vancomycin in the dual-eluting spacer was more likely the culprit. A review of 544 postoperative outcomes following the use of an antibiotic-impregnated cement spacer (AICS) during 2-stage arthroplasty displayed an 8- to 10-fold increase in the development of AKIs compared to the rate of AKIs following primary joint arthroplasty.¹⁰ While our patient’s AKI was not attributed to dapsone, his prominent peripheral motor neuropathy with resultant bilateral thenar atrophy was a rare complication of dapsone use. While dapsone-associated neuropathy has been reported in daily dosages of as low as 75 mg, it typically is seen in doses of at least 300 mg per day and in larger cumulative dosages.¹¹

Despite having a well-characterized vancomycin-induced LABD in the setting of known vancomycin exposure, our patient’s case was particularly challenging given the continued presence of the vancomycin-impregnated cement spacer (VICS) in the left knee, resulting in vancomycin levels at admission and during subsequent measurements over 2 weeks that were all several-fold higher than the renal clearance predicted.

Vancomycin-associated LABD does not appear to be dose dependent and has been reported at both subtherapeutic^1-3 and supratherapeutic levels,^5-9 whereas toxicity reactions are more common at supratherapeutic levels.⁹ The literature on AICS use suggests that drug elution occurs at relatively unpredictable rates based on a variety of factors, including the type of cement used and the initial antibiotic concentration.^12,13 Furthermore, the addition of tobramycin to VICSs has been found to increase the rate of vancomycin delivery through a phenomenon known as passive opportunism.¹⁴

As AICS devices allow for the delivery of higher concentrations of antibiotics to a localized area, systemic complications are considered rare but have been reported.¹³ Our report describes a rare case of LABD in the setting of a VICS. One clinical aspect of our case that supports the implication of VICS as the cause of the patient’s LABD is the concentration of bullae overlying the incision site on the left knee. A case of a desquamating rash in a patient with an implanted VICS has been documented in which the early lesions were localized to the surgical leg, as in our case.¹⁵ Unlike our case, there was a history of Stevens-Johnson syndrome following previous vancomycin exposure. A case of a gentamicin-impregnated cement spacer causing allergic dermatitis that was most prominent in the surgical leg also has been reported.¹⁶ An isomorphic phenomenon (Köbner phenomenon) has been suggested in the setting of vancomycin-induced LABD lesions that intensified at a site of adhesive tape application,¹⁷ but the Köbner phenomenon did not appear to be a major factor in our patient. The removal of the patient’s cement spacer was performed to prevent development of a chronic autoimmune response or autoreactivity state against the skin basement membrane zone structural antigen.

In today’s society there is a ubiquitous pressure to lose weight, reduce fat, and rejuvenate the skin that stems not only from images of idealized bodies in the media but also from our growing knowledge of the detrimental effects of obesity. Along with diet and exercise, it has become popular to use noninvasive devices to attain these goals by means of body contouring—the optimization of the definition, smoothness, and shape of the human physique.¹ In fact, body contouring currently is the fastest-growing area of cosmetic dermatology.²

Previously, body contouring primarily involved invasive procedures (eg, liposuction) that are associated with various adverse effects, financial costs, and lengthy downtime.³ More recently, a growing demand for safer and less painful procedures for adipose tissue reduction and skin tightening have led to the development of several novel modalities for noninvasive body contouring. Although the results achieved using these new technologies may be less dramatic than invasive techniques and are not immediate, they do not carry the risks and adverse effects that are associated with surgical procedures and therefore are increasingly requested by cosmetic patients.^4,5 New noninvasive techniques primarily target the physical properties of fat, resulting in an efflux of triglycerides from fat cells, causing either reduced size, necrosis, or apoptosis of adipocytes.^3,6 Of these modalities, cold-induced adipocyte apoptosis has been commercially available the longest and has been the most researched; however, other noninvasive body contouring techniques have been increasingly explored by researchers since the first reports of human adipose tissue explants exhibiting features of apoptosis after heat injury became available.^7,8

There currently are 4 leading modalities used for noninvasive body contouring: cryolipolysis, radiofrequency (RF), high-intensity focused ultrasound (HIFU), and laser therapy (Table). Although no procedure has yet been accepted as the gold standard, investigators are working to determine which technique is the most effective.⁹ In this article, we provide an overview of these techniques to help dermatologists choose appropriate modalities for their cosmetic patients.

Cryolipolysis

Cryolipolysis is unique in that it employs the principle that lipid-rich adipocytes are more susceptible to freezing than surrounding water-rich cells, allowing selective apoptosis while preserving the adjacent structures. As macrophages digest the apoptotic adipocytes, patients experience a decrease in subcutaneous fat volume over the subsequent 2 to 3 months.^10-13 Cryolipolysis has been gaining popularity since 2010, when it was first approved by the US Food and Drug Administration (FDA) for fat reduction in the flank areas; it was later approved for the abdomen in 2012, thighs in 2014, and submental area in 2015.¹⁴ Most recently, cryolipolysis was approved for fat reduction in the arms, back, and buttocks in 2016.

The most popular cryolipolysis device applies suction to the treatment area and vacuums the tissue between 2 cooling panels for 30 to 60 minutes.⁹ Clinical studies investigating the safety and efficacy of cryolipolysis have reported a high degree of patient satisfaction with the procedure and only minimal side effects.^4,6,15,16 Common complications of cryolipolysis include erythema, swelling, and sensitivity at the treatment site followed by a lesser incidence of pain, tingling, and bruising, all of which generally resolve within a few weeks of treatment.⁶ With the removal of adipocytes, there has been concern regarding elevations in blood lipid levels and liver enzymes; however, these laboratory values have been reported to remain within normal limits during and after cryolipolysis.^17,18 Of note, patients should be advised of the risk of paradoxical adipose hyperplasia, a rare side effect of cryolipolysis in which a large, demarcated, tender fat mass develops at the treatment site 2 to 3 months after treatment, with an estimated incidence of 1 in 20,000.¹⁹ However, the incidence of paradoxical adipose hyperplasia may be underestimated, as a single practice reported an incidence of 0.47% in 422 cryolipolysis treatments.²⁰ This complication has not been associated with any of the heat-induced fat reduction modalities.

Cryolipolysis has been found to be safe for all skin types with no reported pigmentary changes.¹⁶ It should not be performed in patients with cold-induced conditions (eg, cryoglobulinemia, cold urticaria) or in those with severe varicose veins or atopic dermatitis.^21,22 Patients benefitting most from this procedure are those who require only small or moderate amounts of adipose tissue and cellulite removal with separate fat bulges.^12,17 Interestingly, cryolipolysis also has been used off label to treat pseudogynecomastia in male patients.²³

 

Radiofrequency

Radiofrequency has become an important and frequently used modality in cosmetic dermatology.²⁴ This modality differs from cryolipolysis in that it relies on exploiting the difference in water content and impedance between tissues: the skin has low impedance, whereas fat tissue has high impedance. Radiofrequency induces thermal injury to targeted tissue layers, rather than the cold-induced damage seen in cryolipolysis, through devices that focus thermal energy on tissues with high impedance, inducing apoptosis of cells in the subcutaneous adipose tissue with minimal risk of damaging the epidermis, dermis, and muscle.^9,25 Ultimately, thermal exposure to 43°C to 45°C over several minutes results in a delayed adipocyte death response.⁴ In addition to adipocyte death, RF has been shown to cause denaturation of collagen fibrils, leading to subsequent remodeling, neocollagenesis, and skin tightening.²⁶

Radiofrequency devices can be broadly classified as monopolar or bipolar.^24,27 Bipolar devices generally require more frequent treatments, whereas monopolar devices tend to require fewer treatment sessions with superior circumference and fat reduction.²⁸

Overall, RF devices have a favorable side effect profile. The most common side effects are erythema and edema at the treatment site lasting less than 24 hours after the procedure.²⁵ The absence of complications such as abdominal discomfort, erythema, and burning during treatment have been reported,²⁷ with the exception of 1 case of hyperesthesia on the abdomen that lasted for 3 days after a treatment session.⁵ Although RF has beneficial effects on circumference reduction in the abdomen and thighs and can improve the appearance of cellulite, an increase in body weight may occur during treatment. When a localized area of fat such as the thigh is targeted for treatment but the remaining fat cells in the body are not affected, the remaining cells can continue to grow and expand; for instance, although fat cells destroyed with RF will not continue to expand, fat cells in untreated areas may continue to grow due to continued weight gain (eg, from excessive eating), leading to overall weight gain. Thus, patients must understand that weight gain is not an indication of treatment failure after RF or any other method of irreversible fat destruction.⁵

High-intensity Focused Ultrasound

High-intensity focused ultrasound recently was introduced as a new treatment modality for body contouring, specifically for skin tightening and rejuvenation.⁵ The mechanism of HIFU is similar to that of RF in that it also relies on heat to cause adipocyte apoptosis; however, it utilizes acoustic energy rather than electric energy. High-intensity focused ultrasound devices can deliver energy to the deep dermis, subdermal connective tissue, and fibromuscular layers in precise microcoagulation zones without damage to the epidermis. The focused energy induces a high temperature (>65°C) within 1 to 3 seconds, causing cell protein coagulation in the targeted area. In addition to its thermal effects, HIFU induces a mechanical effect that disrupts cell membranes immediately, which contributes to the coagulation necrosis process, further promoting necrosis and apoptosis. The effects of these devices can be visualized, as there always is a sharp demarcation between the targeted and untargeted tissue.²⁹ Additionally, microcoagulation is thought to cause gradual skin tightening through collagen contraction and remodeling.³⁰

High-intensity focused ultrasound first received FDA approval for eyebrow lifting and has been used safely and effectively to treat facial and neck skin in a variety of skin types as well as to improve the clinical appearance of the abdomen and thighs.³¹ This technique is best suited for patients with mild to moderate laxity of the skin or soft tissue who have a body mass index less than 30 kg/m² and are seeking mild body contouring.³² The ideal patient is young with normal wound healing, since the clinical response to treatment is partly dependent on new collagen synthesis.³³ Older patients with extensive photoaging or severe skin laxity are not good candidates for HIFU.

There are a variety of available HIFU devices,³⁴ which utilize special transducers that direct ultrasound energy to a small focal point in the subcutaneous tissues that harmlessly passes through the skin.³⁵ By using newly developed transducers with different energy outputs and focal depths, dermatologists can tailor HIFU treatment to meet the unique physical characteristics of each patient.³¹

Adverse effects of HIFU are limited to transient pain in most patients and occasional erythema and ecchymosis in some cases.³¹ In general, most adverse effects resolve spontaneously within 4 weeks and all by 12 weeks posttreatment. Studies also have reported hard subcutaneous nodules, discomfort, burning sensation, mild blisters, and one case of purpuric lesions, all at the treatment site.^36-39 There is no evidence that HIFU can cause abnormalities in serum lipids or liver function tests.

 

Lasers

Laser technology is a rapidly growing modality in noninvasive body contouring. A novel device recently emerged as the first and only FDA-cleared hyperthermic laser for fat reduction and noninvasive body contouring of the abdomen, flanks, back, inner and outer thighs, and submental area.^40,41 The device is a 1060-nm diode laser that uses thermal energy to destroy adipose tissue, leading to permanent reduction in stubborn fat without surgery or downtime through the use of a flat, nonsuction applicator that is designed for consistent, natural-looking results. The device includes a contact cooling system that helps to limit thermal discomfort and prevent damage to the surface of the skin during the procedure. Initial improvement can be seen as quickly as 6 weeks posttreatment, and optimal results usually occur in as few as 12 weeks. This device was found to have an excellent safety profile and was well tolerated among patients, with only mild pain reported.^42,43

Prior to the development of this new 1060-nm diode laser, the initial application of lasers for noninvasive body contouring involved low-level laser therapy (LLLT), also known as cold laser therapy.⁴⁰ One device has 5 rotating diode laser heads that work at a wavelength of 635 nm. Treatment sessions last up to 30 minutes, and 6 to 8 sessions are required to obtain optimal results. Low-level laser therapy is a unique modality that is not based on thermal tissue damage, but rather on producing transient microscopic pores in adipocytes that allow lipids to leak out, leading to fat reduction.³⁴ Because LLLT causes immediate emptying of targeted adipocytes, results are noticeable as soon as treatment is completed; however, there is no necrosis or apoptosis of adipocytes, so the recurrence of fat deposition is believed to be greater when compared to the other modalities. Because the results are temporary, long-term or permanent results should not be expected with LLLT. Depending on the patient’s goals, the temporary nature of the results can be either an advantage or disadvantage: some may prefer immediate results despite gradual diminishment over subsequent months, whereas others may prefer results that progressively increase over time and are more permanent, as seen with cryolipolysis, HIFU, and RF.³

Complications of LLLT generally are fewer and more mild than with all other body contouring procedures, with several studies reporting no adverse effects.^44-48 Others reported swelling or erythema at the treatment area, pain or tingling during treatment, and increased urination, all of which were temporary and resolved spontaneously.⁴⁹ Additionally, although the lipids released from treatment are cleared through the lymphatic system, LLLT has not been shown to increase serum lipid levels.⁵⁰

Conclusion

The field of noninvasive body contouring is undoubtedly growing and will likely continue to rise in popularity as the efficacy and safety of these treatments improve. Although the available technologies vary by mechanism and side effect profiles, several devices have been revealed to be safe and effective in reducing subcutaneous fat tissue and improving skin laxity.¹ However, additional studies are needed to evaluate these devices in a standardized manner, especially considering the high costs associated with treatment.³² Current studies investigating these devices vary in treatment protocol, treatment area, number and timing of follow-up sessions, and outcome measures, making it challenging to compare the results objectively.³ Dermatologists offering body contouring treatments need to be intimately familiar with the available devices and determine which treatment is appropriate for each patient in order to provide the highest quality care. Most importantly, patients and physicians must discuss individual goals when choosing a body-contouring method in order to maximize patient satisfaction.

In today’s society there is a ubiquitous pressure to lose weight, reduce fat, and rejuvenate the skin that stems not only from images of idealized bodies in the media but also from our growing knowledge of the detrimental effects of obesity. Along with diet and exercise, it has become popular to use noninvasive devices to attain these goals by means of body contouring—the optimization of the definition, smoothness, and shape of the human physique.¹ In fact, body contouring currently is the fastest-growing area of cosmetic dermatology.²

Previously, body contouring primarily involved invasive procedures (eg, liposuction) that are associated with various adverse effects, financial costs, and lengthy downtime.³ More recently, a growing demand for safer and less painful procedures for adipose tissue reduction and skin tightening have led to the development of several novel modalities for noninvasive body contouring. Although the results achieved using these new technologies may be less dramatic than invasive techniques and are not immediate, they do not carry the risks and adverse effects that are associated with surgical procedures and therefore are increasingly requested by cosmetic patients.^4,5 New noninvasive techniques primarily target the physical properties of fat, resulting in an efflux of triglycerides from fat cells, causing either reduced size, necrosis, or apoptosis of adipocytes.^3,6 Of these modalities, cold-induced adipocyte apoptosis has been commercially available the longest and has been the most researched; however, other noninvasive body contouring techniques have been increasingly explored by researchers since the first reports of human adipose tissue explants exhibiting features of apoptosis after heat injury became available.^7,8

There currently are 4 leading modalities used for noninvasive body contouring: cryolipolysis, radiofrequency (RF), high-intensity focused ultrasound (HIFU), and laser therapy (Table). Although no procedure has yet been accepted as the gold standard, investigators are working to determine which technique is the most effective.⁹ In this article, we provide an overview of these techniques to help dermatologists choose appropriate modalities for their cosmetic patients.

Cryolipolysis

Cryolipolysis is unique in that it employs the principle that lipid-rich adipocytes are more susceptible to freezing than surrounding water-rich cells, allowing selective apoptosis while preserving the adjacent structures. As macrophages digest the apoptotic adipocytes, patients experience a decrease in subcutaneous fat volume over the subsequent 2 to 3 months.^10-13 Cryolipolysis has been gaining popularity since 2010, when it was first approved by the US Food and Drug Administration (FDA) for fat reduction in the flank areas; it was later approved for the abdomen in 2012, thighs in 2014, and submental area in 2015.¹⁴ Most recently, cryolipolysis was approved for fat reduction in the arms, back, and buttocks in 2016.

The most popular cryolipolysis device applies suction to the treatment area and vacuums the tissue between 2 cooling panels for 30 to 60 minutes.⁹ Clinical studies investigating the safety and efficacy of cryolipolysis have reported a high degree of patient satisfaction with the procedure and only minimal side effects.^4,6,15,16 Common complications of cryolipolysis include erythema, swelling, and sensitivity at the treatment site followed by a lesser incidence of pain, tingling, and bruising, all of which generally resolve within a few weeks of treatment.⁶ With the removal of adipocytes, there has been concern regarding elevations in blood lipid levels and liver enzymes; however, these laboratory values have been reported to remain within normal limits during and after cryolipolysis.^17,18 Of note, patients should be advised of the risk of paradoxical adipose hyperplasia, a rare side effect of cryolipolysis in which a large, demarcated, tender fat mass develops at the treatment site 2 to 3 months after treatment, with an estimated incidence of 1 in 20,000.¹⁹ However, the incidence of paradoxical adipose hyperplasia may be underestimated, as a single practice reported an incidence of 0.47% in 422 cryolipolysis treatments.²⁰ This complication has not been associated with any of the heat-induced fat reduction modalities.

Cryolipolysis has been found to be safe for all skin types with no reported pigmentary changes.¹⁶ It should not be performed in patients with cold-induced conditions (eg, cryoglobulinemia, cold urticaria) or in those with severe varicose veins or atopic dermatitis.^21,22 Patients benefitting most from this procedure are those who require only small or moderate amounts of adipose tissue and cellulite removal with separate fat bulges.^12,17 Interestingly, cryolipolysis also has been used off label to treat pseudogynecomastia in male patients.²³

 

Radiofrequency

Radiofrequency has become an important and frequently used modality in cosmetic dermatology.²⁴ This modality differs from cryolipolysis in that it relies on exploiting the difference in water content and impedance between tissues: the skin has low impedance, whereas fat tissue has high impedance. Radiofrequency induces thermal injury to targeted tissue layers, rather than the cold-induced damage seen in cryolipolysis, through devices that focus thermal energy on tissues with high impedance, inducing apoptosis of cells in the subcutaneous adipose tissue with minimal risk of damaging the epidermis, dermis, and muscle.^9,25 Ultimately, thermal exposure to 43°C to 45°C over several minutes results in a delayed adipocyte death response.⁴ In addition to adipocyte death, RF has been shown to cause denaturation of collagen fibrils, leading to subsequent remodeling, neocollagenesis, and skin tightening.²⁶

Radiofrequency devices can be broadly classified as monopolar or bipolar.^24,27 Bipolar devices generally require more frequent treatments, whereas monopolar devices tend to require fewer treatment sessions with superior circumference and fat reduction.²⁸

Overall, RF devices have a favorable side effect profile. The most common side effects are erythema and edema at the treatment site lasting less than 24 hours after the procedure.²⁵ The absence of complications such as abdominal discomfort, erythema, and burning during treatment have been reported,²⁷ with the exception of 1 case of hyperesthesia on the abdomen that lasted for 3 days after a treatment session.⁵ Although RF has beneficial effects on circumference reduction in the abdomen and thighs and can improve the appearance of cellulite, an increase in body weight may occur during treatment. When a localized area of fat such as the thigh is targeted for treatment but the remaining fat cells in the body are not affected, the remaining cells can continue to grow and expand; for instance, although fat cells destroyed with RF will not continue to expand, fat cells in untreated areas may continue to grow due to continued weight gain (eg, from excessive eating), leading to overall weight gain. Thus, patients must understand that weight gain is not an indication of treatment failure after RF or any other method of irreversible fat destruction.⁵

High-intensity Focused Ultrasound

High-intensity focused ultrasound recently was introduced as a new treatment modality for body contouring, specifically for skin tightening and rejuvenation.⁵ The mechanism of HIFU is similar to that of RF in that it also relies on heat to cause adipocyte apoptosis; however, it utilizes acoustic energy rather than electric energy. High-intensity focused ultrasound devices can deliver energy to the deep dermis, subdermal connective tissue, and fibromuscular layers in precise microcoagulation zones without damage to the epidermis. The focused energy induces a high temperature (>65°C) within 1 to 3 seconds, causing cell protein coagulation in the targeted area. In addition to its thermal effects, HIFU induces a mechanical effect that disrupts cell membranes immediately, which contributes to the coagulation necrosis process, further promoting necrosis and apoptosis. The effects of these devices can be visualized, as there always is a sharp demarcation between the targeted and untargeted tissue.²⁹ Additionally, microcoagulation is thought to cause gradual skin tightening through collagen contraction and remodeling.³⁰

High-intensity focused ultrasound first received FDA approval for eyebrow lifting and has been used safely and effectively to treat facial and neck skin in a variety of skin types as well as to improve the clinical appearance of the abdomen and thighs.³¹ This technique is best suited for patients with mild to moderate laxity of the skin or soft tissue who have a body mass index less than 30 kg/m² and are seeking mild body contouring.³² The ideal patient is young with normal wound healing, since the clinical response to treatment is partly dependent on new collagen synthesis.³³ Older patients with extensive photoaging or severe skin laxity are not good candidates for HIFU.

There are a variety of available HIFU devices,³⁴ which utilize special transducers that direct ultrasound energy to a small focal point in the subcutaneous tissues that harmlessly passes through the skin.³⁵ By using newly developed transducers with different energy outputs and focal depths, dermatologists can tailor HIFU treatment to meet the unique physical characteristics of each patient.³¹

Adverse effects of HIFU are limited to transient pain in most patients and occasional erythema and ecchymosis in some cases.³¹ In general, most adverse effects resolve spontaneously within 4 weeks and all by 12 weeks posttreatment. Studies also have reported hard subcutaneous nodules, discomfort, burning sensation, mild blisters, and one case of purpuric lesions, all at the treatment site.^36-39 There is no evidence that HIFU can cause abnormalities in serum lipids or liver function tests.

 

Lasers

Laser technology is a rapidly growing modality in noninvasive body contouring. A novel device recently emerged as the first and only FDA-cleared hyperthermic laser for fat reduction and noninvasive body contouring of the abdomen, flanks, back, inner and outer thighs, and submental area.^40,41 The device is a 1060-nm diode laser that uses thermal energy to destroy adipose tissue, leading to permanent reduction in stubborn fat without surgery or downtime through the use of a flat, nonsuction applicator that is designed for consistent, natural-looking results. The device includes a contact cooling system that helps to limit thermal discomfort and prevent damage to the surface of the skin during the procedure. Initial improvement can be seen as quickly as 6 weeks posttreatment, and optimal results usually occur in as few as 12 weeks. This device was found to have an excellent safety profile and was well tolerated among patients, with only mild pain reported.^42,43

Prior to the development of this new 1060-nm diode laser, the initial application of lasers for noninvasive body contouring involved low-level laser therapy (LLLT), also known as cold laser therapy.⁴⁰ One device has 5 rotating diode laser heads that work at a wavelength of 635 nm. Treatment sessions last up to 30 minutes, and 6 to 8 sessions are required to obtain optimal results. Low-level laser therapy is a unique modality that is not based on thermal tissue damage, but rather on producing transient microscopic pores in adipocytes that allow lipids to leak out, leading to fat reduction.³⁴ Because LLLT causes immediate emptying of targeted adipocytes, results are noticeable as soon as treatment is completed; however, there is no necrosis or apoptosis of adipocytes, so the recurrence of fat deposition is believed to be greater when compared to the other modalities. Because the results are temporary, long-term or permanent results should not be expected with LLLT. Depending on the patient’s goals, the temporary nature of the results can be either an advantage or disadvantage: some may prefer immediate results despite gradual diminishment over subsequent months, whereas others may prefer results that progressively increase over time and are more permanent, as seen with cryolipolysis, HIFU, and RF.³

Complications of LLLT generally are fewer and more mild than with all other body contouring procedures, with several studies reporting no adverse effects.^44-48 Others reported swelling or erythema at the treatment area, pain or tingling during treatment, and increased urination, all of which were temporary and resolved spontaneously.⁴⁹ Additionally, although the lipids released from treatment are cleared through the lymphatic system, LLLT has not been shown to increase serum lipid levels.⁵⁰

Conclusion

The field of noninvasive body contouring is undoubtedly growing and will likely continue to rise in popularity as the efficacy and safety of these treatments improve. Although the available technologies vary by mechanism and side effect profiles, several devices have been revealed to be safe and effective in reducing subcutaneous fat tissue and improving skin laxity.¹ However, additional studies are needed to evaluate these devices in a standardized manner, especially considering the high costs associated with treatment.³² Current studies investigating these devices vary in treatment protocol, treatment area, number and timing of follow-up sessions, and outcome measures, making it challenging to compare the results objectively.³ Dermatologists offering body contouring treatments need to be intimately familiar with the available devices and determine which treatment is appropriate for each patient in order to provide the highest quality care. Most importantly, patients and physicians must discuss individual goals when choosing a body-contouring method in order to maximize patient satisfaction.

In today’s society there is a ubiquitous pressure to lose weight, reduce fat, and rejuvenate the skin that stems not only from images of idealized bodies in the media but also from our growing knowledge of the detrimental effects of obesity. Along with diet and exercise, it has become popular to use noninvasive devices to attain these goals by means of body contouring—the optimization of the definition, smoothness, and shape of the human physique.¹ In fact, body contouring currently is the fastest-growing area of cosmetic dermatology.²

Previously, body contouring primarily involved invasive procedures (eg, liposuction) that are associated with various adverse effects, financial costs, and lengthy downtime.³ More recently, a growing demand for safer and less painful procedures for adipose tissue reduction and skin tightening have led to the development of several novel modalities for noninvasive body contouring. Although the results achieved using these new technologies may be less dramatic than invasive techniques and are not immediate, they do not carry the risks and adverse effects that are associated with surgical procedures and therefore are increasingly requested by cosmetic patients.^4,5 New noninvasive techniques primarily target the physical properties of fat, resulting in an efflux of triglycerides from fat cells, causing either reduced size, necrosis, or apoptosis of adipocytes.^3,6 Of these modalities, cold-induced adipocyte apoptosis has been commercially available the longest and has been the most researched; however, other noninvasive body contouring techniques have been increasingly explored by researchers since the first reports of human adipose tissue explants exhibiting features of apoptosis after heat injury became available.^7,8

There currently are 4 leading modalities used for noninvasive body contouring: cryolipolysis, radiofrequency (RF), high-intensity focused ultrasound (HIFU), and laser therapy (Table). Although no procedure has yet been accepted as the gold standard, investigators are working to determine which technique is the most effective.⁹ In this article, we provide an overview of these techniques to help dermatologists choose appropriate modalities for their cosmetic patients.

Cryolipolysis

Cryolipolysis is unique in that it employs the principle that lipid-rich adipocytes are more susceptible to freezing than surrounding water-rich cells, allowing selective apoptosis while preserving the adjacent structures. As macrophages digest the apoptotic adipocytes, patients experience a decrease in subcutaneous fat volume over the subsequent 2 to 3 months.^10-13 Cryolipolysis has been gaining popularity since 2010, when it was first approved by the US Food and Drug Administration (FDA) for fat reduction in the flank areas; it was later approved for the abdomen in 2012, thighs in 2014, and submental area in 2015.¹⁴ Most recently, cryolipolysis was approved for fat reduction in the arms, back, and buttocks in 2016.

The most popular cryolipolysis device applies suction to the treatment area and vacuums the tissue between 2 cooling panels for 30 to 60 minutes.⁹ Clinical studies investigating the safety and efficacy of cryolipolysis have reported a high degree of patient satisfaction with the procedure and only minimal side effects.^4,6,15,16 Common complications of cryolipolysis include erythema, swelling, and sensitivity at the treatment site followed by a lesser incidence of pain, tingling, and bruising, all of which generally resolve within a few weeks of treatment.⁶ With the removal of adipocytes, there has been concern regarding elevations in blood lipid levels and liver enzymes; however, these laboratory values have been reported to remain within normal limits during and after cryolipolysis.^17,18 Of note, patients should be advised of the risk of paradoxical adipose hyperplasia, a rare side effect of cryolipolysis in which a large, demarcated, tender fat mass develops at the treatment site 2 to 3 months after treatment, with an estimated incidence of 1 in 20,000.¹⁹ However, the incidence of paradoxical adipose hyperplasia may be underestimated, as a single practice reported an incidence of 0.47% in 422 cryolipolysis treatments.²⁰ This complication has not been associated with any of the heat-induced fat reduction modalities.

Cryolipolysis has been found to be safe for all skin types with no reported pigmentary changes.¹⁶ It should not be performed in patients with cold-induced conditions (eg, cryoglobulinemia, cold urticaria) or in those with severe varicose veins or atopic dermatitis.^21,22 Patients benefitting most from this procedure are those who require only small or moderate amounts of adipose tissue and cellulite removal with separate fat bulges.^12,17 Interestingly, cryolipolysis also has been used off label to treat pseudogynecomastia in male patients.²³

 

Radiofrequency

Radiofrequency has become an important and frequently used modality in cosmetic dermatology.²⁴ This modality differs from cryolipolysis in that it relies on exploiting the difference in water content and impedance between tissues: the skin has low impedance, whereas fat tissue has high impedance. Radiofrequency induces thermal injury to targeted tissue layers, rather than the cold-induced damage seen in cryolipolysis, through devices that focus thermal energy on tissues with high impedance, inducing apoptosis of cells in the subcutaneous adipose tissue with minimal risk of damaging the epidermis, dermis, and muscle.^9,25 Ultimately, thermal exposure to 43°C to 45°C over several minutes results in a delayed adipocyte death response.⁴ In addition to adipocyte death, RF has been shown to cause denaturation of collagen fibrils, leading to subsequent remodeling, neocollagenesis, and skin tightening.²⁶

Radiofrequency devices can be broadly classified as monopolar or bipolar.^24,27 Bipolar devices generally require more frequent treatments, whereas monopolar devices tend to require fewer treatment sessions with superior circumference and fat reduction.²⁸

Overall, RF devices have a favorable side effect profile. The most common side effects are erythema and edema at the treatment site lasting less than 24 hours after the procedure.²⁵ The absence of complications such as abdominal discomfort, erythema, and burning during treatment have been reported,²⁷ with the exception of 1 case of hyperesthesia on the abdomen that lasted for 3 days after a treatment session.⁵ Although RF has beneficial effects on circumference reduction in the abdomen and thighs and can improve the appearance of cellulite, an increase in body weight may occur during treatment. When a localized area of fat such as the thigh is targeted for treatment but the remaining fat cells in the body are not affected, the remaining cells can continue to grow and expand; for instance, although fat cells destroyed with RF will not continue to expand, fat cells in untreated areas may continue to grow due to continued weight gain (eg, from excessive eating), leading to overall weight gain. Thus, patients must understand that weight gain is not an indication of treatment failure after RF or any other method of irreversible fat destruction.⁵

High-intensity Focused Ultrasound

High-intensity focused ultrasound recently was introduced as a new treatment modality for body contouring, specifically for skin tightening and rejuvenation.⁵ The mechanism of HIFU is similar to that of RF in that it also relies on heat to cause adipocyte apoptosis; however, it utilizes acoustic energy rather than electric energy. High-intensity focused ultrasound devices can deliver energy to the deep dermis, subdermal connective tissue, and fibromuscular layers in precise microcoagulation zones without damage to the epidermis. The focused energy induces a high temperature (>65°C) within 1 to 3 seconds, causing cell protein coagulation in the targeted area. In addition to its thermal effects, HIFU induces a mechanical effect that disrupts cell membranes immediately, which contributes to the coagulation necrosis process, further promoting necrosis and apoptosis. The effects of these devices can be visualized, as there always is a sharp demarcation between the targeted and untargeted tissue.²⁹ Additionally, microcoagulation is thought to cause gradual skin tightening through collagen contraction and remodeling.³⁰

High-intensity focused ultrasound first received FDA approval for eyebrow lifting and has been used safely and effectively to treat facial and neck skin in a variety of skin types as well as to improve the clinical appearance of the abdomen and thighs.³¹ This technique is best suited for patients with mild to moderate laxity of the skin or soft tissue who have a body mass index less than 30 kg/m² and are seeking mild body contouring.³² The ideal patient is young with normal wound healing, since the clinical response to treatment is partly dependent on new collagen synthesis.³³ Older patients with extensive photoaging or severe skin laxity are not good candidates for HIFU.

There are a variety of available HIFU devices,³⁴ which utilize special transducers that direct ultrasound energy to a small focal point in the subcutaneous tissues that harmlessly passes through the skin.³⁵ By using newly developed transducers with different energy outputs and focal depths, dermatologists can tailor HIFU treatment to meet the unique physical characteristics of each patient.³¹

Adverse effects of HIFU are limited to transient pain in most patients and occasional erythema and ecchymosis in some cases.³¹ In general, most adverse effects resolve spontaneously within 4 weeks and all by 12 weeks posttreatment. Studies also have reported hard subcutaneous nodules, discomfort, burning sensation, mild blisters, and one case of purpuric lesions, all at the treatment site.^36-39 There is no evidence that HIFU can cause abnormalities in serum lipids or liver function tests.

 

Lasers

Laser technology is a rapidly growing modality in noninvasive body contouring. A novel device recently emerged as the first and only FDA-cleared hyperthermic laser for fat reduction and noninvasive body contouring of the abdomen, flanks, back, inner and outer thighs, and submental area.^40,41 The device is a 1060-nm diode laser that uses thermal energy to destroy adipose tissue, leading to permanent reduction in stubborn fat without surgery or downtime through the use of a flat, nonsuction applicator that is designed for consistent, natural-looking results. The device includes a contact cooling system that helps to limit thermal discomfort and prevent damage to the surface of the skin during the procedure. Initial improvement can be seen as quickly as 6 weeks posttreatment, and optimal results usually occur in as few as 12 weeks. This device was found to have an excellent safety profile and was well tolerated among patients, with only mild pain reported.^42,43

Prior to the development of this new 1060-nm diode laser, the initial application of lasers for noninvasive body contouring involved low-level laser therapy (LLLT), also known as cold laser therapy.⁴⁰ One device has 5 rotating diode laser heads that work at a wavelength of 635 nm. Treatment sessions last up to 30 minutes, and 6 to 8 sessions are required to obtain optimal results. Low-level laser therapy is a unique modality that is not based on thermal tissue damage, but rather on producing transient microscopic pores in adipocytes that allow lipids to leak out, leading to fat reduction.³⁴ Because LLLT causes immediate emptying of targeted adipocytes, results are noticeable as soon as treatment is completed; however, there is no necrosis or apoptosis of adipocytes, so the recurrence of fat deposition is believed to be greater when compared to the other modalities. Because the results are temporary, long-term or permanent results should not be expected with LLLT. Depending on the patient’s goals, the temporary nature of the results can be either an advantage or disadvantage: some may prefer immediate results despite gradual diminishment over subsequent months, whereas others may prefer results that progressively increase over time and are more permanent, as seen with cryolipolysis, HIFU, and RF.³

Complications of LLLT generally are fewer and more mild than with all other body contouring procedures, with several studies reporting no adverse effects.^44-48 Others reported swelling or erythema at the treatment area, pain or tingling during treatment, and increased urination, all of which were temporary and resolved spontaneously.⁴⁹ Additionally, although the lipids released from treatment are cleared through the lymphatic system, LLLT has not been shown to increase serum lipid levels.⁵⁰

Conclusion

The field of noninvasive body contouring is undoubtedly growing and will likely continue to rise in popularity as the efficacy and safety of these treatments improve. Although the available technologies vary by mechanism and side effect profiles, several devices have been revealed to be safe and effective in reducing subcutaneous fat tissue and improving skin laxity.¹ However, additional studies are needed to evaluate these devices in a standardized manner, especially considering the high costs associated with treatment.³² Current studies investigating these devices vary in treatment protocol, treatment area, number and timing of follow-up sessions, and outcome measures, making it challenging to compare the results objectively.³ Dermatologists offering body contouring treatments need to be intimately familiar with the available devices and determine which treatment is appropriate for each patient in order to provide the highest quality care. Most importantly, patients and physicians must discuss individual goals when choosing a body-contouring method in order to maximize patient satisfaction.

Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformis, is a relatively rare cutaneous disorder of pregnancy wherein lesions typically appear in the third trimester and resolve after delivery; however, lesions may persist through the postpartum period. Pustular psoriasis of pregnancy may be considered a fifth dermatosis of pregnancy, alongside the classic dermatoses of atopic eruption of pregnancy, intrahepatic cholestasis of pregnancy, pemphigoid gestationis, and pruritic urticarial papules and plaques of pregnancy.¹

As PPP is a rare disease, its effects on maternal-fetal health outcomes and management remain to be elucidated. Though maternal mortality is rare in PPP, it is a unique dermatosis of pregnancy because it may be associated with severe systemic maternal symptoms.² Fetal morbidity and mortality are less predictable in PPP, with reported cases of stillbirth, fetal anomalies, and neonatal death thought to be due largely to placental insufficiency, even with control of symptoms.^1,3 Given the risk of serious harm to the fetus, reporting of cases and discussion of PPP management is critical.

Case Report

An otherwise healthy 29-year-old G2P1 woman at 32 weeks’ gestation presented to our emergency department with a 1-week history of a pruritic, burning rash that started on the thighs then spread diffusely. She denied any similar rash in her prior pregnancy. She was not currently taking any medications except for prenatal vitamins and denied any systemic symptoms. The patient’s obstetrician initiated treatment with methylprednisolone 50 mg once daily for the rash 3 days prior to the current presentation, which had not seemed to help. On physical examination, edematous pink plaques studded with 1- to 2-mm collarettes of scaling and sparse 1-mm pustules involving the arms, chest, abdomen, back, groin, buttocks, and legs were noted. The plaques on the back and inner thighs had a peripheral rim of desquamative scaling. There were pink macules on the palms, and superficial desquamation was noted on the lips. The oral mucosa was otherwise spared (Figure 1).

Biopsy specimens from the left arm revealed discrete subcorneal pustules with mild acanthosis of the epidermis with spongiosis (Figure 2). The papillary dermis showed a sparse infiltrate of neutrophils with many marginated neutrophils within vessels. Direct immunofluorescence was negative for human IgG, IgA, IgM, complement component 3, and fibrinogen. Laboratory workup revealed leukocytosis of 21.5×10⁹/L (reference range, 4.5–11.0×10⁹/L) with neutrophilic predominance of 73.6% (reference range, 56%), an elevated erythrocyte sedimentation rate (ESR) of 40 mm/h (reference range, 0–20 mm/h), and a mild hypocalcemia of 8.6 mg/dL (reference range, 8.2–10.2 mg/dL). The patient was started on methylprednisone 40 mg once daily with a plan to taper the dose by 8 mg every 5 days.

At 35 weeks’ gestation, the patient continued to report pruritus and burning in the areas where the rash had developed. The morphology of the rash had changed considerably, as she now had prominent, annular, pink plaques with central clearing, trailing scaling, and a border of subtle pustules on the legs. There also were rings of desquamative scaling on the palms. During follow-up at 37 weeks’ gestation, the back, chest, and abdomen were improved from the initial presentation, and annular pink plaques with central clearing were noted on the legs (Figure 3). Given the clinical and histopathologic findings, a diagnosis of PPP was made. It was recommended that she undergo increased fetal surveillance with close obstetric follow-up. Weekly office visits with obstetrics and twice-weekly Doppler ultrasounds and fetal nonstress tests were deemed appropriate management. The patient was scheduled for induction at 39 weeks’ gestation given the risk for potential harm to the fetus. She was maintained on low-dose methylprednisolone 4 mg once daily for the duration of the pregnancy. The patient continued to have gradual improvement of the rash at the low treatment dose.

Following induction at 39 weeks’ gestation, the patient vaginally delivered a healthy, 6-lb male neonate at an outside hospital. She reported that the burning sensation improved within hours of delivery, and systemic steroids were stopped after delivery. At a follow-up visit 3 weeks postpartum, considerable improvement of the rash was noted with no evidence of pustules. Fading pink patches with a superficial scaling were noted on the back, chest, abdomen, arms, legs (Figure 4), and fingertips. The patient was counseled that PPP could recur in subsequent pregnancies and that she should be aware of the potential risks to the fetus.

 

Comment

In our patient, the diagnosis of PPP was supported by the presence of erythematous, coalescent plaques with small pustules at the margins and central erosions as well as the histologic findings of subcorneal pustules with mild acanthosis of the epidermis with spongiosis and a sparse neutrophilic infiltrate into the dermis. Laboratory studies showing leukocytosis and an elevated ESR, which are often seen in PPP, also were noted.

The typical presentation of PPP is characterized by lesions that initially develop in skin folds with centrifugal spread.³ The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet typically are spared with occasional involvement of oral and esophageal mucosae. Biopsy findings typically include spongiform pustules with neutrophil invasion into the epidermis. Typical laboratory findings include electrolyte derangements with elevated ESR and leukocytosis.¹

Diagnosis of PPP is critical given the potential for associated fetal morbidity and mortality.⁴ Anticipatory guidance for the patient also is necessary, as PPP can recur with subsequent pregnancies or even use of oral contraceptive pills (OCPs). Notably, a patient with recurrences of PPP with each of 9 pregnancies also experienced a recurrence when taking a combination estrogen/progesterone OCP, but not with an estrogen-only diethylstilbestrol OCP.⁵ Although the pathophysiology is not entirely understood, the development of PPP is thought to be related to the hormonal changes that occur in the third trimester, most notably due to elevated progesterone levels.² The presence of progesterone in OCPs and recurrences associated with their use supports this altered hormonal state, contributing to the underlying pathophysiology of PPP.

Pustular psoriasis of pregnancy can occur in women without any personal or family history of psoriasis, and as such, it is unclear whether PPP is a separate entity or a hormonally induced variation of generalized pustular psoriasis. Recent evidence included reports of women with PPP who had a mutation in the IL-36 receptor antagonist, leading to a relative abundance of IL-36 inflammatory cytokines.⁶As the cytokine profile during pregnancy is physiologically altered to favor a T helper 2–cell state, the altered expression of cytokines is believed to trigger an inflammatory response conducive to the development of PPP.² This mutation in the IL-36 receptor antagonist also is found in individuals with generalized pustular psoriasis, suggesting an overlap of disease etiology related to these cytokine interactions.^2,7,8

The mainstay of treatment for PPP is oral corticosteroids. Cases of PPP that are unresponsive to systemic steroids have been documented, requiring treatment with cyclosporine.⁹ Antitumor necrosis factors also have been used safely during pregnancy.¹⁰ Narrowband UVB phototherapy also has been proposed as a treatment alternative for patients who do not respond to oral corticosteroids.¹¹

Conclusion

Pustular psoriasis of pregnancy is a rare dermatosis of pregnancy that, unlike most other common dermatoses of pregnancy, is associated with adverse fetal outcomes. Diagnosis and management of PPP are critical to ensure the best care and outcomes for the patient and fetus and for a successful delivery of a healthy neonate. Our patient with PPP presented with involvement of the body, palms, and oral mucosa in the absence of systemic symptoms. Close follow-up and comanagement with the patient’s obstetrician ensured safe outcomes for the patient and the neonate.

Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformis, is a relatively rare cutaneous disorder of pregnancy wherein lesions typically appear in the third trimester and resolve after delivery; however, lesions may persist through the postpartum period. Pustular psoriasis of pregnancy may be considered a fifth dermatosis of pregnancy, alongside the classic dermatoses of atopic eruption of pregnancy, intrahepatic cholestasis of pregnancy, pemphigoid gestationis, and pruritic urticarial papules and plaques of pregnancy.¹

As PPP is a rare disease, its effects on maternal-fetal health outcomes and management remain to be elucidated. Though maternal mortality is rare in PPP, it is a unique dermatosis of pregnancy because it may be associated with severe systemic maternal symptoms.² Fetal morbidity and mortality are less predictable in PPP, with reported cases of stillbirth, fetal anomalies, and neonatal death thought to be due largely to placental insufficiency, even with control of symptoms.^1,3 Given the risk of serious harm to the fetus, reporting of cases and discussion of PPP management is critical.

Case Report

An otherwise healthy 29-year-old G2P1 woman at 32 weeks’ gestation presented to our emergency department with a 1-week history of a pruritic, burning rash that started on the thighs then spread diffusely. She denied any similar rash in her prior pregnancy. She was not currently taking any medications except for prenatal vitamins and denied any systemic symptoms. The patient’s obstetrician initiated treatment with methylprednisolone 50 mg once daily for the rash 3 days prior to the current presentation, which had not seemed to help. On physical examination, edematous pink plaques studded with 1- to 2-mm collarettes of scaling and sparse 1-mm pustules involving the arms, chest, abdomen, back, groin, buttocks, and legs were noted. The plaques on the back and inner thighs had a peripheral rim of desquamative scaling. There were pink macules on the palms, and superficial desquamation was noted on the lips. The oral mucosa was otherwise spared (Figure 1).

Biopsy specimens from the left arm revealed discrete subcorneal pustules with mild acanthosis of the epidermis with spongiosis (Figure 2). The papillary dermis showed a sparse infiltrate of neutrophils with many marginated neutrophils within vessels. Direct immunofluorescence was negative for human IgG, IgA, IgM, complement component 3, and fibrinogen. Laboratory workup revealed leukocytosis of 21.5×10⁹/L (reference range, 4.5–11.0×10⁹/L) with neutrophilic predominance of 73.6% (reference range, 56%), an elevated erythrocyte sedimentation rate (ESR) of 40 mm/h (reference range, 0–20 mm/h), and a mild hypocalcemia of 8.6 mg/dL (reference range, 8.2–10.2 mg/dL). The patient was started on methylprednisone 40 mg once daily with a plan to taper the dose by 8 mg every 5 days.

At 35 weeks’ gestation, the patient continued to report pruritus and burning in the areas where the rash had developed. The morphology of the rash had changed considerably, as she now had prominent, annular, pink plaques with central clearing, trailing scaling, and a border of subtle pustules on the legs. There also were rings of desquamative scaling on the palms. During follow-up at 37 weeks’ gestation, the back, chest, and abdomen were improved from the initial presentation, and annular pink plaques with central clearing were noted on the legs (Figure 3). Given the clinical and histopathologic findings, a diagnosis of PPP was made. It was recommended that she undergo increased fetal surveillance with close obstetric follow-up. Weekly office visits with obstetrics and twice-weekly Doppler ultrasounds and fetal nonstress tests were deemed appropriate management. The patient was scheduled for induction at 39 weeks’ gestation given the risk for potential harm to the fetus. She was maintained on low-dose methylprednisolone 4 mg once daily for the duration of the pregnancy. The patient continued to have gradual improvement of the rash at the low treatment dose.

Following induction at 39 weeks’ gestation, the patient vaginally delivered a healthy, 6-lb male neonate at an outside hospital. She reported that the burning sensation improved within hours of delivery, and systemic steroids were stopped after delivery. At a follow-up visit 3 weeks postpartum, considerable improvement of the rash was noted with no evidence of pustules. Fading pink patches with a superficial scaling were noted on the back, chest, abdomen, arms, legs (Figure 4), and fingertips. The patient was counseled that PPP could recur in subsequent pregnancies and that she should be aware of the potential risks to the fetus.

 

Comment

In our patient, the diagnosis of PPP was supported by the presence of erythematous, coalescent plaques with small pustules at the margins and central erosions as well as the histologic findings of subcorneal pustules with mild acanthosis of the epidermis with spongiosis and a sparse neutrophilic infiltrate into the dermis. Laboratory studies showing leukocytosis and an elevated ESR, which are often seen in PPP, also were noted.

The typical presentation of PPP is characterized by lesions that initially develop in skin folds with centrifugal spread.³ The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet typically are spared with occasional involvement of oral and esophageal mucosae. Biopsy findings typically include spongiform pustules with neutrophil invasion into the epidermis. Typical laboratory findings include electrolyte derangements with elevated ESR and leukocytosis.¹

Diagnosis of PPP is critical given the potential for associated fetal morbidity and mortality.⁴ Anticipatory guidance for the patient also is necessary, as PPP can recur with subsequent pregnancies or even use of oral contraceptive pills (OCPs). Notably, a patient with recurrences of PPP with each of 9 pregnancies also experienced a recurrence when taking a combination estrogen/progesterone OCP, but not with an estrogen-only diethylstilbestrol OCP.⁵ Although the pathophysiology is not entirely understood, the development of PPP is thought to be related to the hormonal changes that occur in the third trimester, most notably due to elevated progesterone levels.² The presence of progesterone in OCPs and recurrences associated with their use supports this altered hormonal state, contributing to the underlying pathophysiology of PPP.

Pustular psoriasis of pregnancy can occur in women without any personal or family history of psoriasis, and as such, it is unclear whether PPP is a separate entity or a hormonally induced variation of generalized pustular psoriasis. Recent evidence included reports of women with PPP who had a mutation in the IL-36 receptor antagonist, leading to a relative abundance of IL-36 inflammatory cytokines.⁶As the cytokine profile during pregnancy is physiologically altered to favor a T helper 2–cell state, the altered expression of cytokines is believed to trigger an inflammatory response conducive to the development of PPP.² This mutation in the IL-36 receptor antagonist also is found in individuals with generalized pustular psoriasis, suggesting an overlap of disease etiology related to these cytokine interactions.^2,7,8

The mainstay of treatment for PPP is oral corticosteroids. Cases of PPP that are unresponsive to systemic steroids have been documented, requiring treatment with cyclosporine.⁹ Antitumor necrosis factors also have been used safely during pregnancy.¹⁰ Narrowband UVB phototherapy also has been proposed as a treatment alternative for patients who do not respond to oral corticosteroids.¹¹

Conclusion

Pustular psoriasis of pregnancy is a rare dermatosis of pregnancy that, unlike most other common dermatoses of pregnancy, is associated with adverse fetal outcomes. Diagnosis and management of PPP are critical to ensure the best care and outcomes for the patient and fetus and for a successful delivery of a healthy neonate. Our patient with PPP presented with involvement of the body, palms, and oral mucosa in the absence of systemic symptoms. Close follow-up and comanagement with the patient’s obstetrician ensured safe outcomes for the patient and the neonate.

Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformis, is a relatively rare cutaneous disorder of pregnancy wherein lesions typically appear in the third trimester and resolve after delivery; however, lesions may persist through the postpartum period. Pustular psoriasis of pregnancy may be considered a fifth dermatosis of pregnancy, alongside the classic dermatoses of atopic eruption of pregnancy, intrahepatic cholestasis of pregnancy, pemphigoid gestationis, and pruritic urticarial papules and plaques of pregnancy.¹

As PPP is a rare disease, its effects on maternal-fetal health outcomes and management remain to be elucidated. Though maternal mortality is rare in PPP, it is a unique dermatosis of pregnancy because it may be associated with severe systemic maternal symptoms.² Fetal morbidity and mortality are less predictable in PPP, with reported cases of stillbirth, fetal anomalies, and neonatal death thought to be due largely to placental insufficiency, even with control of symptoms.^1,3 Given the risk of serious harm to the fetus, reporting of cases and discussion of PPP management is critical.

Case Report

An otherwise healthy 29-year-old G2P1 woman at 32 weeks’ gestation presented to our emergency department with a 1-week history of a pruritic, burning rash that started on the thighs then spread diffusely. She denied any similar rash in her prior pregnancy. She was not currently taking any medications except for prenatal vitamins and denied any systemic symptoms. The patient’s obstetrician initiated treatment with methylprednisolone 50 mg once daily for the rash 3 days prior to the current presentation, which had not seemed to help. On physical examination, edematous pink plaques studded with 1- to 2-mm collarettes of scaling and sparse 1-mm pustules involving the arms, chest, abdomen, back, groin, buttocks, and legs were noted. The plaques on the back and inner thighs had a peripheral rim of desquamative scaling. There were pink macules on the palms, and superficial desquamation was noted on the lips. The oral mucosa was otherwise spared (Figure 1).

Biopsy specimens from the left arm revealed discrete subcorneal pustules with mild acanthosis of the epidermis with spongiosis (Figure 2). The papillary dermis showed a sparse infiltrate of neutrophils with many marginated neutrophils within vessels. Direct immunofluorescence was negative for human IgG, IgA, IgM, complement component 3, and fibrinogen. Laboratory workup revealed leukocytosis of 21.5×10⁹/L (reference range, 4.5–11.0×10⁹/L) with neutrophilic predominance of 73.6% (reference range, 56%), an elevated erythrocyte sedimentation rate (ESR) of 40 mm/h (reference range, 0–20 mm/h), and a mild hypocalcemia of 8.6 mg/dL (reference range, 8.2–10.2 mg/dL). The patient was started on methylprednisone 40 mg once daily with a plan to taper the dose by 8 mg every 5 days.

At 35 weeks’ gestation, the patient continued to report pruritus and burning in the areas where the rash had developed. The morphology of the rash had changed considerably, as she now had prominent, annular, pink plaques with central clearing, trailing scaling, and a border of subtle pustules on the legs. There also were rings of desquamative scaling on the palms. During follow-up at 37 weeks’ gestation, the back, chest, and abdomen were improved from the initial presentation, and annular pink plaques with central clearing were noted on the legs (Figure 3). Given the clinical and histopathologic findings, a diagnosis of PPP was made. It was recommended that she undergo increased fetal surveillance with close obstetric follow-up. Weekly office visits with obstetrics and twice-weekly Doppler ultrasounds and fetal nonstress tests were deemed appropriate management. The patient was scheduled for induction at 39 weeks’ gestation given the risk for potential harm to the fetus. She was maintained on low-dose methylprednisolone 4 mg once daily for the duration of the pregnancy. The patient continued to have gradual improvement of the rash at the low treatment dose.

Following induction at 39 weeks’ gestation, the patient vaginally delivered a healthy, 6-lb male neonate at an outside hospital. She reported that the burning sensation improved within hours of delivery, and systemic steroids were stopped after delivery. At a follow-up visit 3 weeks postpartum, considerable improvement of the rash was noted with no evidence of pustules. Fading pink patches with a superficial scaling were noted on the back, chest, abdomen, arms, legs (Figure 4), and fingertips. The patient was counseled that PPP could recur in subsequent pregnancies and that she should be aware of the potential risks to the fetus.

 

Comment

In our patient, the diagnosis of PPP was supported by the presence of erythematous, coalescent plaques with small pustules at the margins and central erosions as well as the histologic findings of subcorneal pustules with mild acanthosis of the epidermis with spongiosis and a sparse neutrophilic infiltrate into the dermis. Laboratory studies showing leukocytosis and an elevated ESR, which are often seen in PPP, also were noted.

The typical presentation of PPP is characterized by lesions that initially develop in skin folds with centrifugal spread.³ The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet typically are spared with occasional involvement of oral and esophageal mucosae. Biopsy findings typically include spongiform pustules with neutrophil invasion into the epidermis. Typical laboratory findings include electrolyte derangements with elevated ESR and leukocytosis.¹

Diagnosis of PPP is critical given the potential for associated fetal morbidity and mortality.⁴ Anticipatory guidance for the patient also is necessary, as PPP can recur with subsequent pregnancies or even use of oral contraceptive pills (OCPs). Notably, a patient with recurrences of PPP with each of 9 pregnancies also experienced a recurrence when taking a combination estrogen/progesterone OCP, but not with an estrogen-only diethylstilbestrol OCP.⁵ Although the pathophysiology is not entirely understood, the development of PPP is thought to be related to the hormonal changes that occur in the third trimester, most notably due to elevated progesterone levels.² The presence of progesterone in OCPs and recurrences associated with their use supports this altered hormonal state, contributing to the underlying pathophysiology of PPP.

Pustular psoriasis of pregnancy can occur in women without any personal or family history of psoriasis, and as such, it is unclear whether PPP is a separate entity or a hormonally induced variation of generalized pustular psoriasis. Recent evidence included reports of women with PPP who had a mutation in the IL-36 receptor antagonist, leading to a relative abundance of IL-36 inflammatory cytokines.⁶As the cytokine profile during pregnancy is physiologically altered to favor a T helper 2–cell state, the altered expression of cytokines is believed to trigger an inflammatory response conducive to the development of PPP.² This mutation in the IL-36 receptor antagonist also is found in individuals with generalized pustular psoriasis, suggesting an overlap of disease etiology related to these cytokine interactions.^2,7,8

The mainstay of treatment for PPP is oral corticosteroids. Cases of PPP that are unresponsive to systemic steroids have been documented, requiring treatment with cyclosporine.⁹ Antitumor necrosis factors also have been used safely during pregnancy.¹⁰ Narrowband UVB phototherapy also has been proposed as a treatment alternative for patients who do not respond to oral corticosteroids.¹¹

Conclusion

Pustular psoriasis of pregnancy is a rare dermatosis of pregnancy that, unlike most other common dermatoses of pregnancy, is associated with adverse fetal outcomes. Diagnosis and management of PPP are critical to ensure the best care and outcomes for the patient and fetus and for a successful delivery of a healthy neonate. Our patient with PPP presented with involvement of the body, palms, and oral mucosa in the absence of systemic symptoms. Close follow-up and comanagement with the patient’s obstetrician ensured safe outcomes for the patient and the neonate.