Nonmelanoma Skin Cancer

WAILEA, HAWAII – Nicotinamide is one of the rare proposed agents for skin cancer chemoprevention distinguished by dirt cheap cost combined with a highly reassuring safety profile plus evidence of efficacy – which, together, make it a reasonable option in high risk patients, according to Daniel M. Siegel, MD.

Other agents that fit into that category include the tropical rainforest fern Polypodium leucotomos and milk thistle, added Dr. Siegel, a dermatologist at the State University of New York, Brooklyn.

Bruce Jancin/Frontline Medical News

Nicotinamide

In the case of nicotinamide, the efficacy is actually supported by published level 1 evidence in the form of a highly positive 1-year, double-blind, randomized, placebo-controlled phase III clinical trial.

“You can Google ‘nicotinamide’ and find it at places like Costco and Trader Joe’s for less than 6 cents per day. That makes for a really good risk/benefit ratio. A nickel a day: That’s a cheap one. That’s one where I’d say, ‘Why not?’ It seems to be safe,” Dr. Siegel said.

In the phase III ONTRAC trial, Australian investigators randomized 386 patients who averaged roughly eight nonmelanoma skin cancers in the past 5 years to either 500 mg of oral nicotinamide twice daily or matched placebo for 12 months. During the study period, the nicotinamide group had a statistically significant and clinically meaningful 23% reduction in new nonmelanoma skin cancers, compared with the control group. They also had 13% fewer actinic keratoses at 12 months than controls. And the side effect profile mirrored that of placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26).

“Nicotinamide is vitamin B₃. It’s not niacin. It doesn’t cause flushing and other vasodilatory effects. It’s actually pretty innocuous,” Dr. Siegel said.

In laboratory studies, nicotinamide has been shown to enhance DNA repair following UV exposure, as well as curb UV-induced immunosuppression.

Polypodium leucotomos Samambaia

This plant, commonly known as calaguala in the Spanish-speaking tropics and samambaia in Brazil, has a centuries-long tradition of safe medicinal use. It is commercially available over-the-counter (OTC) as a standardized product called Heliocare, designed to avoid the guesswork involved in topical sunscreen application. Each capsule contains 240 mg of an extract of P. leucotomos. Dr. Siegel said he takes it daily when he’s in a sunny locale, such as Hawaii.

Milk thistle

This plant, known as Silybum marianum, has silymarin as its bioactive compound. Dermatologist Haines Ely, MD, of the University of California, Davis, has reported therapeutic success using it in porphyria cutanea tarda and other conditions. It has been shown to inhibit photocarcinogenesis in animal studies.

Dr. Siegel said that, while Dr. Ely has told him his preferred preparation is a German OTC product, milk thistle seeds can be found in health food stores, ground to a powder using a coffee bean grinder, and used as a food supplement. Like Polypodium leucotomos and nicotinamide, milk thistle is nontoxic.

Rapamycin

This macrolide compound is produced by the bacterium Streptomyces hygroscopicus. Rapamycin is an immunosuppressant used to coat coronary stents and prevent rejection of transplanted organs. It is an mechanistic target of rapamycin signaling pathway inhibitor being studied as a cancer prevention and antiaging agent.

Science magazine called the discovery that rapamycin increased the lifespan of mice one of the top scientific breakthroughs of 2009. Subsequent animal studies have established that the extended lifespan wasn’t solely the result of rapamycin’s antineoplastic effects but of across-the-board delayed onset of all the major age-related diseases. Thus, rapamycin could turn out to be a true antiaging agent, in Dr. Siegel’s view.

Studies in humans are underway. Researchers at Novartis have reported that a rapamycin-related compound curbed the typical decline in immune function that accompanies aging as reflected in a 20% enhancement in the response to influenza vaccine in elderly volunteers (Sci Transl Med. 2014 Dec 24;6[268]:268ra179).

Dr. Siegel reported serving as a consultant to Ferndale, which markets Heliocare. The SDEF and this news organization are owned by the same parent company.

[email protected]

WAILEA, HAWAII – Nicotinamide is one of the rare proposed agents for skin cancer chemoprevention distinguished by dirt cheap cost combined with a highly reassuring safety profile plus evidence of efficacy – which, together, make it a reasonable option in high risk patients, according to Daniel M. Siegel, MD.

Other agents that fit into that category include the tropical rainforest fern Polypodium leucotomos and milk thistle, added Dr. Siegel, a dermatologist at the State University of New York, Brooklyn.

Bruce Jancin/Frontline Medical News

Nicotinamide

In the case of nicotinamide, the efficacy is actually supported by published level 1 evidence in the form of a highly positive 1-year, double-blind, randomized, placebo-controlled phase III clinical trial.

“You can Google ‘nicotinamide’ and find it at places like Costco and Trader Joe’s for less than 6 cents per day. That makes for a really good risk/benefit ratio. A nickel a day: That’s a cheap one. That’s one where I’d say, ‘Why not?’ It seems to be safe,” Dr. Siegel said.

In the phase III ONTRAC trial, Australian investigators randomized 386 patients who averaged roughly eight nonmelanoma skin cancers in the past 5 years to either 500 mg of oral nicotinamide twice daily or matched placebo for 12 months. During the study period, the nicotinamide group had a statistically significant and clinically meaningful 23% reduction in new nonmelanoma skin cancers, compared with the control group. They also had 13% fewer actinic keratoses at 12 months than controls. And the side effect profile mirrored that of placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26).

“Nicotinamide is vitamin B₃. It’s not niacin. It doesn’t cause flushing and other vasodilatory effects. It’s actually pretty innocuous,” Dr. Siegel said.

In laboratory studies, nicotinamide has been shown to enhance DNA repair following UV exposure, as well as curb UV-induced immunosuppression.

Polypodium leucotomos Samambaia

This plant, commonly known as calaguala in the Spanish-speaking tropics and samambaia in Brazil, has a centuries-long tradition of safe medicinal use. It is commercially available over-the-counter (OTC) as a standardized product called Heliocare, designed to avoid the guesswork involved in topical sunscreen application. Each capsule contains 240 mg of an extract of P. leucotomos. Dr. Siegel said he takes it daily when he’s in a sunny locale, such as Hawaii.

Milk thistle

This plant, known as Silybum marianum, has silymarin as its bioactive compound. Dermatologist Haines Ely, MD, of the University of California, Davis, has reported therapeutic success using it in porphyria cutanea tarda and other conditions. It has been shown to inhibit photocarcinogenesis in animal studies.

Dr. Siegel said that, while Dr. Ely has told him his preferred preparation is a German OTC product, milk thistle seeds can be found in health food stores, ground to a powder using a coffee bean grinder, and used as a food supplement. Like Polypodium leucotomos and nicotinamide, milk thistle is nontoxic.

Rapamycin

This macrolide compound is produced by the bacterium Streptomyces hygroscopicus. Rapamycin is an immunosuppressant used to coat coronary stents and prevent rejection of transplanted organs. It is an mechanistic target of rapamycin signaling pathway inhibitor being studied as a cancer prevention and antiaging agent.

Science magazine called the discovery that rapamycin increased the lifespan of mice one of the top scientific breakthroughs of 2009. Subsequent animal studies have established that the extended lifespan wasn’t solely the result of rapamycin’s antineoplastic effects but of across-the-board delayed onset of all the major age-related diseases. Thus, rapamycin could turn out to be a true antiaging agent, in Dr. Siegel’s view.

Studies in humans are underway. Researchers at Novartis have reported that a rapamycin-related compound curbed the typical decline in immune function that accompanies aging as reflected in a 20% enhancement in the response to influenza vaccine in elderly volunteers (Sci Transl Med. 2014 Dec 24;6[268]:268ra179).

Dr. Siegel reported serving as a consultant to Ferndale, which markets Heliocare. The SDEF and this news organization are owned by the same parent company.

[email protected]

WAILEA, HAWAII – Nicotinamide is one of the rare proposed agents for skin cancer chemoprevention distinguished by dirt cheap cost combined with a highly reassuring safety profile plus evidence of efficacy – which, together, make it a reasonable option in high risk patients, according to Daniel M. Siegel, MD.

Other agents that fit into that category include the tropical rainforest fern Polypodium leucotomos and milk thistle, added Dr. Siegel, a dermatologist at the State University of New York, Brooklyn.

Bruce Jancin/Frontline Medical News

Nicotinamide

In the case of nicotinamide, the efficacy is actually supported by published level 1 evidence in the form of a highly positive 1-year, double-blind, randomized, placebo-controlled phase III clinical trial.

“You can Google ‘nicotinamide’ and find it at places like Costco and Trader Joe’s for less than 6 cents per day. That makes for a really good risk/benefit ratio. A nickel a day: That’s a cheap one. That’s one where I’d say, ‘Why not?’ It seems to be safe,” Dr. Siegel said.

In the phase III ONTRAC trial, Australian investigators randomized 386 patients who averaged roughly eight nonmelanoma skin cancers in the past 5 years to either 500 mg of oral nicotinamide twice daily or matched placebo for 12 months. During the study period, the nicotinamide group had a statistically significant and clinically meaningful 23% reduction in new nonmelanoma skin cancers, compared with the control group. They also had 13% fewer actinic keratoses at 12 months than controls. And the side effect profile mirrored that of placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26).

“Nicotinamide is vitamin B₃. It’s not niacin. It doesn’t cause flushing and other vasodilatory effects. It’s actually pretty innocuous,” Dr. Siegel said.

In laboratory studies, nicotinamide has been shown to enhance DNA repair following UV exposure, as well as curb UV-induced immunosuppression.

Polypodium leucotomos Samambaia

This plant, commonly known as calaguala in the Spanish-speaking tropics and samambaia in Brazil, has a centuries-long tradition of safe medicinal use. It is commercially available over-the-counter (OTC) as a standardized product called Heliocare, designed to avoid the guesswork involved in topical sunscreen application. Each capsule contains 240 mg of an extract of P. leucotomos. Dr. Siegel said he takes it daily when he’s in a sunny locale, such as Hawaii.

Milk thistle

This plant, known as Silybum marianum, has silymarin as its bioactive compound. Dermatologist Haines Ely, MD, of the University of California, Davis, has reported therapeutic success using it in porphyria cutanea tarda and other conditions. It has been shown to inhibit photocarcinogenesis in animal studies.

Dr. Siegel said that, while Dr. Ely has told him his preferred preparation is a German OTC product, milk thistle seeds can be found in health food stores, ground to a powder using a coffee bean grinder, and used as a food supplement. Like Polypodium leucotomos and nicotinamide, milk thistle is nontoxic.

Rapamycin

This macrolide compound is produced by the bacterium Streptomyces hygroscopicus. Rapamycin is an immunosuppressant used to coat coronary stents and prevent rejection of transplanted organs. It is an mechanistic target of rapamycin signaling pathway inhibitor being studied as a cancer prevention and antiaging agent.

Science magazine called the discovery that rapamycin increased the lifespan of mice one of the top scientific breakthroughs of 2009. Subsequent animal studies have established that the extended lifespan wasn’t solely the result of rapamycin’s antineoplastic effects but of across-the-board delayed onset of all the major age-related diseases. Thus, rapamycin could turn out to be a true antiaging agent, in Dr. Siegel’s view.

Studies in humans are underway. Researchers at Novartis have reported that a rapamycin-related compound curbed the typical decline in immune function that accompanies aging as reflected in a 20% enhancement in the response to influenza vaccine in elderly volunteers (Sci Transl Med. 2014 Dec 24;6[268]:268ra179).

Dr. Siegel reported serving as a consultant to Ferndale, which markets Heliocare. The SDEF and this news organization are owned by the same parent company.

[email protected]

PORTLAND, ORE. – Patients prescribed photosensitizing antihypertensive drugs had a 16% increase in risk of cutaneous squamous cell carcinoma (cSCC) in a large retrospective cohort study.

These drugs include alpha-2 receptor agonists and loop diuretics, potassium-sparing diuretics, thiazide diuretics, and combination diuretics, Katherine Levandoski said in an oral presentation at the annual meeting of the Society for Investigative Dermatology.

Furthermore, taking antihypertensive drugs of unknown photosensitizing potential conferred a 10% increase in risk of cSCC in the study, she added. Such medications include angiotensin–converting enzyme inhibitors, calcium channel blockers, and vasodilators, she said.

More than 50 million Americans take antihypertensive drugs, many of which are photosensitizing, noted Ms. Levandoski, a research assistant in the Patient Oriented Research on the Epidemiology of Skin Diseases Unit in the department of dermatology, Massachusetts General Hospital, and the department of population medicine, Harvard University, Boston. However, few studies have explored the oncogenic effects of exposure to these drugs, and those that have done so were subject to confounding, small sample sizes, missing data, lack of pathologic verification, and reliance on self-reported medication history, she added.

To help fill this knowledge gap, she and her associates studied 28,357 non-Hispanic whites diagnosed with hypertension and treated at Kaiser Permanente Northern California between 1997 and 2012. They limited the cohort to non-Hispanic whites because they represent the group with most cases of cSCC.

During follow-up, 3,010 patients were diagnosed with new-onset, pathologically verified cSCC, Ms. Levandoski said. Compared with nonusers of antihypertensives, users of photosensitizing antihypertensives had about a 16% increase in the rate of cSCC (hazard ratio, 1.16; 95% confidence interval, 1.06-1.27), even after accounting for age, sex, smoking, comorbidities, health care utilization, skin cancer history, length of health plan membership, and prior exposure to photosensitizing medications.

Strikingly, patients who used antihypertensives of unknown photosensitizing effect had a 10% increase in risk of incident cSCC (RR, 1.10; 95% CI, 1.02-1.19). Some antihypertensive drugs that are classified as unknown photosensitizers “may actually have photosensitizing properties,” Ms. Levandoski commented. Patients taking antihypertensives of known or unknown photosensitizing potential “should be educated on safe sun practices and may benefit from closer screening for cutaneous squamous cell carcinoma,” she added.

The risk of cSCC was not increased among users of nonphotosensitizing antihypertensives (HR, 0.99; 95% CI, 0.91-1.07), including alpha-blockers, beta-blockers, central agonists, and angiotensin receptor blockers, Ms. Levandoski reported.

Patients in the study cohort averaged aged 60 years (standard deviation, 10.6 years), and 56% were female. In all, 1,530 had never been prescribed antihypertensives, while about 17,000-19,000 had been prescribed unknown, known, or nonphotosensitizing antihypertensives.

The work was funded by the National Institutes of Health, a travel award from the Society for Investigative Dermatology, and a Massachusetts General Hospital Medical Student Award. Ms. Levandoski had no conflicts of interest.

PORTLAND, ORE. – Patients prescribed photosensitizing antihypertensive drugs had a 16% increase in risk of cutaneous squamous cell carcinoma (cSCC) in a large retrospective cohort study.

These drugs include alpha-2 receptor agonists and loop diuretics, potassium-sparing diuretics, thiazide diuretics, and combination diuretics, Katherine Levandoski said in an oral presentation at the annual meeting of the Society for Investigative Dermatology.

Furthermore, taking antihypertensive drugs of unknown photosensitizing potential conferred a 10% increase in risk of cSCC in the study, she added. Such medications include angiotensin–converting enzyme inhibitors, calcium channel blockers, and vasodilators, she said.

More than 50 million Americans take antihypertensive drugs, many of which are photosensitizing, noted Ms. Levandoski, a research assistant in the Patient Oriented Research on the Epidemiology of Skin Diseases Unit in the department of dermatology, Massachusetts General Hospital, and the department of population medicine, Harvard University, Boston. However, few studies have explored the oncogenic effects of exposure to these drugs, and those that have done so were subject to confounding, small sample sizes, missing data, lack of pathologic verification, and reliance on self-reported medication history, she added.

To help fill this knowledge gap, she and her associates studied 28,357 non-Hispanic whites diagnosed with hypertension and treated at Kaiser Permanente Northern California between 1997 and 2012. They limited the cohort to non-Hispanic whites because they represent the group with most cases of cSCC.

During follow-up, 3,010 patients were diagnosed with new-onset, pathologically verified cSCC, Ms. Levandoski said. Compared with nonusers of antihypertensives, users of photosensitizing antihypertensives had about a 16% increase in the rate of cSCC (hazard ratio, 1.16; 95% confidence interval, 1.06-1.27), even after accounting for age, sex, smoking, comorbidities, health care utilization, skin cancer history, length of health plan membership, and prior exposure to photosensitizing medications.

Strikingly, patients who used antihypertensives of unknown photosensitizing effect had a 10% increase in risk of incident cSCC (RR, 1.10; 95% CI, 1.02-1.19). Some antihypertensive drugs that are classified as unknown photosensitizers “may actually have photosensitizing properties,” Ms. Levandoski commented. Patients taking antihypertensives of known or unknown photosensitizing potential “should be educated on safe sun practices and may benefit from closer screening for cutaneous squamous cell carcinoma,” she added.

The risk of cSCC was not increased among users of nonphotosensitizing antihypertensives (HR, 0.99; 95% CI, 0.91-1.07), including alpha-blockers, beta-blockers, central agonists, and angiotensin receptor blockers, Ms. Levandoski reported.

Patients in the study cohort averaged aged 60 years (standard deviation, 10.6 years), and 56% were female. In all, 1,530 had never been prescribed antihypertensives, while about 17,000-19,000 had been prescribed unknown, known, or nonphotosensitizing antihypertensives.

The work was funded by the National Institutes of Health, a travel award from the Society for Investigative Dermatology, and a Massachusetts General Hospital Medical Student Award. Ms. Levandoski had no conflicts of interest.

PORTLAND, ORE. – Patients prescribed photosensitizing antihypertensive drugs had a 16% increase in risk of cutaneous squamous cell carcinoma (cSCC) in a large retrospective cohort study.

These drugs include alpha-2 receptor agonists and loop diuretics, potassium-sparing diuretics, thiazide diuretics, and combination diuretics, Katherine Levandoski said in an oral presentation at the annual meeting of the Society for Investigative Dermatology.

Furthermore, taking antihypertensive drugs of unknown photosensitizing potential conferred a 10% increase in risk of cSCC in the study, she added. Such medications include angiotensin–converting enzyme inhibitors, calcium channel blockers, and vasodilators, she said.

More than 50 million Americans take antihypertensive drugs, many of which are photosensitizing, noted Ms. Levandoski, a research assistant in the Patient Oriented Research on the Epidemiology of Skin Diseases Unit in the department of dermatology, Massachusetts General Hospital, and the department of population medicine, Harvard University, Boston. However, few studies have explored the oncogenic effects of exposure to these drugs, and those that have done so were subject to confounding, small sample sizes, missing data, lack of pathologic verification, and reliance on self-reported medication history, she added.

To help fill this knowledge gap, she and her associates studied 28,357 non-Hispanic whites diagnosed with hypertension and treated at Kaiser Permanente Northern California between 1997 and 2012. They limited the cohort to non-Hispanic whites because they represent the group with most cases of cSCC.

During follow-up, 3,010 patients were diagnosed with new-onset, pathologically verified cSCC, Ms. Levandoski said. Compared with nonusers of antihypertensives, users of photosensitizing antihypertensives had about a 16% increase in the rate of cSCC (hazard ratio, 1.16; 95% confidence interval, 1.06-1.27), even after accounting for age, sex, smoking, comorbidities, health care utilization, skin cancer history, length of health plan membership, and prior exposure to photosensitizing medications.

Strikingly, patients who used antihypertensives of unknown photosensitizing effect had a 10% increase in risk of incident cSCC (RR, 1.10; 95% CI, 1.02-1.19). Some antihypertensive drugs that are classified as unknown photosensitizers “may actually have photosensitizing properties,” Ms. Levandoski commented. Patients taking antihypertensives of known or unknown photosensitizing potential “should be educated on safe sun practices and may benefit from closer screening for cutaneous squamous cell carcinoma,” she added.

The risk of cSCC was not increased among users of nonphotosensitizing antihypertensives (HR, 0.99; 95% CI, 0.91-1.07), including alpha-blockers, beta-blockers, central agonists, and angiotensin receptor blockers, Ms. Levandoski reported.

Patients in the study cohort averaged aged 60 years (standard deviation, 10.6 years), and 56% were female. In all, 1,530 had never been prescribed antihypertensives, while about 17,000-19,000 had been prescribed unknown, known, or nonphotosensitizing antihypertensives.

The work was funded by the National Institutes of Health, a travel award from the Society for Investigative Dermatology, and a Massachusetts General Hospital Medical Student Award. Ms. Levandoski had no conflicts of interest.

PORTLAND – Chronic graft versus host disease (GVHD) was associated with a fivefold increase in risk of squamous cell carcinoma and a nearly twofold rise in the rate of basal cell carcinoma, based on a meta-analysis of eight studies.

Acute GVHD was not tied to an increase in secondary nonmelanoma skin cancers, Pooja H. Rambhia and her associates reported in a poster presented at the annual meeting of the Society for Investigative Dermatology. The findings highlight the need for multidisciplinary consults to distinguish malignancies from the cutaneous manifestations of chronic GVHD and for vigorous surveillance for skin cancer even years after hematopoietic stem cell transplantation.

GVHS has been linked to secondary nonmelanoma skin cancers in previous studies, but few have quantified the risk, according to the reviewers, who are from the department of dermatology and dermatopathology at the Cleveland Clinic Foundation. The increased risk may be related to the heavy immunosuppression needed to treat chronic GVHD.

For the meta-analysis, the researchers identified 1,411 studies recorded in academic databases and reviewed those that reported both cases of skin cancers and GVHD. Seven retrospective, and one prospective, studies published between 1997 and 2012 measured both variables in all patients.

The studies included more than 56,000 patients followed for up to 36 years after undergoing allogeneic or syngeneic transplantation, the reviewers reported. During follow-up, between 17% and 73% of patients developed chronic GVHD, and 29% to 67% developed acute GVHD. There were 98 cases of basal cell carcinoma, 49 cases of squamous cell carcinoma, and 34 cases of malignant melanoma. Chronic GVHD was significantly associated with both squamous cell carcinoma (risk ratio, 5.3; 95% confidence interval, 2.4-11.8; P less than .001) and basal cell carcinoma (RR, 2.0; 95% CI, 1.3-3.0; P = .002). In contrast, chronic GVHD showed a nonsignificant trend toward an inverse correlation with the risk of secondary melanoma. Acute GVHD was not linked with squamous cell carcinoma, basal cell carcinoma, or melanoma.

GVHD develops, up to half the time, after hematopoietic stem cell transplantation and often becomes chronic, the reviewers noted. Catching skin cancer early is crucial, and transplant patients should undergo regular skin checks with multidisciplinary consults to promptly, accurately distinguish malignancies from the cutaneous manifestations of GVHD, they added.

The researchers did not report external funding sources. They had no relevant financial conflicts of interest.

PORTLAND – Chronic graft versus host disease (GVHD) was associated with a fivefold increase in risk of squamous cell carcinoma and a nearly twofold rise in the rate of basal cell carcinoma, based on a meta-analysis of eight studies.

Acute GVHD was not tied to an increase in secondary nonmelanoma skin cancers, Pooja H. Rambhia and her associates reported in a poster presented at the annual meeting of the Society for Investigative Dermatology. The findings highlight the need for multidisciplinary consults to distinguish malignancies from the cutaneous manifestations of chronic GVHD and for vigorous surveillance for skin cancer even years after hematopoietic stem cell transplantation.

GVHS has been linked to secondary nonmelanoma skin cancers in previous studies, but few have quantified the risk, according to the reviewers, who are from the department of dermatology and dermatopathology at the Cleveland Clinic Foundation. The increased risk may be related to the heavy immunosuppression needed to treat chronic GVHD.

For the meta-analysis, the researchers identified 1,411 studies recorded in academic databases and reviewed those that reported both cases of skin cancers and GVHD. Seven retrospective, and one prospective, studies published between 1997 and 2012 measured both variables in all patients.

The studies included more than 56,000 patients followed for up to 36 years after undergoing allogeneic or syngeneic transplantation, the reviewers reported. During follow-up, between 17% and 73% of patients developed chronic GVHD, and 29% to 67% developed acute GVHD. There were 98 cases of basal cell carcinoma, 49 cases of squamous cell carcinoma, and 34 cases of malignant melanoma. Chronic GVHD was significantly associated with both squamous cell carcinoma (risk ratio, 5.3; 95% confidence interval, 2.4-11.8; P less than .001) and basal cell carcinoma (RR, 2.0; 95% CI, 1.3-3.0; P = .002). In contrast, chronic GVHD showed a nonsignificant trend toward an inverse correlation with the risk of secondary melanoma. Acute GVHD was not linked with squamous cell carcinoma, basal cell carcinoma, or melanoma.

GVHD develops, up to half the time, after hematopoietic stem cell transplantation and often becomes chronic, the reviewers noted. Catching skin cancer early is crucial, and transplant patients should undergo regular skin checks with multidisciplinary consults to promptly, accurately distinguish malignancies from the cutaneous manifestations of GVHD, they added.

The researchers did not report external funding sources. They had no relevant financial conflicts of interest.

PORTLAND – Chronic graft versus host disease (GVHD) was associated with a fivefold increase in risk of squamous cell carcinoma and a nearly twofold rise in the rate of basal cell carcinoma, based on a meta-analysis of eight studies.

Acute GVHD was not tied to an increase in secondary nonmelanoma skin cancers, Pooja H. Rambhia and her associates reported in a poster presented at the annual meeting of the Society for Investigative Dermatology. The findings highlight the need for multidisciplinary consults to distinguish malignancies from the cutaneous manifestations of chronic GVHD and for vigorous surveillance for skin cancer even years after hematopoietic stem cell transplantation.

GVHS has been linked to secondary nonmelanoma skin cancers in previous studies, but few have quantified the risk, according to the reviewers, who are from the department of dermatology and dermatopathology at the Cleveland Clinic Foundation. The increased risk may be related to the heavy immunosuppression needed to treat chronic GVHD.

For the meta-analysis, the researchers identified 1,411 studies recorded in academic databases and reviewed those that reported both cases of skin cancers and GVHD. Seven retrospective, and one prospective, studies published between 1997 and 2012 measured both variables in all patients.

The studies included more than 56,000 patients followed for up to 36 years after undergoing allogeneic or syngeneic transplantation, the reviewers reported. During follow-up, between 17% and 73% of patients developed chronic GVHD, and 29% to 67% developed acute GVHD. There were 98 cases of basal cell carcinoma, 49 cases of squamous cell carcinoma, and 34 cases of malignant melanoma. Chronic GVHD was significantly associated with both squamous cell carcinoma (risk ratio, 5.3; 95% confidence interval, 2.4-11.8; P less than .001) and basal cell carcinoma (RR, 2.0; 95% CI, 1.3-3.0; P = .002). In contrast, chronic GVHD showed a nonsignificant trend toward an inverse correlation with the risk of secondary melanoma. Acute GVHD was not linked with squamous cell carcinoma, basal cell carcinoma, or melanoma.

GVHD develops, up to half the time, after hematopoietic stem cell transplantation and often becomes chronic, the reviewers noted. Catching skin cancer early is crucial, and transplant patients should undergo regular skin checks with multidisciplinary consults to promptly, accurately distinguish malignancies from the cutaneous manifestations of GVHD, they added.

The researchers did not report external funding sources. They had no relevant financial conflicts of interest.

The importance of educating tattoo artists on identifying and being careful around skin with melanocytic nevi and other lesions was highlighted by the results of a survey of tattoo artists, according to a study from the University of Pittsburgh.

“While most of those surveyed reported deliberately avoiding nevi, a similar proportion reported either tattooing over them or simply deferring to the client’s preference,” wrote Westley S. Mori and his associates in the department of dermatology at the University of Pittsburgh, Pennsylvania. “This is concerning because few clients specifically ask tattoo artists to avoid skin lesions,” they added.

They surveyed 42 tattoo artists in July and August 2016 regarding their encounters with clients with skin lesions and their personal knowledge or experiences they may have had with skin cancer. Of those surveyed, 23 (55%) said they had declined to tattoo skin with a rash or lesion (JAMA Dermatology. 2017;153[4]:328-30).When asked about their reasoning for declining a client’s request, 21 (50%) of respondents said they did so because of a poor cosmetic outcome, while the next highest answer, a concern of potential skin cancer, was only cited by 12 (29%).

Most (74%) said there was no official store policy about tattooing over moles or other skin lesions. When asked about their approaches to tattooing skin with moles or other lesions, many said they choose to tattoo around the lesion (41%), tattoo over the lesion (19%), or defer to the client’s preferences (24%). However, with regards to deferring to a client, 29 artists (69%) reported never being asked to avoid a lesion.

Investigators noted that 12 respondents reported that they had identified a possible cancerous lesion on a client, followed by the same number of respondents reporting having recommended that a client see a dermatologist.

Tattoo artists who had seen a dermatologist for a skin examination were significantly more likely to refuse to tattoo a client with a lesion (P = .01) and recommend that the client see a dermatologist (P less than .001) when they had a lesion. Based on this response, the authors said that they believed that educating both clients and tattoo artists may be the best way to get tattoo artists to engage clients. “Our study highlights an opportunity for dermatologists to educate tattoo artists about skin cancer, particularly melanoma, to help reduce the incidence of skin cancers hidden in tattoos and to encourage appropriate referral to dermatologists for suspicious lesions on clients,” they concluded.

“When you perform a total body skin examination, it’s a little difficult to kind of tease out if a lesion looks suspicious or not if it’s surrounded by ink,” Mr. Mori, a medical student at the university, said in an interview. “Tattoos are becoming more and more common, especially among younger people, and incidence of melanoma has increased in younger populations as well. ... It is very concerning that skin cancers could be hidden in tattoos.”

In fact, Mr. Mori pointed out, there are opportunities for dermatologists to reach out to the tattoo artist community and start the communication process. “Tattoo artists have national conferences where they get together and discuss the state of the industry, and that represents one opportunity where dermatologists could talk about the effects of skin cancer,” he said.

The study was funded by the University of Pittsburgh. The authors reported no relevant financial disclosures.
 

[email protected]

On Twitter @eaztweets

The importance of educating tattoo artists on identifying and being careful around skin with melanocytic nevi and other lesions was highlighted by the results of a survey of tattoo artists, according to a study from the University of Pittsburgh.

“While most of those surveyed reported deliberately avoiding nevi, a similar proportion reported either tattooing over them or simply deferring to the client’s preference,” wrote Westley S. Mori and his associates in the department of dermatology at the University of Pittsburgh, Pennsylvania. “This is concerning because few clients specifically ask tattoo artists to avoid skin lesions,” they added.

They surveyed 42 tattoo artists in July and August 2016 regarding their encounters with clients with skin lesions and their personal knowledge or experiences they may have had with skin cancer. Of those surveyed, 23 (55%) said they had declined to tattoo skin with a rash or lesion (JAMA Dermatology. 2017;153[4]:328-30).When asked about their reasoning for declining a client’s request, 21 (50%) of respondents said they did so because of a poor cosmetic outcome, while the next highest answer, a concern of potential skin cancer, was only cited by 12 (29%).

Most (74%) said there was no official store policy about tattooing over moles or other skin lesions. When asked about their approaches to tattooing skin with moles or other lesions, many said they choose to tattoo around the lesion (41%), tattoo over the lesion (19%), or defer to the client’s preferences (24%). However, with regards to deferring to a client, 29 artists (69%) reported never being asked to avoid a lesion.

Investigators noted that 12 respondents reported that they had identified a possible cancerous lesion on a client, followed by the same number of respondents reporting having recommended that a client see a dermatologist.

Tattoo artists who had seen a dermatologist for a skin examination were significantly more likely to refuse to tattoo a client with a lesion (P = .01) and recommend that the client see a dermatologist (P less than .001) when they had a lesion. Based on this response, the authors said that they believed that educating both clients and tattoo artists may be the best way to get tattoo artists to engage clients. “Our study highlights an opportunity for dermatologists to educate tattoo artists about skin cancer, particularly melanoma, to help reduce the incidence of skin cancers hidden in tattoos and to encourage appropriate referral to dermatologists for suspicious lesions on clients,” they concluded.

“When you perform a total body skin examination, it’s a little difficult to kind of tease out if a lesion looks suspicious or not if it’s surrounded by ink,” Mr. Mori, a medical student at the university, said in an interview. “Tattoos are becoming more and more common, especially among younger people, and incidence of melanoma has increased in younger populations as well. ... It is very concerning that skin cancers could be hidden in tattoos.”

In fact, Mr. Mori pointed out, there are opportunities for dermatologists to reach out to the tattoo artist community and start the communication process. “Tattoo artists have national conferences where they get together and discuss the state of the industry, and that represents one opportunity where dermatologists could talk about the effects of skin cancer,” he said.

The study was funded by the University of Pittsburgh. The authors reported no relevant financial disclosures.
 

[email protected]

On Twitter @eaztweets

The importance of educating tattoo artists on identifying and being careful around skin with melanocytic nevi and other lesions was highlighted by the results of a survey of tattoo artists, according to a study from the University of Pittsburgh.

“While most of those surveyed reported deliberately avoiding nevi, a similar proportion reported either tattooing over them or simply deferring to the client’s preference,” wrote Westley S. Mori and his associates in the department of dermatology at the University of Pittsburgh, Pennsylvania. “This is concerning because few clients specifically ask tattoo artists to avoid skin lesions,” they added.

They surveyed 42 tattoo artists in July and August 2016 regarding their encounters with clients with skin lesions and their personal knowledge or experiences they may have had with skin cancer. Of those surveyed, 23 (55%) said they had declined to tattoo skin with a rash or lesion (JAMA Dermatology. 2017;153[4]:328-30).When asked about their reasoning for declining a client’s request, 21 (50%) of respondents said they did so because of a poor cosmetic outcome, while the next highest answer, a concern of potential skin cancer, was only cited by 12 (29%).

Most (74%) said there was no official store policy about tattooing over moles or other skin lesions. When asked about their approaches to tattooing skin with moles or other lesions, many said they choose to tattoo around the lesion (41%), tattoo over the lesion (19%), or defer to the client’s preferences (24%). However, with regards to deferring to a client, 29 artists (69%) reported never being asked to avoid a lesion.

Investigators noted that 12 respondents reported that they had identified a possible cancerous lesion on a client, followed by the same number of respondents reporting having recommended that a client see a dermatologist.

Tattoo artists who had seen a dermatologist for a skin examination were significantly more likely to refuse to tattoo a client with a lesion (P = .01) and recommend that the client see a dermatologist (P less than .001) when they had a lesion. Based on this response, the authors said that they believed that educating both clients and tattoo artists may be the best way to get tattoo artists to engage clients. “Our study highlights an opportunity for dermatologists to educate tattoo artists about skin cancer, particularly melanoma, to help reduce the incidence of skin cancers hidden in tattoos and to encourage appropriate referral to dermatologists for suspicious lesions on clients,” they concluded.

“When you perform a total body skin examination, it’s a little difficult to kind of tease out if a lesion looks suspicious or not if it’s surrounded by ink,” Mr. Mori, a medical student at the university, said in an interview. “Tattoos are becoming more and more common, especially among younger people, and incidence of melanoma has increased in younger populations as well. ... It is very concerning that skin cancers could be hidden in tattoos.”

In fact, Mr. Mori pointed out, there are opportunities for dermatologists to reach out to the tattoo artist community and start the communication process. “Tattoo artists have national conferences where they get together and discuss the state of the industry, and that represents one opportunity where dermatologists could talk about the effects of skin cancer,” he said.

The study was funded by the University of Pittsburgh. The authors reported no relevant financial disclosures.
 

[email protected]

On Twitter @eaztweets

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

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

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

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

Comment

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

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

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

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

Conclusion

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

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

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

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

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

Comment

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

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

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

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

Conclusion

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

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

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

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

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

Comment

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

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

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

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

Conclusion

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

Case Report

A 72-year-old white man with a history of pancreatic adenocarcinoma presented for Mohs micrographic surgery of a basal cell carcinoma on the right helix. On the day of the surgery, the patient reported a new, rapidly growing, exquisitely painful lesion on the cheek of 3 to 4 weeks’ duration. Physical examination revealed a 0.8×0.8×0.8-cm, extremely tender, firm, pink papule on the right preauricular cheek. A horizontal deep shave excision was done and the histopathology was remarkable for neoplastic cells with necrosis in the dermis. We observed dermal cellular infiltrates in the form of sheets and nodules, some showing central necrosis (Figure 1). At higher magnification, a trabecular arrangement of cells was seen. These cells had a moderate amount of cytoplasm with eccentric nuclei and rare nucleoli (Figure 2). Mitotic figures were seen at higher magnification (Figure 3). Immunohistochemistry of the neoplastic cells exhibited similar positive staining for the neuroendocrine markers chromogranin A and synaptophysin (Figure 4). Staining of the neoplastic cells also was positive for thyroid transcription factor 1 (TTF-1) and cancer antigen 19-9. Villin and caudal type homeobox 2 stains were negative. These results were consistent with cutaneous metastasis from a known pulmonary carcinoid tumor.

On further review of the patient’s medical history, it was discovered that he had undergone a Whipple procedure with adjuvant chemotherapy and radiation for pancreatic adenocarcinoma approximately 4 years prior to the current presentation. He was then followed by oncology, and 3 years later a chest computed tomography suggested possible disease progression with a new pulmonary metastasis. This pulmonary lesion was biopsied and immunologic staining was consistent with a primary neuroendocrine neoplasm of the lung, a new carcinoid tumor. The tissue was positive for cytokeratin (CK) 7,TTF-1, cancer antigen 19-9, CD56, synaptophysin, and chromogranin A, and was negative for villin and CK20. By the time he was seen in our clinic, several trials of chemotherapy had failed. Serial computed tomography subsequently demonstrated progression of the lung disease and he later developed malignant pleural effusions. Approximately 6 months after the cutaneous carcinoid metastasis was diagnosed, the patient died of respiratory failure.

Comment

Carcinoid tumors are uncommon neoplasms of neuroendocrine origin that generally arise in the gastrointestinal or bronchopulmonary tracts. Metastases from these primary neoplasms more commonly affect the regional lymph nodes or viscera, with rare reports of cutaneous metastases to the skin. The true incidence of carcinoid tumors with metastasis to the skin is unknown because it is limited to single case reports in the literature.

The clinical presentation of cutaneous carcinoid metastases has been reported most commonly as firm papules of varying sizes with no specific site predilection.¹ The color of these lesions has ranged from erythematous to violaceous to brown.² Several of the reported cases were noted to be extremely tender and painful, while other reports of lesions were noted to be asymptomatic or only mildly pruritic.^3-7

Carcinoid syndrome is more common with neoplasms present within the gastrointestinal tract, but it also has been reported with large bronchial carcinoid tumors and with metastatic disease.^8,9 Paroxysmal flushing is the most prominent cutaneous manifestation of this syndrome, occurring in 75% of patients.^10,11 Other common symptoms include patchy cyanosis, telangiectasia, and pellagralike skin lesions.³ Carcinoid syndrome secondary to bronchial adenomas is thought to differ from gastrointestinal carcinoid neoplasms in that it has prolonged flushing (hours to days instead of minutes) and is characterized by marked anxiety, fever, disorientation, sweating, and lacrimation.^8,9

Many cases of cutaneous carcinoid metastases have been accompanied by reports of exquisite tenderness,⁷ similar to our patient. The pathogenesis of the pain in these lesions is still unclear, but several hypotheses have been established. It has been postulated that perineural invasion by the tumor is responsible for the pain; however, this finding has been inconsistent, as neural involvement also has been present in nonpainful lesions.^2,5,7,12 Another theory for the pain is that it is secondary to the release of vasoactive substances and peptide hormones from the carcinoid cells, such as kallikrein and serotonin. Lastly, local tissue necrosis and fibrosis also have been suggested as possible etiologies.⁷

The histology of cutaneous carcinoid metastases typically resembles the primary lesion and may demonstrate fascicles of spindle cells with focal areas of necrosis, mild atypia, and a relatively low mitotic rate.¹⁰ Other neoplasms such as Merkel cell carcinoma and carcinoidlike sebaceous carcinoma should be considered in the differential diagnosis. A primary malignant peripheral primitive neuroectodermal tumor or a primary cutaneous carcinoid tumor is less common but should be considered. Differing from carcinoid tumors, Merkel cell carcinomas usually have a higher mitotic rate and positive staining for CK20. The sebaceous neoplasms with a carcinoidlike pattern may appear histologically similar, requiring immunohistochemical evaluation with monoclonal antibodies such as D2-40.¹³ A diffuse granular cytoplasmic reaction to chromogranin A is characteristic of carcinoid tumors. Synaptophysin and TTF-1 also are positive in carcinoid tumors, with TTF-1 being highly specific for neuroendocrine tumors of the lung.¹⁰

Cutaneous metastases of internal malignancies are more common from carcinomas of the lungs, gastrointestinal tract, and breasts.⁵ Occasionally, the cutaneous metastasis will develop directly over the underlying malignancy. Our case of cutaneous metastasis of a carcinoid tumor presented as an exquisitely tender and painful papule on the cheek. The histology of the lesion was consistent with the known carcinoid tumor of the lung. Because these lesions are extremely uncommon, it is imperative to obtain an accurate clinical history and use the appropriate immunohistochemical panel to correctly diagnose these metastases.

Case Report

A 72-year-old white man with a history of pancreatic adenocarcinoma presented for Mohs micrographic surgery of a basal cell carcinoma on the right helix. On the day of the surgery, the patient reported a new, rapidly growing, exquisitely painful lesion on the cheek of 3 to 4 weeks’ duration. Physical examination revealed a 0.8×0.8×0.8-cm, extremely tender, firm, pink papule on the right preauricular cheek. A horizontal deep shave excision was done and the histopathology was remarkable for neoplastic cells with necrosis in the dermis. We observed dermal cellular infiltrates in the form of sheets and nodules, some showing central necrosis (Figure 1). At higher magnification, a trabecular arrangement of cells was seen. These cells had a moderate amount of cytoplasm with eccentric nuclei and rare nucleoli (Figure 2). Mitotic figures were seen at higher magnification (Figure 3). Immunohistochemistry of the neoplastic cells exhibited similar positive staining for the neuroendocrine markers chromogranin A and synaptophysin (Figure 4). Staining of the neoplastic cells also was positive for thyroid transcription factor 1 (TTF-1) and cancer antigen 19-9. Villin and caudal type homeobox 2 stains were negative. These results were consistent with cutaneous metastasis from a known pulmonary carcinoid tumor.

On further review of the patient’s medical history, it was discovered that he had undergone a Whipple procedure with adjuvant chemotherapy and radiation for pancreatic adenocarcinoma approximately 4 years prior to the current presentation. He was then followed by oncology, and 3 years later a chest computed tomography suggested possible disease progression with a new pulmonary metastasis. This pulmonary lesion was biopsied and immunologic staining was consistent with a primary neuroendocrine neoplasm of the lung, a new carcinoid tumor. The tissue was positive for cytokeratin (CK) 7,TTF-1, cancer antigen 19-9, CD56, synaptophysin, and chromogranin A, and was negative for villin and CK20. By the time he was seen in our clinic, several trials of chemotherapy had failed. Serial computed tomography subsequently demonstrated progression of the lung disease and he later developed malignant pleural effusions. Approximately 6 months after the cutaneous carcinoid metastasis was diagnosed, the patient died of respiratory failure.

Comment

Carcinoid tumors are uncommon neoplasms of neuroendocrine origin that generally arise in the gastrointestinal or bronchopulmonary tracts. Metastases from these primary neoplasms more commonly affect the regional lymph nodes or viscera, with rare reports of cutaneous metastases to the skin. The true incidence of carcinoid tumors with metastasis to the skin is unknown because it is limited to single case reports in the literature.

The clinical presentation of cutaneous carcinoid metastases has been reported most commonly as firm papules of varying sizes with no specific site predilection.¹ The color of these lesions has ranged from erythematous to violaceous to brown.² Several of the reported cases were noted to be extremely tender and painful, while other reports of lesions were noted to be asymptomatic or only mildly pruritic.^3-7

Carcinoid syndrome is more common with neoplasms present within the gastrointestinal tract, but it also has been reported with large bronchial carcinoid tumors and with metastatic disease.^8,9 Paroxysmal flushing is the most prominent cutaneous manifestation of this syndrome, occurring in 75% of patients.^10,11 Other common symptoms include patchy cyanosis, telangiectasia, and pellagralike skin lesions.³ Carcinoid syndrome secondary to bronchial adenomas is thought to differ from gastrointestinal carcinoid neoplasms in that it has prolonged flushing (hours to days instead of minutes) and is characterized by marked anxiety, fever, disorientation, sweating, and lacrimation.^8,9

Many cases of cutaneous carcinoid metastases have been accompanied by reports of exquisite tenderness,⁷ similar to our patient. The pathogenesis of the pain in these lesions is still unclear, but several hypotheses have been established. It has been postulated that perineural invasion by the tumor is responsible for the pain; however, this finding has been inconsistent, as neural involvement also has been present in nonpainful lesions.^2,5,7,12 Another theory for the pain is that it is secondary to the release of vasoactive substances and peptide hormones from the carcinoid cells, such as kallikrein and serotonin. Lastly, local tissue necrosis and fibrosis also have been suggested as possible etiologies.⁷

The histology of cutaneous carcinoid metastases typically resembles the primary lesion and may demonstrate fascicles of spindle cells with focal areas of necrosis, mild atypia, and a relatively low mitotic rate.¹⁰ Other neoplasms such as Merkel cell carcinoma and carcinoidlike sebaceous carcinoma should be considered in the differential diagnosis. A primary malignant peripheral primitive neuroectodermal tumor or a primary cutaneous carcinoid tumor is less common but should be considered. Differing from carcinoid tumors, Merkel cell carcinomas usually have a higher mitotic rate and positive staining for CK20. The sebaceous neoplasms with a carcinoidlike pattern may appear histologically similar, requiring immunohistochemical evaluation with monoclonal antibodies such as D2-40.¹³ A diffuse granular cytoplasmic reaction to chromogranin A is characteristic of carcinoid tumors. Synaptophysin and TTF-1 also are positive in carcinoid tumors, with TTF-1 being highly specific for neuroendocrine tumors of the lung.¹⁰

Cutaneous metastases of internal malignancies are more common from carcinomas of the lungs, gastrointestinal tract, and breasts.⁵ Occasionally, the cutaneous metastasis will develop directly over the underlying malignancy. Our case of cutaneous metastasis of a carcinoid tumor presented as an exquisitely tender and painful papule on the cheek. The histology of the lesion was consistent with the known carcinoid tumor of the lung. Because these lesions are extremely uncommon, it is imperative to obtain an accurate clinical history and use the appropriate immunohistochemical panel to correctly diagnose these metastases.

Case Report

A 72-year-old white man with a history of pancreatic adenocarcinoma presented for Mohs micrographic surgery of a basal cell carcinoma on the right helix. On the day of the surgery, the patient reported a new, rapidly growing, exquisitely painful lesion on the cheek of 3 to 4 weeks’ duration. Physical examination revealed a 0.8×0.8×0.8-cm, extremely tender, firm, pink papule on the right preauricular cheek. A horizontal deep shave excision was done and the histopathology was remarkable for neoplastic cells with necrosis in the dermis. We observed dermal cellular infiltrates in the form of sheets and nodules, some showing central necrosis (Figure 1). At higher magnification, a trabecular arrangement of cells was seen. These cells had a moderate amount of cytoplasm with eccentric nuclei and rare nucleoli (Figure 2). Mitotic figures were seen at higher magnification (Figure 3). Immunohistochemistry of the neoplastic cells exhibited similar positive staining for the neuroendocrine markers chromogranin A and synaptophysin (Figure 4). Staining of the neoplastic cells also was positive for thyroid transcription factor 1 (TTF-1) and cancer antigen 19-9. Villin and caudal type homeobox 2 stains were negative. These results were consistent with cutaneous metastasis from a known pulmonary carcinoid tumor.

On further review of the patient’s medical history, it was discovered that he had undergone a Whipple procedure with adjuvant chemotherapy and radiation for pancreatic adenocarcinoma approximately 4 years prior to the current presentation. He was then followed by oncology, and 3 years later a chest computed tomography suggested possible disease progression with a new pulmonary metastasis. This pulmonary lesion was biopsied and immunologic staining was consistent with a primary neuroendocrine neoplasm of the lung, a new carcinoid tumor. The tissue was positive for cytokeratin (CK) 7,TTF-1, cancer antigen 19-9, CD56, synaptophysin, and chromogranin A, and was negative for villin and CK20. By the time he was seen in our clinic, several trials of chemotherapy had failed. Serial computed tomography subsequently demonstrated progression of the lung disease and he later developed malignant pleural effusions. Approximately 6 months after the cutaneous carcinoid metastasis was diagnosed, the patient died of respiratory failure.

Comment

Carcinoid tumors are uncommon neoplasms of neuroendocrine origin that generally arise in the gastrointestinal or bronchopulmonary tracts. Metastases from these primary neoplasms more commonly affect the regional lymph nodes or viscera, with rare reports of cutaneous metastases to the skin. The true incidence of carcinoid tumors with metastasis to the skin is unknown because it is limited to single case reports in the literature.

The clinical presentation of cutaneous carcinoid metastases has been reported most commonly as firm papules of varying sizes with no specific site predilection.¹ The color of these lesions has ranged from erythematous to violaceous to brown.² Several of the reported cases were noted to be extremely tender and painful, while other reports of lesions were noted to be asymptomatic or only mildly pruritic.^3-7

Carcinoid syndrome is more common with neoplasms present within the gastrointestinal tract, but it also has been reported with large bronchial carcinoid tumors and with metastatic disease.^8,9 Paroxysmal flushing is the most prominent cutaneous manifestation of this syndrome, occurring in 75% of patients.^10,11 Other common symptoms include patchy cyanosis, telangiectasia, and pellagralike skin lesions.³ Carcinoid syndrome secondary to bronchial adenomas is thought to differ from gastrointestinal carcinoid neoplasms in that it has prolonged flushing (hours to days instead of minutes) and is characterized by marked anxiety, fever, disorientation, sweating, and lacrimation.^8,9

Many cases of cutaneous carcinoid metastases have been accompanied by reports of exquisite tenderness,⁷ similar to our patient. The pathogenesis of the pain in these lesions is still unclear, but several hypotheses have been established. It has been postulated that perineural invasion by the tumor is responsible for the pain; however, this finding has been inconsistent, as neural involvement also has been present in nonpainful lesions.^2,5,7,12 Another theory for the pain is that it is secondary to the release of vasoactive substances and peptide hormones from the carcinoid cells, such as kallikrein and serotonin. Lastly, local tissue necrosis and fibrosis also have been suggested as possible etiologies.⁷

The histology of cutaneous carcinoid metastases typically resembles the primary lesion and may demonstrate fascicles of spindle cells with focal areas of necrosis, mild atypia, and a relatively low mitotic rate.¹⁰ Other neoplasms such as Merkel cell carcinoma and carcinoidlike sebaceous carcinoma should be considered in the differential diagnosis. A primary malignant peripheral primitive neuroectodermal tumor or a primary cutaneous carcinoid tumor is less common but should be considered. Differing from carcinoid tumors, Merkel cell carcinomas usually have a higher mitotic rate and positive staining for CK20. The sebaceous neoplasms with a carcinoidlike pattern may appear histologically similar, requiring immunohistochemical evaluation with monoclonal antibodies such as D2-40.¹³ A diffuse granular cytoplasmic reaction to chromogranin A is characteristic of carcinoid tumors. Synaptophysin and TTF-1 also are positive in carcinoid tumors, with TTF-1 being highly specific for neuroendocrine tumors of the lung.¹⁰

Cutaneous metastases of internal malignancies are more common from carcinomas of the lungs, gastrointestinal tract, and breasts.⁵ Occasionally, the cutaneous metastasis will develop directly over the underlying malignancy. Our case of cutaneous metastasis of a carcinoid tumor presented as an exquisitely tender and painful papule on the cheek. The histology of the lesion was consistent with the known carcinoid tumor of the lung. Because these lesions are extremely uncommon, it is imperative to obtain an accurate clinical history and use the appropriate immunohistochemical panel to correctly diagnose these metastases.

PORTLAND, ORE. – The first 2 years after diagnosis are crucial when conducting surveillance for recurrence of Merkel cell carcinoma (MCC), Aubriana McEvoy said at the annual meeting of the Society for Investigative Dermatology.

Regardless of stage at diagnosis, the risk of recurrence peaked at about 1 year and leveled off by about year 2 in a retrospective cohort study, according to Ms. McEvoy, a medical student at the University of Washington, Seattle, who conducted the study with colleagues under the mentorship of Paul Nghiem, MD, PhD, professor and head of the division of dermatology. The study also inversely linked primary MCC stage with subsequent recurrence-free survival, highlighted the role of imaging for surveillance of patients who have advanced primary disease, and linked distant metastatic recurrence with significantly worse survival, compared with local or nodal recurrence.

“Patients with Merkel cell carcinoma always ask about recurrence,” Ms. McEvoy said. “Now, for the first time, we have the data to answer their questions.”

Surveillance of MCC is increasingly important, she said: The “treatment landscape is evolving quickly, and immunotherapies such as pembrolizumab can have a good response rate, especially in the setting of lower burden of disease.” But follow-up is costly on several fronts, making it crucial to aim for “enough” and not “too much” surveillance, she added.

“Imaging often costs thousands of dollars, and that’s only one piece of the pie. There’s also the cost of office visits, time spent by the patient and their family, and the emotional investment and uncertainty a patient goes through every time they have to come for a follow-up visit and scan,” Ms. McEvoy said.

Comprehensive, stage-specific guidelines can help clinicians and patients balance the benefits and costs of surveillance, but are lacking in MCC because no published study has characterized recurrence by stage, she said. To fill this gap, she and her associates analyzed 10 years of longitudinal MCC surveillance data on 468 patients who underwent pathologic staging and were followed at the Nghiem laboratory.

The risk of recurrence was highest within the first 2 years after diagnosis, regardless of whether patients had local (pathologic stage I–II) or nodal (stage III) MCC. However, the probability of recurrence-free survival correlated inversely with pathologic stage of primary MCC (P = .003). Median recurrence-free survival time was not reached by the 186 patients with local disease and small (2-cm maximum dimension) primary lesions, or by 135 patients with clinically occult nodal disease.

In contrast, median recurrence-free survival was about 6 years among 84 patients with local disease and lesions measuring more than 2 cm; was less than 2 years among 35 patients with clinically apparent, pathologically confirmed nodal disease or in-transit metastases; and was less than 1 year among patients with distant metastatic disease.

The researchers also investigated the risk of distant metastatic recurrence to confirm which patients need most intensive follow-up. Among 138 individuals with available data, 40% of stage I primary MCC patients developed a distant metastatic recurrence, as did 60% of patients with stage IIA or stage IIB primary MCC. And 80% of recurrences among patients with stage IIIA or stage IIIB primary disease were distant metastases. “I think it’s safe to say that stage III patients should receive appropriate, if not vigilant, surveillance,” Ms. McEvoy said. The site of recurrence also was significantly (P less than .001) tied to the risk of subsequent death from recurrent MCC; median survival time was not reached when recurrence was local or nodal, but was less than 2 years when it was distant or metastatic.

Early in 2018, the American Joint Committee on Cancer will update its MCC staging system to distinguish clinical versus pathologic staging. “This is important, because pathologic staging remains the gold standard, providing a much more in-depth view of the patient’s disease,” Ms. McEvoy commented. Ideally, clinicians would use more information to help predict the prognosis of MCC, including sex and immune and viral status, she noted. “But we hope these data provide information for more consistency across the country, so we can catch recurrences earlier, and avoid unnecessary visits and imaging scans for lower-risk patients.”

The study was supported by the National Institutes of Health, the Seattle Cancer Care Alliance, the University of Washington, and the Institute of Translational Health Sciences. Ms. McEvoy had no conflicts of interest.

PORTLAND, ORE. – The first 2 years after diagnosis are crucial when conducting surveillance for recurrence of Merkel cell carcinoma (MCC), Aubriana McEvoy said at the annual meeting of the Society for Investigative Dermatology.

Regardless of stage at diagnosis, the risk of recurrence peaked at about 1 year and leveled off by about year 2 in a retrospective cohort study, according to Ms. McEvoy, a medical student at the University of Washington, Seattle, who conducted the study with colleagues under the mentorship of Paul Nghiem, MD, PhD, professor and head of the division of dermatology. The study also inversely linked primary MCC stage with subsequent recurrence-free survival, highlighted the role of imaging for surveillance of patients who have advanced primary disease, and linked distant metastatic recurrence with significantly worse survival, compared with local or nodal recurrence.

“Patients with Merkel cell carcinoma always ask about recurrence,” Ms. McEvoy said. “Now, for the first time, we have the data to answer their questions.”

Surveillance of MCC is increasingly important, she said: The “treatment landscape is evolving quickly, and immunotherapies such as pembrolizumab can have a good response rate, especially in the setting of lower burden of disease.” But follow-up is costly on several fronts, making it crucial to aim for “enough” and not “too much” surveillance, she added.

“Imaging often costs thousands of dollars, and that’s only one piece of the pie. There’s also the cost of office visits, time spent by the patient and their family, and the emotional investment and uncertainty a patient goes through every time they have to come for a follow-up visit and scan,” Ms. McEvoy said.

Comprehensive, stage-specific guidelines can help clinicians and patients balance the benefits and costs of surveillance, but are lacking in MCC because no published study has characterized recurrence by stage, she said. To fill this gap, she and her associates analyzed 10 years of longitudinal MCC surveillance data on 468 patients who underwent pathologic staging and were followed at the Nghiem laboratory.

The risk of recurrence was highest within the first 2 years after diagnosis, regardless of whether patients had local (pathologic stage I–II) or nodal (stage III) MCC. However, the probability of recurrence-free survival correlated inversely with pathologic stage of primary MCC (P = .003). Median recurrence-free survival time was not reached by the 186 patients with local disease and small (2-cm maximum dimension) primary lesions, or by 135 patients with clinically occult nodal disease.

In contrast, median recurrence-free survival was about 6 years among 84 patients with local disease and lesions measuring more than 2 cm; was less than 2 years among 35 patients with clinically apparent, pathologically confirmed nodal disease or in-transit metastases; and was less than 1 year among patients with distant metastatic disease.

The researchers also investigated the risk of distant metastatic recurrence to confirm which patients need most intensive follow-up. Among 138 individuals with available data, 40% of stage I primary MCC patients developed a distant metastatic recurrence, as did 60% of patients with stage IIA or stage IIB primary MCC. And 80% of recurrences among patients with stage IIIA or stage IIIB primary disease were distant metastases. “I think it’s safe to say that stage III patients should receive appropriate, if not vigilant, surveillance,” Ms. McEvoy said. The site of recurrence also was significantly (P less than .001) tied to the risk of subsequent death from recurrent MCC; median survival time was not reached when recurrence was local or nodal, but was less than 2 years when it was distant or metastatic.

Early in 2018, the American Joint Committee on Cancer will update its MCC staging system to distinguish clinical versus pathologic staging. “This is important, because pathologic staging remains the gold standard, providing a much more in-depth view of the patient’s disease,” Ms. McEvoy commented. Ideally, clinicians would use more information to help predict the prognosis of MCC, including sex and immune and viral status, she noted. “But we hope these data provide information for more consistency across the country, so we can catch recurrences earlier, and avoid unnecessary visits and imaging scans for lower-risk patients.”

The study was supported by the National Institutes of Health, the Seattle Cancer Care Alliance, the University of Washington, and the Institute of Translational Health Sciences. Ms. McEvoy had no conflicts of interest.

PORTLAND, ORE. – The first 2 years after diagnosis are crucial when conducting surveillance for recurrence of Merkel cell carcinoma (MCC), Aubriana McEvoy said at the annual meeting of the Society for Investigative Dermatology.

Regardless of stage at diagnosis, the risk of recurrence peaked at about 1 year and leveled off by about year 2 in a retrospective cohort study, according to Ms. McEvoy, a medical student at the University of Washington, Seattle, who conducted the study with colleagues under the mentorship of Paul Nghiem, MD, PhD, professor and head of the division of dermatology. The study also inversely linked primary MCC stage with subsequent recurrence-free survival, highlighted the role of imaging for surveillance of patients who have advanced primary disease, and linked distant metastatic recurrence with significantly worse survival, compared with local or nodal recurrence.

“Patients with Merkel cell carcinoma always ask about recurrence,” Ms. McEvoy said. “Now, for the first time, we have the data to answer their questions.”

Surveillance of MCC is increasingly important, she said: The “treatment landscape is evolving quickly, and immunotherapies such as pembrolizumab can have a good response rate, especially in the setting of lower burden of disease.” But follow-up is costly on several fronts, making it crucial to aim for “enough” and not “too much” surveillance, she added.

“Imaging often costs thousands of dollars, and that’s only one piece of the pie. There’s also the cost of office visits, time spent by the patient and their family, and the emotional investment and uncertainty a patient goes through every time they have to come for a follow-up visit and scan,” Ms. McEvoy said.

Comprehensive, stage-specific guidelines can help clinicians and patients balance the benefits and costs of surveillance, but are lacking in MCC because no published study has characterized recurrence by stage, she said. To fill this gap, she and her associates analyzed 10 years of longitudinal MCC surveillance data on 468 patients who underwent pathologic staging and were followed at the Nghiem laboratory.

The risk of recurrence was highest within the first 2 years after diagnosis, regardless of whether patients had local (pathologic stage I–II) or nodal (stage III) MCC. However, the probability of recurrence-free survival correlated inversely with pathologic stage of primary MCC (P = .003). Median recurrence-free survival time was not reached by the 186 patients with local disease and small (2-cm maximum dimension) primary lesions, or by 135 patients with clinically occult nodal disease.

In contrast, median recurrence-free survival was about 6 years among 84 patients with local disease and lesions measuring more than 2 cm; was less than 2 years among 35 patients with clinically apparent, pathologically confirmed nodal disease or in-transit metastases; and was less than 1 year among patients with distant metastatic disease.

The researchers also investigated the risk of distant metastatic recurrence to confirm which patients need most intensive follow-up. Among 138 individuals with available data, 40% of stage I primary MCC patients developed a distant metastatic recurrence, as did 60% of patients with stage IIA or stage IIB primary MCC. And 80% of recurrences among patients with stage IIIA or stage IIIB primary disease were distant metastases. “I think it’s safe to say that stage III patients should receive appropriate, if not vigilant, surveillance,” Ms. McEvoy said. The site of recurrence also was significantly (P less than .001) tied to the risk of subsequent death from recurrent MCC; median survival time was not reached when recurrence was local or nodal, but was less than 2 years when it was distant or metastatic.

Early in 2018, the American Joint Committee on Cancer will update its MCC staging system to distinguish clinical versus pathologic staging. “This is important, because pathologic staging remains the gold standard, providing a much more in-depth view of the patient’s disease,” Ms. McEvoy commented. Ideally, clinicians would use more information to help predict the prognosis of MCC, including sex and immune and viral status, she noted. “But we hope these data provide information for more consistency across the country, so we can catch recurrences earlier, and avoid unnecessary visits and imaging scans for lower-risk patients.”

The study was supported by the National Institutes of Health, the Seattle Cancer Care Alliance, the University of Washington, and the Institute of Translational Health Sciences. Ms. McEvoy had no conflicts of interest.

The Diagnosis: Pagetoid Reticulosis

Histopathologic examination demonstrated a dense infiltrate and psoriasiform pattern epidermal hyperplasia (Figure, A). There was conspicuous epidermotropism of moderately enlarged, hyperchromatic lymphocytes. Intraepidermal lymphocytes were slightly larger, darker, and more convoluted than those in the subjacent dermis (Figure, B). These cells exhibited CD3⁺ T-cell differentiation with an abnormal CD4-CD7-CD8- phenotype (Figure, C). The histopathologic finding of atypical epidermotropic T-cell infiltrate was compatible with a rare variant of mycosis fungoides known as pagetoid reticulosis (PR). After discussing the diagnosis and treatment options, the patient elected to begin with a conservative approach to therapy. We prescribed fluocinonide ointment 0.05% twice daily under occlusion. At 1 month follow-up, the patient experienced marked improvement of the erythema and scaling of the lesion.

Pagetoid reticulosis is a primary cutaneous T-cell lymphoma that has been categorized as an indolent localized variant of mycosis fungoides. This rare skin disorder was originally described by Woringer and Kolopp in 1939¹ and was further renamed in 1973 by Braun-Falco et al.² At that time the term pagetoid reticulosis was introduced due to similarities in histopathologic findings seen in Paget disease of the nipple. Two variants of the disease have been described since then: the localized type and the disseminated type. The localized type, also known as Woringer-Kolopp disease (WKD), typically presents as a persistent, sharply localized, scaly patch that slowly expands over several years. The lesion is classically located on the extensor surface of the hand or foot and often is asymptomatic. Due to the benign presentation, WKD can easily be confused with much more common diseases, such as psoriasis or fungal infections, resulting in a substantial delay in the diagnosis. The patient will often report a medical history notable for frequent office visits and numerous failed therapies. Even though it is exceedingly uncommon, these findings should prompt the practitioner to add WKD to their differential. The disseminated type of PR (also known as Ketron-Goodman disease) is characterized by diffuse cutaneous involvement, carries a much more progressive course, and often leads to a poor outcome.³ The histopathologic features of WKD and Ketron-Goodman disease are identical, and the 2 types are distinguished on clinical grounds alone.

Histopathologic features of PR are unique and often distinct in comparison to mycosis fungoides. Pagetoid reticulosis often is described as epidermal hyperplasia with parakeratosis, prominent acanthosis, and excessive epidermotropism of atypical lymphocytes scattered throughout the epidermis.³ The distinct pattern of epidermotropism seen in PR is the characteristic finding. Review of immunocytochemistry from reported cases has shown that CD marker expression of neoplastic T cells in PR can be variable in nature.⁴ Although it is known that immunophenotyping can be useful in diagnosing and distinguishing PR from other types of primary cutaneous T-cell lymphoma, the clinical significance of the observed phenotypic variation remains a mystery. As of now, it appears to be prognostically irrelevant.⁵

There are numerous therapeutic options available for PR. Depending on the size and extent of the disease, surgical excision and radiotherapy may be an option and are the most effective.⁶ For patients who are not good candidates or opt out of these options, there are various pharmacotherapies that also have proven to work. Traditional therapies include topical corticosteroids, corticosteroid injections, and phototherapy. However, more recent trials with retinoids, such as alitretinoin or bexarotene, appear to offer a promising therapeutic approach.⁷

Pagetoid reticulosis is a true malignant lymphoma of T-cell lineage, but it typically carries an excellent prognosis. Rare cases have been reported to progress to disseminated lymphoma.⁸ Therefore, long-term follow-up for a patient diagnosed with PR is recommended.

The Diagnosis: Pagetoid Reticulosis

Histopathologic examination demonstrated a dense infiltrate and psoriasiform pattern epidermal hyperplasia (Figure, A). There was conspicuous epidermotropism of moderately enlarged, hyperchromatic lymphocytes. Intraepidermal lymphocytes were slightly larger, darker, and more convoluted than those in the subjacent dermis (Figure, B). These cells exhibited CD3⁺ T-cell differentiation with an abnormal CD4-CD7-CD8- phenotype (Figure, C). The histopathologic finding of atypical epidermotropic T-cell infiltrate was compatible with a rare variant of mycosis fungoides known as pagetoid reticulosis (PR). After discussing the diagnosis and treatment options, the patient elected to begin with a conservative approach to therapy. We prescribed fluocinonide ointment 0.05% twice daily under occlusion. At 1 month follow-up, the patient experienced marked improvement of the erythema and scaling of the lesion.

Pagetoid reticulosis is a primary cutaneous T-cell lymphoma that has been categorized as an indolent localized variant of mycosis fungoides. This rare skin disorder was originally described by Woringer and Kolopp in 1939¹ and was further renamed in 1973 by Braun-Falco et al.² At that time the term pagetoid reticulosis was introduced due to similarities in histopathologic findings seen in Paget disease of the nipple. Two variants of the disease have been described since then: the localized type and the disseminated type. The localized type, also known as Woringer-Kolopp disease (WKD), typically presents as a persistent, sharply localized, scaly patch that slowly expands over several years. The lesion is classically located on the extensor surface of the hand or foot and often is asymptomatic. Due to the benign presentation, WKD can easily be confused with much more common diseases, such as psoriasis or fungal infections, resulting in a substantial delay in the diagnosis. The patient will often report a medical history notable for frequent office visits and numerous failed therapies. Even though it is exceedingly uncommon, these findings should prompt the practitioner to add WKD to their differential. The disseminated type of PR (also known as Ketron-Goodman disease) is characterized by diffuse cutaneous involvement, carries a much more progressive course, and often leads to a poor outcome.³ The histopathologic features of WKD and Ketron-Goodman disease are identical, and the 2 types are distinguished on clinical grounds alone.

Histopathologic features of PR are unique and often distinct in comparison to mycosis fungoides. Pagetoid reticulosis often is described as epidermal hyperplasia with parakeratosis, prominent acanthosis, and excessive epidermotropism of atypical lymphocytes scattered throughout the epidermis.³ The distinct pattern of epidermotropism seen in PR is the characteristic finding. Review of immunocytochemistry from reported cases has shown that CD marker expression of neoplastic T cells in PR can be variable in nature.⁴ Although it is known that immunophenotyping can be useful in diagnosing and distinguishing PR from other types of primary cutaneous T-cell lymphoma, the clinical significance of the observed phenotypic variation remains a mystery. As of now, it appears to be prognostically irrelevant.⁵

There are numerous therapeutic options available for PR. Depending on the size and extent of the disease, surgical excision and radiotherapy may be an option and are the most effective.⁶ For patients who are not good candidates or opt out of these options, there are various pharmacotherapies that also have proven to work. Traditional therapies include topical corticosteroids, corticosteroid injections, and phototherapy. However, more recent trials with retinoids, such as alitretinoin or bexarotene, appear to offer a promising therapeutic approach.⁷

Pagetoid reticulosis is a true malignant lymphoma of T-cell lineage, but it typically carries an excellent prognosis. Rare cases have been reported to progress to disseminated lymphoma.⁸ Therefore, long-term follow-up for a patient diagnosed with PR is recommended.

The Diagnosis: Pagetoid Reticulosis

Histopathologic examination demonstrated a dense infiltrate and psoriasiform pattern epidermal hyperplasia (Figure, A). There was conspicuous epidermotropism of moderately enlarged, hyperchromatic lymphocytes. Intraepidermal lymphocytes were slightly larger, darker, and more convoluted than those in the subjacent dermis (Figure, B). These cells exhibited CD3⁺ T-cell differentiation with an abnormal CD4-CD7-CD8- phenotype (Figure, C). The histopathologic finding of atypical epidermotropic T-cell infiltrate was compatible with a rare variant of mycosis fungoides known as pagetoid reticulosis (PR). After discussing the diagnosis and treatment options, the patient elected to begin with a conservative approach to therapy. We prescribed fluocinonide ointment 0.05% twice daily under occlusion. At 1 month follow-up, the patient experienced marked improvement of the erythema and scaling of the lesion.

Pagetoid reticulosis is a primary cutaneous T-cell lymphoma that has been categorized as an indolent localized variant of mycosis fungoides. This rare skin disorder was originally described by Woringer and Kolopp in 1939¹ and was further renamed in 1973 by Braun-Falco et al.² At that time the term pagetoid reticulosis was introduced due to similarities in histopathologic findings seen in Paget disease of the nipple. Two variants of the disease have been described since then: the localized type and the disseminated type. The localized type, also known as Woringer-Kolopp disease (WKD), typically presents as a persistent, sharply localized, scaly patch that slowly expands over several years. The lesion is classically located on the extensor surface of the hand or foot and often is asymptomatic. Due to the benign presentation, WKD can easily be confused with much more common diseases, such as psoriasis or fungal infections, resulting in a substantial delay in the diagnosis. The patient will often report a medical history notable for frequent office visits and numerous failed therapies. Even though it is exceedingly uncommon, these findings should prompt the practitioner to add WKD to their differential. The disseminated type of PR (also known as Ketron-Goodman disease) is characterized by diffuse cutaneous involvement, carries a much more progressive course, and often leads to a poor outcome.³ The histopathologic features of WKD and Ketron-Goodman disease are identical, and the 2 types are distinguished on clinical grounds alone.

Histopathologic features of PR are unique and often distinct in comparison to mycosis fungoides. Pagetoid reticulosis often is described as epidermal hyperplasia with parakeratosis, prominent acanthosis, and excessive epidermotropism of atypical lymphocytes scattered throughout the epidermis.³ The distinct pattern of epidermotropism seen in PR is the characteristic finding. Review of immunocytochemistry from reported cases has shown that CD marker expression of neoplastic T cells in PR can be variable in nature.⁴ Although it is known that immunophenotyping can be useful in diagnosing and distinguishing PR from other types of primary cutaneous T-cell lymphoma, the clinical significance of the observed phenotypic variation remains a mystery. As of now, it appears to be prognostically irrelevant.⁵

There are numerous therapeutic options available for PR. Depending on the size and extent of the disease, surgical excision and radiotherapy may be an option and are the most effective.⁶ For patients who are not good candidates or opt out of these options, there are various pharmacotherapies that also have proven to work. Traditional therapies include topical corticosteroids, corticosteroid injections, and phototherapy. However, more recent trials with retinoids, such as alitretinoin or bexarotene, appear to offer a promising therapeutic approach.⁷

Pagetoid reticulosis is a true malignant lymphoma of T-cell lineage, but it typically carries an excellent prognosis. Rare cases have been reported to progress to disseminated lymphoma.⁸ Therefore, long-term follow-up for a patient diagnosed with PR is recommended.

Skin cancers in patients with skin of color are less prevalent but have a higher morbidity and mortality compared to white patients. Challenges to early detection, including clinical differences in presentation, low public awareness, lower index of suspicion among health care providers, and access to specialty care, likely contribute to observed differences in prognosis between skin of color and white populations.

RELATED AUDIO: Why is skin cancer mortality higher in patients with skin of color? A peer-to-peer audiocast with Dr. Vincent A. DeLeo and Dr. Andrew F. Alexis.

Skin cancer is the most common malignancy in the United States, accounting for approximately 40% of all neoplasms in white patients but only 1% to 4% in Asian American and black patients.^1,2 Largely due to the photoprotective effects of increased constitutive epidermal melanin, melanoma is approximately 10 to 20 times less frequent in black patients and 3 to 7 times less common in Hispanics than age-matched whites.¹ Nonmelanoma skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma also are less prevalent in darker skin types.^3,4

In the United States, Hispanic, American Indian, and black patients have a 2- to 3-fold higher risk of mortality from malignant melanoma than white patients overall, even when diagnosed at the same stage.^2,5 The most recent Surveillance, Epidemiology, and End Results (SEER) Program cancer statistic review found that the 5-year relative survival of individuals with all stages of malignant melanoma from 2006 to 2012 was 91.1% for white patients and67.3% for black patients. Fortunately, the mortality rate for black patients decreased approximately 0.8% per year from 1975 to 2013.^5,6 No statistically significant change was seen in other ethnic groups, though research in East Asia suggests that age-standardized mortality rates from melanoma have increased by up to 7.4% per year over the last 30 years, with the greatest rise seen in Korean females.^5,7 Further epidemiologic research looking at the relative survival of Asian Americans and Pacific Islanders in the United States is needed.^8,9

Similar to melanoma, the mortality from SCC is disproportionately increased in skin of color populations, ranging from 18% to 29% in black patients.^3,10,11 There is a paucity of population-based studies in the United States looking at mortality rates of nonmelanoma skin cancers and their trends over time, but a 1993 study suggests that mortality rates are declining less consistently in black patients than white patients.¹¹

Factors that may contribute to higher mortality rates in patients with skin of color include a greater propensity for inherently aggressive skin cancers (eg, higher risk of SCC) and delays in diagnosis (eg, late-stage diagnosis of melanoma).^1,4 For melanoma, increased mortality has been attributed to a predominance of acral lentiginous melanomas, which are more frequently diagnosed at more advanced stages than other melanoma subtypes.^6,12,13 Black patients, Hispanics, Asians, and Pacific Islanders are all more likely to present with thicker tumors and metastases on initial presentation than their white counterparts (P<.001).^2,8,9,12-14 The higher risk of death from SCC results from the predominance of lesions on non–sun-exposed areas, particularly the legs and anogenital areas, and within sites of chronic scarring or inflammation.⁴ Unlike sun-induced SCC, the most commonly observed type of SCC in lighter skin types, SCCs that develop in association with chronic inflammatory or ulcerative processes are aggressive and invasive, and they metastasize to distant sites in 20% to 40% of cases (versus 1%–4% in sun-induced SCC).^1,3,4 For all skin cancers, poor access to medical care, patients’ unawareness of their skin cancer risk, lack of adequate skin examinations, and prevalence of lesions on uncommon sites that may be inconspicuous or overlooked have all been suggested to delay diagnosis.^1,15,16 Given that more advanced disease is associated with worse outcomes, the implications of this delay are enormous and remain a cause for concern.

RELATED AUDIO: Dr. Alexis discusses factors that contribute to the delayed diagnosis of melanoma in patients with skin of color and what physicians should know about the incidence and presentation of melanoma in this population to help educate their patients.

The alarming skin cancer mortality rates in patients with skin of color are a call to action for the medical community. The consistent use of full-body skin examinations including close inspection of mucosal, acral, and genital areas for all patients independent of skin type and racial/ethnic background is paramount. Advancing skin cancer education in skin of color populations, such as through distribution of patient-directed educational materials produced by organizations such as the American Academy of Dermatology, Skin Cancer Foundation, and Skin of Color Society, is an important step toward increased public awareness.¹⁶ Use of social and traditional media outlets as well as community-directed health outreach campaigns also are important strategies to change the common misconception that darker-skinned individuals do not get skin cancer. We hope that with a multipronged approach, disparities in skin cancer mortality will steadily be eliminated.

Skin cancers in patients with skin of color are less prevalent but have a higher morbidity and mortality compared to white patients. Challenges to early detection, including clinical differences in presentation, low public awareness, lower index of suspicion among health care providers, and access to specialty care, likely contribute to observed differences in prognosis between skin of color and white populations.

RELATED AUDIO: Why is skin cancer mortality higher in patients with skin of color? A peer-to-peer audiocast with Dr. Vincent A. DeLeo and Dr. Andrew F. Alexis.

Skin cancer is the most common malignancy in the United States, accounting for approximately 40% of all neoplasms in white patients but only 1% to 4% in Asian American and black patients.^1,2 Largely due to the photoprotective effects of increased constitutive epidermal melanin, melanoma is approximately 10 to 20 times less frequent in black patients and 3 to 7 times less common in Hispanics than age-matched whites.¹ Nonmelanoma skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma also are less prevalent in darker skin types.^3,4

In the United States, Hispanic, American Indian, and black patients have a 2- to 3-fold higher risk of mortality from malignant melanoma than white patients overall, even when diagnosed at the same stage.^2,5 The most recent Surveillance, Epidemiology, and End Results (SEER) Program cancer statistic review found that the 5-year relative survival of individuals with all stages of malignant melanoma from 2006 to 2012 was 91.1% for white patients and67.3% for black patients. Fortunately, the mortality rate for black patients decreased approximately 0.8% per year from 1975 to 2013.^5,6 No statistically significant change was seen in other ethnic groups, though research in East Asia suggests that age-standardized mortality rates from melanoma have increased by up to 7.4% per year over the last 30 years, with the greatest rise seen in Korean females.^5,7 Further epidemiologic research looking at the relative survival of Asian Americans and Pacific Islanders in the United States is needed.^8,9

Similar to melanoma, the mortality from SCC is disproportionately increased in skin of color populations, ranging from 18% to 29% in black patients.^3,10,11 There is a paucity of population-based studies in the United States looking at mortality rates of nonmelanoma skin cancers and their trends over time, but a 1993 study suggests that mortality rates are declining less consistently in black patients than white patients.¹¹

Factors that may contribute to higher mortality rates in patients with skin of color include a greater propensity for inherently aggressive skin cancers (eg, higher risk of SCC) and delays in diagnosis (eg, late-stage diagnosis of melanoma).^1,4 For melanoma, increased mortality has been attributed to a predominance of acral lentiginous melanomas, which are more frequently diagnosed at more advanced stages than other melanoma subtypes.^6,12,13 Black patients, Hispanics, Asians, and Pacific Islanders are all more likely to present with thicker tumors and metastases on initial presentation than their white counterparts (P<.001).^2,8,9,12-14 The higher risk of death from SCC results from the predominance of lesions on non–sun-exposed areas, particularly the legs and anogenital areas, and within sites of chronic scarring or inflammation.⁴ Unlike sun-induced SCC, the most commonly observed type of SCC in lighter skin types, SCCs that develop in association with chronic inflammatory or ulcerative processes are aggressive and invasive, and they metastasize to distant sites in 20% to 40% of cases (versus 1%–4% in sun-induced SCC).^1,3,4 For all skin cancers, poor access to medical care, patients’ unawareness of their skin cancer risk, lack of adequate skin examinations, and prevalence of lesions on uncommon sites that may be inconspicuous or overlooked have all been suggested to delay diagnosis.^1,15,16 Given that more advanced disease is associated with worse outcomes, the implications of this delay are enormous and remain a cause for concern.

RELATED AUDIO: Dr. Alexis discusses factors that contribute to the delayed diagnosis of melanoma in patients with skin of color and what physicians should know about the incidence and presentation of melanoma in this population to help educate their patients.

The alarming skin cancer mortality rates in patients with skin of color are a call to action for the medical community. The consistent use of full-body skin examinations including close inspection of mucosal, acral, and genital areas for all patients independent of skin type and racial/ethnic background is paramount. Advancing skin cancer education in skin of color populations, such as through distribution of patient-directed educational materials produced by organizations such as the American Academy of Dermatology, Skin Cancer Foundation, and Skin of Color Society, is an important step toward increased public awareness.¹⁶ Use of social and traditional media outlets as well as community-directed health outreach campaigns also are important strategies to change the common misconception that darker-skinned individuals do not get skin cancer. We hope that with a multipronged approach, disparities in skin cancer mortality will steadily be eliminated.

Skin cancers in patients with skin of color are less prevalent but have a higher morbidity and mortality compared to white patients. Challenges to early detection, including clinical differences in presentation, low public awareness, lower index of suspicion among health care providers, and access to specialty care, likely contribute to observed differences in prognosis between skin of color and white populations.

RELATED AUDIO: Why is skin cancer mortality higher in patients with skin of color? A peer-to-peer audiocast with Dr. Vincent A. DeLeo and Dr. Andrew F. Alexis.

Skin cancer is the most common malignancy in the United States, accounting for approximately 40% of all neoplasms in white patients but only 1% to 4% in Asian American and black patients.^1,2 Largely due to the photoprotective effects of increased constitutive epidermal melanin, melanoma is approximately 10 to 20 times less frequent in black patients and 3 to 7 times less common in Hispanics than age-matched whites.¹ Nonmelanoma skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma also are less prevalent in darker skin types.^3,4

In the United States, Hispanic, American Indian, and black patients have a 2- to 3-fold higher risk of mortality from malignant melanoma than white patients overall, even when diagnosed at the same stage.^2,5 The most recent Surveillance, Epidemiology, and End Results (SEER) Program cancer statistic review found that the 5-year relative survival of individuals with all stages of malignant melanoma from 2006 to 2012 was 91.1% for white patients and67.3% for black patients. Fortunately, the mortality rate for black patients decreased approximately 0.8% per year from 1975 to 2013.^5,6 No statistically significant change was seen in other ethnic groups, though research in East Asia suggests that age-standardized mortality rates from melanoma have increased by up to 7.4% per year over the last 30 years, with the greatest rise seen in Korean females.^5,7 Further epidemiologic research looking at the relative survival of Asian Americans and Pacific Islanders in the United States is needed.^8,9

Similar to melanoma, the mortality from SCC is disproportionately increased in skin of color populations, ranging from 18% to 29% in black patients.^3,10,11 There is a paucity of population-based studies in the United States looking at mortality rates of nonmelanoma skin cancers and their trends over time, but a 1993 study suggests that mortality rates are declining less consistently in black patients than white patients.¹¹

Factors that may contribute to higher mortality rates in patients with skin of color include a greater propensity for inherently aggressive skin cancers (eg, higher risk of SCC) and delays in diagnosis (eg, late-stage diagnosis of melanoma).^1,4 For melanoma, increased mortality has been attributed to a predominance of acral lentiginous melanomas, which are more frequently diagnosed at more advanced stages than other melanoma subtypes.^6,12,13 Black patients, Hispanics, Asians, and Pacific Islanders are all more likely to present with thicker tumors and metastases on initial presentation than their white counterparts (P<.001).^2,8,9,12-14 The higher risk of death from SCC results from the predominance of lesions on non–sun-exposed areas, particularly the legs and anogenital areas, and within sites of chronic scarring or inflammation.⁴ Unlike sun-induced SCC, the most commonly observed type of SCC in lighter skin types, SCCs that develop in association with chronic inflammatory or ulcerative processes are aggressive and invasive, and they metastasize to distant sites in 20% to 40% of cases (versus 1%–4% in sun-induced SCC).^1,3,4 For all skin cancers, poor access to medical care, patients’ unawareness of their skin cancer risk, lack of adequate skin examinations, and prevalence of lesions on uncommon sites that may be inconspicuous or overlooked have all been suggested to delay diagnosis.^1,15,16 Given that more advanced disease is associated with worse outcomes, the implications of this delay are enormous and remain a cause for concern.

RELATED AUDIO: Dr. Alexis discusses factors that contribute to the delayed diagnosis of melanoma in patients with skin of color and what physicians should know about the incidence and presentation of melanoma in this population to help educate their patients.

The alarming skin cancer mortality rates in patients with skin of color are a call to action for the medical community. The consistent use of full-body skin examinations including close inspection of mucosal, acral, and genital areas for all patients independent of skin type and racial/ethnic background is paramount. Advancing skin cancer education in skin of color populations, such as through distribution of patient-directed educational materials produced by organizations such as the American Academy of Dermatology, Skin Cancer Foundation, and Skin of Color Society, is an important step toward increased public awareness.¹⁶ Use of social and traditional media outlets as well as community-directed health outreach campaigns also are important strategies to change the common misconception that darker-skinned individuals do not get skin cancer. We hope that with a multipronged approach, disparities in skin cancer mortality will steadily be eliminated.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.