Melanoma

WILLIAMSBURG, VA. — Although large numbers of nevi—especially dysplastic nevi—are clearly associated with an increased melanoma risk, the lesions themselves do not appear to become cancerous, Dr. Terry L. Barrett said at the annual meeting of the American Society for Mohs Surgery.

"I remain unconvinced that either the common acquired nevus or the dysplastic nevus develops into melanoma," said Dr. Barrett, professor of pathology and dermatology at the University of Texas, Dallas. "I think they are both benign lesions the majority of the time. Usually, melanomas in these patients arise on normal-appearing skin and not the site of the nevus. When that happens, I think it's coincidental, not a nevus gone bad."

Few studies have actually investigated this point, although Dr. Barrett did mention a 2007 in vitro study that looked at levels of polycomb group protein EZH2, a cell regulatory protein markedly elevated in malignant skin lesions (J. Cutan. Pathol. 2007;34:597-600). The level in both in situ and invasive melanoma was almost three times that seen in acquired and dysplastic nevi—a finding that seems to support Dr. Barrett's opinion.

Regardless of the source, however, patients with large numbers of nevi are at a significantly increased risk of melanoma and other malignancies. The two commonly recognized nevi syndromes carry different risks, Dr. Barrett said.

Familial atypical mole/melanoma syndrome is an autosomal dominant disorder that increases the lifetime risk of melanoma by almost 100%. Sporadic dysplastic nevus syndrome is a spontaneous mutation that increases the relative risk of malignancy up to 46 times that of the general population, he said.

For patients with the sporadic syndrome, sun exposure seems to play a key role in the development of melanoma. "It's been suggested that intermittent sun exposure manifests the phenotype of the dysplastic nevi [and its attendant increased melanoma risk], while patients without sun exposure manifest the common acquired nevi," Dr. Barrett noted.

"There is no clear agreement among dermatologists about how these lesions should be handled," he said. "If you think a lesion is premalignant, you'll want to excise it, and if the report comes back 'severely atypical,' you'll probably want to have negative margins. If you think the lesions aren't premalignant, then after you exclude a diagnosis of melanoma, you probably won't do anything. We have people in our practice who do both."

The phase in which a dermatologist "catches" the nevus probably influences treatment decisions. "These lesions are dynamic, change throughout life, and can be acquired at any age. I think what's happening is that if we biopsy them in a quiescent phase, we don't see cytological atypia. And if we catch them in a dynamic phase, they have different cellular characteristics, which we then have to define as mild or severe atypia," Dr. Barrett said.

Since the lesions are so changeable, and patients are at such a significantly increased risk of melanoma, close follow-up at 3- to 11-month intervals is crucial. It's probably a good idea to screen first-degree relatives, too, he suggested.

WILLIAMSBURG, VA. — Although large numbers of nevi—especially dysplastic nevi—are clearly associated with an increased melanoma risk, the lesions themselves do not appear to become cancerous, Dr. Terry L. Barrett said at the annual meeting of the American Society for Mohs Surgery.

"I remain unconvinced that either the common acquired nevus or the dysplastic nevus develops into melanoma," said Dr. Barrett, professor of pathology and dermatology at the University of Texas, Dallas. "I think they are both benign lesions the majority of the time. Usually, melanomas in these patients arise on normal-appearing skin and not the site of the nevus. When that happens, I think it's coincidental, not a nevus gone bad."

Few studies have actually investigated this point, although Dr. Barrett did mention a 2007 in vitro study that looked at levels of polycomb group protein EZH2, a cell regulatory protein markedly elevated in malignant skin lesions (J. Cutan. Pathol. 2007;34:597-600). The level in both in situ and invasive melanoma was almost three times that seen in acquired and dysplastic nevi—a finding that seems to support Dr. Barrett's opinion.

Regardless of the source, however, patients with large numbers of nevi are at a significantly increased risk of melanoma and other malignancies. The two commonly recognized nevi syndromes carry different risks, Dr. Barrett said.

Familial atypical mole/melanoma syndrome is an autosomal dominant disorder that increases the lifetime risk of melanoma by almost 100%. Sporadic dysplastic nevus syndrome is a spontaneous mutation that increases the relative risk of malignancy up to 46 times that of the general population, he said.

For patients with the sporadic syndrome, sun exposure seems to play a key role in the development of melanoma. "It's been suggested that intermittent sun exposure manifests the phenotype of the dysplastic nevi [and its attendant increased melanoma risk], while patients without sun exposure manifest the common acquired nevi," Dr. Barrett noted.

"There is no clear agreement among dermatologists about how these lesions should be handled," he said. "If you think a lesion is premalignant, you'll want to excise it, and if the report comes back 'severely atypical,' you'll probably want to have negative margins. If you think the lesions aren't premalignant, then after you exclude a diagnosis of melanoma, you probably won't do anything. We have people in our practice who do both."

The phase in which a dermatologist "catches" the nevus probably influences treatment decisions. "These lesions are dynamic, change throughout life, and can be acquired at any age. I think what's happening is that if we biopsy them in a quiescent phase, we don't see cytological atypia. And if we catch them in a dynamic phase, they have different cellular characteristics, which we then have to define as mild or severe atypia," Dr. Barrett said.

Since the lesions are so changeable, and patients are at such a significantly increased risk of melanoma, close follow-up at 3- to 11-month intervals is crucial. It's probably a good idea to screen first-degree relatives, too, he suggested.

WILLIAMSBURG, VA. — Although large numbers of nevi—especially dysplastic nevi—are clearly associated with an increased melanoma risk, the lesions themselves do not appear to become cancerous, Dr. Terry L. Barrett said at the annual meeting of the American Society for Mohs Surgery.

"I remain unconvinced that either the common acquired nevus or the dysplastic nevus develops into melanoma," said Dr. Barrett, professor of pathology and dermatology at the University of Texas, Dallas. "I think they are both benign lesions the majority of the time. Usually, melanomas in these patients arise on normal-appearing skin and not the site of the nevus. When that happens, I think it's coincidental, not a nevus gone bad."

Few studies have actually investigated this point, although Dr. Barrett did mention a 2007 in vitro study that looked at levels of polycomb group protein EZH2, a cell regulatory protein markedly elevated in malignant skin lesions (J. Cutan. Pathol. 2007;34:597-600). The level in both in situ and invasive melanoma was almost three times that seen in acquired and dysplastic nevi—a finding that seems to support Dr. Barrett's opinion.

Regardless of the source, however, patients with large numbers of nevi are at a significantly increased risk of melanoma and other malignancies. The two commonly recognized nevi syndromes carry different risks, Dr. Barrett said.

Familial atypical mole/melanoma syndrome is an autosomal dominant disorder that increases the lifetime risk of melanoma by almost 100%. Sporadic dysplastic nevus syndrome is a spontaneous mutation that increases the relative risk of malignancy up to 46 times that of the general population, he said.

For patients with the sporadic syndrome, sun exposure seems to play a key role in the development of melanoma. "It's been suggested that intermittent sun exposure manifests the phenotype of the dysplastic nevi [and its attendant increased melanoma risk], while patients without sun exposure manifest the common acquired nevi," Dr. Barrett noted.

"There is no clear agreement among dermatologists about how these lesions should be handled," he said. "If you think a lesion is premalignant, you'll want to excise it, and if the report comes back 'severely atypical,' you'll probably want to have negative margins. If you think the lesions aren't premalignant, then after you exclude a diagnosis of melanoma, you probably won't do anything. We have people in our practice who do both."

The phase in which a dermatologist "catches" the nevus probably influences treatment decisions. "These lesions are dynamic, change throughout life, and can be acquired at any age. I think what's happening is that if we biopsy them in a quiescent phase, we don't see cytological atypia. And if we catch them in a dynamic phase, they have different cellular characteristics, which we then have to define as mild or severe atypia," Dr. Barrett said.

Since the lesions are so changeable, and patients are at such a significantly increased risk of melanoma, close follow-up at 3- to 11-month intervals is crucial. It's probably a good idea to screen first-degree relatives, too, he suggested.

CHICAGO — The investigational agent ipilimumab showed activity against all stages of advanced metastatic melanoma, but was also associated with colitis and diarrhea that were not controlled by oral prophylaxis with the anti-inflammatory budesonide, investigators reported at the annual meeting of the American Society of Clinical Oncology.

"Ipilimumab, which in my opinion is an active drug in melanoma, is associated with autoinflammatory side effects, so-called immune-related adverse events," said Dr. Jeffrey S. Weber of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla.

The hypothesis of the study, funded by Bristol-Myers Squibb, joint developer of the monoclonal antibody ipilimumab, was that prophylactic oral budesonide (Entocort EC), an anti-inflammatory approved for treatment of Crohn's disease, might reduce the rate of grade 2 or greater gastrointestinal immune-related adverse events associated with ipilimumab therapy.

The idea did not pan out and the study did not reach its primary end point, although it did meet several of the secondary end points of melanoma control in both previously treated and treatment-naïve patients, reported Dr. Weber, who shares a patent with the University of Southern California and Bristol-Myers Squibb/Medarex.

Budesonide was chosen because it is a controlled-release oral steroid with minimal systemic corticosteroid exposure, Dr. Weber noted.

The primary end point of the study was diarrhea of grade 2 severity or greater among patients receiving 10 mg/kg of ipilimumab and either placebo or budesonide.

Secondary end points included best overall response rate per modified World Health Organization criteria, disease control rate (a composite of complete and partial response rates and stable disease), overall and 1-year survival, and biologic and pharmacokinetic parameters.

Budesonide was administered at a dose of 9 mg/day during ipilimumab induction every 3 weeks in four cycles over 12 weeks, after which budesonide was tapered. A total of 58 patients received the monoclonal antibody plus budesonide, and 57 received ipilimumab plus placebo.

The authors found that grade 2 or greater diarrhea occurred in 19 of the 58 (32.83%) of patients on budesonide, and 20 of 57 (35.1%) of those on placebo; the difference was not statistically significant, Dr. Weber said.

Objective tumor response to ipilimumab was seen in both the budesonide and control arms, at 15.8% and 12.1% of patients, respectively. Response rates were similar among previously treated and treatment-naïve patients, and in patients with stage M1a, M1b, and M1c disease. At the time of the analysis, 24 months, median overall survival had not been reached. The 1-year survival rate was similar in both groups, at 58.8% among patients on budesonide, and 59.1% of controls.

A Kaplan-Meier estimate for overall survival suggested that at about 20 months the survival rate for previously untreated patients would be 67.2%, and the rate for treatment-experienced patients would be 48.8%.

Among patients with melanoma metastatic to brain, two had a partial response, three had stable disease, one had disease progression, and one patient's status was unknown. Of these patients, one survived less than 6 months after being started on ipilimumab, four lived between 6 and 9 months, and seven were still alive from 10.4 to 19.4 months, the point of most recent follow-up.

Central nervous system adverse events related to ipilimumab were reported in two patients, with grade 2 headache and grade 1 dizziness. Immune-related adverse events were the most common toxicities seen with ipilimumab; 40% were grade 3 or 4 events. There were no bowel perforations or treatment-related deaths.

"My conclusion as to the secondary end points is that ipilimumab showed significant efficacy with an excellent estimated median overall survival in patients who got or did not receive prophylactic budesonide, previously treated or untreated patients, patients at all M stages, and including the 50% who had M1c disease," Dr. Weber said.

CHICAGO — The investigational agent ipilimumab showed activity against all stages of advanced metastatic melanoma, but was also associated with colitis and diarrhea that were not controlled by oral prophylaxis with the anti-inflammatory budesonide, investigators reported at the annual meeting of the American Society of Clinical Oncology.

"Ipilimumab, which in my opinion is an active drug in melanoma, is associated with autoinflammatory side effects, so-called immune-related adverse events," said Dr. Jeffrey S. Weber of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla.

The hypothesis of the study, funded by Bristol-Myers Squibb, joint developer of the monoclonal antibody ipilimumab, was that prophylactic oral budesonide (Entocort EC), an anti-inflammatory approved for treatment of Crohn's disease, might reduce the rate of grade 2 or greater gastrointestinal immune-related adverse events associated with ipilimumab therapy.

The idea did not pan out and the study did not reach its primary end point, although it did meet several of the secondary end points of melanoma control in both previously treated and treatment-naïve patients, reported Dr. Weber, who shares a patent with the University of Southern California and Bristol-Myers Squibb/Medarex.

Budesonide was chosen because it is a controlled-release oral steroid with minimal systemic corticosteroid exposure, Dr. Weber noted.

The primary end point of the study was diarrhea of grade 2 severity or greater among patients receiving 10 mg/kg of ipilimumab and either placebo or budesonide.

Secondary end points included best overall response rate per modified World Health Organization criteria, disease control rate (a composite of complete and partial response rates and stable disease), overall and 1-year survival, and biologic and pharmacokinetic parameters.

Budesonide was administered at a dose of 9 mg/day during ipilimumab induction every 3 weeks in four cycles over 12 weeks, after which budesonide was tapered. A total of 58 patients received the monoclonal antibody plus budesonide, and 57 received ipilimumab plus placebo.

The authors found that grade 2 or greater diarrhea occurred in 19 of the 58 (32.83%) of patients on budesonide, and 20 of 57 (35.1%) of those on placebo; the difference was not statistically significant, Dr. Weber said.

Objective tumor response to ipilimumab was seen in both the budesonide and control arms, at 15.8% and 12.1% of patients, respectively. Response rates were similar among previously treated and treatment-naïve patients, and in patients with stage M1a, M1b, and M1c disease. At the time of the analysis, 24 months, median overall survival had not been reached. The 1-year survival rate was similar in both groups, at 58.8% among patients on budesonide, and 59.1% of controls.

A Kaplan-Meier estimate for overall survival suggested that at about 20 months the survival rate for previously untreated patients would be 67.2%, and the rate for treatment-experienced patients would be 48.8%.

Among patients with melanoma metastatic to brain, two had a partial response, three had stable disease, one had disease progression, and one patient's status was unknown. Of these patients, one survived less than 6 months after being started on ipilimumab, four lived between 6 and 9 months, and seven were still alive from 10.4 to 19.4 months, the point of most recent follow-up.

Central nervous system adverse events related to ipilimumab were reported in two patients, with grade 2 headache and grade 1 dizziness. Immune-related adverse events were the most common toxicities seen with ipilimumab; 40% were grade 3 or 4 events. There were no bowel perforations or treatment-related deaths.

"My conclusion as to the secondary end points is that ipilimumab showed significant efficacy with an excellent estimated median overall survival in patients who got or did not receive prophylactic budesonide, previously treated or untreated patients, patients at all M stages, and including the 50% who had M1c disease," Dr. Weber said.

CHICAGO — The investigational agent ipilimumab showed activity against all stages of advanced metastatic melanoma, but was also associated with colitis and diarrhea that were not controlled by oral prophylaxis with the anti-inflammatory budesonide, investigators reported at the annual meeting of the American Society of Clinical Oncology.

"Ipilimumab, which in my opinion is an active drug in melanoma, is associated with autoinflammatory side effects, so-called immune-related adverse events," said Dr. Jeffrey S. Weber of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla.

The hypothesis of the study, funded by Bristol-Myers Squibb, joint developer of the monoclonal antibody ipilimumab, was that prophylactic oral budesonide (Entocort EC), an anti-inflammatory approved for treatment of Crohn's disease, might reduce the rate of grade 2 or greater gastrointestinal immune-related adverse events associated with ipilimumab therapy.

The idea did not pan out and the study did not reach its primary end point, although it did meet several of the secondary end points of melanoma control in both previously treated and treatment-naïve patients, reported Dr. Weber, who shares a patent with the University of Southern California and Bristol-Myers Squibb/Medarex.

Budesonide was chosen because it is a controlled-release oral steroid with minimal systemic corticosteroid exposure, Dr. Weber noted.

The primary end point of the study was diarrhea of grade 2 severity or greater among patients receiving 10 mg/kg of ipilimumab and either placebo or budesonide.

Secondary end points included best overall response rate per modified World Health Organization criteria, disease control rate (a composite of complete and partial response rates and stable disease), overall and 1-year survival, and biologic and pharmacokinetic parameters.

Budesonide was administered at a dose of 9 mg/day during ipilimumab induction every 3 weeks in four cycles over 12 weeks, after which budesonide was tapered. A total of 58 patients received the monoclonal antibody plus budesonide, and 57 received ipilimumab plus placebo.

The authors found that grade 2 or greater diarrhea occurred in 19 of the 58 (32.83%) of patients on budesonide, and 20 of 57 (35.1%) of those on placebo; the difference was not statistically significant, Dr. Weber said.

Objective tumor response to ipilimumab was seen in both the budesonide and control arms, at 15.8% and 12.1% of patients, respectively. Response rates were similar among previously treated and treatment-naïve patients, and in patients with stage M1a, M1b, and M1c disease. At the time of the analysis, 24 months, median overall survival had not been reached. The 1-year survival rate was similar in both groups, at 58.8% among patients on budesonide, and 59.1% of controls.

A Kaplan-Meier estimate for overall survival suggested that at about 20 months the survival rate for previously untreated patients would be 67.2%, and the rate for treatment-experienced patients would be 48.8%.

Among patients with melanoma metastatic to brain, two had a partial response, three had stable disease, one had disease progression, and one patient's status was unknown. Of these patients, one survived less than 6 months after being started on ipilimumab, four lived between 6 and 9 months, and seven were still alive from 10.4 to 19.4 months, the point of most recent follow-up.

Central nervous system adverse events related to ipilimumab were reported in two patients, with grade 2 headache and grade 1 dizziness. Immune-related adverse events were the most common toxicities seen with ipilimumab; 40% were grade 3 or 4 events. There were no bowel perforations or treatment-related deaths.

"My conclusion as to the secondary end points is that ipilimumab showed significant efficacy with an excellent estimated median overall survival in patients who got or did not receive prophylactic budesonide, previously treated or untreated patients, patients at all M stages, and including the 50% who had M1c disease," Dr. Weber said.

NEW ORLEANS — Although the concept of checking the skin for melanoma may be to "find the ugly duckling," the first challenge is to identify the signature nevus in order to determine the patient's particular phenotype, said Dr. Jean Bolognia.

"Identifying the signature nevus will reduce the number of biopsies you perform," said Dr. Bolognia.

She discussed several varieties of signature melanocytic nevi at a dermatology update sponsored by Tulane University. She highlighted a few of the more common types as well as the two most challenging.

Solid brown nevi, she said, are easier to manage. "This type of signature nevus is easy to follow, as it is symmetric and uniform in color," noted Dr. Bolognia, professor of dermatology at Yale University, New Haven, Conn.

Because of their size, the large moles that resemble fried eggs and are often found on the back are frequently of concern to patients and their relatives as well as to non-dermatologists. These "sensational" nevi are benign, and rather than being labeled as precursors of melanoma, they should be viewed as a phenotypic marker, alerting the physician that the patient's entire skin is at risk and should therefore be carefully examined.

"A melanoma can arise in this type of nevus, just as it can any other compound nevus," she said. "Do look for superimposed changes, but in and of themselves, these nevi are benign." Prophylactic excision is not recommended for fried-egg nevi, as scarring can be significant given their size and truncal location. In addition, these nevi age over time with gradual fading of the shoulder component into the surrounding skin and formation of a skin-colored intradermal nevus centrally.

On other hand, the "cheetah" phenotype, represented by numerous small, dark nevi, can be very difficult to manage, she noted. The signature nevus is a dark brown-black compound or junctional lentiginous nevus that may or may not have a thin medium brown rim. The center of the lesion is extremely dark and solid, without a visible pigment pattern by dermoscopy.

"Usually, the patient has 200 or more of these nevi, often admixed with solar lentigines. The anticipation is that this patient will undergo multiple biopsies, with a lower 'hit rate' for cutaneous melanoma than with other types of nevi," she said. "I share these patients with another dermatologist. Having two sets of eyes doing a skin examination is my solution to the difficult 'cheetah' phenotype."

The "eclipse" nevi resemble a solar eclipse, with a solid tan center and a brown rim that is often stellate. The rim may also be discontinuous, leading to asymmetry. They are often seen on the scalp of children, and can be the first sign that a child will be "moley."

"These nevi are benign but they get attention because of their irregular outline and variation in color. Unless there is a superimposed change, they should not elicit concern," she noted. "When the signature nevus is an eclipse nevus, you should focus on the 10 to 15 other nevi that are not in this 'family' and look for the one with the most atypical features."

Dr. Bolognia does not recommend surgically removing eclipse nevi on the scalp because others will probably develop and parents will expect these to be removed as well. Cockarde or "target" nevi are in the same family as eclipse nevi; these types are often seen together.

Another difficult, though rare, phenotype is represented by multiple pink nevi. These patients tend to be skin type 1 or 2 and they produce little, if any, melanin in their nevi. "In this patient the pigment pattern is missing, the road signs are gone, and these nevi can be difficult to evaluate clinically," she said.

"If the nevus has substance (not soft like an aging dermal nevus), I take a second look. And I also look for the nevus with the darkest pink color or any red lesion. I usually biopsy the latter, unless it is clearly acneiform, and like with the 'cheetah' phenotype, share these patients with another dermatologist," she said.

Multiple halo nevi, seen most often in patients in their late teens and early 20s, can also be problematic. There are four stages of halo nevi, with stages I and II being characterized by a depigmented halo surrounding either a pigmented nevus (I) or a pink nevus (II). Stage III appears as an area of depigmentation that is oval or circular in shape (with no central nevus), thus resembling a patch of vitiligo, while stage IV represents complete repigmentation. While everyone with multiple halo nevi deserves a total body examination, if an older adult presents with multiple halo nevi, the possibility of an immune reaction to an ocular (or cutaneous) melanoma needs to be considered, Dr. Bolognia said.

Exams of the "cheetah" phenotype, represented by numerous small, dark nevi, are best conducted with two sets of eyes. Courtesy Dr. Jean Bolognia

NEW ORLEANS — Although the concept of checking the skin for melanoma may be to "find the ugly duckling," the first challenge is to identify the signature nevus in order to determine the patient's particular phenotype, said Dr. Jean Bolognia.

"Identifying the signature nevus will reduce the number of biopsies you perform," said Dr. Bolognia.

She discussed several varieties of signature melanocytic nevi at a dermatology update sponsored by Tulane University. She highlighted a few of the more common types as well as the two most challenging.

Solid brown nevi, she said, are easier to manage. "This type of signature nevus is easy to follow, as it is symmetric and uniform in color," noted Dr. Bolognia, professor of dermatology at Yale University, New Haven, Conn.

Because of their size, the large moles that resemble fried eggs and are often found on the back are frequently of concern to patients and their relatives as well as to non-dermatologists. These "sensational" nevi are benign, and rather than being labeled as precursors of melanoma, they should be viewed as a phenotypic marker, alerting the physician that the patient's entire skin is at risk and should therefore be carefully examined.

"A melanoma can arise in this type of nevus, just as it can any other compound nevus," she said. "Do look for superimposed changes, but in and of themselves, these nevi are benign." Prophylactic excision is not recommended for fried-egg nevi, as scarring can be significant given their size and truncal location. In addition, these nevi age over time with gradual fading of the shoulder component into the surrounding skin and formation of a skin-colored intradermal nevus centrally.

On other hand, the "cheetah" phenotype, represented by numerous small, dark nevi, can be very difficult to manage, she noted. The signature nevus is a dark brown-black compound or junctional lentiginous nevus that may or may not have a thin medium brown rim. The center of the lesion is extremely dark and solid, without a visible pigment pattern by dermoscopy.

"Usually, the patient has 200 or more of these nevi, often admixed with solar lentigines. The anticipation is that this patient will undergo multiple biopsies, with a lower 'hit rate' for cutaneous melanoma than with other types of nevi," she said. "I share these patients with another dermatologist. Having two sets of eyes doing a skin examination is my solution to the difficult 'cheetah' phenotype."

The "eclipse" nevi resemble a solar eclipse, with a solid tan center and a brown rim that is often stellate. The rim may also be discontinuous, leading to asymmetry. They are often seen on the scalp of children, and can be the first sign that a child will be "moley."

"These nevi are benign but they get attention because of their irregular outline and variation in color. Unless there is a superimposed change, they should not elicit concern," she noted. "When the signature nevus is an eclipse nevus, you should focus on the 10 to 15 other nevi that are not in this 'family' and look for the one with the most atypical features."

Dr. Bolognia does not recommend surgically removing eclipse nevi on the scalp because others will probably develop and parents will expect these to be removed as well. Cockarde or "target" nevi are in the same family as eclipse nevi; these types are often seen together.

Another difficult, though rare, phenotype is represented by multiple pink nevi. These patients tend to be skin type 1 or 2 and they produce little, if any, melanin in their nevi. "In this patient the pigment pattern is missing, the road signs are gone, and these nevi can be difficult to evaluate clinically," she said.

"If the nevus has substance (not soft like an aging dermal nevus), I take a second look. And I also look for the nevus with the darkest pink color or any red lesion. I usually biopsy the latter, unless it is clearly acneiform, and like with the 'cheetah' phenotype, share these patients with another dermatologist," she said.

Multiple halo nevi, seen most often in patients in their late teens and early 20s, can also be problematic. There are four stages of halo nevi, with stages I and II being characterized by a depigmented halo surrounding either a pigmented nevus (I) or a pink nevus (II). Stage III appears as an area of depigmentation that is oval or circular in shape (with no central nevus), thus resembling a patch of vitiligo, while stage IV represents complete repigmentation. While everyone with multiple halo nevi deserves a total body examination, if an older adult presents with multiple halo nevi, the possibility of an immune reaction to an ocular (or cutaneous) melanoma needs to be considered, Dr. Bolognia said.

Exams of the "cheetah" phenotype, represented by numerous small, dark nevi, are best conducted with two sets of eyes. Courtesy Dr. Jean Bolognia

NEW ORLEANS — Although the concept of checking the skin for melanoma may be to "find the ugly duckling," the first challenge is to identify the signature nevus in order to determine the patient's particular phenotype, said Dr. Jean Bolognia.

"Identifying the signature nevus will reduce the number of biopsies you perform," said Dr. Bolognia.

She discussed several varieties of signature melanocytic nevi at a dermatology update sponsored by Tulane University. She highlighted a few of the more common types as well as the two most challenging.

Solid brown nevi, she said, are easier to manage. "This type of signature nevus is easy to follow, as it is symmetric and uniform in color," noted Dr. Bolognia, professor of dermatology at Yale University, New Haven, Conn.

Because of their size, the large moles that resemble fried eggs and are often found on the back are frequently of concern to patients and their relatives as well as to non-dermatologists. These "sensational" nevi are benign, and rather than being labeled as precursors of melanoma, they should be viewed as a phenotypic marker, alerting the physician that the patient's entire skin is at risk and should therefore be carefully examined.

"A melanoma can arise in this type of nevus, just as it can any other compound nevus," she said. "Do look for superimposed changes, but in and of themselves, these nevi are benign." Prophylactic excision is not recommended for fried-egg nevi, as scarring can be significant given their size and truncal location. In addition, these nevi age over time with gradual fading of the shoulder component into the surrounding skin and formation of a skin-colored intradermal nevus centrally.

On other hand, the "cheetah" phenotype, represented by numerous small, dark nevi, can be very difficult to manage, she noted. The signature nevus is a dark brown-black compound or junctional lentiginous nevus that may or may not have a thin medium brown rim. The center of the lesion is extremely dark and solid, without a visible pigment pattern by dermoscopy.

"Usually, the patient has 200 or more of these nevi, often admixed with solar lentigines. The anticipation is that this patient will undergo multiple biopsies, with a lower 'hit rate' for cutaneous melanoma than with other types of nevi," she said. "I share these patients with another dermatologist. Having two sets of eyes doing a skin examination is my solution to the difficult 'cheetah' phenotype."

The "eclipse" nevi resemble a solar eclipse, with a solid tan center and a brown rim that is often stellate. The rim may also be discontinuous, leading to asymmetry. They are often seen on the scalp of children, and can be the first sign that a child will be "moley."

"These nevi are benign but they get attention because of their irregular outline and variation in color. Unless there is a superimposed change, they should not elicit concern," she noted. "When the signature nevus is an eclipse nevus, you should focus on the 10 to 15 other nevi that are not in this 'family' and look for the one with the most atypical features."

Dr. Bolognia does not recommend surgically removing eclipse nevi on the scalp because others will probably develop and parents will expect these to be removed as well. Cockarde or "target" nevi are in the same family as eclipse nevi; these types are often seen together.

Another difficult, though rare, phenotype is represented by multiple pink nevi. These patients tend to be skin type 1 or 2 and they produce little, if any, melanin in their nevi. "In this patient the pigment pattern is missing, the road signs are gone, and these nevi can be difficult to evaluate clinically," she said.

"If the nevus has substance (not soft like an aging dermal nevus), I take a second look. And I also look for the nevus with the darkest pink color or any red lesion. I usually biopsy the latter, unless it is clearly acneiform, and like with the 'cheetah' phenotype, share these patients with another dermatologist," she said.

Multiple halo nevi, seen most often in patients in their late teens and early 20s, can also be problematic. There are four stages of halo nevi, with stages I and II being characterized by a depigmented halo surrounding either a pigmented nevus (I) or a pink nevus (II). Stage III appears as an area of depigmentation that is oval or circular in shape (with no central nevus), thus resembling a patch of vitiligo, while stage IV represents complete repigmentation. While everyone with multiple halo nevi deserves a total body examination, if an older adult presents with multiple halo nevi, the possibility of an immune reaction to an ocular (or cutaneous) melanoma needs to be considered, Dr. Bolognia said.

Exams of the "cheetah" phenotype, represented by numerous small, dark nevi, are best conducted with two sets of eyes. Courtesy Dr. Jean Bolognia

Angiosarcoma is a rare malignant vascular tumor that is localized to the skin or superficial soft tissue in 60% of cases.1,2 More than half of cutaneous angiosarcomas arise on the head or neck.2,3 Skin lesions may be difficult to diagnose early because of their highly variable and often seemingly innocuous appearance1-4; it is not uncommon for there to be extensive local spread and/or distant metastases by the time angiosarcoma is diagnosed. Cutaneous angiosarcoma typically affects elderly patients and is more common in men.1-4 It is relatively rare in black individuals.1,3 Classic presentation is an erythematous or violaceous lesion arising on the scalp of an elderly white man.1-4 Cutaneous angiosarcoma has well-documented associations with a number of conditions and factors, including chronic lymphedema, prior radiation therapy, and exposure to chemicals such as thorotrast and vinyl chloride.1-4 In addition, there are several reported cases of malignant transformation to angiosarcoma of otherwise benign vascular lesions such as hemangiomas.5 To date, there is only one reported case of cutaneous angiosarcoma arising in association with scleroderma on the face of a 77-year-old white woman with systemic sclerosis (SSc).6 We report the case of a 40-year-old black man with SSc who developed a cutaneous angiosarcoma in an area of sclerodermatous scalp. back to top

Case Report
A 40-year-old black man with a 5-year history of SSc involving the skin, lungs, and esophagus developed a painful nodule in a sclerodermatous plaque on the scalp (Figure 1). The patient's medical history was remarkable for Raynaud phenomenon, with recurrent digital ulcerations, a restrictive ventilatory defect, chronic dysphagia, and gastroesophageal reflux disease, as well as diffuse thickening and tightening of the skin, all related to his SSc. Serologic tests revealed antinuclear antibodies (titer ≥640) with a homogeneous nucleolar pattern and high levels of anti–Scl-70 antibodies. Anticentromere and anti-DNA antibodies were absent. His only medications were esomeprazole magnesium (40 mg daily) and amlodipine besylate (5 mg daily).

On physical examination, there was a 1.8-cm faintly erythematous nodule with overlying excoriations and crust on the right anterior parietal scalp. The remainder of the physical examination was notable for diffusely tight, firm, shiny skin involving the scalp, face, neck, chest, arms, hands, and groin. There were areas of depigmentation in several of the scleroderma plaques as well as multiple fingertip ulcerations. On initial evaluation, the scalp lesion was diagnosed as a skin abscess not requiring further intervention. It continued to grow and cause discomfort, eventually necessitating surgical excision. Because of its anatomic position and the extremely taut nature of the surrounding sclerodermatous scalp, the mass was excised only partially so that primary closure would be possible. Histologic evaluation of the 2.5X1.5-cm surgical specimen revealed an epithelioid-type high-grade angiosarcoma composed of cells that were positive for CD31 and CD34 (endothelial cell markers) on immunohistochemical stain (Figure 2). A wide excision of the lesion was then performed. Intraoperatively, the tumor was observed to have involved the galea and pericranium, necessitating removal of full-thickness soft tissue and adjacent bone (Figure 3). The scalp excision defect was closed with a split-thickness skin graft.

 Microscopic examination of the excised tissue revealed extensive invasion of the dermis, perineural tissue, and deep skeletal muscle by angiosarcoma. Both circumferential and deep margins of the surgical specimen were involved by tumor. Tumor size was estimated at 9.5 cm. Computed tomographic (CT) scans of the chest, abdomen, and pelvis revealed a moderately dilated esophagus and moderate diffuse, hazy, ground glass pattern radiodensities of the bilateral lung bases consistent with SSc but no lesions suggestive of metastasis. The extensive local tissue involvement by tumor dictated radiation therapy to the area. Treatment was delayed, however, by failure of the skin graft to completely heal. The open wound was subsequently surgically debrided and closed with an allograft. This second graft began to successfully heal, but an enlarging subcutaneous mass at its anterior border soon developed. Results of a biopsy revealed recurrent angiosarcoma. This lesion grew quickly to encompass over half of the patient's forehead, as well as the nasal root, causing severe periorbital edema and conjunctival congestion. Daily radiation therapy totaling 5000 cGy to the upper face and frontal, parietal, and occipital scalp was initiated. Soon after, the patient was hospitalized for methicillin-resistant Staphylococcus aureus bacteremia thought to have originated from a skin infection near the tumor. He also complained of worsening sharp right retroauricular and left hip pains. Results of a punch biopsy of the right posterior auricular scalp revealed recurrent angiosarcoma, and a CT-guided biopsy specimen of the left iliac bone revealed metastatic angiosarcoma. Magnetic resonance imaging of the pelvis and lower extremities showed bone marrow lesions involving the left ischium, left anterior superior iliac spine, and femoral necks of both legs. Palliative radiation therapy to the left iliac bone was initiated for symptom control. Given the extensive metastatic spread, systemic paclitaxel chemotherapy (100 mg/m2 weekly [3 of 4 weeks]) was administered through a central venous port. Soon after completing the first round of chemotherapy, the patient was hospitalized with a polymicrobial infection of his partially healed scalp wound including Klebsiella pneumoniae, Pseudomonas aeruginosa, and group B streptococci. He was treated with levofloxacin (500 mg daily for 10 days). An abdominal CT scan showed that the patient had a lesion in the right posterior inferior lobe of the liver suggestive of metastatic angiosarcoma. Several weeks after discharge, he presented to the emergency department of an outside hospital complaining of worsening dysphagia and purulent material draining from his central venous port. Shortly thereafter, he died, with sepsis as the presumed cause of death. At autopsy, there were multiple large scalp ulcerations extending to bone. The skin was diffusely firm and taut. Serial sectioning of the liver demonstrated a somewhat hemorrhagic-appearing dark red–brown lesion measuring 3 cm in the right posterior lobe, composed microscopically of diffusely infiltrating metastatic angiosarcoma confirmed by CD31 immunostain. Additionally, there were multifocal microabscesses of the heart, lungs, kidneys, spleen, and skin of the face and neck. 

Comment
Systemic sclerosis, or scleroderma, is a chronic systemic disease characterized by widespread fibrosis of the skin and internal organs, vasculopathy, and autoimmunity.7,8 Black individuals are affected more frequently than white individuals and tend to have an earlier age of disease onset, greater tendency for severe disease, and overall worse prognosis.9 Patients with SSc have a 2.6% to 8.7% risk of malignancy in general, with lung cancer and squamous cell carcinoma (arising in affected pulmonary or skin tissue) among the most commonly associated neoplasms.10,11 To our knowledge, we describe the second reported case of SSc-associated angiosarcoma. Systemic sclerosis is thought to arise from altered endothelial cell function and blood vessel reactivity occurring in association with inflammation and autoimmunity. The earliest disease manifestations are generally vasculature related, with most patients developing Raynaud phenomenon before manifesting signs and symptoms of overt sclerosis.7,8 Characteristic nail fold capillaroscopy findings in patients with SSc include enlarged capillaries, busy capillary formations, microhemorrhages, and variable capillary loss.7 Patients with SSc have increased serum and skin levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis that induces differentiation, proliferation, and migration of endothelial cells.7 Endothelial cell VEGF receptors are up-regulated in SSc as well. This chronic overexpression of VEGF is thought to account for the chaotic vessel morphology observed on nail fold capillaroscopy.7 We hypothesize that elevated levels of VEGF in sclerodermatous skin may also predispose one to the development of angiosarcoma. Studies have shown that the proliferating cells in angiosarcoma overexpress VEGF messenger RNA, VEGF protein, and VEGF receptors, suggesting that VEGF may spur the development and invasion of neoplasia.12-14 Furthermore, Arbiser et al13 found that overexpression of human VEGF in immortalized endothelial cells was sufficient to convert them from benign hemangiomas to malignant angiosarcomas. Cutaneous angiosarcoma can assume a variety of clinical appearances, including bruiselike lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, infectious-appearing lesions, and scarring alopecia.1-4 Tumor tissue usually extends far beyond the apparent borders of the lesion and frequently invades underlying soft tissue and bone. Thus, patients often have advanced disease at the time of diagnosis.1-4 Angiosarcoma prognosis is generally poor, with reported 5-year survival rates ranging from 10% to 35%.1,2 Surgical excision, extended-field radiotherapy, and/or paclitaxel chemotherapy are commonly employed modes of treatment,1,4,15,16 though even with these interventions, local tumor recurrence and distant metastases are common. Importantly, early diagnosis positively correlates with prolonged survival.3,4

Conclusion
We present a case of cutaneous angiosarcoma arising in an area of SSc-affected skin. We suspect that the co-occurrence of these 2 diseases may be related to interconnected underlying pathophysiology. Because early diagnosis can positively impact prognosis, physicians should maintain a high index of clinical suspicion and low threshold for performing a biopsy when suspicious lesions are present on sclerodermatous skin.

Acknowledgment—We thank Frederick M. Wigley, MD, for his detailed clinic and procedure notes. 

Angiosarcoma is a rare malignant vascular tumor that is localized to the skin or superficial soft tissue in 60% of cases.1,2 More than half of cutaneous angiosarcomas arise on the head or neck.2,3 Skin lesions may be difficult to diagnose early because of their highly variable and often seemingly innocuous appearance1-4; it is not uncommon for there to be extensive local spread and/or distant metastases by the time angiosarcoma is diagnosed. Cutaneous angiosarcoma typically affects elderly patients and is more common in men.1-4 It is relatively rare in black individuals.1,3 Classic presentation is an erythematous or violaceous lesion arising on the scalp of an elderly white man.1-4 Cutaneous angiosarcoma has well-documented associations with a number of conditions and factors, including chronic lymphedema, prior radiation therapy, and exposure to chemicals such as thorotrast and vinyl chloride.1-4 In addition, there are several reported cases of malignant transformation to angiosarcoma of otherwise benign vascular lesions such as hemangiomas.5 To date, there is only one reported case of cutaneous angiosarcoma arising in association with scleroderma on the face of a 77-year-old white woman with systemic sclerosis (SSc).6 We report the case of a 40-year-old black man with SSc who developed a cutaneous angiosarcoma in an area of sclerodermatous scalp. back to top

Case Report
A 40-year-old black man with a 5-year history of SSc involving the skin, lungs, and esophagus developed a painful nodule in a sclerodermatous plaque on the scalp (Figure 1). The patient's medical history was remarkable for Raynaud phenomenon, with recurrent digital ulcerations, a restrictive ventilatory defect, chronic dysphagia, and gastroesophageal reflux disease, as well as diffuse thickening and tightening of the skin, all related to his SSc. Serologic tests revealed antinuclear antibodies (titer ≥640) with a homogeneous nucleolar pattern and high levels of anti–Scl-70 antibodies. Anticentromere and anti-DNA antibodies were absent. His only medications were esomeprazole magnesium (40 mg daily) and amlodipine besylate (5 mg daily).

On physical examination, there was a 1.8-cm faintly erythematous nodule with overlying excoriations and crust on the right anterior parietal scalp. The remainder of the physical examination was notable for diffusely tight, firm, shiny skin involving the scalp, face, neck, chest, arms, hands, and groin. There were areas of depigmentation in several of the scleroderma plaques as well as multiple fingertip ulcerations. On initial evaluation, the scalp lesion was diagnosed as a skin abscess not requiring further intervention. It continued to grow and cause discomfort, eventually necessitating surgical excision. Because of its anatomic position and the extremely taut nature of the surrounding sclerodermatous scalp, the mass was excised only partially so that primary closure would be possible. Histologic evaluation of the 2.5X1.5-cm surgical specimen revealed an epithelioid-type high-grade angiosarcoma composed of cells that were positive for CD31 and CD34 (endothelial cell markers) on immunohistochemical stain (Figure 2). A wide excision of the lesion was then performed. Intraoperatively, the tumor was observed to have involved the galea and pericranium, necessitating removal of full-thickness soft tissue and adjacent bone (Figure 3). The scalp excision defect was closed with a split-thickness skin graft.

 Microscopic examination of the excised tissue revealed extensive invasion of the dermis, perineural tissue, and deep skeletal muscle by angiosarcoma. Both circumferential and deep margins of the surgical specimen were involved by tumor. Tumor size was estimated at 9.5 cm. Computed tomographic (CT) scans of the chest, abdomen, and pelvis revealed a moderately dilated esophagus and moderate diffuse, hazy, ground glass pattern radiodensities of the bilateral lung bases consistent with SSc but no lesions suggestive of metastasis. The extensive local tissue involvement by tumor dictated radiation therapy to the area. Treatment was delayed, however, by failure of the skin graft to completely heal. The open wound was subsequently surgically debrided and closed with an allograft. This second graft began to successfully heal, but an enlarging subcutaneous mass at its anterior border soon developed. Results of a biopsy revealed recurrent angiosarcoma. This lesion grew quickly to encompass over half of the patient's forehead, as well as the nasal root, causing severe periorbital edema and conjunctival congestion. Daily radiation therapy totaling 5000 cGy to the upper face and frontal, parietal, and occipital scalp was initiated. Soon after, the patient was hospitalized for methicillin-resistant Staphylococcus aureus bacteremia thought to have originated from a skin infection near the tumor. He also complained of worsening sharp right retroauricular and left hip pains. Results of a punch biopsy of the right posterior auricular scalp revealed recurrent angiosarcoma, and a CT-guided biopsy specimen of the left iliac bone revealed metastatic angiosarcoma. Magnetic resonance imaging of the pelvis and lower extremities showed bone marrow lesions involving the left ischium, left anterior superior iliac spine, and femoral necks of both legs. Palliative radiation therapy to the left iliac bone was initiated for symptom control. Given the extensive metastatic spread, systemic paclitaxel chemotherapy (100 mg/m2 weekly [3 of 4 weeks]) was administered through a central venous port. Soon after completing the first round of chemotherapy, the patient was hospitalized with a polymicrobial infection of his partially healed scalp wound including Klebsiella pneumoniae, Pseudomonas aeruginosa, and group B streptococci. He was treated with levofloxacin (500 mg daily for 10 days). An abdominal CT scan showed that the patient had a lesion in the right posterior inferior lobe of the liver suggestive of metastatic angiosarcoma. Several weeks after discharge, he presented to the emergency department of an outside hospital complaining of worsening dysphagia and purulent material draining from his central venous port. Shortly thereafter, he died, with sepsis as the presumed cause of death. At autopsy, there were multiple large scalp ulcerations extending to bone. The skin was diffusely firm and taut. Serial sectioning of the liver demonstrated a somewhat hemorrhagic-appearing dark red–brown lesion measuring 3 cm in the right posterior lobe, composed microscopically of diffusely infiltrating metastatic angiosarcoma confirmed by CD31 immunostain. Additionally, there were multifocal microabscesses of the heart, lungs, kidneys, spleen, and skin of the face and neck. 

Comment
Systemic sclerosis, or scleroderma, is a chronic systemic disease characterized by widespread fibrosis of the skin and internal organs, vasculopathy, and autoimmunity.7,8 Black individuals are affected more frequently than white individuals and tend to have an earlier age of disease onset, greater tendency for severe disease, and overall worse prognosis.9 Patients with SSc have a 2.6% to 8.7% risk of malignancy in general, with lung cancer and squamous cell carcinoma (arising in affected pulmonary or skin tissue) among the most commonly associated neoplasms.10,11 To our knowledge, we describe the second reported case of SSc-associated angiosarcoma. Systemic sclerosis is thought to arise from altered endothelial cell function and blood vessel reactivity occurring in association with inflammation and autoimmunity. The earliest disease manifestations are generally vasculature related, with most patients developing Raynaud phenomenon before manifesting signs and symptoms of overt sclerosis.7,8 Characteristic nail fold capillaroscopy findings in patients with SSc include enlarged capillaries, busy capillary formations, microhemorrhages, and variable capillary loss.7 Patients with SSc have increased serum and skin levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis that induces differentiation, proliferation, and migration of endothelial cells.7 Endothelial cell VEGF receptors are up-regulated in SSc as well. This chronic overexpression of VEGF is thought to account for the chaotic vessel morphology observed on nail fold capillaroscopy.7 We hypothesize that elevated levels of VEGF in sclerodermatous skin may also predispose one to the development of angiosarcoma. Studies have shown that the proliferating cells in angiosarcoma overexpress VEGF messenger RNA, VEGF protein, and VEGF receptors, suggesting that VEGF may spur the development and invasion of neoplasia.12-14 Furthermore, Arbiser et al13 found that overexpression of human VEGF in immortalized endothelial cells was sufficient to convert them from benign hemangiomas to malignant angiosarcomas. Cutaneous angiosarcoma can assume a variety of clinical appearances, including bruiselike lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, infectious-appearing lesions, and scarring alopecia.1-4 Tumor tissue usually extends far beyond the apparent borders of the lesion and frequently invades underlying soft tissue and bone. Thus, patients often have advanced disease at the time of diagnosis.1-4 Angiosarcoma prognosis is generally poor, with reported 5-year survival rates ranging from 10% to 35%.1,2 Surgical excision, extended-field radiotherapy, and/or paclitaxel chemotherapy are commonly employed modes of treatment,1,4,15,16 though even with these interventions, local tumor recurrence and distant metastases are common. Importantly, early diagnosis positively correlates with prolonged survival.3,4

Conclusion
We present a case of cutaneous angiosarcoma arising in an area of SSc-affected skin. We suspect that the co-occurrence of these 2 diseases may be related to interconnected underlying pathophysiology. Because early diagnosis can positively impact prognosis, physicians should maintain a high index of clinical suspicion and low threshold for performing a biopsy when suspicious lesions are present on sclerodermatous skin.

Acknowledgment—We thank Frederick M. Wigley, MD, for his detailed clinic and procedure notes. 

Angiosarcoma is a rare malignant vascular tumor that is localized to the skin or superficial soft tissue in 60% of cases.1,2 More than half of cutaneous angiosarcomas arise on the head or neck.2,3 Skin lesions may be difficult to diagnose early because of their highly variable and often seemingly innocuous appearance1-4; it is not uncommon for there to be extensive local spread and/or distant metastases by the time angiosarcoma is diagnosed. Cutaneous angiosarcoma typically affects elderly patients and is more common in men.1-4 It is relatively rare in black individuals.1,3 Classic presentation is an erythematous or violaceous lesion arising on the scalp of an elderly white man.1-4 Cutaneous angiosarcoma has well-documented associations with a number of conditions and factors, including chronic lymphedema, prior radiation therapy, and exposure to chemicals such as thorotrast and vinyl chloride.1-4 In addition, there are several reported cases of malignant transformation to angiosarcoma of otherwise benign vascular lesions such as hemangiomas.5 To date, there is only one reported case of cutaneous angiosarcoma arising in association with scleroderma on the face of a 77-year-old white woman with systemic sclerosis (SSc).6 We report the case of a 40-year-old black man with SSc who developed a cutaneous angiosarcoma in an area of sclerodermatous scalp. back to top

Case Report
A 40-year-old black man with a 5-year history of SSc involving the skin, lungs, and esophagus developed a painful nodule in a sclerodermatous plaque on the scalp (Figure 1). The patient's medical history was remarkable for Raynaud phenomenon, with recurrent digital ulcerations, a restrictive ventilatory defect, chronic dysphagia, and gastroesophageal reflux disease, as well as diffuse thickening and tightening of the skin, all related to his SSc. Serologic tests revealed antinuclear antibodies (titer ≥640) with a homogeneous nucleolar pattern and high levels of anti–Scl-70 antibodies. Anticentromere and anti-DNA antibodies were absent. His only medications were esomeprazole magnesium (40 mg daily) and amlodipine besylate (5 mg daily).

On physical examination, there was a 1.8-cm faintly erythematous nodule with overlying excoriations and crust on the right anterior parietal scalp. The remainder of the physical examination was notable for diffusely tight, firm, shiny skin involving the scalp, face, neck, chest, arms, hands, and groin. There were areas of depigmentation in several of the scleroderma plaques as well as multiple fingertip ulcerations. On initial evaluation, the scalp lesion was diagnosed as a skin abscess not requiring further intervention. It continued to grow and cause discomfort, eventually necessitating surgical excision. Because of its anatomic position and the extremely taut nature of the surrounding sclerodermatous scalp, the mass was excised only partially so that primary closure would be possible. Histologic evaluation of the 2.5X1.5-cm surgical specimen revealed an epithelioid-type high-grade angiosarcoma composed of cells that were positive for CD31 and CD34 (endothelial cell markers) on immunohistochemical stain (Figure 2). A wide excision of the lesion was then performed. Intraoperatively, the tumor was observed to have involved the galea and pericranium, necessitating removal of full-thickness soft tissue and adjacent bone (Figure 3). The scalp excision defect was closed with a split-thickness skin graft.

 Microscopic examination of the excised tissue revealed extensive invasion of the dermis, perineural tissue, and deep skeletal muscle by angiosarcoma. Both circumferential and deep margins of the surgical specimen were involved by tumor. Tumor size was estimated at 9.5 cm. Computed tomographic (CT) scans of the chest, abdomen, and pelvis revealed a moderately dilated esophagus and moderate diffuse, hazy, ground glass pattern radiodensities of the bilateral lung bases consistent with SSc but no lesions suggestive of metastasis. The extensive local tissue involvement by tumor dictated radiation therapy to the area. Treatment was delayed, however, by failure of the skin graft to completely heal. The open wound was subsequently surgically debrided and closed with an allograft. This second graft began to successfully heal, but an enlarging subcutaneous mass at its anterior border soon developed. Results of a biopsy revealed recurrent angiosarcoma. This lesion grew quickly to encompass over half of the patient's forehead, as well as the nasal root, causing severe periorbital edema and conjunctival congestion. Daily radiation therapy totaling 5000 cGy to the upper face and frontal, parietal, and occipital scalp was initiated. Soon after, the patient was hospitalized for methicillin-resistant Staphylococcus aureus bacteremia thought to have originated from a skin infection near the tumor. He also complained of worsening sharp right retroauricular and left hip pains. Results of a punch biopsy of the right posterior auricular scalp revealed recurrent angiosarcoma, and a CT-guided biopsy specimen of the left iliac bone revealed metastatic angiosarcoma. Magnetic resonance imaging of the pelvis and lower extremities showed bone marrow lesions involving the left ischium, left anterior superior iliac spine, and femoral necks of both legs. Palliative radiation therapy to the left iliac bone was initiated for symptom control. Given the extensive metastatic spread, systemic paclitaxel chemotherapy (100 mg/m2 weekly [3 of 4 weeks]) was administered through a central venous port. Soon after completing the first round of chemotherapy, the patient was hospitalized with a polymicrobial infection of his partially healed scalp wound including Klebsiella pneumoniae, Pseudomonas aeruginosa, and group B streptococci. He was treated with levofloxacin (500 mg daily for 10 days). An abdominal CT scan showed that the patient had a lesion in the right posterior inferior lobe of the liver suggestive of metastatic angiosarcoma. Several weeks after discharge, he presented to the emergency department of an outside hospital complaining of worsening dysphagia and purulent material draining from his central venous port. Shortly thereafter, he died, with sepsis as the presumed cause of death. At autopsy, there were multiple large scalp ulcerations extending to bone. The skin was diffusely firm and taut. Serial sectioning of the liver demonstrated a somewhat hemorrhagic-appearing dark red–brown lesion measuring 3 cm in the right posterior lobe, composed microscopically of diffusely infiltrating metastatic angiosarcoma confirmed by CD31 immunostain. Additionally, there were multifocal microabscesses of the heart, lungs, kidneys, spleen, and skin of the face and neck. 

Comment
Systemic sclerosis, or scleroderma, is a chronic systemic disease characterized by widespread fibrosis of the skin and internal organs, vasculopathy, and autoimmunity.7,8 Black individuals are affected more frequently than white individuals and tend to have an earlier age of disease onset, greater tendency for severe disease, and overall worse prognosis.9 Patients with SSc have a 2.6% to 8.7% risk of malignancy in general, with lung cancer and squamous cell carcinoma (arising in affected pulmonary or skin tissue) among the most commonly associated neoplasms.10,11 To our knowledge, we describe the second reported case of SSc-associated angiosarcoma. Systemic sclerosis is thought to arise from altered endothelial cell function and blood vessel reactivity occurring in association with inflammation and autoimmunity. The earliest disease manifestations are generally vasculature related, with most patients developing Raynaud phenomenon before manifesting signs and symptoms of overt sclerosis.7,8 Characteristic nail fold capillaroscopy findings in patients with SSc include enlarged capillaries, busy capillary formations, microhemorrhages, and variable capillary loss.7 Patients with SSc have increased serum and skin levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis that induces differentiation, proliferation, and migration of endothelial cells.7 Endothelial cell VEGF receptors are up-regulated in SSc as well. This chronic overexpression of VEGF is thought to account for the chaotic vessel morphology observed on nail fold capillaroscopy.7 We hypothesize that elevated levels of VEGF in sclerodermatous skin may also predispose one to the development of angiosarcoma. Studies have shown that the proliferating cells in angiosarcoma overexpress VEGF messenger RNA, VEGF protein, and VEGF receptors, suggesting that VEGF may spur the development and invasion of neoplasia.12-14 Furthermore, Arbiser et al13 found that overexpression of human VEGF in immortalized endothelial cells was sufficient to convert them from benign hemangiomas to malignant angiosarcomas. Cutaneous angiosarcoma can assume a variety of clinical appearances, including bruiselike lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, infectious-appearing lesions, and scarring alopecia.1-4 Tumor tissue usually extends far beyond the apparent borders of the lesion and frequently invades underlying soft tissue and bone. Thus, patients often have advanced disease at the time of diagnosis.1-4 Angiosarcoma prognosis is generally poor, with reported 5-year survival rates ranging from 10% to 35%.1,2 Surgical excision, extended-field radiotherapy, and/or paclitaxel chemotherapy are commonly employed modes of treatment,1,4,15,16 though even with these interventions, local tumor recurrence and distant metastases are common. Importantly, early diagnosis positively correlates with prolonged survival.3,4

Conclusion
We present a case of cutaneous angiosarcoma arising in an area of SSc-affected skin. We suspect that the co-occurrence of these 2 diseases may be related to interconnected underlying pathophysiology. Because early diagnosis can positively impact prognosis, physicians should maintain a high index of clinical suspicion and low threshold for performing a biopsy when suspicious lesions are present on sclerodermatous skin.

Acknowledgment—We thank Frederick M. Wigley, MD, for his detailed clinic and procedure notes. 

Triterpenoids, to which squalene is the immediate biologic precursor, include steroids and, thus, sterols, and represent the largest group of terpenoids, the most abundant group of botanical constituents and the most common ingredient class found in volatile oils. Consequently, triterpenoids appear in numerous botanical products with traditional and modern applications to dermatology, such as Centella asiatica (gotu kola) and propolis.

Indeed, the naturally occurring triterpenoids, oleanolic acid and ursolic acid, are known to confer anticarcinogenic and anti-inflammatory effects in certain cells (Exp. Dermatol. 2006;15:66–73). Ursolic acid and the natural triterpenoid erythrodiol have also been found to be effective in a multiple-dose 12-O-tetradecanoylphorbol-13-acetate (TPA) model of chronic dermal inflammation (Eur. J. Pharmacol. 1997;334:103–5).

Although triterpenoids are not as prevalent in as many of the highly touted herbal sources as polyphenols, this group of compounds is gaining increased attention for its anti-inflammatory and anti-tumor-promoting activity. In one trial, investigators studying the triterpenoids oleanolic acid and ursolic acid found that the former induced the differentiation of keratinocytes through peroxisome proliferator-activated receptor (PPAR)-α activation. In addition, topical application of oleanolic acid improved the recovery of epidermal permeability barrier function and increased ceramides in epidermis (Exp. Dermatol. 2006;15:66–73).

The preponderance of data on triterpenoids, though, points to the anti-tumor-promoting capacity of this copious botanical class of compounds.

 Anti-Tumor-Promoting Actions

In a study designed to identify potential anti-tumor promoters, investigators screened 21 cucurbitane triterpenoids using an in vitro assay system, and found that several of the compounds significantly inhibited Epstein-Barr virus (EBV) activation induced by the tumor promoter TPA.

These compounds were scandenoside R6, 23,24-dihydrocucurbitacin F, 25-acetyl-23,24-dihydrocucurbitacin F, 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, and cucurbitacin F. Two triterpenoids, 23,24-dihydrocucurbitacin F and 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, also displayed significant activity against skin tumor promotion in an in vivo two-stage murine carcinogenesis model (Biol. Pharm. Bull. 1994;17:668–71).

A later in vitro study conducted by the same lab to identify anti-tumor promoters considered 23 triterpenoid hydrocarbons isolated from ferns. Significant inhibitory activity against EBV induced by TPA was exhibited by hop-17(21)-ene, neohop-13(18)-ene, neohop-12-ene, taraxerane, multiflor-9(11)-ene, multiflor-8-ene, glutin-5(10)-ene, and taraxastane. In a two-stage in vivo murine carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) for initiation and TPA for promotion, hop-17(21)-ene and neohop-13(18)-ene displayed significant anti-tumor promoting effects on mouse skin (Biol. Pharm. Bull. 1996;19:962–5).

Three years later, some of the same investigators, studying triterpenoids derived from Taraxacum japonicum (Compositae) roots, found that taraxasterol and taraxerol significantly inhibited the effects of TPA-induced Epstein-Barr virus early antigen (EBV-EA) induction, which is a preliminary in vitro screening approach to identifying anti-tumor-promoting agents. These compounds also exhibited potent anti-tumor-promoting activity in the two-stage murine skin carcinogenesis model initiated by DMBA and promoted by TPA (Biol. Pharm. Bull. 1999;22:606–10).

In a study from Osaka (Japan) University of Pharmaceutical Sciences, seven serratane-type triterpenoids isolated from different Picea species all exhibited potent inhibitory effects on EBV-EA activation induced by TPA, and did so more strongly than oleanolic acid. In addition, 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol displayed significant anti-tumor-promoting activity in the in vivo two-stage murine carcinogenesis model (Cancer Lett. 2001;172:119–26).

The same lab subsequently studied 11 serratane-type triterpenoids isolated from various Picea species and three synthetic analogues for their potential inhibitory effects on EBV-EA activation induced by TPA. That study yielded more corroborative findings, as several of the compounds showed potent inhibitory activity, again more strongly than the oleanolic control, including 21-episerratenediol, serratenediol, diepiserratenediol, 3-beta-hydroxyserrat-14-en-21-one, and 3-alpha-methoxy-21-beta-hydroxyserrat-14-en-16-one. Furthermore, no cytotoxicity was associated with these compounds.

Of these triterpenoids, 21-episerratenediol was found to demonstrate significant inhibitory effects on skin tumor promotion in the in vivo two-stage mouse skin carcinogenesis model using DMBA for initiation and TPA for promotion. The investigators suggested that the triterpenoid 21-episerratenediol has potential as an effective cancer chemopreventive agent (Cancer Lett. 2003;196:121–6).

In a separate experiment conducted by this lab, two new serratane-type triterpenoids, 3beta-methoxyserrat-13-en-21-beta-ol and 13-beta,14beta-epoxy-3beta-methoxyserratan-21beta-ol, also isolated from Picea plants, exhibited strong anti-tumor-promoting effects on mouse skin carcinogenesis (Planta Med. 2003;69:1041–7).

This lab also showed that, in a test of the lupane-type triterpenoids isolated from the stem bark of Glochidion zeylanicum as well as synthetic analogues, glochidiol and lup-20(29)-ene-1beta,3beta-diol were the strongest inhibitors of EBV-EA activation induced by TPA. Glochidiol also exhibited the greatest inhibitory effect on skin tumor promotion (Planta Med. 2004;70:1234–6).

Other Anticarcinogenic Actions

In 2005, investigators at the University of North Carolina, Chapel Hill, published a report on cimigenol, an acid- and base-stable triterpenoid found in species such as Cimicifuga racemosa, C. dahurica, and C. japonica. These researchers had previously shown that cimigenol and some of its derivatives had strong inhibitory effects on mouse skin tumor promotion induced by TPA in a two-stage carcinogenesis test. Continuing that previous work, the investigators repeated screens of cimigenol and also tested 15 related compounds as potential anti-tumor promoters by using the in vitro, short-term TPA-induced EBV-EA activation assay (Bioorg. Med. Chem. 2005;13:1403–8).

Of these compounds, the researchers found that cimigenol-3,15-dione showed the greatest potency and, in a subsequent two-stage DMBA/TPA carcinogenesis assay, reduced, at 20 weeks, the number of papillomas per mouse to 48% of controls. Both cimigenol and cimigenol-3,15-dione were also nearly as potent as epigallocatechin gallate, a primary constituent of green tea, in terms of anti-tumor initiation activity, as demonstrated in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite (initiator) and TPA (promoter).

The investigators concluded that these two triterpenoids amply demonstrate anti-tumor promotion as well as anti-tumor initiation and warrant consideration as significant cancer chemopreventive agents (Bioorg. Med. Chem. 2005;13:1403–8).

Protection Against UV

Four triterpenoids isolated from the stems of Styrax japonica were recently found to significantly inhibit matrix metalloproteinase-1 (MMP-1) in primary human skin fibroblasts induced by UV radiation. This finding is significant given the association between the upregulation of MMPs and chronic skin damage (Biol. Pharm. Bull. 2005;28:2003–6).

Previously, some of the same investigators studied the effects of 3,23-dihydroxy-20(29)-lupen-27-oic acid, a triterpenoid derived from Tiarella polyphylla, on the regulation of MMP-1 and type 1 procollagen in UV irradiation of cultured old-age human dermal fibroblasts. The triterpenoid dose-dependently induced regulation of type 1 procollagen and diminished regulation of MMP-1 at the protein level (Arch. Pharm. Res. 2004;27:1060–4).

Other Pharmacologic Actions

Triterpenoids also have been found in Boswellia serrata, an herb used in traditional medicine to treat inflammatory and arthritic conditions (and discussed in this column in November 2006, p. 17).

In a study published in 2000, the primary components and derivatives of Boswellia markedly inhibited TPA-induced increases in skin inflammation, epidermal proliferation, the number of epidermal cell layers, and tumor promotion in DMBA-initiated mice. DNA synthesis in human leukemia HL-60 cells was also shown to be inhibited by the addition of various forms of boswellic acid. The investigators suggest that such findings demonstrate the anticarcinogenic and antitumor properties of the major constituents, including triterpenoids, of this herb (Biofactors 2000;13:225–30).

The anti-inflammatory activity of several triterpenoids suggests the potential for numerous additional medical applications. A study evaluating the mechanism of anti-inflammatory activity displayed by triterpenoids on edema induced in mouse ears and paws, as well as rat skin, revealed that the inhibition of protein kinase C may play a crucial role in facilitating the anti-inflammatory activity of this class of compounds (Eur. J. Pharmacol. 2000;410:69–81).

In another study, several triterpene constituents of Vochysia pacifica Cuatrec, a South American tree used by traditional communities to treat inflammation, skin sores, asthma, and pulmonary congestion, were found to exert mild inhibitory activity on the intracellular target for new anti-inflammatory medications, namely the cAMP phosphodiesterase 4 isozyme (PDE4) (Phytother. Res. 2005;19:75–7).

Some triterpenoids have been documented as irritating (J. Asian Nat. Prod. Res. 2003;5:35–41) and others as toxic, which is not unexpected as these compounds comprise the primary constituent class in the volatile oils of plants. Given the breadth of this biochemical class, it is expected that some members would be toxic and others safe and beneficial to human health, such as the triterpenoid saponin glycyrrhizin, derived from licorice root (and featured in this column in March 2007, p. 24, and April 2007, p. 30). Triterpenoid saponins, or sapogenins, are used in some emulsifiers, including some Estée Lauder products, for their capacity to confer antifungal, anti-inflammatory, antimicrobial, and adaptogenic activity.

Conclusion

As we continue to explore botanical sources for medical and cosmetic purposes, we will learn more about the numerous triterpenoids found in plants. This class of biochemical compounds typically receives less attention than polyphenols in discussions of the most potent herbal ingredients used in dermatology, but the considerable potential of triterpenoids to be used in a broad range of cutaneous applications is gradually becoming appreciated.

Triterpenoids, to which squalene is the immediate biologic precursor, include steroids and, thus, sterols, and represent the largest group of terpenoids, the most abundant group of botanical constituents and the most common ingredient class found in volatile oils. Consequently, triterpenoids appear in numerous botanical products with traditional and modern applications to dermatology, such as Centella asiatica (gotu kola) and propolis.

Indeed, the naturally occurring triterpenoids, oleanolic acid and ursolic acid, are known to confer anticarcinogenic and anti-inflammatory effects in certain cells (Exp. Dermatol. 2006;15:66–73). Ursolic acid and the natural triterpenoid erythrodiol have also been found to be effective in a multiple-dose 12-O-tetradecanoylphorbol-13-acetate (TPA) model of chronic dermal inflammation (Eur. J. Pharmacol. 1997;334:103–5).

Although triterpenoids are not as prevalent in as many of the highly touted herbal sources as polyphenols, this group of compounds is gaining increased attention for its anti-inflammatory and anti-tumor-promoting activity. In one trial, investigators studying the triterpenoids oleanolic acid and ursolic acid found that the former induced the differentiation of keratinocytes through peroxisome proliferator-activated receptor (PPAR)-α activation. In addition, topical application of oleanolic acid improved the recovery of epidermal permeability barrier function and increased ceramides in epidermis (Exp. Dermatol. 2006;15:66–73).

The preponderance of data on triterpenoids, though, points to the anti-tumor-promoting capacity of this copious botanical class of compounds.

 Anti-Tumor-Promoting Actions

In a study designed to identify potential anti-tumor promoters, investigators screened 21 cucurbitane triterpenoids using an in vitro assay system, and found that several of the compounds significantly inhibited Epstein-Barr virus (EBV) activation induced by the tumor promoter TPA.

These compounds were scandenoside R6, 23,24-dihydrocucurbitacin F, 25-acetyl-23,24-dihydrocucurbitacin F, 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, and cucurbitacin F. Two triterpenoids, 23,24-dihydrocucurbitacin F and 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, also displayed significant activity against skin tumor promotion in an in vivo two-stage murine carcinogenesis model (Biol. Pharm. Bull. 1994;17:668–71).

A later in vitro study conducted by the same lab to identify anti-tumor promoters considered 23 triterpenoid hydrocarbons isolated from ferns. Significant inhibitory activity against EBV induced by TPA was exhibited by hop-17(21)-ene, neohop-13(18)-ene, neohop-12-ene, taraxerane, multiflor-9(11)-ene, multiflor-8-ene, glutin-5(10)-ene, and taraxastane. In a two-stage in vivo murine carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) for initiation and TPA for promotion, hop-17(21)-ene and neohop-13(18)-ene displayed significant anti-tumor promoting effects on mouse skin (Biol. Pharm. Bull. 1996;19:962–5).

Three years later, some of the same investigators, studying triterpenoids derived from Taraxacum japonicum (Compositae) roots, found that taraxasterol and taraxerol significantly inhibited the effects of TPA-induced Epstein-Barr virus early antigen (EBV-EA) induction, which is a preliminary in vitro screening approach to identifying anti-tumor-promoting agents. These compounds also exhibited potent anti-tumor-promoting activity in the two-stage murine skin carcinogenesis model initiated by DMBA and promoted by TPA (Biol. Pharm. Bull. 1999;22:606–10).

In a study from Osaka (Japan) University of Pharmaceutical Sciences, seven serratane-type triterpenoids isolated from different Picea species all exhibited potent inhibitory effects on EBV-EA activation induced by TPA, and did so more strongly than oleanolic acid. In addition, 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol displayed significant anti-tumor-promoting activity in the in vivo two-stage murine carcinogenesis model (Cancer Lett. 2001;172:119–26).

The same lab subsequently studied 11 serratane-type triterpenoids isolated from various Picea species and three synthetic analogues for their potential inhibitory effects on EBV-EA activation induced by TPA. That study yielded more corroborative findings, as several of the compounds showed potent inhibitory activity, again more strongly than the oleanolic control, including 21-episerratenediol, serratenediol, diepiserratenediol, 3-beta-hydroxyserrat-14-en-21-one, and 3-alpha-methoxy-21-beta-hydroxyserrat-14-en-16-one. Furthermore, no cytotoxicity was associated with these compounds.

Of these triterpenoids, 21-episerratenediol was found to demonstrate significant inhibitory effects on skin tumor promotion in the in vivo two-stage mouse skin carcinogenesis model using DMBA for initiation and TPA for promotion. The investigators suggested that the triterpenoid 21-episerratenediol has potential as an effective cancer chemopreventive agent (Cancer Lett. 2003;196:121–6).

In a separate experiment conducted by this lab, two new serratane-type triterpenoids, 3beta-methoxyserrat-13-en-21-beta-ol and 13-beta,14beta-epoxy-3beta-methoxyserratan-21beta-ol, also isolated from Picea plants, exhibited strong anti-tumor-promoting effects on mouse skin carcinogenesis (Planta Med. 2003;69:1041–7).

This lab also showed that, in a test of the lupane-type triterpenoids isolated from the stem bark of Glochidion zeylanicum as well as synthetic analogues, glochidiol and lup-20(29)-ene-1beta,3beta-diol were the strongest inhibitors of EBV-EA activation induced by TPA. Glochidiol also exhibited the greatest inhibitory effect on skin tumor promotion (Planta Med. 2004;70:1234–6).

Other Anticarcinogenic Actions

In 2005, investigators at the University of North Carolina, Chapel Hill, published a report on cimigenol, an acid- and base-stable triterpenoid found in species such as Cimicifuga racemosa, C. dahurica, and C. japonica. These researchers had previously shown that cimigenol and some of its derivatives had strong inhibitory effects on mouse skin tumor promotion induced by TPA in a two-stage carcinogenesis test. Continuing that previous work, the investigators repeated screens of cimigenol and also tested 15 related compounds as potential anti-tumor promoters by using the in vitro, short-term TPA-induced EBV-EA activation assay (Bioorg. Med. Chem. 2005;13:1403–8).

Of these compounds, the researchers found that cimigenol-3,15-dione showed the greatest potency and, in a subsequent two-stage DMBA/TPA carcinogenesis assay, reduced, at 20 weeks, the number of papillomas per mouse to 48% of controls. Both cimigenol and cimigenol-3,15-dione were also nearly as potent as epigallocatechin gallate, a primary constituent of green tea, in terms of anti-tumor initiation activity, as demonstrated in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite (initiator) and TPA (promoter).

The investigators concluded that these two triterpenoids amply demonstrate anti-tumor promotion as well as anti-tumor initiation and warrant consideration as significant cancer chemopreventive agents (Bioorg. Med. Chem. 2005;13:1403–8).

Protection Against UV

Four triterpenoids isolated from the stems of Styrax japonica were recently found to significantly inhibit matrix metalloproteinase-1 (MMP-1) in primary human skin fibroblasts induced by UV radiation. This finding is significant given the association between the upregulation of MMPs and chronic skin damage (Biol. Pharm. Bull. 2005;28:2003–6).

Previously, some of the same investigators studied the effects of 3,23-dihydroxy-20(29)-lupen-27-oic acid, a triterpenoid derived from Tiarella polyphylla, on the regulation of MMP-1 and type 1 procollagen in UV irradiation of cultured old-age human dermal fibroblasts. The triterpenoid dose-dependently induced regulation of type 1 procollagen and diminished regulation of MMP-1 at the protein level (Arch. Pharm. Res. 2004;27:1060–4).

Other Pharmacologic Actions

Triterpenoids also have been found in Boswellia serrata, an herb used in traditional medicine to treat inflammatory and arthritic conditions (and discussed in this column in November 2006, p. 17).

In a study published in 2000, the primary components and derivatives of Boswellia markedly inhibited TPA-induced increases in skin inflammation, epidermal proliferation, the number of epidermal cell layers, and tumor promotion in DMBA-initiated mice. DNA synthesis in human leukemia HL-60 cells was also shown to be inhibited by the addition of various forms of boswellic acid. The investigators suggest that such findings demonstrate the anticarcinogenic and antitumor properties of the major constituents, including triterpenoids, of this herb (Biofactors 2000;13:225–30).

The anti-inflammatory activity of several triterpenoids suggests the potential for numerous additional medical applications. A study evaluating the mechanism of anti-inflammatory activity displayed by triterpenoids on edema induced in mouse ears and paws, as well as rat skin, revealed that the inhibition of protein kinase C may play a crucial role in facilitating the anti-inflammatory activity of this class of compounds (Eur. J. Pharmacol. 2000;410:69–81).

In another study, several triterpene constituents of Vochysia pacifica Cuatrec, a South American tree used by traditional communities to treat inflammation, skin sores, asthma, and pulmonary congestion, were found to exert mild inhibitory activity on the intracellular target for new anti-inflammatory medications, namely the cAMP phosphodiesterase 4 isozyme (PDE4) (Phytother. Res. 2005;19:75–7).

Some triterpenoids have been documented as irritating (J. Asian Nat. Prod. Res. 2003;5:35–41) and others as toxic, which is not unexpected as these compounds comprise the primary constituent class in the volatile oils of plants. Given the breadth of this biochemical class, it is expected that some members would be toxic and others safe and beneficial to human health, such as the triterpenoid saponin glycyrrhizin, derived from licorice root (and featured in this column in March 2007, p. 24, and April 2007, p. 30). Triterpenoid saponins, or sapogenins, are used in some emulsifiers, including some Estée Lauder products, for their capacity to confer antifungal, anti-inflammatory, antimicrobial, and adaptogenic activity.

Conclusion

As we continue to explore botanical sources for medical and cosmetic purposes, we will learn more about the numerous triterpenoids found in plants. This class of biochemical compounds typically receives less attention than polyphenols in discussions of the most potent herbal ingredients used in dermatology, but the considerable potential of triterpenoids to be used in a broad range of cutaneous applications is gradually becoming appreciated.

Triterpenoids, to which squalene is the immediate biologic precursor, include steroids and, thus, sterols, and represent the largest group of terpenoids, the most abundant group of botanical constituents and the most common ingredient class found in volatile oils. Consequently, triterpenoids appear in numerous botanical products with traditional and modern applications to dermatology, such as Centella asiatica (gotu kola) and propolis.

Indeed, the naturally occurring triterpenoids, oleanolic acid and ursolic acid, are known to confer anticarcinogenic and anti-inflammatory effects in certain cells (Exp. Dermatol. 2006;15:66–73). Ursolic acid and the natural triterpenoid erythrodiol have also been found to be effective in a multiple-dose 12-O-tetradecanoylphorbol-13-acetate (TPA) model of chronic dermal inflammation (Eur. J. Pharmacol. 1997;334:103–5).

Although triterpenoids are not as prevalent in as many of the highly touted herbal sources as polyphenols, this group of compounds is gaining increased attention for its anti-inflammatory and anti-tumor-promoting activity. In one trial, investigators studying the triterpenoids oleanolic acid and ursolic acid found that the former induced the differentiation of keratinocytes through peroxisome proliferator-activated receptor (PPAR)-α activation. In addition, topical application of oleanolic acid improved the recovery of epidermal permeability barrier function and increased ceramides in epidermis (Exp. Dermatol. 2006;15:66–73).

The preponderance of data on triterpenoids, though, points to the anti-tumor-promoting capacity of this copious botanical class of compounds.

 Anti-Tumor-Promoting Actions

In a study designed to identify potential anti-tumor promoters, investigators screened 21 cucurbitane triterpenoids using an in vitro assay system, and found that several of the compounds significantly inhibited Epstein-Barr virus (EBV) activation induced by the tumor promoter TPA.

These compounds were scandenoside R6, 23,24-dihydrocucurbitacin F, 25-acetyl-23,24-dihydrocucurbitacin F, 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, and cucurbitacin F. Two triterpenoids, 23,24-dihydrocucurbitacin F and 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, also displayed significant activity against skin tumor promotion in an in vivo two-stage murine carcinogenesis model (Biol. Pharm. Bull. 1994;17:668–71).

A later in vitro study conducted by the same lab to identify anti-tumor promoters considered 23 triterpenoid hydrocarbons isolated from ferns. Significant inhibitory activity against EBV induced by TPA was exhibited by hop-17(21)-ene, neohop-13(18)-ene, neohop-12-ene, taraxerane, multiflor-9(11)-ene, multiflor-8-ene, glutin-5(10)-ene, and taraxastane. In a two-stage in vivo murine carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) for initiation and TPA for promotion, hop-17(21)-ene and neohop-13(18)-ene displayed significant anti-tumor promoting effects on mouse skin (Biol. Pharm. Bull. 1996;19:962–5).

Three years later, some of the same investigators, studying triterpenoids derived from Taraxacum japonicum (Compositae) roots, found that taraxasterol and taraxerol significantly inhibited the effects of TPA-induced Epstein-Barr virus early antigen (EBV-EA) induction, which is a preliminary in vitro screening approach to identifying anti-tumor-promoting agents. These compounds also exhibited potent anti-tumor-promoting activity in the two-stage murine skin carcinogenesis model initiated by DMBA and promoted by TPA (Biol. Pharm. Bull. 1999;22:606–10).

In a study from Osaka (Japan) University of Pharmaceutical Sciences, seven serratane-type triterpenoids isolated from different Picea species all exhibited potent inhibitory effects on EBV-EA activation induced by TPA, and did so more strongly than oleanolic acid. In addition, 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol displayed significant anti-tumor-promoting activity in the in vivo two-stage murine carcinogenesis model (Cancer Lett. 2001;172:119–26).

The same lab subsequently studied 11 serratane-type triterpenoids isolated from various Picea species and three synthetic analogues for their potential inhibitory effects on EBV-EA activation induced by TPA. That study yielded more corroborative findings, as several of the compounds showed potent inhibitory activity, again more strongly than the oleanolic control, including 21-episerratenediol, serratenediol, diepiserratenediol, 3-beta-hydroxyserrat-14-en-21-one, and 3-alpha-methoxy-21-beta-hydroxyserrat-14-en-16-one. Furthermore, no cytotoxicity was associated with these compounds.

Of these triterpenoids, 21-episerratenediol was found to demonstrate significant inhibitory effects on skin tumor promotion in the in vivo two-stage mouse skin carcinogenesis model using DMBA for initiation and TPA for promotion. The investigators suggested that the triterpenoid 21-episerratenediol has potential as an effective cancer chemopreventive agent (Cancer Lett. 2003;196:121–6).

In a separate experiment conducted by this lab, two new serratane-type triterpenoids, 3beta-methoxyserrat-13-en-21-beta-ol and 13-beta,14beta-epoxy-3beta-methoxyserratan-21beta-ol, also isolated from Picea plants, exhibited strong anti-tumor-promoting effects on mouse skin carcinogenesis (Planta Med. 2003;69:1041–7).

This lab also showed that, in a test of the lupane-type triterpenoids isolated from the stem bark of Glochidion zeylanicum as well as synthetic analogues, glochidiol and lup-20(29)-ene-1beta,3beta-diol were the strongest inhibitors of EBV-EA activation induced by TPA. Glochidiol also exhibited the greatest inhibitory effect on skin tumor promotion (Planta Med. 2004;70:1234–6).

Other Anticarcinogenic Actions

In 2005, investigators at the University of North Carolina, Chapel Hill, published a report on cimigenol, an acid- and base-stable triterpenoid found in species such as Cimicifuga racemosa, C. dahurica, and C. japonica. These researchers had previously shown that cimigenol and some of its derivatives had strong inhibitory effects on mouse skin tumor promotion induced by TPA in a two-stage carcinogenesis test. Continuing that previous work, the investigators repeated screens of cimigenol and also tested 15 related compounds as potential anti-tumor promoters by using the in vitro, short-term TPA-induced EBV-EA activation assay (Bioorg. Med. Chem. 2005;13:1403–8).

Of these compounds, the researchers found that cimigenol-3,15-dione showed the greatest potency and, in a subsequent two-stage DMBA/TPA carcinogenesis assay, reduced, at 20 weeks, the number of papillomas per mouse to 48% of controls. Both cimigenol and cimigenol-3,15-dione were also nearly as potent as epigallocatechin gallate, a primary constituent of green tea, in terms of anti-tumor initiation activity, as demonstrated in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite (initiator) and TPA (promoter).

The investigators concluded that these two triterpenoids amply demonstrate anti-tumor promotion as well as anti-tumor initiation and warrant consideration as significant cancer chemopreventive agents (Bioorg. Med. Chem. 2005;13:1403–8).

Protection Against UV

Four triterpenoids isolated from the stems of Styrax japonica were recently found to significantly inhibit matrix metalloproteinase-1 (MMP-1) in primary human skin fibroblasts induced by UV radiation. This finding is significant given the association between the upregulation of MMPs and chronic skin damage (Biol. Pharm. Bull. 2005;28:2003–6).

Previously, some of the same investigators studied the effects of 3,23-dihydroxy-20(29)-lupen-27-oic acid, a triterpenoid derived from Tiarella polyphylla, on the regulation of MMP-1 and type 1 procollagen in UV irradiation of cultured old-age human dermal fibroblasts. The triterpenoid dose-dependently induced regulation of type 1 procollagen and diminished regulation of MMP-1 at the protein level (Arch. Pharm. Res. 2004;27:1060–4).

Other Pharmacologic Actions

Triterpenoids also have been found in Boswellia serrata, an herb used in traditional medicine to treat inflammatory and arthritic conditions (and discussed in this column in November 2006, p. 17).

In a study published in 2000, the primary components and derivatives of Boswellia markedly inhibited TPA-induced increases in skin inflammation, epidermal proliferation, the number of epidermal cell layers, and tumor promotion in DMBA-initiated mice. DNA synthesis in human leukemia HL-60 cells was also shown to be inhibited by the addition of various forms of boswellic acid. The investigators suggest that such findings demonstrate the anticarcinogenic and antitumor properties of the major constituents, including triterpenoids, of this herb (Biofactors 2000;13:225–30).

The anti-inflammatory activity of several triterpenoids suggests the potential for numerous additional medical applications. A study evaluating the mechanism of anti-inflammatory activity displayed by triterpenoids on edema induced in mouse ears and paws, as well as rat skin, revealed that the inhibition of protein kinase C may play a crucial role in facilitating the anti-inflammatory activity of this class of compounds (Eur. J. Pharmacol. 2000;410:69–81).

In another study, several triterpene constituents of Vochysia pacifica Cuatrec, a South American tree used by traditional communities to treat inflammation, skin sores, asthma, and pulmonary congestion, were found to exert mild inhibitory activity on the intracellular target for new anti-inflammatory medications, namely the cAMP phosphodiesterase 4 isozyme (PDE4) (Phytother. Res. 2005;19:75–7).

Some triterpenoids have been documented as irritating (J. Asian Nat. Prod. Res. 2003;5:35–41) and others as toxic, which is not unexpected as these compounds comprise the primary constituent class in the volatile oils of plants. Given the breadth of this biochemical class, it is expected that some members would be toxic and others safe and beneficial to human health, such as the triterpenoid saponin glycyrrhizin, derived from licorice root (and featured in this column in March 2007, p. 24, and April 2007, p. 30). Triterpenoid saponins, or sapogenins, are used in some emulsifiers, including some Estée Lauder products, for their capacity to confer antifungal, anti-inflammatory, antimicrobial, and adaptogenic activity.

Conclusion

As we continue to explore botanical sources for medical and cosmetic purposes, we will learn more about the numerous triterpenoids found in plants. This class of biochemical compounds typically receives less attention than polyphenols in discussions of the most potent herbal ingredients used in dermatology, but the considerable potential of triterpenoids to be used in a broad range of cutaneous applications is gradually becoming appreciated.

Positive immunostaining with monoclonal antibody D2–40, together with younger patient age and lesion ulceration, might identify which melanoma patients are likely to have nodal metastasis and should undergo sentinel node biopsy, according to Dr. Firouzeh Niakosari of Sunnybrook Health Sciences Centre, Toronto, and associates.

"The recently developed monoclonal antibody [Mab] D2–40 reacts with endothelial cells of lymphatics but not with endothelial cells of blood vessels in normal tissues," the investigators wrote (Arch. Dermatol. 2008;144:462–7).

Mab D2–40 immunostaining more readily identifies lymphatic invasion in primary melanomas than does conventional staining with hematoxylin-eosin. Dr. Niakosari and associates assessed the technique's predictive value using blocks of primary tumor taken from 96 patients who were treated in 1998–2004 and had no clinical evidence of metastasis.

On biopsy, sentinel lymph nodes had been found to be positive in 23 of the cases.

Mab D2–40 immunostaining was positive for invasion of the lymphatic vessels within the tumor samples in 32 of the 96 cases (33%). The result was correct in ruling out lymphatic invasion in 56 (77%) of the cases that proved to have no invasion on sentinel node biopsy, and it was correct in identifying lymphatic invasion in 15 (65%) of the cases that did have lymphatic invasion on sentinel node biopsy.

On its own, then, the technique had a negative predictive value of 88% and a positive predictive value of 47%, the investigators found.

Mab D2–40 immunostaining was even more predictive when the results were combined with two clinical factors: younger patient age and the presence of ulceration in the lesion. "The probability of sentinel lymph node positivity was 13% when lymphatic invasion identified by immunostaining with Mab D2–40 was negative, no ulceration was present, and the patient was 50 years or older," they noted.

In cases in which the immunostaining indicated that there was lymphatic invasion, ulceration was present, and the patient was younger than 50 years, the probability of sentinel lymph node positivity increased to 61%, Dr. Niakosari and associates reported.

Lymphatic invasion on Mab D2–40 immunostaining correlated with deeper Clark Level of Invasion and increased Breslow tumor thickness, "indicating that lymphatic invasion occurs more frequently in later stages of melanoma," they wrote.

Positive immunostaining with monoclonal antibody D2–40, together with younger patient age and lesion ulceration, might identify which melanoma patients are likely to have nodal metastasis and should undergo sentinel node biopsy, according to Dr. Firouzeh Niakosari of Sunnybrook Health Sciences Centre, Toronto, and associates.

"The recently developed monoclonal antibody [Mab] D2–40 reacts with endothelial cells of lymphatics but not with endothelial cells of blood vessels in normal tissues," the investigators wrote (Arch. Dermatol. 2008;144:462–7).

Mab D2–40 immunostaining more readily identifies lymphatic invasion in primary melanomas than does conventional staining with hematoxylin-eosin. Dr. Niakosari and associates assessed the technique's predictive value using blocks of primary tumor taken from 96 patients who were treated in 1998–2004 and had no clinical evidence of metastasis.

On biopsy, sentinel lymph nodes had been found to be positive in 23 of the cases.

Mab D2–40 immunostaining was positive for invasion of the lymphatic vessels within the tumor samples in 32 of the 96 cases (33%). The result was correct in ruling out lymphatic invasion in 56 (77%) of the cases that proved to have no invasion on sentinel node biopsy, and it was correct in identifying lymphatic invasion in 15 (65%) of the cases that did have lymphatic invasion on sentinel node biopsy.

On its own, then, the technique had a negative predictive value of 88% and a positive predictive value of 47%, the investigators found.

Mab D2–40 immunostaining was even more predictive when the results were combined with two clinical factors: younger patient age and the presence of ulceration in the lesion. "The probability of sentinel lymph node positivity was 13% when lymphatic invasion identified by immunostaining with Mab D2–40 was negative, no ulceration was present, and the patient was 50 years or older," they noted.

In cases in which the immunostaining indicated that there was lymphatic invasion, ulceration was present, and the patient was younger than 50 years, the probability of sentinel lymph node positivity increased to 61%, Dr. Niakosari and associates reported.

Lymphatic invasion on Mab D2–40 immunostaining correlated with deeper Clark Level of Invasion and increased Breslow tumor thickness, "indicating that lymphatic invasion occurs more frequently in later stages of melanoma," they wrote.

Positive immunostaining with monoclonal antibody D2–40, together with younger patient age and lesion ulceration, might identify which melanoma patients are likely to have nodal metastasis and should undergo sentinel node biopsy, according to Dr. Firouzeh Niakosari of Sunnybrook Health Sciences Centre, Toronto, and associates.

"The recently developed monoclonal antibody [Mab] D2–40 reacts with endothelial cells of lymphatics but not with endothelial cells of blood vessels in normal tissues," the investigators wrote (Arch. Dermatol. 2008;144:462–7).

Mab D2–40 immunostaining more readily identifies lymphatic invasion in primary melanomas than does conventional staining with hematoxylin-eosin. Dr. Niakosari and associates assessed the technique's predictive value using blocks of primary tumor taken from 96 patients who were treated in 1998–2004 and had no clinical evidence of metastasis.

On biopsy, sentinel lymph nodes had been found to be positive in 23 of the cases.

Mab D2–40 immunostaining was positive for invasion of the lymphatic vessels within the tumor samples in 32 of the 96 cases (33%). The result was correct in ruling out lymphatic invasion in 56 (77%) of the cases that proved to have no invasion on sentinel node biopsy, and it was correct in identifying lymphatic invasion in 15 (65%) of the cases that did have lymphatic invasion on sentinel node biopsy.

On its own, then, the technique had a negative predictive value of 88% and a positive predictive value of 47%, the investigators found.

Mab D2–40 immunostaining was even more predictive when the results were combined with two clinical factors: younger patient age and the presence of ulceration in the lesion. "The probability of sentinel lymph node positivity was 13% when lymphatic invasion identified by immunostaining with Mab D2–40 was negative, no ulceration was present, and the patient was 50 years or older," they noted.

In cases in which the immunostaining indicated that there was lymphatic invasion, ulceration was present, and the patient was younger than 50 years, the probability of sentinel lymph node positivity increased to 61%, Dr. Niakosari and associates reported.

Lymphatic invasion on Mab D2–40 immunostaining correlated with deeper Clark Level of Invasion and increased Breslow tumor thickness, "indicating that lymphatic invasion occurs more frequently in later stages of melanoma," they wrote.

SCOTTSDALE, ARIZ. — There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown during the Harold O. Perry lecture at the annual meeting of the Noah Worcester Dermatological Society.

Lentigo Maligna

Once cavalierly called a "Hutchinson's freckle" because it can resemble a dab of shoe polish, patients may not even notice the subtle appearance and growth of a lentigo maligna. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).

"It's very, very difficult to make the diagnosis," Dr. Brown said. "I've missed it several times."

Lentigo maligna lesions are slow to develop and evolve almost imperceptibly. They may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, as was the case in nearly half of 147 lesions described in a recent study (J. Am. Acad. Dermatol. 2005;52:859–62).

However, it is not a disease to be trivialized, according to Dr. Brown.

"It's my feeling that if you give it a long enough period of time, it will become an invasive tumor," he said.

Two decades ago, when he began performing Mohs surgery, Dr. Brown almost exclusively encountered lentigo malignas on elderly patients. Now he's making it a practice to hunt for them on much younger patients. "It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna," he said.

Finding a surefire treatment approach to lentigo malignas remains challenging.

Increasing evidence suggests that the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but, Dr. Brown advised, "you really have to have an excellent lab and be very good at this."

He said he prefers a "modified Mohs," or "slow Mohs" approach that involves sending sequential sections to a histopathologic laboratory over several days after a "very meticulous" collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.

For elderly patients and difficult anatomic sites, radiation therapy or daily use of imiquimod has been proposed. Dr. Brown cautioned that the use of the immune response modifier should be considered experimental, because only 67 cases in which it has been used are described in the literature, and 8 of those involved treatment failures.

Atypical Fibroxanthoma

Also increasing in incidence is this tumor, which is believed to be secondary to UV exposure, said Dr. Brown.

Unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.

"It usually appears relatively nonspecifically," he said. "Most of the time when I submit a specimen to the pathologist, I don't say, 'Rule out AFX.' It's usually squamous cell versus basal cell cancer [in my mind]."

In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown. He was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:1287–92).

"If it sounds too good to be true, it's too good to be true," he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.

In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.

Fortunately, there is a clue to potential aggressive behavior in such tumors, he said. The immunostain LN-2 (CD74) often "lights up" in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.

Merkel Cell Carcinoma

Unknown until 1972 and then considered exceedingly rare, Merkel cell carcinoma appears to be on the rise. More than 1,000 cases have been reported in patients aged 7–75 years (although most patients are older than 65 years).

Up to 15% of cases are seen in immunocompromised patients, a number that is driven by long-term survivors of HIV, chronic lymphocytic leukemia, and organ transplantation. "I'm seeing a lot of these," said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.

In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. "No way I thought this was a Merkel cell," he admitted.

When the diagnosis is confirmed by its blue cell clusters in sheets or a trabecular pattern in the dermis, with frequent mitosis and cell necrosis, dermatologists should take heed. "This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma," he said.

Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases—50% by some reports—with a 3-year overall survival of 31%.

Treatment is controversial, noted Dr. Brown. Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps adjuvant chemotherapy. A negative sentinel lymph node carries a fairly reassuring prognosis.

He added that an immunostain for anti-CK20 antibody may detect micrometastases in patients who appear to be tumor free on routine histology, according to a small study (J. Am. Acad. Dermatol. 2002;46:661–6).

SCC in Organ Transplant Patients

The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma.

Their cancers may be multiple, fast growing, and atypical in appearance, Dr. Brown said.

In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.

"We're all going to be seeing more and more of these patients," Dr. Brown predicted.

The keys to management of these challenging patients are education first, then vigilance. Many transplant centers fail to warn patients that they may be at elevated risk for skin cancers and that they should be examined frequently.

When a lesion appears, have a low threshold for suspicion, he said. "It is very difficult sometimes to determine which is the bad [lesion] and which is not."

High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites: the scalp, ear, lip, neck, and face. Warning signs histologically include poor cell differentiation and perineural invasion.

"How do you manage these? Aggressively," he emphasized.

Employ whichever tools work: surgery, cryotherapy, 5-fluorouracil, photodynamic therapy, or topical imiquimod. Systemic retinoids, perhaps in conjunction with a reduction in immunosuppressive therapy, may be appropriate for patients with recurrent, aggressive, or metastatic SCCs, he added.

Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His presentation, however, was not sponsored by any company.

Long-term survivors of organ transplantation have a 65-fold increased risk of squamous cell carcinoma. DR. BROWN

SCOTTSDALE, ARIZ. — There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown during the Harold O. Perry lecture at the annual meeting of the Noah Worcester Dermatological Society.

Lentigo Maligna

Once cavalierly called a "Hutchinson's freckle" because it can resemble a dab of shoe polish, patients may not even notice the subtle appearance and growth of a lentigo maligna. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).

"It's very, very difficult to make the diagnosis," Dr. Brown said. "I've missed it several times."

Lentigo maligna lesions are slow to develop and evolve almost imperceptibly. They may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, as was the case in nearly half of 147 lesions described in a recent study (J. Am. Acad. Dermatol. 2005;52:859–62).

However, it is not a disease to be trivialized, according to Dr. Brown.

"It's my feeling that if you give it a long enough period of time, it will become an invasive tumor," he said.

Two decades ago, when he began performing Mohs surgery, Dr. Brown almost exclusively encountered lentigo malignas on elderly patients. Now he's making it a practice to hunt for them on much younger patients. "It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna," he said.

Finding a surefire treatment approach to lentigo malignas remains challenging.

Increasing evidence suggests that the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but, Dr. Brown advised, "you really have to have an excellent lab and be very good at this."

He said he prefers a "modified Mohs," or "slow Mohs" approach that involves sending sequential sections to a histopathologic laboratory over several days after a "very meticulous" collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.

For elderly patients and difficult anatomic sites, radiation therapy or daily use of imiquimod has been proposed. Dr. Brown cautioned that the use of the immune response modifier should be considered experimental, because only 67 cases in which it has been used are described in the literature, and 8 of those involved treatment failures.

Atypical Fibroxanthoma

Also increasing in incidence is this tumor, which is believed to be secondary to UV exposure, said Dr. Brown.

Unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.

"It usually appears relatively nonspecifically," he said. "Most of the time when I submit a specimen to the pathologist, I don't say, 'Rule out AFX.' It's usually squamous cell versus basal cell cancer [in my mind]."

In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown. He was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:1287–92).

"If it sounds too good to be true, it's too good to be true," he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.

In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.

Fortunately, there is a clue to potential aggressive behavior in such tumors, he said. The immunostain LN-2 (CD74) often "lights up" in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.

Merkel Cell Carcinoma

Unknown until 1972 and then considered exceedingly rare, Merkel cell carcinoma appears to be on the rise. More than 1,000 cases have been reported in patients aged 7–75 years (although most patients are older than 65 years).

Up to 15% of cases are seen in immunocompromised patients, a number that is driven by long-term survivors of HIV, chronic lymphocytic leukemia, and organ transplantation. "I'm seeing a lot of these," said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.

In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. "No way I thought this was a Merkel cell," he admitted.

When the diagnosis is confirmed by its blue cell clusters in sheets or a trabecular pattern in the dermis, with frequent mitosis and cell necrosis, dermatologists should take heed. "This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma," he said.

Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases—50% by some reports—with a 3-year overall survival of 31%.

Treatment is controversial, noted Dr. Brown. Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps adjuvant chemotherapy. A negative sentinel lymph node carries a fairly reassuring prognosis.

He added that an immunostain for anti-CK20 antibody may detect micrometastases in patients who appear to be tumor free on routine histology, according to a small study (J. Am. Acad. Dermatol. 2002;46:661–6).

SCC in Organ Transplant Patients

The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma.

Their cancers may be multiple, fast growing, and atypical in appearance, Dr. Brown said.

In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.

"We're all going to be seeing more and more of these patients," Dr. Brown predicted.

The keys to management of these challenging patients are education first, then vigilance. Many transplant centers fail to warn patients that they may be at elevated risk for skin cancers and that they should be examined frequently.

When a lesion appears, have a low threshold for suspicion, he said. "It is very difficult sometimes to determine which is the bad [lesion] and which is not."

High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites: the scalp, ear, lip, neck, and face. Warning signs histologically include poor cell differentiation and perineural invasion.

"How do you manage these? Aggressively," he emphasized.

Employ whichever tools work: surgery, cryotherapy, 5-fluorouracil, photodynamic therapy, or topical imiquimod. Systemic retinoids, perhaps in conjunction with a reduction in immunosuppressive therapy, may be appropriate for patients with recurrent, aggressive, or metastatic SCCs, he added.

Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His presentation, however, was not sponsored by any company.

Long-term survivors of organ transplantation have a 65-fold increased risk of squamous cell carcinoma. DR. BROWN

SCOTTSDALE, ARIZ. — There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown during the Harold O. Perry lecture at the annual meeting of the Noah Worcester Dermatological Society.

Lentigo Maligna

Once cavalierly called a "Hutchinson's freckle" because it can resemble a dab of shoe polish, patients may not even notice the subtle appearance and growth of a lentigo maligna. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).

"It's very, very difficult to make the diagnosis," Dr. Brown said. "I've missed it several times."

Lentigo maligna lesions are slow to develop and evolve almost imperceptibly. They may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, as was the case in nearly half of 147 lesions described in a recent study (J. Am. Acad. Dermatol. 2005;52:859–62).

However, it is not a disease to be trivialized, according to Dr. Brown.

"It's my feeling that if you give it a long enough period of time, it will become an invasive tumor," he said.

Two decades ago, when he began performing Mohs surgery, Dr. Brown almost exclusively encountered lentigo malignas on elderly patients. Now he's making it a practice to hunt for them on much younger patients. "It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna," he said.

Finding a surefire treatment approach to lentigo malignas remains challenging.

Increasing evidence suggests that the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but, Dr. Brown advised, "you really have to have an excellent lab and be very good at this."

He said he prefers a "modified Mohs," or "slow Mohs" approach that involves sending sequential sections to a histopathologic laboratory over several days after a "very meticulous" collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.

For elderly patients and difficult anatomic sites, radiation therapy or daily use of imiquimod has been proposed. Dr. Brown cautioned that the use of the immune response modifier should be considered experimental, because only 67 cases in which it has been used are described in the literature, and 8 of those involved treatment failures.

Atypical Fibroxanthoma

Also increasing in incidence is this tumor, which is believed to be secondary to UV exposure, said Dr. Brown.

Unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.

"It usually appears relatively nonspecifically," he said. "Most of the time when I submit a specimen to the pathologist, I don't say, 'Rule out AFX.' It's usually squamous cell versus basal cell cancer [in my mind]."

In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown. He was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:1287–92).

"If it sounds too good to be true, it's too good to be true," he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.

In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.

Fortunately, there is a clue to potential aggressive behavior in such tumors, he said. The immunostain LN-2 (CD74) often "lights up" in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.

Merkel Cell Carcinoma

Unknown until 1972 and then considered exceedingly rare, Merkel cell carcinoma appears to be on the rise. More than 1,000 cases have been reported in patients aged 7–75 years (although most patients are older than 65 years).

Up to 15% of cases are seen in immunocompromised patients, a number that is driven by long-term survivors of HIV, chronic lymphocytic leukemia, and organ transplantation. "I'm seeing a lot of these," said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.

In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. "No way I thought this was a Merkel cell," he admitted.

When the diagnosis is confirmed by its blue cell clusters in sheets or a trabecular pattern in the dermis, with frequent mitosis and cell necrosis, dermatologists should take heed. "This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma," he said.

Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases—50% by some reports—with a 3-year overall survival of 31%.

Treatment is controversial, noted Dr. Brown. Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps adjuvant chemotherapy. A negative sentinel lymph node carries a fairly reassuring prognosis.

He added that an immunostain for anti-CK20 antibody may detect micrometastases in patients who appear to be tumor free on routine histology, according to a small study (J. Am. Acad. Dermatol. 2002;46:661–6).

SCC in Organ Transplant Patients

The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma.

Their cancers may be multiple, fast growing, and atypical in appearance, Dr. Brown said.

In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.

"We're all going to be seeing more and more of these patients," Dr. Brown predicted.

The keys to management of these challenging patients are education first, then vigilance. Many transplant centers fail to warn patients that they may be at elevated risk for skin cancers and that they should be examined frequently.

When a lesion appears, have a low threshold for suspicion, he said. "It is very difficult sometimes to determine which is the bad [lesion] and which is not."

High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites: the scalp, ear, lip, neck, and face. Warning signs histologically include poor cell differentiation and perineural invasion.

"How do you manage these? Aggressively," he emphasized.

Employ whichever tools work: surgery, cryotherapy, 5-fluorouracil, photodynamic therapy, or topical imiquimod. Systemic retinoids, perhaps in conjunction with a reduction in immunosuppressive therapy, may be appropriate for patients with recurrent, aggressive, or metastatic SCCs, he added.

Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His presentation, however, was not sponsored by any company.

Long-term survivors of organ transplantation have a 65-fold increased risk of squamous cell carcinoma. DR. BROWN

VANCOUVER, B.C. — Cranial neuropathy may be the first sign or symptom of a skin cancer recurrence, and as such it is often misdiagnosed, a dermatologist/otolaryngologist said.

Neurotropic skin cancer is an uncommon but aggressive form of skin cancer, Dr. Joel W. Cook reported at the annual meeting of the American College of Mohs Surgery.

"Most of the neurotropic findings are histologic and any symptoms are reasonably unusual; most studies say that it's very rare. To have [patients] present to your office with neurologic findings as their sentinel event in the recognition of recurrent skin cancer is even rarer," he said.

In the retrospective study, Dr. Cook of the Medical University of South Carolina, Charleston, and his colleagues reviewed the charts of patients who had previously had skin cancer and were referred to the university's head and neck program between 1999 and 2007.

The chart review identified six patients in whom cranial neuropathy was the initial sign or symptom of recurrent skin cancer.

Five of the patients had previously undergone multiple excisions of skin cancer, and two had undergone Mohs surgery for a primary lesion, he said.

The cancer was squamous cell carcinoma in four cases and desmoplastic melanoma in two. "Importantly, none of the six patients" was a transplant patient, he noted.

"One had an indolent chronic myelogenous leukemia, but they were all reasonably immunocompetent," he said.

The majority of the patients had multiple cranial neuropathies; all had deficits of cranial nerve V, and half had deficits of cranial nerve VII.

The presenting symptoms were most commonly facial numbness; facial paralysis or weakness; facial pain; diplopia; and paresthesia.

Less common symptoms were formication and hearing loss. The symptoms had been present for 7 months, on average, before diagnosis.

In nearly all cases, the cranial neuropathy had been misdiagnosed as trigeminal neuralgia, Bell's palsy, or some other condition, said Dr. Cook.

Neurotropism was identified histologically in five patients who underwent surgery or biopsy, and cranial nerve involvement was confirmed in all patients by MRI.

"It's important to know what imaging study to order in these patients," Dr. Cook pointed out. "Although CT is an excellent method to image head and neck malignancies, … it cannot be used to evaluate for the presence or absence of neurotropic tumor. In that case or with that suspicion, you would want to get an MRI; this is by far the preferred imaging modality."

Five of the patients underwent treatment for their recurrence with various combinations of surgery, radiation therapy, and chemotherapy.

"As you can imagine, the surgery in these patients is salvage surgery and is amazingly extensive. These patients have to be counseled preoperatively, they have to be adequately staged, and they need multidisciplinary consultations," Dr. Cook said.

"But surgery is the only chance these patients have to survive," he added.

Three of the patients eventually died, with evidence of metastases. The other three, however, all of whom had undergone surgery, were still alive without evidence of disease 2.5–6 years after their operations.

Dr. Cook concluded that any time a patient is found to have a cranial neuropathy and that patient has previously undergone resection of a high-risk skin cancer, "you need to be very skeptical of an alternative diagnosis other than neurotropic recurrence."

He reported no disclosures in association with the study.

VANCOUVER, B.C. — Cranial neuropathy may be the first sign or symptom of a skin cancer recurrence, and as such it is often misdiagnosed, a dermatologist/otolaryngologist said.

Neurotropic skin cancer is an uncommon but aggressive form of skin cancer, Dr. Joel W. Cook reported at the annual meeting of the American College of Mohs Surgery.

"Most of the neurotropic findings are histologic and any symptoms are reasonably unusual; most studies say that it's very rare. To have [patients] present to your office with neurologic findings as their sentinel event in the recognition of recurrent skin cancer is even rarer," he said.

In the retrospective study, Dr. Cook of the Medical University of South Carolina, Charleston, and his colleagues reviewed the charts of patients who had previously had skin cancer and were referred to the university's head and neck program between 1999 and 2007.

The chart review identified six patients in whom cranial neuropathy was the initial sign or symptom of recurrent skin cancer.

Five of the patients had previously undergone multiple excisions of skin cancer, and two had undergone Mohs surgery for a primary lesion, he said.

The cancer was squamous cell carcinoma in four cases and desmoplastic melanoma in two. "Importantly, none of the six patients" was a transplant patient, he noted.

"One had an indolent chronic myelogenous leukemia, but they were all reasonably immunocompetent," he said.

The majority of the patients had multiple cranial neuropathies; all had deficits of cranial nerve V, and half had deficits of cranial nerve VII.

The presenting symptoms were most commonly facial numbness; facial paralysis or weakness; facial pain; diplopia; and paresthesia.

Less common symptoms were formication and hearing loss. The symptoms had been present for 7 months, on average, before diagnosis.

In nearly all cases, the cranial neuropathy had been misdiagnosed as trigeminal neuralgia, Bell's palsy, or some other condition, said Dr. Cook.

Neurotropism was identified histologically in five patients who underwent surgery or biopsy, and cranial nerve involvement was confirmed in all patients by MRI.

"It's important to know what imaging study to order in these patients," Dr. Cook pointed out. "Although CT is an excellent method to image head and neck malignancies, … it cannot be used to evaluate for the presence or absence of neurotropic tumor. In that case or with that suspicion, you would want to get an MRI; this is by far the preferred imaging modality."

Five of the patients underwent treatment for their recurrence with various combinations of surgery, radiation therapy, and chemotherapy.

"As you can imagine, the surgery in these patients is salvage surgery and is amazingly extensive. These patients have to be counseled preoperatively, they have to be adequately staged, and they need multidisciplinary consultations," Dr. Cook said.

"But surgery is the only chance these patients have to survive," he added.

Three of the patients eventually died, with evidence of metastases. The other three, however, all of whom had undergone surgery, were still alive without evidence of disease 2.5–6 years after their operations.

Dr. Cook concluded that any time a patient is found to have a cranial neuropathy and that patient has previously undergone resection of a high-risk skin cancer, "you need to be very skeptical of an alternative diagnosis other than neurotropic recurrence."

He reported no disclosures in association with the study.

VANCOUVER, B.C. — Cranial neuropathy may be the first sign or symptom of a skin cancer recurrence, and as such it is often misdiagnosed, a dermatologist/otolaryngologist said.

Neurotropic skin cancer is an uncommon but aggressive form of skin cancer, Dr. Joel W. Cook reported at the annual meeting of the American College of Mohs Surgery.

"Most of the neurotropic findings are histologic and any symptoms are reasonably unusual; most studies say that it's very rare. To have [patients] present to your office with neurologic findings as their sentinel event in the recognition of recurrent skin cancer is even rarer," he said.

In the retrospective study, Dr. Cook of the Medical University of South Carolina, Charleston, and his colleagues reviewed the charts of patients who had previously had skin cancer and were referred to the university's head and neck program between 1999 and 2007.

The chart review identified six patients in whom cranial neuropathy was the initial sign or symptom of recurrent skin cancer.

Five of the patients had previously undergone multiple excisions of skin cancer, and two had undergone Mohs surgery for a primary lesion, he said.

The cancer was squamous cell carcinoma in four cases and desmoplastic melanoma in two. "Importantly, none of the six patients" was a transplant patient, he noted.

"One had an indolent chronic myelogenous leukemia, but they were all reasonably immunocompetent," he said.

The majority of the patients had multiple cranial neuropathies; all had deficits of cranial nerve V, and half had deficits of cranial nerve VII.

The presenting symptoms were most commonly facial numbness; facial paralysis or weakness; facial pain; diplopia; and paresthesia.

Less common symptoms were formication and hearing loss. The symptoms had been present for 7 months, on average, before diagnosis.

In nearly all cases, the cranial neuropathy had been misdiagnosed as trigeminal neuralgia, Bell's palsy, or some other condition, said Dr. Cook.

Neurotropism was identified histologically in five patients who underwent surgery or biopsy, and cranial nerve involvement was confirmed in all patients by MRI.

"It's important to know what imaging study to order in these patients," Dr. Cook pointed out. "Although CT is an excellent method to image head and neck malignancies, … it cannot be used to evaluate for the presence or absence of neurotropic tumor. In that case or with that suspicion, you would want to get an MRI; this is by far the preferred imaging modality."

Five of the patients underwent treatment for their recurrence with various combinations of surgery, radiation therapy, and chemotherapy.

"As you can imagine, the surgery in these patients is salvage surgery and is amazingly extensive. These patients have to be counseled preoperatively, they have to be adequately staged, and they need multidisciplinary consultations," Dr. Cook said.

"But surgery is the only chance these patients have to survive," he added.

Three of the patients eventually died, with evidence of metastases. The other three, however, all of whom had undergone surgery, were still alive without evidence of disease 2.5–6 years after their operations.

Dr. Cook concluded that any time a patient is found to have a cranial neuropathy and that patient has previously undergone resection of a high-risk skin cancer, "you need to be very skeptical of an alternative diagnosis other than neurotropic recurrence."

He reported no disclosures in association with the study.

NEW YORK — The greatest malignancy risk in patients receiving tumor necrosis factor antagonists is skin cancer, Dr. Jeffrey Greenberg said at a rheumatology meeting sponsored by New York University.

However, data conflict as to how great malignancy risk is overall for these patients.

Two years ago, a widely noted systematic review and meta-analysis found a threefold increased risk for malignancy in patients with rheumatoid arthritis (RA) treated with infliximab or adalimumab (JAMA 2006;295:2275–85). The meta-analysis included nine randomized, placebo-controlled trials, with 3,493 RA patients who received an active drug and 1,512 RA patients who received placebo.

In the anti-tumor necrosis factor (TNF) arms of this analysis, there were 10 lymphomas, nine nonmelanoma skin cancers, and 12 assorted other cancers, Dr. Greenberg said. "What was most interesting was the cancers that weren't found in the placebo arms—there were two basal cell cancers and one solid tumor—and that's it," he said, adding that in a group of 1,500 RA patients, 8–10 malignancies would be expected.

Aside from the lower-than-expected rates of malignancy in the placebo arms, the meta-analysis had other limitations, according to Dr. Greenberg of New York University, New York, who is chief scientific officer of the Consortium of Rheumatology Researchers of North America (CORRONA).

Among these limitations were the exclusion of etanercept; the association of higher-than-usual doses of infliximab with most malignancies; and the fact that the investigators used a per-patient analysis rather than person-years of drug exposure. Their approach assumes equal time exposure for placebo and the anti-TNF drugs, and four of the nine trials had higher placebo dropout rates.

"Patients on placebo who drop out are not followed for long periods of time looking for malignancies, so of course they are going to have fewer events," he added.

However, a different picture is emerging from observational studies and RA registries in the United States and Europe. In three Swedish registries—one prevalent cohort that included 53,067 patients, one incident cohort that included 3,703 patients, and one TNF antagonist-treated cohort of 4,160 patients—RA patients treated with TNF blockers had a tripled lymphoma risk, compared with the general population. However, after adjustment for sex, age, and disease duration, the lymphoma risk among TNF antagonist-treated patients was no higher than in the other RA cohorts (Ann. Rheum. Dis. 2005;64:1414–20).

In a report from the National Data Bank for Rheumatic Diseases, when RA patients were compared with the general population from the National Cancer Institute's Surveillance, Epidemiology, and End Results database, there was no increased rate of cancer overall, but lymphoma and melanoma were increased, with both having standardized incidence ratios of 1.7. However, only nonmelanoma skin cancer and melanoma were increased among patients on biologics, with odds ratios of 1.5 and 2.3, respectively. No other malignancy was significantly associated with biologic use (Arthritis Rheum. 2007;56:2886–95).

Data from the British Biologics Register also found no increase in malignancy rate, with an adjusted incidence rate ratio (IRR) of 0.7 for patients treated with anti-TNF agents, compared with those treated with nonbiologic disease-modifying antirheumatic drugs.

And in CORRONA, which includes 15,000 RA patients, the adjusted IRR for skin cancer was 2.10, whereas that for lymphoma was 0.74 and that for all cancers was 1.05, according to Dr. Greenberg.

"I think the take-home message of the observational studies is that it's the nonmelanoma skin cancers and possibly the melanomas that are the greatest concern, not the lymphomas," he said.

However, the discrepancy between the findings of the meta-analysis and those of the observational studies remains to be explained, Dr. Greenberg said.

"Frankly, I think they could not be more conflicting. It may be that there is a group of patients with subclinical neoplasms, including lymphomas, that any immunosuppressive or immunomodulatory treatment may unmask or accelerate. We probably should be screening for these cancers more aggressively regardless of treatment," he said.

NEW YORK — The greatest malignancy risk in patients receiving tumor necrosis factor antagonists is skin cancer, Dr. Jeffrey Greenberg said at a rheumatology meeting sponsored by New York University.

However, data conflict as to how great malignancy risk is overall for these patients.

Two years ago, a widely noted systematic review and meta-analysis found a threefold increased risk for malignancy in patients with rheumatoid arthritis (RA) treated with infliximab or adalimumab (JAMA 2006;295:2275–85). The meta-analysis included nine randomized, placebo-controlled trials, with 3,493 RA patients who received an active drug and 1,512 RA patients who received placebo.

In the anti-tumor necrosis factor (TNF) arms of this analysis, there were 10 lymphomas, nine nonmelanoma skin cancers, and 12 assorted other cancers, Dr. Greenberg said. "What was most interesting was the cancers that weren't found in the placebo arms—there were two basal cell cancers and one solid tumor—and that's it," he said, adding that in a group of 1,500 RA patients, 8–10 malignancies would be expected.

Aside from the lower-than-expected rates of malignancy in the placebo arms, the meta-analysis had other limitations, according to Dr. Greenberg of New York University, New York, who is chief scientific officer of the Consortium of Rheumatology Researchers of North America (CORRONA).

Among these limitations were the exclusion of etanercept; the association of higher-than-usual doses of infliximab with most malignancies; and the fact that the investigators used a per-patient analysis rather than person-years of drug exposure. Their approach assumes equal time exposure for placebo and the anti-TNF drugs, and four of the nine trials had higher placebo dropout rates.

"Patients on placebo who drop out are not followed for long periods of time looking for malignancies, so of course they are going to have fewer events," he added.

However, a different picture is emerging from observational studies and RA registries in the United States and Europe. In three Swedish registries—one prevalent cohort that included 53,067 patients, one incident cohort that included 3,703 patients, and one TNF antagonist-treated cohort of 4,160 patients—RA patients treated with TNF blockers had a tripled lymphoma risk, compared with the general population. However, after adjustment for sex, age, and disease duration, the lymphoma risk among TNF antagonist-treated patients was no higher than in the other RA cohorts (Ann. Rheum. Dis. 2005;64:1414–20).

In a report from the National Data Bank for Rheumatic Diseases, when RA patients were compared with the general population from the National Cancer Institute's Surveillance, Epidemiology, and End Results database, there was no increased rate of cancer overall, but lymphoma and melanoma were increased, with both having standardized incidence ratios of 1.7. However, only nonmelanoma skin cancer and melanoma were increased among patients on biologics, with odds ratios of 1.5 and 2.3, respectively. No other malignancy was significantly associated with biologic use (Arthritis Rheum. 2007;56:2886–95).

Data from the British Biologics Register also found no increase in malignancy rate, with an adjusted incidence rate ratio (IRR) of 0.7 for patients treated with anti-TNF agents, compared with those treated with nonbiologic disease-modifying antirheumatic drugs.

And in CORRONA, which includes 15,000 RA patients, the adjusted IRR for skin cancer was 2.10, whereas that for lymphoma was 0.74 and that for all cancers was 1.05, according to Dr. Greenberg.

"I think the take-home message of the observational studies is that it's the nonmelanoma skin cancers and possibly the melanomas that are the greatest concern, not the lymphomas," he said.

However, the discrepancy between the findings of the meta-analysis and those of the observational studies remains to be explained, Dr. Greenberg said.

"Frankly, I think they could not be more conflicting. It may be that there is a group of patients with subclinical neoplasms, including lymphomas, that any immunosuppressive or immunomodulatory treatment may unmask or accelerate. We probably should be screening for these cancers more aggressively regardless of treatment," he said.

NEW YORK — The greatest malignancy risk in patients receiving tumor necrosis factor antagonists is skin cancer, Dr. Jeffrey Greenberg said at a rheumatology meeting sponsored by New York University.

However, data conflict as to how great malignancy risk is overall for these patients.

Two years ago, a widely noted systematic review and meta-analysis found a threefold increased risk for malignancy in patients with rheumatoid arthritis (RA) treated with infliximab or adalimumab (JAMA 2006;295:2275–85). The meta-analysis included nine randomized, placebo-controlled trials, with 3,493 RA patients who received an active drug and 1,512 RA patients who received placebo.

In the anti-tumor necrosis factor (TNF) arms of this analysis, there were 10 lymphomas, nine nonmelanoma skin cancers, and 12 assorted other cancers, Dr. Greenberg said. "What was most interesting was the cancers that weren't found in the placebo arms—there were two basal cell cancers and one solid tumor—and that's it," he said, adding that in a group of 1,500 RA patients, 8–10 malignancies would be expected.

Aside from the lower-than-expected rates of malignancy in the placebo arms, the meta-analysis had other limitations, according to Dr. Greenberg of New York University, New York, who is chief scientific officer of the Consortium of Rheumatology Researchers of North America (CORRONA).

Among these limitations were the exclusion of etanercept; the association of higher-than-usual doses of infliximab with most malignancies; and the fact that the investigators used a per-patient analysis rather than person-years of drug exposure. Their approach assumes equal time exposure for placebo and the anti-TNF drugs, and four of the nine trials had higher placebo dropout rates.

"Patients on placebo who drop out are not followed for long periods of time looking for malignancies, so of course they are going to have fewer events," he added.

However, a different picture is emerging from observational studies and RA registries in the United States and Europe. In three Swedish registries—one prevalent cohort that included 53,067 patients, one incident cohort that included 3,703 patients, and one TNF antagonist-treated cohort of 4,160 patients—RA patients treated with TNF blockers had a tripled lymphoma risk, compared with the general population. However, after adjustment for sex, age, and disease duration, the lymphoma risk among TNF antagonist-treated patients was no higher than in the other RA cohorts (Ann. Rheum. Dis. 2005;64:1414–20).

In a report from the National Data Bank for Rheumatic Diseases, when RA patients were compared with the general population from the National Cancer Institute's Surveillance, Epidemiology, and End Results database, there was no increased rate of cancer overall, but lymphoma and melanoma were increased, with both having standardized incidence ratios of 1.7. However, only nonmelanoma skin cancer and melanoma were increased among patients on biologics, with odds ratios of 1.5 and 2.3, respectively. No other malignancy was significantly associated with biologic use (Arthritis Rheum. 2007;56:2886–95).

Data from the British Biologics Register also found no increase in malignancy rate, with an adjusted incidence rate ratio (IRR) of 0.7 for patients treated with anti-TNF agents, compared with those treated with nonbiologic disease-modifying antirheumatic drugs.

And in CORRONA, which includes 15,000 RA patients, the adjusted IRR for skin cancer was 2.10, whereas that for lymphoma was 0.74 and that for all cancers was 1.05, according to Dr. Greenberg.

"I think the take-home message of the observational studies is that it's the nonmelanoma skin cancers and possibly the melanomas that are the greatest concern, not the lymphomas," he said.

However, the discrepancy between the findings of the meta-analysis and those of the observational studies remains to be explained, Dr. Greenberg said.

"Frankly, I think they could not be more conflicting. It may be that there is a group of patients with subclinical neoplasms, including lymphomas, that any immunosuppressive or immunomodulatory treatment may unmask or accelerate. We probably should be screening for these cancers more aggressively regardless of treatment," he said.

VANCOUVER, B.C. — A new study finds that the local anesthesia used for Mohs surgery appears to be safe, with serum levels of lidocaine remaining well below the threshold for toxicity and an absence of any drug-related adverse events.

Although Mohs procedures are routinely performed using lidocaine anesthesia without any complications, few studies have looked at lidocaine levels specifically in this context, said study author Dr. Murad Alam, chief of cutaneous and aesthetic surgery at Northwestern University, Chicago.

Research on tumescent anesthesia suggests that a greater vascular supply above the clavicle promotes faster systemic absorption of lidocaine (Plast. Reconstr. Surg. 2005;115:1744–51). The concentration of lidocaine in the anesthesia used for Mohs surgery is 5–10 times that of tumescent anesthesia.

The prospective cohort study, reported at the annual meeting of the American College of Mohs Surgery, took place among 20 consecutive adults undergoing Mohs surgery with local anesthesia for nonmelanoma skin cancer. The anesthesia consisted of a lidocaine solution (concentration, 1:100) also containing epinephrine (1:100,000) and 8.4% sodium bicarbonate (1:10); it was injected at the start of each stage of Mohs surgery. Blood was drawn from the patient's arm before and after each of three stages (or two stages plus closure), for a total of six sampling time points over roughly 5 hours.

Serum lidocaine levels were measured by gas chromatography, and both patients and physicians assessed the occurrence of adverse events.

Dr. Alam explained that mild symptoms of lidocaine toxicity occur when the serum level of the drug reaches 3 mcg/mL; moderate symptoms when the level exceeds 5 mcg/mL; and severe and potentially life threatening symptoms when the level exceeds 10 mcg/mL.

Study results indicated that across all time points, lidocaine levels were detectable (greater than 0.1 mcg/mL) in just five (25%) of the patients.

"Even in the worst-case scenario—the sixth and final time point, where you would expect the serum lidocaine level to be the highest because of the cumulated dosage to that point—only 5 of the 20 patients had a detectable serum lidocaine level," Dr. Alam remarked.

Furthermore, the median level for the cohort was undetectable at all time points.

"Assuming the vast majority of patients did absolutely fine, were there some patients who had very high levels and got into trouble? Again, the answer is no," Dr. Alam asserted.

Of all patients, the highest peak serum lidocaine level observed was 0.3 mcg/mL noted during the last three time points. "That is still one-tenth of the amount for even mild symptoms to occur," he pointed out.

When patients who did and did not have detectable serum lidocaine levels were compared, those with detectable levels had been injected with a significantly greater mean volume of lidocaine solution (30 vs. 9.5 mL). They were also significantly older (68.6 vs. 50.7 years) and somewhat more likely to be male, although Dr. Alam cautioned "this might just mean that older men have larger tumors."

A final analysis showed that peak serum lidocaine levels were well correlated with the total volume of solution injected.

Adverse events were reported by two patients—a 56-year-old man who reported a mild headache and a 42-year-old woman who reported feeling shaky. "Both were after the first Mohs stage, and so they were much more likely to be epinephrine effects than lidocaine effects, which would be expected to happen after a lot of lidocaine was injected," Dr. Alam observed. No adverse events related to the drug were noted.

"There was no case in which serious adverse events or even mild adverse events associated with lidocaine toxicity were seen, which suggests what we already knew to be true based on experience—that local anesthesia given during Mohs surgery appears to be safe," Dr. Alam concluded.

He reported having no conflicts of interest in association with the study.

No patient in the study experienced adverse events associated with lidocaine toxicity. DR. ALAM

VANCOUVER, B.C. — A new study finds that the local anesthesia used for Mohs surgery appears to be safe, with serum levels of lidocaine remaining well below the threshold for toxicity and an absence of any drug-related adverse events.

Although Mohs procedures are routinely performed using lidocaine anesthesia without any complications, few studies have looked at lidocaine levels specifically in this context, said study author Dr. Murad Alam, chief of cutaneous and aesthetic surgery at Northwestern University, Chicago.

Research on tumescent anesthesia suggests that a greater vascular supply above the clavicle promotes faster systemic absorption of lidocaine (Plast. Reconstr. Surg. 2005;115:1744–51). The concentration of lidocaine in the anesthesia used for Mohs surgery is 5–10 times that of tumescent anesthesia.

The prospective cohort study, reported at the annual meeting of the American College of Mohs Surgery, took place among 20 consecutive adults undergoing Mohs surgery with local anesthesia for nonmelanoma skin cancer. The anesthesia consisted of a lidocaine solution (concentration, 1:100) also containing epinephrine (1:100,000) and 8.4% sodium bicarbonate (1:10); it was injected at the start of each stage of Mohs surgery. Blood was drawn from the patient's arm before and after each of three stages (or two stages plus closure), for a total of six sampling time points over roughly 5 hours.

Serum lidocaine levels were measured by gas chromatography, and both patients and physicians assessed the occurrence of adverse events.

Dr. Alam explained that mild symptoms of lidocaine toxicity occur when the serum level of the drug reaches 3 mcg/mL; moderate symptoms when the level exceeds 5 mcg/mL; and severe and potentially life threatening symptoms when the level exceeds 10 mcg/mL.

Study results indicated that across all time points, lidocaine levels were detectable (greater than 0.1 mcg/mL) in just five (25%) of the patients.

"Even in the worst-case scenario—the sixth and final time point, where you would expect the serum lidocaine level to be the highest because of the cumulated dosage to that point—only 5 of the 20 patients had a detectable serum lidocaine level," Dr. Alam remarked.

Furthermore, the median level for the cohort was undetectable at all time points.

"Assuming the vast majority of patients did absolutely fine, were there some patients who had very high levels and got into trouble? Again, the answer is no," Dr. Alam asserted.

Of all patients, the highest peak serum lidocaine level observed was 0.3 mcg/mL noted during the last three time points. "That is still one-tenth of the amount for even mild symptoms to occur," he pointed out.

When patients who did and did not have detectable serum lidocaine levels were compared, those with detectable levels had been injected with a significantly greater mean volume of lidocaine solution (30 vs. 9.5 mL). They were also significantly older (68.6 vs. 50.7 years) and somewhat more likely to be male, although Dr. Alam cautioned "this might just mean that older men have larger tumors."

A final analysis showed that peak serum lidocaine levels were well correlated with the total volume of solution injected.

Adverse events were reported by two patients—a 56-year-old man who reported a mild headache and a 42-year-old woman who reported feeling shaky. "Both were after the first Mohs stage, and so they were much more likely to be epinephrine effects than lidocaine effects, which would be expected to happen after a lot of lidocaine was injected," Dr. Alam observed. No adverse events related to the drug were noted.

"There was no case in which serious adverse events or even mild adverse events associated with lidocaine toxicity were seen, which suggests what we already knew to be true based on experience—that local anesthesia given during Mohs surgery appears to be safe," Dr. Alam concluded.

He reported having no conflicts of interest in association with the study.

No patient in the study experienced adverse events associated with lidocaine toxicity. DR. ALAM

VANCOUVER, B.C. — A new study finds that the local anesthesia used for Mohs surgery appears to be safe, with serum levels of lidocaine remaining well below the threshold for toxicity and an absence of any drug-related adverse events.

Although Mohs procedures are routinely performed using lidocaine anesthesia without any complications, few studies have looked at lidocaine levels specifically in this context, said study author Dr. Murad Alam, chief of cutaneous and aesthetic surgery at Northwestern University, Chicago.

Research on tumescent anesthesia suggests that a greater vascular supply above the clavicle promotes faster systemic absorption of lidocaine (Plast. Reconstr. Surg. 2005;115:1744–51). The concentration of lidocaine in the anesthesia used for Mohs surgery is 5–10 times that of tumescent anesthesia.

The prospective cohort study, reported at the annual meeting of the American College of Mohs Surgery, took place among 20 consecutive adults undergoing Mohs surgery with local anesthesia for nonmelanoma skin cancer. The anesthesia consisted of a lidocaine solution (concentration, 1:100) also containing epinephrine (1:100,000) and 8.4% sodium bicarbonate (1:10); it was injected at the start of each stage of Mohs surgery. Blood was drawn from the patient's arm before and after each of three stages (or two stages plus closure), for a total of six sampling time points over roughly 5 hours.

Serum lidocaine levels were measured by gas chromatography, and both patients and physicians assessed the occurrence of adverse events.

Dr. Alam explained that mild symptoms of lidocaine toxicity occur when the serum level of the drug reaches 3 mcg/mL; moderate symptoms when the level exceeds 5 mcg/mL; and severe and potentially life threatening symptoms when the level exceeds 10 mcg/mL.

Study results indicated that across all time points, lidocaine levels were detectable (greater than 0.1 mcg/mL) in just five (25%) of the patients.

"Even in the worst-case scenario—the sixth and final time point, where you would expect the serum lidocaine level to be the highest because of the cumulated dosage to that point—only 5 of the 20 patients had a detectable serum lidocaine level," Dr. Alam remarked.

Furthermore, the median level for the cohort was undetectable at all time points.

"Assuming the vast majority of patients did absolutely fine, were there some patients who had very high levels and got into trouble? Again, the answer is no," Dr. Alam asserted.

Of all patients, the highest peak serum lidocaine level observed was 0.3 mcg/mL noted during the last three time points. "That is still one-tenth of the amount for even mild symptoms to occur," he pointed out.

When patients who did and did not have detectable serum lidocaine levels were compared, those with detectable levels had been injected with a significantly greater mean volume of lidocaine solution (30 vs. 9.5 mL). They were also significantly older (68.6 vs. 50.7 years) and somewhat more likely to be male, although Dr. Alam cautioned "this might just mean that older men have larger tumors."

A final analysis showed that peak serum lidocaine levels were well correlated with the total volume of solution injected.

Adverse events were reported by two patients—a 56-year-old man who reported a mild headache and a 42-year-old woman who reported feeling shaky. "Both were after the first Mohs stage, and so they were much more likely to be epinephrine effects than lidocaine effects, which would be expected to happen after a lot of lidocaine was injected," Dr. Alam observed. No adverse events related to the drug were noted.

"There was no case in which serious adverse events or even mild adverse events associated with lidocaine toxicity were seen, which suggests what we already knew to be true based on experience—that local anesthesia given during Mohs surgery appears to be safe," Dr. Alam concluded.

He reported having no conflicts of interest in association with the study.

No patient in the study experienced adverse events associated with lidocaine toxicity. DR. ALAM