Melanoma

MANCHESTER, ENGLAND – Men over the age of 60 years have the highest incidence of malignant melanoma, European data have highlighted.

In the Netherlands, almost 40% of men and 30% of women with newly diagnosed melanoma are over 60 years old, said Dr. Maryska Janssen-Heijnen of VieCuri Medical Centre in Venlo, the Netherlands.

"Future screening campaigns should focus on the elderly, and especially elderly men, because we have seen a very strong increase in incidence," she said at the annual meeting of the International Society of Geriatric Oncology.

A similar situation exists in England, with 30 years’ worth of data from the Office for National Statistics showing a greater proportion of melanoma being diagnosed in people over age 70.

"Older patients tend to present with worse prognostic features – ulceration, high mitotic rate, thicker melanomas, and head and neck distribution being more likely," said Dr. Alistair Ring of Brighton and Sussex Medical School, Brighton, England.

Dr. Ring presented data on all new cases of melanoma reported in England from 1971 to 2010. In 1971, there were 1,094 malignant melanoma registrations – 32% were in men. In 2009, there were 9,771 registrations – 48% were in men.

Looking at incidence by age, the number of registrations in men versus women in 1971 was lower: 33 vs. 64 cases at age 60-64 years, 23 vs. 59 cases at age 65-70, 30 vs. 43 at age 70-74, and 16 vs. 46 at age 75-79 years.

In 2009, however, the number of registrations was higher in men than in women at 60-64 years (637 vs. 592 cases), 65-69 years (580 vs. 460 cases), 70-74 years (562 vs. 429 cases), and 75-79 years (499 vs. 397).

The incidence of melanoma in Holland between 1989 and 2010 was stable for people aged 15-29 years, Dr. Janssen-Heijnen said, with women more likely to be diagnosed than men. The incidence of melanoma has increased among all patients under age 60, but the rate has increased to a greater extent in older patients, particularly in men.

Campaigns to make the public aware about the risk of sun exposure and skin cancer have perhaps helped to encourage screening and reduce melanoma rates in younger people, but the effect appears to have been minimal in the elderly, Dr. Janssen-Heijnen said.

Overall survival also is worse in older than in younger individuals. The poorer survival in elderly might be due to an increased proportion of nodular melanomas in older patients and the development of the disease without early signs and symptoms. Elderly patients also might be less attentive to skin changes and less likely than their younger counterparts to perform self-examinations, she suggested.

The Dutch study found thick (greater than 4 mm) melanomas in 20% of men and 8% of women over age 65 with melanoma. Thick lesions were noted in 16% of men and 5% of women under age 65 with melanoma.

Older patients are also more likely than younger patients to have comorbid conditions, said Dr. Janssen-Heijnen, with 70% of men and 70% of women aged 80 years or older having one or more comorbid conditions at diagnosis of melanoma, versus 28% of men and 23% of women aged 50–64 years.

Recently published data suggest that patients are more likely to die of comorbidity than of their melanoma (Aust. N. Z. J. Public Health 2012;36:441-5).

Dr. Ring also presented data on 454 patients newly diagnosed with melanoma at his institution between 2001 and 2006; almost half (48%) were aged 60 years or older.

"Older patients were more likely to present with more advanced disease," Dr. Ring said. Indeed, 22% of patients aged over 60 years, versus just 8.5% of patients younger than 60 years, were newly diagnosed with stage IIb or stage III disease (P less than .01).

Dr. Ring noted, however, that 67% of patients aged 60 years or older with stage IIb melanoma had no comorbidities (Charlson Comorbidity Index of 0).

"What is important about [these data] is that we’ve got a lot of [older] people with a high risk of recurrence with potentially a low risk of dying from other causes," he commented.

This has implications for enrollment into adjuvant therapy trials, as these patients may represent a population of patients with good potential to respond to recently available targeted agents.

Dr. Janssen-Heijnen and Dr. Ring had no financial disclosures relevant to their presentations.

MANCHESTER, ENGLAND – Men over the age of 60 years have the highest incidence of malignant melanoma, European data have highlighted.

In the Netherlands, almost 40% of men and 30% of women with newly diagnosed melanoma are over 60 years old, said Dr. Maryska Janssen-Heijnen of VieCuri Medical Centre in Venlo, the Netherlands.

"Future screening campaigns should focus on the elderly, and especially elderly men, because we have seen a very strong increase in incidence," she said at the annual meeting of the International Society of Geriatric Oncology.

A similar situation exists in England, with 30 years’ worth of data from the Office for National Statistics showing a greater proportion of melanoma being diagnosed in people over age 70.

"Older patients tend to present with worse prognostic features – ulceration, high mitotic rate, thicker melanomas, and head and neck distribution being more likely," said Dr. Alistair Ring of Brighton and Sussex Medical School, Brighton, England.

Dr. Ring presented data on all new cases of melanoma reported in England from 1971 to 2010. In 1971, there were 1,094 malignant melanoma registrations – 32% were in men. In 2009, there were 9,771 registrations – 48% were in men.

Looking at incidence by age, the number of registrations in men versus women in 1971 was lower: 33 vs. 64 cases at age 60-64 years, 23 vs. 59 cases at age 65-70, 30 vs. 43 at age 70-74, and 16 vs. 46 at age 75-79 years.

In 2009, however, the number of registrations was higher in men than in women at 60-64 years (637 vs. 592 cases), 65-69 years (580 vs. 460 cases), 70-74 years (562 vs. 429 cases), and 75-79 years (499 vs. 397).

The incidence of melanoma in Holland between 1989 and 2010 was stable for people aged 15-29 years, Dr. Janssen-Heijnen said, with women more likely to be diagnosed than men. The incidence of melanoma has increased among all patients under age 60, but the rate has increased to a greater extent in older patients, particularly in men.

Campaigns to make the public aware about the risk of sun exposure and skin cancer have perhaps helped to encourage screening and reduce melanoma rates in younger people, but the effect appears to have been minimal in the elderly, Dr. Janssen-Heijnen said.

Overall survival also is worse in older than in younger individuals. The poorer survival in elderly might be due to an increased proportion of nodular melanomas in older patients and the development of the disease without early signs and symptoms. Elderly patients also might be less attentive to skin changes and less likely than their younger counterparts to perform self-examinations, she suggested.

The Dutch study found thick (greater than 4 mm) melanomas in 20% of men and 8% of women over age 65 with melanoma. Thick lesions were noted in 16% of men and 5% of women under age 65 with melanoma.

Older patients are also more likely than younger patients to have comorbid conditions, said Dr. Janssen-Heijnen, with 70% of men and 70% of women aged 80 years or older having one or more comorbid conditions at diagnosis of melanoma, versus 28% of men and 23% of women aged 50–64 years.

Recently published data suggest that patients are more likely to die of comorbidity than of their melanoma (Aust. N. Z. J. Public Health 2012;36:441-5).

Dr. Ring also presented data on 454 patients newly diagnosed with melanoma at his institution between 2001 and 2006; almost half (48%) were aged 60 years or older.

"Older patients were more likely to present with more advanced disease," Dr. Ring said. Indeed, 22% of patients aged over 60 years, versus just 8.5% of patients younger than 60 years, were newly diagnosed with stage IIb or stage III disease (P less than .01).

Dr. Ring noted, however, that 67% of patients aged 60 years or older with stage IIb melanoma had no comorbidities (Charlson Comorbidity Index of 0).

"What is important about [these data] is that we’ve got a lot of [older] people with a high risk of recurrence with potentially a low risk of dying from other causes," he commented.

This has implications for enrollment into adjuvant therapy trials, as these patients may represent a population of patients with good potential to respond to recently available targeted agents.

Dr. Janssen-Heijnen and Dr. Ring had no financial disclosures relevant to their presentations.

MANCHESTER, ENGLAND – Men over the age of 60 years have the highest incidence of malignant melanoma, European data have highlighted.

In the Netherlands, almost 40% of men and 30% of women with newly diagnosed melanoma are over 60 years old, said Dr. Maryska Janssen-Heijnen of VieCuri Medical Centre in Venlo, the Netherlands.

"Future screening campaigns should focus on the elderly, and especially elderly men, because we have seen a very strong increase in incidence," she said at the annual meeting of the International Society of Geriatric Oncology.

A similar situation exists in England, with 30 years’ worth of data from the Office for National Statistics showing a greater proportion of melanoma being diagnosed in people over age 70.

"Older patients tend to present with worse prognostic features – ulceration, high mitotic rate, thicker melanomas, and head and neck distribution being more likely," said Dr. Alistair Ring of Brighton and Sussex Medical School, Brighton, England.

Dr. Ring presented data on all new cases of melanoma reported in England from 1971 to 2010. In 1971, there were 1,094 malignant melanoma registrations – 32% were in men. In 2009, there were 9,771 registrations – 48% were in men.

Looking at incidence by age, the number of registrations in men versus women in 1971 was lower: 33 vs. 64 cases at age 60-64 years, 23 vs. 59 cases at age 65-70, 30 vs. 43 at age 70-74, and 16 vs. 46 at age 75-79 years.

In 2009, however, the number of registrations was higher in men than in women at 60-64 years (637 vs. 592 cases), 65-69 years (580 vs. 460 cases), 70-74 years (562 vs. 429 cases), and 75-79 years (499 vs. 397).

The incidence of melanoma in Holland between 1989 and 2010 was stable for people aged 15-29 years, Dr. Janssen-Heijnen said, with women more likely to be diagnosed than men. The incidence of melanoma has increased among all patients under age 60, but the rate has increased to a greater extent in older patients, particularly in men.

Campaigns to make the public aware about the risk of sun exposure and skin cancer have perhaps helped to encourage screening and reduce melanoma rates in younger people, but the effect appears to have been minimal in the elderly, Dr. Janssen-Heijnen said.

Overall survival also is worse in older than in younger individuals. The poorer survival in elderly might be due to an increased proportion of nodular melanomas in older patients and the development of the disease without early signs and symptoms. Elderly patients also might be less attentive to skin changes and less likely than their younger counterparts to perform self-examinations, she suggested.

The Dutch study found thick (greater than 4 mm) melanomas in 20% of men and 8% of women over age 65 with melanoma. Thick lesions were noted in 16% of men and 5% of women under age 65 with melanoma.

Older patients are also more likely than younger patients to have comorbid conditions, said Dr. Janssen-Heijnen, with 70% of men and 70% of women aged 80 years or older having one or more comorbid conditions at diagnosis of melanoma, versus 28% of men and 23% of women aged 50–64 years.

Recently published data suggest that patients are more likely to die of comorbidity than of their melanoma (Aust. N. Z. J. Public Health 2012;36:441-5).

Dr. Ring also presented data on 454 patients newly diagnosed with melanoma at his institution between 2001 and 2006; almost half (48%) were aged 60 years or older.

"Older patients were more likely to present with more advanced disease," Dr. Ring said. Indeed, 22% of patients aged over 60 years, versus just 8.5% of patients younger than 60 years, were newly diagnosed with stage IIb or stage III disease (P less than .01).

Dr. Ring noted, however, that 67% of patients aged 60 years or older with stage IIb melanoma had no comorbidities (Charlson Comorbidity Index of 0).

"What is important about [these data] is that we’ve got a lot of [older] people with a high risk of recurrence with potentially a low risk of dying from other causes," he commented.

This has implications for enrollment into adjuvant therapy trials, as these patients may represent a population of patients with good potential to respond to recently available targeted agents.

Dr. Janssen-Heijnen and Dr. Ring had no financial disclosures relevant to their presentations.

Cancer deaths have declined 20% since 1991, which means there were 1.2 million fewer deaths from cancer in 2009, according to the American Cancer Society.

The overall cancer death rate decreased from 215 per 100,000 in 1991 to 173 per 100,000 in 2009. Death rates declined more sharply for cancers of the lung and prostate in men, for breast cancers in women, and for colon and rectal cancers for men and women. The ACS attributes the drops to decreases in smoking and improvements in early detection and treatment.

The most common causes of cancer death in Americans, accounting for 50% of cancer deaths, are cancers of the lung and bronchus, prostate, and colorectum in men; and cancers of the lung and bronchus, breast, and colorectum in women. This year, there will be 1.6 million cancer cases and 580,350 cancer deaths; lung cancers will account for 25% of cancer deaths in men and women this year, according to estimates from the ACS.

The mortality figures and incidence data are contained in two reports: Cancer Facts & Figures 2013 and Cancer Statistics 2013, both published in CA: A Cancer Journal for Clinicians. (doi:10.3322/caac.21166). The reports were published online on Jan. 18.

Incidence rates are on the decline for most cancers with the exception of melanoma, and liver, thyroid and pancreatic cancer.

Dr. Daniel M. Siegel, president of the American Academy of Dermatology, said in a statement that a rising incidence of melanoma "is particularly concerning because skin cancer can often be easily prevented and detected." Dr. Siegel said that the AAD and its members "are actively working to reduce the incidence of skin cancer and change society’s attitudes and behaviors toward sun exposure and tanning."

Death rates from pancreatic cancer have increased over the last decade, due to what the ACS called "a lack progress in primary prevention, early diagnosis, and treatment of this cancer." The ACS report included a special section devoted to updated information on the occurrence and treatment of pancreatic cancer. Most patients with pancreatic cancer die within a year of diagnosis; the 5-year survival rate is 6%.

The ACS also noted that the disparity in cancer outcomes based on ethnicity and income, "particularly [among] those diagnosed with colorectal or breast cancer where earlier detection and better treatments are credited for the improving trends," said John R. Seffrin, Ph.D., chief executive officer of the ACS, in a statement. "We can and must close this gap so that people are not punished for having the misfortune of being born poor and disadvantaged."

The 5-year survival rate in 2002-2008 for white women with breast cancer, for instance, was 92%, whereas for black women, it was 78%. For colon cancer, the 5-year survival rate was 66% for whites, but 55% for blacks.

[email protected]

On Twitter @aliciaault

Cancer deaths have declined 20% since 1991, which means there were 1.2 million fewer deaths from cancer in 2009, according to the American Cancer Society.

The overall cancer death rate decreased from 215 per 100,000 in 1991 to 173 per 100,000 in 2009. Death rates declined more sharply for cancers of the lung and prostate in men, for breast cancers in women, and for colon and rectal cancers for men and women. The ACS attributes the drops to decreases in smoking and improvements in early detection and treatment.

The most common causes of cancer death in Americans, accounting for 50% of cancer deaths, are cancers of the lung and bronchus, prostate, and colorectum in men; and cancers of the lung and bronchus, breast, and colorectum in women. This year, there will be 1.6 million cancer cases and 580,350 cancer deaths; lung cancers will account for 25% of cancer deaths in men and women this year, according to estimates from the ACS.

The mortality figures and incidence data are contained in two reports: Cancer Facts & Figures 2013 and Cancer Statistics 2013, both published in CA: A Cancer Journal for Clinicians. (doi:10.3322/caac.21166). The reports were published online on Jan. 18.

Incidence rates are on the decline for most cancers with the exception of melanoma, and liver, thyroid and pancreatic cancer.

Dr. Daniel M. Siegel, president of the American Academy of Dermatology, said in a statement that a rising incidence of melanoma "is particularly concerning because skin cancer can often be easily prevented and detected." Dr. Siegel said that the AAD and its members "are actively working to reduce the incidence of skin cancer and change society’s attitudes and behaviors toward sun exposure and tanning."

Death rates from pancreatic cancer have increased over the last decade, due to what the ACS called "a lack progress in primary prevention, early diagnosis, and treatment of this cancer." The ACS report included a special section devoted to updated information on the occurrence and treatment of pancreatic cancer. Most patients with pancreatic cancer die within a year of diagnosis; the 5-year survival rate is 6%.

The ACS also noted that the disparity in cancer outcomes based on ethnicity and income, "particularly [among] those diagnosed with colorectal or breast cancer where earlier detection and better treatments are credited for the improving trends," said John R. Seffrin, Ph.D., chief executive officer of the ACS, in a statement. "We can and must close this gap so that people are not punished for having the misfortune of being born poor and disadvantaged."

The 5-year survival rate in 2002-2008 for white women with breast cancer, for instance, was 92%, whereas for black women, it was 78%. For colon cancer, the 5-year survival rate was 66% for whites, but 55% for blacks.

[email protected]

On Twitter @aliciaault

Cancer deaths have declined 20% since 1991, which means there were 1.2 million fewer deaths from cancer in 2009, according to the American Cancer Society.

The overall cancer death rate decreased from 215 per 100,000 in 1991 to 173 per 100,000 in 2009. Death rates declined more sharply for cancers of the lung and prostate in men, for breast cancers in women, and for colon and rectal cancers for men and women. The ACS attributes the drops to decreases in smoking and improvements in early detection and treatment.

The most common causes of cancer death in Americans, accounting for 50% of cancer deaths, are cancers of the lung and bronchus, prostate, and colorectum in men; and cancers of the lung and bronchus, breast, and colorectum in women. This year, there will be 1.6 million cancer cases and 580,350 cancer deaths; lung cancers will account for 25% of cancer deaths in men and women this year, according to estimates from the ACS.

The mortality figures and incidence data are contained in two reports: Cancer Facts & Figures 2013 and Cancer Statistics 2013, both published in CA: A Cancer Journal for Clinicians. (doi:10.3322/caac.21166). The reports were published online on Jan. 18.

Incidence rates are on the decline for most cancers with the exception of melanoma, and liver, thyroid and pancreatic cancer.

Dr. Daniel M. Siegel, president of the American Academy of Dermatology, said in a statement that a rising incidence of melanoma "is particularly concerning because skin cancer can often be easily prevented and detected." Dr. Siegel said that the AAD and its members "are actively working to reduce the incidence of skin cancer and change society’s attitudes and behaviors toward sun exposure and tanning."

Death rates from pancreatic cancer have increased over the last decade, due to what the ACS called "a lack progress in primary prevention, early diagnosis, and treatment of this cancer." The ACS report included a special section devoted to updated information on the occurrence and treatment of pancreatic cancer. Most patients with pancreatic cancer die within a year of diagnosis; the 5-year survival rate is 6%.

The ACS also noted that the disparity in cancer outcomes based on ethnicity and income, "particularly [among] those diagnosed with colorectal or breast cancer where earlier detection and better treatments are credited for the improving trends," said John R. Seffrin, Ph.D., chief executive officer of the ACS, in a statement. "We can and must close this gap so that people are not punished for having the misfortune of being born poor and disadvantaged."

The 5-year survival rate in 2002-2008 for white women with breast cancer, for instance, was 92%, whereas for black women, it was 78%. For colon cancer, the 5-year survival rate was 66% for whites, but 55% for blacks.

[email protected]

On Twitter @aliciaault

Three out of four smartphone applications designed to assess melanoma risk misclassified at least 30% of melanomas as benign in a case-control diagnostic accuracy study.

Although these applications are intended for educational purposes rather than diagnostic purposes, they pose a potential risk to consumers, according to medical student Joel A. Wolf and his colleagues at the University of Pittsburgh.

"These applications are not subject to any sort of validation or regulatory oversight. Despite disclaimers that these applications are intended for educational purposes, they have the potential to harm users who may believe mistakenly that the evaluation given by such an application is a substitute for medical advice," the investigators wrote. The study was published online Jan. 16 in JAMA Dermatology.

The investigators used the four smartphone applications to evaluate digital images of pigmented cutaneous lesions, including 60 histologically confirmed melanomas and 128 benign control lesions. The applications deemed 85%-98% of the images evaluable.

Based only on the images considered evaluable, the overall sensitivity of the applications ranged from 7% to 98% and the overall specificity ranged from 30% to 94%. Positive predictive value ranged from 33% to 42% and negative predictive value ranged from 65% to 97%.

The highest sensitivity occurred with the only application that sent images to a board-certified dermatologist for analysis within 24 hours; the other three applications relied on automated algorithms for image analysis (JAMA Dermatol. 2013 Jan. 16 [doi:10.1001/jamadermatol.2013.3282]).

"Even the best of these three applications (that used automated algorithms) classified 18 of 60 melanomas (30%) in our study as benign," the investigators said.

The images used for this study were selected from a database of images captured routinely from patients before skin lesion removal. Only close-up images without identifiable features and without equivocal histology were used. The smartphone applications evaluated as part of the study were selected based on their ability to use existing images and on claims or suggestions of "an ability to assist users in determining whether a skin lesion may be malignant," Mr. Wolf and his associates said.

The applications were not identified because the purpose of the study was to determine the accuracy of such applications in general, rather than to make a statement about any particular application, the investigators noted.

Given the ubiquity of smartphone health care applications that are marketed to consumers (13,000 are available in the largest online application store alone, the investigators said), and given that the Food and Drug Administration has announced plans to regulate certain health-related smartphone applications, the findings underscore the need for physicians to be aware of the types of applications available to "aid us in protecting and educating our patients," the investigators noted.

These types of technologies have the potential to improve mortality from melanoma, but extreme care must be taken to prevent potential harm, they added.

"Despite disclaimers presented by each of these applications that they were designed for educational purposes rather than actual diagnosis and that they should not substitute for standard medical care, releasing a tool to the public requires some thought as to how it could be misused. This potential is of particular concern in times of economic hardship, when uninsured and even insured patients, deterred by the cost of copayments for medical visits, may turn to these applications as alternatives to physician evaluation," Mr. Wolf and his associates said.

This study was supported by grants from the National Institutes of Health. Study author Dr. Laura K. Ferris disclosed having served as an investigator and consultant for MELA Sciences Inc. The remaining authors had no disclosures to report.

Three out of four smartphone applications designed to assess melanoma risk misclassified at least 30% of melanomas as benign in a case-control diagnostic accuracy study.

Although these applications are intended for educational purposes rather than diagnostic purposes, they pose a potential risk to consumers, according to medical student Joel A. Wolf and his colleagues at the University of Pittsburgh.

"These applications are not subject to any sort of validation or regulatory oversight. Despite disclaimers that these applications are intended for educational purposes, they have the potential to harm users who may believe mistakenly that the evaluation given by such an application is a substitute for medical advice," the investigators wrote. The study was published online Jan. 16 in JAMA Dermatology.

The investigators used the four smartphone applications to evaluate digital images of pigmented cutaneous lesions, including 60 histologically confirmed melanomas and 128 benign control lesions. The applications deemed 85%-98% of the images evaluable.

Based only on the images considered evaluable, the overall sensitivity of the applications ranged from 7% to 98% and the overall specificity ranged from 30% to 94%. Positive predictive value ranged from 33% to 42% and negative predictive value ranged from 65% to 97%.

The highest sensitivity occurred with the only application that sent images to a board-certified dermatologist for analysis within 24 hours; the other three applications relied on automated algorithms for image analysis (JAMA Dermatol. 2013 Jan. 16 [doi:10.1001/jamadermatol.2013.3282]).

"Even the best of these three applications (that used automated algorithms) classified 18 of 60 melanomas (30%) in our study as benign," the investigators said.

The images used for this study were selected from a database of images captured routinely from patients before skin lesion removal. Only close-up images without identifiable features and without equivocal histology were used. The smartphone applications evaluated as part of the study were selected based on their ability to use existing images and on claims or suggestions of "an ability to assist users in determining whether a skin lesion may be malignant," Mr. Wolf and his associates said.

The applications were not identified because the purpose of the study was to determine the accuracy of such applications in general, rather than to make a statement about any particular application, the investigators noted.

Given the ubiquity of smartphone health care applications that are marketed to consumers (13,000 are available in the largest online application store alone, the investigators said), and given that the Food and Drug Administration has announced plans to regulate certain health-related smartphone applications, the findings underscore the need for physicians to be aware of the types of applications available to "aid us in protecting and educating our patients," the investigators noted.

These types of technologies have the potential to improve mortality from melanoma, but extreme care must be taken to prevent potential harm, they added.

"Despite disclaimers presented by each of these applications that they were designed for educational purposes rather than actual diagnosis and that they should not substitute for standard medical care, releasing a tool to the public requires some thought as to how it could be misused. This potential is of particular concern in times of economic hardship, when uninsured and even insured patients, deterred by the cost of copayments for medical visits, may turn to these applications as alternatives to physician evaluation," Mr. Wolf and his associates said.

This study was supported by grants from the National Institutes of Health. Study author Dr. Laura K. Ferris disclosed having served as an investigator and consultant for MELA Sciences Inc. The remaining authors had no disclosures to report.

Three out of four smartphone applications designed to assess melanoma risk misclassified at least 30% of melanomas as benign in a case-control diagnostic accuracy study.

Although these applications are intended for educational purposes rather than diagnostic purposes, they pose a potential risk to consumers, according to medical student Joel A. Wolf and his colleagues at the University of Pittsburgh.

"These applications are not subject to any sort of validation or regulatory oversight. Despite disclaimers that these applications are intended for educational purposes, they have the potential to harm users who may believe mistakenly that the evaluation given by such an application is a substitute for medical advice," the investigators wrote. The study was published online Jan. 16 in JAMA Dermatology.

The investigators used the four smartphone applications to evaluate digital images of pigmented cutaneous lesions, including 60 histologically confirmed melanomas and 128 benign control lesions. The applications deemed 85%-98% of the images evaluable.

Based only on the images considered evaluable, the overall sensitivity of the applications ranged from 7% to 98% and the overall specificity ranged from 30% to 94%. Positive predictive value ranged from 33% to 42% and negative predictive value ranged from 65% to 97%.

The highest sensitivity occurred with the only application that sent images to a board-certified dermatologist for analysis within 24 hours; the other three applications relied on automated algorithms for image analysis (JAMA Dermatol. 2013 Jan. 16 [doi:10.1001/jamadermatol.2013.3282]).

"Even the best of these three applications (that used automated algorithms) classified 18 of 60 melanomas (30%) in our study as benign," the investigators said.

The images used for this study were selected from a database of images captured routinely from patients before skin lesion removal. Only close-up images without identifiable features and without equivocal histology were used. The smartphone applications evaluated as part of the study were selected based on their ability to use existing images and on claims or suggestions of "an ability to assist users in determining whether a skin lesion may be malignant," Mr. Wolf and his associates said.

The applications were not identified because the purpose of the study was to determine the accuracy of such applications in general, rather than to make a statement about any particular application, the investigators noted.

Given the ubiquity of smartphone health care applications that are marketed to consumers (13,000 are available in the largest online application store alone, the investigators said), and given that the Food and Drug Administration has announced plans to regulate certain health-related smartphone applications, the findings underscore the need for physicians to be aware of the types of applications available to "aid us in protecting and educating our patients," the investigators noted.

These types of technologies have the potential to improve mortality from melanoma, but extreme care must be taken to prevent potential harm, they added.

"Despite disclaimers presented by each of these applications that they were designed for educational purposes rather than actual diagnosis and that they should not substitute for standard medical care, releasing a tool to the public requires some thought as to how it could be misused. This potential is of particular concern in times of economic hardship, when uninsured and even insured patients, deterred by the cost of copayments for medical visits, may turn to these applications as alternatives to physician evaluation," Mr. Wolf and his associates said.

This study was supported by grants from the National Institutes of Health. Study author Dr. Laura K. Ferris disclosed having served as an investigator and consultant for MELA Sciences Inc. The remaining authors had no disclosures to report.

Everolimus for tuberous sclerosis-associated tumors, BRCA testing in underserved women, and thoughts on cancer care site of service are the topics for the December 2012 Community Oncology podcast by Editor in Chief Dr. David Henry.

Everolimus for tuberous sclerosis-associated tumors, BRCA testing in underserved women, and thoughts on cancer care site of service are the topics for the December 2012 Community Oncology podcast by Editor in Chief Dr. David Henry.

Everolimus for tuberous sclerosis-associated tumors, BRCA testing in underserved women, and thoughts on cancer care site of service are the topics for the December 2012 Community Oncology podcast by Editor in Chief Dr. David Henry.

SAN DIEGO – Before he proceeds to close a wound following Mohs surgery, Dr. Howard Steinman employs the mnemonic CAT-STARTS to help him select the repair.

A modification of STARTS, Dr. Steinman uses CAT-STARTS to represent the following factors he considers prior to carrying out the repair: first assess the Cosmetic units, Areas of available skin, and Textures of available skin. Then consider closure options: Second intention and Simple (linear) repairs, Transposition flaps, Advancement flaps, Rotation flaps, Tissue interpolation flaps, and Skin grafts.

"Prior to closing, I draw in the surrounding cosmetic units of the face. Once you’ve done that, you should pay attention to the relaxed skin tension lines," Dr. Steinman said at a meeting sponsored by the American Society for Mohs Surgery.

Courtesy Dr. Howard Steinman

To illustrate, he showed attendees a digital image of a patient’s nasal lesion prior to repair. "I draw in the midline, the side of the nasal dorsum and nasal-jugal lines, and the alar fold," he explained. "Then I look at the skin texture. This case had a mix of sebaceous skin and smooth skin, so I factored that consideration in to my repair."

Candidate wounds for second-intention healing "are small, shallow wounds, usually less than 1 cm in diameter," said Dr. Steinman, who practices dermatology and Mohs surgery in Irving, Tex. "They’re usually less than a half centimeter deep. Second-intention healing is often especially effective for the alar fold and the medial canthus and less effective for the cheeks, chin, and around the lips."

If healing by second intention is not an option, "you want to consider your repair choices, from the simplest to the most complex," he said. Thus, consider simple (linear) repairs. Thereafter, his suggested order of complexity begins with transposition flaps, followed by advancement flaps, rotation flaps, tissue interpolation flaps, and skin grafts.

"The midline of the nose and the midline of the forehead are two of the best places to do linear repairs, as is the cheek and forehead," Dr. Steinman commented. "One thing to remember about straight line repairs is that they cause significant secondary motion perpendicular to the axis of closure. You need to respect that when doing linear repairs near free margins," he added.

If you unable to close a wound in a side-to-side fashion, "a transition flap may be your best option," he continued. "Because rotation flaps require longer, broad incisions, in my view you should often think about an advancement flap as your next choice after transposition flaps in terms of complexity."

Tissue interpolation flaps are reserved "for instances where no local skin flap is a better choice," he said. "The midline forehead flap is excellent for distal nasal defects because you have a broad area of skin and it’s based on a vascular pedicle. Interpolation flaps are two-stage procedures."

He views skin grafts to be a last choice for most wound repairs. "If you do them well and, when needed, laser or abrade them, they often look acceptable, but in my opinion they are the last option for many locations," he said.

Dr. Steinman said that he had no relevant financial conflicts to disclose.

SAN DIEGO – Before he proceeds to close a wound following Mohs surgery, Dr. Howard Steinman employs the mnemonic CAT-STARTS to help him select the repair.

A modification of STARTS, Dr. Steinman uses CAT-STARTS to represent the following factors he considers prior to carrying out the repair: first assess the Cosmetic units, Areas of available skin, and Textures of available skin. Then consider closure options: Second intention and Simple (linear) repairs, Transposition flaps, Advancement flaps, Rotation flaps, Tissue interpolation flaps, and Skin grafts.

"Prior to closing, I draw in the surrounding cosmetic units of the face. Once you’ve done that, you should pay attention to the relaxed skin tension lines," Dr. Steinman said at a meeting sponsored by the American Society for Mohs Surgery.

Courtesy Dr. Howard Steinman

To illustrate, he showed attendees a digital image of a patient’s nasal lesion prior to repair. "I draw in the midline, the side of the nasal dorsum and nasal-jugal lines, and the alar fold," he explained. "Then I look at the skin texture. This case had a mix of sebaceous skin and smooth skin, so I factored that consideration in to my repair."

Candidate wounds for second-intention healing "are small, shallow wounds, usually less than 1 cm in diameter," said Dr. Steinman, who practices dermatology and Mohs surgery in Irving, Tex. "They’re usually less than a half centimeter deep. Second-intention healing is often especially effective for the alar fold and the medial canthus and less effective for the cheeks, chin, and around the lips."

If healing by second intention is not an option, "you want to consider your repair choices, from the simplest to the most complex," he said. Thus, consider simple (linear) repairs. Thereafter, his suggested order of complexity begins with transposition flaps, followed by advancement flaps, rotation flaps, tissue interpolation flaps, and skin grafts.

"The midline of the nose and the midline of the forehead are two of the best places to do linear repairs, as is the cheek and forehead," Dr. Steinman commented. "One thing to remember about straight line repairs is that they cause significant secondary motion perpendicular to the axis of closure. You need to respect that when doing linear repairs near free margins," he added.

If you unable to close a wound in a side-to-side fashion, "a transition flap may be your best option," he continued. "Because rotation flaps require longer, broad incisions, in my view you should often think about an advancement flap as your next choice after transposition flaps in terms of complexity."

Tissue interpolation flaps are reserved "for instances where no local skin flap is a better choice," he said. "The midline forehead flap is excellent for distal nasal defects because you have a broad area of skin and it’s based on a vascular pedicle. Interpolation flaps are two-stage procedures."

He views skin grafts to be a last choice for most wound repairs. "If you do them well and, when needed, laser or abrade them, they often look acceptable, but in my opinion they are the last option for many locations," he said.

Dr. Steinman said that he had no relevant financial conflicts to disclose.

SAN DIEGO – Before he proceeds to close a wound following Mohs surgery, Dr. Howard Steinman employs the mnemonic CAT-STARTS to help him select the repair.

A modification of STARTS, Dr. Steinman uses CAT-STARTS to represent the following factors he considers prior to carrying out the repair: first assess the Cosmetic units, Areas of available skin, and Textures of available skin. Then consider closure options: Second intention and Simple (linear) repairs, Transposition flaps, Advancement flaps, Rotation flaps, Tissue interpolation flaps, and Skin grafts.

"Prior to closing, I draw in the surrounding cosmetic units of the face. Once you’ve done that, you should pay attention to the relaxed skin tension lines," Dr. Steinman said at a meeting sponsored by the American Society for Mohs Surgery.

Courtesy Dr. Howard Steinman

To illustrate, he showed attendees a digital image of a patient’s nasal lesion prior to repair. "I draw in the midline, the side of the nasal dorsum and nasal-jugal lines, and the alar fold," he explained. "Then I look at the skin texture. This case had a mix of sebaceous skin and smooth skin, so I factored that consideration in to my repair."

Candidate wounds for second-intention healing "are small, shallow wounds, usually less than 1 cm in diameter," said Dr. Steinman, who practices dermatology and Mohs surgery in Irving, Tex. "They’re usually less than a half centimeter deep. Second-intention healing is often especially effective for the alar fold and the medial canthus and less effective for the cheeks, chin, and around the lips."

If healing by second intention is not an option, "you want to consider your repair choices, from the simplest to the most complex," he said. Thus, consider simple (linear) repairs. Thereafter, his suggested order of complexity begins with transposition flaps, followed by advancement flaps, rotation flaps, tissue interpolation flaps, and skin grafts.

"The midline of the nose and the midline of the forehead are two of the best places to do linear repairs, as is the cheek and forehead," Dr. Steinman commented. "One thing to remember about straight line repairs is that they cause significant secondary motion perpendicular to the axis of closure. You need to respect that when doing linear repairs near free margins," he added.

If you unable to close a wound in a side-to-side fashion, "a transition flap may be your best option," he continued. "Because rotation flaps require longer, broad incisions, in my view you should often think about an advancement flap as your next choice after transposition flaps in terms of complexity."

Tissue interpolation flaps are reserved "for instances where no local skin flap is a better choice," he said. "The midline forehead flap is excellent for distal nasal defects because you have a broad area of skin and it’s based on a vascular pedicle. Interpolation flaps are two-stage procedures."

He views skin grafts to be a last choice for most wound repairs. "If you do them well and, when needed, laser or abrade them, they often look acceptable, but in my opinion they are the last option for many locations," he said.

Dr. Steinman said that he had no relevant financial conflicts to disclose.

To sustain the role of expert in cutaneous medicine, dermatologists and dermatopathologists must embrace the molecular advances in medicine, according to Dr. Pedram Gerami.

"For the vast majority of dermatologists and dermatopathologists trained in traditional clinical medicine, the sheer volume of newly identified gene mutations, chromosomal aberrations, and related molecular tests, even within a focused area of specialization, is truly overwhelming. As in many aspects of life, such rapid and transformative changes may be met with welcome or resistance," wrote Dr. Gerami, who was a guest editor of the December issue of Seminars in Cutaneous Medicine and Surgery, which focused on molecular medicine.

Rather than giving in to the common fear that new technological advancements may replace years of clinical training, it is important to recognize that these advances are meant to supplement – not replace – the clinical expertise of dermatologists and dermatopathologists (Sem. Cut. Med. Surg. 2012;31:203).

"The greatest threat to our practice is not the technologic advancement but rather loss of certain aspects of our practice to other specialties [that] better embrace the molecular revolution," he said, adding that active leadership with respect to integrating molecular medicine into the specialty will have a protective effect.

The first step is gaining a deeper understanding of these rapidly emerging advances. Among them are:

Diagnosis of Cutaneous Soft-Tissue Tumors

The identification of genetic abnormalities that characterize soft-tissue tumors has led to the development of diagnostic molecular testing, according to Dr. Alison L. Cheah and Dr. Steven D. Billings, both of the department of anatomic pathology at the Cleveland Clinic.

"Specific genetic signatures characterize a growing number of soft-tissue tumors that affect the skin. Molecular testing on FFPE [formalin-fixed paraffin-embedded tissue] complements histology and immunohistochemistry in the diagnosis of these tumors, especially in challenging cases with atypical morphology, nonspecific immunophenotype, and/or limited sampling," they wrote.

Molecular diagnostics also has implications for more accurate classification and prognostication of poorly understood entities (Sem. Cut. Med. Surg. 2012;31:221-33). "The identification of these disease-defining genetic signatures is the basis for the development of targeted therapies," they wrote.

Take dermatofibrosarcoma protuberans (DFSP), for example. "In practice, molecular testing in DFSP has utility both as a diagnostic aid in challenging cases and to guide therapy," they explained.

While most cases are easily diagnosed based on histopathologic features, significant diagnostic challenges can arise in certain cases, such as in CD34-negative tumors that are superficially sampled, or in tumors with varying histology or an unusual presentation.

For guiding treatment, molecular testing can be helpful for confirmation of COL1A1-PDGF-beta, which is vital if treatment with imatinib mesylate is being considered, because tumors lacking the fusion gene do not respond to this drug, they noted. Imatinib mesylate recently received Food and Drug Administration approval for the treatment of unresectable metastatic or recurrent DFSP.

Real-time polymerase chain reaction (RT-PCR) is the most studied test for detecting COL1A1-PDGF-beta and has a reported sensitivity between 74% and 96%. Though not as well studied, fluorescence in situ hybridization (FISH) assays also show promise.

"FISH assays using both PDGF-beta break-apart and COL1A1-PDGF-beta dual-color dual-fusion probe techniques have also been used," they wrote, noting that some reports show a greater sensitivity of FISH than RT-PCR for DFSP.

Molecular assays can also be helpful in confirming the diagnosis of angiomatoid fibrous histiocytoma (AFH).

In a study of 17 cases, FISH assays with dual-color break-apart probes had a sensitivity of 76% for identifying EWSR1 and FUS gene rearrangements, regardless of the translocation partner, they noted. FISH results should be interpreted with caution, though, because a negative result does not rule out the diagnosis of AFH, as rearrangements that are not detectable with the particular FISH probes used, or translocations with different chromosomes altogether, could explain a negative FISH result.

"Of note, EWSR1 rearrangements occur in several other soft tissue sarcomas, including Ewing sarcoma family of tumors, desmoplastic small round-cell tumors, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and a subset of myoepithelial tumors," they noted, adding that correlation with the histologic and immunohistochemical findings remains paramount.

RT-PCR is also a sensitive and specific assay for AFH, but its practical utility is limited by the multiple primers to account for the various fusion transcripts described in AFH.

Another area in which molecular testing plays an important role – albeit complementary– is in the diagnosis of low-grade fibromyxoid sarcoma (LGFMS), they reported. On the basis of RT-PCR results, for example, a significant number of cases previously diagnosed as LGMFS had to be reclassified.

RT-PCR assays performed on FFPE tissues had a sensitivity of 81%-88%, and FISH testing for FUS gene rearrangement is less sensitive at about 70%, but is nonetheless a good alternative to PCR, particularly in paraffin blocks with poor quality RNA.

These are just a few of the areas discussed by Dr. Cheah and Dr. Billings, with respect to molecular testing for cutaneous soft tissue tumors. Others addressed in their article were clear-cell sarcoma (melanoma of the soft parts), postradiation angiosarcoma, epithelioid hemangioendothelioma, and Ewing sarcoma family of tumors.

Knowledge and identification of the recurrent molecular aberrations in these cutaneous mesenchymal tumors allow for more accurate diagnosis and advancement of understanding about their underlying biology.

BRAF V600E Mutation Detection

The identification of BRAF mutations in the mitogen-activated protein kinase pathway revolutionized the treatment of advanced-stage melanoma, bringing selective small-molecule RAF inhibitors, such as vemurafenib, to the clinical trial stage. In the phase III BRIM-3 trial, vemurafenib was associated with a higher response rate and a significant improvement in survival, compared with dacarbazine.

"The knowledge that melanomas harbor recurring hot spot mutations in the BRAF gene has rapidly brought molecular testing to the clinical stage," wrote Dr. Jonathan L. Curry of the department of pathology at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

The cobas 4800 BRAF V600 Mutation Test from Roche, for example, was approved by the FDA as an in vitro diagnostic device to detect mutant BRAF V600E in DNA extracted from a FFPE patient’s sample of melanoma (Sem. Cut. Med. Surg. 2012;31:268-74). The presence of the mutation aids in selecting patients for treatment with vemurafenib.

The authors noted that a number of molecular platforms for BRAF testing have been developed and continue to evolve, offering a more thorough and complex analysis of the genetic components of melanoma.

"The next generation sequencing or massively parallel sequencing will allow sequencing of the entire exon or whole genome. Multiple sequencing molecular platforms are available to examine for BRAF mutations in cutaneous melanoma, and the best technological approach continues to be developed," they wrote.

Among those they described are:

• Sanger Sequencing. Sanger chain–termination sequencing of amplified DNA by PCR was the method used to sequence the human genome, and the Sanger method of sequencing led to the detection of BRAF mutations in cutaneous melanoma. Sensitivity is high (fewer than 5% of tumor cells are necessary in a given specimen), but use in the clinical setting is limited to BRAF testing. Although it remains the gold standard for gene sequencing, the Sanger method has technical and practical limitations. For example, it takes 18-19 hours to perform the test, other tests are more sensitive, and it cannot detect changes in the chromosomal copy number and the translocations.

• Pyrosequencing. Also known as sequencing by synthesis, pyrosequencing is among the platforms more sensitive than Sanger sequencing. The detection ratio of mutant BRAF V600E to wild type is 1:5 for Sanger sequencing, and 1:50 for pyrosequencing. Its clinical application is to detect the presence or absence of known mutations within a specific segment of DNA of a single nucleotide polymorphism.

"Because mutations in melanoma appear to cluster in the BRAF, NRAS, and KIT genes, this molecular platform has been readily incorporated into the mutational analysis of melanoma," the authors explained, noting that pyrosequencing is a rapid and sensitive test for detection of more common BRAF V600E mutations, as well as other variants. It is limited to the length of the DNA template sequenced, and is prone to errors reading through homopolymer sequences.

• Allele-Specific Real-Time PCR. This molecular platform, also known as the amplification-refractory mutation system, enriches known mutations in clinical samples to increase sensitivity of detection, and is particularly useful in FFPE biopsies with low tumor content. It is highly sensitive and is confined to known BRAF mutations that occur in melanomas, but demonstrates greater sensitivity in detecting BRAF V600E mutations in FFPE clinical samples.

• Mass Spectrometry–Based Sequencing (Sequenom). Sequenom uses mass spectrometry to determine the sequence of the FFPE tissue samples of melanoma. The platform allows for simultaneous amplification of multiple genetic hot spots, allowing for analysis of several known mutations in a single clinical sample. In the authors’ experience, it has slightly higher sensitivity than pyrosequencing.

• High Resolution Melting (HRM). Also a highly sensitive method for screening for mutations in clinical samples, high-resolution melting relies on PCR amplification of the DNA template and analysis of the temperature gradient in which the double strands of the PCR products are melted. The strands melt at different temperatures, depending on the sequence of the constituent bases, allowing for detection of the mutant allele in the FFPE tissue sample. An important limitation of this approach is that specific nucleotide alteration is not reported, thus tissues samples that are positive for mutations will require additional sequencing by another method to determine the specific nucleotide alteration.

• The 454 Pyrosequencing (Roche). This powerful platform, one of several next generation sequencing technologies that allows ultra deep sequencing of entire exons, was used to resolve mutation discrepancies between the cobas 4800 BRAF V600 test and the Sanger sequencing method during the vemurafenib trials, the authors noted. It has a mean error rate of only 1.07%, with more than half of the errors at sites of homopolymers, has the lengths of individual reads of DNA sequences of more than 500 base pairs, and can be performed in less than a day.

• Cobas 4800 BRAF V600 Mutation Test. The cobas 4800 BRAF V600 Mutation Test is based on the principles of allele-specific real time PCR, and targets a predefined 116-base pair sequence of the BRAF gene on exon 15. The device, which is intended to identify those with BRAF V600E who might benefit from therapy with vemurafenib, has a sensitivity for detecting BRAF V600E on FFPE samples of melanoma of more than 99%, and a specificity of 88%. The sensitivity appears comparable with the other platforms, including Sequenom and HRM.

Although the platform is not designed to screen for nonrecurrent genetic mutations in melanoma, BRAF V600E appears to account for the highest percentage of mutations in cutaneous melanomas, the authors said.

Cutaneous Lymphoma Analysis

In cutaneous lymphomas, molecular analysis serves to confirm the diagnosis in cases in which the clinical and/or pathologic presentations do not provide a diagnosis and to further characterize the nature of the lymphoma, according to Dr. Janyana M.D. Deonizio and Dr. Joan Guitart.

While the gold standard for diagnosis is a solid clinicopathologic correlation, molecular analysis provides for a more concrete diagnosis that helps both the patient in facing the diagnosis, and the clinician in proceeding with the most appropriate treatment plan (Sem. Cut. Med. Surg. 2012;31:234-40).

Specifically, through immunophenotyping and clonality analysis, molecular analysis helps discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and it subclassifies the tumor.

Methods for establishing T-cell clonality include Southern blot analysis (SBA) and PCR for detection of specific T-cell receptor gene arrangements (TCR-GR). SBA used to be the gold standard, but has been gradually replaced by PCR techniques which are less laborious and lengthy. PCR sensitivity for T-cell clonality detection ranges from 70% to 90%.

"Ideally, TCR clonality should be checked at the time of diagnosis in skin and blood. ... The detection of a dominant clone is important not only to confirm diagnosis but also for some prognostic guidance," they wrote, explaining that T-cell cloning is particularly helpful when early-stage mycosis fungoides is being considered in the differential diagnosis.

It does have limitations, however. False-positive monoclonal or oligoclonal bands may be identified in inflammatory dermatoses when T-cell infiltrates are sparse, resulting in "pseudomonoclonality," which is infrequently associated with a malignant T-cell process, they noted.

"Repeating the analysis using the same DNA template or fresh DNA extraction may solve the problem because in reactive conditions, the predominant PCR products typically vary in repeated PCR analyses of the same sample. In contrast, in neoplastic T-cell proliferations, dominant TCR clones are reproducible and should be routinely verified to confirm monoclonality," they noted.

Some studies suggest a correlation between TCR clonality by PCR and response to treatment; the absence of a detectable clone in cutaneous T-cell lymphoma (CTCL) has been associated with a higher rate of complete remission – although not necessarily with improved survival.

Immunophenotypic and immunogenotypic assays have been used to monitor the response of CTCL to therapy, define remission, and detect early relapse, thereby improving assessment of disease activity.

Flow cytometry analysis, for example, is "an efficient and sensitive method to detect and enumerate abnormal cells in the peripheral blood or any other cell suspension," they wrote. It can also be performed on leukocyte suspension from skin biopsies, and it provides prognostic information.

"Lower counts of circulating CD8+ lymphocytes and higher white cell counts in CTCL patients are associated with a less favorable prognosis," the authors noted.

FISH is used to detect major chromosomal gains or losses and specific translocations using a target-specific probe. Although FISH is not routinely used in the diagnosis of cutaneous lymphomas, it does appear to have potential future applications in various areas, according to recent publications.

Finally, genomic analysis by microarray-based comparative genomic hybridization is allowing quantification and appositional defining of chromosomal imbalances. While still confined to the research arena, this technology is providing some insight into the molecular pathogenesis of CTCL, the reported.

The advances in molecular diagnostics that are outlined in this series of articles are not limited to skin cancers and tumors. Additional articles, for example, addressed the role of genetic and molecular analysis in alopecia and in genodermatoses. Together they underscore the need for, and substantiate the ability of the specialty to take on leadership roles in molecular medicine, noted Dr. Gerami, of the department of dermatology at Northwestern University in Chicago.

"I am hopeful that they can assist other practicing dermatologists and dermatopathologists acquire a better foundation in molecular medicine, allowing them to sustain their primary roles in cutaneous medicine," Dr. Gerami concluded.

The authors reported having no conflicts of interest.

To sustain the role of expert in cutaneous medicine, dermatologists and dermatopathologists must embrace the molecular advances in medicine, according to Dr. Pedram Gerami.

"For the vast majority of dermatologists and dermatopathologists trained in traditional clinical medicine, the sheer volume of newly identified gene mutations, chromosomal aberrations, and related molecular tests, even within a focused area of specialization, is truly overwhelming. As in many aspects of life, such rapid and transformative changes may be met with welcome or resistance," wrote Dr. Gerami, who was a guest editor of the December issue of Seminars in Cutaneous Medicine and Surgery, which focused on molecular medicine.

Rather than giving in to the common fear that new technological advancements may replace years of clinical training, it is important to recognize that these advances are meant to supplement – not replace – the clinical expertise of dermatologists and dermatopathologists (Sem. Cut. Med. Surg. 2012;31:203).

"The greatest threat to our practice is not the technologic advancement but rather loss of certain aspects of our practice to other specialties [that] better embrace the molecular revolution," he said, adding that active leadership with respect to integrating molecular medicine into the specialty will have a protective effect.

The first step is gaining a deeper understanding of these rapidly emerging advances. Among them are:

Diagnosis of Cutaneous Soft-Tissue Tumors

The identification of genetic abnormalities that characterize soft-tissue tumors has led to the development of diagnostic molecular testing, according to Dr. Alison L. Cheah and Dr. Steven D. Billings, both of the department of anatomic pathology at the Cleveland Clinic.

"Specific genetic signatures characterize a growing number of soft-tissue tumors that affect the skin. Molecular testing on FFPE [formalin-fixed paraffin-embedded tissue] complements histology and immunohistochemistry in the diagnosis of these tumors, especially in challenging cases with atypical morphology, nonspecific immunophenotype, and/or limited sampling," they wrote.

Molecular diagnostics also has implications for more accurate classification and prognostication of poorly understood entities (Sem. Cut. Med. Surg. 2012;31:221-33). "The identification of these disease-defining genetic signatures is the basis for the development of targeted therapies," they wrote.

Take dermatofibrosarcoma protuberans (DFSP), for example. "In practice, molecular testing in DFSP has utility both as a diagnostic aid in challenging cases and to guide therapy," they explained.

While most cases are easily diagnosed based on histopathologic features, significant diagnostic challenges can arise in certain cases, such as in CD34-negative tumors that are superficially sampled, or in tumors with varying histology or an unusual presentation.

For guiding treatment, molecular testing can be helpful for confirmation of COL1A1-PDGF-beta, which is vital if treatment with imatinib mesylate is being considered, because tumors lacking the fusion gene do not respond to this drug, they noted. Imatinib mesylate recently received Food and Drug Administration approval for the treatment of unresectable metastatic or recurrent DFSP.

Real-time polymerase chain reaction (RT-PCR) is the most studied test for detecting COL1A1-PDGF-beta and has a reported sensitivity between 74% and 96%. Though not as well studied, fluorescence in situ hybridization (FISH) assays also show promise.

"FISH assays using both PDGF-beta break-apart and COL1A1-PDGF-beta dual-color dual-fusion probe techniques have also been used," they wrote, noting that some reports show a greater sensitivity of FISH than RT-PCR for DFSP.

Molecular assays can also be helpful in confirming the diagnosis of angiomatoid fibrous histiocytoma (AFH).

In a study of 17 cases, FISH assays with dual-color break-apart probes had a sensitivity of 76% for identifying EWSR1 and FUS gene rearrangements, regardless of the translocation partner, they noted. FISH results should be interpreted with caution, though, because a negative result does not rule out the diagnosis of AFH, as rearrangements that are not detectable with the particular FISH probes used, or translocations with different chromosomes altogether, could explain a negative FISH result.

"Of note, EWSR1 rearrangements occur in several other soft tissue sarcomas, including Ewing sarcoma family of tumors, desmoplastic small round-cell tumors, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and a subset of myoepithelial tumors," they noted, adding that correlation with the histologic and immunohistochemical findings remains paramount.

RT-PCR is also a sensitive and specific assay for AFH, but its practical utility is limited by the multiple primers to account for the various fusion transcripts described in AFH.

Another area in which molecular testing plays an important role – albeit complementary– is in the diagnosis of low-grade fibromyxoid sarcoma (LGFMS), they reported. On the basis of RT-PCR results, for example, a significant number of cases previously diagnosed as LGMFS had to be reclassified.

RT-PCR assays performed on FFPE tissues had a sensitivity of 81%-88%, and FISH testing for FUS gene rearrangement is less sensitive at about 70%, but is nonetheless a good alternative to PCR, particularly in paraffin blocks with poor quality RNA.

These are just a few of the areas discussed by Dr. Cheah and Dr. Billings, with respect to molecular testing for cutaneous soft tissue tumors. Others addressed in their article were clear-cell sarcoma (melanoma of the soft parts), postradiation angiosarcoma, epithelioid hemangioendothelioma, and Ewing sarcoma family of tumors.

Knowledge and identification of the recurrent molecular aberrations in these cutaneous mesenchymal tumors allow for more accurate diagnosis and advancement of understanding about their underlying biology.

BRAF V600E Mutation Detection

The identification of BRAF mutations in the mitogen-activated protein kinase pathway revolutionized the treatment of advanced-stage melanoma, bringing selective small-molecule RAF inhibitors, such as vemurafenib, to the clinical trial stage. In the phase III BRIM-3 trial, vemurafenib was associated with a higher response rate and a significant improvement in survival, compared with dacarbazine.

"The knowledge that melanomas harbor recurring hot spot mutations in the BRAF gene has rapidly brought molecular testing to the clinical stage," wrote Dr. Jonathan L. Curry of the department of pathology at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

The cobas 4800 BRAF V600 Mutation Test from Roche, for example, was approved by the FDA as an in vitro diagnostic device to detect mutant BRAF V600E in DNA extracted from a FFPE patient’s sample of melanoma (Sem. Cut. Med. Surg. 2012;31:268-74). The presence of the mutation aids in selecting patients for treatment with vemurafenib.

The authors noted that a number of molecular platforms for BRAF testing have been developed and continue to evolve, offering a more thorough and complex analysis of the genetic components of melanoma.

"The next generation sequencing or massively parallel sequencing will allow sequencing of the entire exon or whole genome. Multiple sequencing molecular platforms are available to examine for BRAF mutations in cutaneous melanoma, and the best technological approach continues to be developed," they wrote.

Among those they described are:

• Sanger Sequencing. Sanger chain–termination sequencing of amplified DNA by PCR was the method used to sequence the human genome, and the Sanger method of sequencing led to the detection of BRAF mutations in cutaneous melanoma. Sensitivity is high (fewer than 5% of tumor cells are necessary in a given specimen), but use in the clinical setting is limited to BRAF testing. Although it remains the gold standard for gene sequencing, the Sanger method has technical and practical limitations. For example, it takes 18-19 hours to perform the test, other tests are more sensitive, and it cannot detect changes in the chromosomal copy number and the translocations.

• Pyrosequencing. Also known as sequencing by synthesis, pyrosequencing is among the platforms more sensitive than Sanger sequencing. The detection ratio of mutant BRAF V600E to wild type is 1:5 for Sanger sequencing, and 1:50 for pyrosequencing. Its clinical application is to detect the presence or absence of known mutations within a specific segment of DNA of a single nucleotide polymorphism.

"Because mutations in melanoma appear to cluster in the BRAF, NRAS, and KIT genes, this molecular platform has been readily incorporated into the mutational analysis of melanoma," the authors explained, noting that pyrosequencing is a rapid and sensitive test for detection of more common BRAF V600E mutations, as well as other variants. It is limited to the length of the DNA template sequenced, and is prone to errors reading through homopolymer sequences.

• Allele-Specific Real-Time PCR. This molecular platform, also known as the amplification-refractory mutation system, enriches known mutations in clinical samples to increase sensitivity of detection, and is particularly useful in FFPE biopsies with low tumor content. It is highly sensitive and is confined to known BRAF mutations that occur in melanomas, but demonstrates greater sensitivity in detecting BRAF V600E mutations in FFPE clinical samples.

• Mass Spectrometry–Based Sequencing (Sequenom). Sequenom uses mass spectrometry to determine the sequence of the FFPE tissue samples of melanoma. The platform allows for simultaneous amplification of multiple genetic hot spots, allowing for analysis of several known mutations in a single clinical sample. In the authors’ experience, it has slightly higher sensitivity than pyrosequencing.

• High Resolution Melting (HRM). Also a highly sensitive method for screening for mutations in clinical samples, high-resolution melting relies on PCR amplification of the DNA template and analysis of the temperature gradient in which the double strands of the PCR products are melted. The strands melt at different temperatures, depending on the sequence of the constituent bases, allowing for detection of the mutant allele in the FFPE tissue sample. An important limitation of this approach is that specific nucleotide alteration is not reported, thus tissues samples that are positive for mutations will require additional sequencing by another method to determine the specific nucleotide alteration.

• The 454 Pyrosequencing (Roche). This powerful platform, one of several next generation sequencing technologies that allows ultra deep sequencing of entire exons, was used to resolve mutation discrepancies between the cobas 4800 BRAF V600 test and the Sanger sequencing method during the vemurafenib trials, the authors noted. It has a mean error rate of only 1.07%, with more than half of the errors at sites of homopolymers, has the lengths of individual reads of DNA sequences of more than 500 base pairs, and can be performed in less than a day.

• Cobas 4800 BRAF V600 Mutation Test. The cobas 4800 BRAF V600 Mutation Test is based on the principles of allele-specific real time PCR, and targets a predefined 116-base pair sequence of the BRAF gene on exon 15. The device, which is intended to identify those with BRAF V600E who might benefit from therapy with vemurafenib, has a sensitivity for detecting BRAF V600E on FFPE samples of melanoma of more than 99%, and a specificity of 88%. The sensitivity appears comparable with the other platforms, including Sequenom and HRM.

Although the platform is not designed to screen for nonrecurrent genetic mutations in melanoma, BRAF V600E appears to account for the highest percentage of mutations in cutaneous melanomas, the authors said.

Cutaneous Lymphoma Analysis

In cutaneous lymphomas, molecular analysis serves to confirm the diagnosis in cases in which the clinical and/or pathologic presentations do not provide a diagnosis and to further characterize the nature of the lymphoma, according to Dr. Janyana M.D. Deonizio and Dr. Joan Guitart.

While the gold standard for diagnosis is a solid clinicopathologic correlation, molecular analysis provides for a more concrete diagnosis that helps both the patient in facing the diagnosis, and the clinician in proceeding with the most appropriate treatment plan (Sem. Cut. Med. Surg. 2012;31:234-40).

Specifically, through immunophenotyping and clonality analysis, molecular analysis helps discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and it subclassifies the tumor.

Methods for establishing T-cell clonality include Southern blot analysis (SBA) and PCR for detection of specific T-cell receptor gene arrangements (TCR-GR). SBA used to be the gold standard, but has been gradually replaced by PCR techniques which are less laborious and lengthy. PCR sensitivity for T-cell clonality detection ranges from 70% to 90%.

"Ideally, TCR clonality should be checked at the time of diagnosis in skin and blood. ... The detection of a dominant clone is important not only to confirm diagnosis but also for some prognostic guidance," they wrote, explaining that T-cell cloning is particularly helpful when early-stage mycosis fungoides is being considered in the differential diagnosis.

It does have limitations, however. False-positive monoclonal or oligoclonal bands may be identified in inflammatory dermatoses when T-cell infiltrates are sparse, resulting in "pseudomonoclonality," which is infrequently associated with a malignant T-cell process, they noted.

"Repeating the analysis using the same DNA template or fresh DNA extraction may solve the problem because in reactive conditions, the predominant PCR products typically vary in repeated PCR analyses of the same sample. In contrast, in neoplastic T-cell proliferations, dominant TCR clones are reproducible and should be routinely verified to confirm monoclonality," they noted.

Some studies suggest a correlation between TCR clonality by PCR and response to treatment; the absence of a detectable clone in cutaneous T-cell lymphoma (CTCL) has been associated with a higher rate of complete remission – although not necessarily with improved survival.

Immunophenotypic and immunogenotypic assays have been used to monitor the response of CTCL to therapy, define remission, and detect early relapse, thereby improving assessment of disease activity.

Flow cytometry analysis, for example, is "an efficient and sensitive method to detect and enumerate abnormal cells in the peripheral blood or any other cell suspension," they wrote. It can also be performed on leukocyte suspension from skin biopsies, and it provides prognostic information.

"Lower counts of circulating CD8+ lymphocytes and higher white cell counts in CTCL patients are associated with a less favorable prognosis," the authors noted.

FISH is used to detect major chromosomal gains or losses and specific translocations using a target-specific probe. Although FISH is not routinely used in the diagnosis of cutaneous lymphomas, it does appear to have potential future applications in various areas, according to recent publications.

Finally, genomic analysis by microarray-based comparative genomic hybridization is allowing quantification and appositional defining of chromosomal imbalances. While still confined to the research arena, this technology is providing some insight into the molecular pathogenesis of CTCL, the reported.

The advances in molecular diagnostics that are outlined in this series of articles are not limited to skin cancers and tumors. Additional articles, for example, addressed the role of genetic and molecular analysis in alopecia and in genodermatoses. Together they underscore the need for, and substantiate the ability of the specialty to take on leadership roles in molecular medicine, noted Dr. Gerami, of the department of dermatology at Northwestern University in Chicago.

"I am hopeful that they can assist other practicing dermatologists and dermatopathologists acquire a better foundation in molecular medicine, allowing them to sustain their primary roles in cutaneous medicine," Dr. Gerami concluded.

The authors reported having no conflicts of interest.

To sustain the role of expert in cutaneous medicine, dermatologists and dermatopathologists must embrace the molecular advances in medicine, according to Dr. Pedram Gerami.

"For the vast majority of dermatologists and dermatopathologists trained in traditional clinical medicine, the sheer volume of newly identified gene mutations, chromosomal aberrations, and related molecular tests, even within a focused area of specialization, is truly overwhelming. As in many aspects of life, such rapid and transformative changes may be met with welcome or resistance," wrote Dr. Gerami, who was a guest editor of the December issue of Seminars in Cutaneous Medicine and Surgery, which focused on molecular medicine.

Rather than giving in to the common fear that new technological advancements may replace years of clinical training, it is important to recognize that these advances are meant to supplement – not replace – the clinical expertise of dermatologists and dermatopathologists (Sem. Cut. Med. Surg. 2012;31:203).

"The greatest threat to our practice is not the technologic advancement but rather loss of certain aspects of our practice to other specialties [that] better embrace the molecular revolution," he said, adding that active leadership with respect to integrating molecular medicine into the specialty will have a protective effect.

The first step is gaining a deeper understanding of these rapidly emerging advances. Among them are:

Diagnosis of Cutaneous Soft-Tissue Tumors

The identification of genetic abnormalities that characterize soft-tissue tumors has led to the development of diagnostic molecular testing, according to Dr. Alison L. Cheah and Dr. Steven D. Billings, both of the department of anatomic pathology at the Cleveland Clinic.

"Specific genetic signatures characterize a growing number of soft-tissue tumors that affect the skin. Molecular testing on FFPE [formalin-fixed paraffin-embedded tissue] complements histology and immunohistochemistry in the diagnosis of these tumors, especially in challenging cases with atypical morphology, nonspecific immunophenotype, and/or limited sampling," they wrote.

Molecular diagnostics also has implications for more accurate classification and prognostication of poorly understood entities (Sem. Cut. Med. Surg. 2012;31:221-33). "The identification of these disease-defining genetic signatures is the basis for the development of targeted therapies," they wrote.

Take dermatofibrosarcoma protuberans (DFSP), for example. "In practice, molecular testing in DFSP has utility both as a diagnostic aid in challenging cases and to guide therapy," they explained.

While most cases are easily diagnosed based on histopathologic features, significant diagnostic challenges can arise in certain cases, such as in CD34-negative tumors that are superficially sampled, or in tumors with varying histology or an unusual presentation.

For guiding treatment, molecular testing can be helpful for confirmation of COL1A1-PDGF-beta, which is vital if treatment with imatinib mesylate is being considered, because tumors lacking the fusion gene do not respond to this drug, they noted. Imatinib mesylate recently received Food and Drug Administration approval for the treatment of unresectable metastatic or recurrent DFSP.

Real-time polymerase chain reaction (RT-PCR) is the most studied test for detecting COL1A1-PDGF-beta and has a reported sensitivity between 74% and 96%. Though not as well studied, fluorescence in situ hybridization (FISH) assays also show promise.

"FISH assays using both PDGF-beta break-apart and COL1A1-PDGF-beta dual-color dual-fusion probe techniques have also been used," they wrote, noting that some reports show a greater sensitivity of FISH than RT-PCR for DFSP.

Molecular assays can also be helpful in confirming the diagnosis of angiomatoid fibrous histiocytoma (AFH).

In a study of 17 cases, FISH assays with dual-color break-apart probes had a sensitivity of 76% for identifying EWSR1 and FUS gene rearrangements, regardless of the translocation partner, they noted. FISH results should be interpreted with caution, though, because a negative result does not rule out the diagnosis of AFH, as rearrangements that are not detectable with the particular FISH probes used, or translocations with different chromosomes altogether, could explain a negative FISH result.

"Of note, EWSR1 rearrangements occur in several other soft tissue sarcomas, including Ewing sarcoma family of tumors, desmoplastic small round-cell tumors, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and a subset of myoepithelial tumors," they noted, adding that correlation with the histologic and immunohistochemical findings remains paramount.

RT-PCR is also a sensitive and specific assay for AFH, but its practical utility is limited by the multiple primers to account for the various fusion transcripts described in AFH.

Another area in which molecular testing plays an important role – albeit complementary– is in the diagnosis of low-grade fibromyxoid sarcoma (LGFMS), they reported. On the basis of RT-PCR results, for example, a significant number of cases previously diagnosed as LGMFS had to be reclassified.

RT-PCR assays performed on FFPE tissues had a sensitivity of 81%-88%, and FISH testing for FUS gene rearrangement is less sensitive at about 70%, but is nonetheless a good alternative to PCR, particularly in paraffin blocks with poor quality RNA.

These are just a few of the areas discussed by Dr. Cheah and Dr. Billings, with respect to molecular testing for cutaneous soft tissue tumors. Others addressed in their article were clear-cell sarcoma (melanoma of the soft parts), postradiation angiosarcoma, epithelioid hemangioendothelioma, and Ewing sarcoma family of tumors.

Knowledge and identification of the recurrent molecular aberrations in these cutaneous mesenchymal tumors allow for more accurate diagnosis and advancement of understanding about their underlying biology.

BRAF V600E Mutation Detection

The identification of BRAF mutations in the mitogen-activated protein kinase pathway revolutionized the treatment of advanced-stage melanoma, bringing selective small-molecule RAF inhibitors, such as vemurafenib, to the clinical trial stage. In the phase III BRIM-3 trial, vemurafenib was associated with a higher response rate and a significant improvement in survival, compared with dacarbazine.

"The knowledge that melanomas harbor recurring hot spot mutations in the BRAF gene has rapidly brought molecular testing to the clinical stage," wrote Dr. Jonathan L. Curry of the department of pathology at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

The cobas 4800 BRAF V600 Mutation Test from Roche, for example, was approved by the FDA as an in vitro diagnostic device to detect mutant BRAF V600E in DNA extracted from a FFPE patient’s sample of melanoma (Sem. Cut. Med. Surg. 2012;31:268-74). The presence of the mutation aids in selecting patients for treatment with vemurafenib.

The authors noted that a number of molecular platforms for BRAF testing have been developed and continue to evolve, offering a more thorough and complex analysis of the genetic components of melanoma.

"The next generation sequencing or massively parallel sequencing will allow sequencing of the entire exon or whole genome. Multiple sequencing molecular platforms are available to examine for BRAF mutations in cutaneous melanoma, and the best technological approach continues to be developed," they wrote.

Among those they described are:

• Sanger Sequencing. Sanger chain–termination sequencing of amplified DNA by PCR was the method used to sequence the human genome, and the Sanger method of sequencing led to the detection of BRAF mutations in cutaneous melanoma. Sensitivity is high (fewer than 5% of tumor cells are necessary in a given specimen), but use in the clinical setting is limited to BRAF testing. Although it remains the gold standard for gene sequencing, the Sanger method has technical and practical limitations. For example, it takes 18-19 hours to perform the test, other tests are more sensitive, and it cannot detect changes in the chromosomal copy number and the translocations.

• Pyrosequencing. Also known as sequencing by synthesis, pyrosequencing is among the platforms more sensitive than Sanger sequencing. The detection ratio of mutant BRAF V600E to wild type is 1:5 for Sanger sequencing, and 1:50 for pyrosequencing. Its clinical application is to detect the presence or absence of known mutations within a specific segment of DNA of a single nucleotide polymorphism.

"Because mutations in melanoma appear to cluster in the BRAF, NRAS, and KIT genes, this molecular platform has been readily incorporated into the mutational analysis of melanoma," the authors explained, noting that pyrosequencing is a rapid and sensitive test for detection of more common BRAF V600E mutations, as well as other variants. It is limited to the length of the DNA template sequenced, and is prone to errors reading through homopolymer sequences.

• Allele-Specific Real-Time PCR. This molecular platform, also known as the amplification-refractory mutation system, enriches known mutations in clinical samples to increase sensitivity of detection, and is particularly useful in FFPE biopsies with low tumor content. It is highly sensitive and is confined to known BRAF mutations that occur in melanomas, but demonstrates greater sensitivity in detecting BRAF V600E mutations in FFPE clinical samples.

• Mass Spectrometry–Based Sequencing (Sequenom). Sequenom uses mass spectrometry to determine the sequence of the FFPE tissue samples of melanoma. The platform allows for simultaneous amplification of multiple genetic hot spots, allowing for analysis of several known mutations in a single clinical sample. In the authors’ experience, it has slightly higher sensitivity than pyrosequencing.

• High Resolution Melting (HRM). Also a highly sensitive method for screening for mutations in clinical samples, high-resolution melting relies on PCR amplification of the DNA template and analysis of the temperature gradient in which the double strands of the PCR products are melted. The strands melt at different temperatures, depending on the sequence of the constituent bases, allowing for detection of the mutant allele in the FFPE tissue sample. An important limitation of this approach is that specific nucleotide alteration is not reported, thus tissues samples that are positive for mutations will require additional sequencing by another method to determine the specific nucleotide alteration.

• The 454 Pyrosequencing (Roche). This powerful platform, one of several next generation sequencing technologies that allows ultra deep sequencing of entire exons, was used to resolve mutation discrepancies between the cobas 4800 BRAF V600 test and the Sanger sequencing method during the vemurafenib trials, the authors noted. It has a mean error rate of only 1.07%, with more than half of the errors at sites of homopolymers, has the lengths of individual reads of DNA sequences of more than 500 base pairs, and can be performed in less than a day.

• Cobas 4800 BRAF V600 Mutation Test. The cobas 4800 BRAF V600 Mutation Test is based on the principles of allele-specific real time PCR, and targets a predefined 116-base pair sequence of the BRAF gene on exon 15. The device, which is intended to identify those with BRAF V600E who might benefit from therapy with vemurafenib, has a sensitivity for detecting BRAF V600E on FFPE samples of melanoma of more than 99%, and a specificity of 88%. The sensitivity appears comparable with the other platforms, including Sequenom and HRM.

Although the platform is not designed to screen for nonrecurrent genetic mutations in melanoma, BRAF V600E appears to account for the highest percentage of mutations in cutaneous melanomas, the authors said.

Cutaneous Lymphoma Analysis

In cutaneous lymphomas, molecular analysis serves to confirm the diagnosis in cases in which the clinical and/or pathologic presentations do not provide a diagnosis and to further characterize the nature of the lymphoma, according to Dr. Janyana M.D. Deonizio and Dr. Joan Guitart.

While the gold standard for diagnosis is a solid clinicopathologic correlation, molecular analysis provides for a more concrete diagnosis that helps both the patient in facing the diagnosis, and the clinician in proceeding with the most appropriate treatment plan (Sem. Cut. Med. Surg. 2012;31:234-40).

Specifically, through immunophenotyping and clonality analysis, molecular analysis helps discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and it subclassifies the tumor.

Methods for establishing T-cell clonality include Southern blot analysis (SBA) and PCR for detection of specific T-cell receptor gene arrangements (TCR-GR). SBA used to be the gold standard, but has been gradually replaced by PCR techniques which are less laborious and lengthy. PCR sensitivity for T-cell clonality detection ranges from 70% to 90%.

"Ideally, TCR clonality should be checked at the time of diagnosis in skin and blood. ... The detection of a dominant clone is important not only to confirm diagnosis but also for some prognostic guidance," they wrote, explaining that T-cell cloning is particularly helpful when early-stage mycosis fungoides is being considered in the differential diagnosis.

It does have limitations, however. False-positive monoclonal or oligoclonal bands may be identified in inflammatory dermatoses when T-cell infiltrates are sparse, resulting in "pseudomonoclonality," which is infrequently associated with a malignant T-cell process, they noted.

"Repeating the analysis using the same DNA template or fresh DNA extraction may solve the problem because in reactive conditions, the predominant PCR products typically vary in repeated PCR analyses of the same sample. In contrast, in neoplastic T-cell proliferations, dominant TCR clones are reproducible and should be routinely verified to confirm monoclonality," they noted.

Some studies suggest a correlation between TCR clonality by PCR and response to treatment; the absence of a detectable clone in cutaneous T-cell lymphoma (CTCL) has been associated with a higher rate of complete remission – although not necessarily with improved survival.

Immunophenotypic and immunogenotypic assays have been used to monitor the response of CTCL to therapy, define remission, and detect early relapse, thereby improving assessment of disease activity.

Flow cytometry analysis, for example, is "an efficient and sensitive method to detect and enumerate abnormal cells in the peripheral blood or any other cell suspension," they wrote. It can also be performed on leukocyte suspension from skin biopsies, and it provides prognostic information.

"Lower counts of circulating CD8+ lymphocytes and higher white cell counts in CTCL patients are associated with a less favorable prognosis," the authors noted.

FISH is used to detect major chromosomal gains or losses and specific translocations using a target-specific probe. Although FISH is not routinely used in the diagnosis of cutaneous lymphomas, it does appear to have potential future applications in various areas, according to recent publications.

Finally, genomic analysis by microarray-based comparative genomic hybridization is allowing quantification and appositional defining of chromosomal imbalances. While still confined to the research arena, this technology is providing some insight into the molecular pathogenesis of CTCL, the reported.

The advances in molecular diagnostics that are outlined in this series of articles are not limited to skin cancers and tumors. Additional articles, for example, addressed the role of genetic and molecular analysis in alopecia and in genodermatoses. Together they underscore the need for, and substantiate the ability of the specialty to take on leadership roles in molecular medicine, noted Dr. Gerami, of the department of dermatology at Northwestern University in Chicago.

"I am hopeful that they can assist other practicing dermatologists and dermatopathologists acquire a better foundation in molecular medicine, allowing them to sustain their primary roles in cutaneous medicine," Dr. Gerami concluded.

The authors reported having no conflicts of interest.

Vasiliki Nikolaou, MD, Alexander J. Stratigos, MD, and Hensin Tsao, MD, PhD

Cutaneous basal and squamous cell carcinomas are among the most frequent malignancies in the white population, with the annual incidence estimates ranging from 1 million to 3.5 million cases in the United States. These tumors can occur either sporadically or in the context of hereditary genodermatoses with cancer predisposition, such as basal cell nevus syndrome, xeroderma pigmentosum, epidermolysis bullosa, or oculocutaneous albinism. Different genes and signaling pathways have been shown to play a central role in the development and growth of these tumors. This article overviews the clinical features, diagnostic criteria, and the most recent data on genetic routes of the major hereditary syndromes predisposed to the development of nonmelanoma skin cancer.

*For a PDF of the full article, click on the link to the left of this introduction.

Vasiliki Nikolaou, MD, Alexander J. Stratigos, MD, and Hensin Tsao, MD, PhD

Cutaneous basal and squamous cell carcinomas are among the most frequent malignancies in the white population, with the annual incidence estimates ranging from 1 million to 3.5 million cases in the United States. These tumors can occur either sporadically or in the context of hereditary genodermatoses with cancer predisposition, such as basal cell nevus syndrome, xeroderma pigmentosum, epidermolysis bullosa, or oculocutaneous albinism. Different genes and signaling pathways have been shown to play a central role in the development and growth of these tumors. This article overviews the clinical features, diagnostic criteria, and the most recent data on genetic routes of the major hereditary syndromes predisposed to the development of nonmelanoma skin cancer.

*For a PDF of the full article, click on the link to the left of this introduction.

Vasiliki Nikolaou, MD, Alexander J. Stratigos, MD, and Hensin Tsao, MD, PhD

Cutaneous basal and squamous cell carcinomas are among the most frequent malignancies in the white population, with the annual incidence estimates ranging from 1 million to 3.5 million cases in the United States. These tumors can occur either sporadically or in the context of hereditary genodermatoses with cancer predisposition, such as basal cell nevus syndrome, xeroderma pigmentosum, epidermolysis bullosa, or oculocutaneous albinism. Different genes and signaling pathways have been shown to play a central role in the development and growth of these tumors. This article overviews the clinical features, diagnostic criteria, and the most recent data on genetic routes of the major hereditary syndromes predisposed to the development of nonmelanoma skin cancer.

*For a PDF of the full article, click on the link to the left of this introduction.

Alison L. Cheah, MBBS, and Steven D. Billings, MD

A number of soft tissue tumors are characterized by recurring genetic abnormalities. The identification of these abnormalities has advanced our understanding of the biology of these tumors and has led to the development of molecular tests that are helpful diagnostically. This review will focus on the application of molecular diagnostic testing in select mesenchymal tumors of the dermis and subcutis.

*For a PDF of the full article, click on the link to the left of this introduction.

Alison L. Cheah, MBBS, and Steven D. Billings, MD

A number of soft tissue tumors are characterized by recurring genetic abnormalities. The identification of these abnormalities has advanced our understanding of the biology of these tumors and has led to the development of molecular tests that are helpful diagnostically. This review will focus on the application of molecular diagnostic testing in select mesenchymal tumors of the dermis and subcutis.

*For a PDF of the full article, click on the link to the left of this introduction.

Alison L. Cheah, MBBS, and Steven D. Billings, MD

A number of soft tissue tumors are characterized by recurring genetic abnormalities. The identification of these abnormalities has advanced our understanding of the biology of these tumors and has led to the development of molecular tests that are helpful diagnostically. This review will focus on the application of molecular diagnostic testing in select mesenchymal tumors of the dermis and subcutis.

*For a PDF of the full article, click on the link to the left of this introduction.