AAD Unveils Updated Melanoma Treatment Guidelines

In patients diagnosed with invasive primary cutaneous melanoma, a detailed patient history is crucial, and a thorough examination of the skin and lymph nodes should be performed to help determine the extent of clinical spread of the disease. However, for patients with melanomas of any thickness, baseline blood tests and imaging studies are not recommended because clinical research does not support their use unless suspicious signs and symptoms are present.

Those are two recommendations contained in the American Academy of Dermatology’s updated guidelines for the treatment of primary cutaneous melanoma, which were published online in the Journal of the American Academy of Dermatology. Last updated in 2001, the new guidelines focus on biopsy techniques, pathology, surgical treatment, and long-term follow-up care.

"There are many factors that must be considered when diagnosing and treating melanoma, and these new guidelines offer physicians clinically sound recommendations on how to treat melanoma patients and potentially increase their chance of survival from this deadly disease," AAD President Dr. Ronald L. Moy said in a statement.

A 15-member work group of melanoma experts convened by the AAD and chaired by Dr. Allan C. Halpern of Memorial Sloan-Kettering Cancer Center, New York, and Timothy M. Johnson of the University of Michigan and its Comprehensive Cancer Center, Ann Arbor, reviewed clinical studies and guidelines related to melanoma treatment that appeared in English-language publications between 2000 and 2010. Members of the work group used a 3-point scale to grade evidence, and then developed clinical recommendations on the best available evidence (J. Am. Acad. Dermatol. 2011 Aug. 26 doi: 10.1016/j.jaad.2011.04.031]).

The recommendations were ranked as "A" (recommendation based on consistent and good-quality patient-oriented evidence); "B" (recommendation based on inconsistent or limited-quality patient-oriented evidence); and "C" (recommendation based on consensus, opinion, case studies, or disease-oriented evidence).

The Increased Value of Mitotic Rate

According to Dr. David E. Kent, the most significant change from the 2001 guidelines relates to staging, with mitotic rate replacing Clark level of invasion as the second factor predicting melanoma survival in addition to tumor (Breslow) thickness for tumors 1 mm or smaller in thickness.

Included as a prognostic value in the 2010 American Joint Committee on Cancer staging system to upstage patients with melanoma, the mitotic rate is defined as the number of mitoses in the dermis per mm².

"The placement of mitotic rate has substantial value for dermatologists because the question we get asked often is, ‘What is the risk of this superficial melanoma spreading to other parts of the body, either regionally to the lymph nodes or distantly to other sites?’" said Dr. Kent, a clinical instructor in the division of dermatology at the Medical College of Georgia, Augusta, who was not involved in assembling the guidelines. "With the mitotic rate less than 1 mm², it gives us a little bit more comfort in recommending to the patient that there’s less risk of spread. However, if there were to be a substantial mitotic rate, such as 2 mm², 3 mm², 4 mm², or even higher, that would lead one to consider referring the patient for evaluation for a staging and lymph node biopsy, even though the depth of the lesion is thin."

The guidelines note that there is "strong evidence" to support mitotic rate and two other histologic features as the most important characteristics of the primary tumor to predict outcome. The other features are maximum tumor (Breslow) thickness, which "is measured from the granular layer of the overlying epidermis or base of a superficial ulceration to the deepest malignant cells invading dermis to the nearest 0.1 mm, not including deeper adventitial extension," and the presence or absence of microscopic ulceration, "defined as tumor-induced full thickness loss of epidermis with subjacent dermal tumor and reactive dermal changes."

A complete physical exam is recommended by the work group and "includes looking through the scalp, looking in the mouth, and a genital exam as well," Dr. Kent said. "In our practice we refer women to their gynecologist for that, because 1% of all melanomas are genital. We also recommend that they see their medical ophthalmologist every 2 years because you can get melanomas in different areas of the eye."

Screening blood tests, including serum lactate dehydrogenase, are "insensitive for the detection of metastatic disease," the guidelines state, while the use of routine imaging studies "is limited by a very low yield and the frequent occurrence of false positive findings. Ample evidence exists that a routine chest X-ray is a cost inefficient test for the detection of metastatic disease with a consistent relatively high false positive rate." The guidelines also note that advanced imaging studies such as positron emission tomography and computed tomography have lower sensitivity, compared with sentinel lymph node biopsy (SLNB).

As for follow-up of patients with newly diagnosed cutaneous melanoma, the guidelines recommend an annual visit with a dermatologist at the least, but note that visits may range from every 3-12 months based on a patient’s history and risk factors. "The goal of follow-up is to detect any evidence of local recurrence and to detect any additional primary melanomas that may have developed," Dr. Kent said. "I have several patients that have personally had over three melanomas. One patient has had five. Some high risk patients we see every 3 or 4 months for follow-up."

Sentinel Lymph Node Biopsy and Lentigo Maligna

The work group also addressed non-surgical treatments for lentigo maligna, a topic that was not contained in the older version of the guidelines. For example, while off-label use of topical imiquimod has been proposed for lentigo maligna, "studies are limited by highly variable treatment regimens and lack of long-term follow-up with an average of approximately 18 months," the work group wrote. "Histologic verification following treatment has shown persistent disease in approximately 25% of treated patients and progression to invasive melanoma has been noted. As an adjunctive modality following surgical excision, the efficacy of topical imiquimod has not been established. High cost of treatment, an appropriate low threshold for subsequent biopsy to exclude residual or recurrent disease, and the risk of a severe inflammatory reaction should be taken into account when considering imiquimod."

SLNB is another topic contained in the guidelines for the first time. While the work group acknowledged that SLNB is "not without controversy," it described sentinel lymph node status as "the most important prognostic factor for disease-specific survival of patients with melanoma greater than 1 mm in thickness. Whether early detection of occult nodal disease provides greater regional control has not been definitively shown, but available evidence suggests a lower rate of post-operative complications in patients who underwent completion lymph node dissection for micrometastatic disease detected by SLNB, compared to those who underwent therapeutic lymph node dissection for clinically palpable disease."

The work group acknowledged that "significant gaps" exist in research related to the management of primary cutaneous melanoma, including "standardization of the interpretation of mitotic rate; placebo-controlled trials for the treatment of lentigo maligna; the use and value of dermoscopy and other imaging modalities; the clinical and prognostic significance of the use of biomarkers and mutational analysis; and the use of sentinel lymph node biopsy."

For his part, Dr. Kent predicted that major advances in the treatment of cutaneous melanoma should occur in the coming years. "Melanoma is a very unpredictable disease," he said. "Hopefully sometime in the future, we’ll have biomarkers that will assist physicians in identifying patients who are a greater risk of more aggressive disease, of spread to both regional and distant sites. That area of research is very exciting."

Dr. Kent said that he had no relevant financial disclosures.

In patients diagnosed with invasive primary cutaneous melanoma, a detailed patient history is crucial, and a thorough examination of the skin and lymph nodes should be performed to help determine the extent of clinical spread of the disease. However, for patients with melanomas of any thickness, baseline blood tests and imaging studies are not recommended because clinical research does not support their use unless suspicious signs and symptoms are present.

Those are two recommendations contained in the American Academy of Dermatology’s updated guidelines for the treatment of primary cutaneous melanoma, which were published online in the Journal of the American Academy of Dermatology. Last updated in 2001, the new guidelines focus on biopsy techniques, pathology, surgical treatment, and long-term follow-up care.

"There are many factors that must be considered when diagnosing and treating melanoma, and these new guidelines offer physicians clinically sound recommendations on how to treat melanoma patients and potentially increase their chance of survival from this deadly disease," AAD President Dr. Ronald L. Moy said in a statement.

A 15-member work group of melanoma experts convened by the AAD and chaired by Dr. Allan C. Halpern of Memorial Sloan-Kettering Cancer Center, New York, and Timothy M. Johnson of the University of Michigan and its Comprehensive Cancer Center, Ann Arbor, reviewed clinical studies and guidelines related to melanoma treatment that appeared in English-language publications between 2000 and 2010. Members of the work group used a 3-point scale to grade evidence, and then developed clinical recommendations on the best available evidence (J. Am. Acad. Dermatol. 2011 Aug. 26 doi: 10.1016/j.jaad.2011.04.031]).

The recommendations were ranked as "A" (recommendation based on consistent and good-quality patient-oriented evidence); "B" (recommendation based on inconsistent or limited-quality patient-oriented evidence); and "C" (recommendation based on consensus, opinion, case studies, or disease-oriented evidence).

The Increased Value of Mitotic Rate

According to Dr. David E. Kent, the most significant change from the 2001 guidelines relates to staging, with mitotic rate replacing Clark level of invasion as the second factor predicting melanoma survival in addition to tumor (Breslow) thickness for tumors 1 mm or smaller in thickness.

Included as a prognostic value in the 2010 American Joint Committee on Cancer staging system to upstage patients with melanoma, the mitotic rate is defined as the number of mitoses in the dermis per mm².

"The placement of mitotic rate has substantial value for dermatologists because the question we get asked often is, ‘What is the risk of this superficial melanoma spreading to other parts of the body, either regionally to the lymph nodes or distantly to other sites?’" said Dr. Kent, a clinical instructor in the division of dermatology at the Medical College of Georgia, Augusta, who was not involved in assembling the guidelines. "With the mitotic rate less than 1 mm², it gives us a little bit more comfort in recommending to the patient that there’s less risk of spread. However, if there were to be a substantial mitotic rate, such as 2 mm², 3 mm², 4 mm², or even higher, that would lead one to consider referring the patient for evaluation for a staging and lymph node biopsy, even though the depth of the lesion is thin."

The guidelines note that there is "strong evidence" to support mitotic rate and two other histologic features as the most important characteristics of the primary tumor to predict outcome. The other features are maximum tumor (Breslow) thickness, which "is measured from the granular layer of the overlying epidermis or base of a superficial ulceration to the deepest malignant cells invading dermis to the nearest 0.1 mm, not including deeper adventitial extension," and the presence or absence of microscopic ulceration, "defined as tumor-induced full thickness loss of epidermis with subjacent dermal tumor and reactive dermal changes."

A complete physical exam is recommended by the work group and "includes looking through the scalp, looking in the mouth, and a genital exam as well," Dr. Kent said. "In our practice we refer women to their gynecologist for that, because 1% of all melanomas are genital. We also recommend that they see their medical ophthalmologist every 2 years because you can get melanomas in different areas of the eye."

Screening blood tests, including serum lactate dehydrogenase, are "insensitive for the detection of metastatic disease," the guidelines state, while the use of routine imaging studies "is limited by a very low yield and the frequent occurrence of false positive findings. Ample evidence exists that a routine chest X-ray is a cost inefficient test for the detection of metastatic disease with a consistent relatively high false positive rate." The guidelines also note that advanced imaging studies such as positron emission tomography and computed tomography have lower sensitivity, compared with sentinel lymph node biopsy (SLNB).

As for follow-up of patients with newly diagnosed cutaneous melanoma, the guidelines recommend an annual visit with a dermatologist at the least, but note that visits may range from every 3-12 months based on a patient’s history and risk factors. "The goal of follow-up is to detect any evidence of local recurrence and to detect any additional primary melanomas that may have developed," Dr. Kent said. "I have several patients that have personally had over three melanomas. One patient has had five. Some high risk patients we see every 3 or 4 months for follow-up."

Sentinel Lymph Node Biopsy and Lentigo Maligna

The work group also addressed non-surgical treatments for lentigo maligna, a topic that was not contained in the older version of the guidelines. For example, while off-label use of topical imiquimod has been proposed for lentigo maligna, "studies are limited by highly variable treatment regimens and lack of long-term follow-up with an average of approximately 18 months," the work group wrote. "Histologic verification following treatment has shown persistent disease in approximately 25% of treated patients and progression to invasive melanoma has been noted. As an adjunctive modality following surgical excision, the efficacy of topical imiquimod has not been established. High cost of treatment, an appropriate low threshold for subsequent biopsy to exclude residual or recurrent disease, and the risk of a severe inflammatory reaction should be taken into account when considering imiquimod."

SLNB is another topic contained in the guidelines for the first time. While the work group acknowledged that SLNB is "not without controversy," it described sentinel lymph node status as "the most important prognostic factor for disease-specific survival of patients with melanoma greater than 1 mm in thickness. Whether early detection of occult nodal disease provides greater regional control has not been definitively shown, but available evidence suggests a lower rate of post-operative complications in patients who underwent completion lymph node dissection for micrometastatic disease detected by SLNB, compared to those who underwent therapeutic lymph node dissection for clinically palpable disease."

The work group acknowledged that "significant gaps" exist in research related to the management of primary cutaneous melanoma, including "standardization of the interpretation of mitotic rate; placebo-controlled trials for the treatment of lentigo maligna; the use and value of dermoscopy and other imaging modalities; the clinical and prognostic significance of the use of biomarkers and mutational analysis; and the use of sentinel lymph node biopsy."

For his part, Dr. Kent predicted that major advances in the treatment of cutaneous melanoma should occur in the coming years. "Melanoma is a very unpredictable disease," he said. "Hopefully sometime in the future, we’ll have biomarkers that will assist physicians in identifying patients who are a greater risk of more aggressive disease, of spread to both regional and distant sites. That area of research is very exciting."

Dr. Kent said that he had no relevant financial disclosures.

In patients diagnosed with invasive primary cutaneous melanoma, a detailed patient history is crucial, and a thorough examination of the skin and lymph nodes should be performed to help determine the extent of clinical spread of the disease. However, for patients with melanomas of any thickness, baseline blood tests and imaging studies are not recommended because clinical research does not support their use unless suspicious signs and symptoms are present.

Those are two recommendations contained in the American Academy of Dermatology’s updated guidelines for the treatment of primary cutaneous melanoma, which were published online in the Journal of the American Academy of Dermatology. Last updated in 2001, the new guidelines focus on biopsy techniques, pathology, surgical treatment, and long-term follow-up care.

"There are many factors that must be considered when diagnosing and treating melanoma, and these new guidelines offer physicians clinically sound recommendations on how to treat melanoma patients and potentially increase their chance of survival from this deadly disease," AAD President Dr. Ronald L. Moy said in a statement.

A 15-member work group of melanoma experts convened by the AAD and chaired by Dr. Allan C. Halpern of Memorial Sloan-Kettering Cancer Center, New York, and Timothy M. Johnson of the University of Michigan and its Comprehensive Cancer Center, Ann Arbor, reviewed clinical studies and guidelines related to melanoma treatment that appeared in English-language publications between 2000 and 2010. Members of the work group used a 3-point scale to grade evidence, and then developed clinical recommendations on the best available evidence (J. Am. Acad. Dermatol. 2011 Aug. 26 doi: 10.1016/j.jaad.2011.04.031]).

The recommendations were ranked as "A" (recommendation based on consistent and good-quality patient-oriented evidence); "B" (recommendation based on inconsistent or limited-quality patient-oriented evidence); and "C" (recommendation based on consensus, opinion, case studies, or disease-oriented evidence).

The Increased Value of Mitotic Rate

According to Dr. David E. Kent, the most significant change from the 2001 guidelines relates to staging, with mitotic rate replacing Clark level of invasion as the second factor predicting melanoma survival in addition to tumor (Breslow) thickness for tumors 1 mm or smaller in thickness.

Included as a prognostic value in the 2010 American Joint Committee on Cancer staging system to upstage patients with melanoma, the mitotic rate is defined as the number of mitoses in the dermis per mm².

"The placement of mitotic rate has substantial value for dermatologists because the question we get asked often is, ‘What is the risk of this superficial melanoma spreading to other parts of the body, either regionally to the lymph nodes or distantly to other sites?’" said Dr. Kent, a clinical instructor in the division of dermatology at the Medical College of Georgia, Augusta, who was not involved in assembling the guidelines. "With the mitotic rate less than 1 mm², it gives us a little bit more comfort in recommending to the patient that there’s less risk of spread. However, if there were to be a substantial mitotic rate, such as 2 mm², 3 mm², 4 mm², or even higher, that would lead one to consider referring the patient for evaluation for a staging and lymph node biopsy, even though the depth of the lesion is thin."

The guidelines note that there is "strong evidence" to support mitotic rate and two other histologic features as the most important characteristics of the primary tumor to predict outcome. The other features are maximum tumor (Breslow) thickness, which "is measured from the granular layer of the overlying epidermis or base of a superficial ulceration to the deepest malignant cells invading dermis to the nearest 0.1 mm, not including deeper adventitial extension," and the presence or absence of microscopic ulceration, "defined as tumor-induced full thickness loss of epidermis with subjacent dermal tumor and reactive dermal changes."

A complete physical exam is recommended by the work group and "includes looking through the scalp, looking in the mouth, and a genital exam as well," Dr. Kent said. "In our practice we refer women to their gynecologist for that, because 1% of all melanomas are genital. We also recommend that they see their medical ophthalmologist every 2 years because you can get melanomas in different areas of the eye."

Screening blood tests, including serum lactate dehydrogenase, are "insensitive for the detection of metastatic disease," the guidelines state, while the use of routine imaging studies "is limited by a very low yield and the frequent occurrence of false positive findings. Ample evidence exists that a routine chest X-ray is a cost inefficient test for the detection of metastatic disease with a consistent relatively high false positive rate." The guidelines also note that advanced imaging studies such as positron emission tomography and computed tomography have lower sensitivity, compared with sentinel lymph node biopsy (SLNB).

As for follow-up of patients with newly diagnosed cutaneous melanoma, the guidelines recommend an annual visit with a dermatologist at the least, but note that visits may range from every 3-12 months based on a patient’s history and risk factors. "The goal of follow-up is to detect any evidence of local recurrence and to detect any additional primary melanomas that may have developed," Dr. Kent said. "I have several patients that have personally had over three melanomas. One patient has had five. Some high risk patients we see every 3 or 4 months for follow-up."

Sentinel Lymph Node Biopsy and Lentigo Maligna

The work group also addressed non-surgical treatments for lentigo maligna, a topic that was not contained in the older version of the guidelines. For example, while off-label use of topical imiquimod has been proposed for lentigo maligna, "studies are limited by highly variable treatment regimens and lack of long-term follow-up with an average of approximately 18 months," the work group wrote. "Histologic verification following treatment has shown persistent disease in approximately 25% of treated patients and progression to invasive melanoma has been noted. As an adjunctive modality following surgical excision, the efficacy of topical imiquimod has not been established. High cost of treatment, an appropriate low threshold for subsequent biopsy to exclude residual or recurrent disease, and the risk of a severe inflammatory reaction should be taken into account when considering imiquimod."

SLNB is another topic contained in the guidelines for the first time. While the work group acknowledged that SLNB is "not without controversy," it described sentinel lymph node status as "the most important prognostic factor for disease-specific survival of patients with melanoma greater than 1 mm in thickness. Whether early detection of occult nodal disease provides greater regional control has not been definitively shown, but available evidence suggests a lower rate of post-operative complications in patients who underwent completion lymph node dissection for micrometastatic disease detected by SLNB, compared to those who underwent therapeutic lymph node dissection for clinically palpable disease."

The work group acknowledged that "significant gaps" exist in research related to the management of primary cutaneous melanoma, including "standardization of the interpretation of mitotic rate; placebo-controlled trials for the treatment of lentigo maligna; the use and value of dermoscopy and other imaging modalities; the clinical and prognostic significance of the use of biomarkers and mutational analysis; and the use of sentinel lymph node biopsy."

For his part, Dr. Kent predicted that major advances in the treatment of cutaneous melanoma should occur in the coming years. "Melanoma is a very unpredictable disease," he said. "Hopefully sometime in the future, we’ll have biomarkers that will assist physicians in identifying patients who are a greater risk of more aggressive disease, of spread to both regional and distant sites. That area of research is very exciting."

Dr. Kent said that he had no relevant financial disclosures.