Melanoma

Vitamin D, skin cancer screening, and chemoprevention top the list of current melanoma prevention controversies, according to Dr. Clara Curiel-Lewandowski.

Vitamin D has been a contentious subject for many years with its being suggested that increased sun protection may be associated with lower vitamin D levels, noted Dr. Lewandowski at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation in Maui.

"A decrease in the serum level of vitamin D has been observed in the general population, particularly here in the United States.

"The challenge is to understand to which degree each modulating factor—such as vitamin D dietary intake, photoprotection, body mass index, and geographical location—contributes to the observed decline in serum levels," she said in an interview.

"There is no randomized prospective study linking vitamin D deficiency to excessive photoprotection. Those studies are very difficult to carry out," said Dr. Curiel-Lewandowski, who is director of the pigmented lesion clinic and multidisciplinary oncology at the Arizona Cancer Center in Tucson.

Another component in declining vitamin D levels is that humans produce less vitamin D as they age. Therefore, rising life expectancy may have a role in decreased vitamin D levels. "We're now living to 60, 70, 80 years and we are converting less vitamin D, irrespective of other sources," she said.

In addition, normal levels of serum 25(OH)D are now in the 70-nmol/L range, where it used to be 35–40 nmol/L, she said. With all of these variables, it is very difficult to tease out which of the components are responsible for declining vitamin D levels.

Advice to skin cancer patients about vitamin D should be based on common sense, said Dr. Curiel-Lewandowski.

She recommends that patients pursue a balanced diet, take daily vitamin D supplements above 400 IU if needed, and limit sun exposure to early morning and late afternoon hours. The specific dose supplementation for individuals with suspected risk factors for vitamin D deficiency should be based on their serum 25(OH)D levels.

Skin Cancer Screening

It's important to make the distinction between screening the general population and screening specific high-risk groups for skin cancer, said Dr. Curiel-Lewandowski.

"Cost effectiveness of massive skin cancer screening in the general population has been questioned," she said. An agreement needs to be reached on who is at risk for melanoma and how to target them for skin cancer screening.

The United States Preventive Services Task Force just released new recommendations on skin cancer screening for the general population (Ann. Intern. Med. 2009;150:188–93).

The task force said that there is insufficient evidence to recommend for or against skin cancer screening in the general population. (See story on pg. 4.)

"It is important to understand—no one is against skin cancer screening," said Dr. Curiel-Lewandowski. There simply are not enough data to recommend for or against it in the general population.

"In order to properly validate the effectiveness of massive or selective screening, randomized prospective studies will need to be completed. However, the incidence of melanoma is lower compared with other cancers and in order to get significance, you need more than 400,000 subjects involved and followed for over 10 years to achieve reasonable outcome data. … It's a very difficult study to accomplish," she said.

The task force did identify high-risk groups of individuals: fair-skinned men and women older than 65 years, patients with atypical nevi, patients with more than 50 nevi, and those with a family history of melanoma.

"What's not clear from this message is what to do with people that are known to be at high risk," she said, noting that the new recommendations identify these groups "but they don't tell you the type of screening and frequency that is recommended."

These are precisely the patients that many dermatologists see—patients with atypical nevi, those with a family history of melanoma, and transplant patients. Screenings should be done for these individuals, said Dr. Curiel-Lewandowski.

Chemoprevention

"The reason why the concept of melanoma chemoprevention is emerging is because new alternatives are necessary to decrease the burden of disease, especially in high risk individuals. This rationale is particularly compelling since we haven't been successful in decreasing mortality rates. … It opens up another option, which is trying to identify systemic agents that can be used in individuals at higher risk for melanoma to slow down the development of disease or even prevent it," Dr. Curiel-Lewandowski commented.

In the 1980s, studies were performed using topical retinoids for atypical nevi. In the late 1990s, statins became the hot topic. Neither option panned out. "What is emerging now among several candidate agents are nonsteroidal anti-inflammatories and green tea derivatives" she said.

The idea of using NSAIDs for the chemoprevention of melanoma comes from experimental and limited epidemiologic and clinical data suggesting that the extended use of NSAIDs decreases the risk of melanoma development. Ongoing larger epidemiologic studies looking in more detail at the strength of this association are expected to be released within the next year.

"Since multiple melanoma pathways have been identified, the effectiveness of a specific chemopreventive agent in a given high-risk population needs to be carefully thought out," Dr. Curiel-Lewandowski said.

Some have advanced this as an argument against chemoprevention.

SDEF and this newspaper are owned by Elsevier.

Vitamin D, skin cancer screening, and chemoprevention top the list of current melanoma prevention controversies, according to Dr. Clara Curiel-Lewandowski.

Vitamin D has been a contentious subject for many years with its being suggested that increased sun protection may be associated with lower vitamin D levels, noted Dr. Lewandowski at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation in Maui.

"A decrease in the serum level of vitamin D has been observed in the general population, particularly here in the United States.

"The challenge is to understand to which degree each modulating factor—such as vitamin D dietary intake, photoprotection, body mass index, and geographical location—contributes to the observed decline in serum levels," she said in an interview.

"There is no randomized prospective study linking vitamin D deficiency to excessive photoprotection. Those studies are very difficult to carry out," said Dr. Curiel-Lewandowski, who is director of the pigmented lesion clinic and multidisciplinary oncology at the Arizona Cancer Center in Tucson.

Another component in declining vitamin D levels is that humans produce less vitamin D as they age. Therefore, rising life expectancy may have a role in decreased vitamin D levels. "We're now living to 60, 70, 80 years and we are converting less vitamin D, irrespective of other sources," she said.

In addition, normal levels of serum 25(OH)D are now in the 70-nmol/L range, where it used to be 35–40 nmol/L, she said. With all of these variables, it is very difficult to tease out which of the components are responsible for declining vitamin D levels.

Advice to skin cancer patients about vitamin D should be based on common sense, said Dr. Curiel-Lewandowski.

She recommends that patients pursue a balanced diet, take daily vitamin D supplements above 400 IU if needed, and limit sun exposure to early morning and late afternoon hours. The specific dose supplementation for individuals with suspected risk factors for vitamin D deficiency should be based on their serum 25(OH)D levels.

Skin Cancer Screening

It's important to make the distinction between screening the general population and screening specific high-risk groups for skin cancer, said Dr. Curiel-Lewandowski.

"Cost effectiveness of massive skin cancer screening in the general population has been questioned," she said. An agreement needs to be reached on who is at risk for melanoma and how to target them for skin cancer screening.

The United States Preventive Services Task Force just released new recommendations on skin cancer screening for the general population (Ann. Intern. Med. 2009;150:188–93).

The task force said that there is insufficient evidence to recommend for or against skin cancer screening in the general population. (See story on pg. 4.)

"It is important to understand—no one is against skin cancer screening," said Dr. Curiel-Lewandowski. There simply are not enough data to recommend for or against it in the general population.

"In order to properly validate the effectiveness of massive or selective screening, randomized prospective studies will need to be completed. However, the incidence of melanoma is lower compared with other cancers and in order to get significance, you need more than 400,000 subjects involved and followed for over 10 years to achieve reasonable outcome data. … It's a very difficult study to accomplish," she said.

The task force did identify high-risk groups of individuals: fair-skinned men and women older than 65 years, patients with atypical nevi, patients with more than 50 nevi, and those with a family history of melanoma.

"What's not clear from this message is what to do with people that are known to be at high risk," she said, noting that the new recommendations identify these groups "but they don't tell you the type of screening and frequency that is recommended."

These are precisely the patients that many dermatologists see—patients with atypical nevi, those with a family history of melanoma, and transplant patients. Screenings should be done for these individuals, said Dr. Curiel-Lewandowski.

Chemoprevention

"The reason why the concept of melanoma chemoprevention is emerging is because new alternatives are necessary to decrease the burden of disease, especially in high risk individuals. This rationale is particularly compelling since we haven't been successful in decreasing mortality rates. … It opens up another option, which is trying to identify systemic agents that can be used in individuals at higher risk for melanoma to slow down the development of disease or even prevent it," Dr. Curiel-Lewandowski commented.

In the 1980s, studies were performed using topical retinoids for atypical nevi. In the late 1990s, statins became the hot topic. Neither option panned out. "What is emerging now among several candidate agents are nonsteroidal anti-inflammatories and green tea derivatives" she said.

The idea of using NSAIDs for the chemoprevention of melanoma comes from experimental and limited epidemiologic and clinical data suggesting that the extended use of NSAIDs decreases the risk of melanoma development. Ongoing larger epidemiologic studies looking in more detail at the strength of this association are expected to be released within the next year.

"Since multiple melanoma pathways have been identified, the effectiveness of a specific chemopreventive agent in a given high-risk population needs to be carefully thought out," Dr. Curiel-Lewandowski said.

Some have advanced this as an argument against chemoprevention.

SDEF and this newspaper are owned by Elsevier.

Vitamin D, skin cancer screening, and chemoprevention top the list of current melanoma prevention controversies, according to Dr. Clara Curiel-Lewandowski.

Vitamin D has been a contentious subject for many years with its being suggested that increased sun protection may be associated with lower vitamin D levels, noted Dr. Lewandowski at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation in Maui.

"A decrease in the serum level of vitamin D has been observed in the general population, particularly here in the United States.

"The challenge is to understand to which degree each modulating factor—such as vitamin D dietary intake, photoprotection, body mass index, and geographical location—contributes to the observed decline in serum levels," she said in an interview.

"There is no randomized prospective study linking vitamin D deficiency to excessive photoprotection. Those studies are very difficult to carry out," said Dr. Curiel-Lewandowski, who is director of the pigmented lesion clinic and multidisciplinary oncology at the Arizona Cancer Center in Tucson.

Another component in declining vitamin D levels is that humans produce less vitamin D as they age. Therefore, rising life expectancy may have a role in decreased vitamin D levels. "We're now living to 60, 70, 80 years and we are converting less vitamin D, irrespective of other sources," she said.

In addition, normal levels of serum 25(OH)D are now in the 70-nmol/L range, where it used to be 35–40 nmol/L, she said. With all of these variables, it is very difficult to tease out which of the components are responsible for declining vitamin D levels.

Advice to skin cancer patients about vitamin D should be based on common sense, said Dr. Curiel-Lewandowski.

She recommends that patients pursue a balanced diet, take daily vitamin D supplements above 400 IU if needed, and limit sun exposure to early morning and late afternoon hours. The specific dose supplementation for individuals with suspected risk factors for vitamin D deficiency should be based on their serum 25(OH)D levels.

Skin Cancer Screening

It's important to make the distinction between screening the general population and screening specific high-risk groups for skin cancer, said Dr. Curiel-Lewandowski.

"Cost effectiveness of massive skin cancer screening in the general population has been questioned," she said. An agreement needs to be reached on who is at risk for melanoma and how to target them for skin cancer screening.

The United States Preventive Services Task Force just released new recommendations on skin cancer screening for the general population (Ann. Intern. Med. 2009;150:188–93).

The task force said that there is insufficient evidence to recommend for or against skin cancer screening in the general population. (See story on pg. 4.)

"It is important to understand—no one is against skin cancer screening," said Dr. Curiel-Lewandowski. There simply are not enough data to recommend for or against it in the general population.

"In order to properly validate the effectiveness of massive or selective screening, randomized prospective studies will need to be completed. However, the incidence of melanoma is lower compared with other cancers and in order to get significance, you need more than 400,000 subjects involved and followed for over 10 years to achieve reasonable outcome data. … It's a very difficult study to accomplish," she said.

The task force did identify high-risk groups of individuals: fair-skinned men and women older than 65 years, patients with atypical nevi, patients with more than 50 nevi, and those with a family history of melanoma.

"What's not clear from this message is what to do with people that are known to be at high risk," she said, noting that the new recommendations identify these groups "but they don't tell you the type of screening and frequency that is recommended."

These are precisely the patients that many dermatologists see—patients with atypical nevi, those with a family history of melanoma, and transplant patients. Screenings should be done for these individuals, said Dr. Curiel-Lewandowski.

Chemoprevention

"The reason why the concept of melanoma chemoprevention is emerging is because new alternatives are necessary to decrease the burden of disease, especially in high risk individuals. This rationale is particularly compelling since we haven't been successful in decreasing mortality rates. … It opens up another option, which is trying to identify systemic agents that can be used in individuals at higher risk for melanoma to slow down the development of disease or even prevent it," Dr. Curiel-Lewandowski commented.

In the 1980s, studies were performed using topical retinoids for atypical nevi. In the late 1990s, statins became the hot topic. Neither option panned out. "What is emerging now among several candidate agents are nonsteroidal anti-inflammatories and green tea derivatives" she said.

The idea of using NSAIDs for the chemoprevention of melanoma comes from experimental and limited epidemiologic and clinical data suggesting that the extended use of NSAIDs decreases the risk of melanoma development. Ongoing larger epidemiologic studies looking in more detail at the strength of this association are expected to be released within the next year.

"Since multiple melanoma pathways have been identified, the effectiveness of a specific chemopreventive agent in a given high-risk population needs to be carefully thought out," Dr. Curiel-Lewandowski said.

Some have advanced this as an argument against chemoprevention.

SDEF and this newspaper are owned by Elsevier.

PALM BEACH, FLA. — The presence of microscopic or even submicroscopic melanoma in a sentinel lymph node may be clinically relevant, a retrospective study has shown.

"We believe patients with microscopic deposits of metastatic melanoma have biologically relevant, potentially life-threatening disease," Dr. David W. Ollila said at the annual meeting of the Southern Surgical Association.

Although other investigators have proposed that submicroscopic disease (a sentinel node tumor that is less than 0.1 mm) is not associated with a significantly increased risk of recurrence or death (Br. J. Surg. 2007;94:1293–9), Dr. Ollila and his associates hypothesized that any sentinel node evidence of metastatic melanoma, regardless of size or stage, may be a cause for concern.

He and his associates retrospectively studied 586 patients (mean age, 55 years) with invasive melanoma and a sentinel node biopsy from 1998 to 2007 in a prospectively maintained database. They classified the 322 men and 264 women as node negative or as having a tumor burden of less than 0.1 mm, 0.1–1.0 mm, or greater than 1.0 mm.

The investigators found a statistically significant difference in recurrence of any type between node-negative patients and those with a tumor burden less than 0.1 mm. During a mean follow-up of 2.7 years, 57 (11%) of the 496 node-negative patients had a recurrence, compared with 8 (24%) of the 33 patients with a sentinel node tumor less than 0.1 mm.

"We [also] found a significant difference in disease-free survival between sentinel node-negative [patients] and the submicroscopic group. They cannot be considered equivalent," said Dr. Ollila, director of the sentinel node program and codirector of the multidisciplinary melanoma program at the University of North Carolina at Chapel Hill.

In the node-negative group, 51 patients (10%) died, as did 5 (15%) of those with a tumor burden less than 0.1 mm, 6 of 27 patients (22%) in the 0.1- to 1.0-mm group, and 12 of 30 patients (40%) who had tumors larger than 1.0 mm.

Dr. Ollila pointed out that the stepwise decrease in survival with increasing diameter of the metastatic deposit was statistically different among the four groups. "This is an interesting [finding], contrary to Rotterdam criteria. I submit to you that these patients are on a continuum, and this is clinically relevant disease," he said.

An increased sentinel node tumor burden was also associated with a greater risk of metastatic disease in other nodes. A total of 7% of node-negative patients had distant recurrence, as did 15% of those with tumors less than 0.1 mm, 22% of the 0.1- to 1.0-mm group, and 47% of those with tumors larger than 1.0 mm.

Dr. Marshall M. Urist, professor of surgery, University of Alabama at Birmingham, commented that this is an excellent study and asked, "Why did you measure these metastases in a two-dimensional way for a three-dimensional process?"

Dr. Ollila replied: "Point well taken. It's a volume disease. It would be more representative if we could do volumetric measures." The two-dimensional measurement was a limitation of the database used in the study, he said.

PALM BEACH, FLA. — The presence of microscopic or even submicroscopic melanoma in a sentinel lymph node may be clinically relevant, a retrospective study has shown.

"We believe patients with microscopic deposits of metastatic melanoma have biologically relevant, potentially life-threatening disease," Dr. David W. Ollila said at the annual meeting of the Southern Surgical Association.

Although other investigators have proposed that submicroscopic disease (a sentinel node tumor that is less than 0.1 mm) is not associated with a significantly increased risk of recurrence or death (Br. J. Surg. 2007;94:1293–9), Dr. Ollila and his associates hypothesized that any sentinel node evidence of metastatic melanoma, regardless of size or stage, may be a cause for concern.

He and his associates retrospectively studied 586 patients (mean age, 55 years) with invasive melanoma and a sentinel node biopsy from 1998 to 2007 in a prospectively maintained database. They classified the 322 men and 264 women as node negative or as having a tumor burden of less than 0.1 mm, 0.1–1.0 mm, or greater than 1.0 mm.

The investigators found a statistically significant difference in recurrence of any type between node-negative patients and those with a tumor burden less than 0.1 mm. During a mean follow-up of 2.7 years, 57 (11%) of the 496 node-negative patients had a recurrence, compared with 8 (24%) of the 33 patients with a sentinel node tumor less than 0.1 mm.

"We [also] found a significant difference in disease-free survival between sentinel node-negative [patients] and the submicroscopic group. They cannot be considered equivalent," said Dr. Ollila, director of the sentinel node program and codirector of the multidisciplinary melanoma program at the University of North Carolina at Chapel Hill.

In the node-negative group, 51 patients (10%) died, as did 5 (15%) of those with a tumor burden less than 0.1 mm, 6 of 27 patients (22%) in the 0.1- to 1.0-mm group, and 12 of 30 patients (40%) who had tumors larger than 1.0 mm.

Dr. Ollila pointed out that the stepwise decrease in survival with increasing diameter of the metastatic deposit was statistically different among the four groups. "This is an interesting [finding], contrary to Rotterdam criteria. I submit to you that these patients are on a continuum, and this is clinically relevant disease," he said.

An increased sentinel node tumor burden was also associated with a greater risk of metastatic disease in other nodes. A total of 7% of node-negative patients had distant recurrence, as did 15% of those with tumors less than 0.1 mm, 22% of the 0.1- to 1.0-mm group, and 47% of those with tumors larger than 1.0 mm.

Dr. Marshall M. Urist, professor of surgery, University of Alabama at Birmingham, commented that this is an excellent study and asked, "Why did you measure these metastases in a two-dimensional way for a three-dimensional process?"

Dr. Ollila replied: "Point well taken. It's a volume disease. It would be more representative if we could do volumetric measures." The two-dimensional measurement was a limitation of the database used in the study, he said.

PALM BEACH, FLA. — The presence of microscopic or even submicroscopic melanoma in a sentinel lymph node may be clinically relevant, a retrospective study has shown.

"We believe patients with microscopic deposits of metastatic melanoma have biologically relevant, potentially life-threatening disease," Dr. David W. Ollila said at the annual meeting of the Southern Surgical Association.

Although other investigators have proposed that submicroscopic disease (a sentinel node tumor that is less than 0.1 mm) is not associated with a significantly increased risk of recurrence or death (Br. J. Surg. 2007;94:1293–9), Dr. Ollila and his associates hypothesized that any sentinel node evidence of metastatic melanoma, regardless of size or stage, may be a cause for concern.

He and his associates retrospectively studied 586 patients (mean age, 55 years) with invasive melanoma and a sentinel node biopsy from 1998 to 2007 in a prospectively maintained database. They classified the 322 men and 264 women as node negative or as having a tumor burden of less than 0.1 mm, 0.1–1.0 mm, or greater than 1.0 mm.

The investigators found a statistically significant difference in recurrence of any type between node-negative patients and those with a tumor burden less than 0.1 mm. During a mean follow-up of 2.7 years, 57 (11%) of the 496 node-negative patients had a recurrence, compared with 8 (24%) of the 33 patients with a sentinel node tumor less than 0.1 mm.

"We [also] found a significant difference in disease-free survival between sentinel node-negative [patients] and the submicroscopic group. They cannot be considered equivalent," said Dr. Ollila, director of the sentinel node program and codirector of the multidisciplinary melanoma program at the University of North Carolina at Chapel Hill.

In the node-negative group, 51 patients (10%) died, as did 5 (15%) of those with a tumor burden less than 0.1 mm, 6 of 27 patients (22%) in the 0.1- to 1.0-mm group, and 12 of 30 patients (40%) who had tumors larger than 1.0 mm.

Dr. Ollila pointed out that the stepwise decrease in survival with increasing diameter of the metastatic deposit was statistically different among the four groups. "This is an interesting [finding], contrary to Rotterdam criteria. I submit to you that these patients are on a continuum, and this is clinically relevant disease," he said.

An increased sentinel node tumor burden was also associated with a greater risk of metastatic disease in other nodes. A total of 7% of node-negative patients had distant recurrence, as did 15% of those with tumors less than 0.1 mm, 22% of the 0.1- to 1.0-mm group, and 47% of those with tumors larger than 1.0 mm.

Dr. Marshall M. Urist, professor of surgery, University of Alabama at Birmingham, commented that this is an excellent study and asked, "Why did you measure these metastases in a two-dimensional way for a three-dimensional process?"

Dr. Ollila replied: "Point well taken. It's a volume disease. It would be more representative if we could do volumetric measures." The two-dimensional measurement was a limitation of the database used in the study, he said.

LAS VEGAS — Early-stage mycosis fungoides appears to be a lympho-accumulative disorder, driven by defects in apoptosis mechanisms designed to regulate T-cell populations in the skin, according to Dr. Gary Wood.

Cell cycle defects that lead to the classic "unchecked growth" that characterizes lymphoproliferative diseases do occur in mycosis fungoides, but likely not until its later stages, Dr. Wood, who is chairman of dermatology at the University of Wisconsin, Madison, said during a dermatology seminar that was sponsored by Skin Disease Education Foundation.

In the beginning, mycosis fungoides demonstrate a low rate of apoptosis, with "cells not growing particularly quickly, but also not dying—like guests that you invite that don't go home," he commented.

Many additional clues point to early mycosis fungoides as a lympho-accumulative, rather than a lympho-proliferative, disorder, he said, including:

▸ An indolent clinical course.

▸ Development of patches, not tumor masses.

▸ Low proliferative rate and mitotic counts.

▸ Relative resistance to chemotherapy, because mycosis fungoides cells are "quite similar to normal T cells. Anything that will kill them will kill the rest of the patient."

▸ Poor growth in vitro.

Research of late has buoyed the theory of lympho-accumulation.

One or more death receptor defects have been identified in the majority of patients with cutaneous T-cell lymphoma, including defects in FAS; TNFR (R1, R2, or the antiapoptotic TRAF1 receptor); or TRAIL (DR4, DR5, DcR1, or DcR2).

Dr. Wood's team and others have found further defects in the death receptor antagonist cFLIP, which is a key player in the death receptor pathway, he noted.

He and his colleagues found low FAS expression in 30 of the 31 patients with cutaneous T-cell lymphoma and in 5 of the 6 patients with large plaque parapsoriasis, a precursor of mycosis fungoides or Sézary syndrome (J. Invest. Dermatol. 2008 Oct. 16 [Epub doi:10.1038/jid.2008.309

No such abnormality was seen in the 15 patients with chronic dermatoses, he noted at the meeting.

A more targeted look identified four cutaneous T-cell lymphoma cell lines (MyLa, HH, SZ4, and SeAx) in which resistance to apoptosis correlated with levels of FAS transcripts and proteins.

Taking it one step further, Dr. Woods and his associates found that, when they triggered FAS upregulation by transfecting genes with a wild-type FAS construct, apoptosis was restored, including spontaneous FAS pathway apoptosis, in which FAS ligands, in essence, self-destruct.

"You can see a big uptake in the amount of killing," he pointed out, demonstrating the effect in each of the four tested cell lines using real time polymerase chain reaction (RT/PCR) technology.

While Dr. Wood's team has focused on FAS transfection to prime FAS and cutaneous T-cell lymphoma cells to self-destruct or to become targets of tumor-infiltrating lymphocytes, there are other ways to upregulate FAS as well.

These include interleukin-2 and bryostatin; interferon-α and -γ; and even epigallocatechin gallate (EGCG), which is the polyphenol antioxidant in green tea, he said.

"In the future, these may be useful therapeutic targets," Dr. Wood said.

SDEF and this newspaper are owned by Elsevier.

LAS VEGAS — Early-stage mycosis fungoides appears to be a lympho-accumulative disorder, driven by defects in apoptosis mechanisms designed to regulate T-cell populations in the skin, according to Dr. Gary Wood.

Cell cycle defects that lead to the classic "unchecked growth" that characterizes lymphoproliferative diseases do occur in mycosis fungoides, but likely not until its later stages, Dr. Wood, who is chairman of dermatology at the University of Wisconsin, Madison, said during a dermatology seminar that was sponsored by Skin Disease Education Foundation.

In the beginning, mycosis fungoides demonstrate a low rate of apoptosis, with "cells not growing particularly quickly, but also not dying—like guests that you invite that don't go home," he commented.

Many additional clues point to early mycosis fungoides as a lympho-accumulative, rather than a lympho-proliferative, disorder, he said, including:

▸ An indolent clinical course.

▸ Development of patches, not tumor masses.

▸ Low proliferative rate and mitotic counts.

▸ Relative resistance to chemotherapy, because mycosis fungoides cells are "quite similar to normal T cells. Anything that will kill them will kill the rest of the patient."

▸ Poor growth in vitro.

Research of late has buoyed the theory of lympho-accumulation.

One or more death receptor defects have been identified in the majority of patients with cutaneous T-cell lymphoma, including defects in FAS; TNFR (R1, R2, or the antiapoptotic TRAF1 receptor); or TRAIL (DR4, DR5, DcR1, or DcR2).

Dr. Wood's team and others have found further defects in the death receptor antagonist cFLIP, which is a key player in the death receptor pathway, he noted.

He and his colleagues found low FAS expression in 30 of the 31 patients with cutaneous T-cell lymphoma and in 5 of the 6 patients with large plaque parapsoriasis, a precursor of mycosis fungoides or Sézary syndrome (J. Invest. Dermatol. 2008 Oct. 16 [Epub doi:10.1038/jid.2008.309

No such abnormality was seen in the 15 patients with chronic dermatoses, he noted at the meeting.

A more targeted look identified four cutaneous T-cell lymphoma cell lines (MyLa, HH, SZ4, and SeAx) in which resistance to apoptosis correlated with levels of FAS transcripts and proteins.

Taking it one step further, Dr. Woods and his associates found that, when they triggered FAS upregulation by transfecting genes with a wild-type FAS construct, apoptosis was restored, including spontaneous FAS pathway apoptosis, in which FAS ligands, in essence, self-destruct.

"You can see a big uptake in the amount of killing," he pointed out, demonstrating the effect in each of the four tested cell lines using real time polymerase chain reaction (RT/PCR) technology.

While Dr. Wood's team has focused on FAS transfection to prime FAS and cutaneous T-cell lymphoma cells to self-destruct or to become targets of tumor-infiltrating lymphocytes, there are other ways to upregulate FAS as well.

These include interleukin-2 and bryostatin; interferon-α and -γ; and even epigallocatechin gallate (EGCG), which is the polyphenol antioxidant in green tea, he said.

"In the future, these may be useful therapeutic targets," Dr. Wood said.

SDEF and this newspaper are owned by Elsevier.

LAS VEGAS — Early-stage mycosis fungoides appears to be a lympho-accumulative disorder, driven by defects in apoptosis mechanisms designed to regulate T-cell populations in the skin, according to Dr. Gary Wood.

Cell cycle defects that lead to the classic "unchecked growth" that characterizes lymphoproliferative diseases do occur in mycosis fungoides, but likely not until its later stages, Dr. Wood, who is chairman of dermatology at the University of Wisconsin, Madison, said during a dermatology seminar that was sponsored by Skin Disease Education Foundation.

In the beginning, mycosis fungoides demonstrate a low rate of apoptosis, with "cells not growing particularly quickly, but also not dying—like guests that you invite that don't go home," he commented.

Many additional clues point to early mycosis fungoides as a lympho-accumulative, rather than a lympho-proliferative, disorder, he said, including:

▸ An indolent clinical course.

▸ Development of patches, not tumor masses.

▸ Low proliferative rate and mitotic counts.

▸ Relative resistance to chemotherapy, because mycosis fungoides cells are "quite similar to normal T cells. Anything that will kill them will kill the rest of the patient."

▸ Poor growth in vitro.

Research of late has buoyed the theory of lympho-accumulation.

One or more death receptor defects have been identified in the majority of patients with cutaneous T-cell lymphoma, including defects in FAS; TNFR (R1, R2, or the antiapoptotic TRAF1 receptor); or TRAIL (DR4, DR5, DcR1, or DcR2).

Dr. Wood's team and others have found further defects in the death receptor antagonist cFLIP, which is a key player in the death receptor pathway, he noted.

He and his colleagues found low FAS expression in 30 of the 31 patients with cutaneous T-cell lymphoma and in 5 of the 6 patients with large plaque parapsoriasis, a precursor of mycosis fungoides or Sézary syndrome (J. Invest. Dermatol. 2008 Oct. 16 [Epub doi:10.1038/jid.2008.309

No such abnormality was seen in the 15 patients with chronic dermatoses, he noted at the meeting.

A more targeted look identified four cutaneous T-cell lymphoma cell lines (MyLa, HH, SZ4, and SeAx) in which resistance to apoptosis correlated with levels of FAS transcripts and proteins.

Taking it one step further, Dr. Woods and his associates found that, when they triggered FAS upregulation by transfecting genes with a wild-type FAS construct, apoptosis was restored, including spontaneous FAS pathway apoptosis, in which FAS ligands, in essence, self-destruct.

"You can see a big uptake in the amount of killing," he pointed out, demonstrating the effect in each of the four tested cell lines using real time polymerase chain reaction (RT/PCR) technology.

While Dr. Wood's team has focused on FAS transfection to prime FAS and cutaneous T-cell lymphoma cells to self-destruct or to become targets of tumor-infiltrating lymphocytes, there are other ways to upregulate FAS as well.

These include interleukin-2 and bryostatin; interferon-α and -γ; and even epigallocatechin gallate (EGCG), which is the polyphenol antioxidant in green tea, he said.

"In the future, these may be useful therapeutic targets," Dr. Wood said.

SDEF and this newspaper are owned by Elsevier.

MAUI, HAWAII — Look for tumor mitotic rate to supplant Clark level in the forthcoming 7th edition of the American Joint Committee on Cancer melanoma staging system.

“Clark level will now only be considered for staging in the rare instances when mitotic rate is not known; otherwise it will no longer be part of the staging system,” Dr. Jeffrey E. Gershenwald said at the annual Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation.

This represents a break with the past. Within melanoma staging, Clark level enjoyed near-equal billing with tumor thickness before being downgraded in clinical relevance in the still-current 6th edition of the AJCC staging system, issued in 2002.

The 6th edition relegated Clark level to a limited role, with Clark level IV and V resulting in upstaging of thin melanomas from T1 to T1b, explained Dr. Gershenwald, vice chair of the AJCC task force charged with developing the new edition of the staging system.

The 7th edition of the AJCC melanoma staging system will be published this spring and will take effect early next year. The same changes will be made in the European staging system in coordinated fashion.

Mitotic rate will be introduced into the staging system on the basis of recent evidence suggesting that it is an independent prognostic factor. The presence of at least one mitosis per square centimeter will be sufficient to upgrade a thin melanoma from T1 to T1b.

As the AJCC staging system is rolled out, reports will be issued detailing how pathologists should determine mitotic rate, according to Dr. Gershenwald, professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston.

Clark level, he added, has caused a great deal of confusion among patients, who often confuse Clark level IV with stage IV melanoma.

“I can't tell you how many patients have come into the clinic thinking they have a stage IV melanoma and are reading their death sentence on the Internet when in fact they might very well have had a thin melanoma that happens to be Clark level IV,” he commented.

“In dialoging with your patients, please make sure they understand the difference,” Dr. Gershenwald urged.

The 7th edition of the staging system will make no major changes in the core TNM (tumor, node, metastasis) and stage grouping criteria for stages I-III melanoma. A thin melanoma will remain one that's up to 1.0 mm in thickness, and a thick one will still have to be greater than 4.0 mm. This was an evidence-based decision in response to analysis of an international database of more than 50,000 melanoma patients which validated the models utilized in the 6th edition.

There will be a few minor changes in the 6th edition having clinical relevance, however. For one, there will no longer be a lower limit as to what constitutes node-positive disease.

Also, immunohistochemical detection of nodal metastases—already in wide use in clinical practice—will for the first time become acceptable for staging purposes in the upcoming edition, Dr. Gershenwald said.

In the 7th edition, the essential elements of a pathology report for primary melanoma will be Breslow thickness, the presence or absence of ulceration, mitotic rate, and margin status.

SDEF and this newspaper are owned by Elsevier.

The 7th edition will make no major changes in the core TNM and stage grouping criteria for stages I-III melanoma. DR. GERSHENWALD

Staging, Lymph Node Assessment Are Key to Surgical Melanoma Management

The surgical management of primary melanoma varies by patient and depends in large part on key elements of the pathology report and the assessment of lymph node involvement, according to Dr. Gershenwald.

In terms of staging the disease, Breslow thickness, ulceration, mitotic rate, Clark level, and margin assessment should be considered prior to wide local excision of the tumor, he noted.

And because nodal involvement is the best predictor of recurrence and survival in melanoma, determining which patients have lymph node involvement and which patients do not is critical to the optimal management of the disease.

Lymphatic mapping together with sentinel lymph node biopsy is a relatively noninvasive way to accurately stage the regional nodal basin and enables a selective approach to regional node dissection, whereby lymphadectomy is reserved only for patients found to have pathologically documented disease, Dr. Gershenwald explained.

This combined diagnostic approach—in which a radioactive tracer is injected around the primary tumor site and a blue dye is used to identify sentinel lymph nodes to be removed for analysis—identifies regional lymph node disease that might not be seen with complete lymph node dissection and identifies patients in whom adjuvant therapy is warranted, he said.

Studies have suggested that early detection by sentinel node biopsy of sentinel lymph node metastasis is associated with a survival benefit when compared with a watch-and-wait approach in patients who develop clinical lymph node recurrence, Dr. Gershenwald noted.

With respect to the use of fluorodeoxyglucose positron-emission tomography (FDG-PET), which has been shown in several reports to be a more sensitive indicator of metastatic melanoma than conventional imaging, limitations in the study designs may overestimate the utility of this imaging modality for this indication, he said.

The literature supports the use of adjunctive PET imaging in properly selected patients with metastatic or recurrent melanoma, but it does not provide evidence suggesting that FDG-PET should be obtained in all melanoma patients, he reported.

Specifically, FDG-PET rarely identifies the presence of occult distant metastases in early stage melanoma patients who have been staged using sentinel node biopsy, whch means the likelihood is low that these patients will be upstaged based on the FDG-PET results.

MAUI, HAWAII — Look for tumor mitotic rate to supplant Clark level in the forthcoming 7th edition of the American Joint Committee on Cancer melanoma staging system.

“Clark level will now only be considered for staging in the rare instances when mitotic rate is not known; otherwise it will no longer be part of the staging system,” Dr. Jeffrey E. Gershenwald said at the annual Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation.

This represents a break with the past. Within melanoma staging, Clark level enjoyed near-equal billing with tumor thickness before being downgraded in clinical relevance in the still-current 6th edition of the AJCC staging system, issued in 2002.

The 6th edition relegated Clark level to a limited role, with Clark level IV and V resulting in upstaging of thin melanomas from T1 to T1b, explained Dr. Gershenwald, vice chair of the AJCC task force charged with developing the new edition of the staging system.

The 7th edition of the AJCC melanoma staging system will be published this spring and will take effect early next year. The same changes will be made in the European staging system in coordinated fashion.

Mitotic rate will be introduced into the staging system on the basis of recent evidence suggesting that it is an independent prognostic factor. The presence of at least one mitosis per square centimeter will be sufficient to upgrade a thin melanoma from T1 to T1b.

As the AJCC staging system is rolled out, reports will be issued detailing how pathologists should determine mitotic rate, according to Dr. Gershenwald, professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston.

Clark level, he added, has caused a great deal of confusion among patients, who often confuse Clark level IV with stage IV melanoma.

“I can't tell you how many patients have come into the clinic thinking they have a stage IV melanoma and are reading their death sentence on the Internet when in fact they might very well have had a thin melanoma that happens to be Clark level IV,” he commented.

“In dialoging with your patients, please make sure they understand the difference,” Dr. Gershenwald urged.

The 7th edition of the staging system will make no major changes in the core TNM (tumor, node, metastasis) and stage grouping criteria for stages I-III melanoma. A thin melanoma will remain one that's up to 1.0 mm in thickness, and a thick one will still have to be greater than 4.0 mm. This was an evidence-based decision in response to analysis of an international database of more than 50,000 melanoma patients which validated the models utilized in the 6th edition.

There will be a few minor changes in the 6th edition having clinical relevance, however. For one, there will no longer be a lower limit as to what constitutes node-positive disease.

Also, immunohistochemical detection of nodal metastases—already in wide use in clinical practice—will for the first time become acceptable for staging purposes in the upcoming edition, Dr. Gershenwald said.

In the 7th edition, the essential elements of a pathology report for primary melanoma will be Breslow thickness, the presence or absence of ulceration, mitotic rate, and margin status.

SDEF and this newspaper are owned by Elsevier.

The 7th edition will make no major changes in the core TNM and stage grouping criteria for stages I-III melanoma. DR. GERSHENWALD

Staging, Lymph Node Assessment Are Key to Surgical Melanoma Management

The surgical management of primary melanoma varies by patient and depends in large part on key elements of the pathology report and the assessment of lymph node involvement, according to Dr. Gershenwald.

In terms of staging the disease, Breslow thickness, ulceration, mitotic rate, Clark level, and margin assessment should be considered prior to wide local excision of the tumor, he noted.

And because nodal involvement is the best predictor of recurrence and survival in melanoma, determining which patients have lymph node involvement and which patients do not is critical to the optimal management of the disease.

Lymphatic mapping together with sentinel lymph node biopsy is a relatively noninvasive way to accurately stage the regional nodal basin and enables a selective approach to regional node dissection, whereby lymphadectomy is reserved only for patients found to have pathologically documented disease, Dr. Gershenwald explained.

This combined diagnostic approach—in which a radioactive tracer is injected around the primary tumor site and a blue dye is used to identify sentinel lymph nodes to be removed for analysis—identifies regional lymph node disease that might not be seen with complete lymph node dissection and identifies patients in whom adjuvant therapy is warranted, he said.

Studies have suggested that early detection by sentinel node biopsy of sentinel lymph node metastasis is associated with a survival benefit when compared with a watch-and-wait approach in patients who develop clinical lymph node recurrence, Dr. Gershenwald noted.

With respect to the use of fluorodeoxyglucose positron-emission tomography (FDG-PET), which has been shown in several reports to be a more sensitive indicator of metastatic melanoma than conventional imaging, limitations in the study designs may overestimate the utility of this imaging modality for this indication, he said.

The literature supports the use of adjunctive PET imaging in properly selected patients with metastatic or recurrent melanoma, but it does not provide evidence suggesting that FDG-PET should be obtained in all melanoma patients, he reported.

Specifically, FDG-PET rarely identifies the presence of occult distant metastases in early stage melanoma patients who have been staged using sentinel node biopsy, whch means the likelihood is low that these patients will be upstaged based on the FDG-PET results.

MAUI, HAWAII — Look for tumor mitotic rate to supplant Clark level in the forthcoming 7th edition of the American Joint Committee on Cancer melanoma staging system.

“Clark level will now only be considered for staging in the rare instances when mitotic rate is not known; otherwise it will no longer be part of the staging system,” Dr. Jeffrey E. Gershenwald said at the annual Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation.

This represents a break with the past. Within melanoma staging, Clark level enjoyed near-equal billing with tumor thickness before being downgraded in clinical relevance in the still-current 6th edition of the AJCC staging system, issued in 2002.

The 6th edition relegated Clark level to a limited role, with Clark level IV and V resulting in upstaging of thin melanomas from T1 to T1b, explained Dr. Gershenwald, vice chair of the AJCC task force charged with developing the new edition of the staging system.

The 7th edition of the AJCC melanoma staging system will be published this spring and will take effect early next year. The same changes will be made in the European staging system in coordinated fashion.

Mitotic rate will be introduced into the staging system on the basis of recent evidence suggesting that it is an independent prognostic factor. The presence of at least one mitosis per square centimeter will be sufficient to upgrade a thin melanoma from T1 to T1b.

As the AJCC staging system is rolled out, reports will be issued detailing how pathologists should determine mitotic rate, according to Dr. Gershenwald, professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston.

Clark level, he added, has caused a great deal of confusion among patients, who often confuse Clark level IV with stage IV melanoma.

“I can't tell you how many patients have come into the clinic thinking they have a stage IV melanoma and are reading their death sentence on the Internet when in fact they might very well have had a thin melanoma that happens to be Clark level IV,” he commented.

“In dialoging with your patients, please make sure they understand the difference,” Dr. Gershenwald urged.

The 7th edition of the staging system will make no major changes in the core TNM (tumor, node, metastasis) and stage grouping criteria for stages I-III melanoma. A thin melanoma will remain one that's up to 1.0 mm in thickness, and a thick one will still have to be greater than 4.0 mm. This was an evidence-based decision in response to analysis of an international database of more than 50,000 melanoma patients which validated the models utilized in the 6th edition.

There will be a few minor changes in the 6th edition having clinical relevance, however. For one, there will no longer be a lower limit as to what constitutes node-positive disease.

Also, immunohistochemical detection of nodal metastases—already in wide use in clinical practice—will for the first time become acceptable for staging purposes in the upcoming edition, Dr. Gershenwald said.

In the 7th edition, the essential elements of a pathology report for primary melanoma will be Breslow thickness, the presence or absence of ulceration, mitotic rate, and margin status.

SDEF and this newspaper are owned by Elsevier.

The 7th edition will make no major changes in the core TNM and stage grouping criteria for stages I-III melanoma. DR. GERSHENWALD

Staging, Lymph Node Assessment Are Key to Surgical Melanoma Management

The surgical management of primary melanoma varies by patient and depends in large part on key elements of the pathology report and the assessment of lymph node involvement, according to Dr. Gershenwald.

In terms of staging the disease, Breslow thickness, ulceration, mitotic rate, Clark level, and margin assessment should be considered prior to wide local excision of the tumor, he noted.

And because nodal involvement is the best predictor of recurrence and survival in melanoma, determining which patients have lymph node involvement and which patients do not is critical to the optimal management of the disease.

Lymphatic mapping together with sentinel lymph node biopsy is a relatively noninvasive way to accurately stage the regional nodal basin and enables a selective approach to regional node dissection, whereby lymphadectomy is reserved only for patients found to have pathologically documented disease, Dr. Gershenwald explained.

This combined diagnostic approach—in which a radioactive tracer is injected around the primary tumor site and a blue dye is used to identify sentinel lymph nodes to be removed for analysis—identifies regional lymph node disease that might not be seen with complete lymph node dissection and identifies patients in whom adjuvant therapy is warranted, he said.

Studies have suggested that early detection by sentinel node biopsy of sentinel lymph node metastasis is associated with a survival benefit when compared with a watch-and-wait approach in patients who develop clinical lymph node recurrence, Dr. Gershenwald noted.

With respect to the use of fluorodeoxyglucose positron-emission tomography (FDG-PET), which has been shown in several reports to be a more sensitive indicator of metastatic melanoma than conventional imaging, limitations in the study designs may overestimate the utility of this imaging modality for this indication, he said.

The literature supports the use of adjunctive PET imaging in properly selected patients with metastatic or recurrent melanoma, but it does not provide evidence suggesting that FDG-PET should be obtained in all melanoma patients, he reported.

Specifically, FDG-PET rarely identifies the presence of occult distant metastases in early stage melanoma patients who have been staged using sentinel node biopsy, whch means the likelihood is low that these patients will be upstaged based on the FDG-PET results.

SAN FRANCISCO — When a dermatopathologist butts heads with a pathologist over a diagnosis, it helps to keep the patient in mind.

"What do you do when your opinion differs radically from that of the contributing pathologist?" asked Dr. Dirk M. Elston, director of dermatology at Geisinger Medical Center, Danville, Pa. "You're getting cases … from all over the country. What you get to look at is sometimes not what the contributor thought. Sometimes it's a sticky situation."

Persistence in the face of diagnostic conflicts—especially when a malignancy is at issue—may be needed to achieve the appropriate treatment. "As long as we keep the patient in mind, we're doing the right thing," said Dr. Elston, who moderated a session at the annual meeting of the American Society of Dermatopathology in which speakers gave examples of cases in which their diagnostic opinions differed from others.

Dr. Ronald P. Rapini described an elderly male patient who had a spindle cell neoplasm on his face in the background of solar elastosis. The biopsy showed relatively bland spindle cells going through the fibrotic sun-damaged dermis. Some areas showed cells that were a little bit atypical, but not strikingly so.

When he looked around the sample more, however, he saw progressively more atypical cells and eventually diagnosed an atypical fibroxanthoma, using the appropriate diagnostic stains, recalled Dr. Rapini, professor and chair of dermatology at the University of Texas M.D. Anderson Cancer Center, Houston.

The patient decided to see a head and neck surgeon at another institution, which requested the biopsy slides for review by their own pathologist. "I'll call him Dr. B, because he diagnosed it as benign," Dr. Rapini said. Dr. B told the head and neck surgeon that the patient had a benign lesion that didn't need excision.

"What would you do?" Dr. Rapini asked. He called a dermatopathologist at the other institution—"I'll call him Dr. C"—and asked him to talk with Dr. B, the pathologist, to request that he at least put an addendum on his report to acknowledge that there was an alternative opinion saying this might be an atypical fibroxanthoma and that it was not a clear-cut case. "So maybe the head and neck surgeon might actually remove the lesion," Dr. Rapini said.

Dr. C reviewed the case and agreed that the lesion looked like an atypical fibroxanthoma. He did speak with Dr. B, but Dr. B refused to modify his pathology report in any way, insisting that this was a benign lesion. Although both Dr. B and Dr. C worked at the same institution, Dr. C felt it would be inappropriate for Dr. C to make an addendum himself on a colleague's case.

"Now what would you do?" Dr. Rapini asked. He asked Dr. C to talk to the head of his institution's pathology department to see what the chair would say. "The actions of the head of the department are not known to me," Dr. Rapini said. The pathology report basically stayed the same.

"Now what would you do?" he repeated. Dr. Rapini called the head and neck surgeon directly to inform him of the alternative opinion, and that Dr. Rapini had diagnosed the lesion as an atypical fibroxanthoma that should be removed.

The surgeon reexcised the area and sent the surgical specimen to the institution's dermatopathologist, who declared it an atypical fibroxanthoma with clear surgical margins. "So it had a happy ending," Dr. Rapini said.

Dr. Elston praised him for sticking with the case: "You were willing to persist, and kept in mind that there was a patient at the other end who had a malignancy that was not being treated appropriately."

Persistence in the face of diagnostic conflicts may be needed to achieve the appropriate treatment. DR. ELSTON

SAN FRANCISCO — When a dermatopathologist butts heads with a pathologist over a diagnosis, it helps to keep the patient in mind.

"What do you do when your opinion differs radically from that of the contributing pathologist?" asked Dr. Dirk M. Elston, director of dermatology at Geisinger Medical Center, Danville, Pa. "You're getting cases … from all over the country. What you get to look at is sometimes not what the contributor thought. Sometimes it's a sticky situation."

Persistence in the face of diagnostic conflicts—especially when a malignancy is at issue—may be needed to achieve the appropriate treatment. "As long as we keep the patient in mind, we're doing the right thing," said Dr. Elston, who moderated a session at the annual meeting of the American Society of Dermatopathology in which speakers gave examples of cases in which their diagnostic opinions differed from others.

Dr. Ronald P. Rapini described an elderly male patient who had a spindle cell neoplasm on his face in the background of solar elastosis. The biopsy showed relatively bland spindle cells going through the fibrotic sun-damaged dermis. Some areas showed cells that were a little bit atypical, but not strikingly so.

When he looked around the sample more, however, he saw progressively more atypical cells and eventually diagnosed an atypical fibroxanthoma, using the appropriate diagnostic stains, recalled Dr. Rapini, professor and chair of dermatology at the University of Texas M.D. Anderson Cancer Center, Houston.

The patient decided to see a head and neck surgeon at another institution, which requested the biopsy slides for review by their own pathologist. "I'll call him Dr. B, because he diagnosed it as benign," Dr. Rapini said. Dr. B told the head and neck surgeon that the patient had a benign lesion that didn't need excision.

"What would you do?" Dr. Rapini asked. He called a dermatopathologist at the other institution—"I'll call him Dr. C"—and asked him to talk with Dr. B, the pathologist, to request that he at least put an addendum on his report to acknowledge that there was an alternative opinion saying this might be an atypical fibroxanthoma and that it was not a clear-cut case. "So maybe the head and neck surgeon might actually remove the lesion," Dr. Rapini said.

Dr. C reviewed the case and agreed that the lesion looked like an atypical fibroxanthoma. He did speak with Dr. B, but Dr. B refused to modify his pathology report in any way, insisting that this was a benign lesion. Although both Dr. B and Dr. C worked at the same institution, Dr. C felt it would be inappropriate for Dr. C to make an addendum himself on a colleague's case.

"Now what would you do?" Dr. Rapini asked. He asked Dr. C to talk to the head of his institution's pathology department to see what the chair would say. "The actions of the head of the department are not known to me," Dr. Rapini said. The pathology report basically stayed the same.

"Now what would you do?" he repeated. Dr. Rapini called the head and neck surgeon directly to inform him of the alternative opinion, and that Dr. Rapini had diagnosed the lesion as an atypical fibroxanthoma that should be removed.

The surgeon reexcised the area and sent the surgical specimen to the institution's dermatopathologist, who declared it an atypical fibroxanthoma with clear surgical margins. "So it had a happy ending," Dr. Rapini said.

Dr. Elston praised him for sticking with the case: "You were willing to persist, and kept in mind that there was a patient at the other end who had a malignancy that was not being treated appropriately."

Persistence in the face of diagnostic conflicts may be needed to achieve the appropriate treatment. DR. ELSTON

SAN FRANCISCO — When a dermatopathologist butts heads with a pathologist over a diagnosis, it helps to keep the patient in mind.

"What do you do when your opinion differs radically from that of the contributing pathologist?" asked Dr. Dirk M. Elston, director of dermatology at Geisinger Medical Center, Danville, Pa. "You're getting cases … from all over the country. What you get to look at is sometimes not what the contributor thought. Sometimes it's a sticky situation."

Persistence in the face of diagnostic conflicts—especially when a malignancy is at issue—may be needed to achieve the appropriate treatment. "As long as we keep the patient in mind, we're doing the right thing," said Dr. Elston, who moderated a session at the annual meeting of the American Society of Dermatopathology in which speakers gave examples of cases in which their diagnostic opinions differed from others.

Dr. Ronald P. Rapini described an elderly male patient who had a spindle cell neoplasm on his face in the background of solar elastosis. The biopsy showed relatively bland spindle cells going through the fibrotic sun-damaged dermis. Some areas showed cells that were a little bit atypical, but not strikingly so.

When he looked around the sample more, however, he saw progressively more atypical cells and eventually diagnosed an atypical fibroxanthoma, using the appropriate diagnostic stains, recalled Dr. Rapini, professor and chair of dermatology at the University of Texas M.D. Anderson Cancer Center, Houston.

The patient decided to see a head and neck surgeon at another institution, which requested the biopsy slides for review by their own pathologist. "I'll call him Dr. B, because he diagnosed it as benign," Dr. Rapini said. Dr. B told the head and neck surgeon that the patient had a benign lesion that didn't need excision.

"What would you do?" Dr. Rapini asked. He called a dermatopathologist at the other institution—"I'll call him Dr. C"—and asked him to talk with Dr. B, the pathologist, to request that he at least put an addendum on his report to acknowledge that there was an alternative opinion saying this might be an atypical fibroxanthoma and that it was not a clear-cut case. "So maybe the head and neck surgeon might actually remove the lesion," Dr. Rapini said.

Dr. C reviewed the case and agreed that the lesion looked like an atypical fibroxanthoma. He did speak with Dr. B, but Dr. B refused to modify his pathology report in any way, insisting that this was a benign lesion. Although both Dr. B and Dr. C worked at the same institution, Dr. C felt it would be inappropriate for Dr. C to make an addendum himself on a colleague's case.

"Now what would you do?" Dr. Rapini asked. He asked Dr. C to talk to the head of his institution's pathology department to see what the chair would say. "The actions of the head of the department are not known to me," Dr. Rapini said. The pathology report basically stayed the same.

"Now what would you do?" he repeated. Dr. Rapini called the head and neck surgeon directly to inform him of the alternative opinion, and that Dr. Rapini had diagnosed the lesion as an atypical fibroxanthoma that should be removed.

The surgeon reexcised the area and sent the surgical specimen to the institution's dermatopathologist, who declared it an atypical fibroxanthoma with clear surgical margins. "So it had a happy ending," Dr. Rapini said.

Dr. Elston praised him for sticking with the case: "You were willing to persist, and kept in mind that there was a patient at the other end who had a malignancy that was not being treated appropriately."

Persistence in the face of diagnostic conflicts may be needed to achieve the appropriate treatment. DR. ELSTON

SAN FRANCISCO — The diagnosis of blastic natural killer-cell lymphoma requires a dermatopathologist who knows the typical immunohistochemical patterns of the disease and is aware of exceptions to rules.

Also called CD4-positive, CD56-positive (CD4+/CD56+) hematodermic neoplasm, the disease is a rare, aggressive malignancy that frequently presents with skin lesions. Immunohistochemical staining typically produces immunopositivity for CD4, CD56, and CD123, but rare cases have been reported of patients who tested negative in one or more of these immunohistochemical studies.

At the annual meeting of the American Society of Dermatopathology, Dr. Rajwant Malhotra and Dr. Alison L. Uzieblo reported on two cases of CD4+/CD56+ hematodermic neoplasm presenting as skin nodules and plaques. One of the cases in their poster was CD123-negative.

"Loss of CD123 expression is a distinctly unusual event" in CD4+/CD56+ hematodermic neoplasm, wrote the authors, both from the anatomic pathology department at Beaumont Hospital, Royal Oak, Mich. Given the poor prognosis associated with this disease, "it is important to be aware of this potential phenomenon when evaluating cutaneous hematolymphoid malignancies."

One patient was a 77-year-old man who presented with skin lesions on his back and trunk. Flow cytometric analysis subsequently showed bone marrow involvement. The second patient, a 70-year-old man, had a 3-cm nodular plaque on his scalp. Further clinical evaluation found no evidence of bone marrow involvement.

Histological examination of biopsies from both patients revealed dense dermal infiltrates composed of sheets of medium-sized cells with angulated to round nuclear contours in the dermis. The lesional cells were positive for CD4, CD43, and CD56, but only one patient's biopsy demonstrated CD123 positivity. Both showed a high proliferation rate with Ki-67 staining noted in approximately 50% of cells in one patient and 70% of cells in the other.

SAN FRANCISCO — The diagnosis of blastic natural killer-cell lymphoma requires a dermatopathologist who knows the typical immunohistochemical patterns of the disease and is aware of exceptions to rules.

Also called CD4-positive, CD56-positive (CD4+/CD56+) hematodermic neoplasm, the disease is a rare, aggressive malignancy that frequently presents with skin lesions. Immunohistochemical staining typically produces immunopositivity for CD4, CD56, and CD123, but rare cases have been reported of patients who tested negative in one or more of these immunohistochemical studies.

At the annual meeting of the American Society of Dermatopathology, Dr. Rajwant Malhotra and Dr. Alison L. Uzieblo reported on two cases of CD4+/CD56+ hematodermic neoplasm presenting as skin nodules and plaques. One of the cases in their poster was CD123-negative.

"Loss of CD123 expression is a distinctly unusual event" in CD4+/CD56+ hematodermic neoplasm, wrote the authors, both from the anatomic pathology department at Beaumont Hospital, Royal Oak, Mich. Given the poor prognosis associated with this disease, "it is important to be aware of this potential phenomenon when evaluating cutaneous hematolymphoid malignancies."

One patient was a 77-year-old man who presented with skin lesions on his back and trunk. Flow cytometric analysis subsequently showed bone marrow involvement. The second patient, a 70-year-old man, had a 3-cm nodular plaque on his scalp. Further clinical evaluation found no evidence of bone marrow involvement.

Histological examination of biopsies from both patients revealed dense dermal infiltrates composed of sheets of medium-sized cells with angulated to round nuclear contours in the dermis. The lesional cells were positive for CD4, CD43, and CD56, but only one patient's biopsy demonstrated CD123 positivity. Both showed a high proliferation rate with Ki-67 staining noted in approximately 50% of cells in one patient and 70% of cells in the other.

SAN FRANCISCO — The diagnosis of blastic natural killer-cell lymphoma requires a dermatopathologist who knows the typical immunohistochemical patterns of the disease and is aware of exceptions to rules.

Also called CD4-positive, CD56-positive (CD4+/CD56+) hematodermic neoplasm, the disease is a rare, aggressive malignancy that frequently presents with skin lesions. Immunohistochemical staining typically produces immunopositivity for CD4, CD56, and CD123, but rare cases have been reported of patients who tested negative in one or more of these immunohistochemical studies.

At the annual meeting of the American Society of Dermatopathology, Dr. Rajwant Malhotra and Dr. Alison L. Uzieblo reported on two cases of CD4+/CD56+ hematodermic neoplasm presenting as skin nodules and plaques. One of the cases in their poster was CD123-negative.

"Loss of CD123 expression is a distinctly unusual event" in CD4+/CD56+ hematodermic neoplasm, wrote the authors, both from the anatomic pathology department at Beaumont Hospital, Royal Oak, Mich. Given the poor prognosis associated with this disease, "it is important to be aware of this potential phenomenon when evaluating cutaneous hematolymphoid malignancies."

One patient was a 77-year-old man who presented with skin lesions on his back and trunk. Flow cytometric analysis subsequently showed bone marrow involvement. The second patient, a 70-year-old man, had a 3-cm nodular plaque on his scalp. Further clinical evaluation found no evidence of bone marrow involvement.

Histological examination of biopsies from both patients revealed dense dermal infiltrates composed of sheets of medium-sized cells with angulated to round nuclear contours in the dermis. The lesional cells were positive for CD4, CD43, and CD56, but only one patient's biopsy demonstrated CD123 positivity. Both showed a high proliferation rate with Ki-67 staining noted in approximately 50% of cells in one patient and 70% of cells in the other.

ORLANDO — It is possible that the presence of micrometastases on sentinel lymph node biopsy may have little clinical prognostic value when predicting the survival of patients with malignant melanoma, according to a review of 415 patients.

The overall survival of those who had micrometastases less than 1 cm was similar to the overall survival achieved by patients with no metastases, Dr. Arun P. Venkat reported at the annual meeting of the American Society for Dermatologic Surgery.

In contrast, overall survival was significantly worse in patients who had macrometastases greater than 1 cm, said Dr. Venkat.

Micrometastases are most often detected with sentinel lymph node biopsy (SLNB), whereas macrometastases can be detected clinically or with positron emission tomography/computed tomography (PET/CT).

"Improved immunohistologic techniques are making it easier to find micrometastases in malignant melanoma, so the real question is whether micrometastases are an accurate predictor of recurrences and prognosis or are we unnecessarily upstaging patients by finding more micrometastases?" said Dr. Venkat, who is a dermatology resident at the University of Iowa Hospitals and Clinics in Iowa City.

The prognostic relevance of micrometastases versus macrometastases "has not been clearly differentiated," he noted.

The 415 patients had been followed for at least 3 months: 73 were deemed to have micrometastases, as evidenced by SLNB, and 81 had macrometastases as evidenced by PET/CT. Patients with macrometastases had a significantly lower probability of survival. Their hazard ratio for all causes of death was 3.73, compared with 2.03 in patients with micrometastastes.

The survival difference between macrometastases versus micrometastases and macrometastases versus no metastases was significant, but the difference between micrometastases and no metastases was not significant, he noted.

"The statistically significant difference in survival using the log-rank test had the following P values: P equal to .029 for macrometastases versus micrometastases, and P less than .0001 for macrometastases versus micrometastases," he said. Adding that "The difference in survival between micrometastases and no metastases was not statistically significant, with a P value of .148."

He offered some explanations as to why micro- and macrometastases would differ prognostically.

"Micrometastases may actually be false positives, as benign nevi can have nevus rests in lymph nodes. Additionally, they might also act as an antigen to activate the immune system to fight against the cutaneous malignant melanoma," he said.

"A few malignant cells in the sentinel lymph nodes may not mean that the prognosis is poor," he added. "The melanoma cells in the lymph nodes may activate the immune system and actually cause an immune response."

Dr. Venkat said he had no conflicts of interest to declare relevant to his presentation.

He noted that the study was funded by an American Society of Dermatologic Surgery Cutting Edge Research Grant.

'Micrometastases may actually be false positives, as benign nevi can have nevus rests in lymph nodes.' DR. VENKAT

ORLANDO — It is possible that the presence of micrometastases on sentinel lymph node biopsy may have little clinical prognostic value when predicting the survival of patients with malignant melanoma, according to a review of 415 patients.

The overall survival of those who had micrometastases less than 1 cm was similar to the overall survival achieved by patients with no metastases, Dr. Arun P. Venkat reported at the annual meeting of the American Society for Dermatologic Surgery.

In contrast, overall survival was significantly worse in patients who had macrometastases greater than 1 cm, said Dr. Venkat.

Micrometastases are most often detected with sentinel lymph node biopsy (SLNB), whereas macrometastases can be detected clinically or with positron emission tomography/computed tomography (PET/CT).

"Improved immunohistologic techniques are making it easier to find micrometastases in malignant melanoma, so the real question is whether micrometastases are an accurate predictor of recurrences and prognosis or are we unnecessarily upstaging patients by finding more micrometastases?" said Dr. Venkat, who is a dermatology resident at the University of Iowa Hospitals and Clinics in Iowa City.

The prognostic relevance of micrometastases versus macrometastases "has not been clearly differentiated," he noted.

The 415 patients had been followed for at least 3 months: 73 were deemed to have micrometastases, as evidenced by SLNB, and 81 had macrometastases as evidenced by PET/CT. Patients with macrometastases had a significantly lower probability of survival. Their hazard ratio for all causes of death was 3.73, compared with 2.03 in patients with micrometastastes.

The survival difference between macrometastases versus micrometastases and macrometastases versus no metastases was significant, but the difference between micrometastases and no metastases was not significant, he noted.

"The statistically significant difference in survival using the log-rank test had the following P values: P equal to .029 for macrometastases versus micrometastases, and P less than .0001 for macrometastases versus micrometastases," he said. Adding that "The difference in survival between micrometastases and no metastases was not statistically significant, with a P value of .148."

He offered some explanations as to why micro- and macrometastases would differ prognostically.

"Micrometastases may actually be false positives, as benign nevi can have nevus rests in lymph nodes. Additionally, they might also act as an antigen to activate the immune system to fight against the cutaneous malignant melanoma," he said.

"A few malignant cells in the sentinel lymph nodes may not mean that the prognosis is poor," he added. "The melanoma cells in the lymph nodes may activate the immune system and actually cause an immune response."

Dr. Venkat said he had no conflicts of interest to declare relevant to his presentation.

He noted that the study was funded by an American Society of Dermatologic Surgery Cutting Edge Research Grant.

'Micrometastases may actually be false positives, as benign nevi can have nevus rests in lymph nodes.' DR. VENKAT

ORLANDO — It is possible that the presence of micrometastases on sentinel lymph node biopsy may have little clinical prognostic value when predicting the survival of patients with malignant melanoma, according to a review of 415 patients.

The overall survival of those who had micrometastases less than 1 cm was similar to the overall survival achieved by patients with no metastases, Dr. Arun P. Venkat reported at the annual meeting of the American Society for Dermatologic Surgery.

In contrast, overall survival was significantly worse in patients who had macrometastases greater than 1 cm, said Dr. Venkat.

Micrometastases are most often detected with sentinel lymph node biopsy (SLNB), whereas macrometastases can be detected clinically or with positron emission tomography/computed tomography (PET/CT).

"Improved immunohistologic techniques are making it easier to find micrometastases in malignant melanoma, so the real question is whether micrometastases are an accurate predictor of recurrences and prognosis or are we unnecessarily upstaging patients by finding more micrometastases?" said Dr. Venkat, who is a dermatology resident at the University of Iowa Hospitals and Clinics in Iowa City.

The prognostic relevance of micrometastases versus macrometastases "has not been clearly differentiated," he noted.

The 415 patients had been followed for at least 3 months: 73 were deemed to have micrometastases, as evidenced by SLNB, and 81 had macrometastases as evidenced by PET/CT. Patients with macrometastases had a significantly lower probability of survival. Their hazard ratio for all causes of death was 3.73, compared with 2.03 in patients with micrometastastes.

The survival difference between macrometastases versus micrometastases and macrometastases versus no metastases was significant, but the difference between micrometastases and no metastases was not significant, he noted.

"The statistically significant difference in survival using the log-rank test had the following P values: P equal to .029 for macrometastases versus micrometastases, and P less than .0001 for macrometastases versus micrometastases," he said. Adding that "The difference in survival between micrometastases and no metastases was not statistically significant, with a P value of .148."

He offered some explanations as to why micro- and macrometastases would differ prognostically.

"Micrometastases may actually be false positives, as benign nevi can have nevus rests in lymph nodes. Additionally, they might also act as an antigen to activate the immune system to fight against the cutaneous malignant melanoma," he said.

"A few malignant cells in the sentinel lymph nodes may not mean that the prognosis is poor," he added. "The melanoma cells in the lymph nodes may activate the immune system and actually cause an immune response."

Dr. Venkat said he had no conflicts of interest to declare relevant to his presentation.

He noted that the study was funded by an American Society of Dermatologic Surgery Cutting Edge Research Grant.

'Micrometastases may actually be false positives, as benign nevi can have nevus rests in lymph nodes.' DR. VENKAT

ORLANDO — Patients who receive multiple solid organ transplants appear to be at significantly higher risk of developing cutaneous malignancy—specifically melanoma and nonmelanoma skin cancer—after their transplants, compared with patients who have had only one transplant.

A total of 6 (26%) of 23 patients who received two or more transplants reported having at least one posttransplant skin cancer, compared with 23 (8%) of 297 patients who had only one transplant. This difference between multiple and single organ transplant recipients was statistically significant, Dr. Murad Alam said at the annual meeting of the American Society for Dermatologic Surgery.

Using a database that was jointly developed by the departments of organ transplantation and dermatology at Northwestern University, Chicago, Dr. Alam and colleagues contacted 320 patients (mean age, 54 years) who received transplanted organs more than 4 years previously. Their transplants included kidney, liver, heart, lung, and pancreas.

The patients were interviewed for 30 minutes by telephone, and asked about their medical and surgical history, including whether they had diabetes. "We postulated that the patients with diabetes who may have had prolonged immunosuppression prior to their transplant might also have a greater incidence of skin cancers after their transplants," explained Dr. Alam of Northwestern.

The patients also provided dates and type of skin cancer, if any, that had developed since their transplants.

Diabetes was not a factor in developing a subsequent skin cancer. Of 91 patients with diabetes, 10 (11%) developed skin cancer, compared with 19 (8%) of 229 patients without diabetes, Dr. Alam said.

The finding that multiple organ transplant is associated with a higher rate of subsequent skin cancer than single organ transplant raises other questions that cannot be answered by a study cohort of this size, he added.

A study with a larger cohort might be able to answer these questions:

▸ Is there a causal link between multiple organ transplants and skin cancer?

▸ Are the risks different for different types of cancer?

▸ Do other comorbidities or medications have an impact on the likelihood of skin cancer in multiple organ transplant recipients?

▸ Which is more likely to increase the risk of skin cancer, concurrent transplants or sequential transplants?

▸ Are there specific types of transplants or specific pairs of transplants that produce greater risk for skin cancer?

"If we can find answers to these questions, we will then be able to tell which patients need to undergo the closest scrutiny for early management of their cancers," Dr. Alam concluded. He disclosed having no conflicts of interest.

The study also found that diabetes was not a factor in developing a subsequent skin cancer. DR. ALAM

ELSEVIER GLOBAL MEDICAL NEWS

ORLANDO — Patients who receive multiple solid organ transplants appear to be at significantly higher risk of developing cutaneous malignancy—specifically melanoma and nonmelanoma skin cancer—after their transplants, compared with patients who have had only one transplant.

A total of 6 (26%) of 23 patients who received two or more transplants reported having at least one posttransplant skin cancer, compared with 23 (8%) of 297 patients who had only one transplant. This difference between multiple and single organ transplant recipients was statistically significant, Dr. Murad Alam said at the annual meeting of the American Society for Dermatologic Surgery.

Using a database that was jointly developed by the departments of organ transplantation and dermatology at Northwestern University, Chicago, Dr. Alam and colleagues contacted 320 patients (mean age, 54 years) who received transplanted organs more than 4 years previously. Their transplants included kidney, liver, heart, lung, and pancreas.

The patients were interviewed for 30 minutes by telephone, and asked about their medical and surgical history, including whether they had diabetes. "We postulated that the patients with diabetes who may have had prolonged immunosuppression prior to their transplant might also have a greater incidence of skin cancers after their transplants," explained Dr. Alam of Northwestern.

The patients also provided dates and type of skin cancer, if any, that had developed since their transplants.

Diabetes was not a factor in developing a subsequent skin cancer. Of 91 patients with diabetes, 10 (11%) developed skin cancer, compared with 19 (8%) of 229 patients without diabetes, Dr. Alam said.

The finding that multiple organ transplant is associated with a higher rate of subsequent skin cancer than single organ transplant raises other questions that cannot be answered by a study cohort of this size, he added.

A study with a larger cohort might be able to answer these questions:

▸ Is there a causal link between multiple organ transplants and skin cancer?

▸ Are the risks different for different types of cancer?

▸ Do other comorbidities or medications have an impact on the likelihood of skin cancer in multiple organ transplant recipients?

▸ Which is more likely to increase the risk of skin cancer, concurrent transplants or sequential transplants?

▸ Are there specific types of transplants or specific pairs of transplants that produce greater risk for skin cancer?

"If we can find answers to these questions, we will then be able to tell which patients need to undergo the closest scrutiny for early management of their cancers," Dr. Alam concluded. He disclosed having no conflicts of interest.

The study also found that diabetes was not a factor in developing a subsequent skin cancer. DR. ALAM

ELSEVIER GLOBAL MEDICAL NEWS

ORLANDO — Patients who receive multiple solid organ transplants appear to be at significantly higher risk of developing cutaneous malignancy—specifically melanoma and nonmelanoma skin cancer—after their transplants, compared with patients who have had only one transplant.

A total of 6 (26%) of 23 patients who received two or more transplants reported having at least one posttransplant skin cancer, compared with 23 (8%) of 297 patients who had only one transplant. This difference between multiple and single organ transplant recipients was statistically significant, Dr. Murad Alam said at the annual meeting of the American Society for Dermatologic Surgery.

Using a database that was jointly developed by the departments of organ transplantation and dermatology at Northwestern University, Chicago, Dr. Alam and colleagues contacted 320 patients (mean age, 54 years) who received transplanted organs more than 4 years previously. Their transplants included kidney, liver, heart, lung, and pancreas.

The patients were interviewed for 30 minutes by telephone, and asked about their medical and surgical history, including whether they had diabetes. "We postulated that the patients with diabetes who may have had prolonged immunosuppression prior to their transplant might also have a greater incidence of skin cancers after their transplants," explained Dr. Alam of Northwestern.

The patients also provided dates and type of skin cancer, if any, that had developed since their transplants.

Diabetes was not a factor in developing a subsequent skin cancer. Of 91 patients with diabetes, 10 (11%) developed skin cancer, compared with 19 (8%) of 229 patients without diabetes, Dr. Alam said.

The finding that multiple organ transplant is associated with a higher rate of subsequent skin cancer than single organ transplant raises other questions that cannot be answered by a study cohort of this size, he added.

A study with a larger cohort might be able to answer these questions:

▸ Is there a causal link between multiple organ transplants and skin cancer?

▸ Are the risks different for different types of cancer?

▸ Do other comorbidities or medications have an impact on the likelihood of skin cancer in multiple organ transplant recipients?

▸ Which is more likely to increase the risk of skin cancer, concurrent transplants or sequential transplants?

▸ Are there specific types of transplants or specific pairs of transplants that produce greater risk for skin cancer?

"If we can find answers to these questions, we will then be able to tell which patients need to undergo the closest scrutiny for early management of their cancers," Dr. Alam concluded. He disclosed having no conflicts of interest.

The study also found that diabetes was not a factor in developing a subsequent skin cancer. DR. ALAM

ELSEVIER GLOBAL MEDICAL NEWS