Melanoma

ZURICH — In vivo confocal laser scanning microscopy is a useful diagnostic tool for pigmented skin lesions that are clinically and dermoscopically equivocal, Dr. Verena Ahlgrimm-Siess said at the annual meeting of the European Society for Dermatological Research.

"The ability to noninvasively analyze the architecture and cytomorphology of pigmented skin lesions permits a preliminary diagnostic evaluation and allows, in context with the clinical and dermoscopic impression, a judgment on the need for biopsy or excision for definitive diagnosis," according to Dr. Ahlgrimm-Siess of the Medical University of Graz (Austria).

Early detection of melanoma is one of the greatest challenges in dermatology, according to Dr. Ahlgrimm-Siess. Studies indicate the sensitivity of clinical diagnosis with the unaided eye is about 65%.

Dermoscopy improves diagnostic accuracy, but it takes a fair amount of time and practice to become skillful. The 10x magnification is another limitation.

Confocal laser scanning microscopy permits real-time noninvasive visualization of epidermal and dermal microanatomic structures and cellular details at a resolution comparable to that obtained in examination of histologic specimens under a conventional microscope.

The novel imaging technology utilizes a near-infrared diode laser at 830 nm wavelength and sufficiently low power—less than 35 mW at the tissue level—that no tissue damage occurs.

Physicians can be taught to use confocal laser scanning microscopy in a 1-hour presentation.

Among the diagnostic features of the laser scanning technique that have proved most helpful to physicians in distinguishing melanomas are monomorphic melanocytic cells, disarray of the melanocytic architecture, and bright collagen fiber bundles.

In a prior study, investigators reported 97.6% sensitivity and 88.2% specificity for confocal laser scanning microscopy in discriminating malignant from benign pigmented skin lesions (J. Invest. Dermatol. 2005;124:493–8) and a positive predictive value of 94.2% in another (Cancer 2006;107:193–200). However, these were lesions in which the distinction using conventional means was relatively clear cut, noted Dr. Ahlgrimm-Siess.

The physician presented a more clinically realistic study involving 50 challenging equivocal pigmented lesions in which melanoma could not be ruled out clinically or dermoscopically. There were 16 melanomas, 3 basal cell carcinomas, 25 melanocytic nevi, and 6 nonmelanocytic pigmented lesions.

Relying solely on the laser scanning microscope images, blinded physicians missed two melanomas, for a diagnostic sensitivity of 89.4% and a specificity of 64.5%.

However, with access to the clinical and dermoscopic images as well as laser scanning microscopy, the specificity climbed to 87% while the sensitivity remained at 89.4%.

Discrimination of benign nevi from early melanoma in situ up to 0.75 mm in thickness could be made in 9 of 11 cases with the laser scanning microscopy alone, for a sensitivity of 81.8% and a specificity of 84%, Dr. Ahlgrimm-Siess added.

The jump in diagnostic specificity from 64.5% with laser scanning microscopy alone to 87% in combination with dermoscopic and clinical evaluation wasn't enough to satisfy the session cochair, Dr. Hywel Williams.

He indicated that he doesn't consider the laser scanning technique ready for prime time as a means of sparing patients from undergoing negative skin biopsies.

"I would be, as a clinician, certainly not happy to be missing 13% or 14% of malignant lesions," said Dr. Williams, professor of dermato-epidemiology at the University of Nottingham (England).

ZURICH — In vivo confocal laser scanning microscopy is a useful diagnostic tool for pigmented skin lesions that are clinically and dermoscopically equivocal, Dr. Verena Ahlgrimm-Siess said at the annual meeting of the European Society for Dermatological Research.

"The ability to noninvasively analyze the architecture and cytomorphology of pigmented skin lesions permits a preliminary diagnostic evaluation and allows, in context with the clinical and dermoscopic impression, a judgment on the need for biopsy or excision for definitive diagnosis," according to Dr. Ahlgrimm-Siess of the Medical University of Graz (Austria).

Early detection of melanoma is one of the greatest challenges in dermatology, according to Dr. Ahlgrimm-Siess. Studies indicate the sensitivity of clinical diagnosis with the unaided eye is about 65%.

Dermoscopy improves diagnostic accuracy, but it takes a fair amount of time and practice to become skillful. The 10x magnification is another limitation.

Confocal laser scanning microscopy permits real-time noninvasive visualization of epidermal and dermal microanatomic structures and cellular details at a resolution comparable to that obtained in examination of histologic specimens under a conventional microscope.

The novel imaging technology utilizes a near-infrared diode laser at 830 nm wavelength and sufficiently low power—less than 35 mW at the tissue level—that no tissue damage occurs.

Physicians can be taught to use confocal laser scanning microscopy in a 1-hour presentation.

Among the diagnostic features of the laser scanning technique that have proved most helpful to physicians in distinguishing melanomas are monomorphic melanocytic cells, disarray of the melanocytic architecture, and bright collagen fiber bundles.

In a prior study, investigators reported 97.6% sensitivity and 88.2% specificity for confocal laser scanning microscopy in discriminating malignant from benign pigmented skin lesions (J. Invest. Dermatol. 2005;124:493–8) and a positive predictive value of 94.2% in another (Cancer 2006;107:193–200). However, these were lesions in which the distinction using conventional means was relatively clear cut, noted Dr. Ahlgrimm-Siess.

The physician presented a more clinically realistic study involving 50 challenging equivocal pigmented lesions in which melanoma could not be ruled out clinically or dermoscopically. There were 16 melanomas, 3 basal cell carcinomas, 25 melanocytic nevi, and 6 nonmelanocytic pigmented lesions.

Relying solely on the laser scanning microscope images, blinded physicians missed two melanomas, for a diagnostic sensitivity of 89.4% and a specificity of 64.5%.

However, with access to the clinical and dermoscopic images as well as laser scanning microscopy, the specificity climbed to 87% while the sensitivity remained at 89.4%.

Discrimination of benign nevi from early melanoma in situ up to 0.75 mm in thickness could be made in 9 of 11 cases with the laser scanning microscopy alone, for a sensitivity of 81.8% and a specificity of 84%, Dr. Ahlgrimm-Siess added.

The jump in diagnostic specificity from 64.5% with laser scanning microscopy alone to 87% in combination with dermoscopic and clinical evaluation wasn't enough to satisfy the session cochair, Dr. Hywel Williams.

He indicated that he doesn't consider the laser scanning technique ready for prime time as a means of sparing patients from undergoing negative skin biopsies.

"I would be, as a clinician, certainly not happy to be missing 13% or 14% of malignant lesions," said Dr. Williams, professor of dermato-epidemiology at the University of Nottingham (England).

ZURICH — In vivo confocal laser scanning microscopy is a useful diagnostic tool for pigmented skin lesions that are clinically and dermoscopically equivocal, Dr. Verena Ahlgrimm-Siess said at the annual meeting of the European Society for Dermatological Research.

"The ability to noninvasively analyze the architecture and cytomorphology of pigmented skin lesions permits a preliminary diagnostic evaluation and allows, in context with the clinical and dermoscopic impression, a judgment on the need for biopsy or excision for definitive diagnosis," according to Dr. Ahlgrimm-Siess of the Medical University of Graz (Austria).

Early detection of melanoma is one of the greatest challenges in dermatology, according to Dr. Ahlgrimm-Siess. Studies indicate the sensitivity of clinical diagnosis with the unaided eye is about 65%.

Dermoscopy improves diagnostic accuracy, but it takes a fair amount of time and practice to become skillful. The 10x magnification is another limitation.

Confocal laser scanning microscopy permits real-time noninvasive visualization of epidermal and dermal microanatomic structures and cellular details at a resolution comparable to that obtained in examination of histologic specimens under a conventional microscope.

The novel imaging technology utilizes a near-infrared diode laser at 830 nm wavelength and sufficiently low power—less than 35 mW at the tissue level—that no tissue damage occurs.

Physicians can be taught to use confocal laser scanning microscopy in a 1-hour presentation.

Among the diagnostic features of the laser scanning technique that have proved most helpful to physicians in distinguishing melanomas are monomorphic melanocytic cells, disarray of the melanocytic architecture, and bright collagen fiber bundles.

In a prior study, investigators reported 97.6% sensitivity and 88.2% specificity for confocal laser scanning microscopy in discriminating malignant from benign pigmented skin lesions (J. Invest. Dermatol. 2005;124:493–8) and a positive predictive value of 94.2% in another (Cancer 2006;107:193–200). However, these were lesions in which the distinction using conventional means was relatively clear cut, noted Dr. Ahlgrimm-Siess.

The physician presented a more clinically realistic study involving 50 challenging equivocal pigmented lesions in which melanoma could not be ruled out clinically or dermoscopically. There were 16 melanomas, 3 basal cell carcinomas, 25 melanocytic nevi, and 6 nonmelanocytic pigmented lesions.

Relying solely on the laser scanning microscope images, blinded physicians missed two melanomas, for a diagnostic sensitivity of 89.4% and a specificity of 64.5%.

However, with access to the clinical and dermoscopic images as well as laser scanning microscopy, the specificity climbed to 87% while the sensitivity remained at 89.4%.

Discrimination of benign nevi from early melanoma in situ up to 0.75 mm in thickness could be made in 9 of 11 cases with the laser scanning microscopy alone, for a sensitivity of 81.8% and a specificity of 84%, Dr. Ahlgrimm-Siess added.

The jump in diagnostic specificity from 64.5% with laser scanning microscopy alone to 87% in combination with dermoscopic and clinical evaluation wasn't enough to satisfy the session cochair, Dr. Hywel Williams.

He indicated that he doesn't consider the laser scanning technique ready for prime time as a means of sparing patients from undergoing negative skin biopsies.

"I would be, as a clinician, certainly not happy to be missing 13% or 14% of malignant lesions," said Dr. Williams, professor of dermato-epidemiology at the University of Nottingham (England).

AMSTERDAM — A panel of immunohistochemical stains, including human epidermal growth factor receptor 2/neu and CDX2, is useful in distinguishing extramammary Paget disease that is limited to the skin versus the subset of secondary extramammary Paget disease that is associated specifically with concurrent or future anogenital cancer, Dr. Jared Abbott said at the 11th World Congress on Cancers of the Skin.

Other investigators have postulated that the triad of cytokeratin 7 (CK7), CK20, and BRST-2 immunohistochemical stains is broadly useful in distinguishing extramammary Paget disease (EMPD) that is limited to the skin—known as primary EMPD—from all forms of secondary extramammary Paget disease, but Dr. Abbott did not find this to be the case in his own large series. Indeed, caution should be exercised in relying upon the triad of immunostains for this purpose, said Dr. Abbott of the Mayo Clinic, Rochester, Minn.

EMPD is an uncommon condition occurring primarily in the elderly, with more women than men affected. It arises as a cutaneous adenocarcinoma with a proclivity for sites rich in apocrine glands. Patients with EMPD often present with a prominent solitary plaque lesion in the anogenital or vulvar region. The lesion is erythematous, eczematous, and often pruritic. The course is often locally aggressive, with frequent recurrences.

The classic histopathologic findings of EMPD consist of clusters of epithelial cells with pagetoid extension throughout the epidermis, often accompanied by a superficial lymphocytic inflammatory infiltrate, he said at the congress, which was sponsored by the Skin Cancer Foundation and Erasmus University.

The distinction between primary and secondary EMPD is important because the prognoses are entirely different. Primary EMPD, which accounts for at least three-quarters of cases, has a good prognosis, whereas secondary EMPD has a very poor prognosis because the skin disorder is often accompanied—or, in the months to come, followed—by a gastrointestinal or genitourinary malignancy. Unfortunately, primary and secondary EMPD can't be differentiated based upon histopathology.

"Their [hematoxylin and eosin stains] look exactly alike," Dr. Abbott said.

Other investigators have turned to immunohistochemical staining patterns in an effort to make the distinction. It has been reported that primary EMPD is often CK7- and BRST-2-positive and CK20-negative, whereas secondary EMPD is BRST-2-negative, CK20-positive, and equivocal in terms of CK7.

To see if he could verify this finding, and to assess the utility of some newer immunohistochemical stains, Dr. Abbott studied excisional biopsy specimens from 61 Mayo Clinic patients with EMPD. The median age at diagnosis was 73 years, and 44 patients were women. A total of 45 patients had primary EMPD. The 16 with secondary EMPD, as determined during a median 4-year follow-up, consisted of seven patients with anorectal carcinomas, four with prostate cancer, and five with urothelial cell cancer.

All patients in both the primary and secondary EMPD groups were CK7-positive, so that was of no help, he said. In addition, CK20, BRST-2, androgen receptor, and cyclin D1 did not prove to be of much assistance in distinguishing primary from secondary EMPD. (See box.)

In contrast, HER2/neu and CDX2 were quite helpful in separating primary from secondary EMPD involving anorectal malignancy. Five of the seven patients with lower GI cancer stained positive for CDX2, and all seven were HER2/neu negative. Unfortunately, no staining pattern proved useful in identifying patients with prostate or urothelial cell cancer.

The finding that more than two-thirds of patients with primary EMPD were HER2/neu-positive, and that the positivity rate was even higher among those with recurrent primary EMPD, raises the possibility that Herceptin (trastuzumab) might be effective in these individuals, although that has never been studied, Dr. Abbott said.

ELSEVIER GLOBAL MEDICAL NEWS

AMSTERDAM — A panel of immunohistochemical stains, including human epidermal growth factor receptor 2/neu and CDX2, is useful in distinguishing extramammary Paget disease that is limited to the skin versus the subset of secondary extramammary Paget disease that is associated specifically with concurrent or future anogenital cancer, Dr. Jared Abbott said at the 11th World Congress on Cancers of the Skin.

Other investigators have postulated that the triad of cytokeratin 7 (CK7), CK20, and BRST-2 immunohistochemical stains is broadly useful in distinguishing extramammary Paget disease (EMPD) that is limited to the skin—known as primary EMPD—from all forms of secondary extramammary Paget disease, but Dr. Abbott did not find this to be the case in his own large series. Indeed, caution should be exercised in relying upon the triad of immunostains for this purpose, said Dr. Abbott of the Mayo Clinic, Rochester, Minn.

EMPD is an uncommon condition occurring primarily in the elderly, with more women than men affected. It arises as a cutaneous adenocarcinoma with a proclivity for sites rich in apocrine glands. Patients with EMPD often present with a prominent solitary plaque lesion in the anogenital or vulvar region. The lesion is erythematous, eczematous, and often pruritic. The course is often locally aggressive, with frequent recurrences.

The classic histopathologic findings of EMPD consist of clusters of epithelial cells with pagetoid extension throughout the epidermis, often accompanied by a superficial lymphocytic inflammatory infiltrate, he said at the congress, which was sponsored by the Skin Cancer Foundation and Erasmus University.

The distinction between primary and secondary EMPD is important because the prognoses are entirely different. Primary EMPD, which accounts for at least three-quarters of cases, has a good prognosis, whereas secondary EMPD has a very poor prognosis because the skin disorder is often accompanied—or, in the months to come, followed—by a gastrointestinal or genitourinary malignancy. Unfortunately, primary and secondary EMPD can't be differentiated based upon histopathology.

"Their [hematoxylin and eosin stains] look exactly alike," Dr. Abbott said.

Other investigators have turned to immunohistochemical staining patterns in an effort to make the distinction. It has been reported that primary EMPD is often CK7- and BRST-2-positive and CK20-negative, whereas secondary EMPD is BRST-2-negative, CK20-positive, and equivocal in terms of CK7.

To see if he could verify this finding, and to assess the utility of some newer immunohistochemical stains, Dr. Abbott studied excisional biopsy specimens from 61 Mayo Clinic patients with EMPD. The median age at diagnosis was 73 years, and 44 patients were women. A total of 45 patients had primary EMPD. The 16 with secondary EMPD, as determined during a median 4-year follow-up, consisted of seven patients with anorectal carcinomas, four with prostate cancer, and five with urothelial cell cancer.

All patients in both the primary and secondary EMPD groups were CK7-positive, so that was of no help, he said. In addition, CK20, BRST-2, androgen receptor, and cyclin D1 did not prove to be of much assistance in distinguishing primary from secondary EMPD. (See box.)

In contrast, HER2/neu and CDX2 were quite helpful in separating primary from secondary EMPD involving anorectal malignancy. Five of the seven patients with lower GI cancer stained positive for CDX2, and all seven were HER2/neu negative. Unfortunately, no staining pattern proved useful in identifying patients with prostate or urothelial cell cancer.

The finding that more than two-thirds of patients with primary EMPD were HER2/neu-positive, and that the positivity rate was even higher among those with recurrent primary EMPD, raises the possibility that Herceptin (trastuzumab) might be effective in these individuals, although that has never been studied, Dr. Abbott said.

ELSEVIER GLOBAL MEDICAL NEWS

AMSTERDAM — A panel of immunohistochemical stains, including human epidermal growth factor receptor 2/neu and CDX2, is useful in distinguishing extramammary Paget disease that is limited to the skin versus the subset of secondary extramammary Paget disease that is associated specifically with concurrent or future anogenital cancer, Dr. Jared Abbott said at the 11th World Congress on Cancers of the Skin.

Other investigators have postulated that the triad of cytokeratin 7 (CK7), CK20, and BRST-2 immunohistochemical stains is broadly useful in distinguishing extramammary Paget disease (EMPD) that is limited to the skin—known as primary EMPD—from all forms of secondary extramammary Paget disease, but Dr. Abbott did not find this to be the case in his own large series. Indeed, caution should be exercised in relying upon the triad of immunostains for this purpose, said Dr. Abbott of the Mayo Clinic, Rochester, Minn.

EMPD is an uncommon condition occurring primarily in the elderly, with more women than men affected. It arises as a cutaneous adenocarcinoma with a proclivity for sites rich in apocrine glands. Patients with EMPD often present with a prominent solitary plaque lesion in the anogenital or vulvar region. The lesion is erythematous, eczematous, and often pruritic. The course is often locally aggressive, with frequent recurrences.

The classic histopathologic findings of EMPD consist of clusters of epithelial cells with pagetoid extension throughout the epidermis, often accompanied by a superficial lymphocytic inflammatory infiltrate, he said at the congress, which was sponsored by the Skin Cancer Foundation and Erasmus University.

The distinction between primary and secondary EMPD is important because the prognoses are entirely different. Primary EMPD, which accounts for at least three-quarters of cases, has a good prognosis, whereas secondary EMPD has a very poor prognosis because the skin disorder is often accompanied—or, in the months to come, followed—by a gastrointestinal or genitourinary malignancy. Unfortunately, primary and secondary EMPD can't be differentiated based upon histopathology.

"Their [hematoxylin and eosin stains] look exactly alike," Dr. Abbott said.

Other investigators have turned to immunohistochemical staining patterns in an effort to make the distinction. It has been reported that primary EMPD is often CK7- and BRST-2-positive and CK20-negative, whereas secondary EMPD is BRST-2-negative, CK20-positive, and equivocal in terms of CK7.

To see if he could verify this finding, and to assess the utility of some newer immunohistochemical stains, Dr. Abbott studied excisional biopsy specimens from 61 Mayo Clinic patients with EMPD. The median age at diagnosis was 73 years, and 44 patients were women. A total of 45 patients had primary EMPD. The 16 with secondary EMPD, as determined during a median 4-year follow-up, consisted of seven patients with anorectal carcinomas, four with prostate cancer, and five with urothelial cell cancer.

All patients in both the primary and secondary EMPD groups were CK7-positive, so that was of no help, he said. In addition, CK20, BRST-2, androgen receptor, and cyclin D1 did not prove to be of much assistance in distinguishing primary from secondary EMPD. (See box.)

In contrast, HER2/neu and CDX2 were quite helpful in separating primary from secondary EMPD involving anorectal malignancy. Five of the seven patients with lower GI cancer stained positive for CDX2, and all seven were HER2/neu negative. Unfortunately, no staining pattern proved useful in identifying patients with prostate or urothelial cell cancer.

The finding that more than two-thirds of patients with primary EMPD were HER2/neu-positive, and that the positivity rate was even higher among those with recurrent primary EMPD, raises the possibility that Herceptin (trastuzumab) might be effective in these individuals, although that has never been studied, Dr. Abbott said.

ELSEVIER GLOBAL MEDICAL NEWS

CORONADO, CALIF. — The side effects associated with epidermal growth factor receptor inhibitors can be so awful that several cancer patients have told Dr. Jonathan Cotliar that they would rather die than continue taking them.

"That's significant when you hear that from many people," Dr. Cotliar said at the annual meeting of the Pacific Dermatologic Association.

One side effect that occurs in 60%–80% of cancer patients who take epidermal growth factor receptor inhibitors (EGFRIs) is skin toxicity, mostly in the form of papulopustular lesions. Paronychia, fissures, xerosis, alopecia, eyelash trichomegaly, telangiectasias, and photosensitivity also can occur.

"I think the companies that developed these drugs underestimated the significance of cutaneous toxicity," said Dr. Cotliar, director of inpatient dermatology services in the division of dermatology at the University of California, Los Angeles.

The incidence of skin toxicity among patients who take the monoclonal antibodies cetuximab (Erbitux) or panitumumab (Vectibix) is somewhat higher compared with those who take the tyrosine kinase inhibitors erlotinib (Tarceva) or gefitinib (Iressa). All of the agents cause apoptosis of keratinocytes. "That's probably the major event that allows for what we see clinically in these patients," he said.

"We also know that there is early initiation of keratinocyte differentiation. In theory, that allows the stratum corneum to become impaired, which leads to many of these toxicities. We also know that inhibition of epidermal growth factor leads to epithelial cell production of proinflammatory mediators. That allows for the adaptive immune response to take hold," he explained.

Papulopustular lesions commonly occur on the face, chest, back, and scalp. The palms and soles are spared.

Histology reveals a thinned stratum corneum, dilated follicular infundibula, necrotic keratinocytes, and mixed inflammation in the upper dermis. "In addition, you may see acantholysis of the follicular epithelium," Dr. Cotliar said.

Ironically, skin toxicity—specifically the papulopustular lesions—is a surrogate marker for treatment efficacy of EGFRIs. "We know that this eruption is more severe and incidence is greater in responders to these medications than in those who don't respond," said Dr. Cotliar, who disclosed that he is a consultant for Amgen Inc., which manufactures panitumumab, and has received honoraria from the company.

"We also know that there is a nice correlation between survival, both overall and progression free, [and] severity of the rash. We don't know if this is an epiphenomenon or if there's something about the cutaneous toxicity that's allowing the immune response to percolate and fight the underlying cancer," he noted.

The severity of papulopustular lesions seems to be linked to the EGFRI dose. "We also know that patients typically develop these lesions 1–3 weeks after their first infusion or their first pills," he said. "The maximal toxicity occurs by weeks 3–5."

Once patients stop taking the EGFRI, the cutaneous side effects usually resolve within a couple of weeks.

There is no current standard for treating skin toxicity associated with EGFRI use. A proposed treatment algorithm was recently published (Oncologist 2007;12:610–21), but "everything we know about treating these patients is based on case reports," Dr. Cotliar said.

A first approach might involve modifying the dose of the EGFRI by following package insert instructions. Most patients referred to Dr. Cotliar and his associates are started on 1% or 2% hydrocortisone or sometimes tetracycline or doxycycline.

"A lot of times I will start patients on doxycycline 100 mg b.i.d.," he said. "I also typically start—for the first week or two—with a mid- to high-potency topical corticosteroid."

One "black hole" among possible treatment options is isotretinoin. "Nobody's sure what effect it has on tumor biology," he said. "We're also not sure of its effect on EGFRIs. We need to know more about that. We do know from case reports that 20–30 mg/day is successful in helping resolve some of these lesions."

Other potential treatments for papulopustular lesions include colloidal oatmeal lotion, topical erythromycin, clindamycin, metronidazole, and topical retinoids.

Potential treatments for xerosis and pruritus triggered by the use of EGFRIs include bland emollients and antihistamines.

Potential treatments for paronychia and fissures include aluminum acetate soaks, 4% thymol, emollients, topical corticosteroids, intralesional steroids, systemic antibiotics, electrodesiccation, cryosurgery, surgical debridement, and nail plate avulsion, Dr. Cotliar said.

Lastly, pulsed dye lasers can be used to treat telangiectasias.

Papulopustular lesions are commonly seen in patients who are taking epidermal growth factor inhibitors. Courtesy Dr. Jonathan Cotliar

CORONADO, CALIF. — The side effects associated with epidermal growth factor receptor inhibitors can be so awful that several cancer patients have told Dr. Jonathan Cotliar that they would rather die than continue taking them.

"That's significant when you hear that from many people," Dr. Cotliar said at the annual meeting of the Pacific Dermatologic Association.

One side effect that occurs in 60%–80% of cancer patients who take epidermal growth factor receptor inhibitors (EGFRIs) is skin toxicity, mostly in the form of papulopustular lesions. Paronychia, fissures, xerosis, alopecia, eyelash trichomegaly, telangiectasias, and photosensitivity also can occur.

"I think the companies that developed these drugs underestimated the significance of cutaneous toxicity," said Dr. Cotliar, director of inpatient dermatology services in the division of dermatology at the University of California, Los Angeles.

The incidence of skin toxicity among patients who take the monoclonal antibodies cetuximab (Erbitux) or panitumumab (Vectibix) is somewhat higher compared with those who take the tyrosine kinase inhibitors erlotinib (Tarceva) or gefitinib (Iressa). All of the agents cause apoptosis of keratinocytes. "That's probably the major event that allows for what we see clinically in these patients," he said.

"We also know that there is early initiation of keratinocyte differentiation. In theory, that allows the stratum corneum to become impaired, which leads to many of these toxicities. We also know that inhibition of epidermal growth factor leads to epithelial cell production of proinflammatory mediators. That allows for the adaptive immune response to take hold," he explained.

Papulopustular lesions commonly occur on the face, chest, back, and scalp. The palms and soles are spared.

Histology reveals a thinned stratum corneum, dilated follicular infundibula, necrotic keratinocytes, and mixed inflammation in the upper dermis. "In addition, you may see acantholysis of the follicular epithelium," Dr. Cotliar said.

Ironically, skin toxicity—specifically the papulopustular lesions—is a surrogate marker for treatment efficacy of EGFRIs. "We know that this eruption is more severe and incidence is greater in responders to these medications than in those who don't respond," said Dr. Cotliar, who disclosed that he is a consultant for Amgen Inc., which manufactures panitumumab, and has received honoraria from the company.

"We also know that there is a nice correlation between survival, both overall and progression free, [and] severity of the rash. We don't know if this is an epiphenomenon or if there's something about the cutaneous toxicity that's allowing the immune response to percolate and fight the underlying cancer," he noted.

The severity of papulopustular lesions seems to be linked to the EGFRI dose. "We also know that patients typically develop these lesions 1–3 weeks after their first infusion or their first pills," he said. "The maximal toxicity occurs by weeks 3–5."

Once patients stop taking the EGFRI, the cutaneous side effects usually resolve within a couple of weeks.

There is no current standard for treating skin toxicity associated with EGFRI use. A proposed treatment algorithm was recently published (Oncologist 2007;12:610–21), but "everything we know about treating these patients is based on case reports," Dr. Cotliar said.

A first approach might involve modifying the dose of the EGFRI by following package insert instructions. Most patients referred to Dr. Cotliar and his associates are started on 1% or 2% hydrocortisone or sometimes tetracycline or doxycycline.

"A lot of times I will start patients on doxycycline 100 mg b.i.d.," he said. "I also typically start—for the first week or two—with a mid- to high-potency topical corticosteroid."

One "black hole" among possible treatment options is isotretinoin. "Nobody's sure what effect it has on tumor biology," he said. "We're also not sure of its effect on EGFRIs. We need to know more about that. We do know from case reports that 20–30 mg/day is successful in helping resolve some of these lesions."

Other potential treatments for papulopustular lesions include colloidal oatmeal lotion, topical erythromycin, clindamycin, metronidazole, and topical retinoids.

Potential treatments for xerosis and pruritus triggered by the use of EGFRIs include bland emollients and antihistamines.

Potential treatments for paronychia and fissures include aluminum acetate soaks, 4% thymol, emollients, topical corticosteroids, intralesional steroids, systemic antibiotics, electrodesiccation, cryosurgery, surgical debridement, and nail plate avulsion, Dr. Cotliar said.

Lastly, pulsed dye lasers can be used to treat telangiectasias.

Papulopustular lesions are commonly seen in patients who are taking epidermal growth factor inhibitors. Courtesy Dr. Jonathan Cotliar

CORONADO, CALIF. — The side effects associated with epidermal growth factor receptor inhibitors can be so awful that several cancer patients have told Dr. Jonathan Cotliar that they would rather die than continue taking them.

"That's significant when you hear that from many people," Dr. Cotliar said at the annual meeting of the Pacific Dermatologic Association.

One side effect that occurs in 60%–80% of cancer patients who take epidermal growth factor receptor inhibitors (EGFRIs) is skin toxicity, mostly in the form of papulopustular lesions. Paronychia, fissures, xerosis, alopecia, eyelash trichomegaly, telangiectasias, and photosensitivity also can occur.

"I think the companies that developed these drugs underestimated the significance of cutaneous toxicity," said Dr. Cotliar, director of inpatient dermatology services in the division of dermatology at the University of California, Los Angeles.

The incidence of skin toxicity among patients who take the monoclonal antibodies cetuximab (Erbitux) or panitumumab (Vectibix) is somewhat higher compared with those who take the tyrosine kinase inhibitors erlotinib (Tarceva) or gefitinib (Iressa). All of the agents cause apoptosis of keratinocytes. "That's probably the major event that allows for what we see clinically in these patients," he said.

"We also know that there is early initiation of keratinocyte differentiation. In theory, that allows the stratum corneum to become impaired, which leads to many of these toxicities. We also know that inhibition of epidermal growth factor leads to epithelial cell production of proinflammatory mediators. That allows for the adaptive immune response to take hold," he explained.

Papulopustular lesions commonly occur on the face, chest, back, and scalp. The palms and soles are spared.

Histology reveals a thinned stratum corneum, dilated follicular infundibula, necrotic keratinocytes, and mixed inflammation in the upper dermis. "In addition, you may see acantholysis of the follicular epithelium," Dr. Cotliar said.

Ironically, skin toxicity—specifically the papulopustular lesions—is a surrogate marker for treatment efficacy of EGFRIs. "We know that this eruption is more severe and incidence is greater in responders to these medications than in those who don't respond," said Dr. Cotliar, who disclosed that he is a consultant for Amgen Inc., which manufactures panitumumab, and has received honoraria from the company.

"We also know that there is a nice correlation between survival, both overall and progression free, [and] severity of the rash. We don't know if this is an epiphenomenon or if there's something about the cutaneous toxicity that's allowing the immune response to percolate and fight the underlying cancer," he noted.

The severity of papulopustular lesions seems to be linked to the EGFRI dose. "We also know that patients typically develop these lesions 1–3 weeks after their first infusion or their first pills," he said. "The maximal toxicity occurs by weeks 3–5."

Once patients stop taking the EGFRI, the cutaneous side effects usually resolve within a couple of weeks.

There is no current standard for treating skin toxicity associated with EGFRI use. A proposed treatment algorithm was recently published (Oncologist 2007;12:610–21), but "everything we know about treating these patients is based on case reports," Dr. Cotliar said.

A first approach might involve modifying the dose of the EGFRI by following package insert instructions. Most patients referred to Dr. Cotliar and his associates are started on 1% or 2% hydrocortisone or sometimes tetracycline or doxycycline.

"A lot of times I will start patients on doxycycline 100 mg b.i.d.," he said. "I also typically start—for the first week or two—with a mid- to high-potency topical corticosteroid."

One "black hole" among possible treatment options is isotretinoin. "Nobody's sure what effect it has on tumor biology," he said. "We're also not sure of its effect on EGFRIs. We need to know more about that. We do know from case reports that 20–30 mg/day is successful in helping resolve some of these lesions."

Other potential treatments for papulopustular lesions include colloidal oatmeal lotion, topical erythromycin, clindamycin, metronidazole, and topical retinoids.

Potential treatments for xerosis and pruritus triggered by the use of EGFRIs include bland emollients and antihistamines.

Potential treatments for paronychia and fissures include aluminum acetate soaks, 4% thymol, emollients, topical corticosteroids, intralesional steroids, systemic antibiotics, electrodesiccation, cryosurgery, surgical debridement, and nail plate avulsion, Dr. Cotliar said.

Lastly, pulsed dye lasers can be used to treat telangiectasias.

Papulopustular lesions are commonly seen in patients who are taking epidermal growth factor inhibitors. Courtesy Dr. Jonathan Cotliar

CORONADO, CALIF. — Topical red wine, green tea, and caffeine polyphenols may play a role as chemopreventive agents for actinic keratoses and photodamaged skin, results from a small pilot study suggest.

The first part of the study was designed to assess the safety and efficacy of the individual polyphenols. The second part of the study was designed to assess the efficacy of combination therapy (green tea polyphenols plus vitamin C or red wine polyphenols plus caffeine), Dr. Karen F. Han said at the annual meeting of the Pacific Dermatologic Association.

Patients were eligible for the study if they had at least three actinic keratoses on each forearm, each dorsal hand, or the face/scalp/neck area, and were otherwise in good health.

In a double-blind, left-to-right placebo-controlled trial, the subjects were randomly assigned to one of the tested gels and a placebo gel. Patients were instructed to apply the gels twice a day for 12 weeks.

Before and after clinical photographs were taken, shave or 2-mm punch biopsies were obtained, and the patients were followed monthly for a total of four visits.

At each monthly follow-up visit, Dr. Han, a dermatologist in group practice in Palo Alto, Calif., mapped and counted actinic keratoses, took clinical photographs, and reviewed each patient's self-assessment form. The main outcome measure was the total number of residual actinic keratoses; the secondary outcome measure was an assessment of signs of photodamage, including dyschromia, wrinkling, texture, and telangiectasia.

In part 1 of the study, Dr. Han saw a statistically significant difference between the treatment sides and placebo sides in 11 of 14 patients. Of those 14 patients, 7 (50%) had reduced numbers of actinic keratoses that favored the treatment side. The reduction ranged from 60% to 100% clearance.

In part 2 of the study, Dr. Han observed a statistically significant difference between the treatment sides and the placebo sides in eight of nine patients who completed this component of the trial. Of those nine patients, seven (78%) had reduced numbers of actinic keratoses that favored the treatment side. The reduction ranged from 50% to 85% clearance.

Shantel Medical Supply Corp. supplied the gels used for the trial, but Dr. Han did not receive any financial support from the company.

Seven of nine patients had significantlyfewer actinic keratoses on the combination therapy side. DR. HAN

CORONADO, CALIF. — Topical red wine, green tea, and caffeine polyphenols may play a role as chemopreventive agents for actinic keratoses and photodamaged skin, results from a small pilot study suggest.

The first part of the study was designed to assess the safety and efficacy of the individual polyphenols. The second part of the study was designed to assess the efficacy of combination therapy (green tea polyphenols plus vitamin C or red wine polyphenols plus caffeine), Dr. Karen F. Han said at the annual meeting of the Pacific Dermatologic Association.

Patients were eligible for the study if they had at least three actinic keratoses on each forearm, each dorsal hand, or the face/scalp/neck area, and were otherwise in good health.

In a double-blind, left-to-right placebo-controlled trial, the subjects were randomly assigned to one of the tested gels and a placebo gel. Patients were instructed to apply the gels twice a day for 12 weeks.

Before and after clinical photographs were taken, shave or 2-mm punch biopsies were obtained, and the patients were followed monthly for a total of four visits.

At each monthly follow-up visit, Dr. Han, a dermatologist in group practice in Palo Alto, Calif., mapped and counted actinic keratoses, took clinical photographs, and reviewed each patient's self-assessment form. The main outcome measure was the total number of residual actinic keratoses; the secondary outcome measure was an assessment of signs of photodamage, including dyschromia, wrinkling, texture, and telangiectasia.

In part 1 of the study, Dr. Han saw a statistically significant difference between the treatment sides and placebo sides in 11 of 14 patients. Of those 14 patients, 7 (50%) had reduced numbers of actinic keratoses that favored the treatment side. The reduction ranged from 60% to 100% clearance.

In part 2 of the study, Dr. Han observed a statistically significant difference between the treatment sides and the placebo sides in eight of nine patients who completed this component of the trial. Of those nine patients, seven (78%) had reduced numbers of actinic keratoses that favored the treatment side. The reduction ranged from 50% to 85% clearance.

Shantel Medical Supply Corp. supplied the gels used for the trial, but Dr. Han did not receive any financial support from the company.

Seven of nine patients had significantlyfewer actinic keratoses on the combination therapy side. DR. HAN

CORONADO, CALIF. — Topical red wine, green tea, and caffeine polyphenols may play a role as chemopreventive agents for actinic keratoses and photodamaged skin, results from a small pilot study suggest.

The first part of the study was designed to assess the safety and efficacy of the individual polyphenols. The second part of the study was designed to assess the efficacy of combination therapy (green tea polyphenols plus vitamin C or red wine polyphenols plus caffeine), Dr. Karen F. Han said at the annual meeting of the Pacific Dermatologic Association.

Patients were eligible for the study if they had at least three actinic keratoses on each forearm, each dorsal hand, or the face/scalp/neck area, and were otherwise in good health.

In a double-blind, left-to-right placebo-controlled trial, the subjects were randomly assigned to one of the tested gels and a placebo gel. Patients were instructed to apply the gels twice a day for 12 weeks.

Before and after clinical photographs were taken, shave or 2-mm punch biopsies were obtained, and the patients were followed monthly for a total of four visits.

At each monthly follow-up visit, Dr. Han, a dermatologist in group practice in Palo Alto, Calif., mapped and counted actinic keratoses, took clinical photographs, and reviewed each patient's self-assessment form. The main outcome measure was the total number of residual actinic keratoses; the secondary outcome measure was an assessment of signs of photodamage, including dyschromia, wrinkling, texture, and telangiectasia.

In part 1 of the study, Dr. Han saw a statistically significant difference between the treatment sides and placebo sides in 11 of 14 patients. Of those 14 patients, 7 (50%) had reduced numbers of actinic keratoses that favored the treatment side. The reduction ranged from 60% to 100% clearance.

In part 2 of the study, Dr. Han observed a statistically significant difference between the treatment sides and the placebo sides in eight of nine patients who completed this component of the trial. Of those nine patients, seven (78%) had reduced numbers of actinic keratoses that favored the treatment side. The reduction ranged from 50% to 85% clearance.

Shantel Medical Supply Corp. supplied the gels used for the trial, but Dr. Han did not receive any financial support from the company.

Seven of nine patients had significantlyfewer actinic keratoses on the combination therapy side. DR. HAN

AMSTERDAM — The natural history of actinic keratoses involves high turnover and far greater lability than generally recognized, according to a first-of-its-kind study.

"When you count three or four AKs on a person at time zero and come back and find three or four at time one you may think you're looking at the same AKs, but this study shows you're not. You're probably looking at six or seven different AKs—three have regressed and three others have taken their place," Dr. Adele C. Green said at the 11th World Congress on Cancers of the Skin.

Indeed, she compared AKs to whitecaps arising in a sea of dysplastic skin, then ebbing below the point of detection before reforming.

"It's striking how high the turnover is. This is such a dynamic population. The more frequently you look at patients and count their AKs, the more turnover you see," added Dr. Green, head of the cancer and population studies group at the Queensland Institute of Medical Research, Brisbane, Australia.

The other impressive finding from this AK substudy—conducted within the larger prospective, longitudinal, community-based Nambour Skin Cancer Study—was that a small percentage of individuals carry a disproportionate load of the total AK burden. While the risk that any individual AK will transform into invasive nonmelanoma skin cancer is extremely low, the high total AK count in this heavily burdened subgroup identifies affected individuals as being at high risk.

The AK substudy involved 96 randomly selected adults, equally divided between men and women, who underwent detailed skin examinations every 2–6 months during which every AK was stenciled onto a clear plastic-wrap body map for purposes of lesion comparison over time.

At baseline, 53 of the 96 participants had no prevalent AKs, while the other 43 had a total of 494 lesions. Twelve percent of subjects had 65% of all prevalent AKs.

During the first 12 months of follow-up, 549 new AKs occurred in men and just 65 in women. Meanwhile, 526 prevalent AKs regressed and 53 prevalent AKs regressed and then recurred. The result was a 1-year net 45% increase in the number of AKs in men and a 44% net decrease in women. Seventy-four percent of prevalent AKs regressed, as did 29% of incident AKs.

Participants with baseline AKs were more than sevenfold more likely to develop additional AKs in the next year, Dr. Green noted at the congress, cosponsored by the Skin Cancer Foundation and Erasmus University.

The clinical relevance of these findings about the natural history of AKs hinges on the fact that the full 1,621-subject Nambour study showed that regular use of a broad-spectrum sunscreen markedly reduced the incidence of both AKs and invasive squamous cell carcinomas. Since AKs arise and regress so frequently in a field of sun-damaged skin and there is no way to identify which ones will transform into skin cancer, it's illogical to treat individual lesions with cryotherapy, as many dermatologists persist in doing, she continued.

This argument struck a responsive chord with other speakers. "For field cancerization, we need field therapy," agreed Dr. Tobias Forschner of the skin cancer center at Charité University Hospital, Berlin.

"We have lots of treatment options—I would say an armada," Dr. Forschner added, citing the intense commercial interest in field therapy using photodynamic therapy, imiquimod, diclofenac, and 5-fluorouracil.

AMSTERDAM — The natural history of actinic keratoses involves high turnover and far greater lability than generally recognized, according to a first-of-its-kind study.

"When you count three or four AKs on a person at time zero and come back and find three or four at time one you may think you're looking at the same AKs, but this study shows you're not. You're probably looking at six or seven different AKs—three have regressed and three others have taken their place," Dr. Adele C. Green said at the 11th World Congress on Cancers of the Skin.

Indeed, she compared AKs to whitecaps arising in a sea of dysplastic skin, then ebbing below the point of detection before reforming.

"It's striking how high the turnover is. This is such a dynamic population. The more frequently you look at patients and count their AKs, the more turnover you see," added Dr. Green, head of the cancer and population studies group at the Queensland Institute of Medical Research, Brisbane, Australia.

The other impressive finding from this AK substudy—conducted within the larger prospective, longitudinal, community-based Nambour Skin Cancer Study—was that a small percentage of individuals carry a disproportionate load of the total AK burden. While the risk that any individual AK will transform into invasive nonmelanoma skin cancer is extremely low, the high total AK count in this heavily burdened subgroup identifies affected individuals as being at high risk.

The AK substudy involved 96 randomly selected adults, equally divided between men and women, who underwent detailed skin examinations every 2–6 months during which every AK was stenciled onto a clear plastic-wrap body map for purposes of lesion comparison over time.

At baseline, 53 of the 96 participants had no prevalent AKs, while the other 43 had a total of 494 lesions. Twelve percent of subjects had 65% of all prevalent AKs.

During the first 12 months of follow-up, 549 new AKs occurred in men and just 65 in women. Meanwhile, 526 prevalent AKs regressed and 53 prevalent AKs regressed and then recurred. The result was a 1-year net 45% increase in the number of AKs in men and a 44% net decrease in women. Seventy-four percent of prevalent AKs regressed, as did 29% of incident AKs.

Participants with baseline AKs were more than sevenfold more likely to develop additional AKs in the next year, Dr. Green noted at the congress, cosponsored by the Skin Cancer Foundation and Erasmus University.

The clinical relevance of these findings about the natural history of AKs hinges on the fact that the full 1,621-subject Nambour study showed that regular use of a broad-spectrum sunscreen markedly reduced the incidence of both AKs and invasive squamous cell carcinomas. Since AKs arise and regress so frequently in a field of sun-damaged skin and there is no way to identify which ones will transform into skin cancer, it's illogical to treat individual lesions with cryotherapy, as many dermatologists persist in doing, she continued.

This argument struck a responsive chord with other speakers. "For field cancerization, we need field therapy," agreed Dr. Tobias Forschner of the skin cancer center at Charité University Hospital, Berlin.

"We have lots of treatment options—I would say an armada," Dr. Forschner added, citing the intense commercial interest in field therapy using photodynamic therapy, imiquimod, diclofenac, and 5-fluorouracil.

AMSTERDAM — The natural history of actinic keratoses involves high turnover and far greater lability than generally recognized, according to a first-of-its-kind study.

"When you count three or four AKs on a person at time zero and come back and find three or four at time one you may think you're looking at the same AKs, but this study shows you're not. You're probably looking at six or seven different AKs—three have regressed and three others have taken their place," Dr. Adele C. Green said at the 11th World Congress on Cancers of the Skin.

Indeed, she compared AKs to whitecaps arising in a sea of dysplastic skin, then ebbing below the point of detection before reforming.

"It's striking how high the turnover is. This is such a dynamic population. The more frequently you look at patients and count their AKs, the more turnover you see," added Dr. Green, head of the cancer and population studies group at the Queensland Institute of Medical Research, Brisbane, Australia.

The other impressive finding from this AK substudy—conducted within the larger prospective, longitudinal, community-based Nambour Skin Cancer Study—was that a small percentage of individuals carry a disproportionate load of the total AK burden. While the risk that any individual AK will transform into invasive nonmelanoma skin cancer is extremely low, the high total AK count in this heavily burdened subgroup identifies affected individuals as being at high risk.

The AK substudy involved 96 randomly selected adults, equally divided between men and women, who underwent detailed skin examinations every 2–6 months during which every AK was stenciled onto a clear plastic-wrap body map for purposes of lesion comparison over time.

At baseline, 53 of the 96 participants had no prevalent AKs, while the other 43 had a total of 494 lesions. Twelve percent of subjects had 65% of all prevalent AKs.

During the first 12 months of follow-up, 549 new AKs occurred in men and just 65 in women. Meanwhile, 526 prevalent AKs regressed and 53 prevalent AKs regressed and then recurred. The result was a 1-year net 45% increase in the number of AKs in men and a 44% net decrease in women. Seventy-four percent of prevalent AKs regressed, as did 29% of incident AKs.

Participants with baseline AKs were more than sevenfold more likely to develop additional AKs in the next year, Dr. Green noted at the congress, cosponsored by the Skin Cancer Foundation and Erasmus University.

The clinical relevance of these findings about the natural history of AKs hinges on the fact that the full 1,621-subject Nambour study showed that regular use of a broad-spectrum sunscreen markedly reduced the incidence of both AKs and invasive squamous cell carcinomas. Since AKs arise and regress so frequently in a field of sun-damaged skin and there is no way to identify which ones will transform into skin cancer, it's illogical to treat individual lesions with cryotherapy, as many dermatologists persist in doing, she continued.

This argument struck a responsive chord with other speakers. "For field cancerization, we need field therapy," agreed Dr. Tobias Forschner of the skin cancer center at Charité University Hospital, Berlin.

"We have lots of treatment options—I would say an armada," Dr. Forschner added, citing the intense commercial interest in field therapy using photodynamic therapy, imiquimod, diclofenac, and 5-fluorouracil.

AMSTERDAM — Recent European guidelines classifying actinic keratoses as in situ squamous cell carcinoma came under fire in a panel discussion at the 11th World Congress on Cancers of the Skin.

"Since our histopathologist started calling AKs carcinoma in situ I've had four patients in my outpatient clinic crying because they were given the diagnosis of cancer. They had to wait 3 weeks for a follow-up appointment to have somebody explain the situation to them, and it was 3 weeks of hell. They were afraid of dying. So I think from the patient's point of view this classification is a big mistake," said Dr. Alexis Sidoroff of the Medical University of Innsbruck (Austria).

Dr. Eggert Stockfleth, lead author of the published guidelines (Eur. J. Dermatol. 2006;16:599–606) developed by the European Dermatology Forum and accepted by the Union of European Medical Specialists, defended the classification scheme on the basis of the histopathologic changes and genetic mutations shared by actinic keratoses (AKs) and squamous cell carcinomas (SCCs).

"Actinic keratosis is an early stage of cancer. It is not a precursor lesion," declared Dr. Stockfleth, director of the skin cancer clinic at Charité University Hospital, Berlin.

With the incidence of nonmelanoma skin cancer climbing worldwide by 7%–10% per year, the guidelines committee felt that routine treatment of AKs is warranted to combat the problem, he said.

Dr. Irene Leigh, however, argued that categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. The chance that any individual AK will transform into invasive SCC is extremely low, so it is better to view AKs as markers of increased risk of SCC. These AKs arise and often regress in a field of sun-damaged, dysplastic skin that is undergoing a process called field cancerization or simply field change, out of which most SCCs arise, she said.

"I don't call these lesions carcinoma in situ. I call them AKs. I don't think every AK is going to progress to squamous cell carcinoma. There's evidence for regression of AKs, and there's not much evidence for anything else," said Dr. Leigh of the University of Dundee (Scotland).

Dr. Hywel Williams expanded on this theme. "We are dealing with a field change. Surely what we see physically is like mushrooms in a mycelium of squamous metaplasia. The mushrooms pop up and others go down. To me, the idea that by freezing or otherwise treating a single lesion of AK we're dealing with the problem seems delusional," said Dr. Williams, professor of dermatology at the University of Nottingham (England).

"We are still in 2007 deluding ourselves about the value of destructive therapies for visible lesions and playing into the agenda of an enormous industry with vested interest in maintaining this ritual that we have," he added at the congress cosponsored by the Skin Cancer Foundation and Erasmus University, Rotterdam, the Netherlands.

Dr. Jean-Jacques Grob agreed that the case for routinely treating AKs to prevent SCC is weak in immunocompetent patients. Nor is there any persuasive evidence as yet that invasive SCCs can be prevented by treating the field cancerization process itself, although clinical trials involving imiquimod, photodynamic therapy, and other treatments are ongoing, noted Dr. Grob, professor of dermatology at the University of Marseille (France).

"Let's face it, aside from a few studies showing regular use of sunscreens prevents AKs, the field is a mess," Dr. Williams agreed. "There's a shocking lack of good-quality evidence to inform the debate. That's especially painful to see in a condition as common as this."

Categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. DR. LEIGH

AMSTERDAM — Recent European guidelines classifying actinic keratoses as in situ squamous cell carcinoma came under fire in a panel discussion at the 11th World Congress on Cancers of the Skin.

"Since our histopathologist started calling AKs carcinoma in situ I've had four patients in my outpatient clinic crying because they were given the diagnosis of cancer. They had to wait 3 weeks for a follow-up appointment to have somebody explain the situation to them, and it was 3 weeks of hell. They were afraid of dying. So I think from the patient's point of view this classification is a big mistake," said Dr. Alexis Sidoroff of the Medical University of Innsbruck (Austria).

Dr. Eggert Stockfleth, lead author of the published guidelines (Eur. J. Dermatol. 2006;16:599–606) developed by the European Dermatology Forum and accepted by the Union of European Medical Specialists, defended the classification scheme on the basis of the histopathologic changes and genetic mutations shared by actinic keratoses (AKs) and squamous cell carcinomas (SCCs).

"Actinic keratosis is an early stage of cancer. It is not a precursor lesion," declared Dr. Stockfleth, director of the skin cancer clinic at Charité University Hospital, Berlin.

With the incidence of nonmelanoma skin cancer climbing worldwide by 7%–10% per year, the guidelines committee felt that routine treatment of AKs is warranted to combat the problem, he said.

Dr. Irene Leigh, however, argued that categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. The chance that any individual AK will transform into invasive SCC is extremely low, so it is better to view AKs as markers of increased risk of SCC. These AKs arise and often regress in a field of sun-damaged, dysplastic skin that is undergoing a process called field cancerization or simply field change, out of which most SCCs arise, she said.

"I don't call these lesions carcinoma in situ. I call them AKs. I don't think every AK is going to progress to squamous cell carcinoma. There's evidence for regression of AKs, and there's not much evidence for anything else," said Dr. Leigh of the University of Dundee (Scotland).

Dr. Hywel Williams expanded on this theme. "We are dealing with a field change. Surely what we see physically is like mushrooms in a mycelium of squamous metaplasia. The mushrooms pop up and others go down. To me, the idea that by freezing or otherwise treating a single lesion of AK we're dealing with the problem seems delusional," said Dr. Williams, professor of dermatology at the University of Nottingham (England).

"We are still in 2007 deluding ourselves about the value of destructive therapies for visible lesions and playing into the agenda of an enormous industry with vested interest in maintaining this ritual that we have," he added at the congress cosponsored by the Skin Cancer Foundation and Erasmus University, Rotterdam, the Netherlands.

Dr. Jean-Jacques Grob agreed that the case for routinely treating AKs to prevent SCC is weak in immunocompetent patients. Nor is there any persuasive evidence as yet that invasive SCCs can be prevented by treating the field cancerization process itself, although clinical trials involving imiquimod, photodynamic therapy, and other treatments are ongoing, noted Dr. Grob, professor of dermatology at the University of Marseille (France).

"Let's face it, aside from a few studies showing regular use of sunscreens prevents AKs, the field is a mess," Dr. Williams agreed. "There's a shocking lack of good-quality evidence to inform the debate. That's especially painful to see in a condition as common as this."

Categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. DR. LEIGH

AMSTERDAM — Recent European guidelines classifying actinic keratoses as in situ squamous cell carcinoma came under fire in a panel discussion at the 11th World Congress on Cancers of the Skin.

"Since our histopathologist started calling AKs carcinoma in situ I've had four patients in my outpatient clinic crying because they were given the diagnosis of cancer. They had to wait 3 weeks for a follow-up appointment to have somebody explain the situation to them, and it was 3 weeks of hell. They were afraid of dying. So I think from the patient's point of view this classification is a big mistake," said Dr. Alexis Sidoroff of the Medical University of Innsbruck (Austria).

Dr. Eggert Stockfleth, lead author of the published guidelines (Eur. J. Dermatol. 2006;16:599–606) developed by the European Dermatology Forum and accepted by the Union of European Medical Specialists, defended the classification scheme on the basis of the histopathologic changes and genetic mutations shared by actinic keratoses (AKs) and squamous cell carcinomas (SCCs).

"Actinic keratosis is an early stage of cancer. It is not a precursor lesion," declared Dr. Stockfleth, director of the skin cancer clinic at Charité University Hospital, Berlin.

With the incidence of nonmelanoma skin cancer climbing worldwide by 7%–10% per year, the guidelines committee felt that routine treatment of AKs is warranted to combat the problem, he said.

Dr. Irene Leigh, however, argued that categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. The chance that any individual AK will transform into invasive SCC is extremely low, so it is better to view AKs as markers of increased risk of SCC. These AKs arise and often regress in a field of sun-damaged, dysplastic skin that is undergoing a process called field cancerization or simply field change, out of which most SCCs arise, she said.

"I don't call these lesions carcinoma in situ. I call them AKs. I don't think every AK is going to progress to squamous cell carcinoma. There's evidence for regression of AKs, and there's not much evidence for anything else," said Dr. Leigh of the University of Dundee (Scotland).

Dr. Hywel Williams expanded on this theme. "We are dealing with a field change. Surely what we see physically is like mushrooms in a mycelium of squamous metaplasia. The mushrooms pop up and others go down. To me, the idea that by freezing or otherwise treating a single lesion of AK we're dealing with the problem seems delusional," said Dr. Williams, professor of dermatology at the University of Nottingham (England).

"We are still in 2007 deluding ourselves about the value of destructive therapies for visible lesions and playing into the agenda of an enormous industry with vested interest in maintaining this ritual that we have," he added at the congress cosponsored by the Skin Cancer Foundation and Erasmus University, Rotterdam, the Netherlands.

Dr. Jean-Jacques Grob agreed that the case for routinely treating AKs to prevent SCC is weak in immunocompetent patients. Nor is there any persuasive evidence as yet that invasive SCCs can be prevented by treating the field cancerization process itself, although clinical trials involving imiquimod, photodynamic therapy, and other treatments are ongoing, noted Dr. Grob, professor of dermatology at the University of Marseille (France).

"Let's face it, aside from a few studies showing regular use of sunscreens prevents AKs, the field is a mess," Dr. Williams agreed. "There's a shocking lack of good-quality evidence to inform the debate. That's especially painful to see in a condition as common as this."

Categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. DR. LEIGH

LOS ANGELES — The proportion of skin excisions for malignant lesions relative to benign lesions increased between 1993 and 2002, Dr. Marta J. Van Beek said at the annual meeting of the Society for Investigational Dermatology.

That finding "is something that we weren't really expecting to see," said Dr. Van Beek of the University of Iowa, Iowa City.

She and her associates studied CPT data between 1993 and 2002 from a random sample of 5% of Medicare recipients living in nine regions covered by the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database.

They weren't surprised to find increasing numbers over time for skin biopsies, shave removals, excisions, and other dermatologic procedures, given the rising incidence of skin cancer. In clinical practice, however, a certain number of benign lesions are biopsied over time to ensure complete ascertainment of malignancies. If clinical thresholds for a skin biopsy remain constant, it would be reasonable to expect a constant ratio of benign to malignant episodes of care over time, even in the setting of an increasing incidence of skin cancer, she explained.

Instead, the rate of benign excisions decreased from 45 per 1,000 Medicare beneficiaries in 1993 to 30/1,000 in 2002, Dr. Van Beek said. Malignant excisions increased from 25/1,000 to 27/1,000 in that period.

Skin biopsies increased from 55/1,000 to 90/1,000 beneficiaries, shave removals increased from 22/1,000 to 38/1,000, and Mohs procedures jumped from 5/1,000 to 11/1,000 beneficiaries.

Since some biopsies or lesion removals are performed not because of suspected cancer but for diagnosis of inflammatory eruptions, or because patients find lesions irritating or unsightly, Dr. Van Beek and her associates created categories that they called malignant, benign, or unknown "episodes of care." The ratio of malignant to benign episodes of care increased from 1.4 in 1993 to 2.2 in 2002, indicating a surge in malignant episodes of care.

Besides the rising incidence of cancer, factors that may have influenced these trends in health care utilization include access to specialist care and changes in coding and billing practices.

LOS ANGELES — The proportion of skin excisions for malignant lesions relative to benign lesions increased between 1993 and 2002, Dr. Marta J. Van Beek said at the annual meeting of the Society for Investigational Dermatology.

That finding "is something that we weren't really expecting to see," said Dr. Van Beek of the University of Iowa, Iowa City.

She and her associates studied CPT data between 1993 and 2002 from a random sample of 5% of Medicare recipients living in nine regions covered by the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database.

They weren't surprised to find increasing numbers over time for skin biopsies, shave removals, excisions, and other dermatologic procedures, given the rising incidence of skin cancer. In clinical practice, however, a certain number of benign lesions are biopsied over time to ensure complete ascertainment of malignancies. If clinical thresholds for a skin biopsy remain constant, it would be reasonable to expect a constant ratio of benign to malignant episodes of care over time, even in the setting of an increasing incidence of skin cancer, she explained.

Instead, the rate of benign excisions decreased from 45 per 1,000 Medicare beneficiaries in 1993 to 30/1,000 in 2002, Dr. Van Beek said. Malignant excisions increased from 25/1,000 to 27/1,000 in that period.

Skin biopsies increased from 55/1,000 to 90/1,000 beneficiaries, shave removals increased from 22/1,000 to 38/1,000, and Mohs procedures jumped from 5/1,000 to 11/1,000 beneficiaries.

Since some biopsies or lesion removals are performed not because of suspected cancer but for diagnosis of inflammatory eruptions, or because patients find lesions irritating or unsightly, Dr. Van Beek and her associates created categories that they called malignant, benign, or unknown "episodes of care." The ratio of malignant to benign episodes of care increased from 1.4 in 1993 to 2.2 in 2002, indicating a surge in malignant episodes of care.

Besides the rising incidence of cancer, factors that may have influenced these trends in health care utilization include access to specialist care and changes in coding and billing practices.

LOS ANGELES — The proportion of skin excisions for malignant lesions relative to benign lesions increased between 1993 and 2002, Dr. Marta J. Van Beek said at the annual meeting of the Society for Investigational Dermatology.

That finding "is something that we weren't really expecting to see," said Dr. Van Beek of the University of Iowa, Iowa City.

She and her associates studied CPT data between 1993 and 2002 from a random sample of 5% of Medicare recipients living in nine regions covered by the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database.

They weren't surprised to find increasing numbers over time for skin biopsies, shave removals, excisions, and other dermatologic procedures, given the rising incidence of skin cancer. In clinical practice, however, a certain number of benign lesions are biopsied over time to ensure complete ascertainment of malignancies. If clinical thresholds for a skin biopsy remain constant, it would be reasonable to expect a constant ratio of benign to malignant episodes of care over time, even in the setting of an increasing incidence of skin cancer, she explained.

Instead, the rate of benign excisions decreased from 45 per 1,000 Medicare beneficiaries in 1993 to 30/1,000 in 2002, Dr. Van Beek said. Malignant excisions increased from 25/1,000 to 27/1,000 in that period.

Skin biopsies increased from 55/1,000 to 90/1,000 beneficiaries, shave removals increased from 22/1,000 to 38/1,000, and Mohs procedures jumped from 5/1,000 to 11/1,000 beneficiaries.

Since some biopsies or lesion removals are performed not because of suspected cancer but for diagnosis of inflammatory eruptions, or because patients find lesions irritating or unsightly, Dr. Van Beek and her associates created categories that they called malignant, benign, or unknown "episodes of care." The ratio of malignant to benign episodes of care increased from 1.4 in 1993 to 2.2 in 2002, indicating a surge in malignant episodes of care.

Besides the rising incidence of cancer, factors that may have influenced these trends in health care utilization include access to specialist care and changes in coding and billing practices.

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Is Gleevec a reasonable therapeutic choice for melanoma?

The question has gotten a fair bit of research attention over the last few years, and for a few specific types of melanoma the outlook is cautiously optimistic, Dr. Philip LeBoit said at the American Academy of Dermatology's summer academy 2007 conference.

Gleevec (imatinib mesylate) will probably not become a first-line therapy for cutaneous melanoma, but it may work for mucosal melanomas, acral melanomas, and others that share genetic similarities to the sort of gastrointestinal lesions that have been highly responsive to this landmark drug. A number of case reports point in this direction, said Dr. LeBoit of the departments of pathology and dermatology at the University of California, San Francisco.

Gleevec was the breakthrough agent representing a class of drugs that target protein tyrosine kinase (PTK), an enzyme that plays an essential role in the proliferation and migration of many kinds of cancer cells. Gleevec-responsive tumors tend to have specific genetic profiles, showing mutations of the c-kit and abl genes, among others.

The drug has been particularly effective against GI stromal tumors, which have distinct c-kit mutations. The good news is that as dermatopathologists and molecular biologists explore genetic profiles of various kinds of skin cancers, they are finding that some melanoma types, especially mucosal melanomas, share these c-kit mutations, said Dr. LeBoit, who has no financial relationship with Novartis, the manufacturer of Gleevec.

"Mucosal melanomas have a lot of c-kit mutations. These tumors are almost impossible to resect. They may be candidates for Gleevec or second-generation drugs of that class," he said. Most mucosal melanomas are positive for c-kit mutations, as are roughly one-third of all cutaneous melanomas.

Dermatopathologists at the M.D. Anderson Cancer Center, Houston, studied before- and after-treatment biopsy specimens from 13 patients with malignant melanoma who were given Gleevec at a dose of 400 mg twice daily for 2 weeks. The drug produced a significant decrease in PTK expression in the tumor tissue, as well as a reduction in the number of malignant melanocytes and the intensity of their proliferation (J. Cutan. Pathol. 2006;33:280–5). The investigators noted that one of the 13 patients showed a "durable clinical response."

Brazilian researchers looked at the impact of Gleevec in tissue samples from uveal melanomas, the most common intraocular form of melanoma. Nearly 80% of the 55 tumors examined were positive for c-kit mutations. Gleevec reduced proliferation of the tumor cells in culture (J. Carcinog. 2005;4:19).

A recent phase II trial, however, showed little clinical impact from Gleevec therapy for cutaneous melanomas (Cancer 2006;106:2005–11).

Dr. Lynn Schuchter of the University of Pennsylvania, Philadelphia, is currently studying Gleevec in combination with temozolomide in 63 patients with advanced melanoma, Dr. LeBoit said. So far, the toxicity profile suggests that the PTK inhibitor is a viable adjunct with no significant added side-effect burden. Clinical outcomes data are not yet available.

It may be that Gleevec only works in tumors with very specific genetic profiles, and the key is to identify tumor susceptibility before treatment, in a way analogous to antibiotic susceptibility testing for microbial pathogens. This, said Dr. LeBoit, is the general trend in cancer therapy: the application of tools like immunohistochemistry and comparative genomic hybridization to subclassify tumors based on their genetic features.

"Cancer is fundamentally a disease of the genome. Something has to be wrong with the cells' DNA. Most cancer cells have gains or losses of whole chromosomes or major parts of chromosomes," he noted.

A few years ago, dermatopathologists were dependent almost exclusively on microscopy because there simply were no practical molecular diagnostic tools, but that scenario is changing fast. Diagnosis of skin cancers like melanoma "is not a simple positive-or-negative, yes-or-no process. We really need to get into the nuclei of cells to see what is going on," Dr. LeBoit said.

NEW YORK — Is Gleevec a reasonable therapeutic choice for melanoma?

The question has gotten a fair bit of research attention over the last few years, and for a few specific types of melanoma the outlook is cautiously optimistic, Dr. Philip LeBoit said at the American Academy of Dermatology's summer academy 2007 conference.

Gleevec (imatinib mesylate) will probably not become a first-line therapy for cutaneous melanoma, but it may work for mucosal melanomas, acral melanomas, and others that share genetic similarities to the sort of gastrointestinal lesions that have been highly responsive to this landmark drug. A number of case reports point in this direction, said Dr. LeBoit of the departments of pathology and dermatology at the University of California, San Francisco.

Gleevec was the breakthrough agent representing a class of drugs that target protein tyrosine kinase (PTK), an enzyme that plays an essential role in the proliferation and migration of many kinds of cancer cells. Gleevec-responsive tumors tend to have specific genetic profiles, showing mutations of the c-kit and abl genes, among others.

The drug has been particularly effective against GI stromal tumors, which have distinct c-kit mutations. The good news is that as dermatopathologists and molecular biologists explore genetic profiles of various kinds of skin cancers, they are finding that some melanoma types, especially mucosal melanomas, share these c-kit mutations, said Dr. LeBoit, who has no financial relationship with Novartis, the manufacturer of Gleevec.

"Mucosal melanomas have a lot of c-kit mutations. These tumors are almost impossible to resect. They may be candidates for Gleevec or second-generation drugs of that class," he said. Most mucosal melanomas are positive for c-kit mutations, as are roughly one-third of all cutaneous melanomas.

Dermatopathologists at the M.D. Anderson Cancer Center, Houston, studied before- and after-treatment biopsy specimens from 13 patients with malignant melanoma who were given Gleevec at a dose of 400 mg twice daily for 2 weeks. The drug produced a significant decrease in PTK expression in the tumor tissue, as well as a reduction in the number of malignant melanocytes and the intensity of their proliferation (J. Cutan. Pathol. 2006;33:280–5). The investigators noted that one of the 13 patients showed a "durable clinical response."

Brazilian researchers looked at the impact of Gleevec in tissue samples from uveal melanomas, the most common intraocular form of melanoma. Nearly 80% of the 55 tumors examined were positive for c-kit mutations. Gleevec reduced proliferation of the tumor cells in culture (J. Carcinog. 2005;4:19).

A recent phase II trial, however, showed little clinical impact from Gleevec therapy for cutaneous melanomas (Cancer 2006;106:2005–11).

Dr. Lynn Schuchter of the University of Pennsylvania, Philadelphia, is currently studying Gleevec in combination with temozolomide in 63 patients with advanced melanoma, Dr. LeBoit said. So far, the toxicity profile suggests that the PTK inhibitor is a viable adjunct with no significant added side-effect burden. Clinical outcomes data are not yet available.

It may be that Gleevec only works in tumors with very specific genetic profiles, and the key is to identify tumor susceptibility before treatment, in a way analogous to antibiotic susceptibility testing for microbial pathogens. This, said Dr. LeBoit, is the general trend in cancer therapy: the application of tools like immunohistochemistry and comparative genomic hybridization to subclassify tumors based on their genetic features.

"Cancer is fundamentally a disease of the genome. Something has to be wrong with the cells' DNA. Most cancer cells have gains or losses of whole chromosomes or major parts of chromosomes," he noted.

A few years ago, dermatopathologists were dependent almost exclusively on microscopy because there simply were no practical molecular diagnostic tools, but that scenario is changing fast. Diagnosis of skin cancers like melanoma "is not a simple positive-or-negative, yes-or-no process. We really need to get into the nuclei of cells to see what is going on," Dr. LeBoit said.

NEW YORK — Is Gleevec a reasonable therapeutic choice for melanoma?

The question has gotten a fair bit of research attention over the last few years, and for a few specific types of melanoma the outlook is cautiously optimistic, Dr. Philip LeBoit said at the American Academy of Dermatology's summer academy 2007 conference.

Gleevec (imatinib mesylate) will probably not become a first-line therapy for cutaneous melanoma, but it may work for mucosal melanomas, acral melanomas, and others that share genetic similarities to the sort of gastrointestinal lesions that have been highly responsive to this landmark drug. A number of case reports point in this direction, said Dr. LeBoit of the departments of pathology and dermatology at the University of California, San Francisco.

Gleevec was the breakthrough agent representing a class of drugs that target protein tyrosine kinase (PTK), an enzyme that plays an essential role in the proliferation and migration of many kinds of cancer cells. Gleevec-responsive tumors tend to have specific genetic profiles, showing mutations of the c-kit and abl genes, among others.

The drug has been particularly effective against GI stromal tumors, which have distinct c-kit mutations. The good news is that as dermatopathologists and molecular biologists explore genetic profiles of various kinds of skin cancers, they are finding that some melanoma types, especially mucosal melanomas, share these c-kit mutations, said Dr. LeBoit, who has no financial relationship with Novartis, the manufacturer of Gleevec.

"Mucosal melanomas have a lot of c-kit mutations. These tumors are almost impossible to resect. They may be candidates for Gleevec or second-generation drugs of that class," he said. Most mucosal melanomas are positive for c-kit mutations, as are roughly one-third of all cutaneous melanomas.

Dermatopathologists at the M.D. Anderson Cancer Center, Houston, studied before- and after-treatment biopsy specimens from 13 patients with malignant melanoma who were given Gleevec at a dose of 400 mg twice daily for 2 weeks. The drug produced a significant decrease in PTK expression in the tumor tissue, as well as a reduction in the number of malignant melanocytes and the intensity of their proliferation (J. Cutan. Pathol. 2006;33:280–5). The investigators noted that one of the 13 patients showed a "durable clinical response."

Brazilian researchers looked at the impact of Gleevec in tissue samples from uveal melanomas, the most common intraocular form of melanoma. Nearly 80% of the 55 tumors examined were positive for c-kit mutations. Gleevec reduced proliferation of the tumor cells in culture (J. Carcinog. 2005;4:19).

A recent phase II trial, however, showed little clinical impact from Gleevec therapy for cutaneous melanomas (Cancer 2006;106:2005–11).

Dr. Lynn Schuchter of the University of Pennsylvania, Philadelphia, is currently studying Gleevec in combination with temozolomide in 63 patients with advanced melanoma, Dr. LeBoit said. So far, the toxicity profile suggests that the PTK inhibitor is a viable adjunct with no significant added side-effect burden. Clinical outcomes data are not yet available.

It may be that Gleevec only works in tumors with very specific genetic profiles, and the key is to identify tumor susceptibility before treatment, in a way analogous to antibiotic susceptibility testing for microbial pathogens. This, said Dr. LeBoit, is the general trend in cancer therapy: the application of tools like immunohistochemistry and comparative genomic hybridization to subclassify tumors based on their genetic features.

"Cancer is fundamentally a disease of the genome. Something has to be wrong with the cells' DNA. Most cancer cells have gains or losses of whole chromosomes or major parts of chromosomes," he noted.

A few years ago, dermatopathologists were dependent almost exclusively on microscopy because there simply were no practical molecular diagnostic tools, but that scenario is changing fast. Diagnosis of skin cancers like melanoma "is not a simple positive-or-negative, yes-or-no process. We really need to get into the nuclei of cells to see what is going on," Dr. LeBoit said.

TORONTO — "Survival of the fittest" might be the best way to explain the genetic and molecular machinery behind cancer metastasis.

Researchers believe that overexpression of some genes in melanoma and other cancers allows some cells to survive the very harsh conditions that occur as they leave a primary tumor, travel to a distant site, and establish a new location for malignancy. "It is a similar theme to Darwin with natural selection, although it works out in a microenvironment," Dr. Youwen Zhou said.

"Why do I think this is a big deal? We still do not have a cure for metastatic melanoma, and next year another 900 or so patients [in Canada] will die from melanoma," Dr. Zhou said.

Melanoma was the sixth most common solid cancer for men in Canada in 2005 and 2006. There were 3,900 new cases last year. Of 840 deaths in 2006 from melanoma, 90% involved metastatic disease, said Dr. Zhou, who is on the faculty in the department of dermatology and skin science at the University of British Columbia, Vancouver.

There are some reasons for optimism, however. Understanding the molecular machinery might permit earlier intervention through better diagnostic or prognostic tools, Dr. Zhou said at the annual conference of the Canadian Dermatology Association.

Serum protein testing, for example, might lead to more accurate estimates of prognosis. The melanoma-inhibiting activity (MIA) protein is detected in high amounts in 100% of patients with metastatic melanoma so far. "About 20% of patients with primary melanoma will have signs of this protein in their serum. If they are negative for MIA protein, not one of them developed metastasis over time," he said.

Genetic insights also may lead to new therapeutic targets. "Selective gene silencing may work to cause metastatic cells to die," Dr. Zhou said.

So how do invasive tumors develop? Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenvironment distant from the primary tumor (Cell 2006;127:679–95).

Other investigators have identified individual genes that are amplified in metastatic melanoma (Cell 2006;125:1269–81).

A high degree of heterogeneity in melanoma tumor cells may in part explain why aggressive gene clones arise.

"If you look at a melanoma clinically, it has signs of molecular and cellular heterogeneity, for example, irregular borders. On a cellular level, pathologists use variation in cell size as a diagnostic factor," he said.

Dominant genetic clones can cause a higher resistance to apoptosis, greater tolerance to hypoxia and nutrient deprivation, altered cell adherence, and increased genomic instability.

The vast majority of the most aberrantly upregulated genes work in concert to modify the microenvironment to their advantage.

Before these breakaway cells become "little tumor thrombi," they must break through local physical barriers, he explained. They do this in part by degrading the collagen matrix. Then they have to overcome the vascular wall and survive the harsh sheering and other forces of the vasculature.

Some will survive intravasation with the right molecular defense mechanisms. Extravasation occurs when they arrive at a destination, change adhesion properties, and again pass through the vascular wall. Finally, the cells must continue to defend themselves against host defenses for distant colonization to be successful, Dr. Zhou said.

Development of novel targeting strategies against this genetic and molecular machinery is needed, he said. Once those strategies are identified, the next step would be large scale trials to assess these therapeutic targets.

TORONTO — "Survival of the fittest" might be the best way to explain the genetic and molecular machinery behind cancer metastasis.

Researchers believe that overexpression of some genes in melanoma and other cancers allows some cells to survive the very harsh conditions that occur as they leave a primary tumor, travel to a distant site, and establish a new location for malignancy. "It is a similar theme to Darwin with natural selection, although it works out in a microenvironment," Dr. Youwen Zhou said.

"Why do I think this is a big deal? We still do not have a cure for metastatic melanoma, and next year another 900 or so patients [in Canada] will die from melanoma," Dr. Zhou said.

Melanoma was the sixth most common solid cancer for men in Canada in 2005 and 2006. There were 3,900 new cases last year. Of 840 deaths in 2006 from melanoma, 90% involved metastatic disease, said Dr. Zhou, who is on the faculty in the department of dermatology and skin science at the University of British Columbia, Vancouver.

There are some reasons for optimism, however. Understanding the molecular machinery might permit earlier intervention through better diagnostic or prognostic tools, Dr. Zhou said at the annual conference of the Canadian Dermatology Association.

Serum protein testing, for example, might lead to more accurate estimates of prognosis. The melanoma-inhibiting activity (MIA) protein is detected in high amounts in 100% of patients with metastatic melanoma so far. "About 20% of patients with primary melanoma will have signs of this protein in their serum. If they are negative for MIA protein, not one of them developed metastasis over time," he said.

Genetic insights also may lead to new therapeutic targets. "Selective gene silencing may work to cause metastatic cells to die," Dr. Zhou said.

So how do invasive tumors develop? Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenvironment distant from the primary tumor (Cell 2006;127:679–95).

Other investigators have identified individual genes that are amplified in metastatic melanoma (Cell 2006;125:1269–81).

A high degree of heterogeneity in melanoma tumor cells may in part explain why aggressive gene clones arise.

"If you look at a melanoma clinically, it has signs of molecular and cellular heterogeneity, for example, irregular borders. On a cellular level, pathologists use variation in cell size as a diagnostic factor," he said.

Dominant genetic clones can cause a higher resistance to apoptosis, greater tolerance to hypoxia and nutrient deprivation, altered cell adherence, and increased genomic instability.

The vast majority of the most aberrantly upregulated genes work in concert to modify the microenvironment to their advantage.

Before these breakaway cells become "little tumor thrombi," they must break through local physical barriers, he explained. They do this in part by degrading the collagen matrix. Then they have to overcome the vascular wall and survive the harsh sheering and other forces of the vasculature.

Some will survive intravasation with the right molecular defense mechanisms. Extravasation occurs when they arrive at a destination, change adhesion properties, and again pass through the vascular wall. Finally, the cells must continue to defend themselves against host defenses for distant colonization to be successful, Dr. Zhou said.

Development of novel targeting strategies against this genetic and molecular machinery is needed, he said. Once those strategies are identified, the next step would be large scale trials to assess these therapeutic targets.

TORONTO — "Survival of the fittest" might be the best way to explain the genetic and molecular machinery behind cancer metastasis.

Researchers believe that overexpression of some genes in melanoma and other cancers allows some cells to survive the very harsh conditions that occur as they leave a primary tumor, travel to a distant site, and establish a new location for malignancy. "It is a similar theme to Darwin with natural selection, although it works out in a microenvironment," Dr. Youwen Zhou said.

"Why do I think this is a big deal? We still do not have a cure for metastatic melanoma, and next year another 900 or so patients [in Canada] will die from melanoma," Dr. Zhou said.

Melanoma was the sixth most common solid cancer for men in Canada in 2005 and 2006. There were 3,900 new cases last year. Of 840 deaths in 2006 from melanoma, 90% involved metastatic disease, said Dr. Zhou, who is on the faculty in the department of dermatology and skin science at the University of British Columbia, Vancouver.

There are some reasons for optimism, however. Understanding the molecular machinery might permit earlier intervention through better diagnostic or prognostic tools, Dr. Zhou said at the annual conference of the Canadian Dermatology Association.

Serum protein testing, for example, might lead to more accurate estimates of prognosis. The melanoma-inhibiting activity (MIA) protein is detected in high amounts in 100% of patients with metastatic melanoma so far. "About 20% of patients with primary melanoma will have signs of this protein in their serum. If they are negative for MIA protein, not one of them developed metastasis over time," he said.

Genetic insights also may lead to new therapeutic targets. "Selective gene silencing may work to cause metastatic cells to die," Dr. Zhou said.

So how do invasive tumors develop? Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenvironment distant from the primary tumor (Cell 2006;127:679–95).

Other investigators have identified individual genes that are amplified in metastatic melanoma (Cell 2006;125:1269–81).

A high degree of heterogeneity in melanoma tumor cells may in part explain why aggressive gene clones arise.

"If you look at a melanoma clinically, it has signs of molecular and cellular heterogeneity, for example, irregular borders. On a cellular level, pathologists use variation in cell size as a diagnostic factor," he said.

Dominant genetic clones can cause a higher resistance to apoptosis, greater tolerance to hypoxia and nutrient deprivation, altered cell adherence, and increased genomic instability.

The vast majority of the most aberrantly upregulated genes work in concert to modify the microenvironment to their advantage.

Before these breakaway cells become "little tumor thrombi," they must break through local physical barriers, he explained. They do this in part by degrading the collagen matrix. Then they have to overcome the vascular wall and survive the harsh sheering and other forces of the vasculature.

Some will survive intravasation with the right molecular defense mechanisms. Extravasation occurs when they arrive at a destination, change adhesion properties, and again pass through the vascular wall. Finally, the cells must continue to defend themselves against host defenses for distant colonization to be successful, Dr. Zhou said.

Development of novel targeting strategies against this genetic and molecular machinery is needed, he said. Once those strategies are identified, the next step would be large scale trials to assess these therapeutic targets.