Melanoma

SAN FRANCISCO — Vulvar granular cell tumors are biologically indolent lesions that may progress clinically over a decade or longer and most often occur in black patients, according to a recent review.

Of 16 granular cell tumors of the vulva that were surgically removed, 7 had positive margins, and only 1 progressed to a size requiring reexcision after 14 years, Dr. John A. Papalas and his associates reported at the annual meeting of the American Society of Dermatopathology. None of the tumors at the time of initial excision met histological criteria for malignancy.

The 16 lesions occurred on 12 patients (including 10 black patients) who were seen at Duke University, Durham, N.C. The patients' average age was 46 years.

The question of whether to reexcise a vulvar granular cell tumor with positive margins should be considered carefully because of the greater morbidity, compared with excisions in other areas of the body, noted Dr. Papalas of Duke University.

In a previous report on 20 patients with vulvar granular cell tumors, investigators suggested obtaining wide negative surgical margins (up to 2 cm), but the study provided follow-up data on only 1 patient and did not report the surgical margin resection status, he pointed out (Am. J. Obstet. Gynecol. 1995;173:1710-3).

Given the findings of the current study, which show that these tumors rarely recurred regardless of surgical margin status, "a 2-cm margin of a benign tumor on the vulva seems a bit excessive," one physician in the audience commented.

Patients with multiple vulvar granular cell tumors rarely have been reported in the literature. Three patients in the current series had multiple vulvar granular cell tumors and additional granular cell tumors in another body area. Another patient had a single vulvar tumor and an isolated lesion in another body area. Eight patients had a single granular cell tumor on the vulva alone. Extravulvar sites included the groin, perirectal area, buttock, esophagus, neck, buccal mucosa, and scalp.

Of the three patients with multiple vulvar granular cell tumors, only one presented with multiple vulvar lesions—a 50-year-old woman (just 2 years older than the average age), Dr. Papalas noted. Two other patients with an average age of 30 years presented with a single vulvar granular cell tumor and later progressed to multiple vulvar lesions over a 14-year period after the initial excision.

The surgical note or pathology report should precisely document the tumor location in order to accurately track recurrence or progression, he advised. Simply saying the tumor is on the "vulva" is not good enough, because the vulva is an anatomically complex region. The most common location of lesions in the current series was the labia majora, for 7 of 16 tumors.

Grossly, the tumors in this series either were well-circumscribed tan/white nodules or infiltrative masses, with an average tumor size of 2 cm.

A granular cell tumor is a Schwann cell-derived neoplasm that can occur throughout the body. Most involve the skin and soft tissue. Biopsies classically show tumor cells with abundant, pink granular cytoplasm and monomorphic, bland nuclei, though they can be mistaken for other lesions. "They're not always a slam-dunk diagnosis," Dr. Papalas said.

Granular cell tumors appear to be the most common peripheral nerve sheath-derived neoplasm in the vulva, he added.

SAN FRANCISCO — Vulvar granular cell tumors are biologically indolent lesions that may progress clinically over a decade or longer and most often occur in black patients, according to a recent review.

Of 16 granular cell tumors of the vulva that were surgically removed, 7 had positive margins, and only 1 progressed to a size requiring reexcision after 14 years, Dr. John A. Papalas and his associates reported at the annual meeting of the American Society of Dermatopathology. None of the tumors at the time of initial excision met histological criteria for malignancy.

The 16 lesions occurred on 12 patients (including 10 black patients) who were seen at Duke University, Durham, N.C. The patients' average age was 46 years.

The question of whether to reexcise a vulvar granular cell tumor with positive margins should be considered carefully because of the greater morbidity, compared with excisions in other areas of the body, noted Dr. Papalas of Duke University.

In a previous report on 20 patients with vulvar granular cell tumors, investigators suggested obtaining wide negative surgical margins (up to 2 cm), but the study provided follow-up data on only 1 patient and did not report the surgical margin resection status, he pointed out (Am. J. Obstet. Gynecol. 1995;173:1710-3).

Given the findings of the current study, which show that these tumors rarely recurred regardless of surgical margin status, "a 2-cm margin of a benign tumor on the vulva seems a bit excessive," one physician in the audience commented.

Patients with multiple vulvar granular cell tumors rarely have been reported in the literature. Three patients in the current series had multiple vulvar granular cell tumors and additional granular cell tumors in another body area. Another patient had a single vulvar tumor and an isolated lesion in another body area. Eight patients had a single granular cell tumor on the vulva alone. Extravulvar sites included the groin, perirectal area, buttock, esophagus, neck, buccal mucosa, and scalp.

Of the three patients with multiple vulvar granular cell tumors, only one presented with multiple vulvar lesions—a 50-year-old woman (just 2 years older than the average age), Dr. Papalas noted. Two other patients with an average age of 30 years presented with a single vulvar granular cell tumor and later progressed to multiple vulvar lesions over a 14-year period after the initial excision.

The surgical note or pathology report should precisely document the tumor location in order to accurately track recurrence or progression, he advised. Simply saying the tumor is on the "vulva" is not good enough, because the vulva is an anatomically complex region. The most common location of lesions in the current series was the labia majora, for 7 of 16 tumors.

Grossly, the tumors in this series either were well-circumscribed tan/white nodules or infiltrative masses, with an average tumor size of 2 cm.

A granular cell tumor is a Schwann cell-derived neoplasm that can occur throughout the body. Most involve the skin and soft tissue. Biopsies classically show tumor cells with abundant, pink granular cytoplasm and monomorphic, bland nuclei, though they can be mistaken for other lesions. "They're not always a slam-dunk diagnosis," Dr. Papalas said.

Granular cell tumors appear to be the most common peripheral nerve sheath-derived neoplasm in the vulva, he added.

SAN FRANCISCO — Vulvar granular cell tumors are biologically indolent lesions that may progress clinically over a decade or longer and most often occur in black patients, according to a recent review.

Of 16 granular cell tumors of the vulva that were surgically removed, 7 had positive margins, and only 1 progressed to a size requiring reexcision after 14 years, Dr. John A. Papalas and his associates reported at the annual meeting of the American Society of Dermatopathology. None of the tumors at the time of initial excision met histological criteria for malignancy.

The 16 lesions occurred on 12 patients (including 10 black patients) who were seen at Duke University, Durham, N.C. The patients' average age was 46 years.

The question of whether to reexcise a vulvar granular cell tumor with positive margins should be considered carefully because of the greater morbidity, compared with excisions in other areas of the body, noted Dr. Papalas of Duke University.

In a previous report on 20 patients with vulvar granular cell tumors, investigators suggested obtaining wide negative surgical margins (up to 2 cm), but the study provided follow-up data on only 1 patient and did not report the surgical margin resection status, he pointed out (Am. J. Obstet. Gynecol. 1995;173:1710-3).

Given the findings of the current study, which show that these tumors rarely recurred regardless of surgical margin status, "a 2-cm margin of a benign tumor on the vulva seems a bit excessive," one physician in the audience commented.

Patients with multiple vulvar granular cell tumors rarely have been reported in the literature. Three patients in the current series had multiple vulvar granular cell tumors and additional granular cell tumors in another body area. Another patient had a single vulvar tumor and an isolated lesion in another body area. Eight patients had a single granular cell tumor on the vulva alone. Extravulvar sites included the groin, perirectal area, buttock, esophagus, neck, buccal mucosa, and scalp.

Of the three patients with multiple vulvar granular cell tumors, only one presented with multiple vulvar lesions—a 50-year-old woman (just 2 years older than the average age), Dr. Papalas noted. Two other patients with an average age of 30 years presented with a single vulvar granular cell tumor and later progressed to multiple vulvar lesions over a 14-year period after the initial excision.

The surgical note or pathology report should precisely document the tumor location in order to accurately track recurrence or progression, he advised. Simply saying the tumor is on the "vulva" is not good enough, because the vulva is an anatomically complex region. The most common location of lesions in the current series was the labia majora, for 7 of 16 tumors.

Grossly, the tumors in this series either were well-circumscribed tan/white nodules or infiltrative masses, with an average tumor size of 2 cm.

A granular cell tumor is a Schwann cell-derived neoplasm that can occur throughout the body. Most involve the skin and soft tissue. Biopsies classically show tumor cells with abundant, pink granular cytoplasm and monomorphic, bland nuclei, though they can be mistaken for other lesions. "They're not always a slam-dunk diagnosis," Dr. Papalas said.

Granular cell tumors appear to be the most common peripheral nerve sheath-derived neoplasm in the vulva, he added.

Case Report
A 69-year-old man with a medical history of psoriasis and hypertension presented with an incidental finding of multiple asymptomatic, noncompressible, blue lesions over his arms, chest, and back. The lesions were present since childhood and had never been subject to a workup. He had no history of gastrointestinal bleeding and no known family history of similar lesions. His medications included amlodipine besylate, efalizumab, and valsartan. Physical examination revealed multiple nontender, blue, subcutaneous nodules that were 1 to 2 cm in diameter and located on the bilateral arms, chest, and back (Figure 1). A punch biopsy was performed from the chest lesions. Histopathologic examination revealed dilated vascular channels (Figure 2) that were positive for endothelial factor VIII and CD34 and surrounded by glomus cells positive for smooth muscle actin (Figure 3). The diagnosis of glomangioma was made and no further treatment was indicated.

Comment
Glomangiomas are benign localized tumors of the skin characterized by abnormal, smooth muscle–like glomus cells.1 In 1924, Masson2 described the neuromyoarterial glomus, which he later renamed the neurovascular glomus, and its tumors. The term glomangioma was coined by Bailey3 in 1935 and is currently applied to lesions with a wide vascular lumen, which are most commonly found in patients with multiple tumors.4 Glomus tumors arise from modified smooth muscle cells normally found in specialized arteriovenous shunts present in acral sites, especially the fingertips. This location reflects their function, as the arteriovenous anastomoses of these areas, also known as the Sucquet-Hoyer canals, are involved in temperature regulation. Sucquet-Hoyer canals are lined with endothelial cells, contain several layers of glomus cells in their walls, and connect afferent arterioles to efferent venules.5 Glomus tumors are thought to be hamartomas6 and account for 1% to 2% of all soft tissue tumors.5 There are 2 forms of glomus tumors, with the more common solitary variant accounting for 90% of cases and a more rare multiple variant, termed glomangioma, accounting for 10% of cases.7 The tumors of the solitary variant are small, painful, purple nodules with predilection for acral areas of the extremities, especially the nail beds of the fingers and toes.8 Aching pain, well-localized tenderness, and temperature sensitivity are the characteristic triad of signs and symptoms.5 They typically are less than 1 cm in diameter.8 In contrast, multiple glomus tumors are characterized as glomangiomas because of the angiomatous appearance of the lesions. Glomangiomas often appear during childhood as small bluish nodules situated deep in the dermis, widely scattered over the skin surface. They are rarely subungual and are less likely to be painful.8 Glomangiomas have a predilection for the upper extremities and occasionally are found on the lower extremities, head, and back. They may be slightly larger and less well-circumscribed than solitary glomus tumors.5 An autosomal dominant inheritance pattern has been described for glomus tumors, with some types being mapped to band 11q23.6 Familial cases have been reported with incomplete penetrance and variable expression.7 Glomangiomas have a male predominance, while females more frequently (in 70% of cases) are found to have solitary glomus tumors.5 Histopathologically, glomus tumors contain dilated vascular channels surrounded by glomus cells. The glomus cells are monomorphic round or polygonal cells with plump nuclei and scant eosinophilic cytoplasm. They are positive for smooth muscle actin, while vascular endothelium is positive for factor VIII and CD34.9 Choosing the appropriate treatment regimen for glomus tumors and glomangiomas should be individualized to the patient and guided by the clinical presentation. Treatment is not always indicated, particularly in asymptomatic cases of glomangioma. Surgical intervention, when needed, typically is excision with primary closure. Laser treatment, electromagnetic radiation, and sclerotherapy also have been used.5 Blue Rubber Bleb Nevus Syndrome—It is important to distinguish glomangioma from blue rubber bleb nevus syndrome (BRBNS), which is associated with venous malformations on both the skin and gastrointestinal tract. The BRBNS venous malformations of the gastrointestinal tract can be associated with clinically significant gastrointestinal bleeding.10 Lesions of BRBNS can be macular, papular, or nodular, and usually are multiple, varying in diameter from a few millimeters to several centimeters. The cutaneous lesions usually are asymptomatic and the overlying skin may show increased sweating. These lesions may appear at birth or in early childhood, and they tend to increase in size and frequency with age. Although they may occur anywhere, they are principally located on the upper limbs, trunk, and perineum. Acral lesions are unusual and the lesions have no evidence of malignant change.11 Cutaneous lesions of BRBNS are blue, soft, and nipplelike, easily compressing and refilling slowly.12 On the other hand, glomangiomas are noted for a distinct raised, often hyperkeratotic, cobblestonelike appearance, and could not be completely emptied by compression.13 Glomangiomas generally do not extend into deep structures.14 Histologically, glomangiomas contain clusters of dilated vascular channels lined by a thin layer of endothelial cells in the dermis or subcutaneous fat. The walls are a fibrous stroma, occasionally containing smooth muscle.12 Dilated vascular channels lined by endothelial cells are characteristic of both diseases. Therefore, biopsy results confirming the presence of glomus cells lining the dilated vascular channels characterize glomangiomas.10 back to top

Case Report
A 69-year-old man with a medical history of psoriasis and hypertension presented with an incidental finding of multiple asymptomatic, noncompressible, blue lesions over his arms, chest, and back. The lesions were present since childhood and had never been subject to a workup. He had no history of gastrointestinal bleeding and no known family history of similar lesions. His medications included amlodipine besylate, efalizumab, and valsartan. Physical examination revealed multiple nontender, blue, subcutaneous nodules that were 1 to 2 cm in diameter and located on the bilateral arms, chest, and back (Figure 1). A punch biopsy was performed from the chest lesions. Histopathologic examination revealed dilated vascular channels (Figure 2) that were positive for endothelial factor VIII and CD34 and surrounded by glomus cells positive for smooth muscle actin (Figure 3). The diagnosis of glomangioma was made and no further treatment was indicated.

Comment
Glomangiomas are benign localized tumors of the skin characterized by abnormal, smooth muscle–like glomus cells.1 In 1924, Masson2 described the neuromyoarterial glomus, which he later renamed the neurovascular glomus, and its tumors. The term glomangioma was coined by Bailey3 in 1935 and is currently applied to lesions with a wide vascular lumen, which are most commonly found in patients with multiple tumors.4 Glomus tumors arise from modified smooth muscle cells normally found in specialized arteriovenous shunts present in acral sites, especially the fingertips. This location reflects their function, as the arteriovenous anastomoses of these areas, also known as the Sucquet-Hoyer canals, are involved in temperature regulation. Sucquet-Hoyer canals are lined with endothelial cells, contain several layers of glomus cells in their walls, and connect afferent arterioles to efferent venules.5 Glomus tumors are thought to be hamartomas6 and account for 1% to 2% of all soft tissue tumors.5 There are 2 forms of glomus tumors, with the more common solitary variant accounting for 90% of cases and a more rare multiple variant, termed glomangioma, accounting for 10% of cases.7 The tumors of the solitary variant are small, painful, purple nodules with predilection for acral areas of the extremities, especially the nail beds of the fingers and toes.8 Aching pain, well-localized tenderness, and temperature sensitivity are the characteristic triad of signs and symptoms.5 They typically are less than 1 cm in diameter.8 In contrast, multiple glomus tumors are characterized as glomangiomas because of the angiomatous appearance of the lesions. Glomangiomas often appear during childhood as small bluish nodules situated deep in the dermis, widely scattered over the skin surface. They are rarely subungual and are less likely to be painful.8 Glomangiomas have a predilection for the upper extremities and occasionally are found on the lower extremities, head, and back. They may be slightly larger and less well-circumscribed than solitary glomus tumors.5 An autosomal dominant inheritance pattern has been described for glomus tumors, with some types being mapped to band 11q23.6 Familial cases have been reported with incomplete penetrance and variable expression.7 Glomangiomas have a male predominance, while females more frequently (in 70% of cases) are found to have solitary glomus tumors.5 Histopathologically, glomus tumors contain dilated vascular channels surrounded by glomus cells. The glomus cells are monomorphic round or polygonal cells with plump nuclei and scant eosinophilic cytoplasm. They are positive for smooth muscle actin, while vascular endothelium is positive for factor VIII and CD34.9 Choosing the appropriate treatment regimen for glomus tumors and glomangiomas should be individualized to the patient and guided by the clinical presentation. Treatment is not always indicated, particularly in asymptomatic cases of glomangioma. Surgical intervention, when needed, typically is excision with primary closure. Laser treatment, electromagnetic radiation, and sclerotherapy also have been used.5 Blue Rubber Bleb Nevus Syndrome—It is important to distinguish glomangioma from blue rubber bleb nevus syndrome (BRBNS), which is associated with venous malformations on both the skin and gastrointestinal tract. The BRBNS venous malformations of the gastrointestinal tract can be associated with clinically significant gastrointestinal bleeding.10 Lesions of BRBNS can be macular, papular, or nodular, and usually are multiple, varying in diameter from a few millimeters to several centimeters. The cutaneous lesions usually are asymptomatic and the overlying skin may show increased sweating. These lesions may appear at birth or in early childhood, and they tend to increase in size and frequency with age. Although they may occur anywhere, they are principally located on the upper limbs, trunk, and perineum. Acral lesions are unusual and the lesions have no evidence of malignant change.11 Cutaneous lesions of BRBNS are blue, soft, and nipplelike, easily compressing and refilling slowly.12 On the other hand, glomangiomas are noted for a distinct raised, often hyperkeratotic, cobblestonelike appearance, and could not be completely emptied by compression.13 Glomangiomas generally do not extend into deep structures.14 Histologically, glomangiomas contain clusters of dilated vascular channels lined by a thin layer of endothelial cells in the dermis or subcutaneous fat. The walls are a fibrous stroma, occasionally containing smooth muscle.12 Dilated vascular channels lined by endothelial cells are characteristic of both diseases. Therefore, biopsy results confirming the presence of glomus cells lining the dilated vascular channels characterize glomangiomas.10 back to top

Case Report
A 69-year-old man with a medical history of psoriasis and hypertension presented with an incidental finding of multiple asymptomatic, noncompressible, blue lesions over his arms, chest, and back. The lesions were present since childhood and had never been subject to a workup. He had no history of gastrointestinal bleeding and no known family history of similar lesions. His medications included amlodipine besylate, efalizumab, and valsartan. Physical examination revealed multiple nontender, blue, subcutaneous nodules that were 1 to 2 cm in diameter and located on the bilateral arms, chest, and back (Figure 1). A punch biopsy was performed from the chest lesions. Histopathologic examination revealed dilated vascular channels (Figure 2) that were positive for endothelial factor VIII and CD34 and surrounded by glomus cells positive for smooth muscle actin (Figure 3). The diagnosis of glomangioma was made and no further treatment was indicated.

Comment
Glomangiomas are benign localized tumors of the skin characterized by abnormal, smooth muscle–like glomus cells.1 In 1924, Masson2 described the neuromyoarterial glomus, which he later renamed the neurovascular glomus, and its tumors. The term glomangioma was coined by Bailey3 in 1935 and is currently applied to lesions with a wide vascular lumen, which are most commonly found in patients with multiple tumors.4 Glomus tumors arise from modified smooth muscle cells normally found in specialized arteriovenous shunts present in acral sites, especially the fingertips. This location reflects their function, as the arteriovenous anastomoses of these areas, also known as the Sucquet-Hoyer canals, are involved in temperature regulation. Sucquet-Hoyer canals are lined with endothelial cells, contain several layers of glomus cells in their walls, and connect afferent arterioles to efferent venules.5 Glomus tumors are thought to be hamartomas6 and account for 1% to 2% of all soft tissue tumors.5 There are 2 forms of glomus tumors, with the more common solitary variant accounting for 90% of cases and a more rare multiple variant, termed glomangioma, accounting for 10% of cases.7 The tumors of the solitary variant are small, painful, purple nodules with predilection for acral areas of the extremities, especially the nail beds of the fingers and toes.8 Aching pain, well-localized tenderness, and temperature sensitivity are the characteristic triad of signs and symptoms.5 They typically are less than 1 cm in diameter.8 In contrast, multiple glomus tumors are characterized as glomangiomas because of the angiomatous appearance of the lesions. Glomangiomas often appear during childhood as small bluish nodules situated deep in the dermis, widely scattered over the skin surface. They are rarely subungual and are less likely to be painful.8 Glomangiomas have a predilection for the upper extremities and occasionally are found on the lower extremities, head, and back. They may be slightly larger and less well-circumscribed than solitary glomus tumors.5 An autosomal dominant inheritance pattern has been described for glomus tumors, with some types being mapped to band 11q23.6 Familial cases have been reported with incomplete penetrance and variable expression.7 Glomangiomas have a male predominance, while females more frequently (in 70% of cases) are found to have solitary glomus tumors.5 Histopathologically, glomus tumors contain dilated vascular channels surrounded by glomus cells. The glomus cells are monomorphic round or polygonal cells with plump nuclei and scant eosinophilic cytoplasm. They are positive for smooth muscle actin, while vascular endothelium is positive for factor VIII and CD34.9 Choosing the appropriate treatment regimen for glomus tumors and glomangiomas should be individualized to the patient and guided by the clinical presentation. Treatment is not always indicated, particularly in asymptomatic cases of glomangioma. Surgical intervention, when needed, typically is excision with primary closure. Laser treatment, electromagnetic radiation, and sclerotherapy also have been used.5 Blue Rubber Bleb Nevus Syndrome—It is important to distinguish glomangioma from blue rubber bleb nevus syndrome (BRBNS), which is associated with venous malformations on both the skin and gastrointestinal tract. The BRBNS venous malformations of the gastrointestinal tract can be associated with clinically significant gastrointestinal bleeding.10 Lesions of BRBNS can be macular, papular, or nodular, and usually are multiple, varying in diameter from a few millimeters to several centimeters. The cutaneous lesions usually are asymptomatic and the overlying skin may show increased sweating. These lesions may appear at birth or in early childhood, and they tend to increase in size and frequency with age. Although they may occur anywhere, they are principally located on the upper limbs, trunk, and perineum. Acral lesions are unusual and the lesions have no evidence of malignant change.11 Cutaneous lesions of BRBNS are blue, soft, and nipplelike, easily compressing and refilling slowly.12 On the other hand, glomangiomas are noted for a distinct raised, often hyperkeratotic, cobblestonelike appearance, and could not be completely emptied by compression.13 Glomangiomas generally do not extend into deep structures.14 Histologically, glomangiomas contain clusters of dilated vascular channels lined by a thin layer of endothelial cells in the dermis or subcutaneous fat. The walls are a fibrous stroma, occasionally containing smooth muscle.12 Dilated vascular channels lined by endothelial cells are characteristic of both diseases. Therefore, biopsy results confirming the presence of glomus cells lining the dilated vascular channels characterize glomangiomas.10 back to top

ORLANDO — Reviewing the original biopsy slides of patients before they undergo Mohs surgery could result in a change of diagnosis, which in some cases could avert unnecessary surgery, according to Dr. Suzy T. Butler.

In a retrospective study of 3,345 patients, a second review of the original biopsy slide resulted in 74 changed diagnoses. Of these, 45 patients had a change in their management and 25 avoided an unnecessary surgery, Dr. Butler said at the annual meeting of the American Society for Dermatologic Surgery. The study reviewed all patients referred to the cutaneous oncology unit for Mohs surgery at St. Louis University from January 2003 to March 2007.

In one case, a 76-year-old white female presented to her dermatologist with a pink papule on her right cheek that had been previously treated with liquid nitrogen. A shaved biopsy showed an atypical spindle cell proliferation that was read as a desmoplastic malignant melanoma.

A review of the biopsy slides, however, diagnosed the patient as having dermal scar, said Dr. Butler of St. Louis University. Because of this discrepancy, additional biopsies were performed. These confirmed the diagnosis of scar. An s100 stain showed a few spindle cells in the dermis. Surgery was cancelled, and close observation was planned.

In another case, a 74-year-old white male presented with a 1-year history of pink scaly plaques at the suprapubic area. A punch biopsy was originally read as superficial spreading melanoma in situ.

A review of the biopsy before surgery, however, suggested extramammary Paget disease, which was confirmed with additional biopsies. The patient underwent "slow Mohs" surgery with permanent section histology, as well as a thorough malignancy work-up that was negative.

"These cases illustrate how second-opinion review of histopathology before treatment can either avoid potentially disfiguring, unnecessary surgery or direct a different surgical approach and guide the need for other testing," said Dr. Butler.

In addition to recording the number of cases in which the diagnosis changed, the investigators noted how the diagnosis changed and then reviewed the patient's chart to see how that change affected the patient's management. They also recorded the board certification of the original pathologist. Nearly half (48%) of the slides that were rediagnosed had been read by certified dermatopathologists, Dr. Butler said.

The most common change in diagnosis was from one malignant tumor to another in 43% of the patients. Most commonly, a basal cell carcinoma (BCC) diagnosis changed to squamous cell carcinoma (SCC), or a melanoma went from in situ to invasive or vice versa, Dr. Butler said.

The next most common change in diagnosis was from malignant to benign in 36% of the patients. This was often a seborrheic keratosis or a verruca vulgaris being misdiagnosed as SCC.

BCC was most likely to be misdiagnosed, followed by SCC, and then by melanoma and melanoma in situ, Dr. Butler noted. Seventeen percent of discordant diagnoses involved melanoma and melanoma in situ.

"Misdiagnoses involving basal cells are likely related to their high representation in our population, as opposed to any diagnostic challenge," she said. "On the flip side, considering the small proportion of total tumors that melanoma and melanomas in situ represent in our population, they comprise a surprisingly substantial proportion of the misdiagnosed tumors."

She suggested that the diagnoses of melanoma or melanoma in situ might be the most cost-effective diseases to target with second-opinion review.

The most common change in patient management was cancellation of surgery in 25 patients. The planned surgical approach was changed in another 10 patients, and 1 patient had to be scheduled for surgery as a result of the second biopsy reading, Dr. Butler said.

The cost of taking a second look at biopsy slides is considerable, however. "We did a cost analysis and found that the estimated cost of reviewing the biopsy slides would be approximately $93,000 a year at our university based on the number of slides we look at per year. That is significant, but it has to be weighed against the other benefits," she said.

Surgeons gain much useful information regarding the nature of the tumor, particularly useful when there are deeply infiltrating, aggressive tumors or in cases of perineural involvement, said Dr. Butler, who disclosed having no conflicts of interest relevant to her presentation.

Melanoma and melanoma in situ might be the most cost-effective diseases to target with second-opinion review. DR. BUTLER

ORLANDO — Reviewing the original biopsy slides of patients before they undergo Mohs surgery could result in a change of diagnosis, which in some cases could avert unnecessary surgery, according to Dr. Suzy T. Butler.

In a retrospective study of 3,345 patients, a second review of the original biopsy slide resulted in 74 changed diagnoses. Of these, 45 patients had a change in their management and 25 avoided an unnecessary surgery, Dr. Butler said at the annual meeting of the American Society for Dermatologic Surgery. The study reviewed all patients referred to the cutaneous oncology unit for Mohs surgery at St. Louis University from January 2003 to March 2007.

In one case, a 76-year-old white female presented to her dermatologist with a pink papule on her right cheek that had been previously treated with liquid nitrogen. A shaved biopsy showed an atypical spindle cell proliferation that was read as a desmoplastic malignant melanoma.

A review of the biopsy slides, however, diagnosed the patient as having dermal scar, said Dr. Butler of St. Louis University. Because of this discrepancy, additional biopsies were performed. These confirmed the diagnosis of scar. An s100 stain showed a few spindle cells in the dermis. Surgery was cancelled, and close observation was planned.

In another case, a 74-year-old white male presented with a 1-year history of pink scaly plaques at the suprapubic area. A punch biopsy was originally read as superficial spreading melanoma in situ.

A review of the biopsy before surgery, however, suggested extramammary Paget disease, which was confirmed with additional biopsies. The patient underwent "slow Mohs" surgery with permanent section histology, as well as a thorough malignancy work-up that was negative.

"These cases illustrate how second-opinion review of histopathology before treatment can either avoid potentially disfiguring, unnecessary surgery or direct a different surgical approach and guide the need for other testing," said Dr. Butler.

In addition to recording the number of cases in which the diagnosis changed, the investigators noted how the diagnosis changed and then reviewed the patient's chart to see how that change affected the patient's management. They also recorded the board certification of the original pathologist. Nearly half (48%) of the slides that were rediagnosed had been read by certified dermatopathologists, Dr. Butler said.

The most common change in diagnosis was from one malignant tumor to another in 43% of the patients. Most commonly, a basal cell carcinoma (BCC) diagnosis changed to squamous cell carcinoma (SCC), or a melanoma went from in situ to invasive or vice versa, Dr. Butler said.

The next most common change in diagnosis was from malignant to benign in 36% of the patients. This was often a seborrheic keratosis or a verruca vulgaris being misdiagnosed as SCC.

BCC was most likely to be misdiagnosed, followed by SCC, and then by melanoma and melanoma in situ, Dr. Butler noted. Seventeen percent of discordant diagnoses involved melanoma and melanoma in situ.

"Misdiagnoses involving basal cells are likely related to their high representation in our population, as opposed to any diagnostic challenge," she said. "On the flip side, considering the small proportion of total tumors that melanoma and melanomas in situ represent in our population, they comprise a surprisingly substantial proportion of the misdiagnosed tumors."

She suggested that the diagnoses of melanoma or melanoma in situ might be the most cost-effective diseases to target with second-opinion review.

The most common change in patient management was cancellation of surgery in 25 patients. The planned surgical approach was changed in another 10 patients, and 1 patient had to be scheduled for surgery as a result of the second biopsy reading, Dr. Butler said.

The cost of taking a second look at biopsy slides is considerable, however. "We did a cost analysis and found that the estimated cost of reviewing the biopsy slides would be approximately $93,000 a year at our university based on the number of slides we look at per year. That is significant, but it has to be weighed against the other benefits," she said.

Surgeons gain much useful information regarding the nature of the tumor, particularly useful when there are deeply infiltrating, aggressive tumors or in cases of perineural involvement, said Dr. Butler, who disclosed having no conflicts of interest relevant to her presentation.

Melanoma and melanoma in situ might be the most cost-effective diseases to target with second-opinion review. DR. BUTLER

ORLANDO — Reviewing the original biopsy slides of patients before they undergo Mohs surgery could result in a change of diagnosis, which in some cases could avert unnecessary surgery, according to Dr. Suzy T. Butler.

In a retrospective study of 3,345 patients, a second review of the original biopsy slide resulted in 74 changed diagnoses. Of these, 45 patients had a change in their management and 25 avoided an unnecessary surgery, Dr. Butler said at the annual meeting of the American Society for Dermatologic Surgery. The study reviewed all patients referred to the cutaneous oncology unit for Mohs surgery at St. Louis University from January 2003 to March 2007.

In one case, a 76-year-old white female presented to her dermatologist with a pink papule on her right cheek that had been previously treated with liquid nitrogen. A shaved biopsy showed an atypical spindle cell proliferation that was read as a desmoplastic malignant melanoma.

A review of the biopsy slides, however, diagnosed the patient as having dermal scar, said Dr. Butler of St. Louis University. Because of this discrepancy, additional biopsies were performed. These confirmed the diagnosis of scar. An s100 stain showed a few spindle cells in the dermis. Surgery was cancelled, and close observation was planned.

In another case, a 74-year-old white male presented with a 1-year history of pink scaly plaques at the suprapubic area. A punch biopsy was originally read as superficial spreading melanoma in situ.

A review of the biopsy before surgery, however, suggested extramammary Paget disease, which was confirmed with additional biopsies. The patient underwent "slow Mohs" surgery with permanent section histology, as well as a thorough malignancy work-up that was negative.

"These cases illustrate how second-opinion review of histopathology before treatment can either avoid potentially disfiguring, unnecessary surgery or direct a different surgical approach and guide the need for other testing," said Dr. Butler.

In addition to recording the number of cases in which the diagnosis changed, the investigators noted how the diagnosis changed and then reviewed the patient's chart to see how that change affected the patient's management. They also recorded the board certification of the original pathologist. Nearly half (48%) of the slides that were rediagnosed had been read by certified dermatopathologists, Dr. Butler said.

The most common change in diagnosis was from one malignant tumor to another in 43% of the patients. Most commonly, a basal cell carcinoma (BCC) diagnosis changed to squamous cell carcinoma (SCC), or a melanoma went from in situ to invasive or vice versa, Dr. Butler said.

The next most common change in diagnosis was from malignant to benign in 36% of the patients. This was often a seborrheic keratosis or a verruca vulgaris being misdiagnosed as SCC.

BCC was most likely to be misdiagnosed, followed by SCC, and then by melanoma and melanoma in situ, Dr. Butler noted. Seventeen percent of discordant diagnoses involved melanoma and melanoma in situ.

"Misdiagnoses involving basal cells are likely related to their high representation in our population, as opposed to any diagnostic challenge," she said. "On the flip side, considering the small proportion of total tumors that melanoma and melanomas in situ represent in our population, they comprise a surprisingly substantial proportion of the misdiagnosed tumors."

She suggested that the diagnoses of melanoma or melanoma in situ might be the most cost-effective diseases to target with second-opinion review.

The most common change in patient management was cancellation of surgery in 25 patients. The planned surgical approach was changed in another 10 patients, and 1 patient had to be scheduled for surgery as a result of the second biopsy reading, Dr. Butler said.

The cost of taking a second look at biopsy slides is considerable, however. "We did a cost analysis and found that the estimated cost of reviewing the biopsy slides would be approximately $93,000 a year at our university based on the number of slides we look at per year. That is significant, but it has to be weighed against the other benefits," she said.

Surgeons gain much useful information regarding the nature of the tumor, particularly useful when there are deeply infiltrating, aggressive tumors or in cases of perineural involvement, said Dr. Butler, who disclosed having no conflicts of interest relevant to her presentation.

Melanoma and melanoma in situ might be the most cost-effective diseases to target with second-opinion review. DR. BUTLER

ORLANDO — Screening and treating methicillin-resistant Staphylococcus aureus nasal carriage in patients before Mohs surgery lowered postoperative MRSA infection rates, according to a new study.

A patient screening and decontamination protocol in the week before surgery brought the postoperative MRSA infection rate to zero. Before such a protocol was in place, the rate was 0.33%, Dr. Katharine Cordova, of Brown University, Providence, R.I., reported in a poster at the annual meeting of the American Society for Dermatologic Surgery.

The protocol screened all patients for nasal MRSA colonization during the preoperative consultation appointment. Patients previously treated with Mohs surgery and patients from the local Veterans Affairs hospital were not screened. Over an 11-month period, 963 nasal swabs were obtained, and 23 MRSA carriers were identified.

Carriers were treated preoperatively with intranasal mupirocin twice daily for 5–7 days and perioperatively with oral trimethoprim-sulfamethoxazole for 5–7 days starting 1 day before surgery.

Patients were also given chlorhexidine or chloroxylenol and cocamidopropyl PG-dimonium chloride phosphate (Techni-Care) body washes to be used the 5 days preceding surgery.

None of the patients developed a MRSA infection.

By mistake, one of the MRSA carriers was not given perioperative treatment. The patient subsequently developed a MRSA wound infection.

Dr. Cordova acknowledged that such a screening program is costly, especially because the incidence of MRSA infections after Mohs surgery is very low. "A large number of negative swabs must be obtained in order to detect one MRSA carrier. At our institution, each negative nasal swab costs $63.00 and a positive screen requires confirmatory testing, which costs an additional $90.00," she said.

A practical approach would be to screen patients with prior MRSA infection or colonization, who are known to be at increased risk for repeat infections and complications, she suggested.

Dr. Cordova declared that she had no conflicts of interest relevant to her presentation.

ORLANDO — Screening and treating methicillin-resistant Staphylococcus aureus nasal carriage in patients before Mohs surgery lowered postoperative MRSA infection rates, according to a new study.

A patient screening and decontamination protocol in the week before surgery brought the postoperative MRSA infection rate to zero. Before such a protocol was in place, the rate was 0.33%, Dr. Katharine Cordova, of Brown University, Providence, R.I., reported in a poster at the annual meeting of the American Society for Dermatologic Surgery.

The protocol screened all patients for nasal MRSA colonization during the preoperative consultation appointment. Patients previously treated with Mohs surgery and patients from the local Veterans Affairs hospital were not screened. Over an 11-month period, 963 nasal swabs were obtained, and 23 MRSA carriers were identified.

Carriers were treated preoperatively with intranasal mupirocin twice daily for 5–7 days and perioperatively with oral trimethoprim-sulfamethoxazole for 5–7 days starting 1 day before surgery.

Patients were also given chlorhexidine or chloroxylenol and cocamidopropyl PG-dimonium chloride phosphate (Techni-Care) body washes to be used the 5 days preceding surgery.

None of the patients developed a MRSA infection.

By mistake, one of the MRSA carriers was not given perioperative treatment. The patient subsequently developed a MRSA wound infection.

Dr. Cordova acknowledged that such a screening program is costly, especially because the incidence of MRSA infections after Mohs surgery is very low. "A large number of negative swabs must be obtained in order to detect one MRSA carrier. At our institution, each negative nasal swab costs $63.00 and a positive screen requires confirmatory testing, which costs an additional $90.00," she said.

A practical approach would be to screen patients with prior MRSA infection or colonization, who are known to be at increased risk for repeat infections and complications, she suggested.

Dr. Cordova declared that she had no conflicts of interest relevant to her presentation.

ORLANDO — Screening and treating methicillin-resistant Staphylococcus aureus nasal carriage in patients before Mohs surgery lowered postoperative MRSA infection rates, according to a new study.

A patient screening and decontamination protocol in the week before surgery brought the postoperative MRSA infection rate to zero. Before such a protocol was in place, the rate was 0.33%, Dr. Katharine Cordova, of Brown University, Providence, R.I., reported in a poster at the annual meeting of the American Society for Dermatologic Surgery.

The protocol screened all patients for nasal MRSA colonization during the preoperative consultation appointment. Patients previously treated with Mohs surgery and patients from the local Veterans Affairs hospital were not screened. Over an 11-month period, 963 nasal swabs were obtained, and 23 MRSA carriers were identified.

Carriers were treated preoperatively with intranasal mupirocin twice daily for 5–7 days and perioperatively with oral trimethoprim-sulfamethoxazole for 5–7 days starting 1 day before surgery.

Patients were also given chlorhexidine or chloroxylenol and cocamidopropyl PG-dimonium chloride phosphate (Techni-Care) body washes to be used the 5 days preceding surgery.

None of the patients developed a MRSA infection.

By mistake, one of the MRSA carriers was not given perioperative treatment. The patient subsequently developed a MRSA wound infection.

Dr. Cordova acknowledged that such a screening program is costly, especially because the incidence of MRSA infections after Mohs surgery is very low. "A large number of negative swabs must be obtained in order to detect one MRSA carrier. At our institution, each negative nasal swab costs $63.00 and a positive screen requires confirmatory testing, which costs an additional $90.00," she said.

A practical approach would be to screen patients with prior MRSA infection or colonization, who are known to be at increased risk for repeat infections and complications, she suggested.

Dr. Cordova declared that she had no conflicts of interest relevant to her presentation.

ORLANDO — Reflectance confocal microscopy can be used as an aid to the clinical exam to help detect either incomplete treatment or recurrence of lentigo maligna and lentigo maligna melanomas that have been treated with nonsurgical methods, a resident in dermatologic surgery said.

After being treated nonsurgically with imiquimod, two patients with biopsy-proven lentigo maligna melanomas were monitored with the aid of reflectance confocal microscopy. In both cases, suspicious areas were detected and were later confirmed to be residual disease on biopsy.

Such cases illustrate the importance of closely following patients with lentigo maligna who are treated with alternative therapies, said Dr. Hari Nadiminti of Memorial Sloan Kettering Cancer Center, New York.

Surgical excision remains the standard of care for treatment of lentigo maligna and lentigo maligna melanoma, but it can be associated with significant morbidity, Dr. Nadiminti said at the annual meeting of the American Society for Dermatologic Surgery.

Alternatives to surgery include cryotherapy, radiotherapy, and topical 5% imiquimod.

Reflectance confocal microscopy is a high-resolution, painless imaging technique that reveals epidermal structures including cells, connective tissue, and blood vessels to a maximum depth of 350 mcm. It has been used to diagnose pigmented basal cell carcinoma and to differentiate between benign and malignant melanocytic lesions and actinic keratoses from normal skin.

Dr. Nadiminti presented five cases to illustrate how microscopy can be useful in monitoring lentigo maligna and lentigo maligna melanoma patients who opt for nonsurgical treatment.

In the first three cases, patients aged 87, 85, and 76 years opted for treatment with imiquimod. In all of these cases, patients had a significant inflammatory response to imiquimod and clinical clearance of pigment after 3 months of treatment.

Reflectance confocal microscopy demonstrated no residual bright structures as well as remodeling of the collagen into a honeycomb pattern in some instances. A confirmatory biopsy revealed no residual melanoma.

In the next two cases, reflectance confocal microscopy revealed persistence of lentigo maligna melanoma after treatment with imiquimod in one case and cryosurgery in the other. Pigmentation cleared completely in one patient and partially in the other. Upon examination with reflectance confocal microscopy, bright structures were observed, and biopsy confirmed the persistence of lentigo maligna melanoma.

After nonsurgical therapies, patients should be followed very closely to monitor for either incomplete treatment or recurrence, Dr. Nadiminti said.

"Even though you have clearance of the pigment with imiquimod, you don't necessarily have clearance of the tumor," he said.

Dr. Nadiminti disclosed no conflicts of interest relevant to his presentation.

ORLANDO — Reflectance confocal microscopy can be used as an aid to the clinical exam to help detect either incomplete treatment or recurrence of lentigo maligna and lentigo maligna melanomas that have been treated with nonsurgical methods, a resident in dermatologic surgery said.

After being treated nonsurgically with imiquimod, two patients with biopsy-proven lentigo maligna melanomas were monitored with the aid of reflectance confocal microscopy. In both cases, suspicious areas were detected and were later confirmed to be residual disease on biopsy.

Such cases illustrate the importance of closely following patients with lentigo maligna who are treated with alternative therapies, said Dr. Hari Nadiminti of Memorial Sloan Kettering Cancer Center, New York.

Surgical excision remains the standard of care for treatment of lentigo maligna and lentigo maligna melanoma, but it can be associated with significant morbidity, Dr. Nadiminti said at the annual meeting of the American Society for Dermatologic Surgery.

Alternatives to surgery include cryotherapy, radiotherapy, and topical 5% imiquimod.

Reflectance confocal microscopy is a high-resolution, painless imaging technique that reveals epidermal structures including cells, connective tissue, and blood vessels to a maximum depth of 350 mcm. It has been used to diagnose pigmented basal cell carcinoma and to differentiate between benign and malignant melanocytic lesions and actinic keratoses from normal skin.

Dr. Nadiminti presented five cases to illustrate how microscopy can be useful in monitoring lentigo maligna and lentigo maligna melanoma patients who opt for nonsurgical treatment.

In the first three cases, patients aged 87, 85, and 76 years opted for treatment with imiquimod. In all of these cases, patients had a significant inflammatory response to imiquimod and clinical clearance of pigment after 3 months of treatment.

Reflectance confocal microscopy demonstrated no residual bright structures as well as remodeling of the collagen into a honeycomb pattern in some instances. A confirmatory biopsy revealed no residual melanoma.

In the next two cases, reflectance confocal microscopy revealed persistence of lentigo maligna melanoma after treatment with imiquimod in one case and cryosurgery in the other. Pigmentation cleared completely in one patient and partially in the other. Upon examination with reflectance confocal microscopy, bright structures were observed, and biopsy confirmed the persistence of lentigo maligna melanoma.

After nonsurgical therapies, patients should be followed very closely to monitor for either incomplete treatment or recurrence, Dr. Nadiminti said.

"Even though you have clearance of the pigment with imiquimod, you don't necessarily have clearance of the tumor," he said.

Dr. Nadiminti disclosed no conflicts of interest relevant to his presentation.

ORLANDO — Reflectance confocal microscopy can be used as an aid to the clinical exam to help detect either incomplete treatment or recurrence of lentigo maligna and lentigo maligna melanomas that have been treated with nonsurgical methods, a resident in dermatologic surgery said.

After being treated nonsurgically with imiquimod, two patients with biopsy-proven lentigo maligna melanomas were monitored with the aid of reflectance confocal microscopy. In both cases, suspicious areas were detected and were later confirmed to be residual disease on biopsy.

Such cases illustrate the importance of closely following patients with lentigo maligna who are treated with alternative therapies, said Dr. Hari Nadiminti of Memorial Sloan Kettering Cancer Center, New York.

Surgical excision remains the standard of care for treatment of lentigo maligna and lentigo maligna melanoma, but it can be associated with significant morbidity, Dr. Nadiminti said at the annual meeting of the American Society for Dermatologic Surgery.

Alternatives to surgery include cryotherapy, radiotherapy, and topical 5% imiquimod.

Reflectance confocal microscopy is a high-resolution, painless imaging technique that reveals epidermal structures including cells, connective tissue, and blood vessels to a maximum depth of 350 mcm. It has been used to diagnose pigmented basal cell carcinoma and to differentiate between benign and malignant melanocytic lesions and actinic keratoses from normal skin.

Dr. Nadiminti presented five cases to illustrate how microscopy can be useful in monitoring lentigo maligna and lentigo maligna melanoma patients who opt for nonsurgical treatment.

In the first three cases, patients aged 87, 85, and 76 years opted for treatment with imiquimod. In all of these cases, patients had a significant inflammatory response to imiquimod and clinical clearance of pigment after 3 months of treatment.

Reflectance confocal microscopy demonstrated no residual bright structures as well as remodeling of the collagen into a honeycomb pattern in some instances. A confirmatory biopsy revealed no residual melanoma.

In the next two cases, reflectance confocal microscopy revealed persistence of lentigo maligna melanoma after treatment with imiquimod in one case and cryosurgery in the other. Pigmentation cleared completely in one patient and partially in the other. Upon examination with reflectance confocal microscopy, bright structures were observed, and biopsy confirmed the persistence of lentigo maligna melanoma.

After nonsurgical therapies, patients should be followed very closely to monitor for either incomplete treatment or recurrence, Dr. Nadiminti said.

"Even though you have clearance of the pigment with imiquimod, you don't necessarily have clearance of the tumor," he said.

Dr. Nadiminti disclosed no conflicts of interest relevant to his presentation.

ORLANDO — Once-daily application of topical fluorouracil cream 0.5% for 4 weeks significantly reduced the number of visible and palpable actinic keratosis lesions on the posterior scalp, ears, neck, lips, arms, and hands by 8 weeks in an open-label, multicenter study of 277 patients.

The effect of the cream was greatest for AK lesions on the lips, ears, and neck. By week 8, 79% of patients with AK lesions on the lips, 62% of patients with AK lesions on the ears, and 65% of patients with AK lesions on the neck, achieved total clearance of their lesions, Dr. Dow Stough reported in a poster at the annual meeting of the American Society of Dermatologic Surgery.

Almost half (48%) of patients were clear of lesions on the posterior scalp, 37% of patients were clear of lesions on the arms, and 31% were clear on the hands. Fourteen percent of patients experienced clearance of AK lesions on all designated treatment areas, wrote Dr. Stough of Burke Pharmaceutical Research and the University of Arkansas, Hot Springs, and his associates.

These results were accomplished with a low incidence of treatment-emergent adverse events, aside from expected application site reactions and eye irritation, according to the investigators.

Topical fluorouracil cream 0.5% is a lower concentration of topical 5-fluourouracil, which has long been used to treat actinic keratoses.

The formulation was developed by Dermik Laboratories, which sponsored the study, and is applied to the AK lesions via the patented Microsponge technology, which permits its controlled release. It is currently approved by the Food and Drug Administration for the treatment of multiple AKs on the face and anterior scalp.

The study was conducted at 25 centers throughout the United States. Patients had at least five lesions on the face or anterior scalp, and at least five lesions on the posterior scalp, ears, neck, lips, arms, or hands. Their mean age was 67 years and 81% were men.

The efficacy and safety of fluorouracil cream 0.5% on facial and anterior scalp AK lesions have already been shown in two randomized, double-blind, vehicle-controlled phase III trials (Cutis 2002;70:335–9; Cutis 2002;70[2 suppl]:22–9). The results of this subanalysis are about the effects of fluorouracil cream 0.5% on AK lesions on sites other than the face, the investigators explained.

Fluorouracil cream 0.5% was applied by the patient to designated lesions once a day for up to 4 weeks, as tolerated. Four weeks after the last application, the patients returned for a follow-up assessment.

There were statistically significant percentage decreases from baseline in the number of AK lesions at the 8-week assessment (P less than .0001). AK lesions decreased by 77% on the lips, 80% on the ears, 79% on the neck, 63% on the arms, 56% on the hands, and 77% on the posterior scalp, Dr. Stough and his associates reported.

The most common adverse event was skin irritation. Symptoms included dryness, erythema, burning, erosion, pruritus, edema, and pain at the application site, they noted.

Patients also reported experiencing symptoms of eye irritation, which included watering, burning, itching, sensitivity, and stinging. One patient was discontinued from the study because of moderate conjunctivitis, and one patient was discontinued because of pancreatitis, which was unrelated to the treatment medication.

Dr. Stough disclosed that his travel expenses to the ASDS annual meeting were funded by Dermik Laboratories.

ORLANDO — Once-daily application of topical fluorouracil cream 0.5% for 4 weeks significantly reduced the number of visible and palpable actinic keratosis lesions on the posterior scalp, ears, neck, lips, arms, and hands by 8 weeks in an open-label, multicenter study of 277 patients.

The effect of the cream was greatest for AK lesions on the lips, ears, and neck. By week 8, 79% of patients with AK lesions on the lips, 62% of patients with AK lesions on the ears, and 65% of patients with AK lesions on the neck, achieved total clearance of their lesions, Dr. Dow Stough reported in a poster at the annual meeting of the American Society of Dermatologic Surgery.

Almost half (48%) of patients were clear of lesions on the posterior scalp, 37% of patients were clear of lesions on the arms, and 31% were clear on the hands. Fourteen percent of patients experienced clearance of AK lesions on all designated treatment areas, wrote Dr. Stough of Burke Pharmaceutical Research and the University of Arkansas, Hot Springs, and his associates.

These results were accomplished with a low incidence of treatment-emergent adverse events, aside from expected application site reactions and eye irritation, according to the investigators.

Topical fluorouracil cream 0.5% is a lower concentration of topical 5-fluourouracil, which has long been used to treat actinic keratoses.

The formulation was developed by Dermik Laboratories, which sponsored the study, and is applied to the AK lesions via the patented Microsponge technology, which permits its controlled release. It is currently approved by the Food and Drug Administration for the treatment of multiple AKs on the face and anterior scalp.

The study was conducted at 25 centers throughout the United States. Patients had at least five lesions on the face or anterior scalp, and at least five lesions on the posterior scalp, ears, neck, lips, arms, or hands. Their mean age was 67 years and 81% were men.

The efficacy and safety of fluorouracil cream 0.5% on facial and anterior scalp AK lesions have already been shown in two randomized, double-blind, vehicle-controlled phase III trials (Cutis 2002;70:335–9; Cutis 2002;70[2 suppl]:22–9). The results of this subanalysis are about the effects of fluorouracil cream 0.5% on AK lesions on sites other than the face, the investigators explained.

Fluorouracil cream 0.5% was applied by the patient to designated lesions once a day for up to 4 weeks, as tolerated. Four weeks after the last application, the patients returned for a follow-up assessment.

There were statistically significant percentage decreases from baseline in the number of AK lesions at the 8-week assessment (P less than .0001). AK lesions decreased by 77% on the lips, 80% on the ears, 79% on the neck, 63% on the arms, 56% on the hands, and 77% on the posterior scalp, Dr. Stough and his associates reported.

The most common adverse event was skin irritation. Symptoms included dryness, erythema, burning, erosion, pruritus, edema, and pain at the application site, they noted.

Patients also reported experiencing symptoms of eye irritation, which included watering, burning, itching, sensitivity, and stinging. One patient was discontinued from the study because of moderate conjunctivitis, and one patient was discontinued because of pancreatitis, which was unrelated to the treatment medication.

Dr. Stough disclosed that his travel expenses to the ASDS annual meeting were funded by Dermik Laboratories.

ORLANDO — Once-daily application of topical fluorouracil cream 0.5% for 4 weeks significantly reduced the number of visible and palpable actinic keratosis lesions on the posterior scalp, ears, neck, lips, arms, and hands by 8 weeks in an open-label, multicenter study of 277 patients.

The effect of the cream was greatest for AK lesions on the lips, ears, and neck. By week 8, 79% of patients with AK lesions on the lips, 62% of patients with AK lesions on the ears, and 65% of patients with AK lesions on the neck, achieved total clearance of their lesions, Dr. Dow Stough reported in a poster at the annual meeting of the American Society of Dermatologic Surgery.

Almost half (48%) of patients were clear of lesions on the posterior scalp, 37% of patients were clear of lesions on the arms, and 31% were clear on the hands. Fourteen percent of patients experienced clearance of AK lesions on all designated treatment areas, wrote Dr. Stough of Burke Pharmaceutical Research and the University of Arkansas, Hot Springs, and his associates.

These results were accomplished with a low incidence of treatment-emergent adverse events, aside from expected application site reactions and eye irritation, according to the investigators.

Topical fluorouracil cream 0.5% is a lower concentration of topical 5-fluourouracil, which has long been used to treat actinic keratoses.

The formulation was developed by Dermik Laboratories, which sponsored the study, and is applied to the AK lesions via the patented Microsponge technology, which permits its controlled release. It is currently approved by the Food and Drug Administration for the treatment of multiple AKs on the face and anterior scalp.

The study was conducted at 25 centers throughout the United States. Patients had at least five lesions on the face or anterior scalp, and at least five lesions on the posterior scalp, ears, neck, lips, arms, or hands. Their mean age was 67 years and 81% were men.

The efficacy and safety of fluorouracil cream 0.5% on facial and anterior scalp AK lesions have already been shown in two randomized, double-blind, vehicle-controlled phase III trials (Cutis 2002;70:335–9; Cutis 2002;70[2 suppl]:22–9). The results of this subanalysis are about the effects of fluorouracil cream 0.5% on AK lesions on sites other than the face, the investigators explained.

Fluorouracil cream 0.5% was applied by the patient to designated lesions once a day for up to 4 weeks, as tolerated. Four weeks after the last application, the patients returned for a follow-up assessment.

There were statistically significant percentage decreases from baseline in the number of AK lesions at the 8-week assessment (P less than .0001). AK lesions decreased by 77% on the lips, 80% on the ears, 79% on the neck, 63% on the arms, 56% on the hands, and 77% on the posterior scalp, Dr. Stough and his associates reported.

The most common adverse event was skin irritation. Symptoms included dryness, erythema, burning, erosion, pruritus, edema, and pain at the application site, they noted.

Patients also reported experiencing symptoms of eye irritation, which included watering, burning, itching, sensitivity, and stinging. One patient was discontinued from the study because of moderate conjunctivitis, and one patient was discontinued because of pancreatitis, which was unrelated to the treatment medication.

Dr. Stough disclosed that his travel expenses to the ASDS annual meeting were funded by Dermik Laboratories.

LAS VEGAS — It goes without saying that protection from excessive ultraviolet light throughout life is advocated by dermatologists to prevent skin cancer and photoaging, noted Dr. James M. Spencer.

“We dermatologists basically tell Americans, 'Use sunscreen or sunblock all the time.' That's our public health message, and it's been a consistent message for 20 years,” Dr. Spencer said at the annual meeting of the American Society of Cosmetic Dermatology and Aesthetic Surgery. “In animal and human studies, sunscreens have clearly proved to help prevent photoaging, lower the incidence of actinic keratoses, and lower the incidence of squamous cell carcinoma. That's beyond dispute.”

The American Academy of Dermatology recently issued a position statement recommending that “an adequate amount of vitamin D should be obtained from a healthy diet that includes food rich in vitamin D, foods/beverages fortified with vitamin D, and/or vitamin D supplements; it should not be obtained from unprotected ultraviolet (UV) radiation.”

The statement also pointed out that the current intake levels recommended by the Institute of Medicine, the health policy research arm of the National Academy of Sciences, “may be revised upward due to evolving research on the increasing clinical benefit of vitamin D.”

The wisdom of avoiding sun and using sunscreen has been questioned over the last few years, initially by epidemiologists who were looking to correlate human behavior with the development of melanoma, Dr. Spencer said. Then came a review article in 2007 by Dr. Michael F. Holick, an endocrinologist at Boston University, which estimated that 40%–60% of the adult population in the United States is vitamin D deficient (N. Engl. J. Med. 2007;357:266–81). The article calls for “sensible sun exposure” to ensure that adequate amounts of vitamin D are made in the skin, noting that exposure of the arms and legs for 5–30 minutes between 10 a.m. and 3 p.m. twice a week is “adequate” for most people.

“Some moderate sun exposure for both children and adults is appropriate,” Dr. Holick said in an interview. “Yes, you can always wear a broad-rimmed hat or some kind of sun protection for your face. It's the most sun damaged area; it's only about 9% of your body surface, and it doesn't provide you with that much of your vitamin D.”

According to the article, which was supported in part by grants from the National Institutes of Health and the UV Foundation, a key cause of vitamin D deficiency is sunscreen use, which “reduces vitamin D₃ synthesis.” It also states that the ultraviolet B radiation emitted from tanning beds is a good source of vitamin D₃ “when used in moderation.”

The importance of obtaining adequate levels of vitamin D is not in dispute, said Dr. Spencer of Mount Sinai School of Medicine, New York. Vitamin D has emerged as a candidate for the chemoprevention of a variety of malignancies and systemic diseases, including melanoma; breast, colon, and prostate cancer; multiple sclerosis; hypertension; cardiovascular disease; type 1 diabetes; Crohn's disease; schizophrenia; and depression.

However, there is no reason to believe that sun protection dangerously lowers vitamin D levels, said Dr. Spencer, who has a private dermatology practice in St. Petersburg, Fla. “Even if it did, the public has largely ignored our sun protection message, based on results of recent surveys of sun protection habits. It is a mistake to encourage the public to get intentional sun exposure for their health.”

He went on to note that vitamin D production in the skin “is highly variable by such factors as skin pigmentation and time of year, and therefore is not a reliable way to elevate vitamin D. It is unlikely that anyone goes to the beach or the tanning parlor to make more vitamin D, but this issue lets them rationalize that doing something they know is bad for them is actually okay. The people most at risk for vitamin D deficiency—dark-skinned nursing home residents—do not go to tanning salons.”

According to the Institute of Medicine guidelines, the recommended minimal daily intake of vitamin D is 200 IU for children and adults to age 50 years, 400 IU for adults aged 50–70 years, and 600 IU for adults older than 70 years.

The American Academy of Pediatrics Committee on Nutrition recently recommended increasing oral intake in children to 400 IU per day but does not recommend increased sun exposure because of skin cancer risk (Pediatrics 2008;122:1142–52).

In a pharmacokinetic study, a team of researchers that included Dr. Holick demonstrated that healthy men use up to 5,000 IU of vitamin D per day (Am. J. Clin. Nutr. 2003;77:204–10). This is “an order of magnitude higher than we thought we needed,” said Dr. Holick, professor of medicine, physiology, and biophysics at the university, and coauthor of the book, “The UV Advantage” (New York: Ibooks Inc., 2004). “We probably need to increase by 10-fold our vitamin intake to satisfy our body's requirement.”

Good dietary sources of vitamin D include salmon and other oily fish, eggs, fortified milk and cereals, orange juice, and vitamin supplements. “Many multivitamins contain D₂, which is poorly absorbed,” said Dr. Spencer, past cochairman of the National Council on Skin Cancer Prevention. “Look for those that contain vitamin D₃.”

Dr. Holick maintains that it is “next to impossible” to get enough vitamin D from diet alone; some exposure to sunlight must play into the mix. “If you were to go outside in a bathing suit on the beach in the summertime and get a light pinkness to your skin, a minimal erythemal dose—which is 15–20 minutes for a white person—that's equivalent to ingesting 10,000–20,000 IU of vitamin D.”

While it's known how much vitamin D is needed to prevent deficiency and bone disease, Dr. Spencer said, “We do not know what level of vitamin D may be optimal for health maintenance. Therefore, we keep an open mind to future research.”

As for Dr. Holick, he points to a position statement on sun exposure issued in 2006 by groups that included the Australian College of Dermatologists and Cancer Council Australia, which support his view (www.cancer.org.au

The importance of obtaining vitamin D is not in dispute; it is how it is obtained that is, according to Dr. James M. Spencer. Courtesy Dr. James M. Spencer

LAS VEGAS — It goes without saying that protection from excessive ultraviolet light throughout life is advocated by dermatologists to prevent skin cancer and photoaging, noted Dr. James M. Spencer.

“We dermatologists basically tell Americans, 'Use sunscreen or sunblock all the time.' That's our public health message, and it's been a consistent message for 20 years,” Dr. Spencer said at the annual meeting of the American Society of Cosmetic Dermatology and Aesthetic Surgery. “In animal and human studies, sunscreens have clearly proved to help prevent photoaging, lower the incidence of actinic keratoses, and lower the incidence of squamous cell carcinoma. That's beyond dispute.”

The American Academy of Dermatology recently issued a position statement recommending that “an adequate amount of vitamin D should be obtained from a healthy diet that includes food rich in vitamin D, foods/beverages fortified with vitamin D, and/or vitamin D supplements; it should not be obtained from unprotected ultraviolet (UV) radiation.”

The statement also pointed out that the current intake levels recommended by the Institute of Medicine, the health policy research arm of the National Academy of Sciences, “may be revised upward due to evolving research on the increasing clinical benefit of vitamin D.”

The wisdom of avoiding sun and using sunscreen has been questioned over the last few years, initially by epidemiologists who were looking to correlate human behavior with the development of melanoma, Dr. Spencer said. Then came a review article in 2007 by Dr. Michael F. Holick, an endocrinologist at Boston University, which estimated that 40%–60% of the adult population in the United States is vitamin D deficient (N. Engl. J. Med. 2007;357:266–81). The article calls for “sensible sun exposure” to ensure that adequate amounts of vitamin D are made in the skin, noting that exposure of the arms and legs for 5–30 minutes between 10 a.m. and 3 p.m. twice a week is “adequate” for most people.

“Some moderate sun exposure for both children and adults is appropriate,” Dr. Holick said in an interview. “Yes, you can always wear a broad-rimmed hat or some kind of sun protection for your face. It's the most sun damaged area; it's only about 9% of your body surface, and it doesn't provide you with that much of your vitamin D.”

According to the article, which was supported in part by grants from the National Institutes of Health and the UV Foundation, a key cause of vitamin D deficiency is sunscreen use, which “reduces vitamin D₃ synthesis.” It also states that the ultraviolet B radiation emitted from tanning beds is a good source of vitamin D₃ “when used in moderation.”

The importance of obtaining adequate levels of vitamin D is not in dispute, said Dr. Spencer of Mount Sinai School of Medicine, New York. Vitamin D has emerged as a candidate for the chemoprevention of a variety of malignancies and systemic diseases, including melanoma; breast, colon, and prostate cancer; multiple sclerosis; hypertension; cardiovascular disease; type 1 diabetes; Crohn's disease; schizophrenia; and depression.

However, there is no reason to believe that sun protection dangerously lowers vitamin D levels, said Dr. Spencer, who has a private dermatology practice in St. Petersburg, Fla. “Even if it did, the public has largely ignored our sun protection message, based on results of recent surveys of sun protection habits. It is a mistake to encourage the public to get intentional sun exposure for their health.”

He went on to note that vitamin D production in the skin “is highly variable by such factors as skin pigmentation and time of year, and therefore is not a reliable way to elevate vitamin D. It is unlikely that anyone goes to the beach or the tanning parlor to make more vitamin D, but this issue lets them rationalize that doing something they know is bad for them is actually okay. The people most at risk for vitamin D deficiency—dark-skinned nursing home residents—do not go to tanning salons.”

According to the Institute of Medicine guidelines, the recommended minimal daily intake of vitamin D is 200 IU for children and adults to age 50 years, 400 IU for adults aged 50–70 years, and 600 IU for adults older than 70 years.

The American Academy of Pediatrics Committee on Nutrition recently recommended increasing oral intake in children to 400 IU per day but does not recommend increased sun exposure because of skin cancer risk (Pediatrics 2008;122:1142–52).

In a pharmacokinetic study, a team of researchers that included Dr. Holick demonstrated that healthy men use up to 5,000 IU of vitamin D per day (Am. J. Clin. Nutr. 2003;77:204–10). This is “an order of magnitude higher than we thought we needed,” said Dr. Holick, professor of medicine, physiology, and biophysics at the university, and coauthor of the book, “The UV Advantage” (New York: Ibooks Inc., 2004). “We probably need to increase by 10-fold our vitamin intake to satisfy our body's requirement.”

Good dietary sources of vitamin D include salmon and other oily fish, eggs, fortified milk and cereals, orange juice, and vitamin supplements. “Many multivitamins contain D₂, which is poorly absorbed,” said Dr. Spencer, past cochairman of the National Council on Skin Cancer Prevention. “Look for those that contain vitamin D₃.”

Dr. Holick maintains that it is “next to impossible” to get enough vitamin D from diet alone; some exposure to sunlight must play into the mix. “If you were to go outside in a bathing suit on the beach in the summertime and get a light pinkness to your skin, a minimal erythemal dose—which is 15–20 minutes for a white person—that's equivalent to ingesting 10,000–20,000 IU of vitamin D.”

While it's known how much vitamin D is needed to prevent deficiency and bone disease, Dr. Spencer said, “We do not know what level of vitamin D may be optimal for health maintenance. Therefore, we keep an open mind to future research.”

As for Dr. Holick, he points to a position statement on sun exposure issued in 2006 by groups that included the Australian College of Dermatologists and Cancer Council Australia, which support his view (www.cancer.org.au

The importance of obtaining vitamin D is not in dispute; it is how it is obtained that is, according to Dr. James M. Spencer. Courtesy Dr. James M. Spencer

LAS VEGAS — It goes without saying that protection from excessive ultraviolet light throughout life is advocated by dermatologists to prevent skin cancer and photoaging, noted Dr. James M. Spencer.

“We dermatologists basically tell Americans, 'Use sunscreen or sunblock all the time.' That's our public health message, and it's been a consistent message for 20 years,” Dr. Spencer said at the annual meeting of the American Society of Cosmetic Dermatology and Aesthetic Surgery. “In animal and human studies, sunscreens have clearly proved to help prevent photoaging, lower the incidence of actinic keratoses, and lower the incidence of squamous cell carcinoma. That's beyond dispute.”

The American Academy of Dermatology recently issued a position statement recommending that “an adequate amount of vitamin D should be obtained from a healthy diet that includes food rich in vitamin D, foods/beverages fortified with vitamin D, and/or vitamin D supplements; it should not be obtained from unprotected ultraviolet (UV) radiation.”

The statement also pointed out that the current intake levels recommended by the Institute of Medicine, the health policy research arm of the National Academy of Sciences, “may be revised upward due to evolving research on the increasing clinical benefit of vitamin D.”

The wisdom of avoiding sun and using sunscreen has been questioned over the last few years, initially by epidemiologists who were looking to correlate human behavior with the development of melanoma, Dr. Spencer said. Then came a review article in 2007 by Dr. Michael F. Holick, an endocrinologist at Boston University, which estimated that 40%–60% of the adult population in the United States is vitamin D deficient (N. Engl. J. Med. 2007;357:266–81). The article calls for “sensible sun exposure” to ensure that adequate amounts of vitamin D are made in the skin, noting that exposure of the arms and legs for 5–30 minutes between 10 a.m. and 3 p.m. twice a week is “adequate” for most people.

“Some moderate sun exposure for both children and adults is appropriate,” Dr. Holick said in an interview. “Yes, you can always wear a broad-rimmed hat or some kind of sun protection for your face. It's the most sun damaged area; it's only about 9% of your body surface, and it doesn't provide you with that much of your vitamin D.”

According to the article, which was supported in part by grants from the National Institutes of Health and the UV Foundation, a key cause of vitamin D deficiency is sunscreen use, which “reduces vitamin D₃ synthesis.” It also states that the ultraviolet B radiation emitted from tanning beds is a good source of vitamin D₃ “when used in moderation.”

The importance of obtaining adequate levels of vitamin D is not in dispute, said Dr. Spencer of Mount Sinai School of Medicine, New York. Vitamin D has emerged as a candidate for the chemoprevention of a variety of malignancies and systemic diseases, including melanoma; breast, colon, and prostate cancer; multiple sclerosis; hypertension; cardiovascular disease; type 1 diabetes; Crohn's disease; schizophrenia; and depression.

However, there is no reason to believe that sun protection dangerously lowers vitamin D levels, said Dr. Spencer, who has a private dermatology practice in St. Petersburg, Fla. “Even if it did, the public has largely ignored our sun protection message, based on results of recent surveys of sun protection habits. It is a mistake to encourage the public to get intentional sun exposure for their health.”

He went on to note that vitamin D production in the skin “is highly variable by such factors as skin pigmentation and time of year, and therefore is not a reliable way to elevate vitamin D. It is unlikely that anyone goes to the beach or the tanning parlor to make more vitamin D, but this issue lets them rationalize that doing something they know is bad for them is actually okay. The people most at risk for vitamin D deficiency—dark-skinned nursing home residents—do not go to tanning salons.”

According to the Institute of Medicine guidelines, the recommended minimal daily intake of vitamin D is 200 IU for children and adults to age 50 years, 400 IU for adults aged 50–70 years, and 600 IU for adults older than 70 years.

The American Academy of Pediatrics Committee on Nutrition recently recommended increasing oral intake in children to 400 IU per day but does not recommend increased sun exposure because of skin cancer risk (Pediatrics 2008;122:1142–52).

In a pharmacokinetic study, a team of researchers that included Dr. Holick demonstrated that healthy men use up to 5,000 IU of vitamin D per day (Am. J. Clin. Nutr. 2003;77:204–10). This is “an order of magnitude higher than we thought we needed,” said Dr. Holick, professor of medicine, physiology, and biophysics at the university, and coauthor of the book, “The UV Advantage” (New York: Ibooks Inc., 2004). “We probably need to increase by 10-fold our vitamin intake to satisfy our body's requirement.”

Good dietary sources of vitamin D include salmon and other oily fish, eggs, fortified milk and cereals, orange juice, and vitamin supplements. “Many multivitamins contain D₂, which is poorly absorbed,” said Dr. Spencer, past cochairman of the National Council on Skin Cancer Prevention. “Look for those that contain vitamin D₃.”

Dr. Holick maintains that it is “next to impossible” to get enough vitamin D from diet alone; some exposure to sunlight must play into the mix. “If you were to go outside in a bathing suit on the beach in the summertime and get a light pinkness to your skin, a minimal erythemal dose—which is 15–20 minutes for a white person—that's equivalent to ingesting 10,000–20,000 IU of vitamin D.”

While it's known how much vitamin D is needed to prevent deficiency and bone disease, Dr. Spencer said, “We do not know what level of vitamin D may be optimal for health maintenance. Therefore, we keep an open mind to future research.”

As for Dr. Holick, he points to a position statement on sun exposure issued in 2006 by groups that included the Australian College of Dermatologists and Cancer Council Australia, which support his view (www.cancer.org.au

The importance of obtaining vitamin D is not in dispute; it is how it is obtained that is, according to Dr. James M. Spencer. Courtesy Dr. James M. Spencer

STOCKHOLM — The failure of the largest randomized phase III trial ever conducted in stage IV melanoma has left investigators around the globe with a question for which they have no easy answer: What next?

Temozolomide did not improve upon the dismal survival rates achieved by standard therapy with dacarbazine (DTIC) in the disappointing multinational study presented at the European Society for Medical Oncology Congress. And some experimental treatments for advanced melanoma produced objective responses in less than 10% of patients reported upon by phase II investigators at the same meeting.

Moreover, DTIC may not be better than best supportive care—the two have never been tested against each other, according to Dr. Lorenz Jost, who painted a glum picture of melanoma research to date in his discussion of the temozolomide study.

"We don't have any proof that dacarbazine extends survival. Even worse, we don't have any proof that DTIC doesn't shorten survival," Dr. Jost of Kantonsspital Bruderholz in Switzerland told Congress attendees.

Except for the historical failure to compare DTIC to best supportive care, Dr. Jost found nothing wrong with the conduct of the European Organisation for Research and Treatment of Cancer (EORTC) 18032 trial comparing oral temozolomide with DTIC injection. At a median 18-month follow-up, median overall survival was little better than 9 months in both arms of the 859-patient study.

No chemotherapy combination has shown a significant advantage over DTIC, Dr. Jost said, citing a study comparing DTIC with vinblastine, bleomycin, and cisplatin (J. Clin. Oncol. 1984;2:164-8), nor have more aggressive regimens, such as one augmenting DTIC with cisplatin and carmustine (J. Clin. Oncol. 1999;17:2745-51).

Vaccines likewise have produced similar survival rates to DTIC (Ann. Onc. 2006;17:563-70), he continued, and a metaanalysis of 18 trials involving 2,621 patients randomized to biochemotherapies versus chemotherapy yielded an odds ratio of 0.99 for overall survival (J. Clin. Oncol. 2007;25:5426-34).

If DTIC cannot clear large tumors, Dr. Jost asked, can it be better used as an adjuvant therapy? No benefit has been seen with that approach, and boosting DTIC with sorafenib also produced no advantage in a study published earlier this year (J. Clin. Oncol. 2008;26:2178-85).

Maybe investigators should move on to a new class of drugs targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), he suggested, showing a list of about a dozen studies, among which only three trials reported patient responses (J. Trans. Med. 2008;6:22).

Despite all these red lights, Dr. Jost urged his audience not to despair. "Keep putting patients onto trials," he said.

But what trials? Even before Dr. Jost discussed the temozolomide results, an audience member suggested that perhaps it was time to stop doing phase III chemotherapy trials in melanoma.

Indeed, so many phase III trials have failed to improve survival rates in patients with late-stage melanoma that asking "What is your next phase III?" is to pose "a below-the-belt question," according to Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute.

"We don't have an idea in the cooperative groups in the United States. Both the Southwest [Oncology Group] and the ECOG [Eastern Cooperative Oncology Group] are totally waiting for something in a blinding streak of brilliance," said Dr. Kirkwood, an ECOG investigator.

He reported on the investigational anti-CTLA-4 agent tremelimumab in a Pfizer Inc.-sponsored trial during the same session (see related story above). The bottom line seen in trials of tremelimumab and another experimental anti-CTLA-4 agent, ipilimumab, is that "objective response rates are very similar and there are people alive who wouldn't have been without these agents," he said in an interview. The main obstacle is anti-CTLA-4 therapy is "not efficient," with only a small number of people responding out of hundreds so far treated. The next step is to study proinflammatory cytokines and proteomics to identify factors predictive of response to these agents, Dr. Kirkwood said.

For Dr. Poulam M. Patel of the University of Nottingham (England), and investigator of the temozolomide trial, finding ways to identify molecular targets and subtype patients is likely to be the next direction taken by collaborative groups in melanoma. In his presentation, he also noted that no therapy has been proved more effective than DTIC in 2 decades.

STOCKHOLM — The failure of the largest randomized phase III trial ever conducted in stage IV melanoma has left investigators around the globe with a question for which they have no easy answer: What next?

Temozolomide did not improve upon the dismal survival rates achieved by standard therapy with dacarbazine (DTIC) in the disappointing multinational study presented at the European Society for Medical Oncology Congress. And some experimental treatments for advanced melanoma produced objective responses in less than 10% of patients reported upon by phase II investigators at the same meeting.

Moreover, DTIC may not be better than best supportive care—the two have never been tested against each other, according to Dr. Lorenz Jost, who painted a glum picture of melanoma research to date in his discussion of the temozolomide study.

"We don't have any proof that dacarbazine extends survival. Even worse, we don't have any proof that DTIC doesn't shorten survival," Dr. Jost of Kantonsspital Bruderholz in Switzerland told Congress attendees.

Except for the historical failure to compare DTIC to best supportive care, Dr. Jost found nothing wrong with the conduct of the European Organisation for Research and Treatment of Cancer (EORTC) 18032 trial comparing oral temozolomide with DTIC injection. At a median 18-month follow-up, median overall survival was little better than 9 months in both arms of the 859-patient study.

No chemotherapy combination has shown a significant advantage over DTIC, Dr. Jost said, citing a study comparing DTIC with vinblastine, bleomycin, and cisplatin (J. Clin. Oncol. 1984;2:164-8), nor have more aggressive regimens, such as one augmenting DTIC with cisplatin and carmustine (J. Clin. Oncol. 1999;17:2745-51).

Vaccines likewise have produced similar survival rates to DTIC (Ann. Onc. 2006;17:563-70), he continued, and a metaanalysis of 18 trials involving 2,621 patients randomized to biochemotherapies versus chemotherapy yielded an odds ratio of 0.99 for overall survival (J. Clin. Oncol. 2007;25:5426-34).

If DTIC cannot clear large tumors, Dr. Jost asked, can it be better used as an adjuvant therapy? No benefit has been seen with that approach, and boosting DTIC with sorafenib also produced no advantage in a study published earlier this year (J. Clin. Oncol. 2008;26:2178-85).

Maybe investigators should move on to a new class of drugs targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), he suggested, showing a list of about a dozen studies, among which only three trials reported patient responses (J. Trans. Med. 2008;6:22).

Despite all these red lights, Dr. Jost urged his audience not to despair. "Keep putting patients onto trials," he said.

But what trials? Even before Dr. Jost discussed the temozolomide results, an audience member suggested that perhaps it was time to stop doing phase III chemotherapy trials in melanoma.

Indeed, so many phase III trials have failed to improve survival rates in patients with late-stage melanoma that asking "What is your next phase III?" is to pose "a below-the-belt question," according to Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute.

"We don't have an idea in the cooperative groups in the United States. Both the Southwest [Oncology Group] and the ECOG [Eastern Cooperative Oncology Group] are totally waiting for something in a blinding streak of brilliance," said Dr. Kirkwood, an ECOG investigator.

He reported on the investigational anti-CTLA-4 agent tremelimumab in a Pfizer Inc.-sponsored trial during the same session (see related story above). The bottom line seen in trials of tremelimumab and another experimental anti-CTLA-4 agent, ipilimumab, is that "objective response rates are very similar and there are people alive who wouldn't have been without these agents," he said in an interview. The main obstacle is anti-CTLA-4 therapy is "not efficient," with only a small number of people responding out of hundreds so far treated. The next step is to study proinflammatory cytokines and proteomics to identify factors predictive of response to these agents, Dr. Kirkwood said.

For Dr. Poulam M. Patel of the University of Nottingham (England), and investigator of the temozolomide trial, finding ways to identify molecular targets and subtype patients is likely to be the next direction taken by collaborative groups in melanoma. In his presentation, he also noted that no therapy has been proved more effective than DTIC in 2 decades.

STOCKHOLM — The failure of the largest randomized phase III trial ever conducted in stage IV melanoma has left investigators around the globe with a question for which they have no easy answer: What next?

Temozolomide did not improve upon the dismal survival rates achieved by standard therapy with dacarbazine (DTIC) in the disappointing multinational study presented at the European Society for Medical Oncology Congress. And some experimental treatments for advanced melanoma produced objective responses in less than 10% of patients reported upon by phase II investigators at the same meeting.

Moreover, DTIC may not be better than best supportive care—the two have never been tested against each other, according to Dr. Lorenz Jost, who painted a glum picture of melanoma research to date in his discussion of the temozolomide study.

"We don't have any proof that dacarbazine extends survival. Even worse, we don't have any proof that DTIC doesn't shorten survival," Dr. Jost of Kantonsspital Bruderholz in Switzerland told Congress attendees.

Except for the historical failure to compare DTIC to best supportive care, Dr. Jost found nothing wrong with the conduct of the European Organisation for Research and Treatment of Cancer (EORTC) 18032 trial comparing oral temozolomide with DTIC injection. At a median 18-month follow-up, median overall survival was little better than 9 months in both arms of the 859-patient study.

No chemotherapy combination has shown a significant advantage over DTIC, Dr. Jost said, citing a study comparing DTIC with vinblastine, bleomycin, and cisplatin (J. Clin. Oncol. 1984;2:164-8), nor have more aggressive regimens, such as one augmenting DTIC with cisplatin and carmustine (J. Clin. Oncol. 1999;17:2745-51).

Vaccines likewise have produced similar survival rates to DTIC (Ann. Onc. 2006;17:563-70), he continued, and a metaanalysis of 18 trials involving 2,621 patients randomized to biochemotherapies versus chemotherapy yielded an odds ratio of 0.99 for overall survival (J. Clin. Oncol. 2007;25:5426-34).

If DTIC cannot clear large tumors, Dr. Jost asked, can it be better used as an adjuvant therapy? No benefit has been seen with that approach, and boosting DTIC with sorafenib also produced no advantage in a study published earlier this year (J. Clin. Oncol. 2008;26:2178-85).

Maybe investigators should move on to a new class of drugs targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), he suggested, showing a list of about a dozen studies, among which only three trials reported patient responses (J. Trans. Med. 2008;6:22).

Despite all these red lights, Dr. Jost urged his audience not to despair. "Keep putting patients onto trials," he said.

But what trials? Even before Dr. Jost discussed the temozolomide results, an audience member suggested that perhaps it was time to stop doing phase III chemotherapy trials in melanoma.

Indeed, so many phase III trials have failed to improve survival rates in patients with late-stage melanoma that asking "What is your next phase III?" is to pose "a below-the-belt question," according to Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute.

"We don't have an idea in the cooperative groups in the United States. Both the Southwest [Oncology Group] and the ECOG [Eastern Cooperative Oncology Group] are totally waiting for something in a blinding streak of brilliance," said Dr. Kirkwood, an ECOG investigator.

He reported on the investigational anti-CTLA-4 agent tremelimumab in a Pfizer Inc.-sponsored trial during the same session (see related story above). The bottom line seen in trials of tremelimumab and another experimental anti-CTLA-4 agent, ipilimumab, is that "objective response rates are very similar and there are people alive who wouldn't have been without these agents," he said in an interview. The main obstacle is anti-CTLA-4 therapy is "not efficient," with only a small number of people responding out of hundreds so far treated. The next step is to study proinflammatory cytokines and proteomics to identify factors predictive of response to these agents, Dr. Kirkwood said.

For Dr. Poulam M. Patel of the University of Nottingham (England), and investigator of the temozolomide trial, finding ways to identify molecular targets and subtype patients is likely to be the next direction taken by collaborative groups in melanoma. In his presentation, he also noted that no therapy has been proved more effective than DTIC in 2 decades.

STOCKHOLM — Clinical studies of two experimental agents—tremelimumab and ipilimumab—have shown delayed and mixed responses among patients who gained control of refractory melanomas with these therapies.

Both agents come from a new class of monoclonal antibodies that seeks to promote immune response by blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In three phase II trials presented at the European Society for Medical Oncology Congress, tremelimumab and ipilimumab ultimately achieved disease control rates of 14%–29% as second-line therapies.

Among patients classified as having progressive disease after ipilimumab treatment, however, were some people who subsequently improved. Likewise, among six patients with "mixed response" to tremelimumab were five patients who initially developed new lesions, but then had slow decreases in targeted lesions. All six were still alive at the time of the presentation.

Investigators suggested that the modified World Health Organization (WHO) criteria used to assess activity of cytotoxic agents may not capture the benefit in some patients classified with progressive disease. They cited four observed patterns of response, which were described in a poster by Dr. Kaan Harmankaya, of the department of dermatology at University of Vienna, and associates:

▸ Response in baseline lesions.

▸ Stable disease with a slow, steady decline in tumor volume.

▸ Response after increase in total tumor volume.

▸ Response in index and new lesions after the appearance of new lesions.

While delayed response is an issue for researchers, the clinical impact could be more important, according to a discussion of the tremelimumab and ipilimumab studies by Dr. Ulrich Keilholz of the Charité University in Berlin and the European Organisation for Research and Treatment of Cancer melanoma group.

"Nonclassical assessment does change the response rate, but it does not change the survival rate," Dr. Keilholz said, downplaying the importance of response, compared with overall survival in phase IIItrials.

Tremelimumab

Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute, presented the tremelimumab data from an open-label phase II trial in 251 patients (nearly all with stage IV disease), of whom 242 were evaluable. The protocol called for a 15- mg/kg dose to be delivered intravenously on the first day of up to four 12-week cycles. Sixteen (7%) patients achieved partial responses and 36 (15%) had stable disease—a clinical benefit rate of 22%.

Dr. Kirkwood said all but 1 of the partial responses lasted at least 170 days, and 11 were ongoing. Median overall survival reached 10.1 months, he said; median progression-free survival reached 2.8 months, with 15.6% of patients progression-free 6 months after treatment. Factors correlating with survival were still being analyzed. The trial was sponsored by Pfizer Inc.

Ipilimumab

The first ipilimumab trial was a multinational, open-label study of 155 patients with advanced disease that had failed previous therapies. Patients received 10 mg/kg of ipilimumab every 3 weeks for four cycles, followed by maintenance therapy at the same dose every 12 weeks from week 12 to week 60.

Dr. Vanna Chiarion Sileni of the Instituto Oncologo Veneto in Padua, Italy, reported 9 patients had partial responses and 33 had stable disease by modified WHO criteria, adding up to a disease control rate of 27% (42/155). The median duration of stable disease was 4.1 months at a median follow-up of 5.7 months, she said; 19 patients were still stable at their last assessment.

Among those classified with progressive disease were patients with the four patterns of response. Small subgroups had a "slow steady decline" in tumor volume after an initial increase in target lesions or the appearance of new lesions, she said.

In the second ipilimumab trial, Dr. Celeste Lebbé of Saint-Louis Hospital in Paris reported on a multinational dose-finding study that randomized patients with unresectable relapsed stage III or IV melanoma to 10 mg/kg, 3 mg/kg, or 0.3 mg/kg of ipilimumab given once every 3 weeks for four cycles followed by maintenance treatment once every 12 weeks.

The 10-mg/kg dose produced the best overall response rate, a composite measure of complete and partial responses, at 11%, and a disease control rate of 29%. Nearly half, 48% of 73 patients given the highest dose were alive at 1 year. Their median survival was estimated at 11 months at a median follow-up of 10.4 months.

The four patterns of response were observed in this study as well, Dr. Lebbé reported, and about 35% of patients at the highest dose had a decline in total tumor volume. Patients at this dose also had the most toxicity, she said; about a quarter had grade III adverse events, including gastrointestinal side effects in 16%.

The ipilimumab studies were sponsored by Bristol-Myer Squibb and Medarex Inc, which are jointly developing the agent. Dr. Lebbé was the only investigator to disclose a conflict of interest, having served on two advisory boards for Bristol-Myer Squibb.

Dr. Kirkwood said phase III trials for both agents have been completed and are being analyzed, but applications for approval have not yet been filed.

ELSEVIER GLOBAL MEDICAL NEWS

STOCKHOLM — Clinical studies of two experimental agents—tremelimumab and ipilimumab—have shown delayed and mixed responses among patients who gained control of refractory melanomas with these therapies.

Both agents come from a new class of monoclonal antibodies that seeks to promote immune response by blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In three phase II trials presented at the European Society for Medical Oncology Congress, tremelimumab and ipilimumab ultimately achieved disease control rates of 14%–29% as second-line therapies.

Among patients classified as having progressive disease after ipilimumab treatment, however, were some people who subsequently improved. Likewise, among six patients with "mixed response" to tremelimumab were five patients who initially developed new lesions, but then had slow decreases in targeted lesions. All six were still alive at the time of the presentation.

Investigators suggested that the modified World Health Organization (WHO) criteria used to assess activity of cytotoxic agents may not capture the benefit in some patients classified with progressive disease. They cited four observed patterns of response, which were described in a poster by Dr. Kaan Harmankaya, of the department of dermatology at University of Vienna, and associates:

▸ Response in baseline lesions.

▸ Stable disease with a slow, steady decline in tumor volume.

▸ Response after increase in total tumor volume.

▸ Response in index and new lesions after the appearance of new lesions.

While delayed response is an issue for researchers, the clinical impact could be more important, according to a discussion of the tremelimumab and ipilimumab studies by Dr. Ulrich Keilholz of the Charité University in Berlin and the European Organisation for Research and Treatment of Cancer melanoma group.

"Nonclassical assessment does change the response rate, but it does not change the survival rate," Dr. Keilholz said, downplaying the importance of response, compared with overall survival in phase IIItrials.

Tremelimumab

Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute, presented the tremelimumab data from an open-label phase II trial in 251 patients (nearly all with stage IV disease), of whom 242 were evaluable. The protocol called for a 15- mg/kg dose to be delivered intravenously on the first day of up to four 12-week cycles. Sixteen (7%) patients achieved partial responses and 36 (15%) had stable disease—a clinical benefit rate of 22%.

Dr. Kirkwood said all but 1 of the partial responses lasted at least 170 days, and 11 were ongoing. Median overall survival reached 10.1 months, he said; median progression-free survival reached 2.8 months, with 15.6% of patients progression-free 6 months after treatment. Factors correlating with survival were still being analyzed. The trial was sponsored by Pfizer Inc.

Ipilimumab

The first ipilimumab trial was a multinational, open-label study of 155 patients with advanced disease that had failed previous therapies. Patients received 10 mg/kg of ipilimumab every 3 weeks for four cycles, followed by maintenance therapy at the same dose every 12 weeks from week 12 to week 60.

Dr. Vanna Chiarion Sileni of the Instituto Oncologo Veneto in Padua, Italy, reported 9 patients had partial responses and 33 had stable disease by modified WHO criteria, adding up to a disease control rate of 27% (42/155). The median duration of stable disease was 4.1 months at a median follow-up of 5.7 months, she said; 19 patients were still stable at their last assessment.

Among those classified with progressive disease were patients with the four patterns of response. Small subgroups had a "slow steady decline" in tumor volume after an initial increase in target lesions or the appearance of new lesions, she said.

In the second ipilimumab trial, Dr. Celeste Lebbé of Saint-Louis Hospital in Paris reported on a multinational dose-finding study that randomized patients with unresectable relapsed stage III or IV melanoma to 10 mg/kg, 3 mg/kg, or 0.3 mg/kg of ipilimumab given once every 3 weeks for four cycles followed by maintenance treatment once every 12 weeks.

The 10-mg/kg dose produced the best overall response rate, a composite measure of complete and partial responses, at 11%, and a disease control rate of 29%. Nearly half, 48% of 73 patients given the highest dose were alive at 1 year. Their median survival was estimated at 11 months at a median follow-up of 10.4 months.

The four patterns of response were observed in this study as well, Dr. Lebbé reported, and about 35% of patients at the highest dose had a decline in total tumor volume. Patients at this dose also had the most toxicity, she said; about a quarter had grade III adverse events, including gastrointestinal side effects in 16%.

The ipilimumab studies were sponsored by Bristol-Myer Squibb and Medarex Inc, which are jointly developing the agent. Dr. Lebbé was the only investigator to disclose a conflict of interest, having served on two advisory boards for Bristol-Myer Squibb.

Dr. Kirkwood said phase III trials for both agents have been completed and are being analyzed, but applications for approval have not yet been filed.

ELSEVIER GLOBAL MEDICAL NEWS

STOCKHOLM — Clinical studies of two experimental agents—tremelimumab and ipilimumab—have shown delayed and mixed responses among patients who gained control of refractory melanomas with these therapies.

Both agents come from a new class of monoclonal antibodies that seeks to promote immune response by blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In three phase II trials presented at the European Society for Medical Oncology Congress, tremelimumab and ipilimumab ultimately achieved disease control rates of 14%–29% as second-line therapies.

Among patients classified as having progressive disease after ipilimumab treatment, however, were some people who subsequently improved. Likewise, among six patients with "mixed response" to tremelimumab were five patients who initially developed new lesions, but then had slow decreases in targeted lesions. All six were still alive at the time of the presentation.

Investigators suggested that the modified World Health Organization (WHO) criteria used to assess activity of cytotoxic agents may not capture the benefit in some patients classified with progressive disease. They cited four observed patterns of response, which were described in a poster by Dr. Kaan Harmankaya, of the department of dermatology at University of Vienna, and associates:

▸ Response in baseline lesions.

▸ Stable disease with a slow, steady decline in tumor volume.

▸ Response after increase in total tumor volume.

▸ Response in index and new lesions after the appearance of new lesions.

While delayed response is an issue for researchers, the clinical impact could be more important, according to a discussion of the tremelimumab and ipilimumab studies by Dr. Ulrich Keilholz of the Charité University in Berlin and the European Organisation for Research and Treatment of Cancer melanoma group.

"Nonclassical assessment does change the response rate, but it does not change the survival rate," Dr. Keilholz said, downplaying the importance of response, compared with overall survival in phase IIItrials.

Tremelimumab

Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute, presented the tremelimumab data from an open-label phase II trial in 251 patients (nearly all with stage IV disease), of whom 242 were evaluable. The protocol called for a 15- mg/kg dose to be delivered intravenously on the first day of up to four 12-week cycles. Sixteen (7%) patients achieved partial responses and 36 (15%) had stable disease—a clinical benefit rate of 22%.

Dr. Kirkwood said all but 1 of the partial responses lasted at least 170 days, and 11 were ongoing. Median overall survival reached 10.1 months, he said; median progression-free survival reached 2.8 months, with 15.6% of patients progression-free 6 months after treatment. Factors correlating with survival were still being analyzed. The trial was sponsored by Pfizer Inc.

Ipilimumab

The first ipilimumab trial was a multinational, open-label study of 155 patients with advanced disease that had failed previous therapies. Patients received 10 mg/kg of ipilimumab every 3 weeks for four cycles, followed by maintenance therapy at the same dose every 12 weeks from week 12 to week 60.

Dr. Vanna Chiarion Sileni of the Instituto Oncologo Veneto in Padua, Italy, reported 9 patients had partial responses and 33 had stable disease by modified WHO criteria, adding up to a disease control rate of 27% (42/155). The median duration of stable disease was 4.1 months at a median follow-up of 5.7 months, she said; 19 patients were still stable at their last assessment.

Among those classified with progressive disease were patients with the four patterns of response. Small subgroups had a "slow steady decline" in tumor volume after an initial increase in target lesions or the appearance of new lesions, she said.

In the second ipilimumab trial, Dr. Celeste Lebbé of Saint-Louis Hospital in Paris reported on a multinational dose-finding study that randomized patients with unresectable relapsed stage III or IV melanoma to 10 mg/kg, 3 mg/kg, or 0.3 mg/kg of ipilimumab given once every 3 weeks for four cycles followed by maintenance treatment once every 12 weeks.

The 10-mg/kg dose produced the best overall response rate, a composite measure of complete and partial responses, at 11%, and a disease control rate of 29%. Nearly half, 48% of 73 patients given the highest dose were alive at 1 year. Their median survival was estimated at 11 months at a median follow-up of 10.4 months.

The four patterns of response were observed in this study as well, Dr. Lebbé reported, and about 35% of patients at the highest dose had a decline in total tumor volume. Patients at this dose also had the most toxicity, she said; about a quarter had grade III adverse events, including gastrointestinal side effects in 16%.

The ipilimumab studies were sponsored by Bristol-Myer Squibb and Medarex Inc, which are jointly developing the agent. Dr. Lebbé was the only investigator to disclose a conflict of interest, having served on two advisory boards for Bristol-Myer Squibb.

Dr. Kirkwood said phase III trials for both agents have been completed and are being analyzed, but applications for approval have not yet been filed.

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — Remote review of digital immunohistochemistry slides by pathologists seemed to be as accurate as in-person evaluations by light microscopy for diagnosis of dysplastic nevi, but was less successful for diagnosing early malignant melanoma.

Three pathologists viewed 55–60 cases of dysplastic nevi with varying atypia and early melanomas on hematoxylin and eosin- and immunohistochemical-stained slides via telepathology. A remote site hosted the digital slides, and the consulting pathologists evaluated them via a Java-enabled Web browser. The pathologists also evaluated a glass set of slides for the cases.

Preliminary results showed that there was a high concordance rate between digital and light microscopic diagnoses for dysplastic nevi, but a few diagnostic discrepancies were seen between telepathology and microscopy when early malignant melanomas were evaluated, Dr. Jill Buckthal-McCuin of the University of Pittsburgh reported in a poster that was presented at the annual meeting of the American Society of Dermatopathology.

Evaluations by telepathology took more than twice as long to perform as microscopy evaluations, mainly because focusing was slow during telepathology. If the time spent on shipping the glass slides for microscopic evaluation were included, however, telepathology was faster, Dr. Buckthal-McCuin added.

An individual evaluator's level of experience in dermatopathology and experience with telepathology may have been a factor in diagnostic accuracy, she suggested.

A dermatopathology fellow made the correct diagnosis in 21 (36%) of 59 cases evaluated with digital telepathology. A staff dermatologist with 1 year of experience was correct in 19 (45%) of 42 diagnoses via telepathology, and said he was not comfortable evaluating 18 other cases, including 8 cases of suspected melanoma.

An attending dermatopathologist with more than 5 years' experience was correct in 23 (42%) of 55 diagnoses via telepathology.

Each of the evaluators misgraded some dysplastic nevi by one degree, which would not affect decisions regarding treatment.

Overall, the diagnoses that were made via telepathology would have resulted in correct treatment in 90% of the cases evaluated by the fellow, 76% of cases that the junior attending dermatopathologist agreed to evaluate, and 67% of the cases reviewed by the senior attending dermatopathologist.

Increasing demands are being placed on pathologists, and in some settings a trained pathologist in a specific subspecialty is not available on site, Dr. Buckthal-McCuin noted.

Digital telepathology might contribute to the more efficient use of pathologists by allowing real-time review of remote cases, delayed image review, subspecialty reviews, and second opinions in a timely fashion, but more study is needed to confirm the utility of this diagnostic method, she said.

The three pathologists in the study reported not feeling comfortable when the slide was moved at the remote site, because an area of interest often was omitted or out of focus. They agreed that the robotic microscope provided excellent detail and would be useful in nonprimary diagnosis.

The fellow complained that the inability to evaluate the immunohistochemical and hematoxylin and eosin slides together hampered the remote diagnosis by telepathology.

Dr. Buckthal-McCuin and her associates plan to study telepathology evaluation of hematoxylin and eosin and immunohistochemical slides together, and said that they expect the degree of concordance with glass-based evaluation to be similar to the findings in this preliminary study.

SAN FRANCISCO — Remote review of digital immunohistochemistry slides by pathologists seemed to be as accurate as in-person evaluations by light microscopy for diagnosis of dysplastic nevi, but was less successful for diagnosing early malignant melanoma.

Three pathologists viewed 55–60 cases of dysplastic nevi with varying atypia and early melanomas on hematoxylin and eosin- and immunohistochemical-stained slides via telepathology. A remote site hosted the digital slides, and the consulting pathologists evaluated them via a Java-enabled Web browser. The pathologists also evaluated a glass set of slides for the cases.

Preliminary results showed that there was a high concordance rate between digital and light microscopic diagnoses for dysplastic nevi, but a few diagnostic discrepancies were seen between telepathology and microscopy when early malignant melanomas were evaluated, Dr. Jill Buckthal-McCuin of the University of Pittsburgh reported in a poster that was presented at the annual meeting of the American Society of Dermatopathology.

Evaluations by telepathology took more than twice as long to perform as microscopy evaluations, mainly because focusing was slow during telepathology. If the time spent on shipping the glass slides for microscopic evaluation were included, however, telepathology was faster, Dr. Buckthal-McCuin added.

An individual evaluator's level of experience in dermatopathology and experience with telepathology may have been a factor in diagnostic accuracy, she suggested.

A dermatopathology fellow made the correct diagnosis in 21 (36%) of 59 cases evaluated with digital telepathology. A staff dermatologist with 1 year of experience was correct in 19 (45%) of 42 diagnoses via telepathology, and said he was not comfortable evaluating 18 other cases, including 8 cases of suspected melanoma.

An attending dermatopathologist with more than 5 years' experience was correct in 23 (42%) of 55 diagnoses via telepathology.

Each of the evaluators misgraded some dysplastic nevi by one degree, which would not affect decisions regarding treatment.

Overall, the diagnoses that were made via telepathology would have resulted in correct treatment in 90% of the cases evaluated by the fellow, 76% of cases that the junior attending dermatopathologist agreed to evaluate, and 67% of the cases reviewed by the senior attending dermatopathologist.

Increasing demands are being placed on pathologists, and in some settings a trained pathologist in a specific subspecialty is not available on site, Dr. Buckthal-McCuin noted.

Digital telepathology might contribute to the more efficient use of pathologists by allowing real-time review of remote cases, delayed image review, subspecialty reviews, and second opinions in a timely fashion, but more study is needed to confirm the utility of this diagnostic method, she said.

The three pathologists in the study reported not feeling comfortable when the slide was moved at the remote site, because an area of interest often was omitted or out of focus. They agreed that the robotic microscope provided excellent detail and would be useful in nonprimary diagnosis.

The fellow complained that the inability to evaluate the immunohistochemical and hematoxylin and eosin slides together hampered the remote diagnosis by telepathology.

Dr. Buckthal-McCuin and her associates plan to study telepathology evaluation of hematoxylin and eosin and immunohistochemical slides together, and said that they expect the degree of concordance with glass-based evaluation to be similar to the findings in this preliminary study.

SAN FRANCISCO — Remote review of digital immunohistochemistry slides by pathologists seemed to be as accurate as in-person evaluations by light microscopy for diagnosis of dysplastic nevi, but was less successful for diagnosing early malignant melanoma.

Three pathologists viewed 55–60 cases of dysplastic nevi with varying atypia and early melanomas on hematoxylin and eosin- and immunohistochemical-stained slides via telepathology. A remote site hosted the digital slides, and the consulting pathologists evaluated them via a Java-enabled Web browser. The pathologists also evaluated a glass set of slides for the cases.

Preliminary results showed that there was a high concordance rate between digital and light microscopic diagnoses for dysplastic nevi, but a few diagnostic discrepancies were seen between telepathology and microscopy when early malignant melanomas were evaluated, Dr. Jill Buckthal-McCuin of the University of Pittsburgh reported in a poster that was presented at the annual meeting of the American Society of Dermatopathology.

Evaluations by telepathology took more than twice as long to perform as microscopy evaluations, mainly because focusing was slow during telepathology. If the time spent on shipping the glass slides for microscopic evaluation were included, however, telepathology was faster, Dr. Buckthal-McCuin added.

An individual evaluator's level of experience in dermatopathology and experience with telepathology may have been a factor in diagnostic accuracy, she suggested.

A dermatopathology fellow made the correct diagnosis in 21 (36%) of 59 cases evaluated with digital telepathology. A staff dermatologist with 1 year of experience was correct in 19 (45%) of 42 diagnoses via telepathology, and said he was not comfortable evaluating 18 other cases, including 8 cases of suspected melanoma.

An attending dermatopathologist with more than 5 years' experience was correct in 23 (42%) of 55 diagnoses via telepathology.

Each of the evaluators misgraded some dysplastic nevi by one degree, which would not affect decisions regarding treatment.

Overall, the diagnoses that were made via telepathology would have resulted in correct treatment in 90% of the cases evaluated by the fellow, 76% of cases that the junior attending dermatopathologist agreed to evaluate, and 67% of the cases reviewed by the senior attending dermatopathologist.

Increasing demands are being placed on pathologists, and in some settings a trained pathologist in a specific subspecialty is not available on site, Dr. Buckthal-McCuin noted.

Digital telepathology might contribute to the more efficient use of pathologists by allowing real-time review of remote cases, delayed image review, subspecialty reviews, and second opinions in a timely fashion, but more study is needed to confirm the utility of this diagnostic method, she said.

The three pathologists in the study reported not feeling comfortable when the slide was moved at the remote site, because an area of interest often was omitted or out of focus. They agreed that the robotic microscope provided excellent detail and would be useful in nonprimary diagnosis.

The fellow complained that the inability to evaluate the immunohistochemical and hematoxylin and eosin slides together hampered the remote diagnosis by telepathology.

Dr. Buckthal-McCuin and her associates plan to study telepathology evaluation of hematoxylin and eosin and immunohistochemical slides together, and said that they expect the degree of concordance with glass-based evaluation to be similar to the findings in this preliminary study.