Melanoma

Angiosarcoma is a rare malignant vascular tumor that is localized to the skin or superficial soft tissue in 60% of cases.1,2 More than half of cutaneous angiosarcomas arise on the head or neck.2,3 Skin lesions may be difficult to diagnose early because of their highly variable and often seemingly innocuous appearance1-4; it is not uncommon for there to be extensive local spread and/or distant metastases by the time angiosarcoma is diagnosed. Cutaneous angiosarcoma typically affects elderly patients and is more common in men.1-4 It is relatively rare in black individuals.1,3 Classic presentation is an erythematous or violaceous lesion arising on the scalp of an elderly white man.1-4 Cutaneous angiosarcoma has well-documented associations with a number of conditions and factors, including chronic lymphedema, prior radiation therapy, and exposure to chemicals such as thorotrast and vinyl chloride.1-4 In addition, there are several reported cases of malignant transformation to angiosarcoma of otherwise benign vascular lesions such as hemangiomas.5 To date, there is only one reported case of cutaneous angiosarcoma arising in association with scleroderma on the face of a 77-year-old white woman with systemic sclerosis (SSc).6 We report the case of a 40-year-old black man with SSc who developed a cutaneous angiosarcoma in an area of sclerodermatous scalp. back to top

Case Report
A 40-year-old black man with a 5-year history of SSc involving the skin, lungs, and esophagus developed a painful nodule in a sclerodermatous plaque on the scalp (Figure 1). The patient's medical history was remarkable for Raynaud phenomenon, with recurrent digital ulcerations, a restrictive ventilatory defect, chronic dysphagia, and gastroesophageal reflux disease, as well as diffuse thickening and tightening of the skin, all related to his SSc. Serologic tests revealed antinuclear antibodies (titer ≥640) with a homogeneous nucleolar pattern and high levels of anti–Scl-70 antibodies. Anticentromere and anti-DNA antibodies were absent. His only medications were esomeprazole magnesium (40 mg daily) and amlodipine besylate (5 mg daily).

On physical examination, there was a 1.8-cm faintly erythematous nodule with overlying excoriations and crust on the right anterior parietal scalp. The remainder of the physical examination was notable for diffusely tight, firm, shiny skin involving the scalp, face, neck, chest, arms, hands, and groin. There were areas of depigmentation in several of the scleroderma plaques as well as multiple fingertip ulcerations. On initial evaluation, the scalp lesion was diagnosed as a skin abscess not requiring further intervention. It continued to grow and cause discomfort, eventually necessitating surgical excision. Because of its anatomic position and the extremely taut nature of the surrounding sclerodermatous scalp, the mass was excised only partially so that primary closure would be possible. Histologic evaluation of the 2.5X1.5-cm surgical specimen revealed an epithelioid-type high-grade angiosarcoma composed of cells that were positive for CD31 and CD34 (endothelial cell markers) on immunohistochemical stain (Figure 2). A wide excision of the lesion was then performed. Intraoperatively, the tumor was observed to have involved the galea and pericranium, necessitating removal of full-thickness soft tissue and adjacent bone (Figure 3). The scalp excision defect was closed with a split-thickness skin graft.

 Microscopic examination of the excised tissue revealed extensive invasion of the dermis, perineural tissue, and deep skeletal muscle by angiosarcoma. Both circumferential and deep margins of the surgical specimen were involved by tumor. Tumor size was estimated at 9.5 cm. Computed tomographic (CT) scans of the chest, abdomen, and pelvis revealed a moderately dilated esophagus and moderate diffuse, hazy, ground glass pattern radiodensities of the bilateral lung bases consistent with SSc but no lesions suggestive of metastasis. The extensive local tissue involvement by tumor dictated radiation therapy to the area. Treatment was delayed, however, by failure of the skin graft to completely heal. The open wound was subsequently surgically debrided and closed with an allograft. This second graft began to successfully heal, but an enlarging subcutaneous mass at its anterior border soon developed. Results of a biopsy revealed recurrent angiosarcoma. This lesion grew quickly to encompass over half of the patient's forehead, as well as the nasal root, causing severe periorbital edema and conjunctival congestion. Daily radiation therapy totaling 5000 cGy to the upper face and frontal, parietal, and occipital scalp was initiated. Soon after, the patient was hospitalized for methicillin-resistant Staphylococcus aureus bacteremia thought to have originated from a skin infection near the tumor. He also complained of worsening sharp right retroauricular and left hip pains. Results of a punch biopsy of the right posterior auricular scalp revealed recurrent angiosarcoma, and a CT-guided biopsy specimen of the left iliac bone revealed metastatic angiosarcoma. Magnetic resonance imaging of the pelvis and lower extremities showed bone marrow lesions involving the left ischium, left anterior superior iliac spine, and femoral necks of both legs. Palliative radiation therapy to the left iliac bone was initiated for symptom control. Given the extensive metastatic spread, systemic paclitaxel chemotherapy (100 mg/m2 weekly [3 of 4 weeks]) was administered through a central venous port. Soon after completing the first round of chemotherapy, the patient was hospitalized with a polymicrobial infection of his partially healed scalp wound including Klebsiella pneumoniae, Pseudomonas aeruginosa, and group B streptococci. He was treated with levofloxacin (500 mg daily for 10 days). An abdominal CT scan showed that the patient had a lesion in the right posterior inferior lobe of the liver suggestive of metastatic angiosarcoma. Several weeks after discharge, he presented to the emergency department of an outside hospital complaining of worsening dysphagia and purulent material draining from his central venous port. Shortly thereafter, he died, with sepsis as the presumed cause of death. At autopsy, there were multiple large scalp ulcerations extending to bone. The skin was diffusely firm and taut. Serial sectioning of the liver demonstrated a somewhat hemorrhagic-appearing dark red–brown lesion measuring 3 cm in the right posterior lobe, composed microscopically of diffusely infiltrating metastatic angiosarcoma confirmed by CD31 immunostain. Additionally, there were multifocal microabscesses of the heart, lungs, kidneys, spleen, and skin of the face and neck. 

Comment
Systemic sclerosis, or scleroderma, is a chronic systemic disease characterized by widespread fibrosis of the skin and internal organs, vasculopathy, and autoimmunity.7,8 Black individuals are affected more frequently than white individuals and tend to have an earlier age of disease onset, greater tendency for severe disease, and overall worse prognosis.9 Patients with SSc have a 2.6% to 8.7% risk of malignancy in general, with lung cancer and squamous cell carcinoma (arising in affected pulmonary or skin tissue) among the most commonly associated neoplasms.10,11 To our knowledge, we describe the second reported case of SSc-associated angiosarcoma. Systemic sclerosis is thought to arise from altered endothelial cell function and blood vessel reactivity occurring in association with inflammation and autoimmunity. The earliest disease manifestations are generally vasculature related, with most patients developing Raynaud phenomenon before manifesting signs and symptoms of overt sclerosis.7,8 Characteristic nail fold capillaroscopy findings in patients with SSc include enlarged capillaries, busy capillary formations, microhemorrhages, and variable capillary loss.7 Patients with SSc have increased serum and skin levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis that induces differentiation, proliferation, and migration of endothelial cells.7 Endothelial cell VEGF receptors are up-regulated in SSc as well. This chronic overexpression of VEGF is thought to account for the chaotic vessel morphology observed on nail fold capillaroscopy.7 We hypothesize that elevated levels of VEGF in sclerodermatous skin may also predispose one to the development of angiosarcoma. Studies have shown that the proliferating cells in angiosarcoma overexpress VEGF messenger RNA, VEGF protein, and VEGF receptors, suggesting that VEGF may spur the development and invasion of neoplasia.12-14 Furthermore, Arbiser et al13 found that overexpression of human VEGF in immortalized endothelial cells was sufficient to convert them from benign hemangiomas to malignant angiosarcomas. Cutaneous angiosarcoma can assume a variety of clinical appearances, including bruiselike lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, infectious-appearing lesions, and scarring alopecia.1-4 Tumor tissue usually extends far beyond the apparent borders of the lesion and frequently invades underlying soft tissue and bone. Thus, patients often have advanced disease at the time of diagnosis.1-4 Angiosarcoma prognosis is generally poor, with reported 5-year survival rates ranging from 10% to 35%.1,2 Surgical excision, extended-field radiotherapy, and/or paclitaxel chemotherapy are commonly employed modes of treatment,1,4,15,16 though even with these interventions, local tumor recurrence and distant metastases are common. Importantly, early diagnosis positively correlates with prolonged survival.3,4

Conclusion
We present a case of cutaneous angiosarcoma arising in an area of SSc-affected skin. We suspect that the co-occurrence of these 2 diseases may be related to interconnected underlying pathophysiology. Because early diagnosis can positively impact prognosis, physicians should maintain a high index of clinical suspicion and low threshold for performing a biopsy when suspicious lesions are present on sclerodermatous skin.

Acknowledgment—We thank Frederick M. Wigley, MD, for his detailed clinic and procedure notes. 

Angiosarcoma is a rare malignant vascular tumor that is localized to the skin or superficial soft tissue in 60% of cases.1,2 More than half of cutaneous angiosarcomas arise on the head or neck.2,3 Skin lesions may be difficult to diagnose early because of their highly variable and often seemingly innocuous appearance1-4; it is not uncommon for there to be extensive local spread and/or distant metastases by the time angiosarcoma is diagnosed. Cutaneous angiosarcoma typically affects elderly patients and is more common in men.1-4 It is relatively rare in black individuals.1,3 Classic presentation is an erythematous or violaceous lesion arising on the scalp of an elderly white man.1-4 Cutaneous angiosarcoma has well-documented associations with a number of conditions and factors, including chronic lymphedema, prior radiation therapy, and exposure to chemicals such as thorotrast and vinyl chloride.1-4 In addition, there are several reported cases of malignant transformation to angiosarcoma of otherwise benign vascular lesions such as hemangiomas.5 To date, there is only one reported case of cutaneous angiosarcoma arising in association with scleroderma on the face of a 77-year-old white woman with systemic sclerosis (SSc).6 We report the case of a 40-year-old black man with SSc who developed a cutaneous angiosarcoma in an area of sclerodermatous scalp. back to top

Case Report
A 40-year-old black man with a 5-year history of SSc involving the skin, lungs, and esophagus developed a painful nodule in a sclerodermatous plaque on the scalp (Figure 1). The patient's medical history was remarkable for Raynaud phenomenon, with recurrent digital ulcerations, a restrictive ventilatory defect, chronic dysphagia, and gastroesophageal reflux disease, as well as diffuse thickening and tightening of the skin, all related to his SSc. Serologic tests revealed antinuclear antibodies (titer ≥640) with a homogeneous nucleolar pattern and high levels of anti–Scl-70 antibodies. Anticentromere and anti-DNA antibodies were absent. His only medications were esomeprazole magnesium (40 mg daily) and amlodipine besylate (5 mg daily).

On physical examination, there was a 1.8-cm faintly erythematous nodule with overlying excoriations and crust on the right anterior parietal scalp. The remainder of the physical examination was notable for diffusely tight, firm, shiny skin involving the scalp, face, neck, chest, arms, hands, and groin. There were areas of depigmentation in several of the scleroderma plaques as well as multiple fingertip ulcerations. On initial evaluation, the scalp lesion was diagnosed as a skin abscess not requiring further intervention. It continued to grow and cause discomfort, eventually necessitating surgical excision. Because of its anatomic position and the extremely taut nature of the surrounding sclerodermatous scalp, the mass was excised only partially so that primary closure would be possible. Histologic evaluation of the 2.5X1.5-cm surgical specimen revealed an epithelioid-type high-grade angiosarcoma composed of cells that were positive for CD31 and CD34 (endothelial cell markers) on immunohistochemical stain (Figure 2). A wide excision of the lesion was then performed. Intraoperatively, the tumor was observed to have involved the galea and pericranium, necessitating removal of full-thickness soft tissue and adjacent bone (Figure 3). The scalp excision defect was closed with a split-thickness skin graft.

 Microscopic examination of the excised tissue revealed extensive invasion of the dermis, perineural tissue, and deep skeletal muscle by angiosarcoma. Both circumferential and deep margins of the surgical specimen were involved by tumor. Tumor size was estimated at 9.5 cm. Computed tomographic (CT) scans of the chest, abdomen, and pelvis revealed a moderately dilated esophagus and moderate diffuse, hazy, ground glass pattern radiodensities of the bilateral lung bases consistent with SSc but no lesions suggestive of metastasis. The extensive local tissue involvement by tumor dictated radiation therapy to the area. Treatment was delayed, however, by failure of the skin graft to completely heal. The open wound was subsequently surgically debrided and closed with an allograft. This second graft began to successfully heal, but an enlarging subcutaneous mass at its anterior border soon developed. Results of a biopsy revealed recurrent angiosarcoma. This lesion grew quickly to encompass over half of the patient's forehead, as well as the nasal root, causing severe periorbital edema and conjunctival congestion. Daily radiation therapy totaling 5000 cGy to the upper face and frontal, parietal, and occipital scalp was initiated. Soon after, the patient was hospitalized for methicillin-resistant Staphylococcus aureus bacteremia thought to have originated from a skin infection near the tumor. He also complained of worsening sharp right retroauricular and left hip pains. Results of a punch biopsy of the right posterior auricular scalp revealed recurrent angiosarcoma, and a CT-guided biopsy specimen of the left iliac bone revealed metastatic angiosarcoma. Magnetic resonance imaging of the pelvis and lower extremities showed bone marrow lesions involving the left ischium, left anterior superior iliac spine, and femoral necks of both legs. Palliative radiation therapy to the left iliac bone was initiated for symptom control. Given the extensive metastatic spread, systemic paclitaxel chemotherapy (100 mg/m2 weekly [3 of 4 weeks]) was administered through a central venous port. Soon after completing the first round of chemotherapy, the patient was hospitalized with a polymicrobial infection of his partially healed scalp wound including Klebsiella pneumoniae, Pseudomonas aeruginosa, and group B streptococci. He was treated with levofloxacin (500 mg daily for 10 days). An abdominal CT scan showed that the patient had a lesion in the right posterior inferior lobe of the liver suggestive of metastatic angiosarcoma. Several weeks after discharge, he presented to the emergency department of an outside hospital complaining of worsening dysphagia and purulent material draining from his central venous port. Shortly thereafter, he died, with sepsis as the presumed cause of death. At autopsy, there were multiple large scalp ulcerations extending to bone. The skin was diffusely firm and taut. Serial sectioning of the liver demonstrated a somewhat hemorrhagic-appearing dark red–brown lesion measuring 3 cm in the right posterior lobe, composed microscopically of diffusely infiltrating metastatic angiosarcoma confirmed by CD31 immunostain. Additionally, there were multifocal microabscesses of the heart, lungs, kidneys, spleen, and skin of the face and neck. 

Comment
Systemic sclerosis, or scleroderma, is a chronic systemic disease characterized by widespread fibrosis of the skin and internal organs, vasculopathy, and autoimmunity.7,8 Black individuals are affected more frequently than white individuals and tend to have an earlier age of disease onset, greater tendency for severe disease, and overall worse prognosis.9 Patients with SSc have a 2.6% to 8.7% risk of malignancy in general, with lung cancer and squamous cell carcinoma (arising in affected pulmonary or skin tissue) among the most commonly associated neoplasms.10,11 To our knowledge, we describe the second reported case of SSc-associated angiosarcoma. Systemic sclerosis is thought to arise from altered endothelial cell function and blood vessel reactivity occurring in association with inflammation and autoimmunity. The earliest disease manifestations are generally vasculature related, with most patients developing Raynaud phenomenon before manifesting signs and symptoms of overt sclerosis.7,8 Characteristic nail fold capillaroscopy findings in patients with SSc include enlarged capillaries, busy capillary formations, microhemorrhages, and variable capillary loss.7 Patients with SSc have increased serum and skin levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis that induces differentiation, proliferation, and migration of endothelial cells.7 Endothelial cell VEGF receptors are up-regulated in SSc as well. This chronic overexpression of VEGF is thought to account for the chaotic vessel morphology observed on nail fold capillaroscopy.7 We hypothesize that elevated levels of VEGF in sclerodermatous skin may also predispose one to the development of angiosarcoma. Studies have shown that the proliferating cells in angiosarcoma overexpress VEGF messenger RNA, VEGF protein, and VEGF receptors, suggesting that VEGF may spur the development and invasion of neoplasia.12-14 Furthermore, Arbiser et al13 found that overexpression of human VEGF in immortalized endothelial cells was sufficient to convert them from benign hemangiomas to malignant angiosarcomas. Cutaneous angiosarcoma can assume a variety of clinical appearances, including bruiselike lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, infectious-appearing lesions, and scarring alopecia.1-4 Tumor tissue usually extends far beyond the apparent borders of the lesion and frequently invades underlying soft tissue and bone. Thus, patients often have advanced disease at the time of diagnosis.1-4 Angiosarcoma prognosis is generally poor, with reported 5-year survival rates ranging from 10% to 35%.1,2 Surgical excision, extended-field radiotherapy, and/or paclitaxel chemotherapy are commonly employed modes of treatment,1,4,15,16 though even with these interventions, local tumor recurrence and distant metastases are common. Importantly, early diagnosis positively correlates with prolonged survival.3,4

Conclusion
We present a case of cutaneous angiosarcoma arising in an area of SSc-affected skin. We suspect that the co-occurrence of these 2 diseases may be related to interconnected underlying pathophysiology. Because early diagnosis can positively impact prognosis, physicians should maintain a high index of clinical suspicion and low threshold for performing a biopsy when suspicious lesions are present on sclerodermatous skin.

Acknowledgment—We thank Frederick M. Wigley, MD, for his detailed clinic and procedure notes. 

Angiosarcoma is a rare malignant vascular tumor that is localized to the skin or superficial soft tissue in 60% of cases.1,2 More than half of cutaneous angiosarcomas arise on the head or neck.2,3 Skin lesions may be difficult to diagnose early because of their highly variable and often seemingly innocuous appearance1-4; it is not uncommon for there to be extensive local spread and/or distant metastases by the time angiosarcoma is diagnosed. Cutaneous angiosarcoma typically affects elderly patients and is more common in men.1-4 It is relatively rare in black individuals.1,3 Classic presentation is an erythematous or violaceous lesion arising on the scalp of an elderly white man.1-4 Cutaneous angiosarcoma has well-documented associations with a number of conditions and factors, including chronic lymphedema, prior radiation therapy, and exposure to chemicals such as thorotrast and vinyl chloride.1-4 In addition, there are several reported cases of malignant transformation to angiosarcoma of otherwise benign vascular lesions such as hemangiomas.5 To date, there is only one reported case of cutaneous angiosarcoma arising in association with scleroderma on the face of a 77-year-old white woman with systemic sclerosis (SSc).6 We report the case of a 40-year-old black man with SSc who developed a cutaneous angiosarcoma in an area of sclerodermatous scalp. back to top

Case Report
A 40-year-old black man with a 5-year history of SSc involving the skin, lungs, and esophagus developed a painful nodule in a sclerodermatous plaque on the scalp (Figure 1). The patient's medical history was remarkable for Raynaud phenomenon, with recurrent digital ulcerations, a restrictive ventilatory defect, chronic dysphagia, and gastroesophageal reflux disease, as well as diffuse thickening and tightening of the skin, all related to his SSc. Serologic tests revealed antinuclear antibodies (titer ≥640) with a homogeneous nucleolar pattern and high levels of anti–Scl-70 antibodies. Anticentromere and anti-DNA antibodies were absent. His only medications were esomeprazole magnesium (40 mg daily) and amlodipine besylate (5 mg daily).

On physical examination, there was a 1.8-cm faintly erythematous nodule with overlying excoriations and crust on the right anterior parietal scalp. The remainder of the physical examination was notable for diffusely tight, firm, shiny skin involving the scalp, face, neck, chest, arms, hands, and groin. There were areas of depigmentation in several of the scleroderma plaques as well as multiple fingertip ulcerations. On initial evaluation, the scalp lesion was diagnosed as a skin abscess not requiring further intervention. It continued to grow and cause discomfort, eventually necessitating surgical excision. Because of its anatomic position and the extremely taut nature of the surrounding sclerodermatous scalp, the mass was excised only partially so that primary closure would be possible. Histologic evaluation of the 2.5X1.5-cm surgical specimen revealed an epithelioid-type high-grade angiosarcoma composed of cells that were positive for CD31 and CD34 (endothelial cell markers) on immunohistochemical stain (Figure 2). A wide excision of the lesion was then performed. Intraoperatively, the tumor was observed to have involved the galea and pericranium, necessitating removal of full-thickness soft tissue and adjacent bone (Figure 3). The scalp excision defect was closed with a split-thickness skin graft.

 Microscopic examination of the excised tissue revealed extensive invasion of the dermis, perineural tissue, and deep skeletal muscle by angiosarcoma. Both circumferential and deep margins of the surgical specimen were involved by tumor. Tumor size was estimated at 9.5 cm. Computed tomographic (CT) scans of the chest, abdomen, and pelvis revealed a moderately dilated esophagus and moderate diffuse, hazy, ground glass pattern radiodensities of the bilateral lung bases consistent with SSc but no lesions suggestive of metastasis. The extensive local tissue involvement by tumor dictated radiation therapy to the area. Treatment was delayed, however, by failure of the skin graft to completely heal. The open wound was subsequently surgically debrided and closed with an allograft. This second graft began to successfully heal, but an enlarging subcutaneous mass at its anterior border soon developed. Results of a biopsy revealed recurrent angiosarcoma. This lesion grew quickly to encompass over half of the patient's forehead, as well as the nasal root, causing severe periorbital edema and conjunctival congestion. Daily radiation therapy totaling 5000 cGy to the upper face and frontal, parietal, and occipital scalp was initiated. Soon after, the patient was hospitalized for methicillin-resistant Staphylococcus aureus bacteremia thought to have originated from a skin infection near the tumor. He also complained of worsening sharp right retroauricular and left hip pains. Results of a punch biopsy of the right posterior auricular scalp revealed recurrent angiosarcoma, and a CT-guided biopsy specimen of the left iliac bone revealed metastatic angiosarcoma. Magnetic resonance imaging of the pelvis and lower extremities showed bone marrow lesions involving the left ischium, left anterior superior iliac spine, and femoral necks of both legs. Palliative radiation therapy to the left iliac bone was initiated for symptom control. Given the extensive metastatic spread, systemic paclitaxel chemotherapy (100 mg/m2 weekly [3 of 4 weeks]) was administered through a central venous port. Soon after completing the first round of chemotherapy, the patient was hospitalized with a polymicrobial infection of his partially healed scalp wound including Klebsiella pneumoniae, Pseudomonas aeruginosa, and group B streptococci. He was treated with levofloxacin (500 mg daily for 10 days). An abdominal CT scan showed that the patient had a lesion in the right posterior inferior lobe of the liver suggestive of metastatic angiosarcoma. Several weeks after discharge, he presented to the emergency department of an outside hospital complaining of worsening dysphagia and purulent material draining from his central venous port. Shortly thereafter, he died, with sepsis as the presumed cause of death. At autopsy, there were multiple large scalp ulcerations extending to bone. The skin was diffusely firm and taut. Serial sectioning of the liver demonstrated a somewhat hemorrhagic-appearing dark red–brown lesion measuring 3 cm in the right posterior lobe, composed microscopically of diffusely infiltrating metastatic angiosarcoma confirmed by CD31 immunostain. Additionally, there were multifocal microabscesses of the heart, lungs, kidneys, spleen, and skin of the face and neck. 

Comment
Systemic sclerosis, or scleroderma, is a chronic systemic disease characterized by widespread fibrosis of the skin and internal organs, vasculopathy, and autoimmunity.7,8 Black individuals are affected more frequently than white individuals and tend to have an earlier age of disease onset, greater tendency for severe disease, and overall worse prognosis.9 Patients with SSc have a 2.6% to 8.7% risk of malignancy in general, with lung cancer and squamous cell carcinoma (arising in affected pulmonary or skin tissue) among the most commonly associated neoplasms.10,11 To our knowledge, we describe the second reported case of SSc-associated angiosarcoma. Systemic sclerosis is thought to arise from altered endothelial cell function and blood vessel reactivity occurring in association with inflammation and autoimmunity. The earliest disease manifestations are generally vasculature related, with most patients developing Raynaud phenomenon before manifesting signs and symptoms of overt sclerosis.7,8 Characteristic nail fold capillaroscopy findings in patients with SSc include enlarged capillaries, busy capillary formations, microhemorrhages, and variable capillary loss.7 Patients with SSc have increased serum and skin levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis that induces differentiation, proliferation, and migration of endothelial cells.7 Endothelial cell VEGF receptors are up-regulated in SSc as well. This chronic overexpression of VEGF is thought to account for the chaotic vessel morphology observed on nail fold capillaroscopy.7 We hypothesize that elevated levels of VEGF in sclerodermatous skin may also predispose one to the development of angiosarcoma. Studies have shown that the proliferating cells in angiosarcoma overexpress VEGF messenger RNA, VEGF protein, and VEGF receptors, suggesting that VEGF may spur the development and invasion of neoplasia.12-14 Furthermore, Arbiser et al13 found that overexpression of human VEGF in immortalized endothelial cells was sufficient to convert them from benign hemangiomas to malignant angiosarcomas. Cutaneous angiosarcoma can assume a variety of clinical appearances, including bruiselike lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, infectious-appearing lesions, and scarring alopecia.1-4 Tumor tissue usually extends far beyond the apparent borders of the lesion and frequently invades underlying soft tissue and bone. Thus, patients often have advanced disease at the time of diagnosis.1-4 Angiosarcoma prognosis is generally poor, with reported 5-year survival rates ranging from 10% to 35%.1,2 Surgical excision, extended-field radiotherapy, and/or paclitaxel chemotherapy are commonly employed modes of treatment,1,4,15,16 though even with these interventions, local tumor recurrence and distant metastases are common. Importantly, early diagnosis positively correlates with prolonged survival.3,4

Conclusion
We present a case of cutaneous angiosarcoma arising in an area of SSc-affected skin. We suspect that the co-occurrence of these 2 diseases may be related to interconnected underlying pathophysiology. Because early diagnosis can positively impact prognosis, physicians should maintain a high index of clinical suspicion and low threshold for performing a biopsy when suspicious lesions are present on sclerodermatous skin.

Acknowledgment—We thank Frederick M. Wigley, MD, for his detailed clinic and procedure notes. 

Triterpenoids, to which squalene is the immediate biologic precursor, include steroids and, thus, sterols, and represent the largest group of terpenoids, the most abundant group of botanical constituents and the most common ingredient class found in volatile oils. Consequently, triterpenoids appear in numerous botanical products with traditional and modern applications to dermatology, such as Centella asiatica (gotu kola) and propolis.

Indeed, the naturally occurring triterpenoids, oleanolic acid and ursolic acid, are known to confer anticarcinogenic and anti-inflammatory effects in certain cells (Exp. Dermatol. 2006;15:66–73). Ursolic acid and the natural triterpenoid erythrodiol have also been found to be effective in a multiple-dose 12-O-tetradecanoylphorbol-13-acetate (TPA) model of chronic dermal inflammation (Eur. J. Pharmacol. 1997;334:103–5).

Although triterpenoids are not as prevalent in as many of the highly touted herbal sources as polyphenols, this group of compounds is gaining increased attention for its anti-inflammatory and anti-tumor-promoting activity. In one trial, investigators studying the triterpenoids oleanolic acid and ursolic acid found that the former induced the differentiation of keratinocytes through peroxisome proliferator-activated receptor (PPAR)-α activation. In addition, topical application of oleanolic acid improved the recovery of epidermal permeability barrier function and increased ceramides in epidermis (Exp. Dermatol. 2006;15:66–73).

The preponderance of data on triterpenoids, though, points to the anti-tumor-promoting capacity of this copious botanical class of compounds.

 Anti-Tumor-Promoting Actions

In a study designed to identify potential anti-tumor promoters, investigators screened 21 cucurbitane triterpenoids using an in vitro assay system, and found that several of the compounds significantly inhibited Epstein-Barr virus (EBV) activation induced by the tumor promoter TPA.

These compounds were scandenoside R6, 23,24-dihydrocucurbitacin F, 25-acetyl-23,24-dihydrocucurbitacin F, 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, and cucurbitacin F. Two triterpenoids, 23,24-dihydrocucurbitacin F and 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, also displayed significant activity against skin tumor promotion in an in vivo two-stage murine carcinogenesis model (Biol. Pharm. Bull. 1994;17:668–71).

A later in vitro study conducted by the same lab to identify anti-tumor promoters considered 23 triterpenoid hydrocarbons isolated from ferns. Significant inhibitory activity against EBV induced by TPA was exhibited by hop-17(21)-ene, neohop-13(18)-ene, neohop-12-ene, taraxerane, multiflor-9(11)-ene, multiflor-8-ene, glutin-5(10)-ene, and taraxastane. In a two-stage in vivo murine carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) for initiation and TPA for promotion, hop-17(21)-ene and neohop-13(18)-ene displayed significant anti-tumor promoting effects on mouse skin (Biol. Pharm. Bull. 1996;19:962–5).

Three years later, some of the same investigators, studying triterpenoids derived from Taraxacum japonicum (Compositae) roots, found that taraxasterol and taraxerol significantly inhibited the effects of TPA-induced Epstein-Barr virus early antigen (EBV-EA) induction, which is a preliminary in vitro screening approach to identifying anti-tumor-promoting agents. These compounds also exhibited potent anti-tumor-promoting activity in the two-stage murine skin carcinogenesis model initiated by DMBA and promoted by TPA (Biol. Pharm. Bull. 1999;22:606–10).

In a study from Osaka (Japan) University of Pharmaceutical Sciences, seven serratane-type triterpenoids isolated from different Picea species all exhibited potent inhibitory effects on EBV-EA activation induced by TPA, and did so more strongly than oleanolic acid. In addition, 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol displayed significant anti-tumor-promoting activity in the in vivo two-stage murine carcinogenesis model (Cancer Lett. 2001;172:119–26).

The same lab subsequently studied 11 serratane-type triterpenoids isolated from various Picea species and three synthetic analogues for their potential inhibitory effects on EBV-EA activation induced by TPA. That study yielded more corroborative findings, as several of the compounds showed potent inhibitory activity, again more strongly than the oleanolic control, including 21-episerratenediol, serratenediol, diepiserratenediol, 3-beta-hydroxyserrat-14-en-21-one, and 3-alpha-methoxy-21-beta-hydroxyserrat-14-en-16-one. Furthermore, no cytotoxicity was associated with these compounds.

Of these triterpenoids, 21-episerratenediol was found to demonstrate significant inhibitory effects on skin tumor promotion in the in vivo two-stage mouse skin carcinogenesis model using DMBA for initiation and TPA for promotion. The investigators suggested that the triterpenoid 21-episerratenediol has potential as an effective cancer chemopreventive agent (Cancer Lett. 2003;196:121–6).

In a separate experiment conducted by this lab, two new serratane-type triterpenoids, 3beta-methoxyserrat-13-en-21-beta-ol and 13-beta,14beta-epoxy-3beta-methoxyserratan-21beta-ol, also isolated from Picea plants, exhibited strong anti-tumor-promoting effects on mouse skin carcinogenesis (Planta Med. 2003;69:1041–7).

This lab also showed that, in a test of the lupane-type triterpenoids isolated from the stem bark of Glochidion zeylanicum as well as synthetic analogues, glochidiol and lup-20(29)-ene-1beta,3beta-diol were the strongest inhibitors of EBV-EA activation induced by TPA. Glochidiol also exhibited the greatest inhibitory effect on skin tumor promotion (Planta Med. 2004;70:1234–6).

Other Anticarcinogenic Actions

In 2005, investigators at the University of North Carolina, Chapel Hill, published a report on cimigenol, an acid- and base-stable triterpenoid found in species such as Cimicifuga racemosa, C. dahurica, and C. japonica. These researchers had previously shown that cimigenol and some of its derivatives had strong inhibitory effects on mouse skin tumor promotion induced by TPA in a two-stage carcinogenesis test. Continuing that previous work, the investigators repeated screens of cimigenol and also tested 15 related compounds as potential anti-tumor promoters by using the in vitro, short-term TPA-induced EBV-EA activation assay (Bioorg. Med. Chem. 2005;13:1403–8).

Of these compounds, the researchers found that cimigenol-3,15-dione showed the greatest potency and, in a subsequent two-stage DMBA/TPA carcinogenesis assay, reduced, at 20 weeks, the number of papillomas per mouse to 48% of controls. Both cimigenol and cimigenol-3,15-dione were also nearly as potent as epigallocatechin gallate, a primary constituent of green tea, in terms of anti-tumor initiation activity, as demonstrated in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite (initiator) and TPA (promoter).

The investigators concluded that these two triterpenoids amply demonstrate anti-tumor promotion as well as anti-tumor initiation and warrant consideration as significant cancer chemopreventive agents (Bioorg. Med. Chem. 2005;13:1403–8).

Protection Against UV

Four triterpenoids isolated from the stems of Styrax japonica were recently found to significantly inhibit matrix metalloproteinase-1 (MMP-1) in primary human skin fibroblasts induced by UV radiation. This finding is significant given the association between the upregulation of MMPs and chronic skin damage (Biol. Pharm. Bull. 2005;28:2003–6).

Previously, some of the same investigators studied the effects of 3,23-dihydroxy-20(29)-lupen-27-oic acid, a triterpenoid derived from Tiarella polyphylla, on the regulation of MMP-1 and type 1 procollagen in UV irradiation of cultured old-age human dermal fibroblasts. The triterpenoid dose-dependently induced regulation of type 1 procollagen and diminished regulation of MMP-1 at the protein level (Arch. Pharm. Res. 2004;27:1060–4).

Other Pharmacologic Actions

Triterpenoids also have been found in Boswellia serrata, an herb used in traditional medicine to treat inflammatory and arthritic conditions (and discussed in this column in November 2006, p. 17).

In a study published in 2000, the primary components and derivatives of Boswellia markedly inhibited TPA-induced increases in skin inflammation, epidermal proliferation, the number of epidermal cell layers, and tumor promotion in DMBA-initiated mice. DNA synthesis in human leukemia HL-60 cells was also shown to be inhibited by the addition of various forms of boswellic acid. The investigators suggest that such findings demonstrate the anticarcinogenic and antitumor properties of the major constituents, including triterpenoids, of this herb (Biofactors 2000;13:225–30).

The anti-inflammatory activity of several triterpenoids suggests the potential for numerous additional medical applications. A study evaluating the mechanism of anti-inflammatory activity displayed by triterpenoids on edema induced in mouse ears and paws, as well as rat skin, revealed that the inhibition of protein kinase C may play a crucial role in facilitating the anti-inflammatory activity of this class of compounds (Eur. J. Pharmacol. 2000;410:69–81).

In another study, several triterpene constituents of Vochysia pacifica Cuatrec, a South American tree used by traditional communities to treat inflammation, skin sores, asthma, and pulmonary congestion, were found to exert mild inhibitory activity on the intracellular target for new anti-inflammatory medications, namely the cAMP phosphodiesterase 4 isozyme (PDE4) (Phytother. Res. 2005;19:75–7).

Some triterpenoids have been documented as irritating (J. Asian Nat. Prod. Res. 2003;5:35–41) and others as toxic, which is not unexpected as these compounds comprise the primary constituent class in the volatile oils of plants. Given the breadth of this biochemical class, it is expected that some members would be toxic and others safe and beneficial to human health, such as the triterpenoid saponin glycyrrhizin, derived from licorice root (and featured in this column in March 2007, p. 24, and April 2007, p. 30). Triterpenoid saponins, or sapogenins, are used in some emulsifiers, including some Estée Lauder products, for their capacity to confer antifungal, anti-inflammatory, antimicrobial, and adaptogenic activity.

Conclusion

As we continue to explore botanical sources for medical and cosmetic purposes, we will learn more about the numerous triterpenoids found in plants. This class of biochemical compounds typically receives less attention than polyphenols in discussions of the most potent herbal ingredients used in dermatology, but the considerable potential of triterpenoids to be used in a broad range of cutaneous applications is gradually becoming appreciated.

Triterpenoids, to which squalene is the immediate biologic precursor, include steroids and, thus, sterols, and represent the largest group of terpenoids, the most abundant group of botanical constituents and the most common ingredient class found in volatile oils. Consequently, triterpenoids appear in numerous botanical products with traditional and modern applications to dermatology, such as Centella asiatica (gotu kola) and propolis.

Indeed, the naturally occurring triterpenoids, oleanolic acid and ursolic acid, are known to confer anticarcinogenic and anti-inflammatory effects in certain cells (Exp. Dermatol. 2006;15:66–73). Ursolic acid and the natural triterpenoid erythrodiol have also been found to be effective in a multiple-dose 12-O-tetradecanoylphorbol-13-acetate (TPA) model of chronic dermal inflammation (Eur. J. Pharmacol. 1997;334:103–5).

Although triterpenoids are not as prevalent in as many of the highly touted herbal sources as polyphenols, this group of compounds is gaining increased attention for its anti-inflammatory and anti-tumor-promoting activity. In one trial, investigators studying the triterpenoids oleanolic acid and ursolic acid found that the former induced the differentiation of keratinocytes through peroxisome proliferator-activated receptor (PPAR)-α activation. In addition, topical application of oleanolic acid improved the recovery of epidermal permeability barrier function and increased ceramides in epidermis (Exp. Dermatol. 2006;15:66–73).

The preponderance of data on triterpenoids, though, points to the anti-tumor-promoting capacity of this copious botanical class of compounds.

 Anti-Tumor-Promoting Actions

In a study designed to identify potential anti-tumor promoters, investigators screened 21 cucurbitane triterpenoids using an in vitro assay system, and found that several of the compounds significantly inhibited Epstein-Barr virus (EBV) activation induced by the tumor promoter TPA.

These compounds were scandenoside R6, 23,24-dihydrocucurbitacin F, 25-acetyl-23,24-dihydrocucurbitacin F, 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, and cucurbitacin F. Two triterpenoids, 23,24-dihydrocucurbitacin F and 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, also displayed significant activity against skin tumor promotion in an in vivo two-stage murine carcinogenesis model (Biol. Pharm. Bull. 1994;17:668–71).

A later in vitro study conducted by the same lab to identify anti-tumor promoters considered 23 triterpenoid hydrocarbons isolated from ferns. Significant inhibitory activity against EBV induced by TPA was exhibited by hop-17(21)-ene, neohop-13(18)-ene, neohop-12-ene, taraxerane, multiflor-9(11)-ene, multiflor-8-ene, glutin-5(10)-ene, and taraxastane. In a two-stage in vivo murine carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) for initiation and TPA for promotion, hop-17(21)-ene and neohop-13(18)-ene displayed significant anti-tumor promoting effects on mouse skin (Biol. Pharm. Bull. 1996;19:962–5).

Three years later, some of the same investigators, studying triterpenoids derived from Taraxacum japonicum (Compositae) roots, found that taraxasterol and taraxerol significantly inhibited the effects of TPA-induced Epstein-Barr virus early antigen (EBV-EA) induction, which is a preliminary in vitro screening approach to identifying anti-tumor-promoting agents. These compounds also exhibited potent anti-tumor-promoting activity in the two-stage murine skin carcinogenesis model initiated by DMBA and promoted by TPA (Biol. Pharm. Bull. 1999;22:606–10).

In a study from Osaka (Japan) University of Pharmaceutical Sciences, seven serratane-type triterpenoids isolated from different Picea species all exhibited potent inhibitory effects on EBV-EA activation induced by TPA, and did so more strongly than oleanolic acid. In addition, 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol displayed significant anti-tumor-promoting activity in the in vivo two-stage murine carcinogenesis model (Cancer Lett. 2001;172:119–26).

The same lab subsequently studied 11 serratane-type triterpenoids isolated from various Picea species and three synthetic analogues for their potential inhibitory effects on EBV-EA activation induced by TPA. That study yielded more corroborative findings, as several of the compounds showed potent inhibitory activity, again more strongly than the oleanolic control, including 21-episerratenediol, serratenediol, diepiserratenediol, 3-beta-hydroxyserrat-14-en-21-one, and 3-alpha-methoxy-21-beta-hydroxyserrat-14-en-16-one. Furthermore, no cytotoxicity was associated with these compounds.

Of these triterpenoids, 21-episerratenediol was found to demonstrate significant inhibitory effects on skin tumor promotion in the in vivo two-stage mouse skin carcinogenesis model using DMBA for initiation and TPA for promotion. The investigators suggested that the triterpenoid 21-episerratenediol has potential as an effective cancer chemopreventive agent (Cancer Lett. 2003;196:121–6).

In a separate experiment conducted by this lab, two new serratane-type triterpenoids, 3beta-methoxyserrat-13-en-21-beta-ol and 13-beta,14beta-epoxy-3beta-methoxyserratan-21beta-ol, also isolated from Picea plants, exhibited strong anti-tumor-promoting effects on mouse skin carcinogenesis (Planta Med. 2003;69:1041–7).

This lab also showed that, in a test of the lupane-type triterpenoids isolated from the stem bark of Glochidion zeylanicum as well as synthetic analogues, glochidiol and lup-20(29)-ene-1beta,3beta-diol were the strongest inhibitors of EBV-EA activation induced by TPA. Glochidiol also exhibited the greatest inhibitory effect on skin tumor promotion (Planta Med. 2004;70:1234–6).

Other Anticarcinogenic Actions

In 2005, investigators at the University of North Carolina, Chapel Hill, published a report on cimigenol, an acid- and base-stable triterpenoid found in species such as Cimicifuga racemosa, C. dahurica, and C. japonica. These researchers had previously shown that cimigenol and some of its derivatives had strong inhibitory effects on mouse skin tumor promotion induced by TPA in a two-stage carcinogenesis test. Continuing that previous work, the investigators repeated screens of cimigenol and also tested 15 related compounds as potential anti-tumor promoters by using the in vitro, short-term TPA-induced EBV-EA activation assay (Bioorg. Med. Chem. 2005;13:1403–8).

Of these compounds, the researchers found that cimigenol-3,15-dione showed the greatest potency and, in a subsequent two-stage DMBA/TPA carcinogenesis assay, reduced, at 20 weeks, the number of papillomas per mouse to 48% of controls. Both cimigenol and cimigenol-3,15-dione were also nearly as potent as epigallocatechin gallate, a primary constituent of green tea, in terms of anti-tumor initiation activity, as demonstrated in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite (initiator) and TPA (promoter).

The investigators concluded that these two triterpenoids amply demonstrate anti-tumor promotion as well as anti-tumor initiation and warrant consideration as significant cancer chemopreventive agents (Bioorg. Med. Chem. 2005;13:1403–8).

Protection Against UV

Four triterpenoids isolated from the stems of Styrax japonica were recently found to significantly inhibit matrix metalloproteinase-1 (MMP-1) in primary human skin fibroblasts induced by UV radiation. This finding is significant given the association between the upregulation of MMPs and chronic skin damage (Biol. Pharm. Bull. 2005;28:2003–6).

Previously, some of the same investigators studied the effects of 3,23-dihydroxy-20(29)-lupen-27-oic acid, a triterpenoid derived from Tiarella polyphylla, on the regulation of MMP-1 and type 1 procollagen in UV irradiation of cultured old-age human dermal fibroblasts. The triterpenoid dose-dependently induced regulation of type 1 procollagen and diminished regulation of MMP-1 at the protein level (Arch. Pharm. Res. 2004;27:1060–4).

Other Pharmacologic Actions

Triterpenoids also have been found in Boswellia serrata, an herb used in traditional medicine to treat inflammatory and arthritic conditions (and discussed in this column in November 2006, p. 17).

In a study published in 2000, the primary components and derivatives of Boswellia markedly inhibited TPA-induced increases in skin inflammation, epidermal proliferation, the number of epidermal cell layers, and tumor promotion in DMBA-initiated mice. DNA synthesis in human leukemia HL-60 cells was also shown to be inhibited by the addition of various forms of boswellic acid. The investigators suggest that such findings demonstrate the anticarcinogenic and antitumor properties of the major constituents, including triterpenoids, of this herb (Biofactors 2000;13:225–30).

The anti-inflammatory activity of several triterpenoids suggests the potential for numerous additional medical applications. A study evaluating the mechanism of anti-inflammatory activity displayed by triterpenoids on edema induced in mouse ears and paws, as well as rat skin, revealed that the inhibition of protein kinase C may play a crucial role in facilitating the anti-inflammatory activity of this class of compounds (Eur. J. Pharmacol. 2000;410:69–81).

In another study, several triterpene constituents of Vochysia pacifica Cuatrec, a South American tree used by traditional communities to treat inflammation, skin sores, asthma, and pulmonary congestion, were found to exert mild inhibitory activity on the intracellular target for new anti-inflammatory medications, namely the cAMP phosphodiesterase 4 isozyme (PDE4) (Phytother. Res. 2005;19:75–7).

Some triterpenoids have been documented as irritating (J. Asian Nat. Prod. Res. 2003;5:35–41) and others as toxic, which is not unexpected as these compounds comprise the primary constituent class in the volatile oils of plants. Given the breadth of this biochemical class, it is expected that some members would be toxic and others safe and beneficial to human health, such as the triterpenoid saponin glycyrrhizin, derived from licorice root (and featured in this column in March 2007, p. 24, and April 2007, p. 30). Triterpenoid saponins, or sapogenins, are used in some emulsifiers, including some Estée Lauder products, for their capacity to confer antifungal, anti-inflammatory, antimicrobial, and adaptogenic activity.

Conclusion

As we continue to explore botanical sources for medical and cosmetic purposes, we will learn more about the numerous triterpenoids found in plants. This class of biochemical compounds typically receives less attention than polyphenols in discussions of the most potent herbal ingredients used in dermatology, but the considerable potential of triterpenoids to be used in a broad range of cutaneous applications is gradually becoming appreciated.

Triterpenoids, to which squalene is the immediate biologic precursor, include steroids and, thus, sterols, and represent the largest group of terpenoids, the most abundant group of botanical constituents and the most common ingredient class found in volatile oils. Consequently, triterpenoids appear in numerous botanical products with traditional and modern applications to dermatology, such as Centella asiatica (gotu kola) and propolis.

Indeed, the naturally occurring triterpenoids, oleanolic acid and ursolic acid, are known to confer anticarcinogenic and anti-inflammatory effects in certain cells (Exp. Dermatol. 2006;15:66–73). Ursolic acid and the natural triterpenoid erythrodiol have also been found to be effective in a multiple-dose 12-O-tetradecanoylphorbol-13-acetate (TPA) model of chronic dermal inflammation (Eur. J. Pharmacol. 1997;334:103–5).

Although triterpenoids are not as prevalent in as many of the highly touted herbal sources as polyphenols, this group of compounds is gaining increased attention for its anti-inflammatory and anti-tumor-promoting activity. In one trial, investigators studying the triterpenoids oleanolic acid and ursolic acid found that the former induced the differentiation of keratinocytes through peroxisome proliferator-activated receptor (PPAR)-α activation. In addition, topical application of oleanolic acid improved the recovery of epidermal permeability barrier function and increased ceramides in epidermis (Exp. Dermatol. 2006;15:66–73).

The preponderance of data on triterpenoids, though, points to the anti-tumor-promoting capacity of this copious botanical class of compounds.

 Anti-Tumor-Promoting Actions

In a study designed to identify potential anti-tumor promoters, investigators screened 21 cucurbitane triterpenoids using an in vitro assay system, and found that several of the compounds significantly inhibited Epstein-Barr virus (EBV) activation induced by the tumor promoter TPA.

These compounds were scandenoside R6, 23,24-dihydrocucurbitacin F, 25-acetyl-23,24-dihydrocucurbitacin F, 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, and cucurbitacin F. Two triterpenoids, 23,24-dihydrocucurbitacin F and 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, also displayed significant activity against skin tumor promotion in an in vivo two-stage murine carcinogenesis model (Biol. Pharm. Bull. 1994;17:668–71).

A later in vitro study conducted by the same lab to identify anti-tumor promoters considered 23 triterpenoid hydrocarbons isolated from ferns. Significant inhibitory activity against EBV induced by TPA was exhibited by hop-17(21)-ene, neohop-13(18)-ene, neohop-12-ene, taraxerane, multiflor-9(11)-ene, multiflor-8-ene, glutin-5(10)-ene, and taraxastane. In a two-stage in vivo murine carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) for initiation and TPA for promotion, hop-17(21)-ene and neohop-13(18)-ene displayed significant anti-tumor promoting effects on mouse skin (Biol. Pharm. Bull. 1996;19:962–5).

Three years later, some of the same investigators, studying triterpenoids derived from Taraxacum japonicum (Compositae) roots, found that taraxasterol and taraxerol significantly inhibited the effects of TPA-induced Epstein-Barr virus early antigen (EBV-EA) induction, which is a preliminary in vitro screening approach to identifying anti-tumor-promoting agents. These compounds also exhibited potent anti-tumor-promoting activity in the two-stage murine skin carcinogenesis model initiated by DMBA and promoted by TPA (Biol. Pharm. Bull. 1999;22:606–10).

In a study from Osaka (Japan) University of Pharmaceutical Sciences, seven serratane-type triterpenoids isolated from different Picea species all exhibited potent inhibitory effects on EBV-EA activation induced by TPA, and did so more strongly than oleanolic acid. In addition, 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol displayed significant anti-tumor-promoting activity in the in vivo two-stage murine carcinogenesis model (Cancer Lett. 2001;172:119–26).

The same lab subsequently studied 11 serratane-type triterpenoids isolated from various Picea species and three synthetic analogues for their potential inhibitory effects on EBV-EA activation induced by TPA. That study yielded more corroborative findings, as several of the compounds showed potent inhibitory activity, again more strongly than the oleanolic control, including 21-episerratenediol, serratenediol, diepiserratenediol, 3-beta-hydroxyserrat-14-en-21-one, and 3-alpha-methoxy-21-beta-hydroxyserrat-14-en-16-one. Furthermore, no cytotoxicity was associated with these compounds.

Of these triterpenoids, 21-episerratenediol was found to demonstrate significant inhibitory effects on skin tumor promotion in the in vivo two-stage mouse skin carcinogenesis model using DMBA for initiation and TPA for promotion. The investigators suggested that the triterpenoid 21-episerratenediol has potential as an effective cancer chemopreventive agent (Cancer Lett. 2003;196:121–6).

In a separate experiment conducted by this lab, two new serratane-type triterpenoids, 3beta-methoxyserrat-13-en-21-beta-ol and 13-beta,14beta-epoxy-3beta-methoxyserratan-21beta-ol, also isolated from Picea plants, exhibited strong anti-tumor-promoting effects on mouse skin carcinogenesis (Planta Med. 2003;69:1041–7).

This lab also showed that, in a test of the lupane-type triterpenoids isolated from the stem bark of Glochidion zeylanicum as well as synthetic analogues, glochidiol and lup-20(29)-ene-1beta,3beta-diol were the strongest inhibitors of EBV-EA activation induced by TPA. Glochidiol also exhibited the greatest inhibitory effect on skin tumor promotion (Planta Med. 2004;70:1234–6).

Other Anticarcinogenic Actions

In 2005, investigators at the University of North Carolina, Chapel Hill, published a report on cimigenol, an acid- and base-stable triterpenoid found in species such as Cimicifuga racemosa, C. dahurica, and C. japonica. These researchers had previously shown that cimigenol and some of its derivatives had strong inhibitory effects on mouse skin tumor promotion induced by TPA in a two-stage carcinogenesis test. Continuing that previous work, the investigators repeated screens of cimigenol and also tested 15 related compounds as potential anti-tumor promoters by using the in vitro, short-term TPA-induced EBV-EA activation assay (Bioorg. Med. Chem. 2005;13:1403–8).

Of these compounds, the researchers found that cimigenol-3,15-dione showed the greatest potency and, in a subsequent two-stage DMBA/TPA carcinogenesis assay, reduced, at 20 weeks, the number of papillomas per mouse to 48% of controls. Both cimigenol and cimigenol-3,15-dione were also nearly as potent as epigallocatechin gallate, a primary constituent of green tea, in terms of anti-tumor initiation activity, as demonstrated in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite (initiator) and TPA (promoter).

The investigators concluded that these two triterpenoids amply demonstrate anti-tumor promotion as well as anti-tumor initiation and warrant consideration as significant cancer chemopreventive agents (Bioorg. Med. Chem. 2005;13:1403–8).

Protection Against UV

Four triterpenoids isolated from the stems of Styrax japonica were recently found to significantly inhibit matrix metalloproteinase-1 (MMP-1) in primary human skin fibroblasts induced by UV radiation. This finding is significant given the association between the upregulation of MMPs and chronic skin damage (Biol. Pharm. Bull. 2005;28:2003–6).

Previously, some of the same investigators studied the effects of 3,23-dihydroxy-20(29)-lupen-27-oic acid, a triterpenoid derived from Tiarella polyphylla, on the regulation of MMP-1 and type 1 procollagen in UV irradiation of cultured old-age human dermal fibroblasts. The triterpenoid dose-dependently induced regulation of type 1 procollagen and diminished regulation of MMP-1 at the protein level (Arch. Pharm. Res. 2004;27:1060–4).

Other Pharmacologic Actions

Triterpenoids also have been found in Boswellia serrata, an herb used in traditional medicine to treat inflammatory and arthritic conditions (and discussed in this column in November 2006, p. 17).

In a study published in 2000, the primary components and derivatives of Boswellia markedly inhibited TPA-induced increases in skin inflammation, epidermal proliferation, the number of epidermal cell layers, and tumor promotion in DMBA-initiated mice. DNA synthesis in human leukemia HL-60 cells was also shown to be inhibited by the addition of various forms of boswellic acid. The investigators suggest that such findings demonstrate the anticarcinogenic and antitumor properties of the major constituents, including triterpenoids, of this herb (Biofactors 2000;13:225–30).

The anti-inflammatory activity of several triterpenoids suggests the potential for numerous additional medical applications. A study evaluating the mechanism of anti-inflammatory activity displayed by triterpenoids on edema induced in mouse ears and paws, as well as rat skin, revealed that the inhibition of protein kinase C may play a crucial role in facilitating the anti-inflammatory activity of this class of compounds (Eur. J. Pharmacol. 2000;410:69–81).

In another study, several triterpene constituents of Vochysia pacifica Cuatrec, a South American tree used by traditional communities to treat inflammation, skin sores, asthma, and pulmonary congestion, were found to exert mild inhibitory activity on the intracellular target for new anti-inflammatory medications, namely the cAMP phosphodiesterase 4 isozyme (PDE4) (Phytother. Res. 2005;19:75–7).

Some triterpenoids have been documented as irritating (J. Asian Nat. Prod. Res. 2003;5:35–41) and others as toxic, which is not unexpected as these compounds comprise the primary constituent class in the volatile oils of plants. Given the breadth of this biochemical class, it is expected that some members would be toxic and others safe and beneficial to human health, such as the triterpenoid saponin glycyrrhizin, derived from licorice root (and featured in this column in March 2007, p. 24, and April 2007, p. 30). Triterpenoid saponins, or sapogenins, are used in some emulsifiers, including some Estée Lauder products, for their capacity to confer antifungal, anti-inflammatory, antimicrobial, and adaptogenic activity.

Conclusion

As we continue to explore botanical sources for medical and cosmetic purposes, we will learn more about the numerous triterpenoids found in plants. This class of biochemical compounds typically receives less attention than polyphenols in discussions of the most potent herbal ingredients used in dermatology, but the considerable potential of triterpenoids to be used in a broad range of cutaneous applications is gradually becoming appreciated.

Positive immunostaining with monoclonal antibody D2–40, together with younger patient age and lesion ulceration, might identify which melanoma patients are likely to have nodal metastasis and should undergo sentinel node biopsy, according to Dr. Firouzeh Niakosari of Sunnybrook Health Sciences Centre, Toronto, and associates.

"The recently developed monoclonal antibody [Mab] D2–40 reacts with endothelial cells of lymphatics but not with endothelial cells of blood vessels in normal tissues," the investigators wrote (Arch. Dermatol. 2008;144:462–7).

Mab D2–40 immunostaining more readily identifies lymphatic invasion in primary melanomas than does conventional staining with hematoxylin-eosin. Dr. Niakosari and associates assessed the technique's predictive value using blocks of primary tumor taken from 96 patients who were treated in 1998–2004 and had no clinical evidence of metastasis.

On biopsy, sentinel lymph nodes had been found to be positive in 23 of the cases.

Mab D2–40 immunostaining was positive for invasion of the lymphatic vessels within the tumor samples in 32 of the 96 cases (33%). The result was correct in ruling out lymphatic invasion in 56 (77%) of the cases that proved to have no invasion on sentinel node biopsy, and it was correct in identifying lymphatic invasion in 15 (65%) of the cases that did have lymphatic invasion on sentinel node biopsy.

On its own, then, the technique had a negative predictive value of 88% and a positive predictive value of 47%, the investigators found.

Mab D2–40 immunostaining was even more predictive when the results were combined with two clinical factors: younger patient age and the presence of ulceration in the lesion. "The probability of sentinel lymph node positivity was 13% when lymphatic invasion identified by immunostaining with Mab D2–40 was negative, no ulceration was present, and the patient was 50 years or older," they noted.

In cases in which the immunostaining indicated that there was lymphatic invasion, ulceration was present, and the patient was younger than 50 years, the probability of sentinel lymph node positivity increased to 61%, Dr. Niakosari and associates reported.

Lymphatic invasion on Mab D2–40 immunostaining correlated with deeper Clark Level of Invasion and increased Breslow tumor thickness, "indicating that lymphatic invasion occurs more frequently in later stages of melanoma," they wrote.

Positive immunostaining with monoclonal antibody D2–40, together with younger patient age and lesion ulceration, might identify which melanoma patients are likely to have nodal metastasis and should undergo sentinel node biopsy, according to Dr. Firouzeh Niakosari of Sunnybrook Health Sciences Centre, Toronto, and associates.

"The recently developed monoclonal antibody [Mab] D2–40 reacts with endothelial cells of lymphatics but not with endothelial cells of blood vessels in normal tissues," the investigators wrote (Arch. Dermatol. 2008;144:462–7).

Mab D2–40 immunostaining more readily identifies lymphatic invasion in primary melanomas than does conventional staining with hematoxylin-eosin. Dr. Niakosari and associates assessed the technique's predictive value using blocks of primary tumor taken from 96 patients who were treated in 1998–2004 and had no clinical evidence of metastasis.

On biopsy, sentinel lymph nodes had been found to be positive in 23 of the cases.

Mab D2–40 immunostaining was positive for invasion of the lymphatic vessels within the tumor samples in 32 of the 96 cases (33%). The result was correct in ruling out lymphatic invasion in 56 (77%) of the cases that proved to have no invasion on sentinel node biopsy, and it was correct in identifying lymphatic invasion in 15 (65%) of the cases that did have lymphatic invasion on sentinel node biopsy.

On its own, then, the technique had a negative predictive value of 88% and a positive predictive value of 47%, the investigators found.

Mab D2–40 immunostaining was even more predictive when the results were combined with two clinical factors: younger patient age and the presence of ulceration in the lesion. "The probability of sentinel lymph node positivity was 13% when lymphatic invasion identified by immunostaining with Mab D2–40 was negative, no ulceration was present, and the patient was 50 years or older," they noted.

In cases in which the immunostaining indicated that there was lymphatic invasion, ulceration was present, and the patient was younger than 50 years, the probability of sentinel lymph node positivity increased to 61%, Dr. Niakosari and associates reported.

Lymphatic invasion on Mab D2–40 immunostaining correlated with deeper Clark Level of Invasion and increased Breslow tumor thickness, "indicating that lymphatic invasion occurs more frequently in later stages of melanoma," they wrote.

Positive immunostaining with monoclonal antibody D2–40, together with younger patient age and lesion ulceration, might identify which melanoma patients are likely to have nodal metastasis and should undergo sentinel node biopsy, according to Dr. Firouzeh Niakosari of Sunnybrook Health Sciences Centre, Toronto, and associates.

"The recently developed monoclonal antibody [Mab] D2–40 reacts with endothelial cells of lymphatics but not with endothelial cells of blood vessels in normal tissues," the investigators wrote (Arch. Dermatol. 2008;144:462–7).

Mab D2–40 immunostaining more readily identifies lymphatic invasion in primary melanomas than does conventional staining with hematoxylin-eosin. Dr. Niakosari and associates assessed the technique's predictive value using blocks of primary tumor taken from 96 patients who were treated in 1998–2004 and had no clinical evidence of metastasis.

On biopsy, sentinel lymph nodes had been found to be positive in 23 of the cases.

Mab D2–40 immunostaining was positive for invasion of the lymphatic vessels within the tumor samples in 32 of the 96 cases (33%). The result was correct in ruling out lymphatic invasion in 56 (77%) of the cases that proved to have no invasion on sentinel node biopsy, and it was correct in identifying lymphatic invasion in 15 (65%) of the cases that did have lymphatic invasion on sentinel node biopsy.

On its own, then, the technique had a negative predictive value of 88% and a positive predictive value of 47%, the investigators found.

Mab D2–40 immunostaining was even more predictive when the results were combined with two clinical factors: younger patient age and the presence of ulceration in the lesion. "The probability of sentinel lymph node positivity was 13% when lymphatic invasion identified by immunostaining with Mab D2–40 was negative, no ulceration was present, and the patient was 50 years or older," they noted.

In cases in which the immunostaining indicated that there was lymphatic invasion, ulceration was present, and the patient was younger than 50 years, the probability of sentinel lymph node positivity increased to 61%, Dr. Niakosari and associates reported.

Lymphatic invasion on Mab D2–40 immunostaining correlated with deeper Clark Level of Invasion and increased Breslow tumor thickness, "indicating that lymphatic invasion occurs more frequently in later stages of melanoma," they wrote.

SCOTTSDALE, ARIZ. — There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown during the Harold O. Perry lecture at the annual meeting of the Noah Worcester Dermatological Society.

Lentigo Maligna

Once cavalierly called a "Hutchinson's freckle" because it can resemble a dab of shoe polish, patients may not even notice the subtle appearance and growth of a lentigo maligna. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).

"It's very, very difficult to make the diagnosis," Dr. Brown said. "I've missed it several times."

Lentigo maligna lesions are slow to develop and evolve almost imperceptibly. They may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, as was the case in nearly half of 147 lesions described in a recent study (J. Am. Acad. Dermatol. 2005;52:859–62).

However, it is not a disease to be trivialized, according to Dr. Brown.

"It's my feeling that if you give it a long enough period of time, it will become an invasive tumor," he said.

Two decades ago, when he began performing Mohs surgery, Dr. Brown almost exclusively encountered lentigo malignas on elderly patients. Now he's making it a practice to hunt for them on much younger patients. "It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna," he said.

Finding a surefire treatment approach to lentigo malignas remains challenging.

Increasing evidence suggests that the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but, Dr. Brown advised, "you really have to have an excellent lab and be very good at this."

He said he prefers a "modified Mohs," or "slow Mohs" approach that involves sending sequential sections to a histopathologic laboratory over several days after a "very meticulous" collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.

For elderly patients and difficult anatomic sites, radiation therapy or daily use of imiquimod has been proposed. Dr. Brown cautioned that the use of the immune response modifier should be considered experimental, because only 67 cases in which it has been used are described in the literature, and 8 of those involved treatment failures.

Atypical Fibroxanthoma

Also increasing in incidence is this tumor, which is believed to be secondary to UV exposure, said Dr. Brown.

Unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.

"It usually appears relatively nonspecifically," he said. "Most of the time when I submit a specimen to the pathologist, I don't say, 'Rule out AFX.' It's usually squamous cell versus basal cell cancer [in my mind]."

In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown. He was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:1287–92).

"If it sounds too good to be true, it's too good to be true," he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.

In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.

Fortunately, there is a clue to potential aggressive behavior in such tumors, he said. The immunostain LN-2 (CD74) often "lights up" in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.

Merkel Cell Carcinoma

Unknown until 1972 and then considered exceedingly rare, Merkel cell carcinoma appears to be on the rise. More than 1,000 cases have been reported in patients aged 7–75 years (although most patients are older than 65 years).

Up to 15% of cases are seen in immunocompromised patients, a number that is driven by long-term survivors of HIV, chronic lymphocytic leukemia, and organ transplantation. "I'm seeing a lot of these," said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.

In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. "No way I thought this was a Merkel cell," he admitted.

When the diagnosis is confirmed by its blue cell clusters in sheets or a trabecular pattern in the dermis, with frequent mitosis and cell necrosis, dermatologists should take heed. "This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma," he said.

Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases—50% by some reports—with a 3-year overall survival of 31%.

Treatment is controversial, noted Dr. Brown. Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps adjuvant chemotherapy. A negative sentinel lymph node carries a fairly reassuring prognosis.

He added that an immunostain for anti-CK20 antibody may detect micrometastases in patients who appear to be tumor free on routine histology, according to a small study (J. Am. Acad. Dermatol. 2002;46:661–6).

SCC in Organ Transplant Patients

The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma.

Their cancers may be multiple, fast growing, and atypical in appearance, Dr. Brown said.

In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.

"We're all going to be seeing more and more of these patients," Dr. Brown predicted.

The keys to management of these challenging patients are education first, then vigilance. Many transplant centers fail to warn patients that they may be at elevated risk for skin cancers and that they should be examined frequently.

When a lesion appears, have a low threshold for suspicion, he said. "It is very difficult sometimes to determine which is the bad [lesion] and which is not."

High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites: the scalp, ear, lip, neck, and face. Warning signs histologically include poor cell differentiation and perineural invasion.

"How do you manage these? Aggressively," he emphasized.

Employ whichever tools work: surgery, cryotherapy, 5-fluorouracil, photodynamic therapy, or topical imiquimod. Systemic retinoids, perhaps in conjunction with a reduction in immunosuppressive therapy, may be appropriate for patients with recurrent, aggressive, or metastatic SCCs, he added.

Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His presentation, however, was not sponsored by any company.

Long-term survivors of organ transplantation have a 65-fold increased risk of squamous cell carcinoma. DR. BROWN

SCOTTSDALE, ARIZ. — There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown during the Harold O. Perry lecture at the annual meeting of the Noah Worcester Dermatological Society.

Lentigo Maligna

Once cavalierly called a "Hutchinson's freckle" because it can resemble a dab of shoe polish, patients may not even notice the subtle appearance and growth of a lentigo maligna. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).

"It's very, very difficult to make the diagnosis," Dr. Brown said. "I've missed it several times."

Lentigo maligna lesions are slow to develop and evolve almost imperceptibly. They may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, as was the case in nearly half of 147 lesions described in a recent study (J. Am. Acad. Dermatol. 2005;52:859–62).

However, it is not a disease to be trivialized, according to Dr. Brown.

"It's my feeling that if you give it a long enough period of time, it will become an invasive tumor," he said.

Two decades ago, when he began performing Mohs surgery, Dr. Brown almost exclusively encountered lentigo malignas on elderly patients. Now he's making it a practice to hunt for them on much younger patients. "It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna," he said.

Finding a surefire treatment approach to lentigo malignas remains challenging.

Increasing evidence suggests that the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but, Dr. Brown advised, "you really have to have an excellent lab and be very good at this."

He said he prefers a "modified Mohs," or "slow Mohs" approach that involves sending sequential sections to a histopathologic laboratory over several days after a "very meticulous" collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.

For elderly patients and difficult anatomic sites, radiation therapy or daily use of imiquimod has been proposed. Dr. Brown cautioned that the use of the immune response modifier should be considered experimental, because only 67 cases in which it has been used are described in the literature, and 8 of those involved treatment failures.

Atypical Fibroxanthoma

Also increasing in incidence is this tumor, which is believed to be secondary to UV exposure, said Dr. Brown.

Unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.

"It usually appears relatively nonspecifically," he said. "Most of the time when I submit a specimen to the pathologist, I don't say, 'Rule out AFX.' It's usually squamous cell versus basal cell cancer [in my mind]."

In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown. He was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:1287–92).

"If it sounds too good to be true, it's too good to be true," he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.

In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.

Fortunately, there is a clue to potential aggressive behavior in such tumors, he said. The immunostain LN-2 (CD74) often "lights up" in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.

Merkel Cell Carcinoma

Unknown until 1972 and then considered exceedingly rare, Merkel cell carcinoma appears to be on the rise. More than 1,000 cases have been reported in patients aged 7–75 years (although most patients are older than 65 years).

Up to 15% of cases are seen in immunocompromised patients, a number that is driven by long-term survivors of HIV, chronic lymphocytic leukemia, and organ transplantation. "I'm seeing a lot of these," said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.

In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. "No way I thought this was a Merkel cell," he admitted.

When the diagnosis is confirmed by its blue cell clusters in sheets or a trabecular pattern in the dermis, with frequent mitosis and cell necrosis, dermatologists should take heed. "This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma," he said.

Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases—50% by some reports—with a 3-year overall survival of 31%.

Treatment is controversial, noted Dr. Brown. Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps adjuvant chemotherapy. A negative sentinel lymph node carries a fairly reassuring prognosis.

He added that an immunostain for anti-CK20 antibody may detect micrometastases in patients who appear to be tumor free on routine histology, according to a small study (J. Am. Acad. Dermatol. 2002;46:661–6).

SCC in Organ Transplant Patients

The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma.

Their cancers may be multiple, fast growing, and atypical in appearance, Dr. Brown said.

In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.

"We're all going to be seeing more and more of these patients," Dr. Brown predicted.

The keys to management of these challenging patients are education first, then vigilance. Many transplant centers fail to warn patients that they may be at elevated risk for skin cancers and that they should be examined frequently.

When a lesion appears, have a low threshold for suspicion, he said. "It is very difficult sometimes to determine which is the bad [lesion] and which is not."

High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites: the scalp, ear, lip, neck, and face. Warning signs histologically include poor cell differentiation and perineural invasion.

"How do you manage these? Aggressively," he emphasized.

Employ whichever tools work: surgery, cryotherapy, 5-fluorouracil, photodynamic therapy, or topical imiquimod. Systemic retinoids, perhaps in conjunction with a reduction in immunosuppressive therapy, may be appropriate for patients with recurrent, aggressive, or metastatic SCCs, he added.

Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His presentation, however, was not sponsored by any company.

Long-term survivors of organ transplantation have a 65-fold increased risk of squamous cell carcinoma. DR. BROWN

SCOTTSDALE, ARIZ. — There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown during the Harold O. Perry lecture at the annual meeting of the Noah Worcester Dermatological Society.

Lentigo Maligna

Once cavalierly called a "Hutchinson's freckle" because it can resemble a dab of shoe polish, patients may not even notice the subtle appearance and growth of a lentigo maligna. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).

"It's very, very difficult to make the diagnosis," Dr. Brown said. "I've missed it several times."

Lentigo maligna lesions are slow to develop and evolve almost imperceptibly. They may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, as was the case in nearly half of 147 lesions described in a recent study (J. Am. Acad. Dermatol. 2005;52:859–62).

However, it is not a disease to be trivialized, according to Dr. Brown.

"It's my feeling that if you give it a long enough period of time, it will become an invasive tumor," he said.

Two decades ago, when he began performing Mohs surgery, Dr. Brown almost exclusively encountered lentigo malignas on elderly patients. Now he's making it a practice to hunt for them on much younger patients. "It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna," he said.

Finding a surefire treatment approach to lentigo malignas remains challenging.

Increasing evidence suggests that the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but, Dr. Brown advised, "you really have to have an excellent lab and be very good at this."

He said he prefers a "modified Mohs," or "slow Mohs" approach that involves sending sequential sections to a histopathologic laboratory over several days after a "very meticulous" collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.

For elderly patients and difficult anatomic sites, radiation therapy or daily use of imiquimod has been proposed. Dr. Brown cautioned that the use of the immune response modifier should be considered experimental, because only 67 cases in which it has been used are described in the literature, and 8 of those involved treatment failures.

Atypical Fibroxanthoma

Also increasing in incidence is this tumor, which is believed to be secondary to UV exposure, said Dr. Brown.

Unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.

"It usually appears relatively nonspecifically," he said. "Most of the time when I submit a specimen to the pathologist, I don't say, 'Rule out AFX.' It's usually squamous cell versus basal cell cancer [in my mind]."

In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown. He was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:1287–92).

"If it sounds too good to be true, it's too good to be true," he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.

In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.

Fortunately, there is a clue to potential aggressive behavior in such tumors, he said. The immunostain LN-2 (CD74) often "lights up" in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.

Merkel Cell Carcinoma

Unknown until 1972 and then considered exceedingly rare, Merkel cell carcinoma appears to be on the rise. More than 1,000 cases have been reported in patients aged 7–75 years (although most patients are older than 65 years).

Up to 15% of cases are seen in immunocompromised patients, a number that is driven by long-term survivors of HIV, chronic lymphocytic leukemia, and organ transplantation. "I'm seeing a lot of these," said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.

In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. "No way I thought this was a Merkel cell," he admitted.

When the diagnosis is confirmed by its blue cell clusters in sheets or a trabecular pattern in the dermis, with frequent mitosis and cell necrosis, dermatologists should take heed. "This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma," he said.

Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases—50% by some reports—with a 3-year overall survival of 31%.

Treatment is controversial, noted Dr. Brown. Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps adjuvant chemotherapy. A negative sentinel lymph node carries a fairly reassuring prognosis.

He added that an immunostain for anti-CK20 antibody may detect micrometastases in patients who appear to be tumor free on routine histology, according to a small study (J. Am. Acad. Dermatol. 2002;46:661–6).

SCC in Organ Transplant Patients

The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma.

Their cancers may be multiple, fast growing, and atypical in appearance, Dr. Brown said.

In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.

"We're all going to be seeing more and more of these patients," Dr. Brown predicted.

The keys to management of these challenging patients are education first, then vigilance. Many transplant centers fail to warn patients that they may be at elevated risk for skin cancers and that they should be examined frequently.

When a lesion appears, have a low threshold for suspicion, he said. "It is very difficult sometimes to determine which is the bad [lesion] and which is not."

High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites: the scalp, ear, lip, neck, and face. Warning signs histologically include poor cell differentiation and perineural invasion.

"How do you manage these? Aggressively," he emphasized.

Employ whichever tools work: surgery, cryotherapy, 5-fluorouracil, photodynamic therapy, or topical imiquimod. Systemic retinoids, perhaps in conjunction with a reduction in immunosuppressive therapy, may be appropriate for patients with recurrent, aggressive, or metastatic SCCs, he added.

Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His presentation, however, was not sponsored by any company.

Long-term survivors of organ transplantation have a 65-fold increased risk of squamous cell carcinoma. DR. BROWN

VANCOUVER, B.C. — Cranial neuropathy may be the first sign or symptom of a skin cancer recurrence, and as such it is often misdiagnosed, a dermatologist/otolaryngologist said.

Neurotropic skin cancer is an uncommon but aggressive form of skin cancer, Dr. Joel W. Cook reported at the annual meeting of the American College of Mohs Surgery.

"Most of the neurotropic findings are histologic and any symptoms are reasonably unusual; most studies say that it's very rare. To have [patients] present to your office with neurologic findings as their sentinel event in the recognition of recurrent skin cancer is even rarer," he said.

In the retrospective study, Dr. Cook of the Medical University of South Carolina, Charleston, and his colleagues reviewed the charts of patients who had previously had skin cancer and were referred to the university's head and neck program between 1999 and 2007.

The chart review identified six patients in whom cranial neuropathy was the initial sign or symptom of recurrent skin cancer.

Five of the patients had previously undergone multiple excisions of skin cancer, and two had undergone Mohs surgery for a primary lesion, he said.

The cancer was squamous cell carcinoma in four cases and desmoplastic melanoma in two. "Importantly, none of the six patients" was a transplant patient, he noted.

"One had an indolent chronic myelogenous leukemia, but they were all reasonably immunocompetent," he said.

The majority of the patients had multiple cranial neuropathies; all had deficits of cranial nerve V, and half had deficits of cranial nerve VII.

The presenting symptoms were most commonly facial numbness; facial paralysis or weakness; facial pain; diplopia; and paresthesia.

Less common symptoms were formication and hearing loss. The symptoms had been present for 7 months, on average, before diagnosis.

In nearly all cases, the cranial neuropathy had been misdiagnosed as trigeminal neuralgia, Bell's palsy, or some other condition, said Dr. Cook.

Neurotropism was identified histologically in five patients who underwent surgery or biopsy, and cranial nerve involvement was confirmed in all patients by MRI.

"It's important to know what imaging study to order in these patients," Dr. Cook pointed out. "Although CT is an excellent method to image head and neck malignancies, … it cannot be used to evaluate for the presence or absence of neurotropic tumor. In that case or with that suspicion, you would want to get an MRI; this is by far the preferred imaging modality."

Five of the patients underwent treatment for their recurrence with various combinations of surgery, radiation therapy, and chemotherapy.

"As you can imagine, the surgery in these patients is salvage surgery and is amazingly extensive. These patients have to be counseled preoperatively, they have to be adequately staged, and they need multidisciplinary consultations," Dr. Cook said.

"But surgery is the only chance these patients have to survive," he added.

Three of the patients eventually died, with evidence of metastases. The other three, however, all of whom had undergone surgery, were still alive without evidence of disease 2.5–6 years after their operations.

Dr. Cook concluded that any time a patient is found to have a cranial neuropathy and that patient has previously undergone resection of a high-risk skin cancer, "you need to be very skeptical of an alternative diagnosis other than neurotropic recurrence."

He reported no disclosures in association with the study.

VANCOUVER, B.C. — Cranial neuropathy may be the first sign or symptom of a skin cancer recurrence, and as such it is often misdiagnosed, a dermatologist/otolaryngologist said.

Neurotropic skin cancer is an uncommon but aggressive form of skin cancer, Dr. Joel W. Cook reported at the annual meeting of the American College of Mohs Surgery.

"Most of the neurotropic findings are histologic and any symptoms are reasonably unusual; most studies say that it's very rare. To have [patients] present to your office with neurologic findings as their sentinel event in the recognition of recurrent skin cancer is even rarer," he said.

In the retrospective study, Dr. Cook of the Medical University of South Carolina, Charleston, and his colleagues reviewed the charts of patients who had previously had skin cancer and were referred to the university's head and neck program between 1999 and 2007.

The chart review identified six patients in whom cranial neuropathy was the initial sign or symptom of recurrent skin cancer.

Five of the patients had previously undergone multiple excisions of skin cancer, and two had undergone Mohs surgery for a primary lesion, he said.

The cancer was squamous cell carcinoma in four cases and desmoplastic melanoma in two. "Importantly, none of the six patients" was a transplant patient, he noted.

"One had an indolent chronic myelogenous leukemia, but they were all reasonably immunocompetent," he said.

The majority of the patients had multiple cranial neuropathies; all had deficits of cranial nerve V, and half had deficits of cranial nerve VII.

The presenting symptoms were most commonly facial numbness; facial paralysis or weakness; facial pain; diplopia; and paresthesia.

Less common symptoms were formication and hearing loss. The symptoms had been present for 7 months, on average, before diagnosis.

In nearly all cases, the cranial neuropathy had been misdiagnosed as trigeminal neuralgia, Bell's palsy, or some other condition, said Dr. Cook.

Neurotropism was identified histologically in five patients who underwent surgery or biopsy, and cranial nerve involvement was confirmed in all patients by MRI.

"It's important to know what imaging study to order in these patients," Dr. Cook pointed out. "Although CT is an excellent method to image head and neck malignancies, … it cannot be used to evaluate for the presence or absence of neurotropic tumor. In that case or with that suspicion, you would want to get an MRI; this is by far the preferred imaging modality."

Five of the patients underwent treatment for their recurrence with various combinations of surgery, radiation therapy, and chemotherapy.

"As you can imagine, the surgery in these patients is salvage surgery and is amazingly extensive. These patients have to be counseled preoperatively, they have to be adequately staged, and they need multidisciplinary consultations," Dr. Cook said.

"But surgery is the only chance these patients have to survive," he added.

Three of the patients eventually died, with evidence of metastases. The other three, however, all of whom had undergone surgery, were still alive without evidence of disease 2.5–6 years after their operations.

Dr. Cook concluded that any time a patient is found to have a cranial neuropathy and that patient has previously undergone resection of a high-risk skin cancer, "you need to be very skeptical of an alternative diagnosis other than neurotropic recurrence."

He reported no disclosures in association with the study.

VANCOUVER, B.C. — Cranial neuropathy may be the first sign or symptom of a skin cancer recurrence, and as such it is often misdiagnosed, a dermatologist/otolaryngologist said.

Neurotropic skin cancer is an uncommon but aggressive form of skin cancer, Dr. Joel W. Cook reported at the annual meeting of the American College of Mohs Surgery.

"Most of the neurotropic findings are histologic and any symptoms are reasonably unusual; most studies say that it's very rare. To have [patients] present to your office with neurologic findings as their sentinel event in the recognition of recurrent skin cancer is even rarer," he said.

In the retrospective study, Dr. Cook of the Medical University of South Carolina, Charleston, and his colleagues reviewed the charts of patients who had previously had skin cancer and were referred to the university's head and neck program between 1999 and 2007.

The chart review identified six patients in whom cranial neuropathy was the initial sign or symptom of recurrent skin cancer.

Five of the patients had previously undergone multiple excisions of skin cancer, and two had undergone Mohs surgery for a primary lesion, he said.

The cancer was squamous cell carcinoma in four cases and desmoplastic melanoma in two. "Importantly, none of the six patients" was a transplant patient, he noted.

"One had an indolent chronic myelogenous leukemia, but they were all reasonably immunocompetent," he said.

The majority of the patients had multiple cranial neuropathies; all had deficits of cranial nerve V, and half had deficits of cranial nerve VII.

The presenting symptoms were most commonly facial numbness; facial paralysis or weakness; facial pain; diplopia; and paresthesia.

Less common symptoms were formication and hearing loss. The symptoms had been present for 7 months, on average, before diagnosis.

In nearly all cases, the cranial neuropathy had been misdiagnosed as trigeminal neuralgia, Bell's palsy, or some other condition, said Dr. Cook.

Neurotropism was identified histologically in five patients who underwent surgery or biopsy, and cranial nerve involvement was confirmed in all patients by MRI.

"It's important to know what imaging study to order in these patients," Dr. Cook pointed out. "Although CT is an excellent method to image head and neck malignancies, … it cannot be used to evaluate for the presence or absence of neurotropic tumor. In that case or with that suspicion, you would want to get an MRI; this is by far the preferred imaging modality."

Five of the patients underwent treatment for their recurrence with various combinations of surgery, radiation therapy, and chemotherapy.

"As you can imagine, the surgery in these patients is salvage surgery and is amazingly extensive. These patients have to be counseled preoperatively, they have to be adequately staged, and they need multidisciplinary consultations," Dr. Cook said.

"But surgery is the only chance these patients have to survive," he added.

Three of the patients eventually died, with evidence of metastases. The other three, however, all of whom had undergone surgery, were still alive without evidence of disease 2.5–6 years after their operations.

Dr. Cook concluded that any time a patient is found to have a cranial neuropathy and that patient has previously undergone resection of a high-risk skin cancer, "you need to be very skeptical of an alternative diagnosis other than neurotropic recurrence."

He reported no disclosures in association with the study.

NEW YORK — The greatest malignancy risk in patients receiving tumor necrosis factor antagonists is skin cancer, Dr. Jeffrey Greenberg said at a rheumatology meeting sponsored by New York University.

However, data conflict as to how great malignancy risk is overall for these patients.

Two years ago, a widely noted systematic review and meta-analysis found a threefold increased risk for malignancy in patients with rheumatoid arthritis (RA) treated with infliximab or adalimumab (JAMA 2006;295:2275–85). The meta-analysis included nine randomized, placebo-controlled trials, with 3,493 RA patients who received an active drug and 1,512 RA patients who received placebo.

In the anti-tumor necrosis factor (TNF) arms of this analysis, there were 10 lymphomas, nine nonmelanoma skin cancers, and 12 assorted other cancers, Dr. Greenberg said. "What was most interesting was the cancers that weren't found in the placebo arms—there were two basal cell cancers and one solid tumor—and that's it," he said, adding that in a group of 1,500 RA patients, 8–10 malignancies would be expected.

Aside from the lower-than-expected rates of malignancy in the placebo arms, the meta-analysis had other limitations, according to Dr. Greenberg of New York University, New York, who is chief scientific officer of the Consortium of Rheumatology Researchers of North America (CORRONA).

Among these limitations were the exclusion of etanercept; the association of higher-than-usual doses of infliximab with most malignancies; and the fact that the investigators used a per-patient analysis rather than person-years of drug exposure. Their approach assumes equal time exposure for placebo and the anti-TNF drugs, and four of the nine trials had higher placebo dropout rates.

"Patients on placebo who drop out are not followed for long periods of time looking for malignancies, so of course they are going to have fewer events," he added.

However, a different picture is emerging from observational studies and RA registries in the United States and Europe. In three Swedish registries—one prevalent cohort that included 53,067 patients, one incident cohort that included 3,703 patients, and one TNF antagonist-treated cohort of 4,160 patients—RA patients treated with TNF blockers had a tripled lymphoma risk, compared with the general population. However, after adjustment for sex, age, and disease duration, the lymphoma risk among TNF antagonist-treated patients was no higher than in the other RA cohorts (Ann. Rheum. Dis. 2005;64:1414–20).

In a report from the National Data Bank for Rheumatic Diseases, when RA patients were compared with the general population from the National Cancer Institute's Surveillance, Epidemiology, and End Results database, there was no increased rate of cancer overall, but lymphoma and melanoma were increased, with both having standardized incidence ratios of 1.7. However, only nonmelanoma skin cancer and melanoma were increased among patients on biologics, with odds ratios of 1.5 and 2.3, respectively. No other malignancy was significantly associated with biologic use (Arthritis Rheum. 2007;56:2886–95).

Data from the British Biologics Register also found no increase in malignancy rate, with an adjusted incidence rate ratio (IRR) of 0.7 for patients treated with anti-TNF agents, compared with those treated with nonbiologic disease-modifying antirheumatic drugs.

And in CORRONA, which includes 15,000 RA patients, the adjusted IRR for skin cancer was 2.10, whereas that for lymphoma was 0.74 and that for all cancers was 1.05, according to Dr. Greenberg.

"I think the take-home message of the observational studies is that it's the nonmelanoma skin cancers and possibly the melanomas that are the greatest concern, not the lymphomas," he said.

However, the discrepancy between the findings of the meta-analysis and those of the observational studies remains to be explained, Dr. Greenberg said.

"Frankly, I think they could not be more conflicting. It may be that there is a group of patients with subclinical neoplasms, including lymphomas, that any immunosuppressive or immunomodulatory treatment may unmask or accelerate. We probably should be screening for these cancers more aggressively regardless of treatment," he said.

NEW YORK — The greatest malignancy risk in patients receiving tumor necrosis factor antagonists is skin cancer, Dr. Jeffrey Greenberg said at a rheumatology meeting sponsored by New York University.

However, data conflict as to how great malignancy risk is overall for these patients.

Two years ago, a widely noted systematic review and meta-analysis found a threefold increased risk for malignancy in patients with rheumatoid arthritis (RA) treated with infliximab or adalimumab (JAMA 2006;295:2275–85). The meta-analysis included nine randomized, placebo-controlled trials, with 3,493 RA patients who received an active drug and 1,512 RA patients who received placebo.

In the anti-tumor necrosis factor (TNF) arms of this analysis, there were 10 lymphomas, nine nonmelanoma skin cancers, and 12 assorted other cancers, Dr. Greenberg said. "What was most interesting was the cancers that weren't found in the placebo arms—there were two basal cell cancers and one solid tumor—and that's it," he said, adding that in a group of 1,500 RA patients, 8–10 malignancies would be expected.

Aside from the lower-than-expected rates of malignancy in the placebo arms, the meta-analysis had other limitations, according to Dr. Greenberg of New York University, New York, who is chief scientific officer of the Consortium of Rheumatology Researchers of North America (CORRONA).

Among these limitations were the exclusion of etanercept; the association of higher-than-usual doses of infliximab with most malignancies; and the fact that the investigators used a per-patient analysis rather than person-years of drug exposure. Their approach assumes equal time exposure for placebo and the anti-TNF drugs, and four of the nine trials had higher placebo dropout rates.

"Patients on placebo who drop out are not followed for long periods of time looking for malignancies, so of course they are going to have fewer events," he added.

However, a different picture is emerging from observational studies and RA registries in the United States and Europe. In three Swedish registries—one prevalent cohort that included 53,067 patients, one incident cohort that included 3,703 patients, and one TNF antagonist-treated cohort of 4,160 patients—RA patients treated with TNF blockers had a tripled lymphoma risk, compared with the general population. However, after adjustment for sex, age, and disease duration, the lymphoma risk among TNF antagonist-treated patients was no higher than in the other RA cohorts (Ann. Rheum. Dis. 2005;64:1414–20).

In a report from the National Data Bank for Rheumatic Diseases, when RA patients were compared with the general population from the National Cancer Institute's Surveillance, Epidemiology, and End Results database, there was no increased rate of cancer overall, but lymphoma and melanoma were increased, with both having standardized incidence ratios of 1.7. However, only nonmelanoma skin cancer and melanoma were increased among patients on biologics, with odds ratios of 1.5 and 2.3, respectively. No other malignancy was significantly associated with biologic use (Arthritis Rheum. 2007;56:2886–95).

Data from the British Biologics Register also found no increase in malignancy rate, with an adjusted incidence rate ratio (IRR) of 0.7 for patients treated with anti-TNF agents, compared with those treated with nonbiologic disease-modifying antirheumatic drugs.

And in CORRONA, which includes 15,000 RA patients, the adjusted IRR for skin cancer was 2.10, whereas that for lymphoma was 0.74 and that for all cancers was 1.05, according to Dr. Greenberg.

"I think the take-home message of the observational studies is that it's the nonmelanoma skin cancers and possibly the melanomas that are the greatest concern, not the lymphomas," he said.

However, the discrepancy between the findings of the meta-analysis and those of the observational studies remains to be explained, Dr. Greenberg said.

"Frankly, I think they could not be more conflicting. It may be that there is a group of patients with subclinical neoplasms, including lymphomas, that any immunosuppressive or immunomodulatory treatment may unmask or accelerate. We probably should be screening for these cancers more aggressively regardless of treatment," he said.

NEW YORK — The greatest malignancy risk in patients receiving tumor necrosis factor antagonists is skin cancer, Dr. Jeffrey Greenberg said at a rheumatology meeting sponsored by New York University.

However, data conflict as to how great malignancy risk is overall for these patients.

Two years ago, a widely noted systematic review and meta-analysis found a threefold increased risk for malignancy in patients with rheumatoid arthritis (RA) treated with infliximab or adalimumab (JAMA 2006;295:2275–85). The meta-analysis included nine randomized, placebo-controlled trials, with 3,493 RA patients who received an active drug and 1,512 RA patients who received placebo.

In the anti-tumor necrosis factor (TNF) arms of this analysis, there were 10 lymphomas, nine nonmelanoma skin cancers, and 12 assorted other cancers, Dr. Greenberg said. "What was most interesting was the cancers that weren't found in the placebo arms—there were two basal cell cancers and one solid tumor—and that's it," he said, adding that in a group of 1,500 RA patients, 8–10 malignancies would be expected.

Aside from the lower-than-expected rates of malignancy in the placebo arms, the meta-analysis had other limitations, according to Dr. Greenberg of New York University, New York, who is chief scientific officer of the Consortium of Rheumatology Researchers of North America (CORRONA).

Among these limitations were the exclusion of etanercept; the association of higher-than-usual doses of infliximab with most malignancies; and the fact that the investigators used a per-patient analysis rather than person-years of drug exposure. Their approach assumes equal time exposure for placebo and the anti-TNF drugs, and four of the nine trials had higher placebo dropout rates.

"Patients on placebo who drop out are not followed for long periods of time looking for malignancies, so of course they are going to have fewer events," he added.

However, a different picture is emerging from observational studies and RA registries in the United States and Europe. In three Swedish registries—one prevalent cohort that included 53,067 patients, one incident cohort that included 3,703 patients, and one TNF antagonist-treated cohort of 4,160 patients—RA patients treated with TNF blockers had a tripled lymphoma risk, compared with the general population. However, after adjustment for sex, age, and disease duration, the lymphoma risk among TNF antagonist-treated patients was no higher than in the other RA cohorts (Ann. Rheum. Dis. 2005;64:1414–20).

In a report from the National Data Bank for Rheumatic Diseases, when RA patients were compared with the general population from the National Cancer Institute's Surveillance, Epidemiology, and End Results database, there was no increased rate of cancer overall, but lymphoma and melanoma were increased, with both having standardized incidence ratios of 1.7. However, only nonmelanoma skin cancer and melanoma were increased among patients on biologics, with odds ratios of 1.5 and 2.3, respectively. No other malignancy was significantly associated with biologic use (Arthritis Rheum. 2007;56:2886–95).

Data from the British Biologics Register also found no increase in malignancy rate, with an adjusted incidence rate ratio (IRR) of 0.7 for patients treated with anti-TNF agents, compared with those treated with nonbiologic disease-modifying antirheumatic drugs.

And in CORRONA, which includes 15,000 RA patients, the adjusted IRR for skin cancer was 2.10, whereas that for lymphoma was 0.74 and that for all cancers was 1.05, according to Dr. Greenberg.

"I think the take-home message of the observational studies is that it's the nonmelanoma skin cancers and possibly the melanomas that are the greatest concern, not the lymphomas," he said.

However, the discrepancy between the findings of the meta-analysis and those of the observational studies remains to be explained, Dr. Greenberg said.

"Frankly, I think they could not be more conflicting. It may be that there is a group of patients with subclinical neoplasms, including lymphomas, that any immunosuppressive or immunomodulatory treatment may unmask or accelerate. We probably should be screening for these cancers more aggressively regardless of treatment," he said.

VANCOUVER, B.C. — A new study finds that the local anesthesia used for Mohs surgery appears to be safe, with serum levels of lidocaine remaining well below the threshold for toxicity and an absence of any drug-related adverse events.

Although Mohs procedures are routinely performed using lidocaine anesthesia without any complications, few studies have looked at lidocaine levels specifically in this context, said study author Dr. Murad Alam, chief of cutaneous and aesthetic surgery at Northwestern University, Chicago.

Research on tumescent anesthesia suggests that a greater vascular supply above the clavicle promotes faster systemic absorption of lidocaine (Plast. Reconstr. Surg. 2005;115:1744–51). The concentration of lidocaine in the anesthesia used for Mohs surgery is 5–10 times that of tumescent anesthesia.

The prospective cohort study, reported at the annual meeting of the American College of Mohs Surgery, took place among 20 consecutive adults undergoing Mohs surgery with local anesthesia for nonmelanoma skin cancer. The anesthesia consisted of a lidocaine solution (concentration, 1:100) also containing epinephrine (1:100,000) and 8.4% sodium bicarbonate (1:10); it was injected at the start of each stage of Mohs surgery. Blood was drawn from the patient's arm before and after each of three stages (or two stages plus closure), for a total of six sampling time points over roughly 5 hours.

Serum lidocaine levels were measured by gas chromatography, and both patients and physicians assessed the occurrence of adverse events.

Dr. Alam explained that mild symptoms of lidocaine toxicity occur when the serum level of the drug reaches 3 mcg/mL; moderate symptoms when the level exceeds 5 mcg/mL; and severe and potentially life threatening symptoms when the level exceeds 10 mcg/mL.

Study results indicated that across all time points, lidocaine levels were detectable (greater than 0.1 mcg/mL) in just five (25%) of the patients.

"Even in the worst-case scenario—the sixth and final time point, where you would expect the serum lidocaine level to be the highest because of the cumulated dosage to that point—only 5 of the 20 patients had a detectable serum lidocaine level," Dr. Alam remarked.

Furthermore, the median level for the cohort was undetectable at all time points.

"Assuming the vast majority of patients did absolutely fine, were there some patients who had very high levels and got into trouble? Again, the answer is no," Dr. Alam asserted.

Of all patients, the highest peak serum lidocaine level observed was 0.3 mcg/mL noted during the last three time points. "That is still one-tenth of the amount for even mild symptoms to occur," he pointed out.

When patients who did and did not have detectable serum lidocaine levels were compared, those with detectable levels had been injected with a significantly greater mean volume of lidocaine solution (30 vs. 9.5 mL). They were also significantly older (68.6 vs. 50.7 years) and somewhat more likely to be male, although Dr. Alam cautioned "this might just mean that older men have larger tumors."

A final analysis showed that peak serum lidocaine levels were well correlated with the total volume of solution injected.

Adverse events were reported by two patients—a 56-year-old man who reported a mild headache and a 42-year-old woman who reported feeling shaky. "Both were after the first Mohs stage, and so they were much more likely to be epinephrine effects than lidocaine effects, which would be expected to happen after a lot of lidocaine was injected," Dr. Alam observed. No adverse events related to the drug were noted.

"There was no case in which serious adverse events or even mild adverse events associated with lidocaine toxicity were seen, which suggests what we already knew to be true based on experience—that local anesthesia given during Mohs surgery appears to be safe," Dr. Alam concluded.

He reported having no conflicts of interest in association with the study.

No patient in the study experienced adverse events associated with lidocaine toxicity. DR. ALAM

VANCOUVER, B.C. — A new study finds that the local anesthesia used for Mohs surgery appears to be safe, with serum levels of lidocaine remaining well below the threshold for toxicity and an absence of any drug-related adverse events.

Although Mohs procedures are routinely performed using lidocaine anesthesia without any complications, few studies have looked at lidocaine levels specifically in this context, said study author Dr. Murad Alam, chief of cutaneous and aesthetic surgery at Northwestern University, Chicago.

Research on tumescent anesthesia suggests that a greater vascular supply above the clavicle promotes faster systemic absorption of lidocaine (Plast. Reconstr. Surg. 2005;115:1744–51). The concentration of lidocaine in the anesthesia used for Mohs surgery is 5–10 times that of tumescent anesthesia.

The prospective cohort study, reported at the annual meeting of the American College of Mohs Surgery, took place among 20 consecutive adults undergoing Mohs surgery with local anesthesia for nonmelanoma skin cancer. The anesthesia consisted of a lidocaine solution (concentration, 1:100) also containing epinephrine (1:100,000) and 8.4% sodium bicarbonate (1:10); it was injected at the start of each stage of Mohs surgery. Blood was drawn from the patient's arm before and after each of three stages (or two stages plus closure), for a total of six sampling time points over roughly 5 hours.

Serum lidocaine levels were measured by gas chromatography, and both patients and physicians assessed the occurrence of adverse events.

Dr. Alam explained that mild symptoms of lidocaine toxicity occur when the serum level of the drug reaches 3 mcg/mL; moderate symptoms when the level exceeds 5 mcg/mL; and severe and potentially life threatening symptoms when the level exceeds 10 mcg/mL.

Study results indicated that across all time points, lidocaine levels were detectable (greater than 0.1 mcg/mL) in just five (25%) of the patients.

"Even in the worst-case scenario—the sixth and final time point, where you would expect the serum lidocaine level to be the highest because of the cumulated dosage to that point—only 5 of the 20 patients had a detectable serum lidocaine level," Dr. Alam remarked.

Furthermore, the median level for the cohort was undetectable at all time points.

"Assuming the vast majority of patients did absolutely fine, were there some patients who had very high levels and got into trouble? Again, the answer is no," Dr. Alam asserted.

Of all patients, the highest peak serum lidocaine level observed was 0.3 mcg/mL noted during the last three time points. "That is still one-tenth of the amount for even mild symptoms to occur," he pointed out.

When patients who did and did not have detectable serum lidocaine levels were compared, those with detectable levels had been injected with a significantly greater mean volume of lidocaine solution (30 vs. 9.5 mL). They were also significantly older (68.6 vs. 50.7 years) and somewhat more likely to be male, although Dr. Alam cautioned "this might just mean that older men have larger tumors."

A final analysis showed that peak serum lidocaine levels were well correlated with the total volume of solution injected.

Adverse events were reported by two patients—a 56-year-old man who reported a mild headache and a 42-year-old woman who reported feeling shaky. "Both were after the first Mohs stage, and so they were much more likely to be epinephrine effects than lidocaine effects, which would be expected to happen after a lot of lidocaine was injected," Dr. Alam observed. No adverse events related to the drug were noted.

"There was no case in which serious adverse events or even mild adverse events associated with lidocaine toxicity were seen, which suggests what we already knew to be true based on experience—that local anesthesia given during Mohs surgery appears to be safe," Dr. Alam concluded.

He reported having no conflicts of interest in association with the study.

No patient in the study experienced adverse events associated with lidocaine toxicity. DR. ALAM

VANCOUVER, B.C. — A new study finds that the local anesthesia used for Mohs surgery appears to be safe, with serum levels of lidocaine remaining well below the threshold for toxicity and an absence of any drug-related adverse events.

Although Mohs procedures are routinely performed using lidocaine anesthesia without any complications, few studies have looked at lidocaine levels specifically in this context, said study author Dr. Murad Alam, chief of cutaneous and aesthetic surgery at Northwestern University, Chicago.

Research on tumescent anesthesia suggests that a greater vascular supply above the clavicle promotes faster systemic absorption of lidocaine (Plast. Reconstr. Surg. 2005;115:1744–51). The concentration of lidocaine in the anesthesia used for Mohs surgery is 5–10 times that of tumescent anesthesia.

The prospective cohort study, reported at the annual meeting of the American College of Mohs Surgery, took place among 20 consecutive adults undergoing Mohs surgery with local anesthesia for nonmelanoma skin cancer. The anesthesia consisted of a lidocaine solution (concentration, 1:100) also containing epinephrine (1:100,000) and 8.4% sodium bicarbonate (1:10); it was injected at the start of each stage of Mohs surgery. Blood was drawn from the patient's arm before and after each of three stages (or two stages plus closure), for a total of six sampling time points over roughly 5 hours.

Serum lidocaine levels were measured by gas chromatography, and both patients and physicians assessed the occurrence of adverse events.

Dr. Alam explained that mild symptoms of lidocaine toxicity occur when the serum level of the drug reaches 3 mcg/mL; moderate symptoms when the level exceeds 5 mcg/mL; and severe and potentially life threatening symptoms when the level exceeds 10 mcg/mL.

Study results indicated that across all time points, lidocaine levels were detectable (greater than 0.1 mcg/mL) in just five (25%) of the patients.

"Even in the worst-case scenario—the sixth and final time point, where you would expect the serum lidocaine level to be the highest because of the cumulated dosage to that point—only 5 of the 20 patients had a detectable serum lidocaine level," Dr. Alam remarked.

Furthermore, the median level for the cohort was undetectable at all time points.

"Assuming the vast majority of patients did absolutely fine, were there some patients who had very high levels and got into trouble? Again, the answer is no," Dr. Alam asserted.

Of all patients, the highest peak serum lidocaine level observed was 0.3 mcg/mL noted during the last three time points. "That is still one-tenth of the amount for even mild symptoms to occur," he pointed out.

When patients who did and did not have detectable serum lidocaine levels were compared, those with detectable levels had been injected with a significantly greater mean volume of lidocaine solution (30 vs. 9.5 mL). They were also significantly older (68.6 vs. 50.7 years) and somewhat more likely to be male, although Dr. Alam cautioned "this might just mean that older men have larger tumors."

A final analysis showed that peak serum lidocaine levels were well correlated with the total volume of solution injected.

Adverse events were reported by two patients—a 56-year-old man who reported a mild headache and a 42-year-old woman who reported feeling shaky. "Both were after the first Mohs stage, and so they were much more likely to be epinephrine effects than lidocaine effects, which would be expected to happen after a lot of lidocaine was injected," Dr. Alam observed. No adverse events related to the drug were noted.

"There was no case in which serious adverse events or even mild adverse events associated with lidocaine toxicity were seen, which suggests what we already knew to be true based on experience—that local anesthesia given during Mohs surgery appears to be safe," Dr. Alam concluded.

He reported having no conflicts of interest in association with the study.

No patient in the study experienced adverse events associated with lidocaine toxicity. DR. ALAM

VANCOUVER, B.C. — Some patients undergoing Mohs micrographic surgery have undiagnosed bleeding disorders, but careful history taking, vigilance during surgery, and tailored management can prevent complications in most cases, according to results of a study of more than 2,500 patients.

Dr. Carl Vinciullo and his colleague, Dr. Ross Baker, both of Royal Perth Hospital in Australia, prospectively assessed the prevalence of bleeding disorders among 2,517 patients undergoing Mohs surgery between 2003 and 2007. The investigators obtained a detailed bleeding history from all patients and performed a hematologic workup in those who had a positive history or who had unexplained excessive bleeding during their Mohs surgery.

A total of 18 patients (0.7%) had a previously undiagnosed bleeding disorder. Eleven of them had a positive bleeding history, while seven had a negative history but bled excessively during surgery. Dr. Vinciullo noted that most of the affected patients had normal routine coagulation profiles on hematologic testing and that one patient had even undergone general surgery uneventfully 2 years earlier.

The hematologic workup further revealed that 6 of the 18 patients had von Willebrand disease (alone or with other abnormalities), three had acquired platelet abnormalities with myelodysplasia and other abnormalities, two had suspected increased capillary fragility, one had a clopidogrel-like platelet secretion defect, and one had suspected impaired vasoconstriction with hereditary hemorrhagic telangiectasia.

Another two patients—one with refractory immune thrombocytopenia and antiplatelet antibodies, and another with disseminated intravascular coagulation, thrombocytopenia, and cancer-associated fibrinogen deficiency—were treated with radiation therapy instead because their disorders were judged to be contraindications to surgery.

Finally, three of the patients had no definable hematologic abnormality. "This does not mean that they do not have a bleeding abnormality," Dr. Vinciullo said of the last group. "It is quite conceivable that there are bleeding abnormalities which are yet not possible to define with the investigations available to us."

Among the patients who were surgical candidates, those with von Willebrand disease were treated with preoperative desmopressin infusion, oral tranexamic acid, or a combination thereof. Those with platelet function abnormalities were all treated with preoperative platelet infusions; one also received desmopressin, and another also received additional platelet cross-matching, recombinant factor VIIa, and tranexamic acid. The remaining patients were given tranexamic acid or were not treated, Dr. Vinciullo reported at the annual meeting of the American College of Mohs Surgery.

With this management approach, 17 of the 18 patients did not experience initial or additional excessive bleeding and did not require further intervention, according to Dr. Vinciullo. The remaining patient, who had an acquired platelet function abnormality, antiplatelet antibodies, low factor XII levels, and myelodysplasia, was hospitalized for 3 days because of surgery-associated bleeding, despite all measures.

Summing up the study's findings, Dr. Vinciullo said that the incidence of undiagnosed bleeding disorders is low in Mohs surgical patients, but physicians nonetheless should be alert for such disorders—even when a bleeding history is negative and the results of routine coagulation studies are normal.

"Hematology assessment is essential, and specialized prophylactic treatment can prevent the vast majority of bleeding complications," he said.

However, he added, routine preoperative hematologic testing is not warranted in patients with a negative bleeding history. "The most sensitive sign is a positive history, so you must take a detailed bleeding history," he emphasized. (See box.) "The sort of questions I listed are the questions you need to ask. It's absolutely incredible how many of these patients have simply never been asked those questions, or the physician knows they bleed but has never done anything about it."

Finally, Dr. Vinciullo advised, "unexplained excessive bleeding during Mohs surgery should be investigated." He noted that a watery consistency of the blood and bleeding from suture holes can be additional telltale signs of underlying bleeding disorders.

"If you have a patient where you place a stitch and blood comes out of the suture hole, to me, that's a reason to send [that person] off for a hematology investigation," he said.

Dr. Vinciullo reported no conflicts of interest in association with the study.

'Hematology assessment is essential, and specialized prophylactic treatment can prevent' bleeding. DR. VINCIULLO

Take a Detailed Bleeding History

Ask patients if they have had excessive bleeding during any of the following:

▸ Menstrual periods or childbirth?

▸ Nosebleeds?

▸ Skin surgery?

▸ Dental work, tonsillectomy, or general surgery? And also ask:

▸ Have you had to return to a physician's office or hospital because of bleeding?

▸ Do you bruise excessively?

▸ Do you take supplements or complementary products (vitamin E, garlic, ginkgo biloba)?

▸ Do you have a family history of bleeding, hemophilia, or von Willebrand disease?

▸ Do you have any blood disorders or leukemia?

Source: Dr. Vinciullo

VANCOUVER, B.C. — Some patients undergoing Mohs micrographic surgery have undiagnosed bleeding disorders, but careful history taking, vigilance during surgery, and tailored management can prevent complications in most cases, according to results of a study of more than 2,500 patients.

Dr. Carl Vinciullo and his colleague, Dr. Ross Baker, both of Royal Perth Hospital in Australia, prospectively assessed the prevalence of bleeding disorders among 2,517 patients undergoing Mohs surgery between 2003 and 2007. The investigators obtained a detailed bleeding history from all patients and performed a hematologic workup in those who had a positive history or who had unexplained excessive bleeding during their Mohs surgery.

A total of 18 patients (0.7%) had a previously undiagnosed bleeding disorder. Eleven of them had a positive bleeding history, while seven had a negative history but bled excessively during surgery. Dr. Vinciullo noted that most of the affected patients had normal routine coagulation profiles on hematologic testing and that one patient had even undergone general surgery uneventfully 2 years earlier.

The hematologic workup further revealed that 6 of the 18 patients had von Willebrand disease (alone or with other abnormalities), three had acquired platelet abnormalities with myelodysplasia and other abnormalities, two had suspected increased capillary fragility, one had a clopidogrel-like platelet secretion defect, and one had suspected impaired vasoconstriction with hereditary hemorrhagic telangiectasia.

Another two patients—one with refractory immune thrombocytopenia and antiplatelet antibodies, and another with disseminated intravascular coagulation, thrombocytopenia, and cancer-associated fibrinogen deficiency—were treated with radiation therapy instead because their disorders were judged to be contraindications to surgery.

Finally, three of the patients had no definable hematologic abnormality. "This does not mean that they do not have a bleeding abnormality," Dr. Vinciullo said of the last group. "It is quite conceivable that there are bleeding abnormalities which are yet not possible to define with the investigations available to us."

Among the patients who were surgical candidates, those with von Willebrand disease were treated with preoperative desmopressin infusion, oral tranexamic acid, or a combination thereof. Those with platelet function abnormalities were all treated with preoperative platelet infusions; one also received desmopressin, and another also received additional platelet cross-matching, recombinant factor VIIa, and tranexamic acid. The remaining patients were given tranexamic acid or were not treated, Dr. Vinciullo reported at the annual meeting of the American College of Mohs Surgery.

With this management approach, 17 of the 18 patients did not experience initial or additional excessive bleeding and did not require further intervention, according to Dr. Vinciullo. The remaining patient, who had an acquired platelet function abnormality, antiplatelet antibodies, low factor XII levels, and myelodysplasia, was hospitalized for 3 days because of surgery-associated bleeding, despite all measures.

Summing up the study's findings, Dr. Vinciullo said that the incidence of undiagnosed bleeding disorders is low in Mohs surgical patients, but physicians nonetheless should be alert for such disorders—even when a bleeding history is negative and the results of routine coagulation studies are normal.

"Hematology assessment is essential, and specialized prophylactic treatment can prevent the vast majority of bleeding complications," he said.

However, he added, routine preoperative hematologic testing is not warranted in patients with a negative bleeding history. "The most sensitive sign is a positive history, so you must take a detailed bleeding history," he emphasized. (See box.) "The sort of questions I listed are the questions you need to ask. It's absolutely incredible how many of these patients have simply never been asked those questions, or the physician knows they bleed but has never done anything about it."

Finally, Dr. Vinciullo advised, "unexplained excessive bleeding during Mohs surgery should be investigated." He noted that a watery consistency of the blood and bleeding from suture holes can be additional telltale signs of underlying bleeding disorders.

"If you have a patient where you place a stitch and blood comes out of the suture hole, to me, that's a reason to send [that person] off for a hematology investigation," he said.

Dr. Vinciullo reported no conflicts of interest in association with the study.

'Hematology assessment is essential, and specialized prophylactic treatment can prevent' bleeding. DR. VINCIULLO

Take a Detailed Bleeding History

Ask patients if they have had excessive bleeding during any of the following:

▸ Menstrual periods or childbirth?

▸ Nosebleeds?

▸ Skin surgery?

▸ Dental work, tonsillectomy, or general surgery? And also ask:

▸ Have you had to return to a physician's office or hospital because of bleeding?

▸ Do you bruise excessively?

▸ Do you take supplements or complementary products (vitamin E, garlic, ginkgo biloba)?

▸ Do you have a family history of bleeding, hemophilia, or von Willebrand disease?

▸ Do you have any blood disorders or leukemia?

Source: Dr. Vinciullo

VANCOUVER, B.C. — Some patients undergoing Mohs micrographic surgery have undiagnosed bleeding disorders, but careful history taking, vigilance during surgery, and tailored management can prevent complications in most cases, according to results of a study of more than 2,500 patients.

Dr. Carl Vinciullo and his colleague, Dr. Ross Baker, both of Royal Perth Hospital in Australia, prospectively assessed the prevalence of bleeding disorders among 2,517 patients undergoing Mohs surgery between 2003 and 2007. The investigators obtained a detailed bleeding history from all patients and performed a hematologic workup in those who had a positive history or who had unexplained excessive bleeding during their Mohs surgery.

A total of 18 patients (0.7%) had a previously undiagnosed bleeding disorder. Eleven of them had a positive bleeding history, while seven had a negative history but bled excessively during surgery. Dr. Vinciullo noted that most of the affected patients had normal routine coagulation profiles on hematologic testing and that one patient had even undergone general surgery uneventfully 2 years earlier.

The hematologic workup further revealed that 6 of the 18 patients had von Willebrand disease (alone or with other abnormalities), three had acquired platelet abnormalities with myelodysplasia and other abnormalities, two had suspected increased capillary fragility, one had a clopidogrel-like platelet secretion defect, and one had suspected impaired vasoconstriction with hereditary hemorrhagic telangiectasia.

Another two patients—one with refractory immune thrombocytopenia and antiplatelet antibodies, and another with disseminated intravascular coagulation, thrombocytopenia, and cancer-associated fibrinogen deficiency—were treated with radiation therapy instead because their disorders were judged to be contraindications to surgery.

Finally, three of the patients had no definable hematologic abnormality. "This does not mean that they do not have a bleeding abnormality," Dr. Vinciullo said of the last group. "It is quite conceivable that there are bleeding abnormalities which are yet not possible to define with the investigations available to us."

Among the patients who were surgical candidates, those with von Willebrand disease were treated with preoperative desmopressin infusion, oral tranexamic acid, or a combination thereof. Those with platelet function abnormalities were all treated with preoperative platelet infusions; one also received desmopressin, and another also received additional platelet cross-matching, recombinant factor VIIa, and tranexamic acid. The remaining patients were given tranexamic acid or were not treated, Dr. Vinciullo reported at the annual meeting of the American College of Mohs Surgery.

With this management approach, 17 of the 18 patients did not experience initial or additional excessive bleeding and did not require further intervention, according to Dr. Vinciullo. The remaining patient, who had an acquired platelet function abnormality, antiplatelet antibodies, low factor XII levels, and myelodysplasia, was hospitalized for 3 days because of surgery-associated bleeding, despite all measures.

Summing up the study's findings, Dr. Vinciullo said that the incidence of undiagnosed bleeding disorders is low in Mohs surgical patients, but physicians nonetheless should be alert for such disorders—even when a bleeding history is negative and the results of routine coagulation studies are normal.

"Hematology assessment is essential, and specialized prophylactic treatment can prevent the vast majority of bleeding complications," he said.

However, he added, routine preoperative hematologic testing is not warranted in patients with a negative bleeding history. "The most sensitive sign is a positive history, so you must take a detailed bleeding history," he emphasized. (See box.) "The sort of questions I listed are the questions you need to ask. It's absolutely incredible how many of these patients have simply never been asked those questions, or the physician knows they bleed but has never done anything about it."

Finally, Dr. Vinciullo advised, "unexplained excessive bleeding during Mohs surgery should be investigated." He noted that a watery consistency of the blood and bleeding from suture holes can be additional telltale signs of underlying bleeding disorders.

"If you have a patient where you place a stitch and blood comes out of the suture hole, to me, that's a reason to send [that person] off for a hematology investigation," he said.

Dr. Vinciullo reported no conflicts of interest in association with the study.

'Hematology assessment is essential, and specialized prophylactic treatment can prevent' bleeding. DR. VINCIULLO

Take a Detailed Bleeding History

Ask patients if they have had excessive bleeding during any of the following:

▸ Menstrual periods or childbirth?

▸ Nosebleeds?

▸ Skin surgery?

▸ Dental work, tonsillectomy, or general surgery? And also ask:

▸ Have you had to return to a physician's office or hospital because of bleeding?

▸ Do you bruise excessively?

▸ Do you take supplements or complementary products (vitamin E, garlic, ginkgo biloba)?

▸ Do you have a family history of bleeding, hemophilia, or von Willebrand disease?

▸ Do you have any blood disorders or leukemia?

Source: Dr. Vinciullo

CHICAGO — The modified Keystone Island skin flap avoids the need for skin grafting in most patients with lower limb primary melanoma, a prospective study from Australia suggests.

The flap, which takes its name from architectural terminology because of its curvilinear, trapezoidal shape, is technically straightforward to perform, substantially reduces hospitalization, and affords better cosmesis compared with skin grafting, investigator Marc Moncrieff said at a symposium sponsored by the Society of Surgical Oncology. The flap also can be used in patients with significant comorbidities that are often regarded as contraindications for fasciocutaneous flap reconstruction in the lower limb.

"Defects resulting from incision of primary melanomas in the lower limb can usually be reconstructed using the modified Keystone flap," he said. "In our experience, a skin graft is rarely required."

Dr. Moncrieff and associates reported on a prospective cohort of 176 consecutive patients, mean age 57 years (range 21–93), with stage I or II invasive primary cutaneous melanoma treated over a 3-year-period at the Sydney Melanoma Unit, where Dr. Moncrieff is a fellow and the Keystone flap is the standard reconstruction technique for lower limb primary melanoma defects.

Major complications were reported in 5 (2.8%) patients. These included one partial flap necrosis, one total flap loss, two infections, and one deep vein thrombosis. Minor complications, including transient neuralgia, minor wound problems, and seroma, were reported in 8 patients (4.5%).

At baseline, the average Breslow thickness was 1.33 mm (range in situ to 9.0 mm), average radial margin 1.5 cm (0.5–2.0 cm), and average defect width 3 cm (1.1–6.3 cm).

The flaps were performed from the proximal lower leg to the dorsum of the foot, with 14% performed on the upper-third of the lower leg, 45% on the middle-third, and 41% on the lower-third. There was no significant increase in complications in the distal third of the limb, a traditionally difficult area to close because of its anatomical tightness, he said.

The reconstructions included 106 standard Keystone flaps, 65 modified, and 5 double-opposing type flaps. Modification of the flap design significantly reduced the major complication rate, and all double-opposing flaps healed without incident.

The standard Keystone flap originally reported by fellow Australian Dr. Felix Behan (ANZ J Surg. 2003;73:112–20) is essentially two conjoined V-Y flaps end to side that are advanced to fill the defect.

Surgeons at the Sydney Melanoma Unit modified the flap by dividing the lateral deep fascia margin to allow for adequate advancement of the flap and to improve vascularity. For larger defects, two opposing Keystone flaps can be used to fill the defect. In all three types, once the skin is incised, the subcutaneous tissue is divided by blunt dissection to preserve the integrity of the vascular network, including the fascial and muscular perforators.

Because the skin is taken from the surrounding tissue, the color match is superior to that of split-thickness skin grafts, which are typically taken from the abdomen, and can result in a crocodile-like appearance of the skin and lengthy rehabilitation, Dr. Moncrieff said.

Dr. Michael Sabel, session moderator, acknowledged that the Keystone flap is "a great improvement" over the split-thickness skin graft, but that the full-thickness skin graft is a simple and widely used technique that provides well-matched tissue from the sentinel lymph node biopsy site or abdomen, with its main disadvantage being that patients are typically immobilized for 5 days.

Dr. Moncrieff responded that the Keystone flap can be performed in the same amount of time as a full-thickness graft and that most patients elevate their limb overnight and return home and walk the next day. Of the 176 patients, 39 (22%) had the procedure performed in a day-case setting.

An audience member questioned whether the technique can be used to fill larger defects or upper limb defects. The modified Keystone flap has been used to reconstruct distal upper limb defects, and requires no special allowances when closing larger defects, said Dr. Moncrieff, who reported no conflicts of interest.

CHICAGO — The modified Keystone Island skin flap avoids the need for skin grafting in most patients with lower limb primary melanoma, a prospective study from Australia suggests.

The flap, which takes its name from architectural terminology because of its curvilinear, trapezoidal shape, is technically straightforward to perform, substantially reduces hospitalization, and affords better cosmesis compared with skin grafting, investigator Marc Moncrieff said at a symposium sponsored by the Society of Surgical Oncology. The flap also can be used in patients with significant comorbidities that are often regarded as contraindications for fasciocutaneous flap reconstruction in the lower limb.

"Defects resulting from incision of primary melanomas in the lower limb can usually be reconstructed using the modified Keystone flap," he said. "In our experience, a skin graft is rarely required."

Dr. Moncrieff and associates reported on a prospective cohort of 176 consecutive patients, mean age 57 years (range 21–93), with stage I or II invasive primary cutaneous melanoma treated over a 3-year-period at the Sydney Melanoma Unit, where Dr. Moncrieff is a fellow and the Keystone flap is the standard reconstruction technique for lower limb primary melanoma defects.

Major complications were reported in 5 (2.8%) patients. These included one partial flap necrosis, one total flap loss, two infections, and one deep vein thrombosis. Minor complications, including transient neuralgia, minor wound problems, and seroma, were reported in 8 patients (4.5%).

At baseline, the average Breslow thickness was 1.33 mm (range in situ to 9.0 mm), average radial margin 1.5 cm (0.5–2.0 cm), and average defect width 3 cm (1.1–6.3 cm).

The flaps were performed from the proximal lower leg to the dorsum of the foot, with 14% performed on the upper-third of the lower leg, 45% on the middle-third, and 41% on the lower-third. There was no significant increase in complications in the distal third of the limb, a traditionally difficult area to close because of its anatomical tightness, he said.

The reconstructions included 106 standard Keystone flaps, 65 modified, and 5 double-opposing type flaps. Modification of the flap design significantly reduced the major complication rate, and all double-opposing flaps healed without incident.

The standard Keystone flap originally reported by fellow Australian Dr. Felix Behan (ANZ J Surg. 2003;73:112–20) is essentially two conjoined V-Y flaps end to side that are advanced to fill the defect.

Surgeons at the Sydney Melanoma Unit modified the flap by dividing the lateral deep fascia margin to allow for adequate advancement of the flap and to improve vascularity. For larger defects, two opposing Keystone flaps can be used to fill the defect. In all three types, once the skin is incised, the subcutaneous tissue is divided by blunt dissection to preserve the integrity of the vascular network, including the fascial and muscular perforators.

Because the skin is taken from the surrounding tissue, the color match is superior to that of split-thickness skin grafts, which are typically taken from the abdomen, and can result in a crocodile-like appearance of the skin and lengthy rehabilitation, Dr. Moncrieff said.

Dr. Michael Sabel, session moderator, acknowledged that the Keystone flap is "a great improvement" over the split-thickness skin graft, but that the full-thickness skin graft is a simple and widely used technique that provides well-matched tissue from the sentinel lymph node biopsy site or abdomen, with its main disadvantage being that patients are typically immobilized for 5 days.

Dr. Moncrieff responded that the Keystone flap can be performed in the same amount of time as a full-thickness graft and that most patients elevate their limb overnight and return home and walk the next day. Of the 176 patients, 39 (22%) had the procedure performed in a day-case setting.

An audience member questioned whether the technique can be used to fill larger defects or upper limb defects. The modified Keystone flap has been used to reconstruct distal upper limb defects, and requires no special allowances when closing larger defects, said Dr. Moncrieff, who reported no conflicts of interest.

CHICAGO — The modified Keystone Island skin flap avoids the need for skin grafting in most patients with lower limb primary melanoma, a prospective study from Australia suggests.

The flap, which takes its name from architectural terminology because of its curvilinear, trapezoidal shape, is technically straightforward to perform, substantially reduces hospitalization, and affords better cosmesis compared with skin grafting, investigator Marc Moncrieff said at a symposium sponsored by the Society of Surgical Oncology. The flap also can be used in patients with significant comorbidities that are often regarded as contraindications for fasciocutaneous flap reconstruction in the lower limb.

"Defects resulting from incision of primary melanomas in the lower limb can usually be reconstructed using the modified Keystone flap," he said. "In our experience, a skin graft is rarely required."

Dr. Moncrieff and associates reported on a prospective cohort of 176 consecutive patients, mean age 57 years (range 21–93), with stage I or II invasive primary cutaneous melanoma treated over a 3-year-period at the Sydney Melanoma Unit, where Dr. Moncrieff is a fellow and the Keystone flap is the standard reconstruction technique for lower limb primary melanoma defects.

Major complications were reported in 5 (2.8%) patients. These included one partial flap necrosis, one total flap loss, two infections, and one deep vein thrombosis. Minor complications, including transient neuralgia, minor wound problems, and seroma, were reported in 8 patients (4.5%).

At baseline, the average Breslow thickness was 1.33 mm (range in situ to 9.0 mm), average radial margin 1.5 cm (0.5–2.0 cm), and average defect width 3 cm (1.1–6.3 cm).

The flaps were performed from the proximal lower leg to the dorsum of the foot, with 14% performed on the upper-third of the lower leg, 45% on the middle-third, and 41% on the lower-third. There was no significant increase in complications in the distal third of the limb, a traditionally difficult area to close because of its anatomical tightness, he said.

The reconstructions included 106 standard Keystone flaps, 65 modified, and 5 double-opposing type flaps. Modification of the flap design significantly reduced the major complication rate, and all double-opposing flaps healed without incident.

The standard Keystone flap originally reported by fellow Australian Dr. Felix Behan (ANZ J Surg. 2003;73:112–20) is essentially two conjoined V-Y flaps end to side that are advanced to fill the defect.

Surgeons at the Sydney Melanoma Unit modified the flap by dividing the lateral deep fascia margin to allow for adequate advancement of the flap and to improve vascularity. For larger defects, two opposing Keystone flaps can be used to fill the defect. In all three types, once the skin is incised, the subcutaneous tissue is divided by blunt dissection to preserve the integrity of the vascular network, including the fascial and muscular perforators.

Because the skin is taken from the surrounding tissue, the color match is superior to that of split-thickness skin grafts, which are typically taken from the abdomen, and can result in a crocodile-like appearance of the skin and lengthy rehabilitation, Dr. Moncrieff said.

Dr. Michael Sabel, session moderator, acknowledged that the Keystone flap is "a great improvement" over the split-thickness skin graft, but that the full-thickness skin graft is a simple and widely used technique that provides well-matched tissue from the sentinel lymph node biopsy site or abdomen, with its main disadvantage being that patients are typically immobilized for 5 days.

Dr. Moncrieff responded that the Keystone flap can be performed in the same amount of time as a full-thickness graft and that most patients elevate their limb overnight and return home and walk the next day. Of the 176 patients, 39 (22%) had the procedure performed in a day-case setting.

An audience member questioned whether the technique can be used to fill larger defects or upper limb defects. The modified Keystone flap has been used to reconstruct distal upper limb defects, and requires no special allowances when closing larger defects, said Dr. Moncrieff, who reported no conflicts of interest.

The Women's Dermatologic Society has launched a campaign in conjunction with the Ladies' Professional Golf Association to promote proper skin protection during outdoor activities. The campaign, "Play Safe in the Sun," is part of a 3-year outreach program sponsored by L'Oreal USA and involves outreach at a series of LPGA events. The activities include free skin cancer screenings, sun damage assessment, free sunscreen, and sun safety education information for all tournament attendees. In addition, local volunteer dermatologists will provide free, private skin cancer screenings for LPGA players, caddies, and media personnel. For more information, contact the Women's Dermatologic Society by visiting www.womensderm.orgwww.playsafeinthesun.org

The Women's Dermatologic Society has launched a campaign in conjunction with the Ladies' Professional Golf Association to promote proper skin protection during outdoor activities. The campaign, "Play Safe in the Sun," is part of a 3-year outreach program sponsored by L'Oreal USA and involves outreach at a series of LPGA events. The activities include free skin cancer screenings, sun damage assessment, free sunscreen, and sun safety education information for all tournament attendees. In addition, local volunteer dermatologists will provide free, private skin cancer screenings for LPGA players, caddies, and media personnel. For more information, contact the Women's Dermatologic Society by visiting www.womensderm.orgwww.playsafeinthesun.org

The Women's Dermatologic Society has launched a campaign in conjunction with the Ladies' Professional Golf Association to promote proper skin protection during outdoor activities. The campaign, "Play Safe in the Sun," is part of a 3-year outreach program sponsored by L'Oreal USA and involves outreach at a series of LPGA events. The activities include free skin cancer screenings, sun damage assessment, free sunscreen, and sun safety education information for all tournament attendees. In addition, local volunteer dermatologists will provide free, private skin cancer screenings for LPGA players, caddies, and media personnel. For more information, contact the Women's Dermatologic Society by visiting www.womensderm.orgwww.playsafeinthesun.org