Melanoma

BUENOS AIRES — The successful treatment of melanoma in the future is likely to be a two-step process involving combination therapy, Meenhard Herlyn, D.Sc., said in a keynote address at the 21st World Congress of Dermatology.

The aim of the initial treatment will be to debulk the tumor from the major transit-amplifying cells. The second stage will then be to focus on eradication of the cancer stem cells.

"If you do not eliminate these tumor stem cells with therapy, the tumor will come back over and over again," said Dr. Herlyn, professor and program leader in the molecular and cellular oncogenesis program at the Wistar Institute, Philadelphia.

Melanoma arises from malignant transformation of melanocytes or nevus cells, which are formed by overproliferation of melanocytes. Progression from nevi occurs in approximately 50% of melanomas. In normal skin, keratinocytes control the growth of melanocytes in a sort of master-slave relationship.

The decoupling of melanocytes from keratinocytes is the first step in the development of nevi. Overproduction of growth factors from fibroblasts then drives melanocyte proliferation, Dr. Herlyn explained.

For development of melanoma, the most important pathway is the mitogen-activated protein (MAP) kinase pathway, he said.

A genomewide screen performed at the Wellcome Trust Sanger Institute showed that approximately two-thirds of melanomas harbor an activating mutation in BRAF, one of the Raf isoforms in the MAP kinase pathway (Nature 2002;417:949–54).

In 98% of these cases, the BRAF mutation is V600E. A single mutation, however, is not sufficient for the development of melanoma.

Mutations in other signaling pathways, such as the P13-kinase/Akt pathways or cell cycle regulatory pathways, have also been implicated in the development of melanoma, said Dr. Herlyn, who reported no conflicts of interest.

Earlier models of cancer development assumed that melanoma arose as the accumulation of sequential mutations in a mature, differentiated melanocyte eventually leading to malignant transformation of the cell. Identification of another type of cell in melanomas, however, suggests that this model may be too simplistic.

"There are rare cells in tumors that act like stem cells and always replenish the tumor with new cells," said Dr. Herlyn.

The cell that undergoes malignant transformation to produce melanoma might not be a terminally differentiated cell, but instead might be a type of stem cell.

When they are grown under conditions suitable for embryonic stem cells, melanoma cells form spheres that look similar to embryoid bodies formed by human stem cells (Cancer Res. 2005;65:9328–37).

These melanoma spheres meet the definition of tumor stem cells. Melanoma spheres are capable of self-renewal. The cells are highly tumorigenic and quickly form lethal melanomas when injected into nude mice.

They also are multipotent—under laboratory conditions, melanoma spheres can differentiate into melanocytes, adipocytes, chondrocytes, and osteoblasts.

"There is an incredible plasticity in melanoma cells that we have not known before," said Dr. Herlyn. "The question is: What is the true melanoma stem cell?"

Melanoma spheres consist of a mixed cell population. Among the population are cells expressing the hematopoietic marker CD20 and cells expressing the embryonic stem cell marker CD133. Melanoma spheres include side population cells that extrude Hoechst dye via active efflux.

Particularly intriguing are the label-retaining melanoma cells, which proliferate slowly or not at all. When removed from the surrounding cells, however, the label-retaining cells begin to divide rapidly. "If you isolate them, they literally explode," he said.

The label-retaining cells may be the melanoma stem cells, responsible for tumor dormancy and relapse. In this model, the CD20 cells, the CD133 cells, and the side population cells function as progenitor cells.

The label-retaining cells and the progenitor cells could give rise to transit-amplifying cells, Dr. Herlyn suggested at the meeting.

Melanomas are phenotypically heterogeneous tumors. "Tumor heterogeneity is not random," he noted. "Tumor heterogeneity represents a clonal hierarchy in which the different populations compete with each other."

In the center of the hierarchy is the melanoma stem cell. Although melanomas may differ from one patient to the next, they all contain melanoma stem cells. Targeting the stem cell is critical for treatment outcome. "This one cell can give rise to all the others," said Dr. Herlyn. "If we let the cancer stem cell escape, we will always get the cancer back."

Under suitable conditions, melanoma cells form spheres (shown here at 40X magnification) that are capable of self-renewal and are highly tumorigenic. Courtesy Meenhard Herlyn, D.Sc.

'This one cell can give rise to all the others. If we let the cancer stem cell escape, we will always get the cancer back.' DR. HERLYN

BUENOS AIRES — The successful treatment of melanoma in the future is likely to be a two-step process involving combination therapy, Meenhard Herlyn, D.Sc., said in a keynote address at the 21st World Congress of Dermatology.

The aim of the initial treatment will be to debulk the tumor from the major transit-amplifying cells. The second stage will then be to focus on eradication of the cancer stem cells.

"If you do not eliminate these tumor stem cells with therapy, the tumor will come back over and over again," said Dr. Herlyn, professor and program leader in the molecular and cellular oncogenesis program at the Wistar Institute, Philadelphia.

Melanoma arises from malignant transformation of melanocytes or nevus cells, which are formed by overproliferation of melanocytes. Progression from nevi occurs in approximately 50% of melanomas. In normal skin, keratinocytes control the growth of melanocytes in a sort of master-slave relationship.

The decoupling of melanocytes from keratinocytes is the first step in the development of nevi. Overproduction of growth factors from fibroblasts then drives melanocyte proliferation, Dr. Herlyn explained.

For development of melanoma, the most important pathway is the mitogen-activated protein (MAP) kinase pathway, he said.

A genomewide screen performed at the Wellcome Trust Sanger Institute showed that approximately two-thirds of melanomas harbor an activating mutation in BRAF, one of the Raf isoforms in the MAP kinase pathway (Nature 2002;417:949–54).

In 98% of these cases, the BRAF mutation is V600E. A single mutation, however, is not sufficient for the development of melanoma.

Mutations in other signaling pathways, such as the P13-kinase/Akt pathways or cell cycle regulatory pathways, have also been implicated in the development of melanoma, said Dr. Herlyn, who reported no conflicts of interest.

Earlier models of cancer development assumed that melanoma arose as the accumulation of sequential mutations in a mature, differentiated melanocyte eventually leading to malignant transformation of the cell. Identification of another type of cell in melanomas, however, suggests that this model may be too simplistic.

"There are rare cells in tumors that act like stem cells and always replenish the tumor with new cells," said Dr. Herlyn.

The cell that undergoes malignant transformation to produce melanoma might not be a terminally differentiated cell, but instead might be a type of stem cell.

When they are grown under conditions suitable for embryonic stem cells, melanoma cells form spheres that look similar to embryoid bodies formed by human stem cells (Cancer Res. 2005;65:9328–37).

These melanoma spheres meet the definition of tumor stem cells. Melanoma spheres are capable of self-renewal. The cells are highly tumorigenic and quickly form lethal melanomas when injected into nude mice.

They also are multipotent—under laboratory conditions, melanoma spheres can differentiate into melanocytes, adipocytes, chondrocytes, and osteoblasts.

"There is an incredible plasticity in melanoma cells that we have not known before," said Dr. Herlyn. "The question is: What is the true melanoma stem cell?"

Melanoma spheres consist of a mixed cell population. Among the population are cells expressing the hematopoietic marker CD20 and cells expressing the embryonic stem cell marker CD133. Melanoma spheres include side population cells that extrude Hoechst dye via active efflux.

Particularly intriguing are the label-retaining melanoma cells, which proliferate slowly or not at all. When removed from the surrounding cells, however, the label-retaining cells begin to divide rapidly. "If you isolate them, they literally explode," he said.

The label-retaining cells may be the melanoma stem cells, responsible for tumor dormancy and relapse. In this model, the CD20 cells, the CD133 cells, and the side population cells function as progenitor cells.

The label-retaining cells and the progenitor cells could give rise to transit-amplifying cells, Dr. Herlyn suggested at the meeting.

Melanomas are phenotypically heterogeneous tumors. "Tumor heterogeneity is not random," he noted. "Tumor heterogeneity represents a clonal hierarchy in which the different populations compete with each other."

In the center of the hierarchy is the melanoma stem cell. Although melanomas may differ from one patient to the next, they all contain melanoma stem cells. Targeting the stem cell is critical for treatment outcome. "This one cell can give rise to all the others," said Dr. Herlyn. "If we let the cancer stem cell escape, we will always get the cancer back."

Under suitable conditions, melanoma cells form spheres (shown here at 40X magnification) that are capable of self-renewal and are highly tumorigenic. Courtesy Meenhard Herlyn, D.Sc.

'This one cell can give rise to all the others. If we let the cancer stem cell escape, we will always get the cancer back.' DR. HERLYN

BUENOS AIRES — The successful treatment of melanoma in the future is likely to be a two-step process involving combination therapy, Meenhard Herlyn, D.Sc., said in a keynote address at the 21st World Congress of Dermatology.

The aim of the initial treatment will be to debulk the tumor from the major transit-amplifying cells. The second stage will then be to focus on eradication of the cancer stem cells.

"If you do not eliminate these tumor stem cells with therapy, the tumor will come back over and over again," said Dr. Herlyn, professor and program leader in the molecular and cellular oncogenesis program at the Wistar Institute, Philadelphia.

Melanoma arises from malignant transformation of melanocytes or nevus cells, which are formed by overproliferation of melanocytes. Progression from nevi occurs in approximately 50% of melanomas. In normal skin, keratinocytes control the growth of melanocytes in a sort of master-slave relationship.

The decoupling of melanocytes from keratinocytes is the first step in the development of nevi. Overproduction of growth factors from fibroblasts then drives melanocyte proliferation, Dr. Herlyn explained.

For development of melanoma, the most important pathway is the mitogen-activated protein (MAP) kinase pathway, he said.

A genomewide screen performed at the Wellcome Trust Sanger Institute showed that approximately two-thirds of melanomas harbor an activating mutation in BRAF, one of the Raf isoforms in the MAP kinase pathway (Nature 2002;417:949–54).

In 98% of these cases, the BRAF mutation is V600E. A single mutation, however, is not sufficient for the development of melanoma.

Mutations in other signaling pathways, such as the P13-kinase/Akt pathways or cell cycle regulatory pathways, have also been implicated in the development of melanoma, said Dr. Herlyn, who reported no conflicts of interest.

Earlier models of cancer development assumed that melanoma arose as the accumulation of sequential mutations in a mature, differentiated melanocyte eventually leading to malignant transformation of the cell. Identification of another type of cell in melanomas, however, suggests that this model may be too simplistic.

"There are rare cells in tumors that act like stem cells and always replenish the tumor with new cells," said Dr. Herlyn.

The cell that undergoes malignant transformation to produce melanoma might not be a terminally differentiated cell, but instead might be a type of stem cell.

When they are grown under conditions suitable for embryonic stem cells, melanoma cells form spheres that look similar to embryoid bodies formed by human stem cells (Cancer Res. 2005;65:9328–37).

These melanoma spheres meet the definition of tumor stem cells. Melanoma spheres are capable of self-renewal. The cells are highly tumorigenic and quickly form lethal melanomas when injected into nude mice.

They also are multipotent—under laboratory conditions, melanoma spheres can differentiate into melanocytes, adipocytes, chondrocytes, and osteoblasts.

"There is an incredible plasticity in melanoma cells that we have not known before," said Dr. Herlyn. "The question is: What is the true melanoma stem cell?"

Melanoma spheres consist of a mixed cell population. Among the population are cells expressing the hematopoietic marker CD20 and cells expressing the embryonic stem cell marker CD133. Melanoma spheres include side population cells that extrude Hoechst dye via active efflux.

Particularly intriguing are the label-retaining melanoma cells, which proliferate slowly or not at all. When removed from the surrounding cells, however, the label-retaining cells begin to divide rapidly. "If you isolate them, they literally explode," he said.

The label-retaining cells may be the melanoma stem cells, responsible for tumor dormancy and relapse. In this model, the CD20 cells, the CD133 cells, and the side population cells function as progenitor cells.

The label-retaining cells and the progenitor cells could give rise to transit-amplifying cells, Dr. Herlyn suggested at the meeting.

Melanomas are phenotypically heterogeneous tumors. "Tumor heterogeneity is not random," he noted. "Tumor heterogeneity represents a clonal hierarchy in which the different populations compete with each other."

In the center of the hierarchy is the melanoma stem cell. Although melanomas may differ from one patient to the next, they all contain melanoma stem cells. Targeting the stem cell is critical for treatment outcome. "This one cell can give rise to all the others," said Dr. Herlyn. "If we let the cancer stem cell escape, we will always get the cancer back."

Under suitable conditions, melanoma cells form spheres (shown here at 40X magnification) that are capable of self-renewal and are highly tumorigenic. Courtesy Meenhard Herlyn, D.Sc.

'This one cell can give rise to all the others. If we let the cancer stem cell escape, we will always get the cancer back.' DR. HERLYN

ORLANDO — Ablation with a CO₂ laser caused no side effects, scarring, or recurrence in a small study of patients with actinic cheilitis, according to Dr. Keyvan Nouri.

In the study, 25 patients with this precancerous condition of the lips were treated at the University of Miami with Lumenis Ltd.'s UltraPulse CO₂ laser, said Dr. Nouri at the annual meeting of the Florida Society of Dermatologic Surgeons.

Study subjects were initially treated conservatively, at the device's proprietary density setting of 6, but Dr. Nouri now uses a density of 7 because it allows him to achieve better ablation and a similar side effect profile.

After the first pass over the suspicious and surrounding areas, the treated area was wiped. A second pass was then made at 300 mJ over the suspicious area at a density of 5. The area was then allowed to granulate, said Dr. Nouri, who is professor of dermatology at the University of Miami and director of the university's laser center.

A variety of other actinic cheilitis treatments have been used, including surgical and nonsurgical approaches, but the CO₂ laser appears to be a good treatment option, said Dr. Nouri, who owns the UltraPulse laser that was used for the treatment but disclosed having no financial interest in the company that makes the device.

This laser is easier to use than many other modalities, and may be safer as well, he said, noting that other treatments include topical agents (such as 5-fluorouracil, which can be very irritating), chemexfoliation, systemic retinoids, interferon-α, curettage and electrodesiccation, and cryosurgery.

Other advantages of the CO₂ laser, he noted, are a minimal risk of transferring precancerous cells and a low risk of infection from the procedure itself. (Most patients are premedicated with antivirals and sometimes with antibiotics.)

"I'm not saying this is a panacea, because even with the UltraPulse there can be a high recurrence rate, but it is a pretty good option," he said.

Most cases of actinic cheilitis (about 97%) occur on the lower lip. Exposure to ultraviolet radiation is a risk factor for the condition, and thus it is particularly common in those with outdoor occupations and hobbies, said Dr. Nouri. Tobacco exposure has also been linked with this condition. Men in the fifth and sixth decades of life are most often affected.

Actinic cheilitis presents as whitish or reddish lesions that are ulcerated, erosive unulcerated, or erosive ulcerated. Histologically, they present as mild epithelial dysplasia with thickening of the keratin and spinous layer.

Connective tissue and perivascular inflammation can also be seen, but basophilic changes within the connective tissue are a universal finding.

A patient with actinic cheilitis is shown before the laser ablation was performed.

The same patient is shown 1 month after treatment with the UltraPulse CO₂ laser. Photos courtesy Dr. Keyvan Nouri

ORLANDO — Ablation with a CO₂ laser caused no side effects, scarring, or recurrence in a small study of patients with actinic cheilitis, according to Dr. Keyvan Nouri.

In the study, 25 patients with this precancerous condition of the lips were treated at the University of Miami with Lumenis Ltd.'s UltraPulse CO₂ laser, said Dr. Nouri at the annual meeting of the Florida Society of Dermatologic Surgeons.

Study subjects were initially treated conservatively, at the device's proprietary density setting of 6, but Dr. Nouri now uses a density of 7 because it allows him to achieve better ablation and a similar side effect profile.

After the first pass over the suspicious and surrounding areas, the treated area was wiped. A second pass was then made at 300 mJ over the suspicious area at a density of 5. The area was then allowed to granulate, said Dr. Nouri, who is professor of dermatology at the University of Miami and director of the university's laser center.

A variety of other actinic cheilitis treatments have been used, including surgical and nonsurgical approaches, but the CO₂ laser appears to be a good treatment option, said Dr. Nouri, who owns the UltraPulse laser that was used for the treatment but disclosed having no financial interest in the company that makes the device.

This laser is easier to use than many other modalities, and may be safer as well, he said, noting that other treatments include topical agents (such as 5-fluorouracil, which can be very irritating), chemexfoliation, systemic retinoids, interferon-α, curettage and electrodesiccation, and cryosurgery.

Other advantages of the CO₂ laser, he noted, are a minimal risk of transferring precancerous cells and a low risk of infection from the procedure itself. (Most patients are premedicated with antivirals and sometimes with antibiotics.)

"I'm not saying this is a panacea, because even with the UltraPulse there can be a high recurrence rate, but it is a pretty good option," he said.

Most cases of actinic cheilitis (about 97%) occur on the lower lip. Exposure to ultraviolet radiation is a risk factor for the condition, and thus it is particularly common in those with outdoor occupations and hobbies, said Dr. Nouri. Tobacco exposure has also been linked with this condition. Men in the fifth and sixth decades of life are most often affected.

Actinic cheilitis presents as whitish or reddish lesions that are ulcerated, erosive unulcerated, or erosive ulcerated. Histologically, they present as mild epithelial dysplasia with thickening of the keratin and spinous layer.

Connective tissue and perivascular inflammation can also be seen, but basophilic changes within the connective tissue are a universal finding.

A patient with actinic cheilitis is shown before the laser ablation was performed.

The same patient is shown 1 month after treatment with the UltraPulse CO₂ laser. Photos courtesy Dr. Keyvan Nouri

ORLANDO — Ablation with a CO₂ laser caused no side effects, scarring, or recurrence in a small study of patients with actinic cheilitis, according to Dr. Keyvan Nouri.

In the study, 25 patients with this precancerous condition of the lips were treated at the University of Miami with Lumenis Ltd.'s UltraPulse CO₂ laser, said Dr. Nouri at the annual meeting of the Florida Society of Dermatologic Surgeons.

Study subjects were initially treated conservatively, at the device's proprietary density setting of 6, but Dr. Nouri now uses a density of 7 because it allows him to achieve better ablation and a similar side effect profile.

After the first pass over the suspicious and surrounding areas, the treated area was wiped. A second pass was then made at 300 mJ over the suspicious area at a density of 5. The area was then allowed to granulate, said Dr. Nouri, who is professor of dermatology at the University of Miami and director of the university's laser center.

A variety of other actinic cheilitis treatments have been used, including surgical and nonsurgical approaches, but the CO₂ laser appears to be a good treatment option, said Dr. Nouri, who owns the UltraPulse laser that was used for the treatment but disclosed having no financial interest in the company that makes the device.

This laser is easier to use than many other modalities, and may be safer as well, he said, noting that other treatments include topical agents (such as 5-fluorouracil, which can be very irritating), chemexfoliation, systemic retinoids, interferon-α, curettage and electrodesiccation, and cryosurgery.

Other advantages of the CO₂ laser, he noted, are a minimal risk of transferring precancerous cells and a low risk of infection from the procedure itself. (Most patients are premedicated with antivirals and sometimes with antibiotics.)

"I'm not saying this is a panacea, because even with the UltraPulse there can be a high recurrence rate, but it is a pretty good option," he said.

Most cases of actinic cheilitis (about 97%) occur on the lower lip. Exposure to ultraviolet radiation is a risk factor for the condition, and thus it is particularly common in those with outdoor occupations and hobbies, said Dr. Nouri. Tobacco exposure has also been linked with this condition. Men in the fifth and sixth decades of life are most often affected.

Actinic cheilitis presents as whitish or reddish lesions that are ulcerated, erosive unulcerated, or erosive ulcerated. Histologically, they present as mild epithelial dysplasia with thickening of the keratin and spinous layer.

Connective tissue and perivascular inflammation can also be seen, but basophilic changes within the connective tissue are a universal finding.

A patient with actinic cheilitis is shown before the laser ablation was performed.

The same patient is shown 1 month after treatment with the UltraPulse CO₂ laser. Photos courtesy Dr. Keyvan Nouri

Dermatologists have a unique opportunity to recognize hereditary syndromes associated with renal tumors. By doing so, it may be possible to diagnose these tumors before they become life threatening. Although these syndromes are rare, it is incumbent upon dermatologists to recognize these disorders and recommend appropriate screening tests and referral to other specialists, including urologists, oncologists, and geneticists. Of the 9 known hereditary syndromes with renal tumors, 4 demonstrate cutaneous manifestations: von Hippel-Lindau (VHL) syndrome, Birt-Hogg-Dube (BHD) syndrome, tuberous sclerosis (TS), and hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome. Renal cell carcinoma (RCC) is diagnosed in more than 30,000 individuals in the United States each year, causes 12,000 deaths annually, and is increasing in incidence.1 Known risk factors for sporadic renal cancer include smoking, chemical exposure, asbestosis, obesity, hypertension, and end-stage renal disease. There is growing recognition that heredity also plays a role, and it is estimated that approximately 4% of renal cancers are hereditary. In these individuals, a germ line mutation is associated with a predisposition to develop renal tumors of specific histologic types.2 In the past 10 years, advances in genomics and the widespread use of modern imaging techniques have contributed to the awareness of hereditary renal cancer syndromes. Increased knowledge of these syndromes will allow dermatologists to screen and counsel family members as well as identify those patients at risk for multiple cancer development. Early screening to identify localized tumors will provide opportunities to therapeutically intervene while cancers are still treatable.3 Because 4 of these syndromes involve cutaneous manifestations, the dermatologist may have the opportunity to make the diagnosis at an early stage. Hereditary renal cancers differ from sporadic renal cancers in several important respects.2 A hallmark of hereditary renal cancer is that tumors often are multiple and bilateral. Unlike sporadic renal cancers, which develop in the sixth and seventh decades of life, hereditary renal cancers may develop much earlier, even in teenaged individuals. Although sporadic renal tumors are more common in men, hereditary renal cancers often are found with equal frequency in both sexes. Disease severity can be highly variable, even within a family, and the absence of a family history never completely excludes the possibility of a hereditary cause for renal cancer.2 

Renal Tumor Classification
There are several histologic types of renal cancer in adults and each is linked with a specific hereditary syndrome.2 The most common histologic subtype is clear cell carcinoma, which accounts for 75% of renal cancers. Clear cell carcinomas arise from the proximal tubular epithelium. Grossly, they appear yellow because of their high lipid content. Microscopically, these cells appear lucent because of their high glycogen content. Clear cell carcinomas are seen in VHL syndrome and TS.2 The second most common type of renal cancer is papillary cell carcinoma (15%).4 It is subclassified into type 1 and type 2. Type 1 is found in hereditary papillary renal cancer and is associated with a good long-term prognosis. It is characterized by cells with scant pale cytoplasm arranged in a single layer. Type 2 is found in HLRCC syndrome and is a more aggressive form. Type 2 cells are pseudostratified with an eosinophilic cytoplasm.4 Chromophobe carcinoma is the third most common cell type.3 This tumor contains cells with well-defined borders, large eosinophilic cytoplasm, and pyknotic nuclei with a perinuclear halo. The cell of origin is most likely the intercalated cell of the cortical collecting duct. Chromophobe carcinomas account for approximately 5% of renal cancers and are found in BHD syndrome.3 Oncocytomas account for 2% to 3% of renal tumors and are considered to be benign renal neoplasms.5 Grossly, they are mahogany brown and are not necrotic. Histologically, they are composed of tightly packed tubular structures or nesting cells surrounded by a reticulin skeleton. They commonly grow centrifugally from a central avascular scar. Oncocytomas can be found in BHD syndrome and hereditary renal oncocytoma.5 Rare malignant tumors of the kidney include collecting duct and medullary carcinomas, which represent only 1% of renal tumors. Transitional cell carcinoma of the renal pelvis is another cause of malignancy in the kidneys and is associated with hereditary nonpolyposis colon cancer syndrome (Lynch syndrome).6 A common benign tumor of the renal parenchyma is angiomyolipoma, which is a hamartoma of the kidneys that contains vascular, lipomatous, and myeloid elements. Most of these tumors are small and slow growing. The primary risk associated with angiomyolipoma is hemorrhage. These tumors are found in TS.7 The Table lists the hereditary renal cancers and their respective chromosomal and clinical associations.

 
Clinical Manifestations of Renal Tumors
Because of their insidious course and varied clinical presentations, renal tumors most commonly are diagnosed as incidental findings during radiologic procedures.8 The classic triad of symptoms—hematuria, flank pain, and an abdominal mass—is seen only in approximately 10% of patients; in most cases, only one of these symptoms is the initial manifestation of the tumor. Systemic symptoms may be present, including weight loss, fatigue, and fever. RCC also is associated with several paraneoplastic syndromes, such as polycythemia (from ectopic erythropoietin production) and hypercalcemia (from ectopic production of parathyroid hormone–related peptide). Metastases mainly are through hematologic spread, and the lungs, bones, and liver are the most frequent sites. 8 back to top

Prognosis and Staging of Renal Tumors
RCC remains a major source of morbidity and mortality.9 Approximately 40% of patients eventually die of cancer progression, making RCC the most lethal of the common urologic malignancies. Although modern imaging has led to earlier diagnosis of RCC, more than 20% of patients present with metastatic disease. Tumor stage remains the most important prognostic factor for RCC. When renal cancers are organ confined, the 5-year survival rate is between 74% and 96%. This rate decreases to 40% to 60% when the renal veins are involved. With locally advanced renal cancers, as well as those with lymphatic involvement or metastasis, the 5-year survival rate is 0% to 20%.9

Treatment of Renal Tumors
Surgical resection (nephrectomy, partial nephrectomy) remains the most viable treatment option for RCC, regardless of the stage of disease at presentation. For localized tumors, surgical cure of disease is strongly dependent on stage and grade of disease.10 For locally advanced or metastatic disease, nephrectomy should be considered for palliation or as part of an adjuvant therapy protocol. Curative lymphadenectomy is not possible in most cases, and the value of lymphadenectomy is limited to those patients with lymph node involvement. Limited dissection of tissue and resection of the visible or palpable nodes usually is sufficient.11 Renal tumors respond poorly to radiation, chemotherapy, and immunotherapy, with response rates of less than 20%.12 However, advances in the understanding of immune responses to RCC have led to new therapeutic strategies based on immune manipulation. The identification of numerous T-cell epitopes associated with RCC has led to the development of new treatment approaches using DNA vaccination, peptide vaccination, and dendritic cell therapy; combined with new and more efficient gene-delivery techniques, these treatments may have considerable clinical implications for patients with RCC.12 Targeted therapies that are currently being investigated for metastatic RCC include tyrosine kinase inhibitors (ie, sorafenib), anti–vascular endothelial growth factor therapy (ie, bevacizumab), and inhibition of the mammalian target of rapamycin (mTOR) pathway (ie, temsirolimus).13 back to top

VHL Syndrome
VHL syndrome represents a constellation of central nervous system (CNS) and visceral neoplasms that result from a germ line mutation of the VHL tumor suppressor gene on chromosome arm 3p25-26.14 In this autosomal dominant neurocutaneous syndrome, 80% of cases are hereditary and 20% are sporadic. The incidence of VHL syndrome is approximately 1 in 36,000 individuals.15 Patients with VHL syndrome typically present before the age of 40 years.16 Although less than 5% of cases of VHL syndrome have dermatologic manifestations, capillary malformations are the most common cutaneous features. Thus, the dermatologist must be vigilant to observe for VHL syndrome in the appropriate clinical context. More than 70% of sporadic clear cell RCCs display mutations in the VHL gene.17 The VHL protein produced via this gene is a ubiquitin ligase that degrades hypoxia-inducible factors (HIFs) including HIF-1α and HIF-2α. A mutation of the VHL gene can increase the levels of HIF, which subsequently activate additional genes that produce vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor α, and carbonic anhydrase IX. In concert, these factors facilitate neoangiogenesis and tumorigenesis.17 The mutation of the VHL gene leads to the development of both benign and malignant tumors that affect multiple organ systems. CNS tumors include retinal hemangioblastomas (20%–60%); endolymphatic sac tumors (11%–16%); and craniospinal hemangiomas, most frequently of the cerebellum (44%–72%), brainstem (10%–25%), and spinal cord (13%–50%). Additional manifestations of VHL syndrome include RCC or kidney cyst (25%–60%), epididymal cystadenoma (25%–60% of men), pancreatic cyst or cystadenoma (17%–56%), pheochromocytoma or paraganglioma (10%–20%), and broad ligament cystadenoma (10% of women).18 The capillary malformations of VHL syndrome often occur in but are not limited to the head and neck. Also, café au lait spots that frequently are associated with neurofibromatosis may be evident in VHL syndrome, suggesting overlap between these phakomatoses.19 VHL syndrome is a progressive disease, with death characteristically occurring by the fourth decade of life. The diagnosis of VHL syndrome is based on clinical criteria. Patients with a family history of VHL syndrome and a CNS hemangioblastoma, pheochromocytoma, or clear cell RCC are diagnosed with the syndrome. In the absence of a family history, the diagnosis can be made with 2 or more CNS hemangioblastomas and a visceral tumor, with the exclusion of renal and epididymal cysts. Confirmation of diagnosis and screening for possibly affected family members can be achieved with DNA testing for mutation in the VHL gene. Recommended laboratory tests include a complete blood count and screenings for serum catecholamine and urine vanillylmandelic acid levels, as well as a computed tomographic scan (CT scan) and/or magnetic resonance imaging of the brain, spinal cord, and abdomen. Patients diagnosed with VHL syndrome should be referred to an ophthalmologist for photocoagulation or cryocoagulation of tumors. Neurosurgeons and urologists may surgically remove CNS and renal tumors, respectively, with preoperative angiography. Patients with VHL syndrome also may consider renal transplantation.

BHD Syndrome
BHD syndrome, an autosomal dominant genodermatosis occurring in 1 in 200,000 individuals, is characterized by the cutaneous triad of fibrofolliculomas, trichodiscomas, and acrochordons. Vincent and colleagues20 offer a comprehensive analysis of these papules, which frequently appear in the third to fourth decades of life. Protein-truncating mutations of the BHD gene on chromosome arm 17p11.2 encode the BHD protein folliculin, which is expressed in the kidneys, lungs, and skin.21 Although the function of the protein is unknown, the BHD gene is presumptively involved in tumor suppression. Fibrofolliculomas and trichodiscomas are clinically indistinguishable; both are skin-colored, well-circumscribed, smooth, firm, 2- to 4-mm papules distributed over the forehead, nose, and cheeks.22 Acrochordons appear as soft pedunculated lesions. The clinical appearance of fibrofolliculomas and trichodiscomas is associated with familial spontaneous pneumothorax and RCCs. Notably, patients with BHD syndrome have a 50-fold increased risk of pneumothorax presenting with tachypnea, decreased breath sounds, and hyperresonance.23 Lung cysts and bullous emphysema also have been associated with BHD syndrome. In addition to the cutaneous and pulmonary features, a 7-fold increase in renal tumors with varying histology has been associated with BHD syndrome, including hybrid chromophobe and oncocytoma (50%), chromophobe (34%), clear cell RCC (9%), and oncocytoma (5%).23 Multiple histologic types can be found in the same family, patient, and kidney, suggesting a role for the BHD gene in the differentiation processes of renal cells. Fibrofolliculomas possess a circumscribed fibrous tissue layer around the hair follicles.24 These follicles demonstrate a widened infundibulum containing laminated keratin. Encasing the follicle is a mantle of loose connective tissue embedded in a mucoid ground substance with high concentrations of hyaluronic acid. The elastin fibers may not be visible or appear sparse. Radiating from the follicular epithelium are 2 to 4 thin layers of epithelial strands that extend into the fibrous tissue where they combine with epithelial strands or connect with follicular or sebaceous epithelium. In contrast, the histology of the trichodiscomas demonstrates hair follicles at the margin of these tumors. The stroma is highly vascularized, with collagen fibers and cells containing melanin.24 A diagnosis of BHD syndrome requires 5 or more facial or truncal papules; 1 papule must be confirmed as a fibrofolliculoma or trichodiscoma using the histologic criteria above. The differential diagnosis includes TS, Cowden syndrome, Brooke-Spiegler syndrome, Rombo syndrome, and basaloid follicular hamartoma syndrome. It is recommended that all patients who are diagnosed with BHD syndrome get a chest x-ray, abdominal CT scan, and renal ultrasound. Thereafter, patients may be screened every 3 to 5 years. Siblings of patients require physical examinations and biopsies of suspicious skin lesions as early as the second decade of life. Treatment options for fibrofolliculomas and trichodiscomas include CO2 laser ablation and/or erbium:YAG laser, copper vapor laser, and systemic isotretinoin, though these therapies have shown variable results in some patients.24 Resection is recommended for RCC. If the tumor is less than 3 cm in size, surgery that conserves the parenchyma may be appropriate to optimize renal function without increasing the risk of metastases. The prognosis depends on the renal and pulmonary sequelae. 

Tuberous Sclerosis
TS, also called tuberous sclerosis complex (TSC), is a rare genetic disease that causes benign tumors to grow in the brain and other organs, such as the kidneys, lungs, skin, and eyes.25 Its incidence is 1 in 10,000 individuals and the age of presentation is variable. TS is an autosomal dominant disorder; approximately 40% of cases are hereditary and 60% are sporadic.26 Two gene mutations have been identified in contributing to the development of TS: the hamartin gene TSC1 on the chromosome arm 9q34 and tuberin gene TSC2 on the chromosome arm 16p13.3. The latter is adjacent to the PKD1 site, which is responsible for autosomal dominant polycystic kidney disease, thereby explaining the association of these 2 disorders in patients with contiguous gene defects. Hamartin and tuberin associate in vivo to form a tumor suppressor complex. This complex functions within the P13K-Akt-mTOR pathway and regulates nutrient and growth factor signaling to mTOR. As a result, rapamycin has potential therapeutic use in TS.26 The clinical features of TS include neurologic involvement with mental cognitive deficiency and epilepsy; psychiatric and behavioral problems such as attention deficit hyperactivity disorder and generalized development delays; and organic brain anomalies such as cortical tubera, subependymal giant cell astrocytomas, and subependymal nodules.25 Cardiac rhabdomyomas, retinal hamartomas, and dental pits also are typical findings of TS. Pulmonary lymphangioleiomyomatosis related to TS has been described, usually presenting exclusively in women. Classic cutaneous lesions include facial angiofibromas (adenoma sebaceum), the shagreen patch, and periungual or subungual fibromas (Koenen tumors).25 Renal manifestations are mainly angiomyolipomas, renal cysts, and cancer.27 In patients with TS, multiple lesions appear concomitantly and are likely to be bilateral. Larger lesions may present with flank pain, hypertension, hematuria, and renal failure. These lesions characteristically are benign, though there are some reports of sarcomatous degeneration and rare malignant epithelioid variants.27 Angiomyolipomas are not hamartomas per se, rather they are clonal perivascular epithelioid cell tumors (PEComas).28 PEComas are tumors composed of mostly epithelioid cells positive for HMB-45 and/or melan-A as well as actin- and/or desmin-positive cells. These PEComas have a perivascular propensity. They belong to a family of me-senchymal neoplasms that include angiomyolipomas, lymphangioleiomyomatosis, clear cell tumor (sugar tumor) of the lung, and other soft tissue and visceral neoplasms with similar histology and immunohistochemistry. Pan et al29 studied the cytogenetic feature of these tumors and reported that all cells studied had gross chromosomal anomalies, with the most frequent being a deletion of chromosome arm 16p, in which TSC2 is located. Alam et al30 concluded that PEComas are distinctive tumors based on the common chromosomal changes found in both renal and extrarenal tumors. Starting in childhood, renal ultrasounds can be used to detect and monitor the growth of angiomyolipomas. Because complications correlate with increasing size, surgery is recommended when the tumor is greater than 3.5 to 4.0 cm in size. Surgical options include tumor embolization, tumor enucleation, partial nephrectomy, or total nephrectomy depending on the presentation. Patients with TS are at a higher risk for renal cancer than the general population (2.0%–4.0% vs 1.27%, respectively) and are more likely to present at a younger age (30 years vs 60 years, respectively). Renal cancer in patients with TS is most commonly of the clear cell carcinoma type and is more likely to be multifocal and bilateral.2 For these reasons, lifelong periodic radiologic evaluation is essential. 

HLRCC Syndrome
HLRCC syndrome is an autosomal dominant disease that is an expansion of Reed syndrome (multiple cutaneous and uterine leiomyoma syndrome). It is characterized by the presence of leiomyomas in the skin and uterus of affected females and in the skin of affected males. Its prevalence in the general population is not known, though one limited study estimated the presence of a heterozygous fumarate hydratase, FH, gene mutation at 1 in 676 individuals.30 Germ line mutations in the FH gene at chromosome arm 1q42.3-43 are associated with the HLRCC syndrome.31 In the Krebs cycle, the FH and succinate dehydrogenase, SD, genes act as tumor suppressors. Mutations in the SD gene are associated with pheochromocytomas and paragangliomas. Mutations in the FH gene lead to the overexpression of HIF-1α and its targets (eg, vascular endothelial growth factor), which contributes to tumorigenesis by the so-called pseudohypoxic drive. There is a low frequency of FH mutations in sporadic cases of leiomyomas and leiomyosarcomas.31 The clinical features of patients with HLRCC syndrome include benign cutaneous and uterine leiomyomas and, more rarely, cutaneous leiomyosarcomas and uterine leiomyosarcomas. Cutaneous leiomyomas usually present in late childhood to early adulthood. They typically present as multiple disseminated lesions, most commonly on the face, trunk, and extremities, though segmental distribution also has been described.30 The individual lesions appear as intradermal papules. Alam et al30 stated that 90% of patients complain of pain from cutaneous leiomyoma, which is exacerbated by cold or trauma. Although leiomyomas may be solitary and sporadic lesions, Chuang et al32 noted that the finding of a cutaneous leiomyoma in a patient should compel dermatologists to examine the individual and his/her family for multiple lesions and to screen for the FH gene, which is crucial because FH mutations in HLRCC syndrome lead to increased susceptibility to early-onset RCC. These RCCs usually are solitary, fast growing, and very aggressive, and they display papillary cell carcinoma type 2 or renal collecting duct histology. Alam et al30 reported a case of a 16-year-old patient who presented with metastatic renal disease, which led the authors to urge the consideration of early screenings for FH mutations for patients. Toro et al33 screened 35 families with cutaneous leiomyomas for mutations in the FH gene. They identified mutations in 31 families (89%). Eighty-one individuals had cutaneous leiomyomas, of which 47 were women and 34 were men. Forty-six of 47 women (98%) had uterine leiomyomas. The authors also found 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from 4 families had papillary cell carcinoma type 2, and 1 individual from 1 of these families had renal collecting duct carcinoma.33 Patients who present with lesions that are diagnosed as cutaneous leiomyomas should prompt a complete history, including a history of fibroids in women as well as a family history of fibroids or renal tumors.34 Tests for mutations in the FH gene may be of value. Renal imaging studies should be performed in suspect cases. Although some papillary cell carcinoma type 2 or collecting duct RCCs can be found only with a CT scan or magnetic resonance imaging, a simple ultrasound is successful in most cases and can sometimes provide superior information about the characteristics of the renal tumor.34 

Conclusion
Dermatologists have a unique opportunity to diagnose hereditary renal tumors before they become life threatening. When examining patients with capillary malformations, fibrofolliculomas, angiofibromas, or leiomyomas, the dermatologist should consider the possibility of VHL syndrome, BHD syndrome, TS, or HLRCC syndrome, respectively. With a positive family history, renal imaging studies should be obtained. Although these syndromes are rare, it is essential that dermatologists recognize them for the benefit of the patients and their kin.

Dermatologists have a unique opportunity to recognize hereditary syndromes associated with renal tumors. By doing so, it may be possible to diagnose these tumors before they become life threatening. Although these syndromes are rare, it is incumbent upon dermatologists to recognize these disorders and recommend appropriate screening tests and referral to other specialists, including urologists, oncologists, and geneticists. Of the 9 known hereditary syndromes with renal tumors, 4 demonstrate cutaneous manifestations: von Hippel-Lindau (VHL) syndrome, Birt-Hogg-Dube (BHD) syndrome, tuberous sclerosis (TS), and hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome. Renal cell carcinoma (RCC) is diagnosed in more than 30,000 individuals in the United States each year, causes 12,000 deaths annually, and is increasing in incidence.1 Known risk factors for sporadic renal cancer include smoking, chemical exposure, asbestosis, obesity, hypertension, and end-stage renal disease. There is growing recognition that heredity also plays a role, and it is estimated that approximately 4% of renal cancers are hereditary. In these individuals, a germ line mutation is associated with a predisposition to develop renal tumors of specific histologic types.2 In the past 10 years, advances in genomics and the widespread use of modern imaging techniques have contributed to the awareness of hereditary renal cancer syndromes. Increased knowledge of these syndromes will allow dermatologists to screen and counsel family members as well as identify those patients at risk for multiple cancer development. Early screening to identify localized tumors will provide opportunities to therapeutically intervene while cancers are still treatable.3 Because 4 of these syndromes involve cutaneous manifestations, the dermatologist may have the opportunity to make the diagnosis at an early stage. Hereditary renal cancers differ from sporadic renal cancers in several important respects.2 A hallmark of hereditary renal cancer is that tumors often are multiple and bilateral. Unlike sporadic renal cancers, which develop in the sixth and seventh decades of life, hereditary renal cancers may develop much earlier, even in teenaged individuals. Although sporadic renal tumors are more common in men, hereditary renal cancers often are found with equal frequency in both sexes. Disease severity can be highly variable, even within a family, and the absence of a family history never completely excludes the possibility of a hereditary cause for renal cancer.2 

Renal Tumor Classification
There are several histologic types of renal cancer in adults and each is linked with a specific hereditary syndrome.2 The most common histologic subtype is clear cell carcinoma, which accounts for 75% of renal cancers. Clear cell carcinomas arise from the proximal tubular epithelium. Grossly, they appear yellow because of their high lipid content. Microscopically, these cells appear lucent because of their high glycogen content. Clear cell carcinomas are seen in VHL syndrome and TS.2 The second most common type of renal cancer is papillary cell carcinoma (15%).4 It is subclassified into type 1 and type 2. Type 1 is found in hereditary papillary renal cancer and is associated with a good long-term prognosis. It is characterized by cells with scant pale cytoplasm arranged in a single layer. Type 2 is found in HLRCC syndrome and is a more aggressive form. Type 2 cells are pseudostratified with an eosinophilic cytoplasm.4 Chromophobe carcinoma is the third most common cell type.3 This tumor contains cells with well-defined borders, large eosinophilic cytoplasm, and pyknotic nuclei with a perinuclear halo. The cell of origin is most likely the intercalated cell of the cortical collecting duct. Chromophobe carcinomas account for approximately 5% of renal cancers and are found in BHD syndrome.3 Oncocytomas account for 2% to 3% of renal tumors and are considered to be benign renal neoplasms.5 Grossly, they are mahogany brown and are not necrotic. Histologically, they are composed of tightly packed tubular structures or nesting cells surrounded by a reticulin skeleton. They commonly grow centrifugally from a central avascular scar. Oncocytomas can be found in BHD syndrome and hereditary renal oncocytoma.5 Rare malignant tumors of the kidney include collecting duct and medullary carcinomas, which represent only 1% of renal tumors. Transitional cell carcinoma of the renal pelvis is another cause of malignancy in the kidneys and is associated with hereditary nonpolyposis colon cancer syndrome (Lynch syndrome).6 A common benign tumor of the renal parenchyma is angiomyolipoma, which is a hamartoma of the kidneys that contains vascular, lipomatous, and myeloid elements. Most of these tumors are small and slow growing. The primary risk associated with angiomyolipoma is hemorrhage. These tumors are found in TS.7 The Table lists the hereditary renal cancers and their respective chromosomal and clinical associations.

 
Clinical Manifestations of Renal Tumors
Because of their insidious course and varied clinical presentations, renal tumors most commonly are diagnosed as incidental findings during radiologic procedures.8 The classic triad of symptoms—hematuria, flank pain, and an abdominal mass—is seen only in approximately 10% of patients; in most cases, only one of these symptoms is the initial manifestation of the tumor. Systemic symptoms may be present, including weight loss, fatigue, and fever. RCC also is associated with several paraneoplastic syndromes, such as polycythemia (from ectopic erythropoietin production) and hypercalcemia (from ectopic production of parathyroid hormone–related peptide). Metastases mainly are through hematologic spread, and the lungs, bones, and liver are the most frequent sites. 8 back to top

Prognosis and Staging of Renal Tumors
RCC remains a major source of morbidity and mortality.9 Approximately 40% of patients eventually die of cancer progression, making RCC the most lethal of the common urologic malignancies. Although modern imaging has led to earlier diagnosis of RCC, more than 20% of patients present with metastatic disease. Tumor stage remains the most important prognostic factor for RCC. When renal cancers are organ confined, the 5-year survival rate is between 74% and 96%. This rate decreases to 40% to 60% when the renal veins are involved. With locally advanced renal cancers, as well as those with lymphatic involvement or metastasis, the 5-year survival rate is 0% to 20%.9

Treatment of Renal Tumors
Surgical resection (nephrectomy, partial nephrectomy) remains the most viable treatment option for RCC, regardless of the stage of disease at presentation. For localized tumors, surgical cure of disease is strongly dependent on stage and grade of disease.10 For locally advanced or metastatic disease, nephrectomy should be considered for palliation or as part of an adjuvant therapy protocol. Curative lymphadenectomy is not possible in most cases, and the value of lymphadenectomy is limited to those patients with lymph node involvement. Limited dissection of tissue and resection of the visible or palpable nodes usually is sufficient.11 Renal tumors respond poorly to radiation, chemotherapy, and immunotherapy, with response rates of less than 20%.12 However, advances in the understanding of immune responses to RCC have led to new therapeutic strategies based on immune manipulation. The identification of numerous T-cell epitopes associated with RCC has led to the development of new treatment approaches using DNA vaccination, peptide vaccination, and dendritic cell therapy; combined with new and more efficient gene-delivery techniques, these treatments may have considerable clinical implications for patients with RCC.12 Targeted therapies that are currently being investigated for metastatic RCC include tyrosine kinase inhibitors (ie, sorafenib), anti–vascular endothelial growth factor therapy (ie, bevacizumab), and inhibition of the mammalian target of rapamycin (mTOR) pathway (ie, temsirolimus).13 back to top

VHL Syndrome
VHL syndrome represents a constellation of central nervous system (CNS) and visceral neoplasms that result from a germ line mutation of the VHL tumor suppressor gene on chromosome arm 3p25-26.14 In this autosomal dominant neurocutaneous syndrome, 80% of cases are hereditary and 20% are sporadic. The incidence of VHL syndrome is approximately 1 in 36,000 individuals.15 Patients with VHL syndrome typically present before the age of 40 years.16 Although less than 5% of cases of VHL syndrome have dermatologic manifestations, capillary malformations are the most common cutaneous features. Thus, the dermatologist must be vigilant to observe for VHL syndrome in the appropriate clinical context. More than 70% of sporadic clear cell RCCs display mutations in the VHL gene.17 The VHL protein produced via this gene is a ubiquitin ligase that degrades hypoxia-inducible factors (HIFs) including HIF-1α and HIF-2α. A mutation of the VHL gene can increase the levels of HIF, which subsequently activate additional genes that produce vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor α, and carbonic anhydrase IX. In concert, these factors facilitate neoangiogenesis and tumorigenesis.17 The mutation of the VHL gene leads to the development of both benign and malignant tumors that affect multiple organ systems. CNS tumors include retinal hemangioblastomas (20%–60%); endolymphatic sac tumors (11%–16%); and craniospinal hemangiomas, most frequently of the cerebellum (44%–72%), brainstem (10%–25%), and spinal cord (13%–50%). Additional manifestations of VHL syndrome include RCC or kidney cyst (25%–60%), epididymal cystadenoma (25%–60% of men), pancreatic cyst or cystadenoma (17%–56%), pheochromocytoma or paraganglioma (10%–20%), and broad ligament cystadenoma (10% of women).18 The capillary malformations of VHL syndrome often occur in but are not limited to the head and neck. Also, café au lait spots that frequently are associated with neurofibromatosis may be evident in VHL syndrome, suggesting overlap between these phakomatoses.19 VHL syndrome is a progressive disease, with death characteristically occurring by the fourth decade of life. The diagnosis of VHL syndrome is based on clinical criteria. Patients with a family history of VHL syndrome and a CNS hemangioblastoma, pheochromocytoma, or clear cell RCC are diagnosed with the syndrome. In the absence of a family history, the diagnosis can be made with 2 or more CNS hemangioblastomas and a visceral tumor, with the exclusion of renal and epididymal cysts. Confirmation of diagnosis and screening for possibly affected family members can be achieved with DNA testing for mutation in the VHL gene. Recommended laboratory tests include a complete blood count and screenings for serum catecholamine and urine vanillylmandelic acid levels, as well as a computed tomographic scan (CT scan) and/or magnetic resonance imaging of the brain, spinal cord, and abdomen. Patients diagnosed with VHL syndrome should be referred to an ophthalmologist for photocoagulation or cryocoagulation of tumors. Neurosurgeons and urologists may surgically remove CNS and renal tumors, respectively, with preoperative angiography. Patients with VHL syndrome also may consider renal transplantation.

BHD Syndrome
BHD syndrome, an autosomal dominant genodermatosis occurring in 1 in 200,000 individuals, is characterized by the cutaneous triad of fibrofolliculomas, trichodiscomas, and acrochordons. Vincent and colleagues20 offer a comprehensive analysis of these papules, which frequently appear in the third to fourth decades of life. Protein-truncating mutations of the BHD gene on chromosome arm 17p11.2 encode the BHD protein folliculin, which is expressed in the kidneys, lungs, and skin.21 Although the function of the protein is unknown, the BHD gene is presumptively involved in tumor suppression. Fibrofolliculomas and trichodiscomas are clinically indistinguishable; both are skin-colored, well-circumscribed, smooth, firm, 2- to 4-mm papules distributed over the forehead, nose, and cheeks.22 Acrochordons appear as soft pedunculated lesions. The clinical appearance of fibrofolliculomas and trichodiscomas is associated with familial spontaneous pneumothorax and RCCs. Notably, patients with BHD syndrome have a 50-fold increased risk of pneumothorax presenting with tachypnea, decreased breath sounds, and hyperresonance.23 Lung cysts and bullous emphysema also have been associated with BHD syndrome. In addition to the cutaneous and pulmonary features, a 7-fold increase in renal tumors with varying histology has been associated with BHD syndrome, including hybrid chromophobe and oncocytoma (50%), chromophobe (34%), clear cell RCC (9%), and oncocytoma (5%).23 Multiple histologic types can be found in the same family, patient, and kidney, suggesting a role for the BHD gene in the differentiation processes of renal cells. Fibrofolliculomas possess a circumscribed fibrous tissue layer around the hair follicles.24 These follicles demonstrate a widened infundibulum containing laminated keratin. Encasing the follicle is a mantle of loose connective tissue embedded in a mucoid ground substance with high concentrations of hyaluronic acid. The elastin fibers may not be visible or appear sparse. Radiating from the follicular epithelium are 2 to 4 thin layers of epithelial strands that extend into the fibrous tissue where they combine with epithelial strands or connect with follicular or sebaceous epithelium. In contrast, the histology of the trichodiscomas demonstrates hair follicles at the margin of these tumors. The stroma is highly vascularized, with collagen fibers and cells containing melanin.24 A diagnosis of BHD syndrome requires 5 or more facial or truncal papules; 1 papule must be confirmed as a fibrofolliculoma or trichodiscoma using the histologic criteria above. The differential diagnosis includes TS, Cowden syndrome, Brooke-Spiegler syndrome, Rombo syndrome, and basaloid follicular hamartoma syndrome. It is recommended that all patients who are diagnosed with BHD syndrome get a chest x-ray, abdominal CT scan, and renal ultrasound. Thereafter, patients may be screened every 3 to 5 years. Siblings of patients require physical examinations and biopsies of suspicious skin lesions as early as the second decade of life. Treatment options for fibrofolliculomas and trichodiscomas include CO2 laser ablation and/or erbium:YAG laser, copper vapor laser, and systemic isotretinoin, though these therapies have shown variable results in some patients.24 Resection is recommended for RCC. If the tumor is less than 3 cm in size, surgery that conserves the parenchyma may be appropriate to optimize renal function without increasing the risk of metastases. The prognosis depends on the renal and pulmonary sequelae. 

Tuberous Sclerosis
TS, also called tuberous sclerosis complex (TSC), is a rare genetic disease that causes benign tumors to grow in the brain and other organs, such as the kidneys, lungs, skin, and eyes.25 Its incidence is 1 in 10,000 individuals and the age of presentation is variable. TS is an autosomal dominant disorder; approximately 40% of cases are hereditary and 60% are sporadic.26 Two gene mutations have been identified in contributing to the development of TS: the hamartin gene TSC1 on the chromosome arm 9q34 and tuberin gene TSC2 on the chromosome arm 16p13.3. The latter is adjacent to the PKD1 site, which is responsible for autosomal dominant polycystic kidney disease, thereby explaining the association of these 2 disorders in patients with contiguous gene defects. Hamartin and tuberin associate in vivo to form a tumor suppressor complex. This complex functions within the P13K-Akt-mTOR pathway and regulates nutrient and growth factor signaling to mTOR. As a result, rapamycin has potential therapeutic use in TS.26 The clinical features of TS include neurologic involvement with mental cognitive deficiency and epilepsy; psychiatric and behavioral problems such as attention deficit hyperactivity disorder and generalized development delays; and organic brain anomalies such as cortical tubera, subependymal giant cell astrocytomas, and subependymal nodules.25 Cardiac rhabdomyomas, retinal hamartomas, and dental pits also are typical findings of TS. Pulmonary lymphangioleiomyomatosis related to TS has been described, usually presenting exclusively in women. Classic cutaneous lesions include facial angiofibromas (adenoma sebaceum), the shagreen patch, and periungual or subungual fibromas (Koenen tumors).25 Renal manifestations are mainly angiomyolipomas, renal cysts, and cancer.27 In patients with TS, multiple lesions appear concomitantly and are likely to be bilateral. Larger lesions may present with flank pain, hypertension, hematuria, and renal failure. These lesions characteristically are benign, though there are some reports of sarcomatous degeneration and rare malignant epithelioid variants.27 Angiomyolipomas are not hamartomas per se, rather they are clonal perivascular epithelioid cell tumors (PEComas).28 PEComas are tumors composed of mostly epithelioid cells positive for HMB-45 and/or melan-A as well as actin- and/or desmin-positive cells. These PEComas have a perivascular propensity. They belong to a family of me-senchymal neoplasms that include angiomyolipomas, lymphangioleiomyomatosis, clear cell tumor (sugar tumor) of the lung, and other soft tissue and visceral neoplasms with similar histology and immunohistochemistry. Pan et al29 studied the cytogenetic feature of these tumors and reported that all cells studied had gross chromosomal anomalies, with the most frequent being a deletion of chromosome arm 16p, in which TSC2 is located. Alam et al30 concluded that PEComas are distinctive tumors based on the common chromosomal changes found in both renal and extrarenal tumors. Starting in childhood, renal ultrasounds can be used to detect and monitor the growth of angiomyolipomas. Because complications correlate with increasing size, surgery is recommended when the tumor is greater than 3.5 to 4.0 cm in size. Surgical options include tumor embolization, tumor enucleation, partial nephrectomy, or total nephrectomy depending on the presentation. Patients with TS are at a higher risk for renal cancer than the general population (2.0%–4.0% vs 1.27%, respectively) and are more likely to present at a younger age (30 years vs 60 years, respectively). Renal cancer in patients with TS is most commonly of the clear cell carcinoma type and is more likely to be multifocal and bilateral.2 For these reasons, lifelong periodic radiologic evaluation is essential. 

HLRCC Syndrome
HLRCC syndrome is an autosomal dominant disease that is an expansion of Reed syndrome (multiple cutaneous and uterine leiomyoma syndrome). It is characterized by the presence of leiomyomas in the skin and uterus of affected females and in the skin of affected males. Its prevalence in the general population is not known, though one limited study estimated the presence of a heterozygous fumarate hydratase, FH, gene mutation at 1 in 676 individuals.30 Germ line mutations in the FH gene at chromosome arm 1q42.3-43 are associated with the HLRCC syndrome.31 In the Krebs cycle, the FH and succinate dehydrogenase, SD, genes act as tumor suppressors. Mutations in the SD gene are associated with pheochromocytomas and paragangliomas. Mutations in the FH gene lead to the overexpression of HIF-1α and its targets (eg, vascular endothelial growth factor), which contributes to tumorigenesis by the so-called pseudohypoxic drive. There is a low frequency of FH mutations in sporadic cases of leiomyomas and leiomyosarcomas.31 The clinical features of patients with HLRCC syndrome include benign cutaneous and uterine leiomyomas and, more rarely, cutaneous leiomyosarcomas and uterine leiomyosarcomas. Cutaneous leiomyomas usually present in late childhood to early adulthood. They typically present as multiple disseminated lesions, most commonly on the face, trunk, and extremities, though segmental distribution also has been described.30 The individual lesions appear as intradermal papules. Alam et al30 stated that 90% of patients complain of pain from cutaneous leiomyoma, which is exacerbated by cold or trauma. Although leiomyomas may be solitary and sporadic lesions, Chuang et al32 noted that the finding of a cutaneous leiomyoma in a patient should compel dermatologists to examine the individual and his/her family for multiple lesions and to screen for the FH gene, which is crucial because FH mutations in HLRCC syndrome lead to increased susceptibility to early-onset RCC. These RCCs usually are solitary, fast growing, and very aggressive, and they display papillary cell carcinoma type 2 or renal collecting duct histology. Alam et al30 reported a case of a 16-year-old patient who presented with metastatic renal disease, which led the authors to urge the consideration of early screenings for FH mutations for patients. Toro et al33 screened 35 families with cutaneous leiomyomas for mutations in the FH gene. They identified mutations in 31 families (89%). Eighty-one individuals had cutaneous leiomyomas, of which 47 were women and 34 were men. Forty-six of 47 women (98%) had uterine leiomyomas. The authors also found 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from 4 families had papillary cell carcinoma type 2, and 1 individual from 1 of these families had renal collecting duct carcinoma.33 Patients who present with lesions that are diagnosed as cutaneous leiomyomas should prompt a complete history, including a history of fibroids in women as well as a family history of fibroids or renal tumors.34 Tests for mutations in the FH gene may be of value. Renal imaging studies should be performed in suspect cases. Although some papillary cell carcinoma type 2 or collecting duct RCCs can be found only with a CT scan or magnetic resonance imaging, a simple ultrasound is successful in most cases and can sometimes provide superior information about the characteristics of the renal tumor.34 

Conclusion
Dermatologists have a unique opportunity to diagnose hereditary renal tumors before they become life threatening. When examining patients with capillary malformations, fibrofolliculomas, angiofibromas, or leiomyomas, the dermatologist should consider the possibility of VHL syndrome, BHD syndrome, TS, or HLRCC syndrome, respectively. With a positive family history, renal imaging studies should be obtained. Although these syndromes are rare, it is essential that dermatologists recognize them for the benefit of the patients and their kin.

Dermatologists have a unique opportunity to recognize hereditary syndromes associated with renal tumors. By doing so, it may be possible to diagnose these tumors before they become life threatening. Although these syndromes are rare, it is incumbent upon dermatologists to recognize these disorders and recommend appropriate screening tests and referral to other specialists, including urologists, oncologists, and geneticists. Of the 9 known hereditary syndromes with renal tumors, 4 demonstrate cutaneous manifestations: von Hippel-Lindau (VHL) syndrome, Birt-Hogg-Dube (BHD) syndrome, tuberous sclerosis (TS), and hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome. Renal cell carcinoma (RCC) is diagnosed in more than 30,000 individuals in the United States each year, causes 12,000 deaths annually, and is increasing in incidence.1 Known risk factors for sporadic renal cancer include smoking, chemical exposure, asbestosis, obesity, hypertension, and end-stage renal disease. There is growing recognition that heredity also plays a role, and it is estimated that approximately 4% of renal cancers are hereditary. In these individuals, a germ line mutation is associated with a predisposition to develop renal tumors of specific histologic types.2 In the past 10 years, advances in genomics and the widespread use of modern imaging techniques have contributed to the awareness of hereditary renal cancer syndromes. Increased knowledge of these syndromes will allow dermatologists to screen and counsel family members as well as identify those patients at risk for multiple cancer development. Early screening to identify localized tumors will provide opportunities to therapeutically intervene while cancers are still treatable.3 Because 4 of these syndromes involve cutaneous manifestations, the dermatologist may have the opportunity to make the diagnosis at an early stage. Hereditary renal cancers differ from sporadic renal cancers in several important respects.2 A hallmark of hereditary renal cancer is that tumors often are multiple and bilateral. Unlike sporadic renal cancers, which develop in the sixth and seventh decades of life, hereditary renal cancers may develop much earlier, even in teenaged individuals. Although sporadic renal tumors are more common in men, hereditary renal cancers often are found with equal frequency in both sexes. Disease severity can be highly variable, even within a family, and the absence of a family history never completely excludes the possibility of a hereditary cause for renal cancer.2 

Renal Tumor Classification
There are several histologic types of renal cancer in adults and each is linked with a specific hereditary syndrome.2 The most common histologic subtype is clear cell carcinoma, which accounts for 75% of renal cancers. Clear cell carcinomas arise from the proximal tubular epithelium. Grossly, they appear yellow because of their high lipid content. Microscopically, these cells appear lucent because of their high glycogen content. Clear cell carcinomas are seen in VHL syndrome and TS.2 The second most common type of renal cancer is papillary cell carcinoma (15%).4 It is subclassified into type 1 and type 2. Type 1 is found in hereditary papillary renal cancer and is associated with a good long-term prognosis. It is characterized by cells with scant pale cytoplasm arranged in a single layer. Type 2 is found in HLRCC syndrome and is a more aggressive form. Type 2 cells are pseudostratified with an eosinophilic cytoplasm.4 Chromophobe carcinoma is the third most common cell type.3 This tumor contains cells with well-defined borders, large eosinophilic cytoplasm, and pyknotic nuclei with a perinuclear halo. The cell of origin is most likely the intercalated cell of the cortical collecting duct. Chromophobe carcinomas account for approximately 5% of renal cancers and are found in BHD syndrome.3 Oncocytomas account for 2% to 3% of renal tumors and are considered to be benign renal neoplasms.5 Grossly, they are mahogany brown and are not necrotic. Histologically, they are composed of tightly packed tubular structures or nesting cells surrounded by a reticulin skeleton. They commonly grow centrifugally from a central avascular scar. Oncocytomas can be found in BHD syndrome and hereditary renal oncocytoma.5 Rare malignant tumors of the kidney include collecting duct and medullary carcinomas, which represent only 1% of renal tumors. Transitional cell carcinoma of the renal pelvis is another cause of malignancy in the kidneys and is associated with hereditary nonpolyposis colon cancer syndrome (Lynch syndrome).6 A common benign tumor of the renal parenchyma is angiomyolipoma, which is a hamartoma of the kidneys that contains vascular, lipomatous, and myeloid elements. Most of these tumors are small and slow growing. The primary risk associated with angiomyolipoma is hemorrhage. These tumors are found in TS.7 The Table lists the hereditary renal cancers and their respective chromosomal and clinical associations.

 
Clinical Manifestations of Renal Tumors
Because of their insidious course and varied clinical presentations, renal tumors most commonly are diagnosed as incidental findings during radiologic procedures.8 The classic triad of symptoms—hematuria, flank pain, and an abdominal mass—is seen only in approximately 10% of patients; in most cases, only one of these symptoms is the initial manifestation of the tumor. Systemic symptoms may be present, including weight loss, fatigue, and fever. RCC also is associated with several paraneoplastic syndromes, such as polycythemia (from ectopic erythropoietin production) and hypercalcemia (from ectopic production of parathyroid hormone–related peptide). Metastases mainly are through hematologic spread, and the lungs, bones, and liver are the most frequent sites. 8 back to top

Prognosis and Staging of Renal Tumors
RCC remains a major source of morbidity and mortality.9 Approximately 40% of patients eventually die of cancer progression, making RCC the most lethal of the common urologic malignancies. Although modern imaging has led to earlier diagnosis of RCC, more than 20% of patients present with metastatic disease. Tumor stage remains the most important prognostic factor for RCC. When renal cancers are organ confined, the 5-year survival rate is between 74% and 96%. This rate decreases to 40% to 60% when the renal veins are involved. With locally advanced renal cancers, as well as those with lymphatic involvement or metastasis, the 5-year survival rate is 0% to 20%.9

Treatment of Renal Tumors
Surgical resection (nephrectomy, partial nephrectomy) remains the most viable treatment option for RCC, regardless of the stage of disease at presentation. For localized tumors, surgical cure of disease is strongly dependent on stage and grade of disease.10 For locally advanced or metastatic disease, nephrectomy should be considered for palliation or as part of an adjuvant therapy protocol. Curative lymphadenectomy is not possible in most cases, and the value of lymphadenectomy is limited to those patients with lymph node involvement. Limited dissection of tissue and resection of the visible or palpable nodes usually is sufficient.11 Renal tumors respond poorly to radiation, chemotherapy, and immunotherapy, with response rates of less than 20%.12 However, advances in the understanding of immune responses to RCC have led to new therapeutic strategies based on immune manipulation. The identification of numerous T-cell epitopes associated with RCC has led to the development of new treatment approaches using DNA vaccination, peptide vaccination, and dendritic cell therapy; combined with new and more efficient gene-delivery techniques, these treatments may have considerable clinical implications for patients with RCC.12 Targeted therapies that are currently being investigated for metastatic RCC include tyrosine kinase inhibitors (ie, sorafenib), anti–vascular endothelial growth factor therapy (ie, bevacizumab), and inhibition of the mammalian target of rapamycin (mTOR) pathway (ie, temsirolimus).13 back to top

VHL Syndrome
VHL syndrome represents a constellation of central nervous system (CNS) and visceral neoplasms that result from a germ line mutation of the VHL tumor suppressor gene on chromosome arm 3p25-26.14 In this autosomal dominant neurocutaneous syndrome, 80% of cases are hereditary and 20% are sporadic. The incidence of VHL syndrome is approximately 1 in 36,000 individuals.15 Patients with VHL syndrome typically present before the age of 40 years.16 Although less than 5% of cases of VHL syndrome have dermatologic manifestations, capillary malformations are the most common cutaneous features. Thus, the dermatologist must be vigilant to observe for VHL syndrome in the appropriate clinical context. More than 70% of sporadic clear cell RCCs display mutations in the VHL gene.17 The VHL protein produced via this gene is a ubiquitin ligase that degrades hypoxia-inducible factors (HIFs) including HIF-1α and HIF-2α. A mutation of the VHL gene can increase the levels of HIF, which subsequently activate additional genes that produce vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor α, and carbonic anhydrase IX. In concert, these factors facilitate neoangiogenesis and tumorigenesis.17 The mutation of the VHL gene leads to the development of both benign and malignant tumors that affect multiple organ systems. CNS tumors include retinal hemangioblastomas (20%–60%); endolymphatic sac tumors (11%–16%); and craniospinal hemangiomas, most frequently of the cerebellum (44%–72%), brainstem (10%–25%), and spinal cord (13%–50%). Additional manifestations of VHL syndrome include RCC or kidney cyst (25%–60%), epididymal cystadenoma (25%–60% of men), pancreatic cyst or cystadenoma (17%–56%), pheochromocytoma or paraganglioma (10%–20%), and broad ligament cystadenoma (10% of women).18 The capillary malformations of VHL syndrome often occur in but are not limited to the head and neck. Also, café au lait spots that frequently are associated with neurofibromatosis may be evident in VHL syndrome, suggesting overlap between these phakomatoses.19 VHL syndrome is a progressive disease, with death characteristically occurring by the fourth decade of life. The diagnosis of VHL syndrome is based on clinical criteria. Patients with a family history of VHL syndrome and a CNS hemangioblastoma, pheochromocytoma, or clear cell RCC are diagnosed with the syndrome. In the absence of a family history, the diagnosis can be made with 2 or more CNS hemangioblastomas and a visceral tumor, with the exclusion of renal and epididymal cysts. Confirmation of diagnosis and screening for possibly affected family members can be achieved with DNA testing for mutation in the VHL gene. Recommended laboratory tests include a complete blood count and screenings for serum catecholamine and urine vanillylmandelic acid levels, as well as a computed tomographic scan (CT scan) and/or magnetic resonance imaging of the brain, spinal cord, and abdomen. Patients diagnosed with VHL syndrome should be referred to an ophthalmologist for photocoagulation or cryocoagulation of tumors. Neurosurgeons and urologists may surgically remove CNS and renal tumors, respectively, with preoperative angiography. Patients with VHL syndrome also may consider renal transplantation.

BHD Syndrome
BHD syndrome, an autosomal dominant genodermatosis occurring in 1 in 200,000 individuals, is characterized by the cutaneous triad of fibrofolliculomas, trichodiscomas, and acrochordons. Vincent and colleagues20 offer a comprehensive analysis of these papules, which frequently appear in the third to fourth decades of life. Protein-truncating mutations of the BHD gene on chromosome arm 17p11.2 encode the BHD protein folliculin, which is expressed in the kidneys, lungs, and skin.21 Although the function of the protein is unknown, the BHD gene is presumptively involved in tumor suppression. Fibrofolliculomas and trichodiscomas are clinically indistinguishable; both are skin-colored, well-circumscribed, smooth, firm, 2- to 4-mm papules distributed over the forehead, nose, and cheeks.22 Acrochordons appear as soft pedunculated lesions. The clinical appearance of fibrofolliculomas and trichodiscomas is associated with familial spontaneous pneumothorax and RCCs. Notably, patients with BHD syndrome have a 50-fold increased risk of pneumothorax presenting with tachypnea, decreased breath sounds, and hyperresonance.23 Lung cysts and bullous emphysema also have been associated with BHD syndrome. In addition to the cutaneous and pulmonary features, a 7-fold increase in renal tumors with varying histology has been associated with BHD syndrome, including hybrid chromophobe and oncocytoma (50%), chromophobe (34%), clear cell RCC (9%), and oncocytoma (5%).23 Multiple histologic types can be found in the same family, patient, and kidney, suggesting a role for the BHD gene in the differentiation processes of renal cells. Fibrofolliculomas possess a circumscribed fibrous tissue layer around the hair follicles.24 These follicles demonstrate a widened infundibulum containing laminated keratin. Encasing the follicle is a mantle of loose connective tissue embedded in a mucoid ground substance with high concentrations of hyaluronic acid. The elastin fibers may not be visible or appear sparse. Radiating from the follicular epithelium are 2 to 4 thin layers of epithelial strands that extend into the fibrous tissue where they combine with epithelial strands or connect with follicular or sebaceous epithelium. In contrast, the histology of the trichodiscomas demonstrates hair follicles at the margin of these tumors. The stroma is highly vascularized, with collagen fibers and cells containing melanin.24 A diagnosis of BHD syndrome requires 5 or more facial or truncal papules; 1 papule must be confirmed as a fibrofolliculoma or trichodiscoma using the histologic criteria above. The differential diagnosis includes TS, Cowden syndrome, Brooke-Spiegler syndrome, Rombo syndrome, and basaloid follicular hamartoma syndrome. It is recommended that all patients who are diagnosed with BHD syndrome get a chest x-ray, abdominal CT scan, and renal ultrasound. Thereafter, patients may be screened every 3 to 5 years. Siblings of patients require physical examinations and biopsies of suspicious skin lesions as early as the second decade of life. Treatment options for fibrofolliculomas and trichodiscomas include CO2 laser ablation and/or erbium:YAG laser, copper vapor laser, and systemic isotretinoin, though these therapies have shown variable results in some patients.24 Resection is recommended for RCC. If the tumor is less than 3 cm in size, surgery that conserves the parenchyma may be appropriate to optimize renal function without increasing the risk of metastases. The prognosis depends on the renal and pulmonary sequelae. 

Tuberous Sclerosis
TS, also called tuberous sclerosis complex (TSC), is a rare genetic disease that causes benign tumors to grow in the brain and other organs, such as the kidneys, lungs, skin, and eyes.25 Its incidence is 1 in 10,000 individuals and the age of presentation is variable. TS is an autosomal dominant disorder; approximately 40% of cases are hereditary and 60% are sporadic.26 Two gene mutations have been identified in contributing to the development of TS: the hamartin gene TSC1 on the chromosome arm 9q34 and tuberin gene TSC2 on the chromosome arm 16p13.3. The latter is adjacent to the PKD1 site, which is responsible for autosomal dominant polycystic kidney disease, thereby explaining the association of these 2 disorders in patients with contiguous gene defects. Hamartin and tuberin associate in vivo to form a tumor suppressor complex. This complex functions within the P13K-Akt-mTOR pathway and regulates nutrient and growth factor signaling to mTOR. As a result, rapamycin has potential therapeutic use in TS.26 The clinical features of TS include neurologic involvement with mental cognitive deficiency and epilepsy; psychiatric and behavioral problems such as attention deficit hyperactivity disorder and generalized development delays; and organic brain anomalies such as cortical tubera, subependymal giant cell astrocytomas, and subependymal nodules.25 Cardiac rhabdomyomas, retinal hamartomas, and dental pits also are typical findings of TS. Pulmonary lymphangioleiomyomatosis related to TS has been described, usually presenting exclusively in women. Classic cutaneous lesions include facial angiofibromas (adenoma sebaceum), the shagreen patch, and periungual or subungual fibromas (Koenen tumors).25 Renal manifestations are mainly angiomyolipomas, renal cysts, and cancer.27 In patients with TS, multiple lesions appear concomitantly and are likely to be bilateral. Larger lesions may present with flank pain, hypertension, hematuria, and renal failure. These lesions characteristically are benign, though there are some reports of sarcomatous degeneration and rare malignant epithelioid variants.27 Angiomyolipomas are not hamartomas per se, rather they are clonal perivascular epithelioid cell tumors (PEComas).28 PEComas are tumors composed of mostly epithelioid cells positive for HMB-45 and/or melan-A as well as actin- and/or desmin-positive cells. These PEComas have a perivascular propensity. They belong to a family of me-senchymal neoplasms that include angiomyolipomas, lymphangioleiomyomatosis, clear cell tumor (sugar tumor) of the lung, and other soft tissue and visceral neoplasms with similar histology and immunohistochemistry. Pan et al29 studied the cytogenetic feature of these tumors and reported that all cells studied had gross chromosomal anomalies, with the most frequent being a deletion of chromosome arm 16p, in which TSC2 is located. Alam et al30 concluded that PEComas are distinctive tumors based on the common chromosomal changes found in both renal and extrarenal tumors. Starting in childhood, renal ultrasounds can be used to detect and monitor the growth of angiomyolipomas. Because complications correlate with increasing size, surgery is recommended when the tumor is greater than 3.5 to 4.0 cm in size. Surgical options include tumor embolization, tumor enucleation, partial nephrectomy, or total nephrectomy depending on the presentation. Patients with TS are at a higher risk for renal cancer than the general population (2.0%–4.0% vs 1.27%, respectively) and are more likely to present at a younger age (30 years vs 60 years, respectively). Renal cancer in patients with TS is most commonly of the clear cell carcinoma type and is more likely to be multifocal and bilateral.2 For these reasons, lifelong periodic radiologic evaluation is essential. 

HLRCC Syndrome
HLRCC syndrome is an autosomal dominant disease that is an expansion of Reed syndrome (multiple cutaneous and uterine leiomyoma syndrome). It is characterized by the presence of leiomyomas in the skin and uterus of affected females and in the skin of affected males. Its prevalence in the general population is not known, though one limited study estimated the presence of a heterozygous fumarate hydratase, FH, gene mutation at 1 in 676 individuals.30 Germ line mutations in the FH gene at chromosome arm 1q42.3-43 are associated with the HLRCC syndrome.31 In the Krebs cycle, the FH and succinate dehydrogenase, SD, genes act as tumor suppressors. Mutations in the SD gene are associated with pheochromocytomas and paragangliomas. Mutations in the FH gene lead to the overexpression of HIF-1α and its targets (eg, vascular endothelial growth factor), which contributes to tumorigenesis by the so-called pseudohypoxic drive. There is a low frequency of FH mutations in sporadic cases of leiomyomas and leiomyosarcomas.31 The clinical features of patients with HLRCC syndrome include benign cutaneous and uterine leiomyomas and, more rarely, cutaneous leiomyosarcomas and uterine leiomyosarcomas. Cutaneous leiomyomas usually present in late childhood to early adulthood. They typically present as multiple disseminated lesions, most commonly on the face, trunk, and extremities, though segmental distribution also has been described.30 The individual lesions appear as intradermal papules. Alam et al30 stated that 90% of patients complain of pain from cutaneous leiomyoma, which is exacerbated by cold or trauma. Although leiomyomas may be solitary and sporadic lesions, Chuang et al32 noted that the finding of a cutaneous leiomyoma in a patient should compel dermatologists to examine the individual and his/her family for multiple lesions and to screen for the FH gene, which is crucial because FH mutations in HLRCC syndrome lead to increased susceptibility to early-onset RCC. These RCCs usually are solitary, fast growing, and very aggressive, and they display papillary cell carcinoma type 2 or renal collecting duct histology. Alam et al30 reported a case of a 16-year-old patient who presented with metastatic renal disease, which led the authors to urge the consideration of early screenings for FH mutations for patients. Toro et al33 screened 35 families with cutaneous leiomyomas for mutations in the FH gene. They identified mutations in 31 families (89%). Eighty-one individuals had cutaneous leiomyomas, of which 47 were women and 34 were men. Forty-six of 47 women (98%) had uterine leiomyomas. The authors also found 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from 4 families had papillary cell carcinoma type 2, and 1 individual from 1 of these families had renal collecting duct carcinoma.33 Patients who present with lesions that are diagnosed as cutaneous leiomyomas should prompt a complete history, including a history of fibroids in women as well as a family history of fibroids or renal tumors.34 Tests for mutations in the FH gene may be of value. Renal imaging studies should be performed in suspect cases. Although some papillary cell carcinoma type 2 or collecting duct RCCs can be found only with a CT scan or magnetic resonance imaging, a simple ultrasound is successful in most cases and can sometimes provide superior information about the characteristics of the renal tumor.34 

Conclusion
Dermatologists have a unique opportunity to diagnose hereditary renal tumors before they become life threatening. When examining patients with capillary malformations, fibrofolliculomas, angiofibromas, or leiomyomas, the dermatologist should consider the possibility of VHL syndrome, BHD syndrome, TS, or HLRCC syndrome, respectively. With a positive family history, renal imaging studies should be obtained. Although these syndromes are rare, it is essential that dermatologists recognize them for the benefit of the patients and their kin.

BALTIMORE — Several classic parameters of melanoma histology are associated with survival and thus have a role in evaluating black patients, according to a poster presented at the annual meeting of the American Society of Dermatopathology.

"The incidence of melanoma in [blacks] is approximately 20 times lower than in [whites], presumptively because of the protective effects of melanin," wrote Dr. Doru T. Alexandrescu of the melanoma center at the Washington (D.C.) Hospital Center and his colleagues.

When blacks do present with melanoma, they are more likely to have stage III or IV disease, thicker primaries, and a poor prognosis. Histologic parameters of melanoma have not previously been described in black patients, the investigators noted.

For this study, the researchers analyzed the biopsy specimens of 68 black patients with malignant melanoma, of which 34 were evaluable histologically. The average patient age was 62 years.

Classic "histological parameters in melanoma such as Breslow depth, Clark level, ulceration, number of mitoses, and neutropism confirm their value in [black] patients by associating a statistically significant influence on survival," Dr. Alexandrescu and his associates wrote.

The mean Breslow depth of the biopsy specimens was 3.28 mm, and the mean Clark level was IV.

Pagetoid spread was found in 90% of specimens. Vertical growth phase was found in 70%, ulceration in 44%, neutropism in 36%, and necrosis in 30%.

The mean number of mitoses per high-power field was 1.36. Sentinel lymph-node positivity was 38%, and the local recurrence rate was 25%.

Tumor fibrosis was rated as none (0), mild (1), moderate (2), and severe (3). Mean tumor fibrosis was 1.5. In addition, the microvascular density inside the tumor was less (0.85) than it was under the tumor (1.85), compared with the surrounding skin.

BALTIMORE — Several classic parameters of melanoma histology are associated with survival and thus have a role in evaluating black patients, according to a poster presented at the annual meeting of the American Society of Dermatopathology.

"The incidence of melanoma in [blacks] is approximately 20 times lower than in [whites], presumptively because of the protective effects of melanin," wrote Dr. Doru T. Alexandrescu of the melanoma center at the Washington (D.C.) Hospital Center and his colleagues.

When blacks do present with melanoma, they are more likely to have stage III or IV disease, thicker primaries, and a poor prognosis. Histologic parameters of melanoma have not previously been described in black patients, the investigators noted.

For this study, the researchers analyzed the biopsy specimens of 68 black patients with malignant melanoma, of which 34 were evaluable histologically. The average patient age was 62 years.

Classic "histological parameters in melanoma such as Breslow depth, Clark level, ulceration, number of mitoses, and neutropism confirm their value in [black] patients by associating a statistically significant influence on survival," Dr. Alexandrescu and his associates wrote.

The mean Breslow depth of the biopsy specimens was 3.28 mm, and the mean Clark level was IV.

Pagetoid spread was found in 90% of specimens. Vertical growth phase was found in 70%, ulceration in 44%, neutropism in 36%, and necrosis in 30%.

The mean number of mitoses per high-power field was 1.36. Sentinel lymph-node positivity was 38%, and the local recurrence rate was 25%.

Tumor fibrosis was rated as none (0), mild (1), moderate (2), and severe (3). Mean tumor fibrosis was 1.5. In addition, the microvascular density inside the tumor was less (0.85) than it was under the tumor (1.85), compared with the surrounding skin.

BALTIMORE — Several classic parameters of melanoma histology are associated with survival and thus have a role in evaluating black patients, according to a poster presented at the annual meeting of the American Society of Dermatopathology.

"The incidence of melanoma in [blacks] is approximately 20 times lower than in [whites], presumptively because of the protective effects of melanin," wrote Dr. Doru T. Alexandrescu of the melanoma center at the Washington (D.C.) Hospital Center and his colleagues.

When blacks do present with melanoma, they are more likely to have stage III or IV disease, thicker primaries, and a poor prognosis. Histologic parameters of melanoma have not previously been described in black patients, the investigators noted.

For this study, the researchers analyzed the biopsy specimens of 68 black patients with malignant melanoma, of which 34 were evaluable histologically. The average patient age was 62 years.

Classic "histological parameters in melanoma such as Breslow depth, Clark level, ulceration, number of mitoses, and neutropism confirm their value in [black] patients by associating a statistically significant influence on survival," Dr. Alexandrescu and his associates wrote.

The mean Breslow depth of the biopsy specimens was 3.28 mm, and the mean Clark level was IV.

Pagetoid spread was found in 90% of specimens. Vertical growth phase was found in 70%, ulceration in 44%, neutropism in 36%, and necrosis in 30%.

The mean number of mitoses per high-power field was 1.36. Sentinel lymph-node positivity was 38%, and the local recurrence rate was 25%.

Tumor fibrosis was rated as none (0), mild (1), moderate (2), and severe (3). Mean tumor fibrosis was 1.5. In addition, the microvascular density inside the tumor was less (0.85) than it was under the tumor (1.85), compared with the surrounding skin.

NEW YORK — Subungual melanomas are often difficult to diagnose and thus present in an advanced clinical stage with poor prognosis, Dr. Richard Scolyer said at the Fourth International Melanoma Congress.

A review of the Sydney Melanoma Unit's experience between 1951 and 2004 showed that 124 patients presented with subungual melanoma (64 men and 60 women). The median patient age was 59 years, and the most common site was the great toe (24%). Most melanomas were locally advanced, with median Breslow thickness of 3.2 mm. Sentinel lymph node biopsy was positive in 24% (7 of 29 patients).

Follow-up data were available for 9 of 11 patients with in situ melanoma. American Joint Committee on Cancer disease stage at diagnosis, which was known in 121 patients, was the most important survival factor. Eleven patients (9%) were stage 0 (melanoma in situ), 16 (13%) were stage I, 50 (40%) were stage II, 39 (31%) were stage III, and 5 (4%) were stage IV.

The most common presentation in this group of patients was a pigmented subungual lesion or a raised or polypoid nodule, but "in more than one-third of patients (35%), there was no visible pigmentation in the affected area," said Dr. Scolyer of the University of Sydney.

Biopsies can be challenging to pathologists, in part because the features of melanoma in situ and the radial growth phase of melanoma are subtle. The most common early sign is longitudinal melanonychia. Particular red flags in these pigmented bands are increasing width, irregular width, and irregular spacing under dermoscopy, as well as extensions onto the proximal lateral nail fold (Hutchinson's sign). Subungual hematoma is important in the differential diagnosis, he said.

Unlike other melanomas, subungual melanoma is not associated with exposure to UV light, given that the nail plate is a UV barrier. Thus, incidence is similar among different ethnic backgrounds and skin tones. However, because melanomas in general are rare in people with darker skin, subungual melanomas make up a greater portion of melanomas among such persons, Dr. Scolyer noted.

NEW YORK — Subungual melanomas are often difficult to diagnose and thus present in an advanced clinical stage with poor prognosis, Dr. Richard Scolyer said at the Fourth International Melanoma Congress.

A review of the Sydney Melanoma Unit's experience between 1951 and 2004 showed that 124 patients presented with subungual melanoma (64 men and 60 women). The median patient age was 59 years, and the most common site was the great toe (24%). Most melanomas were locally advanced, with median Breslow thickness of 3.2 mm. Sentinel lymph node biopsy was positive in 24% (7 of 29 patients).

Follow-up data were available for 9 of 11 patients with in situ melanoma. American Joint Committee on Cancer disease stage at diagnosis, which was known in 121 patients, was the most important survival factor. Eleven patients (9%) were stage 0 (melanoma in situ), 16 (13%) were stage I, 50 (40%) were stage II, 39 (31%) were stage III, and 5 (4%) were stage IV.

The most common presentation in this group of patients was a pigmented subungual lesion or a raised or polypoid nodule, but "in more than one-third of patients (35%), there was no visible pigmentation in the affected area," said Dr. Scolyer of the University of Sydney.

Biopsies can be challenging to pathologists, in part because the features of melanoma in situ and the radial growth phase of melanoma are subtle. The most common early sign is longitudinal melanonychia. Particular red flags in these pigmented bands are increasing width, irregular width, and irregular spacing under dermoscopy, as well as extensions onto the proximal lateral nail fold (Hutchinson's sign). Subungual hematoma is important in the differential diagnosis, he said.

Unlike other melanomas, subungual melanoma is not associated with exposure to UV light, given that the nail plate is a UV barrier. Thus, incidence is similar among different ethnic backgrounds and skin tones. However, because melanomas in general are rare in people with darker skin, subungual melanomas make up a greater portion of melanomas among such persons, Dr. Scolyer noted.

NEW YORK — Subungual melanomas are often difficult to diagnose and thus present in an advanced clinical stage with poor prognosis, Dr. Richard Scolyer said at the Fourth International Melanoma Congress.

A review of the Sydney Melanoma Unit's experience between 1951 and 2004 showed that 124 patients presented with subungual melanoma (64 men and 60 women). The median patient age was 59 years, and the most common site was the great toe (24%). Most melanomas were locally advanced, with median Breslow thickness of 3.2 mm. Sentinel lymph node biopsy was positive in 24% (7 of 29 patients).

Follow-up data were available for 9 of 11 patients with in situ melanoma. American Joint Committee on Cancer disease stage at diagnosis, which was known in 121 patients, was the most important survival factor. Eleven patients (9%) were stage 0 (melanoma in situ), 16 (13%) were stage I, 50 (40%) were stage II, 39 (31%) were stage III, and 5 (4%) were stage IV.

The most common presentation in this group of patients was a pigmented subungual lesion or a raised or polypoid nodule, but "in more than one-third of patients (35%), there was no visible pigmentation in the affected area," said Dr. Scolyer of the University of Sydney.

Biopsies can be challenging to pathologists, in part because the features of melanoma in situ and the radial growth phase of melanoma are subtle. The most common early sign is longitudinal melanonychia. Particular red flags in these pigmented bands are increasing width, irregular width, and irregular spacing under dermoscopy, as well as extensions onto the proximal lateral nail fold (Hutchinson's sign). Subungual hematoma is important in the differential diagnosis, he said.

Unlike other melanomas, subungual melanoma is not associated with exposure to UV light, given that the nail plate is a UV barrier. Thus, incidence is similar among different ethnic backgrounds and skin tones. However, because melanomas in general are rare in people with darker skin, subungual melanomas make up a greater portion of melanomas among such persons, Dr. Scolyer noted.

LOS ANGELES — Use of intensity-modulated radiation therapy rather than conventional radiation significantly reduced the severity and duration of acute dermatitis in a review of consecutive cancer patients who underwent whole breast radiation after breast-conserving surgery.

All but 3% of 804 women experienced some acute dermatitis during the treatments, which typically lasted 7-8 weeks, Dr. Gary M. Freedman of Fox Chase Cancer Center in Philadelphia reported at the annual meeting of the American Society for Therapeutic Radiation and Oncology.

Of all patients who were treated from 2001 to 2006 in the multivariate analysis that considered week of treatment and breast size, 61% experienced grade 2 toxicity (with 0 being no toxicity and 5 being death), according to the National Cancer Institute Common Toxicity Criteria scale for acute dermatitis. For these women, skin reactions included moderate to brisk erythema, patchy moist desquamation (mostly confined to skinfolds and creases), and moderate edema.

Of all the women who underwent radiation therapy, 34% had grade 1 skin toxicity, a category comprising faint erythema or dry desquamation. For 2%, radiation treatments resulted in grade 3 toxicity, by which minor trauma or abrasion could cause the breast to bleed and moist desquamation went beyond the skinfolds and creases.

The investigators then stratified the women and found acute dermatitis tended to be milder with the newer intensity-modulated radiation therapy (IMRT). The advantage was seen every week that treatment was given in women with all breast sizes.

Nearly half, 48%, of the 399 women undergoing IMRT had nothing worse than grade 1 dermatitis, compared with 25% of 405 women given radiation with conventional wedged photon tangents. Conversely, three-fourths of the women treated with conventional radiation, but only 52% of the IMRT cohort, experienced grade 2 and 3 dermatitis, a statistically significant difference.

The duration of grade 2 and 3 dermatitis also was shorter with IMRT. Women treated with this technique spent only 18% of their treatment weeks in this combined category, as opposed to 71% of the time for women given conventional radiation.

IMRT conveys "less toxicity to the skin during treatment and less risk of peeling of the skin," Dr. Freedman said in an interview. Longer follow-up is needed before investigators can show better cosmetic results 5 years after treatment. However, "we feel that is going to translate long term into better cosmetic results," he said.

At Fox Chase, radiation oncologists transitioned to IMRT around 2004, and use it in most cases, "insurance permitting," according to Dr. Freedman. Some major carriers have balked at the higher cost of IMRT, which employs more radiation beams and requires more planning. Where they don't disallow it outright, they may pay for IMRT only in cases of left-sided breast cancer where there is a risk of radiation damaging the heart.

"The majority of women in this country are still being treated with conventional radiation," he said, questioning the fairness of insurance industry practices limiting access to IMRT for women with breast cancer.

IMRT is favored as a way of reducing radiation doses to the bladder and rectum in men with prostate cancer, Dr. Freedman maintained. "The first thing to come through was prostate cancer, and insurance companies welcomed that with open arms," he said. "I feel breast cancer is being held to a higher standard. The same is true for head and neck cancer."

LOS ANGELES — Use of intensity-modulated radiation therapy rather than conventional radiation significantly reduced the severity and duration of acute dermatitis in a review of consecutive cancer patients who underwent whole breast radiation after breast-conserving surgery.

All but 3% of 804 women experienced some acute dermatitis during the treatments, which typically lasted 7-8 weeks, Dr. Gary M. Freedman of Fox Chase Cancer Center in Philadelphia reported at the annual meeting of the American Society for Therapeutic Radiation and Oncology.

Of all patients who were treated from 2001 to 2006 in the multivariate analysis that considered week of treatment and breast size, 61% experienced grade 2 toxicity (with 0 being no toxicity and 5 being death), according to the National Cancer Institute Common Toxicity Criteria scale for acute dermatitis. For these women, skin reactions included moderate to brisk erythema, patchy moist desquamation (mostly confined to skinfolds and creases), and moderate edema.

Of all the women who underwent radiation therapy, 34% had grade 1 skin toxicity, a category comprising faint erythema or dry desquamation. For 2%, radiation treatments resulted in grade 3 toxicity, by which minor trauma or abrasion could cause the breast to bleed and moist desquamation went beyond the skinfolds and creases.

The investigators then stratified the women and found acute dermatitis tended to be milder with the newer intensity-modulated radiation therapy (IMRT). The advantage was seen every week that treatment was given in women with all breast sizes.

Nearly half, 48%, of the 399 women undergoing IMRT had nothing worse than grade 1 dermatitis, compared with 25% of 405 women given radiation with conventional wedged photon tangents. Conversely, three-fourths of the women treated with conventional radiation, but only 52% of the IMRT cohort, experienced grade 2 and 3 dermatitis, a statistically significant difference.

The duration of grade 2 and 3 dermatitis also was shorter with IMRT. Women treated with this technique spent only 18% of their treatment weeks in this combined category, as opposed to 71% of the time for women given conventional radiation.

IMRT conveys "less toxicity to the skin during treatment and less risk of peeling of the skin," Dr. Freedman said in an interview. Longer follow-up is needed before investigators can show better cosmetic results 5 years after treatment. However, "we feel that is going to translate long term into better cosmetic results," he said.

At Fox Chase, radiation oncologists transitioned to IMRT around 2004, and use it in most cases, "insurance permitting," according to Dr. Freedman. Some major carriers have balked at the higher cost of IMRT, which employs more radiation beams and requires more planning. Where they don't disallow it outright, they may pay for IMRT only in cases of left-sided breast cancer where there is a risk of radiation damaging the heart.

"The majority of women in this country are still being treated with conventional radiation," he said, questioning the fairness of insurance industry practices limiting access to IMRT for women with breast cancer.

IMRT is favored as a way of reducing radiation doses to the bladder and rectum in men with prostate cancer, Dr. Freedman maintained. "The first thing to come through was prostate cancer, and insurance companies welcomed that with open arms," he said. "I feel breast cancer is being held to a higher standard. The same is true for head and neck cancer."

LOS ANGELES — Use of intensity-modulated radiation therapy rather than conventional radiation significantly reduced the severity and duration of acute dermatitis in a review of consecutive cancer patients who underwent whole breast radiation after breast-conserving surgery.

All but 3% of 804 women experienced some acute dermatitis during the treatments, which typically lasted 7-8 weeks, Dr. Gary M. Freedman of Fox Chase Cancer Center in Philadelphia reported at the annual meeting of the American Society for Therapeutic Radiation and Oncology.

Of all patients who were treated from 2001 to 2006 in the multivariate analysis that considered week of treatment and breast size, 61% experienced grade 2 toxicity (with 0 being no toxicity and 5 being death), according to the National Cancer Institute Common Toxicity Criteria scale for acute dermatitis. For these women, skin reactions included moderate to brisk erythema, patchy moist desquamation (mostly confined to skinfolds and creases), and moderate edema.

Of all the women who underwent radiation therapy, 34% had grade 1 skin toxicity, a category comprising faint erythema or dry desquamation. For 2%, radiation treatments resulted in grade 3 toxicity, by which minor trauma or abrasion could cause the breast to bleed and moist desquamation went beyond the skinfolds and creases.

The investigators then stratified the women and found acute dermatitis tended to be milder with the newer intensity-modulated radiation therapy (IMRT). The advantage was seen every week that treatment was given in women with all breast sizes.

Nearly half, 48%, of the 399 women undergoing IMRT had nothing worse than grade 1 dermatitis, compared with 25% of 405 women given radiation with conventional wedged photon tangents. Conversely, three-fourths of the women treated with conventional radiation, but only 52% of the IMRT cohort, experienced grade 2 and 3 dermatitis, a statistically significant difference.

The duration of grade 2 and 3 dermatitis also was shorter with IMRT. Women treated with this technique spent only 18% of their treatment weeks in this combined category, as opposed to 71% of the time for women given conventional radiation.

IMRT conveys "less toxicity to the skin during treatment and less risk of peeling of the skin," Dr. Freedman said in an interview. Longer follow-up is needed before investigators can show better cosmetic results 5 years after treatment. However, "we feel that is going to translate long term into better cosmetic results," he said.

At Fox Chase, radiation oncologists transitioned to IMRT around 2004, and use it in most cases, "insurance permitting," according to Dr. Freedman. Some major carriers have balked at the higher cost of IMRT, which employs more radiation beams and requires more planning. Where they don't disallow it outright, they may pay for IMRT only in cases of left-sided breast cancer where there is a risk of radiation damaging the heart.

"The majority of women in this country are still being treated with conventional radiation," he said, questioning the fairness of insurance industry practices limiting access to IMRT for women with breast cancer.

IMRT is favored as a way of reducing radiation doses to the bladder and rectum in men with prostate cancer, Dr. Freedman maintained. "The first thing to come through was prostate cancer, and insurance companies welcomed that with open arms," he said. "I feel breast cancer is being held to a higher standard. The same is true for head and neck cancer."

MONTEREY, CALIF. — The initial preoperative diagnoses of nail lesions that prove to be squamous cell carcinoma run the gamut from onychomycosis to subungual verruca, Dr. Phoebe Rich said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

In her own practice, one such lesion was oozing and appeared onycholytic, she explained, displaying a slide of the crusty lesion at the nail edge.

"It doesn't look like much," said Dr. Rich, director of the nail center at Oregon Health and Science University, Portland.

Among 13 SCC cases diagnosed by Dr. Rich, who is also in private practice, six appeared verrucous and six eczematoid, in addition to the onycholytic case.

Earlier this year, a clinicopathological review of SCC of the nail apparatus by French researchers revealed that subungual SCC was the preoperative diagnosis in only 10 of 35 patients (Br. J. Dermatol. 2007;156:871-4). Nine cases were originally thought to be onychomycosis, five were diagnosed as subungual verruca, and five were thought to be "longitudinal melanonychia (nevus, melanoma)." Six cases carried a variety of other preoperative diagnoses, including exostosis and onychomatricoma.

The lesson is to always be thinking of SCC of the nail as a possibility, she stressed.

MONTEREY, CALIF. — The initial preoperative diagnoses of nail lesions that prove to be squamous cell carcinoma run the gamut from onychomycosis to subungual verruca, Dr. Phoebe Rich said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

In her own practice, one such lesion was oozing and appeared onycholytic, she explained, displaying a slide of the crusty lesion at the nail edge.

"It doesn't look like much," said Dr. Rich, director of the nail center at Oregon Health and Science University, Portland.

Among 13 SCC cases diagnosed by Dr. Rich, who is also in private practice, six appeared verrucous and six eczematoid, in addition to the onycholytic case.

Earlier this year, a clinicopathological review of SCC of the nail apparatus by French researchers revealed that subungual SCC was the preoperative diagnosis in only 10 of 35 patients (Br. J. Dermatol. 2007;156:871-4). Nine cases were originally thought to be onychomycosis, five were diagnosed as subungual verruca, and five were thought to be "longitudinal melanonychia (nevus, melanoma)." Six cases carried a variety of other preoperative diagnoses, including exostosis and onychomatricoma.

The lesson is to always be thinking of SCC of the nail as a possibility, she stressed.

MONTEREY, CALIF. — The initial preoperative diagnoses of nail lesions that prove to be squamous cell carcinoma run the gamut from onychomycosis to subungual verruca, Dr. Phoebe Rich said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

In her own practice, one such lesion was oozing and appeared onycholytic, she explained, displaying a slide of the crusty lesion at the nail edge.

"It doesn't look like much," said Dr. Rich, director of the nail center at Oregon Health and Science University, Portland.

Among 13 SCC cases diagnosed by Dr. Rich, who is also in private practice, six appeared verrucous and six eczematoid, in addition to the onycholytic case.

Earlier this year, a clinicopathological review of SCC of the nail apparatus by French researchers revealed that subungual SCC was the preoperative diagnosis in only 10 of 35 patients (Br. J. Dermatol. 2007;156:871-4). Nine cases were originally thought to be onychomycosis, five were diagnosed as subungual verruca, and five were thought to be "longitudinal melanonychia (nevus, melanoma)." Six cases carried a variety of other preoperative diagnoses, including exostosis and onychomatricoma.

The lesson is to always be thinking of SCC of the nail as a possibility, she stressed.

MONTEREY, CALIF. — Proper management and orientation of nail biopsy specimens will help ensure that the ensuing diagnosis is accurate, Dr. Phoebe Rich advised colleagues at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

"If you send these in and they're sectioned wrong, you're going to get the wrong answer or you're not going to get an answer at all," said Dr. Rich, director of the nail center at Oregon Health and Science University in Portland.

She places the properly oriented specimen on a piece of paper that contains a photocopied template of a nail. "I orient it the way that I want the pathologist to look at it," she said.

As an example, she showed how she oriented the biopsy specimen from a lesion suspicious for melanoma in which she took the nail plate, matrix, part of the nail fold, and the nail bed. The tissue was placed directly on the diagram of the nail, and the nail plate was sent to the pathologist as well.

"The pathologist knows to section this in a longitudinal way. If you were to 'breadloaf' this, you're probably not going to get your answer," she said.

The pathologist sections right through the specimen and the paper, preserving the orientation.

There is no need to affix the specimen to the paper. "If you put it down right away on the paper, it actually sticks. I let it sit there for a few minutes before I put it in the formalin and it actually will adhere to the paper," Dr. Rich explained.

She noted that in many cases, an accurate diagnosis will not require removal of the entire nail plate.

"I tell the residents: 'Unless the nail plate is deformed by the tumor, you're not dealing with a deep lesion. You can really just take off the top part and you're still going to get your answer very, very nicely,'" she said.

Biopsy any unexplained pigmented lesion at the origin of the band by cutting along and peeling back the affected part of the nail as necessary, saucerizing the lesion, and scoring around it, she explained.

The distal plate can often be preserved, she said.

In response to a question from the audience, Dr. Rich acknowledged the difficulty in knowing whether or when to biopsy a pigmented nail in a person with naturally pigmented nails, such as is often the case in African American patients.

Look for pigment that is different from that in the other nails, changing, or larger than the norm for that patient, she recommended.

"Just like in patients with a lot of moles, you look for the ugly duckling."

MONTEREY, CALIF. — Proper management and orientation of nail biopsy specimens will help ensure that the ensuing diagnosis is accurate, Dr. Phoebe Rich advised colleagues at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

"If you send these in and they're sectioned wrong, you're going to get the wrong answer or you're not going to get an answer at all," said Dr. Rich, director of the nail center at Oregon Health and Science University in Portland.

She places the properly oriented specimen on a piece of paper that contains a photocopied template of a nail. "I orient it the way that I want the pathologist to look at it," she said.

As an example, she showed how she oriented the biopsy specimen from a lesion suspicious for melanoma in which she took the nail plate, matrix, part of the nail fold, and the nail bed. The tissue was placed directly on the diagram of the nail, and the nail plate was sent to the pathologist as well.

"The pathologist knows to section this in a longitudinal way. If you were to 'breadloaf' this, you're probably not going to get your answer," she said.

The pathologist sections right through the specimen and the paper, preserving the orientation.

There is no need to affix the specimen to the paper. "If you put it down right away on the paper, it actually sticks. I let it sit there for a few minutes before I put it in the formalin and it actually will adhere to the paper," Dr. Rich explained.

She noted that in many cases, an accurate diagnosis will not require removal of the entire nail plate.

"I tell the residents: 'Unless the nail plate is deformed by the tumor, you're not dealing with a deep lesion. You can really just take off the top part and you're still going to get your answer very, very nicely,'" she said.

Biopsy any unexplained pigmented lesion at the origin of the band by cutting along and peeling back the affected part of the nail as necessary, saucerizing the lesion, and scoring around it, she explained.

The distal plate can often be preserved, she said.

In response to a question from the audience, Dr. Rich acknowledged the difficulty in knowing whether or when to biopsy a pigmented nail in a person with naturally pigmented nails, such as is often the case in African American patients.

Look for pigment that is different from that in the other nails, changing, or larger than the norm for that patient, she recommended.

"Just like in patients with a lot of moles, you look for the ugly duckling."

MONTEREY, CALIF. — Proper management and orientation of nail biopsy specimens will help ensure that the ensuing diagnosis is accurate, Dr. Phoebe Rich advised colleagues at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

"If you send these in and they're sectioned wrong, you're going to get the wrong answer or you're not going to get an answer at all," said Dr. Rich, director of the nail center at Oregon Health and Science University in Portland.

She places the properly oriented specimen on a piece of paper that contains a photocopied template of a nail. "I orient it the way that I want the pathologist to look at it," she said.

As an example, she showed how she oriented the biopsy specimen from a lesion suspicious for melanoma in which she took the nail plate, matrix, part of the nail fold, and the nail bed. The tissue was placed directly on the diagram of the nail, and the nail plate was sent to the pathologist as well.

"The pathologist knows to section this in a longitudinal way. If you were to 'breadloaf' this, you're probably not going to get your answer," she said.

The pathologist sections right through the specimen and the paper, preserving the orientation.

There is no need to affix the specimen to the paper. "If you put it down right away on the paper, it actually sticks. I let it sit there for a few minutes before I put it in the formalin and it actually will adhere to the paper," Dr. Rich explained.

She noted that in many cases, an accurate diagnosis will not require removal of the entire nail plate.

"I tell the residents: 'Unless the nail plate is deformed by the tumor, you're not dealing with a deep lesion. You can really just take off the top part and you're still going to get your answer very, very nicely,'" she said.

Biopsy any unexplained pigmented lesion at the origin of the band by cutting along and peeling back the affected part of the nail as necessary, saucerizing the lesion, and scoring around it, she explained.

The distal plate can often be preserved, she said.

In response to a question from the audience, Dr. Rich acknowledged the difficulty in knowing whether or when to biopsy a pigmented nail in a person with naturally pigmented nails, such as is often the case in African American patients.

Look for pigment that is different from that in the other nails, changing, or larger than the norm for that patient, she recommended.

"Just like in patients with a lot of moles, you look for the ugly duckling."

ZURICH — Intravenous paclitaxel is the treatment of choice in patients whose AIDS-related Kaposi sarcoma isn't responsive to liposomal anthracyclines, Dr. Erwin Tschachler said at the annual meeting of the European Society for Dermatological Research.

"It's more cytotoxic, has more side effects, but works in a considerable percentage of patients in which other cytotoxic therapies have failed. So it's not a first-line treatment," explained Dr. Tschachler, professor of dermatology at the Medical University of Vienna. For localized Kaposi sarcoma, surgery, cryotherapy, radiation therapy, intralesional cytotoxic agents, photodynamic therapy, and topical retinoids remain good options.

But for rapidly progressive cutaneous or symptomatic visceral disease, liposomal anthracyclines have replaced older combination chemotherapy regimens because they have higher remission rates and are much better tolerated, said Dr. Tschachler.

These liposomal agents and paclitaxel—all of which are approved by the Food and Drug Administration for the treatment of AIDS-related Kaposi sarcoma—are given with palliative rather than curative intent.

Dr. Tschachler and colleagues typically start treatment with liposomal doxorubicin (Doxil) at 20 mg/m2 IV every 2-3 weeks, although it can be given at up to 40 mg/m2. Remission rates of 38%-92% have been reported. Liposomal daunorubicin (DaunoXome) is slightly less effective. The dosing is 40-60 mg/m2 IV every 2 weeks.

Eventually the Kaposi sarcoma is likely to return despite liposomal anthracycline therapy, which is when it's time to switch to paclitaxel (Taxol), he said. Paclitaxel has double the response rate and twice as long an average duration of remission. The recommended dosing is 135-175 mg/m2 IV given over 3 hours every 3 weeks initially, then 100 mg/m2 every 2 weeks to maintain remission.

Dr. Tschachler reported having no conflicts of interest.

ZURICH — Intravenous paclitaxel is the treatment of choice in patients whose AIDS-related Kaposi sarcoma isn't responsive to liposomal anthracyclines, Dr. Erwin Tschachler said at the annual meeting of the European Society for Dermatological Research.

"It's more cytotoxic, has more side effects, but works in a considerable percentage of patients in which other cytotoxic therapies have failed. So it's not a first-line treatment," explained Dr. Tschachler, professor of dermatology at the Medical University of Vienna. For localized Kaposi sarcoma, surgery, cryotherapy, radiation therapy, intralesional cytotoxic agents, photodynamic therapy, and topical retinoids remain good options.

But for rapidly progressive cutaneous or symptomatic visceral disease, liposomal anthracyclines have replaced older combination chemotherapy regimens because they have higher remission rates and are much better tolerated, said Dr. Tschachler.

These liposomal agents and paclitaxel—all of which are approved by the Food and Drug Administration for the treatment of AIDS-related Kaposi sarcoma—are given with palliative rather than curative intent.

Dr. Tschachler and colleagues typically start treatment with liposomal doxorubicin (Doxil) at 20 mg/m2 IV every 2-3 weeks, although it can be given at up to 40 mg/m2. Remission rates of 38%-92% have been reported. Liposomal daunorubicin (DaunoXome) is slightly less effective. The dosing is 40-60 mg/m2 IV every 2 weeks.

Eventually the Kaposi sarcoma is likely to return despite liposomal anthracycline therapy, which is when it's time to switch to paclitaxel (Taxol), he said. Paclitaxel has double the response rate and twice as long an average duration of remission. The recommended dosing is 135-175 mg/m2 IV given over 3 hours every 3 weeks initially, then 100 mg/m2 every 2 weeks to maintain remission.

Dr. Tschachler reported having no conflicts of interest.

ZURICH — Intravenous paclitaxel is the treatment of choice in patients whose AIDS-related Kaposi sarcoma isn't responsive to liposomal anthracyclines, Dr. Erwin Tschachler said at the annual meeting of the European Society for Dermatological Research.

"It's more cytotoxic, has more side effects, but works in a considerable percentage of patients in which other cytotoxic therapies have failed. So it's not a first-line treatment," explained Dr. Tschachler, professor of dermatology at the Medical University of Vienna. For localized Kaposi sarcoma, surgery, cryotherapy, radiation therapy, intralesional cytotoxic agents, photodynamic therapy, and topical retinoids remain good options.

But for rapidly progressive cutaneous or symptomatic visceral disease, liposomal anthracyclines have replaced older combination chemotherapy regimens because they have higher remission rates and are much better tolerated, said Dr. Tschachler.

These liposomal agents and paclitaxel—all of which are approved by the Food and Drug Administration for the treatment of AIDS-related Kaposi sarcoma—are given with palliative rather than curative intent.

Dr. Tschachler and colleagues typically start treatment with liposomal doxorubicin (Doxil) at 20 mg/m2 IV every 2-3 weeks, although it can be given at up to 40 mg/m2. Remission rates of 38%-92% have been reported. Liposomal daunorubicin (DaunoXome) is slightly less effective. The dosing is 40-60 mg/m2 IV every 2 weeks.

Eventually the Kaposi sarcoma is likely to return despite liposomal anthracycline therapy, which is when it's time to switch to paclitaxel (Taxol), he said. Paclitaxel has double the response rate and twice as long an average duration of remission. The recommended dosing is 135-175 mg/m2 IV given over 3 hours every 3 weeks initially, then 100 mg/m2 every 2 weeks to maintain remission.

Dr. Tschachler reported having no conflicts of interest.

ZURICH — The effectiveness of sirolimus for treatment of Kaposi sarcoma arising in solid organ transplant recipients has opened the door to development of novel therapeutic approaches in the often more aggressive AIDS-related form of the malignancy, said Dr. Erwin Tschachler.

Sirolimus itself would be inappropriate for use in AIDS patients, since it is a potent immunosuppressive agent. But the drug also is believed to have antitumor properties resulting from its ability to block the mammalian target of rapamycin (mTOR), he said at the annual meeting of the European Society for Dermatological Research.

The mTOR molecule occupies a key role in the Akt signaling pathway by which human herpesvirus 8 (HHV-8) directs endothelial cell proliferation and transformation along with elaboration of angiogenic factors including vascular endothelial growth factor, ultimately resulting in Kaposi sarcoma (KS), explained Dr. Tschachler, professor of dermatology at the Medical University of Vienna.

In recent years, it has become clear that HHV-8 is the etiologic agent in all forms of KS. "There is no Kaposi sarcoma without HHV-8," he said. The incidence of KS in transplant recipients is roughly 500-fold greater than in the general population. In organ transplant recipients who either have preexisting latent HHV-8 infection or acquire the virus from an infected organ donor, the average time from initiation of chronic immunosuppressive therapy to development of KS is about 2 years.

Cyclosporine, the linchpin of chronic antigraft-rejection therapy, figures prominently in KS in transplant recipients. The drug has tumor-promoting effects. The traditional approach to managing transplant-related KS has been to reduce cyclosporine or discontinue it, he continued.

A major development in transplant medicine occurred several years ago when investigators at the University of Bari (Italy) reported that upon switching 15 kidney-transplant recipients with KS from cyclosporine to sirolimus, all cutaneous KS lesions disappeared within 3 months. Histologic confirmation of remission was obtained by biopsy at the former lesion sites at 6 months. KS remission was achieved without any episodes of graft rejection or reduction in donor-kidney function (N. Engl. J. Med. 2005;352:1317-23).

This report prompted discussion as to whether the tumor regression might have been brought about by halting cyclosporine. However, the consensus is that most of the observed benefit resulted from sirolimus-induced inhibition of angiogenesis and tumor cell proliferation, according to Dr. Tschachler.

He singled out as particularly influential the work of Silvia Montaner, Ph.D., of the University of Maryland, Baltimore, who has shown that a single HHV-8 gene encoding a chemokinelike viral G protein-coupled receptor called vGPCR is sufficient to induce formation of KS-like tumors in mice. Pharmacologic inhibition of the Akt signaling pathway prevented vGPCR-induced endothelial cell proliferation and tumor formation in the animal model (Cancer Res. 2006;66:168-74).

Dr. Tschachler reported having no conflicts of interest.

ZURICH — The effectiveness of sirolimus for treatment of Kaposi sarcoma arising in solid organ transplant recipients has opened the door to development of novel therapeutic approaches in the often more aggressive AIDS-related form of the malignancy, said Dr. Erwin Tschachler.

Sirolimus itself would be inappropriate for use in AIDS patients, since it is a potent immunosuppressive agent. But the drug also is believed to have antitumor properties resulting from its ability to block the mammalian target of rapamycin (mTOR), he said at the annual meeting of the European Society for Dermatological Research.

The mTOR molecule occupies a key role in the Akt signaling pathway by which human herpesvirus 8 (HHV-8) directs endothelial cell proliferation and transformation along with elaboration of angiogenic factors including vascular endothelial growth factor, ultimately resulting in Kaposi sarcoma (KS), explained Dr. Tschachler, professor of dermatology at the Medical University of Vienna.

In recent years, it has become clear that HHV-8 is the etiologic agent in all forms of KS. "There is no Kaposi sarcoma without HHV-8," he said. The incidence of KS in transplant recipients is roughly 500-fold greater than in the general population. In organ transplant recipients who either have preexisting latent HHV-8 infection or acquire the virus from an infected organ donor, the average time from initiation of chronic immunosuppressive therapy to development of KS is about 2 years.

Cyclosporine, the linchpin of chronic antigraft-rejection therapy, figures prominently in KS in transplant recipients. The drug has tumor-promoting effects. The traditional approach to managing transplant-related KS has been to reduce cyclosporine or discontinue it, he continued.

A major development in transplant medicine occurred several years ago when investigators at the University of Bari (Italy) reported that upon switching 15 kidney-transplant recipients with KS from cyclosporine to sirolimus, all cutaneous KS lesions disappeared within 3 months. Histologic confirmation of remission was obtained by biopsy at the former lesion sites at 6 months. KS remission was achieved without any episodes of graft rejection or reduction in donor-kidney function (N. Engl. J. Med. 2005;352:1317-23).

This report prompted discussion as to whether the tumor regression might have been brought about by halting cyclosporine. However, the consensus is that most of the observed benefit resulted from sirolimus-induced inhibition of angiogenesis and tumor cell proliferation, according to Dr. Tschachler.

He singled out as particularly influential the work of Silvia Montaner, Ph.D., of the University of Maryland, Baltimore, who has shown that a single HHV-8 gene encoding a chemokinelike viral G protein-coupled receptor called vGPCR is sufficient to induce formation of KS-like tumors in mice. Pharmacologic inhibition of the Akt signaling pathway prevented vGPCR-induced endothelial cell proliferation and tumor formation in the animal model (Cancer Res. 2006;66:168-74).

Dr. Tschachler reported having no conflicts of interest.

ZURICH — The effectiveness of sirolimus for treatment of Kaposi sarcoma arising in solid organ transplant recipients has opened the door to development of novel therapeutic approaches in the often more aggressive AIDS-related form of the malignancy, said Dr. Erwin Tschachler.

Sirolimus itself would be inappropriate for use in AIDS patients, since it is a potent immunosuppressive agent. But the drug also is believed to have antitumor properties resulting from its ability to block the mammalian target of rapamycin (mTOR), he said at the annual meeting of the European Society for Dermatological Research.

The mTOR molecule occupies a key role in the Akt signaling pathway by which human herpesvirus 8 (HHV-8) directs endothelial cell proliferation and transformation along with elaboration of angiogenic factors including vascular endothelial growth factor, ultimately resulting in Kaposi sarcoma (KS), explained Dr. Tschachler, professor of dermatology at the Medical University of Vienna.

In recent years, it has become clear that HHV-8 is the etiologic agent in all forms of KS. "There is no Kaposi sarcoma without HHV-8," he said. The incidence of KS in transplant recipients is roughly 500-fold greater than in the general population. In organ transplant recipients who either have preexisting latent HHV-8 infection or acquire the virus from an infected organ donor, the average time from initiation of chronic immunosuppressive therapy to development of KS is about 2 years.

Cyclosporine, the linchpin of chronic antigraft-rejection therapy, figures prominently in KS in transplant recipients. The drug has tumor-promoting effects. The traditional approach to managing transplant-related KS has been to reduce cyclosporine or discontinue it, he continued.

A major development in transplant medicine occurred several years ago when investigators at the University of Bari (Italy) reported that upon switching 15 kidney-transplant recipients with KS from cyclosporine to sirolimus, all cutaneous KS lesions disappeared within 3 months. Histologic confirmation of remission was obtained by biopsy at the former lesion sites at 6 months. KS remission was achieved without any episodes of graft rejection or reduction in donor-kidney function (N. Engl. J. Med. 2005;352:1317-23).

This report prompted discussion as to whether the tumor regression might have been brought about by halting cyclosporine. However, the consensus is that most of the observed benefit resulted from sirolimus-induced inhibition of angiogenesis and tumor cell proliferation, according to Dr. Tschachler.

He singled out as particularly influential the work of Silvia Montaner, Ph.D., of the University of Maryland, Baltimore, who has shown that a single HHV-8 gene encoding a chemokinelike viral G protein-coupled receptor called vGPCR is sufficient to induce formation of KS-like tumors in mice. Pharmacologic inhibition of the Akt signaling pathway prevented vGPCR-induced endothelial cell proliferation and tumor formation in the animal model (Cancer Res. 2006;66:168-74).

Dr. Tschachler reported having no conflicts of interest.