Melanoma

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.

Biologic treatment of rheumatoid arthritis patients has spurred an increase in melanoma and other skin cancers but not malignancies other than those of the skin, according to an observational study of 13,001 patients, reported Dr. Frederick Wolfe, a rheumatologist at the National Data Bank for Rheumatic Diseases, and the University of Kansas, Wichita, and his colleague, Kaleb Michaud, Ph.D., of the University of Nebraska, Omaha

Extrapolating from previous data in immunosuppressed transplantation patients, some have theorized that immunosuppression from biologics would increase the risk of cancer database (Arthr. Rheum. 2007;56:2886-95).

The hypothesis gained some credence when a meta-analysis found a 3.3-fold increased risk of malignancy in general among transplantation recipients who were treated with infliximab or adalimumab, compared with those who received nonbiologic therapy (JAMA 2006;295:2275-85).

Findings from studies in patients taking biologic agents for rheumatoid arthritis conflict, however.

An observational study using the Swedish inpatient registry found cancer risks "largely similar" between 4,160 patients treated with a tumor necrosis factor (TNF) antagonist, compared with 53,067 other rheumatoid arthritis patients not treated with such an agent (Ann. Rheum. Dis. 2005;64:1421-6).

To address this discrepancy, Dr. Wolfe and Dr. Michaud studied 13,001 rheumatoid arthritis patients who were included in the National Data Bank for Rheumatic Diseases.

In an assessment of the national rheumatoid arthritis database sample only, risk of melanoma (odds ratio, 2.3) and nonmelanotic skin cancer (OR, 1.5) increased among those ever treated with a biologic, compared with the others.

These associations were consistent across the different agents in the biologics class. A total of 4,277 patients (33%) received infliximab; 3,011 received etanercept (23%); 763 received adalimumab (6%); and 319 received anakinra (3%) in the study.

Cancer incidence was based on self-reports from semiannual questionnaires.

Researchers compared their specific cancer rates with a comparison population from the Surveillance, Epidemiology, and End Results (SEER) database.

The overall cancer rate did not differ between rheumatoid arthritis patients and SEER database participants (standardized incidence ratio [SIR] = 1.0). "This result is substantially different from the OR of 3.3 noted by Bongartz et al. [above] in their meta-analysis of clinical trials," the authors wrote.

The mean duration of any type of biologic therapy was 3 years, which the authors of the current study cited as a possible limitation. However, Dr. Wolfe and Dr. Michaud wrote, "true associations are usually seen within this time frame, since post-transplantation studies have shown increased risk after the first year of treatment."

Melanoma (SIR, 1.7) and lymphoma (SIR, 1.7) occurred more often in the rheumatoid arthritis database versus the SEER database participants. Rates of lung cancer and bladder cancer were not statistically different between groups. Some cancer rates were lower among rheumatoid arthritis patients, including breast cancer (SIR, 0.8) and colon cancer (SIR, 0.5), compared with the comparison group.

"In summary, biologic therapy is associated with increased risk for skin cancers, but not for solid tumors or lymphoproliferative malignancies."

During the period when these data were collected, the National Data Bank for Rheumatic Diseases received funding from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, and Wyeth-Australia. Centocor reviewed the completed manuscript.

Biologic treatment of rheumatoid arthritis patients has spurred an increase in melanoma and other skin cancers but not malignancies other than those of the skin, according to an observational study of 13,001 patients, reported Dr. Frederick Wolfe, a rheumatologist at the National Data Bank for Rheumatic Diseases, and the University of Kansas, Wichita, and his colleague, Kaleb Michaud, Ph.D., of the University of Nebraska, Omaha

Extrapolating from previous data in immunosuppressed transplantation patients, some have theorized that immunosuppression from biologics would increase the risk of cancer database (Arthr. Rheum. 2007;56:2886-95).

The hypothesis gained some credence when a meta-analysis found a 3.3-fold increased risk of malignancy in general among transplantation recipients who were treated with infliximab or adalimumab, compared with those who received nonbiologic therapy (JAMA 2006;295:2275-85).

Findings from studies in patients taking biologic agents for rheumatoid arthritis conflict, however.

An observational study using the Swedish inpatient registry found cancer risks "largely similar" between 4,160 patients treated with a tumor necrosis factor (TNF) antagonist, compared with 53,067 other rheumatoid arthritis patients not treated with such an agent (Ann. Rheum. Dis. 2005;64:1421-6).

To address this discrepancy, Dr. Wolfe and Dr. Michaud studied 13,001 rheumatoid arthritis patients who were included in the National Data Bank for Rheumatic Diseases.

In an assessment of the national rheumatoid arthritis database sample only, risk of melanoma (odds ratio, 2.3) and nonmelanotic skin cancer (OR, 1.5) increased among those ever treated with a biologic, compared with the others.

These associations were consistent across the different agents in the biologics class. A total of 4,277 patients (33%) received infliximab; 3,011 received etanercept (23%); 763 received adalimumab (6%); and 319 received anakinra (3%) in the study.

Cancer incidence was based on self-reports from semiannual questionnaires.

Researchers compared their specific cancer rates with a comparison population from the Surveillance, Epidemiology, and End Results (SEER) database.

The overall cancer rate did not differ between rheumatoid arthritis patients and SEER database participants (standardized incidence ratio [SIR] = 1.0). "This result is substantially different from the OR of 3.3 noted by Bongartz et al. [above] in their meta-analysis of clinical trials," the authors wrote.

The mean duration of any type of biologic therapy was 3 years, which the authors of the current study cited as a possible limitation. However, Dr. Wolfe and Dr. Michaud wrote, "true associations are usually seen within this time frame, since post-transplantation studies have shown increased risk after the first year of treatment."

Melanoma (SIR, 1.7) and lymphoma (SIR, 1.7) occurred more often in the rheumatoid arthritis database versus the SEER database participants. Rates of lung cancer and bladder cancer were not statistically different between groups. Some cancer rates were lower among rheumatoid arthritis patients, including breast cancer (SIR, 0.8) and colon cancer (SIR, 0.5), compared with the comparison group.

"In summary, biologic therapy is associated with increased risk for skin cancers, but not for solid tumors or lymphoproliferative malignancies."

During the period when these data were collected, the National Data Bank for Rheumatic Diseases received funding from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, and Wyeth-Australia. Centocor reviewed the completed manuscript.

Biologic treatment of rheumatoid arthritis patients has spurred an increase in melanoma and other skin cancers but not malignancies other than those of the skin, according to an observational study of 13,001 patients, reported Dr. Frederick Wolfe, a rheumatologist at the National Data Bank for Rheumatic Diseases, and the University of Kansas, Wichita, and his colleague, Kaleb Michaud, Ph.D., of the University of Nebraska, Omaha

Extrapolating from previous data in immunosuppressed transplantation patients, some have theorized that immunosuppression from biologics would increase the risk of cancer database (Arthr. Rheum. 2007;56:2886-95).

The hypothesis gained some credence when a meta-analysis found a 3.3-fold increased risk of malignancy in general among transplantation recipients who were treated with infliximab or adalimumab, compared with those who received nonbiologic therapy (JAMA 2006;295:2275-85).

Findings from studies in patients taking biologic agents for rheumatoid arthritis conflict, however.

An observational study using the Swedish inpatient registry found cancer risks "largely similar" between 4,160 patients treated with a tumor necrosis factor (TNF) antagonist, compared with 53,067 other rheumatoid arthritis patients not treated with such an agent (Ann. Rheum. Dis. 2005;64:1421-6).

To address this discrepancy, Dr. Wolfe and Dr. Michaud studied 13,001 rheumatoid arthritis patients who were included in the National Data Bank for Rheumatic Diseases.

In an assessment of the national rheumatoid arthritis database sample only, risk of melanoma (odds ratio, 2.3) and nonmelanotic skin cancer (OR, 1.5) increased among those ever treated with a biologic, compared with the others.

These associations were consistent across the different agents in the biologics class. A total of 4,277 patients (33%) received infliximab; 3,011 received etanercept (23%); 763 received adalimumab (6%); and 319 received anakinra (3%) in the study.

Cancer incidence was based on self-reports from semiannual questionnaires.

Researchers compared their specific cancer rates with a comparison population from the Surveillance, Epidemiology, and End Results (SEER) database.

The overall cancer rate did not differ between rheumatoid arthritis patients and SEER database participants (standardized incidence ratio [SIR] = 1.0). "This result is substantially different from the OR of 3.3 noted by Bongartz et al. [above] in their meta-analysis of clinical trials," the authors wrote.

The mean duration of any type of biologic therapy was 3 years, which the authors of the current study cited as a possible limitation. However, Dr. Wolfe and Dr. Michaud wrote, "true associations are usually seen within this time frame, since post-transplantation studies have shown increased risk after the first year of treatment."

Melanoma (SIR, 1.7) and lymphoma (SIR, 1.7) occurred more often in the rheumatoid arthritis database versus the SEER database participants. Rates of lung cancer and bladder cancer were not statistically different between groups. Some cancer rates were lower among rheumatoid arthritis patients, including breast cancer (SIR, 0.8) and colon cancer (SIR, 0.5), compared with the comparison group.

"In summary, biologic therapy is associated with increased risk for skin cancers, but not for solid tumors or lymphoproliferative malignancies."

During the period when these data were collected, the National Data Bank for Rheumatic Diseases received funding from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, and Wyeth-Australia. Centocor reviewed the completed manuscript.

A metastatic malignancy of the umbilicus is commonly termed Sister Mary Joseph nodule (SMJN). It is a rare occurrence but may represent the first sign of a visceral malignancy and therefore should prompt a thorough search for the primary tumor. Typically, the most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. The presence of SMJN carries a poor prognosis with the average survival time at the appearance of an umbilical metastasis being 10 months. We report a case of a 66-year-old man who was referred for evaluation of an enlarging umbilical lesion. Histopathology revealed adenocarcinoma. After a full metastatic workup, the tumor of origin was identified as adenocarcinoma of the sigmoid colon. Benign tumors of the umbilicus are uncommon. This case report serves to emphasize the importance of obtaining a histologic diagnosis when any new lesion presents in the umbilical region.

Case Report
A 66-year-old white man presented for evaluation of an umbilical lesion of 3 weeks' duration. The lesion was asymptomatic and nontender but was bleeding and oozing. The lesion, diagnosed by the patient's primary care physician as an infected pyogenic granuloma, was treated with oral antibiotics, without relief. His past medical history was unremarkable. He took no medications at that time and had an allergy to quinolones. His dermatologic history was positive for numerous actinic keratoses and a basal cell carcinoma on the forehead. Physical examination upon presentation revealed a 3-cm fungating polypoid umbilical mass with copious purulent exudates similar to Figure 1.1 The clinical differential diagnosis at that time included a pyogenic granuloma versus a Sister Mary Joseph nodule (SMJN). A shave biopsy was performed. Histopathology revealed multiple cystic and ductal spaces lined by atypical epithelial cells with numerous mitotic figures in the dermis (Figures 2 and 3). These changes favored a gastrointestinal primary lesion, supporting the clinical diagnosis of SMJN. The patient subsequently underwent a full metastatic workup. A computed tomographic scan of the abdomen and pelvis demonstrated no definite metastases to the lungs or liver but suggested a near-obstructing distal bowel primary tumor. A colonoscopy demonstrated a near-obstructing sigmoid colon carcinoma. The patient subsequently underwent an exploratory laparotomy, sigmoid resection, and primary colonic reanastomosis. Liver biopsies and resection of the omentum and the periumbilical abdominal wall including the eroding metastasis were performed as well as multiple peritoneal biopsies. Pathologic evaluation confirmed the presence of extensive carcinomatosis. The primary tumor was a 5.0X3.0-cm moderately differentiated adenocarcinoma of the sigmoid colon with extension through the bowel wall. Biopsies of the liver, lymph nodes, periumbilical soft tissue, omentum, and peritoneum were all positive for metastatic carcinoma. Postoperatively, the patient was started on the FOLFOX regimen incorporating folinic acid, 5-fluorouracil, and oxaliplatin. Currently, the patient remains clinically stable and without evidence of progressive sigmoid colon carcinoma.

Comment
SMJN is the term applied to an uncommon metastatic malignancy of the umbilicus. This eponym, coined by Sir Hamilton Bailey in his book Physical Signs in Clinical Surgery,2 honors Sister Mary Joseph Dempsey, a nun in the Franciscan order who was the first surgical assistant to Dr. William J. Mayo at St. Mary's Hospital in Rochester, Minnesota.3,4 Sister Mary Joseph made the astute observation that patients with gastrointestinal and gynecologic tumors may have involvement of the umbilicus; if there is involvement of the umbilicus, the prognosis is poor.5 Although Dr. Mayo gives credit to Sister Mary Joseph, contrary to what some believe, he is not responsible for the eponym. Dr. Mayo used the term pants button umbilicus in his article; Sir Bailey definitively coined the term SMJN. Some authors argue that the correct name is Sister Joseph's nodule; however, SMJN remains the more commonly used term.6 Frequency—Cutaneous metastasis, in and of itself, is a rare feature of visceral malignancy, occurring in about 1% to 2% of cases, with umbilical metastasis occurring even less frequently. There are approximately 265 cases of SMJN reported in the literature up to 1990, emphasizing its infrequency. The most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. In a review of the world literature on metastatic umbilical tumors, Barrow7 found that the most common primary tumor identified was carcinoma of the stomach. The second most common was ovarian tumor,7 with colon, rectal, and pancreatic cancers following in descending order of frequency.8 In very rare cases, the primary tumor involved the breast, cervix, endometrium, small bowel, liver, gallbladder, lung, prostate, kidney, fallopian tube, appendix, and penis.9 In approximately 20% to 30% of cases, the primary tumor could not be identified.9 Umbilical Anatomy—A neoplasm may metastasize to the umbilicus by one of many mechanisms, most commonly direct extension from the anterior peritoneal surface from adjacent organs. Other mechanisms of metastasis include vascular spread via arterial and venous channels, lymphatic spread, and umbilical ligamentous spread. The rich vascular supply to the anterior abdominal wall facilitates metastasis of a neoplasm. The main arteries supplying the umbilical region are the inferior epigastric, deep circumflex iliac, and superior epigastric arteries. Venous drainage of the umbilical region stems from a network of veins radiating from the umbilicus, including the axillary vein above and the femoral vein below the umbilicus. There also are small paraumbilical veins that connect with the portal system along the ligamentum teres hepatis, the superior portion of the falciform ligament.10 The superficial lymphatic drainage of the periumbilical region leads to axillary lymph nodes above and inguinal lymph nodes below the periumbilical region. The deep lymphatic drainage runs along the falciform ligament of the liver and then enters the anterior mediastinum by traversing the diaphragm. Inferiorly, the deep lymphatics communicate by coursing to the lymph nodes of the iliac arteries. Because the lymphatic channels of the periumbilical region communicate with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes, once a neoplasm is established at the umbilicus, it can metastasize to any part of the body,8 supporting the notion that the presence of SMJN portends a poor prognosis. In the fetus, the umbilicus serves as the opening for the umbilical vessels. In the adult, there are several ligaments that contain remnants of obliterated fetal structures and connect to the umbilicus. For example, the median umbilical ligament, also known as the urachus, represents the obliterated umbilical arteries that formerly connected the umbilicus to the bladder. The falciform ligament in the adult contains the obliterated umbilical vein and runs along the hepatic surface. Therefore, a firm command of the anatomy and embryology of the periumbilical region is essential for an accurate clinical workup once the diagnosis of SMJN has been established. Physical Examination—Clinically, SMJN usually presents as a firm indurated plaque or nodule that is 0.5 to 2 cm in size, though lesions up to 10 cm have been reported. The lesion is occasionally painful and may have a fibrous consistency with irregular edges that are attached to the anterior abdominal wall. It tends to have a vascular appearance and can be fissured, ulcerated, or necrotic. Purulent discharge may be present if it is secondarily infected. Typically, there are no gross features to distinguish between a primary and secondary umbilical tumor. Differential Diagnosis—The differential diagnosis of SMJN includes a primary carcinoma of the umbilicus, a benign umbilical lesion, and a metastatic lesion of the umbilicus. Primary umbilical carcinomas are rare and include malignant melanoma, basal cell carcinoma, and omphalomesenteric duct carcinoma. Endometriosis is the most common benign lesion of the umbilicus. Other benign umbilical lesions include papillomas, epidermal/inclusion cysts, seborrheic keratoses, dermal nevi, polyps, congenital malformations, foreign bodies, talc granulomas, angiomas, pyogenic and pilonidal granulomas, keloids, incarcerated hernias, angiokeratomas, and lymphangiomas.11 Histopathology—In general, the histology of a cutaneous metastatic lesion is of finite value in determining the site of the primary malignancy. In contrast, when speaking of an umbilical metastasis, histologic sampling more often aids in determining the derivation.11 The histopathology is dependent on the primary tumor and is most often adenocarcinoma, which was the case with our patient. Prognosis—Although the presence of umbilical disease indicates metastasis, it does not suggest unresectability and, in fact, may be the first sign of a recurrence.11 However, in general, SMJN portends a poor prognosis and is considered an ominous sign. The presence of SMJN should prompt a thorough metastatic workup and appropriate clinical staging. Survival time in untreated patients ranges from 2 to 11 months, with 10 months as the average survival time from the appearance of an umbilical metastasis.6,9 This rapid deterioration may be, in part, caused by the rich lymphatic network in the abdominal wall providing communication with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes. Therefore, from the umbilicus, a tumor may spread to many parts of the body.

Conclusion
Cutaneous metastasis is a rare occurrence, making SMJN exceptionally infrequent. The finding of SMJN should prompt a thorough search for the primary malignancy. As demonstrated by our patient, SMJN may be the first sign of a visceral malignancy, making proper and timely diagnosis lifesaving.

A metastatic malignancy of the umbilicus is commonly termed Sister Mary Joseph nodule (SMJN). It is a rare occurrence but may represent the first sign of a visceral malignancy and therefore should prompt a thorough search for the primary tumor. Typically, the most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. The presence of SMJN carries a poor prognosis with the average survival time at the appearance of an umbilical metastasis being 10 months. We report a case of a 66-year-old man who was referred for evaluation of an enlarging umbilical lesion. Histopathology revealed adenocarcinoma. After a full metastatic workup, the tumor of origin was identified as adenocarcinoma of the sigmoid colon. Benign tumors of the umbilicus are uncommon. This case report serves to emphasize the importance of obtaining a histologic diagnosis when any new lesion presents in the umbilical region.

Case Report
A 66-year-old white man presented for evaluation of an umbilical lesion of 3 weeks' duration. The lesion was asymptomatic and nontender but was bleeding and oozing. The lesion, diagnosed by the patient's primary care physician as an infected pyogenic granuloma, was treated with oral antibiotics, without relief. His past medical history was unremarkable. He took no medications at that time and had an allergy to quinolones. His dermatologic history was positive for numerous actinic keratoses and a basal cell carcinoma on the forehead. Physical examination upon presentation revealed a 3-cm fungating polypoid umbilical mass with copious purulent exudates similar to Figure 1.1 The clinical differential diagnosis at that time included a pyogenic granuloma versus a Sister Mary Joseph nodule (SMJN). A shave biopsy was performed. Histopathology revealed multiple cystic and ductal spaces lined by atypical epithelial cells with numerous mitotic figures in the dermis (Figures 2 and 3). These changes favored a gastrointestinal primary lesion, supporting the clinical diagnosis of SMJN. The patient subsequently underwent a full metastatic workup. A computed tomographic scan of the abdomen and pelvis demonstrated no definite metastases to the lungs or liver but suggested a near-obstructing distal bowel primary tumor. A colonoscopy demonstrated a near-obstructing sigmoid colon carcinoma. The patient subsequently underwent an exploratory laparotomy, sigmoid resection, and primary colonic reanastomosis. Liver biopsies and resection of the omentum and the periumbilical abdominal wall including the eroding metastasis were performed as well as multiple peritoneal biopsies. Pathologic evaluation confirmed the presence of extensive carcinomatosis. The primary tumor was a 5.0X3.0-cm moderately differentiated adenocarcinoma of the sigmoid colon with extension through the bowel wall. Biopsies of the liver, lymph nodes, periumbilical soft tissue, omentum, and peritoneum were all positive for metastatic carcinoma. Postoperatively, the patient was started on the FOLFOX regimen incorporating folinic acid, 5-fluorouracil, and oxaliplatin. Currently, the patient remains clinically stable and without evidence of progressive sigmoid colon carcinoma.

Comment
SMJN is the term applied to an uncommon metastatic malignancy of the umbilicus. This eponym, coined by Sir Hamilton Bailey in his book Physical Signs in Clinical Surgery,2 honors Sister Mary Joseph Dempsey, a nun in the Franciscan order who was the first surgical assistant to Dr. William J. Mayo at St. Mary's Hospital in Rochester, Minnesota.3,4 Sister Mary Joseph made the astute observation that patients with gastrointestinal and gynecologic tumors may have involvement of the umbilicus; if there is involvement of the umbilicus, the prognosis is poor.5 Although Dr. Mayo gives credit to Sister Mary Joseph, contrary to what some believe, he is not responsible for the eponym. Dr. Mayo used the term pants button umbilicus in his article; Sir Bailey definitively coined the term SMJN. Some authors argue that the correct name is Sister Joseph's nodule; however, SMJN remains the more commonly used term.6 Frequency—Cutaneous metastasis, in and of itself, is a rare feature of visceral malignancy, occurring in about 1% to 2% of cases, with umbilical metastasis occurring even less frequently. There are approximately 265 cases of SMJN reported in the literature up to 1990, emphasizing its infrequency. The most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. In a review of the world literature on metastatic umbilical tumors, Barrow7 found that the most common primary tumor identified was carcinoma of the stomach. The second most common was ovarian tumor,7 with colon, rectal, and pancreatic cancers following in descending order of frequency.8 In very rare cases, the primary tumor involved the breast, cervix, endometrium, small bowel, liver, gallbladder, lung, prostate, kidney, fallopian tube, appendix, and penis.9 In approximately 20% to 30% of cases, the primary tumor could not be identified.9 Umbilical Anatomy—A neoplasm may metastasize to the umbilicus by one of many mechanisms, most commonly direct extension from the anterior peritoneal surface from adjacent organs. Other mechanisms of metastasis include vascular spread via arterial and venous channels, lymphatic spread, and umbilical ligamentous spread. The rich vascular supply to the anterior abdominal wall facilitates metastasis of a neoplasm. The main arteries supplying the umbilical region are the inferior epigastric, deep circumflex iliac, and superior epigastric arteries. Venous drainage of the umbilical region stems from a network of veins radiating from the umbilicus, including the axillary vein above and the femoral vein below the umbilicus. There also are small paraumbilical veins that connect with the portal system along the ligamentum teres hepatis, the superior portion of the falciform ligament.10 The superficial lymphatic drainage of the periumbilical region leads to axillary lymph nodes above and inguinal lymph nodes below the periumbilical region. The deep lymphatic drainage runs along the falciform ligament of the liver and then enters the anterior mediastinum by traversing the diaphragm. Inferiorly, the deep lymphatics communicate by coursing to the lymph nodes of the iliac arteries. Because the lymphatic channels of the periumbilical region communicate with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes, once a neoplasm is established at the umbilicus, it can metastasize to any part of the body,8 supporting the notion that the presence of SMJN portends a poor prognosis. In the fetus, the umbilicus serves as the opening for the umbilical vessels. In the adult, there are several ligaments that contain remnants of obliterated fetal structures and connect to the umbilicus. For example, the median umbilical ligament, also known as the urachus, represents the obliterated umbilical arteries that formerly connected the umbilicus to the bladder. The falciform ligament in the adult contains the obliterated umbilical vein and runs along the hepatic surface. Therefore, a firm command of the anatomy and embryology of the periumbilical region is essential for an accurate clinical workup once the diagnosis of SMJN has been established. Physical Examination—Clinically, SMJN usually presents as a firm indurated plaque or nodule that is 0.5 to 2 cm in size, though lesions up to 10 cm have been reported. The lesion is occasionally painful and may have a fibrous consistency with irregular edges that are attached to the anterior abdominal wall. It tends to have a vascular appearance and can be fissured, ulcerated, or necrotic. Purulent discharge may be present if it is secondarily infected. Typically, there are no gross features to distinguish between a primary and secondary umbilical tumor. Differential Diagnosis—The differential diagnosis of SMJN includes a primary carcinoma of the umbilicus, a benign umbilical lesion, and a metastatic lesion of the umbilicus. Primary umbilical carcinomas are rare and include malignant melanoma, basal cell carcinoma, and omphalomesenteric duct carcinoma. Endometriosis is the most common benign lesion of the umbilicus. Other benign umbilical lesions include papillomas, epidermal/inclusion cysts, seborrheic keratoses, dermal nevi, polyps, congenital malformations, foreign bodies, talc granulomas, angiomas, pyogenic and pilonidal granulomas, keloids, incarcerated hernias, angiokeratomas, and lymphangiomas.11 Histopathology—In general, the histology of a cutaneous metastatic lesion is of finite value in determining the site of the primary malignancy. In contrast, when speaking of an umbilical metastasis, histologic sampling more often aids in determining the derivation.11 The histopathology is dependent on the primary tumor and is most often adenocarcinoma, which was the case with our patient. Prognosis—Although the presence of umbilical disease indicates metastasis, it does not suggest unresectability and, in fact, may be the first sign of a recurrence.11 However, in general, SMJN portends a poor prognosis and is considered an ominous sign. The presence of SMJN should prompt a thorough metastatic workup and appropriate clinical staging. Survival time in untreated patients ranges from 2 to 11 months, with 10 months as the average survival time from the appearance of an umbilical metastasis.6,9 This rapid deterioration may be, in part, caused by the rich lymphatic network in the abdominal wall providing communication with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes. Therefore, from the umbilicus, a tumor may spread to many parts of the body.

Conclusion
Cutaneous metastasis is a rare occurrence, making SMJN exceptionally infrequent. The finding of SMJN should prompt a thorough search for the primary malignancy. As demonstrated by our patient, SMJN may be the first sign of a visceral malignancy, making proper and timely diagnosis lifesaving.

A metastatic malignancy of the umbilicus is commonly termed Sister Mary Joseph nodule (SMJN). It is a rare occurrence but may represent the first sign of a visceral malignancy and therefore should prompt a thorough search for the primary tumor. Typically, the most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. The presence of SMJN carries a poor prognosis with the average survival time at the appearance of an umbilical metastasis being 10 months. We report a case of a 66-year-old man who was referred for evaluation of an enlarging umbilical lesion. Histopathology revealed adenocarcinoma. After a full metastatic workup, the tumor of origin was identified as adenocarcinoma of the sigmoid colon. Benign tumors of the umbilicus are uncommon. This case report serves to emphasize the importance of obtaining a histologic diagnosis when any new lesion presents in the umbilical region.

Case Report
A 66-year-old white man presented for evaluation of an umbilical lesion of 3 weeks' duration. The lesion was asymptomatic and nontender but was bleeding and oozing. The lesion, diagnosed by the patient's primary care physician as an infected pyogenic granuloma, was treated with oral antibiotics, without relief. His past medical history was unremarkable. He took no medications at that time and had an allergy to quinolones. His dermatologic history was positive for numerous actinic keratoses and a basal cell carcinoma on the forehead. Physical examination upon presentation revealed a 3-cm fungating polypoid umbilical mass with copious purulent exudates similar to Figure 1.1 The clinical differential diagnosis at that time included a pyogenic granuloma versus a Sister Mary Joseph nodule (SMJN). A shave biopsy was performed. Histopathology revealed multiple cystic and ductal spaces lined by atypical epithelial cells with numerous mitotic figures in the dermis (Figures 2 and 3). These changes favored a gastrointestinal primary lesion, supporting the clinical diagnosis of SMJN. The patient subsequently underwent a full metastatic workup. A computed tomographic scan of the abdomen and pelvis demonstrated no definite metastases to the lungs or liver but suggested a near-obstructing distal bowel primary tumor. A colonoscopy demonstrated a near-obstructing sigmoid colon carcinoma. The patient subsequently underwent an exploratory laparotomy, sigmoid resection, and primary colonic reanastomosis. Liver biopsies and resection of the omentum and the periumbilical abdominal wall including the eroding metastasis were performed as well as multiple peritoneal biopsies. Pathologic evaluation confirmed the presence of extensive carcinomatosis. The primary tumor was a 5.0X3.0-cm moderately differentiated adenocarcinoma of the sigmoid colon with extension through the bowel wall. Biopsies of the liver, lymph nodes, periumbilical soft tissue, omentum, and peritoneum were all positive for metastatic carcinoma. Postoperatively, the patient was started on the FOLFOX regimen incorporating folinic acid, 5-fluorouracil, and oxaliplatin. Currently, the patient remains clinically stable and without evidence of progressive sigmoid colon carcinoma.

Comment
SMJN is the term applied to an uncommon metastatic malignancy of the umbilicus. This eponym, coined by Sir Hamilton Bailey in his book Physical Signs in Clinical Surgery,2 honors Sister Mary Joseph Dempsey, a nun in the Franciscan order who was the first surgical assistant to Dr. William J. Mayo at St. Mary's Hospital in Rochester, Minnesota.3,4 Sister Mary Joseph made the astute observation that patients with gastrointestinal and gynecologic tumors may have involvement of the umbilicus; if there is involvement of the umbilicus, the prognosis is poor.5 Although Dr. Mayo gives credit to Sister Mary Joseph, contrary to what some believe, he is not responsible for the eponym. Dr. Mayo used the term pants button umbilicus in his article; Sir Bailey definitively coined the term SMJN. Some authors argue that the correct name is Sister Joseph's nodule; however, SMJN remains the more commonly used term.6 Frequency—Cutaneous metastasis, in and of itself, is a rare feature of visceral malignancy, occurring in about 1% to 2% of cases, with umbilical metastasis occurring even less frequently. There are approximately 265 cases of SMJN reported in the literature up to 1990, emphasizing its infrequency. The most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. In a review of the world literature on metastatic umbilical tumors, Barrow7 found that the most common primary tumor identified was carcinoma of the stomach. The second most common was ovarian tumor,7 with colon, rectal, and pancreatic cancers following in descending order of frequency.8 In very rare cases, the primary tumor involved the breast, cervix, endometrium, small bowel, liver, gallbladder, lung, prostate, kidney, fallopian tube, appendix, and penis.9 In approximately 20% to 30% of cases, the primary tumor could not be identified.9 Umbilical Anatomy—A neoplasm may metastasize to the umbilicus by one of many mechanisms, most commonly direct extension from the anterior peritoneal surface from adjacent organs. Other mechanisms of metastasis include vascular spread via arterial and venous channels, lymphatic spread, and umbilical ligamentous spread. The rich vascular supply to the anterior abdominal wall facilitates metastasis of a neoplasm. The main arteries supplying the umbilical region are the inferior epigastric, deep circumflex iliac, and superior epigastric arteries. Venous drainage of the umbilical region stems from a network of veins radiating from the umbilicus, including the axillary vein above and the femoral vein below the umbilicus. There also are small paraumbilical veins that connect with the portal system along the ligamentum teres hepatis, the superior portion of the falciform ligament.10 The superficial lymphatic drainage of the periumbilical region leads to axillary lymph nodes above and inguinal lymph nodes below the periumbilical region. The deep lymphatic drainage runs along the falciform ligament of the liver and then enters the anterior mediastinum by traversing the diaphragm. Inferiorly, the deep lymphatics communicate by coursing to the lymph nodes of the iliac arteries. Because the lymphatic channels of the periumbilical region communicate with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes, once a neoplasm is established at the umbilicus, it can metastasize to any part of the body,8 supporting the notion that the presence of SMJN portends a poor prognosis. In the fetus, the umbilicus serves as the opening for the umbilical vessels. In the adult, there are several ligaments that contain remnants of obliterated fetal structures and connect to the umbilicus. For example, the median umbilical ligament, also known as the urachus, represents the obliterated umbilical arteries that formerly connected the umbilicus to the bladder. The falciform ligament in the adult contains the obliterated umbilical vein and runs along the hepatic surface. Therefore, a firm command of the anatomy and embryology of the periumbilical region is essential for an accurate clinical workup once the diagnosis of SMJN has been established. Physical Examination—Clinically, SMJN usually presents as a firm indurated plaque or nodule that is 0.5 to 2 cm in size, though lesions up to 10 cm have been reported. The lesion is occasionally painful and may have a fibrous consistency with irregular edges that are attached to the anterior abdominal wall. It tends to have a vascular appearance and can be fissured, ulcerated, or necrotic. Purulent discharge may be present if it is secondarily infected. Typically, there are no gross features to distinguish between a primary and secondary umbilical tumor. Differential Diagnosis—The differential diagnosis of SMJN includes a primary carcinoma of the umbilicus, a benign umbilical lesion, and a metastatic lesion of the umbilicus. Primary umbilical carcinomas are rare and include malignant melanoma, basal cell carcinoma, and omphalomesenteric duct carcinoma. Endometriosis is the most common benign lesion of the umbilicus. Other benign umbilical lesions include papillomas, epidermal/inclusion cysts, seborrheic keratoses, dermal nevi, polyps, congenital malformations, foreign bodies, talc granulomas, angiomas, pyogenic and pilonidal granulomas, keloids, incarcerated hernias, angiokeratomas, and lymphangiomas.11 Histopathology—In general, the histology of a cutaneous metastatic lesion is of finite value in determining the site of the primary malignancy. In contrast, when speaking of an umbilical metastasis, histologic sampling more often aids in determining the derivation.11 The histopathology is dependent on the primary tumor and is most often adenocarcinoma, which was the case with our patient. Prognosis—Although the presence of umbilical disease indicates metastasis, it does not suggest unresectability and, in fact, may be the first sign of a recurrence.11 However, in general, SMJN portends a poor prognosis and is considered an ominous sign. The presence of SMJN should prompt a thorough metastatic workup and appropriate clinical staging. Survival time in untreated patients ranges from 2 to 11 months, with 10 months as the average survival time from the appearance of an umbilical metastasis.6,9 This rapid deterioration may be, in part, caused by the rich lymphatic network in the abdominal wall providing communication with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes. Therefore, from the umbilicus, a tumor may spread to many parts of the body.

Conclusion
Cutaneous metastasis is a rare occurrence, making SMJN exceptionally infrequent. The finding of SMJN should prompt a thorough search for the primary malignancy. As demonstrated by our patient, SMJN may be the first sign of a visceral malignancy, making proper and timely diagnosis lifesaving.

NEW YORK — Although melanoma is known for metastasizing to various sites, the most common site of metastasis is the locoregional lymph nodes, according to Dr. Richard Shapiro. They can be large and bulky or microscopic.

In a review of the literature on sentinel lymph node biopsy (SNLB), he noted that lymph node metastasis has been greatly associated with a decline in patient survival. However, "patients with nonpalpable, microscopic melanoma metastases tend to do much better than the patients who present with palpable metastases," he said at the American Academy of Dermatology's Academy 2007 meeting.

The thickness of a melanoma is key to its likelihood of having metastasized, he said. Thin melanomas—less than 0.76 mm in Breslow thickness—have a very small chance of having regional or distant metastases. However, patients with thick melanomas—4 mm or greater often have distant metastatic disease at presentation, said Dr. Shapiro of New York University, New York.

"It's the patients with so-called intermediate thickness lesions—that are approximately 0.76 mm to 4 mm thick—that have a much higher likelihood of having microscopic metastatic disease when they present than they do with having distant metastases. And so it would make sense in that intermediate thickness melanoma group to remove the lymph nodes in those patients and to see if we can decrease recurrence and increase survival."

Approximately 100 retrospective trials in the last 50 years have assessed associations between melanoma thickness and survival, with the only survival advantage seen in the patients with intermediate-thickness melanomas. However, prospective trials have found no survival advantage to elective lymph node dissection in patients with no clinical evidence of metastatic melanoma in the regional lymph nodes at presentation, Dr. Shapiro noted.

"Right now I would say the ideal candidate to undergo sentinel lymph node mapping and biopsy is the patient with a primary cutaneous melanoma 1 mm thick or greater, with no clinical evidence of regional lymph node metastases and in a patient where successful scintigraphy preoperatively can be performed and demonstrate regional lymph node draining," he said.

NEW YORK — Although melanoma is known for metastasizing to various sites, the most common site of metastasis is the locoregional lymph nodes, according to Dr. Richard Shapiro. They can be large and bulky or microscopic.

In a review of the literature on sentinel lymph node biopsy (SNLB), he noted that lymph node metastasis has been greatly associated with a decline in patient survival. However, "patients with nonpalpable, microscopic melanoma metastases tend to do much better than the patients who present with palpable metastases," he said at the American Academy of Dermatology's Academy 2007 meeting.

The thickness of a melanoma is key to its likelihood of having metastasized, he said. Thin melanomas—less than 0.76 mm in Breslow thickness—have a very small chance of having regional or distant metastases. However, patients with thick melanomas—4 mm or greater often have distant metastatic disease at presentation, said Dr. Shapiro of New York University, New York.

"It's the patients with so-called intermediate thickness lesions—that are approximately 0.76 mm to 4 mm thick—that have a much higher likelihood of having microscopic metastatic disease when they present than they do with having distant metastases. And so it would make sense in that intermediate thickness melanoma group to remove the lymph nodes in those patients and to see if we can decrease recurrence and increase survival."

Approximately 100 retrospective trials in the last 50 years have assessed associations between melanoma thickness and survival, with the only survival advantage seen in the patients with intermediate-thickness melanomas. However, prospective trials have found no survival advantage to elective lymph node dissection in patients with no clinical evidence of metastatic melanoma in the regional lymph nodes at presentation, Dr. Shapiro noted.

"Right now I would say the ideal candidate to undergo sentinel lymph node mapping and biopsy is the patient with a primary cutaneous melanoma 1 mm thick or greater, with no clinical evidence of regional lymph node metastases and in a patient where successful scintigraphy preoperatively can be performed and demonstrate regional lymph node draining," he said.

NEW YORK — Although melanoma is known for metastasizing to various sites, the most common site of metastasis is the locoregional lymph nodes, according to Dr. Richard Shapiro. They can be large and bulky or microscopic.

In a review of the literature on sentinel lymph node biopsy (SNLB), he noted that lymph node metastasis has been greatly associated with a decline in patient survival. However, "patients with nonpalpable, microscopic melanoma metastases tend to do much better than the patients who present with palpable metastases," he said at the American Academy of Dermatology's Academy 2007 meeting.

The thickness of a melanoma is key to its likelihood of having metastasized, he said. Thin melanomas—less than 0.76 mm in Breslow thickness—have a very small chance of having regional or distant metastases. However, patients with thick melanomas—4 mm or greater often have distant metastatic disease at presentation, said Dr. Shapiro of New York University, New York.

"It's the patients with so-called intermediate thickness lesions—that are approximately 0.76 mm to 4 mm thick—that have a much higher likelihood of having microscopic metastatic disease when they present than they do with having distant metastases. And so it would make sense in that intermediate thickness melanoma group to remove the lymph nodes in those patients and to see if we can decrease recurrence and increase survival."

Approximately 100 retrospective trials in the last 50 years have assessed associations between melanoma thickness and survival, with the only survival advantage seen in the patients with intermediate-thickness melanomas. However, prospective trials have found no survival advantage to elective lymph node dissection in patients with no clinical evidence of metastatic melanoma in the regional lymph nodes at presentation, Dr. Shapiro noted.

"Right now I would say the ideal candidate to undergo sentinel lymph node mapping and biopsy is the patient with a primary cutaneous melanoma 1 mm thick or greater, with no clinical evidence of regional lymph node metastases and in a patient where successful scintigraphy preoperatively can be performed and demonstrate regional lymph node draining," he said.

LOS ANGELES — Two rare types of non-Hodgkin's lymphomas responded to treatment with intratumoral injections of an investigational immunomodulator plus radiotherapy in a pilot study of seven patients, Dr. Anjali V. Morales reported at the annual meeting of the Society for Investigative Dermatology.

Six patients with mycosis fungoides and one patient with primary cutaneous B-cell lymphoma (CBCL) underwent low-dose radiotherapy to a single tumor site on day 1 and 2 plus injections of CpG 7909 to the same tumor within 24 hours before and after the radiotherapy. This treatment regimen was repeated weekly for a total of nine sessions. Noninjected tumors were monitored to assess systemic effects of the treatment.

CpG 7909 is an agonist to the protein TLR 9 (toll-like receptor 9) and belongs to a new class of immunomodulators that activate B cells and plasmacytoid dendritic cells. It showed promise as monotherapy for cutaneous T-cell lymphoma in a previous trial, said Dr. Morales of Stanford (Calif.) University.

In the current study, the combination of CpG 7909 and low-dose radiotherapy produced partial responses in two patients with mycosis fungoides and the one patient with CBCL. Another patient with mycosis fungoides showed a minor response, and the other three patients had stable disease, she reported.

A partial response was defined as greater than a 50% reduction in tumor volume or severity-weighted assessment tool (SWAT) score, compared with baseline. A minor response was defined as a 25%-50% reduction in tumor volume or SWAT score, compared with baseline.

The responses appeared after 6-9 weeks in patients with mycosis fungoides and after 4 weeks in the patient with CBCL. "We did note that responses were short-lived," so the protocol has been amended to enhance the systemic antitumor response, Dr. Morales said.

The investigators are enrolling patients now in a study that will administer low-dose radiotherapy and CpG 7909 injections to one tumor site on day 1 and 2, followed by two weekly CpG 7909 injections. At week 4, a second tumor site will be treated with radiotherapy and injections, followed by four weekly injections of CpG 7909. Nontreated lesions will be assessed for response.

The treatment appeared to be well tolerated, with grade 1-2 adverse events in all patients, she said. These included erythema, pain, and induration at the injection sites plus fever and fatigue in all patients. Six patients reported myalgia and arthralgia, three complained of headache, and one had nausea.

Researchers have theorized that intratumoral injection of CpG 7909 activates dendritic cells, which migrate to lymph nodes and promote a systemic antitumor immune response.

The study was initiated by Stanford faculty and funded by the National Institutes of Health, Dr. Morales said.

LOS ANGELES — Two rare types of non-Hodgkin's lymphomas responded to treatment with intratumoral injections of an investigational immunomodulator plus radiotherapy in a pilot study of seven patients, Dr. Anjali V. Morales reported at the annual meeting of the Society for Investigative Dermatology.

Six patients with mycosis fungoides and one patient with primary cutaneous B-cell lymphoma (CBCL) underwent low-dose radiotherapy to a single tumor site on day 1 and 2 plus injections of CpG 7909 to the same tumor within 24 hours before and after the radiotherapy. This treatment regimen was repeated weekly for a total of nine sessions. Noninjected tumors were monitored to assess systemic effects of the treatment.

CpG 7909 is an agonist to the protein TLR 9 (toll-like receptor 9) and belongs to a new class of immunomodulators that activate B cells and plasmacytoid dendritic cells. It showed promise as monotherapy for cutaneous T-cell lymphoma in a previous trial, said Dr. Morales of Stanford (Calif.) University.

In the current study, the combination of CpG 7909 and low-dose radiotherapy produced partial responses in two patients with mycosis fungoides and the one patient with CBCL. Another patient with mycosis fungoides showed a minor response, and the other three patients had stable disease, she reported.

A partial response was defined as greater than a 50% reduction in tumor volume or severity-weighted assessment tool (SWAT) score, compared with baseline. A minor response was defined as a 25%-50% reduction in tumor volume or SWAT score, compared with baseline.

The responses appeared after 6-9 weeks in patients with mycosis fungoides and after 4 weeks in the patient with CBCL. "We did note that responses were short-lived," so the protocol has been amended to enhance the systemic antitumor response, Dr. Morales said.

The investigators are enrolling patients now in a study that will administer low-dose radiotherapy and CpG 7909 injections to one tumor site on day 1 and 2, followed by two weekly CpG 7909 injections. At week 4, a second tumor site will be treated with radiotherapy and injections, followed by four weekly injections of CpG 7909. Nontreated lesions will be assessed for response.

The treatment appeared to be well tolerated, with grade 1-2 adverse events in all patients, she said. These included erythema, pain, and induration at the injection sites plus fever and fatigue in all patients. Six patients reported myalgia and arthralgia, three complained of headache, and one had nausea.

Researchers have theorized that intratumoral injection of CpG 7909 activates dendritic cells, which migrate to lymph nodes and promote a systemic antitumor immune response.

The study was initiated by Stanford faculty and funded by the National Institutes of Health, Dr. Morales said.

LOS ANGELES — Two rare types of non-Hodgkin's lymphomas responded to treatment with intratumoral injections of an investigational immunomodulator plus radiotherapy in a pilot study of seven patients, Dr. Anjali V. Morales reported at the annual meeting of the Society for Investigative Dermatology.

Six patients with mycosis fungoides and one patient with primary cutaneous B-cell lymphoma (CBCL) underwent low-dose radiotherapy to a single tumor site on day 1 and 2 plus injections of CpG 7909 to the same tumor within 24 hours before and after the radiotherapy. This treatment regimen was repeated weekly for a total of nine sessions. Noninjected tumors were monitored to assess systemic effects of the treatment.

CpG 7909 is an agonist to the protein TLR 9 (toll-like receptor 9) and belongs to a new class of immunomodulators that activate B cells and plasmacytoid dendritic cells. It showed promise as monotherapy for cutaneous T-cell lymphoma in a previous trial, said Dr. Morales of Stanford (Calif.) University.

In the current study, the combination of CpG 7909 and low-dose radiotherapy produced partial responses in two patients with mycosis fungoides and the one patient with CBCL. Another patient with mycosis fungoides showed a minor response, and the other three patients had stable disease, she reported.

A partial response was defined as greater than a 50% reduction in tumor volume or severity-weighted assessment tool (SWAT) score, compared with baseline. A minor response was defined as a 25%-50% reduction in tumor volume or SWAT score, compared with baseline.

The responses appeared after 6-9 weeks in patients with mycosis fungoides and after 4 weeks in the patient with CBCL. "We did note that responses were short-lived," so the protocol has been amended to enhance the systemic antitumor response, Dr. Morales said.

The investigators are enrolling patients now in a study that will administer low-dose radiotherapy and CpG 7909 injections to one tumor site on day 1 and 2, followed by two weekly CpG 7909 injections. At week 4, a second tumor site will be treated with radiotherapy and injections, followed by four weekly injections of CpG 7909. Nontreated lesions will be assessed for response.

The treatment appeared to be well tolerated, with grade 1-2 adverse events in all patients, she said. These included erythema, pain, and induration at the injection sites plus fever and fatigue in all patients. Six patients reported myalgia and arthralgia, three complained of headache, and one had nausea.

Researchers have theorized that intratumoral injection of CpG 7909 activates dendritic cells, which migrate to lymph nodes and promote a systemic antitumor immune response.

The study was initiated by Stanford faculty and funded by the National Institutes of Health, Dr. Morales said.

ZURICH — Intralesional adenoviral vector-delivered interferon-gamma gene transfer is a novel and promising immunotherapy for primary cutaneous lymphomas, Dr. Mirjana Urosevic said at the annual meeting of the European Society for Dermatological Research.

Although adenovirus is the most utilized vector in the field of gene therapy, in the setting of primary cutaneous lymphoma the adenoviral vector is not merely a gene therapy delivery system. It has therapeutic activity in its own right, according to Dr. Urosevic of the University of Zurich.

She and her colleagues found that adenoviral vector activates innate immunity and induces type 1 interferons, most prominently interferon-α(1FN-α), a toll-like receptor agonist that stimulates antitumor immunity and has strong antiproliferative and antiangiogenic effects. They demonstrated this in gene expression profile studies of skin lesions obtained before and after treatment in 20 patients with various primary cutaneous lymphomas.

The appeal of adenovirus-mediated interferon-gamma (IFN-γ gene transfer is that it provides a complementary two-pronged approach to immunotherapy, calling forth both innate and adaptive immunity. The adenovirus induces IFN-α, while the gene insert comprised of human cDNA induces IFN-γ, a type II interferon. Both IFN-α and IFN-γ are believed to be crucial for the most efficient tumor rejection.

In preliminary studies, the researchers found that adenovirus-mediated IFN-γ gene transfer provided impressive clinical efficacy. Favorable responses have been universal in the small number of treated patients with cutaneous B-cell lymphomas. The majority of patients with cutaneous T-cell lymphomas have also responded.

Although direct intralesional injection of IFN-α or IFN-γ also results in tumor regression, adenovirus-mediated IFN-γ gene transfer is better tolerated, as it induces the patient's own cells to produce the interferons. It's a local intralesional therapy without systemic toxicity, said Dr. Urosevic.

The chief side effect is pain at the injection site lasting no longer than an hour. A strong local erythematous reaction can also occur. In addition, patients lacking antibodies to adenovirus experience febrile episodes in response to the initial injections.

The primary cutaneous lymphomas are uncommon malignancies characterized by accumulation of clonal T or B lymphocytes in the skin. Most are indolent chronic diseases with a good prognosis, so the preference is for low-morbidity treatments that provide good control for long periods, she said. The primary cutaneous lymphomas don't offer tumor antigens as targets for immunotherapy, but nonspecific immunostimulation can be applied using cytokines such as IFN-α and IFN-γ.

The primary cutaneous B-cell lymphomas are a heterogeneous group of disorders defined by skin involvement without extracutaneous disease at the time of diagnosis. They account for about one-quarter of all primary cutaneous lymphomas.

Two of the three major subtypes of primary cutaneous B-cell lymphomas in the World Health Organization classification—marginal zone B-cell lymphoma and follicle center lymphoma—particularly lend themselves as a testing ground for less aggressive treatments such as immunotherapy because they are low-grade lymphomas that progress slowly, often over decades. The third major subtype—large B-cell lymphoma, leg type—is considerably more aggressive and doesn't qualify for immunotherapy, Dr. Urosevic explained.

There are at present no approved therapies for primary cutaneous B-cell lymphomas. The most widely used treatments are surgery and radiotherapy. Off-label therapies include corticosteroids, rituximab, and imiquimod.

Adenovirus-mediated IFN-γ gene transfer is being developed by Transgene SA of Strasbourg, France, the company that funded the study. A phase II clinical trial in 40 patients with radiotherapy-resistant primary cutaneous B-cell lymphomas is under way.

The treatment regimen entails once-weekly injections for 3 weeks followed by a 2-week pause to assess for disease progression. If the disease is stable or there is an objective response, weekly treatment resumes. Recently, however, Dr. Urosevic and colleagues showed that if the genes for IFN-α and IFN-γ are induced shortly after treatment starts, a later favorable therapeutic response is predicted.

Successfully treated lesions—and in many cases untreated ones as well—slowly disappear, with complete responses often seen after three to six injections.

ZURICH — Intralesional adenoviral vector-delivered interferon-gamma gene transfer is a novel and promising immunotherapy for primary cutaneous lymphomas, Dr. Mirjana Urosevic said at the annual meeting of the European Society for Dermatological Research.

Although adenovirus is the most utilized vector in the field of gene therapy, in the setting of primary cutaneous lymphoma the adenoviral vector is not merely a gene therapy delivery system. It has therapeutic activity in its own right, according to Dr. Urosevic of the University of Zurich.

She and her colleagues found that adenoviral vector activates innate immunity and induces type 1 interferons, most prominently interferon-α(1FN-α), a toll-like receptor agonist that stimulates antitumor immunity and has strong antiproliferative and antiangiogenic effects. They demonstrated this in gene expression profile studies of skin lesions obtained before and after treatment in 20 patients with various primary cutaneous lymphomas.

The appeal of adenovirus-mediated interferon-gamma (IFN-γ gene transfer is that it provides a complementary two-pronged approach to immunotherapy, calling forth both innate and adaptive immunity. The adenovirus induces IFN-α, while the gene insert comprised of human cDNA induces IFN-γ, a type II interferon. Both IFN-α and IFN-γ are believed to be crucial for the most efficient tumor rejection.

In preliminary studies, the researchers found that adenovirus-mediated IFN-γ gene transfer provided impressive clinical efficacy. Favorable responses have been universal in the small number of treated patients with cutaneous B-cell lymphomas. The majority of patients with cutaneous T-cell lymphomas have also responded.

Although direct intralesional injection of IFN-α or IFN-γ also results in tumor regression, adenovirus-mediated IFN-γ gene transfer is better tolerated, as it induces the patient's own cells to produce the interferons. It's a local intralesional therapy without systemic toxicity, said Dr. Urosevic.

The chief side effect is pain at the injection site lasting no longer than an hour. A strong local erythematous reaction can also occur. In addition, patients lacking antibodies to adenovirus experience febrile episodes in response to the initial injections.

The primary cutaneous lymphomas are uncommon malignancies characterized by accumulation of clonal T or B lymphocytes in the skin. Most are indolent chronic diseases with a good prognosis, so the preference is for low-morbidity treatments that provide good control for long periods, she said. The primary cutaneous lymphomas don't offer tumor antigens as targets for immunotherapy, but nonspecific immunostimulation can be applied using cytokines such as IFN-α and IFN-γ.

The primary cutaneous B-cell lymphomas are a heterogeneous group of disorders defined by skin involvement without extracutaneous disease at the time of diagnosis. They account for about one-quarter of all primary cutaneous lymphomas.

Two of the three major subtypes of primary cutaneous B-cell lymphomas in the World Health Organization classification—marginal zone B-cell lymphoma and follicle center lymphoma—particularly lend themselves as a testing ground for less aggressive treatments such as immunotherapy because they are low-grade lymphomas that progress slowly, often over decades. The third major subtype—large B-cell lymphoma, leg type—is considerably more aggressive and doesn't qualify for immunotherapy, Dr. Urosevic explained.

There are at present no approved therapies for primary cutaneous B-cell lymphomas. The most widely used treatments are surgery and radiotherapy. Off-label therapies include corticosteroids, rituximab, and imiquimod.

Adenovirus-mediated IFN-γ gene transfer is being developed by Transgene SA of Strasbourg, France, the company that funded the study. A phase II clinical trial in 40 patients with radiotherapy-resistant primary cutaneous B-cell lymphomas is under way.

The treatment regimen entails once-weekly injections for 3 weeks followed by a 2-week pause to assess for disease progression. If the disease is stable or there is an objective response, weekly treatment resumes. Recently, however, Dr. Urosevic and colleagues showed that if the genes for IFN-α and IFN-γ are induced shortly after treatment starts, a later favorable therapeutic response is predicted.

Successfully treated lesions—and in many cases untreated ones as well—slowly disappear, with complete responses often seen after three to six injections.

ZURICH — Intralesional adenoviral vector-delivered interferon-gamma gene transfer is a novel and promising immunotherapy for primary cutaneous lymphomas, Dr. Mirjana Urosevic said at the annual meeting of the European Society for Dermatological Research.

Although adenovirus is the most utilized vector in the field of gene therapy, in the setting of primary cutaneous lymphoma the adenoviral vector is not merely a gene therapy delivery system. It has therapeutic activity in its own right, according to Dr. Urosevic of the University of Zurich.

She and her colleagues found that adenoviral vector activates innate immunity and induces type 1 interferons, most prominently interferon-α(1FN-α), a toll-like receptor agonist that stimulates antitumor immunity and has strong antiproliferative and antiangiogenic effects. They demonstrated this in gene expression profile studies of skin lesions obtained before and after treatment in 20 patients with various primary cutaneous lymphomas.

The appeal of adenovirus-mediated interferon-gamma (IFN-γ gene transfer is that it provides a complementary two-pronged approach to immunotherapy, calling forth both innate and adaptive immunity. The adenovirus induces IFN-α, while the gene insert comprised of human cDNA induces IFN-γ, a type II interferon. Both IFN-α and IFN-γ are believed to be crucial for the most efficient tumor rejection.

In preliminary studies, the researchers found that adenovirus-mediated IFN-γ gene transfer provided impressive clinical efficacy. Favorable responses have been universal in the small number of treated patients with cutaneous B-cell lymphomas. The majority of patients with cutaneous T-cell lymphomas have also responded.

Although direct intralesional injection of IFN-α or IFN-γ also results in tumor regression, adenovirus-mediated IFN-γ gene transfer is better tolerated, as it induces the patient's own cells to produce the interferons. It's a local intralesional therapy without systemic toxicity, said Dr. Urosevic.

The chief side effect is pain at the injection site lasting no longer than an hour. A strong local erythematous reaction can also occur. In addition, patients lacking antibodies to adenovirus experience febrile episodes in response to the initial injections.

The primary cutaneous lymphomas are uncommon malignancies characterized by accumulation of clonal T or B lymphocytes in the skin. Most are indolent chronic diseases with a good prognosis, so the preference is for low-morbidity treatments that provide good control for long periods, she said. The primary cutaneous lymphomas don't offer tumor antigens as targets for immunotherapy, but nonspecific immunostimulation can be applied using cytokines such as IFN-α and IFN-γ.

The primary cutaneous B-cell lymphomas are a heterogeneous group of disorders defined by skin involvement without extracutaneous disease at the time of diagnosis. They account for about one-quarter of all primary cutaneous lymphomas.

Two of the three major subtypes of primary cutaneous B-cell lymphomas in the World Health Organization classification—marginal zone B-cell lymphoma and follicle center lymphoma—particularly lend themselves as a testing ground for less aggressive treatments such as immunotherapy because they are low-grade lymphomas that progress slowly, often over decades. The third major subtype—large B-cell lymphoma, leg type—is considerably more aggressive and doesn't qualify for immunotherapy, Dr. Urosevic explained.

There are at present no approved therapies for primary cutaneous B-cell lymphomas. The most widely used treatments are surgery and radiotherapy. Off-label therapies include corticosteroids, rituximab, and imiquimod.

Adenovirus-mediated IFN-γ gene transfer is being developed by Transgene SA of Strasbourg, France, the company that funded the study. A phase II clinical trial in 40 patients with radiotherapy-resistant primary cutaneous B-cell lymphomas is under way.

The treatment regimen entails once-weekly injections for 3 weeks followed by a 2-week pause to assess for disease progression. If the disease is stable or there is an objective response, weekly treatment resumes. Recently, however, Dr. Urosevic and colleagues showed that if the genes for IFN-α and IFN-γ are induced shortly after treatment starts, a later favorable therapeutic response is predicted.

Successfully treated lesions—and in many cases untreated ones as well—slowly disappear, with complete responses often seen after three to six injections.

CORONADO, CALIF. — Some day patients may reach for Lipitor or Celebrex as a melanoma prevention agent, Dr. Michael E. Ming speculated at the annual meeting of the Pacific Dermatologic Association.

He described the ideal chemopreventive agent for melanoma as one that is effective, has an acceptable toxicity profile, and is already widely available.

One class of agents that could potentially meet those criteria if effectiveness in humans can be demonstrated is statins, which may prevent melanoma by decreasing production of intermediate products such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate in the pathway from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to cholesterol.

"These intermediate products may activate proteins important in cell growth and cell cycle progression, so decreased production of these products may lead to decreased activity of mutant forms of those proteins," said Dr. Ming, director of the pigmented lesion clinic at the University of Pennsylvania, Philadelphia.

Supportive evidence comes from several laboratory studies on melanoma cell lines and in mice, and from one clinical trial with melanoma as a secondary outcome (JAMA 1998;279:1615-22), and from a Dutch case-control study of statins and cancer in general (J. Clin. Oncol. 2004;22:2388-94). Other studies, however, have not shown a link between melanoma and statins, including meta-analyses and systematic reviews (JAMA 2006;295:74-80 and Cochrane Database Syst. Rev. 2005:CD003697), and it is difficult to say at this time whether statins are effective preventive agents against melanoma.

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent another class of agents that may protect against melanoma, most likely through inhibition of cyclooxygenase-2 (COX-2), which in turn reduces prostaglandin production, Dr. Ming said.

Supportive evidence comes from a few laboratory studies on melanoma cell lines, including one case-control study in women (Oncol. Rep. 2001;8:655-7) and one case-control study in patients who already had melanoma (Dermatol. Surg. 2005;31:748-52). So far, though, the body of literature on this topic is too small and inadequate to state definitively that there is a link between NSAID use and lower rates of melanoma. In addition, some studies fail to show that COX-2 is expressed in all melanomas (Melanoma Res. 2001;11:587-99).

Other available agents that might help prevent melanoma include vitamins A, C, D, and E, but the current evidence in the medical literature is unclear, and it is difficult to draw meaningful conclusions, said Dr. Ming, who had no relevant conflicts of interest to disclose.

He emphasized that no candidate agent has been definitively established as having chemopreventive properties against melanoma. "Are there agents we can use against melanoma?" he asked. "The answer you have to say right now is not yet, but maybe soon."

'These intermediate products may activate proteins important in cell growth and cell cycle progression.' DR. MING

CORONADO, CALIF. — Some day patients may reach for Lipitor or Celebrex as a melanoma prevention agent, Dr. Michael E. Ming speculated at the annual meeting of the Pacific Dermatologic Association.

He described the ideal chemopreventive agent for melanoma as one that is effective, has an acceptable toxicity profile, and is already widely available.

One class of agents that could potentially meet those criteria if effectiveness in humans can be demonstrated is statins, which may prevent melanoma by decreasing production of intermediate products such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate in the pathway from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to cholesterol.

"These intermediate products may activate proteins important in cell growth and cell cycle progression, so decreased production of these products may lead to decreased activity of mutant forms of those proteins," said Dr. Ming, director of the pigmented lesion clinic at the University of Pennsylvania, Philadelphia.

Supportive evidence comes from several laboratory studies on melanoma cell lines and in mice, and from one clinical trial with melanoma as a secondary outcome (JAMA 1998;279:1615-22), and from a Dutch case-control study of statins and cancer in general (J. Clin. Oncol. 2004;22:2388-94). Other studies, however, have not shown a link between melanoma and statins, including meta-analyses and systematic reviews (JAMA 2006;295:74-80 and Cochrane Database Syst. Rev. 2005:CD003697), and it is difficult to say at this time whether statins are effective preventive agents against melanoma.

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent another class of agents that may protect against melanoma, most likely through inhibition of cyclooxygenase-2 (COX-2), which in turn reduces prostaglandin production, Dr. Ming said.

Supportive evidence comes from a few laboratory studies on melanoma cell lines, including one case-control study in women (Oncol. Rep. 2001;8:655-7) and one case-control study in patients who already had melanoma (Dermatol. Surg. 2005;31:748-52). So far, though, the body of literature on this topic is too small and inadequate to state definitively that there is a link between NSAID use and lower rates of melanoma. In addition, some studies fail to show that COX-2 is expressed in all melanomas (Melanoma Res. 2001;11:587-99).

Other available agents that might help prevent melanoma include vitamins A, C, D, and E, but the current evidence in the medical literature is unclear, and it is difficult to draw meaningful conclusions, said Dr. Ming, who had no relevant conflicts of interest to disclose.

He emphasized that no candidate agent has been definitively established as having chemopreventive properties against melanoma. "Are there agents we can use against melanoma?" he asked. "The answer you have to say right now is not yet, but maybe soon."

'These intermediate products may activate proteins important in cell growth and cell cycle progression.' DR. MING

CORONADO, CALIF. — Some day patients may reach for Lipitor or Celebrex as a melanoma prevention agent, Dr. Michael E. Ming speculated at the annual meeting of the Pacific Dermatologic Association.

He described the ideal chemopreventive agent for melanoma as one that is effective, has an acceptable toxicity profile, and is already widely available.

One class of agents that could potentially meet those criteria if effectiveness in humans can be demonstrated is statins, which may prevent melanoma by decreasing production of intermediate products such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate in the pathway from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to cholesterol.

"These intermediate products may activate proteins important in cell growth and cell cycle progression, so decreased production of these products may lead to decreased activity of mutant forms of those proteins," said Dr. Ming, director of the pigmented lesion clinic at the University of Pennsylvania, Philadelphia.

Supportive evidence comes from several laboratory studies on melanoma cell lines and in mice, and from one clinical trial with melanoma as a secondary outcome (JAMA 1998;279:1615-22), and from a Dutch case-control study of statins and cancer in general (J. Clin. Oncol. 2004;22:2388-94). Other studies, however, have not shown a link between melanoma and statins, including meta-analyses and systematic reviews (JAMA 2006;295:74-80 and Cochrane Database Syst. Rev. 2005:CD003697), and it is difficult to say at this time whether statins are effective preventive agents against melanoma.

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent another class of agents that may protect against melanoma, most likely through inhibition of cyclooxygenase-2 (COX-2), which in turn reduces prostaglandin production, Dr. Ming said.

Supportive evidence comes from a few laboratory studies on melanoma cell lines, including one case-control study in women (Oncol. Rep. 2001;8:655-7) and one case-control study in patients who already had melanoma (Dermatol. Surg. 2005;31:748-52). So far, though, the body of literature on this topic is too small and inadequate to state definitively that there is a link between NSAID use and lower rates of melanoma. In addition, some studies fail to show that COX-2 is expressed in all melanomas (Melanoma Res. 2001;11:587-99).

Other available agents that might help prevent melanoma include vitamins A, C, D, and E, but the current evidence in the medical literature is unclear, and it is difficult to draw meaningful conclusions, said Dr. Ming, who had no relevant conflicts of interest to disclose.

He emphasized that no candidate agent has been definitively established as having chemopreventive properties against melanoma. "Are there agents we can use against melanoma?" he asked. "The answer you have to say right now is not yet, but maybe soon."

'These intermediate products may activate proteins important in cell growth and cell cycle progression.' DR. MING