Melanoma

PORTLAND, ORE. – Long-term exposure to commonly used estrogen-based contraceptives was not associated with malignant melanoma in a single-center retrospective study of more than 77,000 women.

This null result belied decades-old studies performed when contraceptives contained much higher doses of estrogen, Kelly A. Mueller of Northwestern University, Chicago, said in a poster presented at the annual meeting of the Society for Investigative Dermatology. Current microdosing of ethinyl estradiol (EE) “is not associated with subsequent diagnosis of melanoma in our population, and is not inconsistent with the full prescribing information for commonly prescribed contraceptives containing EE,” she said. The study also shows how large retrospective analyses of long-term follow-up data can inform pharmacovigilance for rare, serious medical events.

©Zerbor/Thinkstock

PORTLAND, ORE. – Long-term exposure to commonly used estrogen-based contraceptives was not associated with malignant melanoma in a single-center retrospective study of more than 77,000 women.

This null result belied decades-old studies performed when contraceptives contained much higher doses of estrogen, Kelly A. Mueller of Northwestern University, Chicago, said in a poster presented at the annual meeting of the Society for Investigative Dermatology. Current microdosing of ethinyl estradiol (EE) “is not associated with subsequent diagnosis of melanoma in our population, and is not inconsistent with the full prescribing information for commonly prescribed contraceptives containing EE,” she said. The study also shows how large retrospective analyses of long-term follow-up data can inform pharmacovigilance for rare, serious medical events.

©Zerbor/Thinkstock

PORTLAND, ORE. – Long-term exposure to commonly used estrogen-based contraceptives was not associated with malignant melanoma in a single-center retrospective study of more than 77,000 women.

This null result belied decades-old studies performed when contraceptives contained much higher doses of estrogen, Kelly A. Mueller of Northwestern University, Chicago, said in a poster presented at the annual meeting of the Society for Investigative Dermatology. Current microdosing of ethinyl estradiol (EE) “is not associated with subsequent diagnosis of melanoma in our population, and is not inconsistent with the full prescribing information for commonly prescribed contraceptives containing EE,” she said. The study also shows how large retrospective analyses of long-term follow-up data can inform pharmacovigilance for rare, serious medical events.

©Zerbor/Thinkstock

WAILEA, HAWAII – Nicotinamide is one of the rare proposed agents for skin cancer chemoprevention distinguished by dirt cheap cost combined with a highly reassuring safety profile plus evidence of efficacy – which, together, make it a reasonable option in high risk patients, according to Daniel M. Siegel, MD.

Other agents that fit into that category include the tropical rainforest fern Polypodium leucotomos and milk thistle, added Dr. Siegel, a dermatologist at the State University of New York, Brooklyn.

Bruce Jancin/Frontline Medical News

Nicotinamide

In the case of nicotinamide, the efficacy is actually supported by published level 1 evidence in the form of a highly positive 1-year, double-blind, randomized, placebo-controlled phase III clinical trial.

“You can Google ‘nicotinamide’ and find it at places like Costco and Trader Joe’s for less than 6 cents per day. That makes for a really good risk/benefit ratio. A nickel a day: That’s a cheap one. That’s one where I’d say, ‘Why not?’ It seems to be safe,” Dr. Siegel said.

In the phase III ONTRAC trial, Australian investigators randomized 386 patients who averaged roughly eight nonmelanoma skin cancers in the past 5 years to either 500 mg of oral nicotinamide twice daily or matched placebo for 12 months. During the study period, the nicotinamide group had a statistically significant and clinically meaningful 23% reduction in new nonmelanoma skin cancers, compared with the control group. They also had 13% fewer actinic keratoses at 12 months than controls. And the side effect profile mirrored that of placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26).

“Nicotinamide is vitamin B₃. It’s not niacin. It doesn’t cause flushing and other vasodilatory effects. It’s actually pretty innocuous,” Dr. Siegel said.

In laboratory studies, nicotinamide has been shown to enhance DNA repair following UV exposure, as well as curb UV-induced immunosuppression.

Polypodium leucotomos Samambaia

This plant, commonly known as calaguala in the Spanish-speaking tropics and samambaia in Brazil, has a centuries-long tradition of safe medicinal use. It is commercially available over-the-counter (OTC) as a standardized product called Heliocare, designed to avoid the guesswork involved in topical sunscreen application. Each capsule contains 240 mg of an extract of P. leucotomos. Dr. Siegel said he takes it daily when he’s in a sunny locale, such as Hawaii.

Milk thistle

This plant, known as Silybum marianum, has silymarin as its bioactive compound. Dermatologist Haines Ely, MD, of the University of California, Davis, has reported therapeutic success using it in porphyria cutanea tarda and other conditions. It has been shown to inhibit photocarcinogenesis in animal studies.

Dr. Siegel said that, while Dr. Ely has told him his preferred preparation is a German OTC product, milk thistle seeds can be found in health food stores, ground to a powder using a coffee bean grinder, and used as a food supplement. Like Polypodium leucotomos and nicotinamide, milk thistle is nontoxic.

Rapamycin

This macrolide compound is produced by the bacterium Streptomyces hygroscopicus. Rapamycin is an immunosuppressant used to coat coronary stents and prevent rejection of transplanted organs. It is an mechanistic target of rapamycin signaling pathway inhibitor being studied as a cancer prevention and antiaging agent.

Science magazine called the discovery that rapamycin increased the lifespan of mice one of the top scientific breakthroughs of 2009. Subsequent animal studies have established that the extended lifespan wasn’t solely the result of rapamycin’s antineoplastic effects but of across-the-board delayed onset of all the major age-related diseases. Thus, rapamycin could turn out to be a true antiaging agent, in Dr. Siegel’s view.

Studies in humans are underway. Researchers at Novartis have reported that a rapamycin-related compound curbed the typical decline in immune function that accompanies aging as reflected in a 20% enhancement in the response to influenza vaccine in elderly volunteers (Sci Transl Med. 2014 Dec 24;6[268]:268ra179).

Dr. Siegel reported serving as a consultant to Ferndale, which markets Heliocare. The SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com

WAILEA, HAWAII – Nicotinamide is one of the rare proposed agents for skin cancer chemoprevention distinguished by dirt cheap cost combined with a highly reassuring safety profile plus evidence of efficacy – which, together, make it a reasonable option in high risk patients, according to Daniel M. Siegel, MD.

Other agents that fit into that category include the tropical rainforest fern Polypodium leucotomos and milk thistle, added Dr. Siegel, a dermatologist at the State University of New York, Brooklyn.

Bruce Jancin/Frontline Medical News

Nicotinamide

In the case of nicotinamide, the efficacy is actually supported by published level 1 evidence in the form of a highly positive 1-year, double-blind, randomized, placebo-controlled phase III clinical trial.

“You can Google ‘nicotinamide’ and find it at places like Costco and Trader Joe’s for less than 6 cents per day. That makes for a really good risk/benefit ratio. A nickel a day: That’s a cheap one. That’s one where I’d say, ‘Why not?’ It seems to be safe,” Dr. Siegel said.

In the phase III ONTRAC trial, Australian investigators randomized 386 patients who averaged roughly eight nonmelanoma skin cancers in the past 5 years to either 500 mg of oral nicotinamide twice daily or matched placebo for 12 months. During the study period, the nicotinamide group had a statistically significant and clinically meaningful 23% reduction in new nonmelanoma skin cancers, compared with the control group. They also had 13% fewer actinic keratoses at 12 months than controls. And the side effect profile mirrored that of placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26).

“Nicotinamide is vitamin B₃. It’s not niacin. It doesn’t cause flushing and other vasodilatory effects. It’s actually pretty innocuous,” Dr. Siegel said.

In laboratory studies, nicotinamide has been shown to enhance DNA repair following UV exposure, as well as curb UV-induced immunosuppression.

Polypodium leucotomos Samambaia

This plant, commonly known as calaguala in the Spanish-speaking tropics and samambaia in Brazil, has a centuries-long tradition of safe medicinal use. It is commercially available over-the-counter (OTC) as a standardized product called Heliocare, designed to avoid the guesswork involved in topical sunscreen application. Each capsule contains 240 mg of an extract of P. leucotomos. Dr. Siegel said he takes it daily when he’s in a sunny locale, such as Hawaii.

Milk thistle

This plant, known as Silybum marianum, has silymarin as its bioactive compound. Dermatologist Haines Ely, MD, of the University of California, Davis, has reported therapeutic success using it in porphyria cutanea tarda and other conditions. It has been shown to inhibit photocarcinogenesis in animal studies.

Dr. Siegel said that, while Dr. Ely has told him his preferred preparation is a German OTC product, milk thistle seeds can be found in health food stores, ground to a powder using a coffee bean grinder, and used as a food supplement. Like Polypodium leucotomos and nicotinamide, milk thistle is nontoxic.

Rapamycin

This macrolide compound is produced by the bacterium Streptomyces hygroscopicus. Rapamycin is an immunosuppressant used to coat coronary stents and prevent rejection of transplanted organs. It is an mechanistic target of rapamycin signaling pathway inhibitor being studied as a cancer prevention and antiaging agent.

Science magazine called the discovery that rapamycin increased the lifespan of mice one of the top scientific breakthroughs of 2009. Subsequent animal studies have established that the extended lifespan wasn’t solely the result of rapamycin’s antineoplastic effects but of across-the-board delayed onset of all the major age-related diseases. Thus, rapamycin could turn out to be a true antiaging agent, in Dr. Siegel’s view.

Studies in humans are underway. Researchers at Novartis have reported that a rapamycin-related compound curbed the typical decline in immune function that accompanies aging as reflected in a 20% enhancement in the response to influenza vaccine in elderly volunteers (Sci Transl Med. 2014 Dec 24;6[268]:268ra179).

Dr. Siegel reported serving as a consultant to Ferndale, which markets Heliocare. The SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com

WAILEA, HAWAII – Nicotinamide is one of the rare proposed agents for skin cancer chemoprevention distinguished by dirt cheap cost combined with a highly reassuring safety profile plus evidence of efficacy – which, together, make it a reasonable option in high risk patients, according to Daniel M. Siegel, MD.

Other agents that fit into that category include the tropical rainforest fern Polypodium leucotomos and milk thistle, added Dr. Siegel, a dermatologist at the State University of New York, Brooklyn.

Bruce Jancin/Frontline Medical News

Nicotinamide

In the case of nicotinamide, the efficacy is actually supported by published level 1 evidence in the form of a highly positive 1-year, double-blind, randomized, placebo-controlled phase III clinical trial.

“You can Google ‘nicotinamide’ and find it at places like Costco and Trader Joe’s for less than 6 cents per day. That makes for a really good risk/benefit ratio. A nickel a day: That’s a cheap one. That’s one where I’d say, ‘Why not?’ It seems to be safe,” Dr. Siegel said.

In the phase III ONTRAC trial, Australian investigators randomized 386 patients who averaged roughly eight nonmelanoma skin cancers in the past 5 years to either 500 mg of oral nicotinamide twice daily or matched placebo for 12 months. During the study period, the nicotinamide group had a statistically significant and clinically meaningful 23% reduction in new nonmelanoma skin cancers, compared with the control group. They also had 13% fewer actinic keratoses at 12 months than controls. And the side effect profile mirrored that of placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26).

“Nicotinamide is vitamin B₃. It’s not niacin. It doesn’t cause flushing and other vasodilatory effects. It’s actually pretty innocuous,” Dr. Siegel said.

In laboratory studies, nicotinamide has been shown to enhance DNA repair following UV exposure, as well as curb UV-induced immunosuppression.

Polypodium leucotomos Samambaia

This plant, commonly known as calaguala in the Spanish-speaking tropics and samambaia in Brazil, has a centuries-long tradition of safe medicinal use. It is commercially available over-the-counter (OTC) as a standardized product called Heliocare, designed to avoid the guesswork involved in topical sunscreen application. Each capsule contains 240 mg of an extract of P. leucotomos. Dr. Siegel said he takes it daily when he’s in a sunny locale, such as Hawaii.

Milk thistle

This plant, known as Silybum marianum, has silymarin as its bioactive compound. Dermatologist Haines Ely, MD, of the University of California, Davis, has reported therapeutic success using it in porphyria cutanea tarda and other conditions. It has been shown to inhibit photocarcinogenesis in animal studies.

Dr. Siegel said that, while Dr. Ely has told him his preferred preparation is a German OTC product, milk thistle seeds can be found in health food stores, ground to a powder using a coffee bean grinder, and used as a food supplement. Like Polypodium leucotomos and nicotinamide, milk thistle is nontoxic.

Rapamycin

This macrolide compound is produced by the bacterium Streptomyces hygroscopicus. Rapamycin is an immunosuppressant used to coat coronary stents and prevent rejection of transplanted organs. It is an mechanistic target of rapamycin signaling pathway inhibitor being studied as a cancer prevention and antiaging agent.

Science magazine called the discovery that rapamycin increased the lifespan of mice one of the top scientific breakthroughs of 2009. Subsequent animal studies have established that the extended lifespan wasn’t solely the result of rapamycin’s antineoplastic effects but of across-the-board delayed onset of all the major age-related diseases. Thus, rapamycin could turn out to be a true antiaging agent, in Dr. Siegel’s view.

Studies in humans are underway. Researchers at Novartis have reported that a rapamycin-related compound curbed the typical decline in immune function that accompanies aging as reflected in a 20% enhancement in the response to influenza vaccine in elderly volunteers (Sci Transl Med. 2014 Dec 24;6[268]:268ra179).

Dr. Siegel reported serving as a consultant to Ferndale, which markets Heliocare. The SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com

PORTLAND, ORE. – A diagnosis of systemic lupus erythematosus (SLE) significantly increases the risk of a subsequent diagnosis of malignant melanoma, according to the results of a large, first-in-kind, single-center longitudinal analysis of electronic medical records.

This finding expands the list of known associations between SLE and cancer, and highlights the need for careful surveillance of this population, Solomiya Grushchak, of the department of dermatology at Northwestern University, Chicago, and her associates, reported in a poster presented at the annual meeting of the Society for Investigative Dermatology.

SLE is increasingly being treated with immune checkpoint inhibitors, which can aggressively disrupt immune reactivity and trigger uncontrolled cellular responses in patients with SLE, Ms. Grushchak noted. “The findings in this large population warrant further exploration of the association between malignant melanoma and SLE to promote optimal patient management, especially in light of recent advances [in the use of] checkpoint inhibitors,” she added.

Past work has linked SLE with several other malignancies, including nonmelanoma skin cancers, non-Hodgkin and Hodgkin lymphomas, and cancers of the larynx, lungs, liver, vulva, vagina, and thyroid gland. Even when patients are not receiving checkpoint inhibitors, SLE causes chronic inflammation and is known to increase cellular dysplasia, which can ultimately trigger uncontrolled proliferation of tumor cells. In 2015, a meta-analysis showed that SLE was associated with a decreased risk of melanoma, but no studies had conclusively evaluated this relationship (PLoS One. 2015;10[4]:e0122964).

Therefore, Ms. Grushchak and her associates analyzed medical records from 2,351 patients from the urban Midwest with SLE diagnosed by a dermatologist or rheumatologist between 2000 and 2016. The data source was the Northwestern Enterprise Data Warehouse, which integrates clinical and research information from more than 50 health data systems used by the Northwestern University Feinberg School of Medicine and its health care partners. To avoid detection bias, the researchers constructed a comparison group from the same database of 1,676 patients diagnosed with systemic sclerosis.

Ten patients (0.4%) with a diagnostic code for SLE were later diagnosed with malignant melanoma, compared with one patient with systemic sclerosis (0.06%), the investigators reported. A Fisher’s exact test confirmed a statistically significant difference between these rates (P = .03). Among the 10 SLE patients with melanoma, 7 were white, 2 were black, and 1 was of Asian ancestry. Nine were females, and one was male. The patient with systemic sclerosis and melanoma was a white male.

The study had several limitations. The investigators did not report how much time elapsed between the diagnoses of SLE and melanoma, or the rates or cumulative exposure to checkpoint inhibitors.

The National Institutes of Health provides support to the Northwestern Enterprise Data Warehouse. The investigators had no relevant financial conflicts.

PORTLAND, ORE. – A diagnosis of systemic lupus erythematosus (SLE) significantly increases the risk of a subsequent diagnosis of malignant melanoma, according to the results of a large, first-in-kind, single-center longitudinal analysis of electronic medical records.

This finding expands the list of known associations between SLE and cancer, and highlights the need for careful surveillance of this population, Solomiya Grushchak, of the department of dermatology at Northwestern University, Chicago, and her associates, reported in a poster presented at the annual meeting of the Society for Investigative Dermatology.

SLE is increasingly being treated with immune checkpoint inhibitors, which can aggressively disrupt immune reactivity and trigger uncontrolled cellular responses in patients with SLE, Ms. Grushchak noted. “The findings in this large population warrant further exploration of the association between malignant melanoma and SLE to promote optimal patient management, especially in light of recent advances [in the use of] checkpoint inhibitors,” she added.

Past work has linked SLE with several other malignancies, including nonmelanoma skin cancers, non-Hodgkin and Hodgkin lymphomas, and cancers of the larynx, lungs, liver, vulva, vagina, and thyroid gland. Even when patients are not receiving checkpoint inhibitors, SLE causes chronic inflammation and is known to increase cellular dysplasia, which can ultimately trigger uncontrolled proliferation of tumor cells. In 2015, a meta-analysis showed that SLE was associated with a decreased risk of melanoma, but no studies had conclusively evaluated this relationship (PLoS One. 2015;10[4]:e0122964).

Therefore, Ms. Grushchak and her associates analyzed medical records from 2,351 patients from the urban Midwest with SLE diagnosed by a dermatologist or rheumatologist between 2000 and 2016. The data source was the Northwestern Enterprise Data Warehouse, which integrates clinical and research information from more than 50 health data systems used by the Northwestern University Feinberg School of Medicine and its health care partners. To avoid detection bias, the researchers constructed a comparison group from the same database of 1,676 patients diagnosed with systemic sclerosis.

Ten patients (0.4%) with a diagnostic code for SLE were later diagnosed with malignant melanoma, compared with one patient with systemic sclerosis (0.06%), the investigators reported. A Fisher’s exact test confirmed a statistically significant difference between these rates (P = .03). Among the 10 SLE patients with melanoma, 7 were white, 2 were black, and 1 was of Asian ancestry. Nine were females, and one was male. The patient with systemic sclerosis and melanoma was a white male.

The study had several limitations. The investigators did not report how much time elapsed between the diagnoses of SLE and melanoma, or the rates or cumulative exposure to checkpoint inhibitors.

The National Institutes of Health provides support to the Northwestern Enterprise Data Warehouse. The investigators had no relevant financial conflicts.

PORTLAND, ORE. – A diagnosis of systemic lupus erythematosus (SLE) significantly increases the risk of a subsequent diagnosis of malignant melanoma, according to the results of a large, first-in-kind, single-center longitudinal analysis of electronic medical records.

This finding expands the list of known associations between SLE and cancer, and highlights the need for careful surveillance of this population, Solomiya Grushchak, of the department of dermatology at Northwestern University, Chicago, and her associates, reported in a poster presented at the annual meeting of the Society for Investigative Dermatology.

SLE is increasingly being treated with immune checkpoint inhibitors, which can aggressively disrupt immune reactivity and trigger uncontrolled cellular responses in patients with SLE, Ms. Grushchak noted. “The findings in this large population warrant further exploration of the association between malignant melanoma and SLE to promote optimal patient management, especially in light of recent advances [in the use of] checkpoint inhibitors,” she added.

Past work has linked SLE with several other malignancies, including nonmelanoma skin cancers, non-Hodgkin and Hodgkin lymphomas, and cancers of the larynx, lungs, liver, vulva, vagina, and thyroid gland. Even when patients are not receiving checkpoint inhibitors, SLE causes chronic inflammation and is known to increase cellular dysplasia, which can ultimately trigger uncontrolled proliferation of tumor cells. In 2015, a meta-analysis showed that SLE was associated with a decreased risk of melanoma, but no studies had conclusively evaluated this relationship (PLoS One. 2015;10[4]:e0122964).

Therefore, Ms. Grushchak and her associates analyzed medical records from 2,351 patients from the urban Midwest with SLE diagnosed by a dermatologist or rheumatologist between 2000 and 2016. The data source was the Northwestern Enterprise Data Warehouse, which integrates clinical and research information from more than 50 health data systems used by the Northwestern University Feinberg School of Medicine and its health care partners. To avoid detection bias, the researchers constructed a comparison group from the same database of 1,676 patients diagnosed with systemic sclerosis.

Ten patients (0.4%) with a diagnostic code for SLE were later diagnosed with malignant melanoma, compared with one patient with systemic sclerosis (0.06%), the investigators reported. A Fisher’s exact test confirmed a statistically significant difference between these rates (P = .03). Among the 10 SLE patients with melanoma, 7 were white, 2 were black, and 1 was of Asian ancestry. Nine were females, and one was male. The patient with systemic sclerosis and melanoma was a white male.

The study had several limitations. The investigators did not report how much time elapsed between the diagnoses of SLE and melanoma, or the rates or cumulative exposure to checkpoint inhibitors.

The National Institutes of Health provides support to the Northwestern Enterprise Data Warehouse. The investigators had no relevant financial conflicts.

Skin cancer is an important public health issue in the United States, as 1 in 5 Americans are projected to develop a cutaneous malignancy during their lifetime. Currently, 75% of all skin cancer–related deaths are due to malignant melanomas (MMs), though melanomas account for less than 5% of all skin cancers.¹ Early detection of MM is essential, as prognosis depends on tumor stage, particularly the depth of the melanoma.^2-4 In general, patients with thin, early-stage melanomas have a more than 96% survival rate, which drops to 14% in late-stage disease.^5,6 Five percent to 30% of all melanomas are identified incidentally on total-body skin examinations (TBSEs) performed by a trained provider and thus would not have been caught with only a focused skin examination or patient self-examination.^7,8 Nonetheless, the clinical utility of skin cancer screening with TBSEs remains controversial, largely due to the poor quality of data available to establish a notable mortality benefit from skin cancer screening. As a result, obtaining endorsement from the larger medical community, federal government, and health insurance industry to include routine TBSEs as part of a preventive care health care strategy has not occurred. The absence of definitive clinical care guidelines mandating routine TBSEs is one of the greatest barriers preventing access to appropriate dermatologic screening along with the paucity of trained providers; however, standardized total-body photography (TBP) promises to provide a way forward by lowering the costs of dermatologic screening while simultaneously leveraging technology to increase availability.

Impact on Biopsy Efficiency

Current US Preventive Services Task Force (USPSTF) guidelines state that evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults. The USPSTF noted that “[d]irect evidence on the effectiveness of screening in reducing melanoma morbidity and mortality is limited to a single fair-quality ecologic study with important methodological limitations” (ie, the Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany [SCREEN] study), and although information on harm is similarly sparse, “[t]he potential for harm clearly exists, including a high rate of unnecessary biopsies, possibly resulting in cosmetic or, more rarely, functional adverse effects, and the risk of overdiagnosis and overtreatment.”⁹ The majority of suspicious skin lesions excised during screenings are not cancerous. For example, the SCREEN study found that 20 to 55 excisions were performed to detect 1 case of melanoma.¹⁰ At that rate, the USPSTF also noted that approximately 4000 excisions would be required to prevent a single death from melanoma.⁹ Following the lead of the USPSTF, the Patient Protection and Affordable Care Act did not mandate that skin examinations be included as essential preventive coverage in its requirements for insurance coverage of primary care prevention. As such, dermatologists face financial pressure to avoid performing time-consuming TBSEs, regardless of their perceived utility.¹¹

As the USPSTF points out, the value of TBSEs relies on the examiner’s ability to correctly identify malignant lesions and minimize biopsies of benign lesions, a concept known as biopsy efficiency.⁹ Secondarily, a TBSE is time consuming, and the time required for a dermatologist to complete a TBSE given the high rate of benign findings may not be financially viable. We argue that the routine use of total-body skin imaging may offer a way forward in addressing these issues. Total-body photography involves a photographic system that can allow dermatologists to acquire standardized images that can be used for primary diagnosis and to track individual lesions over time. Nonmedical personnel and medical assistants can be easily trained to use standardized photography devices to quickly obtain high-quality clinical images, thereby greatly reducing the time and cost of obtaining these images. Studies have found that the use of photographic monitoring may improve biopsy efficiency.^12-15 A recent study by Truong et al¹⁶ found that TBP used to monitor all existing melanocytic lesions on patients substantially reduced the number of biopsies that patients required. These results reflect that most nevi, including clinically atypical nevi, are usually stable and unlikely to exhibit suspicious changes over time.^17,18 For this reason, the use of TBP could minimize unnecessary biopsies because clinically suspicious but stable nevi can be objectively documented and followed over time.

Standardized TBP also offers the ability for dermatologists to work synergistically with modern computer technology involving algorithms capable of analyzing high-quality images to autodiagnose or flag concerning lesions that may require biopsy. Esteva et al¹⁹ described their development of a deep learning algorithm that relies on a convolutional neural network (CNN). This CNN was trained to identify melanomas using a large data set of clinical dermatologic images and subsequently was able to distinguish MMs from benign nevi at a rate on par with a board-certified dermatologist.¹⁹ Widespread use of total-body imaging would create an enormous database of high-resolution images that would be ideally suited to the development of such computerized algorithms, which could then be applied to future images by way of artificial intelligence. Convolutional neural networks that use a single patient’s imaging over time could be developed to assess the change in number or size of benign nevi and identify lesions that are concerning for MM while simultaneously comparing them to a population-based data set.

On a large scale, such a capability would minimize the inefficiency and subjectivity of TBSEs as a tool for identifying malignancy. Currently, dermatologists are only able to track and document a few concerning lesions on a patient’s body, rendering the choice of which lesions require biopsy more subjective. Total-body photography, particularly if used with an algorithm capable of quickly analyzing all the nevi on a person’s body, largely eliminates such subjectivity by creating a standardized set of images that can be tracked over time and flagging concerning lesions prior to the dermatologist examining the patient. In this way, the specialty of dermatology could achieve the same model of objective evaluation of standardized clinical images as those employed in radiology, cardiology, and other clinical disciplines. The additional benefit of such a system would be lower costs, as the images could be acquired by nonmedical personnel and then undergo initial assessment by an algorithm, which would flag concerning lesions, similar to a modern electrocardiogram machine, allowing the dermatologist to use his/her time more efficiently by only focusing on concerning lesions with the confidence that the patient’s entire body has already been rigorously screened.

By using TBP to improve biopsy efficiency and the objectivity of the TBSE as a tool to detect skin cancer, we propose that the benefit-to-harm ratio of the TBSE would remarkably improve. Ultimately, this type of screening would meet the strict requirements to be included in preventive health care strategies and thereby improve access to dermatologic care.

The Use of TBP in the Military

Total-body photography has several specific applications in the military. Standardized imaging has the potential to improve dermatologic care for active-duty soldiers across space and time. First, a large percentage of deployment medical care is devoted to dermatologic issues. From 2008 to 2015, 5% of all medical encounters in the combat theaters of Iraq and Afghanistan involved dermatologic concerns.²⁰ Access to appropriate dermatologic care in a combat theater is important, as poorly controlled dermatologic conditions (eg, psoriasis, eczema) often require evacuation when left untreated. Although current TBP systems may not be portable or durable enough to survive in an austere deployment environment, we propose it would be feasible to have skin imaging booths at larger forward operating bases. The images could then be transported to a remote dermatologist to assess and recommend treatment. The expense of transporting and maintaining the imaging system in country would be offset by the expenses spared by not requiring a dermatologist in country and the reductions in costly medical evacuations from theater.

Although the US military population is younger and generally healthier than the general adult population due to extensive medical screening on admission, age limitations for active-duty service, a mandated active lifestyle, and access to good health care, there are still a substantial number of service members diagnosed with skin cancer each year.²¹ From 2005 through 2014, MM was the most common non–gender-specific cancer (n=1571); in men, only testicular cancer was more prevalent (1591 vs 1298 cases), and in women, only breast cancer was more prevalent (773 vs 273 cases). Furthermore, from 2004 to 2013, the incidence rates of melanoma have increased by 1.4%, while with other cancer rates have declined during the same time period.²¹ Thus, TBP as a screening modality across the military population is a promising method for improving detection of skin cancer and reducing morbidity and mortality.

Military medicine often is on the forefront of medical advances in technology, disease understanding, and clinical care due to the unique resources available in the military health care system, which allow investigators the ability to obtain vast amounts of epidemiologic data.²² The military health care system also is unique in its ability to mandate that its members obtain preventive health services. Thus, it would be possible for the military to mandate TBP at accession and retirement, for instance, or more frequently for annual screening. The implementation of such a program would improve the health of the military population and be a public health service by pioneering the use of a standardized TBP system across a large health care system to improve skin cancer detection.

Current Studies in the Military

The Dermatology Service at the Walter Reed National Military Medical Center (WRNMMC)(Bethesda, Maryland) is evaluating the use of a total-body digital skin imaging system under a grant from the Telemedicine and Advanced Technology Research Center of the US Army. The system in use was found to be particularly well suited for military dermatology because it offers standardized TBP processing, produces a report that can be uploaded to the US Department of Defense (DoD) electronic medical record system, and requires relatively brief training for ancillary personnel to operate. Regardless of the platform the DoD ultimately finds most suitable, it is critical that a standard exist for TBP to ensure that uniform data sets are generated to allow military and other DoD dermatologists as well as civilian health care providers to share clinical information. The goal of the current study at WRNMMC is to vet TBP platforms at WRNMMC so the military can then develop standards to procure additional platforms for placement throughout the Military Health System, Military Entrance Processing Stations, operational environments, and collaborating health care systems (eg, the Veterans Health Administration).

Once deployed broadly across the Military Health System, these TBP platforms would be part of a network of telehealth care. For acute dermatologic issues, diagnoses provided via teledermatology platforms can then be managed by health care providers utilizing appropriate clinical practice guidelines or by non–health care providers utilizing general medical knowledge databases. Such a system with TBP information collected at multiple access points across a service member’s career would build a repository of data that would be immensely useful to patients and to clinical research. Of particular interest to military researchers is that TBP data could be used to study which patients require in-person examinations or more careful monitoring; the proper intervals for skin cancer screening; and the assessment of the benefits of TBP in improving morbidity, mortality, and biopsy efficiency in the detection of MM as well as nonmelanoma skin cancers.

Limitations to Progress

Currently, there are multiple limitations to the implementation of TBP as a part of TBSE screening. First, the potential improvement in biopsy efficiency using TBP is predicated on its ability to prove nevi stability over time, but in younger populations, benign nevi are more likely to change or increase in number, which may reduce the biopsy efficiency of screening in a younger population, thereby negating some of the benefit of imaging and CNN assessment. For instance, Truong et al¹⁶ found that younger age (<30 years) did not show the same improvement in biopsy efficiency with the use of TBP, which the authors theorized may reflect “the dynamic nature of nevi in younger patients” that has been documented in other studies.^23,24 Approximately 65% of the active-duty military population is aged 18 to 30 years, and 98% of accessions to active duty occur in individuals aged 17 to 30 years.²⁵ As such, TBP may not improve biopsy efficiency in the active-duty military population as dramatically as it would across the general population.

A second limitation of the use of TBP in the active-duty military population is the ethics of implementing DoD-wide mandatory TBP. Although the TBP platform will be compliant with the Health Insurance Portability and Accountability Act, mandating that soldiers contribute their TBP to a repository of data that will then be used for research without explicitly requesting their consent is ethically problematic; however, since the 1950s, the DoD has collected serum samples from its service members for force protection and operations reasons as well as for the purpose of research.^22,26 Currently, the DoD Serum Repository collects serum samples as part of a mandatory human immunodeficiency virus screening program that evaluates service members every 2 years; this repository of human serum samples is accessible for research purposes without the consent of the individuals being studied.²⁷ These individuals are not informed of potential use of their serum specimens for research purposes and no consent forms or opt-out options are provided. Thus, although there is precedent in the DoD for such mass data collection, it is an ongoing ethical consideration.²⁸

RELATED ARTICLE: Gigapixel Photography for Skin Cancer Surveillance

Finally, although the potential use of TBP and computer algorithms to improve the efficiency and affordability of TBSEs is exciting, there are no existing computer algorithms that we are aware of that can be used with existing TBP platforms in the manner we proposed. However, we feel that computer algorithms, such as the one created by Esteva et al,¹⁹ are just the beginning and that the use of artificial intelligence is not far off. Even after the creation of a TBP-compatible algorithm adept at analyzing malignant lesions, however, this technology would need to be further evaluated in the clinical setting to determine its capability and practicality. Current TBP platforms also are limited by their large size, cost, and complexity. As TBP platforms improve, it is likely that more streamlined and less expensive versions of current models will greatly enhance the field of teledermatology, particularly in the military setting.

Skin cancer is an important public health issue in the United States, as 1 in 5 Americans are projected to develop a cutaneous malignancy during their lifetime. Currently, 75% of all skin cancer–related deaths are due to malignant melanomas (MMs), though melanomas account for less than 5% of all skin cancers.¹ Early detection of MM is essential, as prognosis depends on tumor stage, particularly the depth of the melanoma.^2-4 In general, patients with thin, early-stage melanomas have a more than 96% survival rate, which drops to 14% in late-stage disease.^5,6 Five percent to 30% of all melanomas are identified incidentally on total-body skin examinations (TBSEs) performed by a trained provider and thus would not have been caught with only a focused skin examination or patient self-examination.^7,8 Nonetheless, the clinical utility of skin cancer screening with TBSEs remains controversial, largely due to the poor quality of data available to establish a notable mortality benefit from skin cancer screening. As a result, obtaining endorsement from the larger medical community, federal government, and health insurance industry to include routine TBSEs as part of a preventive care health care strategy has not occurred. The absence of definitive clinical care guidelines mandating routine TBSEs is one of the greatest barriers preventing access to appropriate dermatologic screening along with the paucity of trained providers; however, standardized total-body photography (TBP) promises to provide a way forward by lowering the costs of dermatologic screening while simultaneously leveraging technology to increase availability.

Impact on Biopsy Efficiency

Current US Preventive Services Task Force (USPSTF) guidelines state that evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults. The USPSTF noted that “[d]irect evidence on the effectiveness of screening in reducing melanoma morbidity and mortality is limited to a single fair-quality ecologic study with important methodological limitations” (ie, the Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany [SCREEN] study), and although information on harm is similarly sparse, “[t]he potential for harm clearly exists, including a high rate of unnecessary biopsies, possibly resulting in cosmetic or, more rarely, functional adverse effects, and the risk of overdiagnosis and overtreatment.”⁹ The majority of suspicious skin lesions excised during screenings are not cancerous. For example, the SCREEN study found that 20 to 55 excisions were performed to detect 1 case of melanoma.¹⁰ At that rate, the USPSTF also noted that approximately 4000 excisions would be required to prevent a single death from melanoma.⁹ Following the lead of the USPSTF, the Patient Protection and Affordable Care Act did not mandate that skin examinations be included as essential preventive coverage in its requirements for insurance coverage of primary care prevention. As such, dermatologists face financial pressure to avoid performing time-consuming TBSEs, regardless of their perceived utility.¹¹

As the USPSTF points out, the value of TBSEs relies on the examiner’s ability to correctly identify malignant lesions and minimize biopsies of benign lesions, a concept known as biopsy efficiency.⁹ Secondarily, a TBSE is time consuming, and the time required for a dermatologist to complete a TBSE given the high rate of benign findings may not be financially viable. We argue that the routine use of total-body skin imaging may offer a way forward in addressing these issues. Total-body photography involves a photographic system that can allow dermatologists to acquire standardized images that can be used for primary diagnosis and to track individual lesions over time. Nonmedical personnel and medical assistants can be easily trained to use standardized photography devices to quickly obtain high-quality clinical images, thereby greatly reducing the time and cost of obtaining these images. Studies have found that the use of photographic monitoring may improve biopsy efficiency.^12-15 A recent study by Truong et al¹⁶ found that TBP used to monitor all existing melanocytic lesions on patients substantially reduced the number of biopsies that patients required. These results reflect that most nevi, including clinically atypical nevi, are usually stable and unlikely to exhibit suspicious changes over time.^17,18 For this reason, the use of TBP could minimize unnecessary biopsies because clinically suspicious but stable nevi can be objectively documented and followed over time.

Standardized TBP also offers the ability for dermatologists to work synergistically with modern computer technology involving algorithms capable of analyzing high-quality images to autodiagnose or flag concerning lesions that may require biopsy. Esteva et al¹⁹ described their development of a deep learning algorithm that relies on a convolutional neural network (CNN). This CNN was trained to identify melanomas using a large data set of clinical dermatologic images and subsequently was able to distinguish MMs from benign nevi at a rate on par with a board-certified dermatologist.¹⁹ Widespread use of total-body imaging would create an enormous database of high-resolution images that would be ideally suited to the development of such computerized algorithms, which could then be applied to future images by way of artificial intelligence. Convolutional neural networks that use a single patient’s imaging over time could be developed to assess the change in number or size of benign nevi and identify lesions that are concerning for MM while simultaneously comparing them to a population-based data set.

On a large scale, such a capability would minimize the inefficiency and subjectivity of TBSEs as a tool for identifying malignancy. Currently, dermatologists are only able to track and document a few concerning lesions on a patient’s body, rendering the choice of which lesions require biopsy more subjective. Total-body photography, particularly if used with an algorithm capable of quickly analyzing all the nevi on a person’s body, largely eliminates such subjectivity by creating a standardized set of images that can be tracked over time and flagging concerning lesions prior to the dermatologist examining the patient. In this way, the specialty of dermatology could achieve the same model of objective evaluation of standardized clinical images as those employed in radiology, cardiology, and other clinical disciplines. The additional benefit of such a system would be lower costs, as the images could be acquired by nonmedical personnel and then undergo initial assessment by an algorithm, which would flag concerning lesions, similar to a modern electrocardiogram machine, allowing the dermatologist to use his/her time more efficiently by only focusing on concerning lesions with the confidence that the patient’s entire body has already been rigorously screened.

By using TBP to improve biopsy efficiency and the objectivity of the TBSE as a tool to detect skin cancer, we propose that the benefit-to-harm ratio of the TBSE would remarkably improve. Ultimately, this type of screening would meet the strict requirements to be included in preventive health care strategies and thereby improve access to dermatologic care.

The Use of TBP in the Military

Total-body photography has several specific applications in the military. Standardized imaging has the potential to improve dermatologic care for active-duty soldiers across space and time. First, a large percentage of deployment medical care is devoted to dermatologic issues. From 2008 to 2015, 5% of all medical encounters in the combat theaters of Iraq and Afghanistan involved dermatologic concerns.²⁰ Access to appropriate dermatologic care in a combat theater is important, as poorly controlled dermatologic conditions (eg, psoriasis, eczema) often require evacuation when left untreated. Although current TBP systems may not be portable or durable enough to survive in an austere deployment environment, we propose it would be feasible to have skin imaging booths at larger forward operating bases. The images could then be transported to a remote dermatologist to assess and recommend treatment. The expense of transporting and maintaining the imaging system in country would be offset by the expenses spared by not requiring a dermatologist in country and the reductions in costly medical evacuations from theater.

Although the US military population is younger and generally healthier than the general adult population due to extensive medical screening on admission, age limitations for active-duty service, a mandated active lifestyle, and access to good health care, there are still a substantial number of service members diagnosed with skin cancer each year.²¹ From 2005 through 2014, MM was the most common non–gender-specific cancer (n=1571); in men, only testicular cancer was more prevalent (1591 vs 1298 cases), and in women, only breast cancer was more prevalent (773 vs 273 cases). Furthermore, from 2004 to 2013, the incidence rates of melanoma have increased by 1.4%, while with other cancer rates have declined during the same time period.²¹ Thus, TBP as a screening modality across the military population is a promising method for improving detection of skin cancer and reducing morbidity and mortality.

Military medicine often is on the forefront of medical advances in technology, disease understanding, and clinical care due to the unique resources available in the military health care system, which allow investigators the ability to obtain vast amounts of epidemiologic data.²² The military health care system also is unique in its ability to mandate that its members obtain preventive health services. Thus, it would be possible for the military to mandate TBP at accession and retirement, for instance, or more frequently for annual screening. The implementation of such a program would improve the health of the military population and be a public health service by pioneering the use of a standardized TBP system across a large health care system to improve skin cancer detection.

Current Studies in the Military

The Dermatology Service at the Walter Reed National Military Medical Center (WRNMMC)(Bethesda, Maryland) is evaluating the use of a total-body digital skin imaging system under a grant from the Telemedicine and Advanced Technology Research Center of the US Army. The system in use was found to be particularly well suited for military dermatology because it offers standardized TBP processing, produces a report that can be uploaded to the US Department of Defense (DoD) electronic medical record system, and requires relatively brief training for ancillary personnel to operate. Regardless of the platform the DoD ultimately finds most suitable, it is critical that a standard exist for TBP to ensure that uniform data sets are generated to allow military and other DoD dermatologists as well as civilian health care providers to share clinical information. The goal of the current study at WRNMMC is to vet TBP platforms at WRNMMC so the military can then develop standards to procure additional platforms for placement throughout the Military Health System, Military Entrance Processing Stations, operational environments, and collaborating health care systems (eg, the Veterans Health Administration).

Once deployed broadly across the Military Health System, these TBP platforms would be part of a network of telehealth care. For acute dermatologic issues, diagnoses provided via teledermatology platforms can then be managed by health care providers utilizing appropriate clinical practice guidelines or by non–health care providers utilizing general medical knowledge databases. Such a system with TBP information collected at multiple access points across a service member’s career would build a repository of data that would be immensely useful to patients and to clinical research. Of particular interest to military researchers is that TBP data could be used to study which patients require in-person examinations or more careful monitoring; the proper intervals for skin cancer screening; and the assessment of the benefits of TBP in improving morbidity, mortality, and biopsy efficiency in the detection of MM as well as nonmelanoma skin cancers.

Limitations to Progress

Currently, there are multiple limitations to the implementation of TBP as a part of TBSE screening. First, the potential improvement in biopsy efficiency using TBP is predicated on its ability to prove nevi stability over time, but in younger populations, benign nevi are more likely to change or increase in number, which may reduce the biopsy efficiency of screening in a younger population, thereby negating some of the benefit of imaging and CNN assessment. For instance, Truong et al¹⁶ found that younger age (<30 years) did not show the same improvement in biopsy efficiency with the use of TBP, which the authors theorized may reflect “the dynamic nature of nevi in younger patients” that has been documented in other studies.^23,24 Approximately 65% of the active-duty military population is aged 18 to 30 years, and 98% of accessions to active duty occur in individuals aged 17 to 30 years.²⁵ As such, TBP may not improve biopsy efficiency in the active-duty military population as dramatically as it would across the general population.

A second limitation of the use of TBP in the active-duty military population is the ethics of implementing DoD-wide mandatory TBP. Although the TBP platform will be compliant with the Health Insurance Portability and Accountability Act, mandating that soldiers contribute their TBP to a repository of data that will then be used for research without explicitly requesting their consent is ethically problematic; however, since the 1950s, the DoD has collected serum samples from its service members for force protection and operations reasons as well as for the purpose of research.^22,26 Currently, the DoD Serum Repository collects serum samples as part of a mandatory human immunodeficiency virus screening program that evaluates service members every 2 years; this repository of human serum samples is accessible for research purposes without the consent of the individuals being studied.²⁷ These individuals are not informed of potential use of their serum specimens for research purposes and no consent forms or opt-out options are provided. Thus, although there is precedent in the DoD for such mass data collection, it is an ongoing ethical consideration.²⁸

RELATED ARTICLE: Gigapixel Photography for Skin Cancer Surveillance

Finally, although the potential use of TBP and computer algorithms to improve the efficiency and affordability of TBSEs is exciting, there are no existing computer algorithms that we are aware of that can be used with existing TBP platforms in the manner we proposed. However, we feel that computer algorithms, such as the one created by Esteva et al,¹⁹ are just the beginning and that the use of artificial intelligence is not far off. Even after the creation of a TBP-compatible algorithm adept at analyzing malignant lesions, however, this technology would need to be further evaluated in the clinical setting to determine its capability and practicality. Current TBP platforms also are limited by their large size, cost, and complexity. As TBP platforms improve, it is likely that more streamlined and less expensive versions of current models will greatly enhance the field of teledermatology, particularly in the military setting.

Skin cancer is an important public health issue in the United States, as 1 in 5 Americans are projected to develop a cutaneous malignancy during their lifetime. Currently, 75% of all skin cancer–related deaths are due to malignant melanomas (MMs), though melanomas account for less than 5% of all skin cancers.¹ Early detection of MM is essential, as prognosis depends on tumor stage, particularly the depth of the melanoma.^2-4 In general, patients with thin, early-stage melanomas have a more than 96% survival rate, which drops to 14% in late-stage disease.^5,6 Five percent to 30% of all melanomas are identified incidentally on total-body skin examinations (TBSEs) performed by a trained provider and thus would not have been caught with only a focused skin examination or patient self-examination.^7,8 Nonetheless, the clinical utility of skin cancer screening with TBSEs remains controversial, largely due to the poor quality of data available to establish a notable mortality benefit from skin cancer screening. As a result, obtaining endorsement from the larger medical community, federal government, and health insurance industry to include routine TBSEs as part of a preventive care health care strategy has not occurred. The absence of definitive clinical care guidelines mandating routine TBSEs is one of the greatest barriers preventing access to appropriate dermatologic screening along with the paucity of trained providers; however, standardized total-body photography (TBP) promises to provide a way forward by lowering the costs of dermatologic screening while simultaneously leveraging technology to increase availability.

Impact on Biopsy Efficiency

Current US Preventive Services Task Force (USPSTF) guidelines state that evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults. The USPSTF noted that “[d]irect evidence on the effectiveness of screening in reducing melanoma morbidity and mortality is limited to a single fair-quality ecologic study with important methodological limitations” (ie, the Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany [SCREEN] study), and although information on harm is similarly sparse, “[t]he potential for harm clearly exists, including a high rate of unnecessary biopsies, possibly resulting in cosmetic or, more rarely, functional adverse effects, and the risk of overdiagnosis and overtreatment.”⁹ The majority of suspicious skin lesions excised during screenings are not cancerous. For example, the SCREEN study found that 20 to 55 excisions were performed to detect 1 case of melanoma.¹⁰ At that rate, the USPSTF also noted that approximately 4000 excisions would be required to prevent a single death from melanoma.⁹ Following the lead of the USPSTF, the Patient Protection and Affordable Care Act did not mandate that skin examinations be included as essential preventive coverage in its requirements for insurance coverage of primary care prevention. As such, dermatologists face financial pressure to avoid performing time-consuming TBSEs, regardless of their perceived utility.¹¹

As the USPSTF points out, the value of TBSEs relies on the examiner’s ability to correctly identify malignant lesions and minimize biopsies of benign lesions, a concept known as biopsy efficiency.⁹ Secondarily, a TBSE is time consuming, and the time required for a dermatologist to complete a TBSE given the high rate of benign findings may not be financially viable. We argue that the routine use of total-body skin imaging may offer a way forward in addressing these issues. Total-body photography involves a photographic system that can allow dermatologists to acquire standardized images that can be used for primary diagnosis and to track individual lesions over time. Nonmedical personnel and medical assistants can be easily trained to use standardized photography devices to quickly obtain high-quality clinical images, thereby greatly reducing the time and cost of obtaining these images. Studies have found that the use of photographic monitoring may improve biopsy efficiency.^12-15 A recent study by Truong et al¹⁶ found that TBP used to monitor all existing melanocytic lesions on patients substantially reduced the number of biopsies that patients required. These results reflect that most nevi, including clinically atypical nevi, are usually stable and unlikely to exhibit suspicious changes over time.^17,18 For this reason, the use of TBP could minimize unnecessary biopsies because clinically suspicious but stable nevi can be objectively documented and followed over time.

Standardized TBP also offers the ability for dermatologists to work synergistically with modern computer technology involving algorithms capable of analyzing high-quality images to autodiagnose or flag concerning lesions that may require biopsy. Esteva et al¹⁹ described their development of a deep learning algorithm that relies on a convolutional neural network (CNN). This CNN was trained to identify melanomas using a large data set of clinical dermatologic images and subsequently was able to distinguish MMs from benign nevi at a rate on par with a board-certified dermatologist.¹⁹ Widespread use of total-body imaging would create an enormous database of high-resolution images that would be ideally suited to the development of such computerized algorithms, which could then be applied to future images by way of artificial intelligence. Convolutional neural networks that use a single patient’s imaging over time could be developed to assess the change in number or size of benign nevi and identify lesions that are concerning for MM while simultaneously comparing them to a population-based data set.

On a large scale, such a capability would minimize the inefficiency and subjectivity of TBSEs as a tool for identifying malignancy. Currently, dermatologists are only able to track and document a few concerning lesions on a patient’s body, rendering the choice of which lesions require biopsy more subjective. Total-body photography, particularly if used with an algorithm capable of quickly analyzing all the nevi on a person’s body, largely eliminates such subjectivity by creating a standardized set of images that can be tracked over time and flagging concerning lesions prior to the dermatologist examining the patient. In this way, the specialty of dermatology could achieve the same model of objective evaluation of standardized clinical images as those employed in radiology, cardiology, and other clinical disciplines. The additional benefit of such a system would be lower costs, as the images could be acquired by nonmedical personnel and then undergo initial assessment by an algorithm, which would flag concerning lesions, similar to a modern electrocardiogram machine, allowing the dermatologist to use his/her time more efficiently by only focusing on concerning lesions with the confidence that the patient’s entire body has already been rigorously screened.

By using TBP to improve biopsy efficiency and the objectivity of the TBSE as a tool to detect skin cancer, we propose that the benefit-to-harm ratio of the TBSE would remarkably improve. Ultimately, this type of screening would meet the strict requirements to be included in preventive health care strategies and thereby improve access to dermatologic care.

The Use of TBP in the Military

Total-body photography has several specific applications in the military. Standardized imaging has the potential to improve dermatologic care for active-duty soldiers across space and time. First, a large percentage of deployment medical care is devoted to dermatologic issues. From 2008 to 2015, 5% of all medical encounters in the combat theaters of Iraq and Afghanistan involved dermatologic concerns.²⁰ Access to appropriate dermatologic care in a combat theater is important, as poorly controlled dermatologic conditions (eg, psoriasis, eczema) often require evacuation when left untreated. Although current TBP systems may not be portable or durable enough to survive in an austere deployment environment, we propose it would be feasible to have skin imaging booths at larger forward operating bases. The images could then be transported to a remote dermatologist to assess and recommend treatment. The expense of transporting and maintaining the imaging system in country would be offset by the expenses spared by not requiring a dermatologist in country and the reductions in costly medical evacuations from theater.

Although the US military population is younger and generally healthier than the general adult population due to extensive medical screening on admission, age limitations for active-duty service, a mandated active lifestyle, and access to good health care, there are still a substantial number of service members diagnosed with skin cancer each year.²¹ From 2005 through 2014, MM was the most common non–gender-specific cancer (n=1571); in men, only testicular cancer was more prevalent (1591 vs 1298 cases), and in women, only breast cancer was more prevalent (773 vs 273 cases). Furthermore, from 2004 to 2013, the incidence rates of melanoma have increased by 1.4%, while with other cancer rates have declined during the same time period.²¹ Thus, TBP as a screening modality across the military population is a promising method for improving detection of skin cancer and reducing morbidity and mortality.

Military medicine often is on the forefront of medical advances in technology, disease understanding, and clinical care due to the unique resources available in the military health care system, which allow investigators the ability to obtain vast amounts of epidemiologic data.²² The military health care system also is unique in its ability to mandate that its members obtain preventive health services. Thus, it would be possible for the military to mandate TBP at accession and retirement, for instance, or more frequently for annual screening. The implementation of such a program would improve the health of the military population and be a public health service by pioneering the use of a standardized TBP system across a large health care system to improve skin cancer detection.

Current Studies in the Military

The Dermatology Service at the Walter Reed National Military Medical Center (WRNMMC)(Bethesda, Maryland) is evaluating the use of a total-body digital skin imaging system under a grant from the Telemedicine and Advanced Technology Research Center of the US Army. The system in use was found to be particularly well suited for military dermatology because it offers standardized TBP processing, produces a report that can be uploaded to the US Department of Defense (DoD) electronic medical record system, and requires relatively brief training for ancillary personnel to operate. Regardless of the platform the DoD ultimately finds most suitable, it is critical that a standard exist for TBP to ensure that uniform data sets are generated to allow military and other DoD dermatologists as well as civilian health care providers to share clinical information. The goal of the current study at WRNMMC is to vet TBP platforms at WRNMMC so the military can then develop standards to procure additional platforms for placement throughout the Military Health System, Military Entrance Processing Stations, operational environments, and collaborating health care systems (eg, the Veterans Health Administration).

Once deployed broadly across the Military Health System, these TBP platforms would be part of a network of telehealth care. For acute dermatologic issues, diagnoses provided via teledermatology platforms can then be managed by health care providers utilizing appropriate clinical practice guidelines or by non–health care providers utilizing general medical knowledge databases. Such a system with TBP information collected at multiple access points across a service member’s career would build a repository of data that would be immensely useful to patients and to clinical research. Of particular interest to military researchers is that TBP data could be used to study which patients require in-person examinations or more careful monitoring; the proper intervals for skin cancer screening; and the assessment of the benefits of TBP in improving morbidity, mortality, and biopsy efficiency in the detection of MM as well as nonmelanoma skin cancers.

Limitations to Progress

Currently, there are multiple limitations to the implementation of TBP as a part of TBSE screening. First, the potential improvement in biopsy efficiency using TBP is predicated on its ability to prove nevi stability over time, but in younger populations, benign nevi are more likely to change or increase in number, which may reduce the biopsy efficiency of screening in a younger population, thereby negating some of the benefit of imaging and CNN assessment. For instance, Truong et al¹⁶ found that younger age (<30 years) did not show the same improvement in biopsy efficiency with the use of TBP, which the authors theorized may reflect “the dynamic nature of nevi in younger patients” that has been documented in other studies.^23,24 Approximately 65% of the active-duty military population is aged 18 to 30 years, and 98% of accessions to active duty occur in individuals aged 17 to 30 years.²⁵ As such, TBP may not improve biopsy efficiency in the active-duty military population as dramatically as it would across the general population.

A second limitation of the use of TBP in the active-duty military population is the ethics of implementing DoD-wide mandatory TBP. Although the TBP platform will be compliant with the Health Insurance Portability and Accountability Act, mandating that soldiers contribute their TBP to a repository of data that will then be used for research without explicitly requesting their consent is ethically problematic; however, since the 1950s, the DoD has collected serum samples from its service members for force protection and operations reasons as well as for the purpose of research.^22,26 Currently, the DoD Serum Repository collects serum samples as part of a mandatory human immunodeficiency virus screening program that evaluates service members every 2 years; this repository of human serum samples is accessible for research purposes without the consent of the individuals being studied.²⁷ These individuals are not informed of potential use of their serum specimens for research purposes and no consent forms or opt-out options are provided. Thus, although there is precedent in the DoD for such mass data collection, it is an ongoing ethical consideration.²⁸

RELATED ARTICLE: Gigapixel Photography for Skin Cancer Surveillance

Finally, although the potential use of TBP and computer algorithms to improve the efficiency and affordability of TBSEs is exciting, there are no existing computer algorithms that we are aware of that can be used with existing TBP platforms in the manner we proposed. However, we feel that computer algorithms, such as the one created by Esteva et al,¹⁹ are just the beginning and that the use of artificial intelligence is not far off. Even after the creation of a TBP-compatible algorithm adept at analyzing malignant lesions, however, this technology would need to be further evaluated in the clinical setting to determine its capability and practicality. Current TBP platforms also are limited by their large size, cost, and complexity. As TBP platforms improve, it is likely that more streamlined and less expensive versions of current models will greatly enhance the field of teledermatology, particularly in the military setting.

Skin cancers in patients with skin of color are less prevalent but have a higher morbidity and mortality compared to white patients. Challenges to early detection, including clinical differences in presentation, low public awareness, lower index of suspicion among health care providers, and access to specialty care, likely contribute to observed differences in prognosis between skin of color and white populations.

RELATED AUDIO: Why is skin cancer mortality higher in patients with skin of color? A peer-to-peer audiocast with Dr. Vincent A. DeLeo and Dr. Andrew F. Alexis.

Skin cancer is the most common malignancy in the United States, accounting for approximately 40% of all neoplasms in white patients but only 1% to 4% in Asian American and black patients.^1,2 Largely due to the photoprotective effects of increased constitutive epidermal melanin, melanoma is approximately 10 to 20 times less frequent in black patients and 3 to 7 times less common in Hispanics than age-matched whites.¹ Nonmelanoma skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma also are less prevalent in darker skin types.^3,4

In the United States, Hispanic, American Indian, and black patients have a 2- to 3-fold higher risk of mortality from malignant melanoma than white patients overall, even when diagnosed at the same stage.^2,5 The most recent Surveillance, Epidemiology, and End Results (SEER) Program cancer statistic review found that the 5-year relative survival of individuals with all stages of malignant melanoma from 2006 to 2012 was 91.1% for white patients and67.3% for black patients. Fortunately, the mortality rate for black patients decreased approximately 0.8% per year from 1975 to 2013.^5,6 No statistically significant change was seen in other ethnic groups, though research in East Asia suggests that age-standardized mortality rates from melanoma have increased by up to 7.4% per year over the last 30 years, with the greatest rise seen in Korean females.^5,7 Further epidemiologic research looking at the relative survival of Asian Americans and Pacific Islanders in the United States is needed.^8,9

Similar to melanoma, the mortality from SCC is disproportionately increased in skin of color populations, ranging from 18% to 29% in black patients.^3,10,11 There is a paucity of population-based studies in the United States looking at mortality rates of nonmelanoma skin cancers and their trends over time, but a 1993 study suggests that mortality rates are declining less consistently in black patients than white patients.¹¹

Factors that may contribute to higher mortality rates in patients with skin of color include a greater propensity for inherently aggressive skin cancers (eg, higher risk of SCC) and delays in diagnosis (eg, late-stage diagnosis of melanoma).^1,4 For melanoma, increased mortality has been attributed to a predominance of acral lentiginous melanomas, which are more frequently diagnosed at more advanced stages than other melanoma subtypes.^6,12,13 Black patients, Hispanics, Asians, and Pacific Islanders are all more likely to present with thicker tumors and metastases on initial presentation than their white counterparts (P<.001).^2,8,9,12-14 The higher risk of death from SCC results from the predominance of lesions on non–sun-exposed areas, particularly the legs and anogenital areas, and within sites of chronic scarring or inflammation.⁴ Unlike sun-induced SCC, the most commonly observed type of SCC in lighter skin types, SCCs that develop in association with chronic inflammatory or ulcerative processes are aggressive and invasive, and they metastasize to distant sites in 20% to 40% of cases (versus 1%–4% in sun-induced SCC).^1,3,4 For all skin cancers, poor access to medical care, patients’ unawareness of their skin cancer risk, lack of adequate skin examinations, and prevalence of lesions on uncommon sites that may be inconspicuous or overlooked have all been suggested to delay diagnosis.^1,15,16 Given that more advanced disease is associated with worse outcomes, the implications of this delay are enormous and remain a cause for concern.

RELATED AUDIO: Dr. Alexis discusses factors that contribute to the delayed diagnosis of melanoma in patients with skin of color and what physicians should know about the incidence and presentation of melanoma in this population to help educate their patients.

The alarming skin cancer mortality rates in patients with skin of color are a call to action for the medical community. The consistent use of full-body skin examinations including close inspection of mucosal, acral, and genital areas for all patients independent of skin type and racial/ethnic background is paramount. Advancing skin cancer education in skin of color populations, such as through distribution of patient-directed educational materials produced by organizations such as the American Academy of Dermatology, Skin Cancer Foundation, and Skin of Color Society, is an important step toward increased public awareness.¹⁶ Use of social and traditional media outlets as well as community-directed health outreach campaigns also are important strategies to change the common misconception that darker-skinned individuals do not get skin cancer. We hope that with a multipronged approach, disparities in skin cancer mortality will steadily be eliminated.

Skin cancers in patients with skin of color are less prevalent but have a higher morbidity and mortality compared to white patients. Challenges to early detection, including clinical differences in presentation, low public awareness, lower index of suspicion among health care providers, and access to specialty care, likely contribute to observed differences in prognosis between skin of color and white populations.

RELATED AUDIO: Why is skin cancer mortality higher in patients with skin of color? A peer-to-peer audiocast with Dr. Vincent A. DeLeo and Dr. Andrew F. Alexis.

Skin cancer is the most common malignancy in the United States, accounting for approximately 40% of all neoplasms in white patients but only 1% to 4% in Asian American and black patients.^1,2 Largely due to the photoprotective effects of increased constitutive epidermal melanin, melanoma is approximately 10 to 20 times less frequent in black patients and 3 to 7 times less common in Hispanics than age-matched whites.¹ Nonmelanoma skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma also are less prevalent in darker skin types.^3,4

In the United States, Hispanic, American Indian, and black patients have a 2- to 3-fold higher risk of mortality from malignant melanoma than white patients overall, even when diagnosed at the same stage.^2,5 The most recent Surveillance, Epidemiology, and End Results (SEER) Program cancer statistic review found that the 5-year relative survival of individuals with all stages of malignant melanoma from 2006 to 2012 was 91.1% for white patients and67.3% for black patients. Fortunately, the mortality rate for black patients decreased approximately 0.8% per year from 1975 to 2013.^5,6 No statistically significant change was seen in other ethnic groups, though research in East Asia suggests that age-standardized mortality rates from melanoma have increased by up to 7.4% per year over the last 30 years, with the greatest rise seen in Korean females.^5,7 Further epidemiologic research looking at the relative survival of Asian Americans and Pacific Islanders in the United States is needed.^8,9

Similar to melanoma, the mortality from SCC is disproportionately increased in skin of color populations, ranging from 18% to 29% in black patients.^3,10,11 There is a paucity of population-based studies in the United States looking at mortality rates of nonmelanoma skin cancers and their trends over time, but a 1993 study suggests that mortality rates are declining less consistently in black patients than white patients.¹¹

Factors that may contribute to higher mortality rates in patients with skin of color include a greater propensity for inherently aggressive skin cancers (eg, higher risk of SCC) and delays in diagnosis (eg, late-stage diagnosis of melanoma).^1,4 For melanoma, increased mortality has been attributed to a predominance of acral lentiginous melanomas, which are more frequently diagnosed at more advanced stages than other melanoma subtypes.^6,12,13 Black patients, Hispanics, Asians, and Pacific Islanders are all more likely to present with thicker tumors and metastases on initial presentation than their white counterparts (P<.001).^2,8,9,12-14 The higher risk of death from SCC results from the predominance of lesions on non–sun-exposed areas, particularly the legs and anogenital areas, and within sites of chronic scarring or inflammation.⁴ Unlike sun-induced SCC, the most commonly observed type of SCC in lighter skin types, SCCs that develop in association with chronic inflammatory or ulcerative processes are aggressive and invasive, and they metastasize to distant sites in 20% to 40% of cases (versus 1%–4% in sun-induced SCC).^1,3,4 For all skin cancers, poor access to medical care, patients’ unawareness of their skin cancer risk, lack of adequate skin examinations, and prevalence of lesions on uncommon sites that may be inconspicuous or overlooked have all been suggested to delay diagnosis.^1,15,16 Given that more advanced disease is associated with worse outcomes, the implications of this delay are enormous and remain a cause for concern.

RELATED AUDIO: Dr. Alexis discusses factors that contribute to the delayed diagnosis of melanoma in patients with skin of color and what physicians should know about the incidence and presentation of melanoma in this population to help educate their patients.

The alarming skin cancer mortality rates in patients with skin of color are a call to action for the medical community. The consistent use of full-body skin examinations including close inspection of mucosal, acral, and genital areas for all patients independent of skin type and racial/ethnic background is paramount. Advancing skin cancer education in skin of color populations, such as through distribution of patient-directed educational materials produced by organizations such as the American Academy of Dermatology, Skin Cancer Foundation, and Skin of Color Society, is an important step toward increased public awareness.¹⁶ Use of social and traditional media outlets as well as community-directed health outreach campaigns also are important strategies to change the common misconception that darker-skinned individuals do not get skin cancer. We hope that with a multipronged approach, disparities in skin cancer mortality will steadily be eliminated.

Skin cancers in patients with skin of color are less prevalent but have a higher morbidity and mortality compared to white patients. Challenges to early detection, including clinical differences in presentation, low public awareness, lower index of suspicion among health care providers, and access to specialty care, likely contribute to observed differences in prognosis between skin of color and white populations.

RELATED AUDIO: Why is skin cancer mortality higher in patients with skin of color? A peer-to-peer audiocast with Dr. Vincent A. DeLeo and Dr. Andrew F. Alexis.

Skin cancer is the most common malignancy in the United States, accounting for approximately 40% of all neoplasms in white patients but only 1% to 4% in Asian American and black patients.^1,2 Largely due to the photoprotective effects of increased constitutive epidermal melanin, melanoma is approximately 10 to 20 times less frequent in black patients and 3 to 7 times less common in Hispanics than age-matched whites.¹ Nonmelanoma skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma also are less prevalent in darker skin types.^3,4

In the United States, Hispanic, American Indian, and black patients have a 2- to 3-fold higher risk of mortality from malignant melanoma than white patients overall, even when diagnosed at the same stage.^2,5 The most recent Surveillance, Epidemiology, and End Results (SEER) Program cancer statistic review found that the 5-year relative survival of individuals with all stages of malignant melanoma from 2006 to 2012 was 91.1% for white patients and67.3% for black patients. Fortunately, the mortality rate for black patients decreased approximately 0.8% per year from 1975 to 2013.^5,6 No statistically significant change was seen in other ethnic groups, though research in East Asia suggests that age-standardized mortality rates from melanoma have increased by up to 7.4% per year over the last 30 years, with the greatest rise seen in Korean females.^5,7 Further epidemiologic research looking at the relative survival of Asian Americans and Pacific Islanders in the United States is needed.^8,9

Similar to melanoma, the mortality from SCC is disproportionately increased in skin of color populations, ranging from 18% to 29% in black patients.^3,10,11 There is a paucity of population-based studies in the United States looking at mortality rates of nonmelanoma skin cancers and their trends over time, but a 1993 study suggests that mortality rates are declining less consistently in black patients than white patients.¹¹

Factors that may contribute to higher mortality rates in patients with skin of color include a greater propensity for inherently aggressive skin cancers (eg, higher risk of SCC) and delays in diagnosis (eg, late-stage diagnosis of melanoma).^1,4 For melanoma, increased mortality has been attributed to a predominance of acral lentiginous melanomas, which are more frequently diagnosed at more advanced stages than other melanoma subtypes.^6,12,13 Black patients, Hispanics, Asians, and Pacific Islanders are all more likely to present with thicker tumors and metastases on initial presentation than their white counterparts (P<.001).^2,8,9,12-14 The higher risk of death from SCC results from the predominance of lesions on non–sun-exposed areas, particularly the legs and anogenital areas, and within sites of chronic scarring or inflammation.⁴ Unlike sun-induced SCC, the most commonly observed type of SCC in lighter skin types, SCCs that develop in association with chronic inflammatory or ulcerative processes are aggressive and invasive, and they metastasize to distant sites in 20% to 40% of cases (versus 1%–4% in sun-induced SCC).^1,3,4 For all skin cancers, poor access to medical care, patients’ unawareness of their skin cancer risk, lack of adequate skin examinations, and prevalence of lesions on uncommon sites that may be inconspicuous or overlooked have all been suggested to delay diagnosis.^1,15,16 Given that more advanced disease is associated with worse outcomes, the implications of this delay are enormous and remain a cause for concern.

RELATED AUDIO: Dr. Alexis discusses factors that contribute to the delayed diagnosis of melanoma in patients with skin of color and what physicians should know about the incidence and presentation of melanoma in this population to help educate their patients.

The alarming skin cancer mortality rates in patients with skin of color are a call to action for the medical community. The consistent use of full-body skin examinations including close inspection of mucosal, acral, and genital areas for all patients independent of skin type and racial/ethnic background is paramount. Advancing skin cancer education in skin of color populations, such as through distribution of patient-directed educational materials produced by organizations such as the American Academy of Dermatology, Skin Cancer Foundation, and Skin of Color Society, is an important step toward increased public awareness.¹⁶ Use of social and traditional media outlets as well as community-directed health outreach campaigns also are important strategies to change the common misconception that darker-skinned individuals do not get skin cancer. We hope that with a multipronged approach, disparities in skin cancer mortality will steadily be eliminated.

Lentigo maligna (LM) and LM melanoma (LMM) represent diagnostic and therapeutic challenges due to their heterogeneous nature and location on cosmetically sensitive areas. Newer ancillary technologies such as reflectance confocal microscopy (RCM) have helped improve diagnosis and management of these challenging lesions.^1,2

Reflectance confocal microscopy is a noninvasive laser system that provides real-time imaging of the epidermis and dermis with cellular resolution and improves diagnostic accuracy of melanocytic lesions.^2,3 Normal melanocytes appear as round bright structures on RCM that are similar in size to surrounding keratinocytes located in the basal layer and regularly distributed around the dermal papillae (junctional nevi) or form regular dense nests in the dermis (intradermal nevi).^4,5 In LM/LMM, there may be widespread infiltration of atypical melanocytes invading hair follicles; large, round, pagetoid melanocytes (larger than surrounding keratinocytes); sheets of large atypical cells at the dermoepidermal junction (DEJ); loss of contour in the dermal papillae; and atypical melanocytes invading the dermal papillae.² Indeed, RCM has good correlation with the degree of histologic atypia and is useful to distinguish between benign nevi, atypical nevi, and melanoma.⁶ By combining lateral mosaics with vertical stacks, RCM allows 3-dimensional approximation of tumor margins and monitoring of nonsurgical therapies.^7,8 The advent of handheld RCM (HRCM) has allowed assessment of large lesions as well as those presenting in difficult locations.⁹ Furthermore, the generation of videomosaics overcomes the limited field of view of traditional RCM and allows for accurate assessment of large lesions.¹⁰

Traditional and handheld RCM have been used to diagnose and map primary LM.^1,2,11 Guitera et al² developed an algorithm using traditional RCM to distinguish benign facial macules and LM. In their training set, they found that when their score resulted in 2 or more points, the sensitivity and specificity to diagnose LM was 85% and 76%, respectively, with an odds ratio of 18.6 for LM. They later applied the algorithm in a test set of 44 benign facial macules and 29 LM and obtained an odds ratio of 60.7 for LM, with sensitivity and specificity rates of 93% and 82%, respectively.² This algorithm also was tested by Menge et al11 using the HRCM. They found 100% sensitivity and 71% specificity for LM when evaluating 63 equivocal facial lesions. Although these results suggest that RCM can accurately distinguish LM from benign lesions in the primary setting, few reports have studied the impact of HRCM in the recurrent setting and its impact in monitoring treatment of LM.^12,13

Herein, we present 5 cases in which HRCM was used to manage complex facial LM/LMM, highlighting its versatility and potential for use in the clinical setting (eTable).

Case Series

Following institutional review board approval, cases of facial LM/LMM presenting for assessment and treatment from January 2014 to December 2015 were retrospectively reviewed. Initially, the clinical margins of the lesions were determined using Wood lamp and/or dermoscopy. Using HRCM, vertical stacks were taken at the 12-, 3-, 6-, and 9-o'clock positions, and videos were captured along the peripheral margins at the DEJ. To create videomosaics, HRCM video frames were extracted and later stitched using a computer algorithm written in a fourth-generation programming language based on prior studies.^10,14 An example HRCM video that was captured and turned into a videomosaic accompanies this article online (http://bit.ly/2oDYS6k). Additional stacks were taken in suspicious areas. We considered an area positive for LM under HRCM when the LM score developed by Guitera et al² was 2 or more. The algorithm scoring includes 2 major criteria--nonedged papillae and round large pagetoid cells--which score 2 points, and 4 minor criteria, including 3 positive criteria--atypical cells at the DEJ, follicular invasion, nucleated cells in the papillae--which each score 1 point, and 1 negative criterion--broadened honeycomb pattern--which scores -1 point.²

RELATED VIDEO: RCM Videomosaic of Melanoma In Situ

Patient 1

An 82-year-old woman was referred to us for management of an LMM on the left side of the forehead (Figure 1A). Handheld RCM from the biopsy site showed large atypical cells in the epidermis, DEJ, and papillary dermis. Superiorly, HRCM showed large dendritic processes but did not reveal LM features in 3 additional clinically worrisome areas. Biopsies showed LMM at the prior biopsy site, LM superiorly, and actinic keratosis in the remaining 3 areas, supporting the HRCM findings. Due to upstaging, the patient was referred for head and neck surgery. To aid in resection, HRCM was performed intraoperatively in a multidisciplinary approach (Figure 1B). Due to the large size of the lesion, surgical margins were taken right outside the HRCM border. Pathology showed LMM extending focally into the margins that were reexcised, achieving clearance.

Patient 2

An 88-year-old woman presented with a slightly pigmented, 2.5×2.3-cm LMM on the left cheek. Because of her age and comorbidities (eg, osteoporosis, deep vein thrombosis in both lower legs requiring anticoagulation therapy, presence of an inferior vena cava filter, bilateral lymphedema of the legs, irritable bowel syndrome, hyperparathyroidism), she was treated with imiquimod cream 5% achieving partial response. The lesion was subsequently excised showing LMM extending to the margins. Not wanting to undergo further surgery, she opted for radiation therapy. Handheld RCM was performed to guide the radiation field, showing pagetoid cells within 1 cm of the scar and clear margins beyond 2 cm. She underwent radiation therapy followed by treatment with imiquimod. On 6-month follow-up, no clinical lesion was apparent, but HRCM showed atypical cells. Biopsies revealed an atypical intraepidermal melanocytic proliferation, but due to patient's comorbidities, close observation was decided.

Patient 3

A 78-year-old man presented with an LMM on the right preauricular area. Handheld RCM demonstrated pleomorphic pagetoid cells along and beyond the clinical margins. Wide excision with sentinel lymph node biopsy was planned, and to aid surgery a confocal map was created (Figure 2). Margins were clear at 1 cm, except inferiorly where they extended to 1.5 cm. Using this preoperative HRCM map, all intraoperative sections were clear. Final pathology confirmed clear margins throughout.

Patient 4

A 62-year-old man presented with hyperpigmentation and bleeding on the left cheek where an LMM was previously removed 8 times over 18 years. Handheld RCM showed pleomorphic cells along the graft border and interestingly within the graft. Ten biopsies were taken, 8 at sites with confocal features that were worrisome for LM (Figures 3A and 3B) and 2 at clinically suspicious sites. The former revealed melanomas (2 that were invasive to 0.3 mm), and the latter revealed solar lentigines. The patient underwent staged excision guided by HRCM (Figure 3C), achieving clear histologic margins except for a focus in the helix. This area was RCM positive but was intentionally not resected due to reconstructive difficulties; imiquimod was indicated in this area.

Patient 5

An 85-year-old woman with 6 prior melanomas over 15 years presented with ill-defined light brown patches on the left cheek at the site where an LM was previously excised 15 years prior. Biopsies showed LM, and due to the patient's age, health, and personal preference to avoid extensive surgery, treatment with imiquimod cream 5% was decided. Over a period of 6 to 12 months, she developed multiple erythematous macules with 2 faintly pigmented areas. Handheld RCM demonstrated atypical cells within the papillae in previously biopsied sites that were rebiopsied, revealing LMM (Breslow depth, 0.2 mm). Staged excision achieved clear margins, but after 8 months HRCM showed LM features. Histology confirmed the diagnosis and imiquimod was reapplied.

Comment

Diagnosis and choice of treatment modality for cases of facial LM is a challenge, and there are a number of factors that may create even more of a clinical dilemma. Surgical excision is the treatment of choice for LM/LMM, and better results are achieved when using histologically controlled surgical procedures such as Mohs micrographic surgery, staged excision, or the "spaghetti technique."^15-17 However, advanced patient age, multiple comorbidities (eg, coronary artery disease, deep vein thrombosis, other conditions requiring anticoagulation therapy), large lesion size in functionally or aesthetically sensitive areas, and indiscriminate borders on photodamaged skin may make surgical excision complicated or not feasible. Additionally, prior treatments to the affected area may further obscure clinical borders, complicating the diagnosis of recurrence/persistence when observed with the naked eye, dermoscopy, or Wood lamp. Because RCM can detect small amounts of melanin and has cellular resolution, it has been suggested as a great diagnostic tool to be combined with dermoscopy when evaluating lightly pigmented/amelanotic facial lesions arising on sun-damaged skin.^18,19 In this case series, we highlighted these difficulties and showed how HRCM can be useful in a variety of scenarios, both pretreatment and posttreatment in complex LM/LMM cases.

Pretreatment Evaluation

Blind mapping biopsies of LM are prone to sample bias and depend greatly on biopsy technique; however, HRCM can guide mapping biopsies by detecting features of LM in vivo with high sensitivity.¹¹ Due to the cosmetically sensitive nature of the lesions, many physicians are discouraged to do multiple mapping biopsies, making it difficult to assess the breadth of the lesion and occult invasion. Multiple studies have shown that occult invasion was not apparent until complete lesion excision was done.^15,20,21 Agarwal-Antal et al²⁰ reported 92 cases of LM, of which 16% (15/92) had unsuspected invasion on final excisional pathology. A long-standing disadvantage of treating LM with nonsurgical modalities has been the inability to detect occult invasion or multifocal invasion within the lesion. As described in patients 1, 4, and 5 in the current case series, utilizing real-time video imaging of the DEJ at the margins and within the lesion has allowed for the detection of deep atypical melanocytes suspicious for perifollicular infiltration and invasion. Knowing the depth of invasion before treatment is essential for not only counseling the patient about disease risk but also for choosing an appropriate treatment modality. Therefore, prospective studies evaluating the performance of RCM to identify invasion are crucial to improve sampling error and avoid unnecessary biopsies.

Surgical Treatment

Although surgery is the first-line treatment option for facial LM, it is not without associated morbidity, and LM is known to have histological subclinical extension, which makes margin assessment difficult. Wide surgical margins on the face are not always possible and become further complicated when trying to maintain adequate functional and cosmetic outcomes. Additionally, the margin for surgical clearance may not be straightforward for facial lesions. Hazan et al¹⁵ showed the mean total surgical margins required for excision of LM and LMM was 7.1 and 10.3 mm, respectively; of the 91 tumors initially diagnosed as LM on biopsy, 16% (15/91) had unsuspected invasion. Guitera et al² reported that the presence of atypical cells within the dermal papillae might be a sign of invasion, which occasionally is not detected histologically due to sampling bias. Handheld RCM offers the advantage of a rapid real-time assessment in areas that may not have been amenable to previous iterations of the device, and it also provides a larger field of view that would be time consuming if performed using conventional RCM. Compared to prior RCM devices that were not handheld, the use of the HRCM does not need to attach a ring to the skin and is less bulky, permitting its use at the bedside of the patient or even intraoperatively.13 In our experience, HRCM has helped to better characterize subclinical spread of LM during the initial consultation and better counsel patients about the extent of the lesion. Handheld RCM also has been used to guide the spaghetti technique in patients with LM/LMM with good correlation between HRCM and histology.²² In our case series, HRCM was used in complex LM/LMM to delineate surgical margins, though in some cases the histologic margins were too close or affected, suggesting HRCM underestimation. Lentigo maligna margin assessment with RCM uses an algorithm that evaluates confocal features in the center of the lesion.^1,2 Therefore, further studies using HRCM should evaluate minor confocal features in the margins as potential markers of positivity to accurately delineate surgical margins.

Nonsurgical Treatment Options

For patients unable or unwilling to pursue surgical treatment, therapies such as imiquimod or radiation have been suggested.^23,24 However, the lack of histological confirmation and possibility for invasive spread has limited these modalities. Lentigo malignas treated with radiation have a 5% recurrence rate, with a median follow-up time of 3 years.²³ Recurrence often can be difficult to detect clinically, as it may manifest as an amelanotic lesion, or postradiation changes can hinder detection. Handheld RCM allows for a cellular-level observation of the irradiated field and can identify radiation-induced changes in LM lesions, including superficial necrosis, apoptotic cells, dilated vessels, and increased inflammatory cells.²⁵ Handheld RCM has previously been used to assess LM treated with radiation and, as in patient 2, can help define the radiation field and detect treatment failure or recurrence.^12,25

Similarly, as described in patient 5, HRCM was utilized to monitor treatment with imiquimod. Many reports use imiquimod for treatment of LM, but application and response vary greatly. Reflectance confocal microscopy has been shown to be useful in monitoring LM treated with imiquimod,⁸ which is important because clinical findings such as inflammation and erythema do not correlate well with response to therapy. Thus, RCM is an appealing noninvasive modality to monitor response to treatment and assess the need for longer treatment duration. Moreover, similar to postradiation changes, treatment with imiquimod may cause an alteration of the clinically apparent pigment. Therefore, it is difficult to assess treatment success by clinical inspection alone. The use of RCM before, during, and after treatment provides a longitudinal assessment of the lesion and has augmented dermatologists' ability to determine treatment success or failure; however, prospective studies evaluating the usefulness of HRCM in the recurrent setting are needed to validate these results.

Limitations

Limitations of this technology include the time needed to image large areas; technology cost; and associated learning curve, which may take from 6 months to 1 year based on our experience. Others have reported the training required for accurate RCM interpretation to be less than that of dermoscopy.²⁶ It has been shown that key RCM diagnostic criteria for lesions including melanoma and basal cell carcinoma are reproducibly recognized among RCM users and that diagnostic accuracy increases with experience.²⁷ These limitations can be overcome with advances in videomosaicing that may streamline the imaging as well as an eventual decrease in cost with greater user adoption and the development of training platforms that enable a faster learning of RCM.²⁸

Conclusion

The use of HRCM can help in the diagnosis and management of facial LMs. Handheld RCM provides longitudinal assessment of LM/LMM that may help determine treatment success or failure and has proven to be useful in detecting the presence of recurrence/persistence in cases that were clinically poorly evident. Moreover, HRCM is a notable ancillary tool, as it can be performed at the bedside of the patient or even intraoperatively and provides a faster approach than conventional RCM in cases where large areas need to be mapped.

In summary, HRCM may eventually be a useful screening tool to guide scouting biopsies to diagnose de novo LM; guide surgical and nonsurgical therapies; and evaluate the presence of recurrence/persistence, especially in large, complex, amelanotic or poorly pigmented lesions. A more standardized use of HRCM in mapping surgical and nonsurgical approaches needs to be evaluated in further studies to provide a fast and reliable complement to histology in such complex cases; therefore, larger studies need to be performed to validate this technique in such complex cases.

Lentigo maligna (LM) and LM melanoma (LMM) represent diagnostic and therapeutic challenges due to their heterogeneous nature and location on cosmetically sensitive areas. Newer ancillary technologies such as reflectance confocal microscopy (RCM) have helped improve diagnosis and management of these challenging lesions.^1,2

Reflectance confocal microscopy is a noninvasive laser system that provides real-time imaging of the epidermis and dermis with cellular resolution and improves diagnostic accuracy of melanocytic lesions.^2,3 Normal melanocytes appear as round bright structures on RCM that are similar in size to surrounding keratinocytes located in the basal layer and regularly distributed around the dermal papillae (junctional nevi) or form regular dense nests in the dermis (intradermal nevi).^4,5 In LM/LMM, there may be widespread infiltration of atypical melanocytes invading hair follicles; large, round, pagetoid melanocytes (larger than surrounding keratinocytes); sheets of large atypical cells at the dermoepidermal junction (DEJ); loss of contour in the dermal papillae; and atypical melanocytes invading the dermal papillae.² Indeed, RCM has good correlation with the degree of histologic atypia and is useful to distinguish between benign nevi, atypical nevi, and melanoma.⁶ By combining lateral mosaics with vertical stacks, RCM allows 3-dimensional approximation of tumor margins and monitoring of nonsurgical therapies.^7,8 The advent of handheld RCM (HRCM) has allowed assessment of large lesions as well as those presenting in difficult locations.⁹ Furthermore, the generation of videomosaics overcomes the limited field of view of traditional RCM and allows for accurate assessment of large lesions.¹⁰

Traditional and handheld RCM have been used to diagnose and map primary LM.^1,2,11 Guitera et al² developed an algorithm using traditional RCM to distinguish benign facial macules and LM. In their training set, they found that when their score resulted in 2 or more points, the sensitivity and specificity to diagnose LM was 85% and 76%, respectively, with an odds ratio of 18.6 for LM. They later applied the algorithm in a test set of 44 benign facial macules and 29 LM and obtained an odds ratio of 60.7 for LM, with sensitivity and specificity rates of 93% and 82%, respectively.² This algorithm also was tested by Menge et al11 using the HRCM. They found 100% sensitivity and 71% specificity for LM when evaluating 63 equivocal facial lesions. Although these results suggest that RCM can accurately distinguish LM from benign lesions in the primary setting, few reports have studied the impact of HRCM in the recurrent setting and its impact in monitoring treatment of LM.^12,13

Herein, we present 5 cases in which HRCM was used to manage complex facial LM/LMM, highlighting its versatility and potential for use in the clinical setting (eTable).

Case Series

Following institutional review board approval, cases of facial LM/LMM presenting for assessment and treatment from January 2014 to December 2015 were retrospectively reviewed. Initially, the clinical margins of the lesions were determined using Wood lamp and/or dermoscopy. Using HRCM, vertical stacks were taken at the 12-, 3-, 6-, and 9-o'clock positions, and videos were captured along the peripheral margins at the DEJ. To create videomosaics, HRCM video frames were extracted and later stitched using a computer algorithm written in a fourth-generation programming language based on prior studies.^10,14 An example HRCM video that was captured and turned into a videomosaic accompanies this article online (http://bit.ly/2oDYS6k). Additional stacks were taken in suspicious areas. We considered an area positive for LM under HRCM when the LM score developed by Guitera et al² was 2 or more. The algorithm scoring includes 2 major criteria--nonedged papillae and round large pagetoid cells--which score 2 points, and 4 minor criteria, including 3 positive criteria--atypical cells at the DEJ, follicular invasion, nucleated cells in the papillae--which each score 1 point, and 1 negative criterion--broadened honeycomb pattern--which scores -1 point.²

RELATED VIDEO: RCM Videomosaic of Melanoma In Situ

Patient 1

An 82-year-old woman was referred to us for management of an LMM on the left side of the forehead (Figure 1A). Handheld RCM from the biopsy site showed large atypical cells in the epidermis, DEJ, and papillary dermis. Superiorly, HRCM showed large dendritic processes but did not reveal LM features in 3 additional clinically worrisome areas. Biopsies showed LMM at the prior biopsy site, LM superiorly, and actinic keratosis in the remaining 3 areas, supporting the HRCM findings. Due to upstaging, the patient was referred for head and neck surgery. To aid in resection, HRCM was performed intraoperatively in a multidisciplinary approach (Figure 1B). Due to the large size of the lesion, surgical margins were taken right outside the HRCM border. Pathology showed LMM extending focally into the margins that were reexcised, achieving clearance.

Patient 2

An 88-year-old woman presented with a slightly pigmented, 2.5×2.3-cm LMM on the left cheek. Because of her age and comorbidities (eg, osteoporosis, deep vein thrombosis in both lower legs requiring anticoagulation therapy, presence of an inferior vena cava filter, bilateral lymphedema of the legs, irritable bowel syndrome, hyperparathyroidism), she was treated with imiquimod cream 5% achieving partial response. The lesion was subsequently excised showing LMM extending to the margins. Not wanting to undergo further surgery, she opted for radiation therapy. Handheld RCM was performed to guide the radiation field, showing pagetoid cells within 1 cm of the scar and clear margins beyond 2 cm. She underwent radiation therapy followed by treatment with imiquimod. On 6-month follow-up, no clinical lesion was apparent, but HRCM showed atypical cells. Biopsies revealed an atypical intraepidermal melanocytic proliferation, but due to patient's comorbidities, close observation was decided.

Patient 3

A 78-year-old man presented with an LMM on the right preauricular area. Handheld RCM demonstrated pleomorphic pagetoid cells along and beyond the clinical margins. Wide excision with sentinel lymph node biopsy was planned, and to aid surgery a confocal map was created (Figure 2). Margins were clear at 1 cm, except inferiorly where they extended to 1.5 cm. Using this preoperative HRCM map, all intraoperative sections were clear. Final pathology confirmed clear margins throughout.

Patient 4

A 62-year-old man presented with hyperpigmentation and bleeding on the left cheek where an LMM was previously removed 8 times over 18 years. Handheld RCM showed pleomorphic cells along the graft border and interestingly within the graft. Ten biopsies were taken, 8 at sites with confocal features that were worrisome for LM (Figures 3A and 3B) and 2 at clinically suspicious sites. The former revealed melanomas (2 that were invasive to 0.3 mm), and the latter revealed solar lentigines. The patient underwent staged excision guided by HRCM (Figure 3C), achieving clear histologic margins except for a focus in the helix. This area was RCM positive but was intentionally not resected due to reconstructive difficulties; imiquimod was indicated in this area.

Patient 5

An 85-year-old woman with 6 prior melanomas over 15 years presented with ill-defined light brown patches on the left cheek at the site where an LM was previously excised 15 years prior. Biopsies showed LM, and due to the patient's age, health, and personal preference to avoid extensive surgery, treatment with imiquimod cream 5% was decided. Over a period of 6 to 12 months, she developed multiple erythematous macules with 2 faintly pigmented areas. Handheld RCM demonstrated atypical cells within the papillae in previously biopsied sites that were rebiopsied, revealing LMM (Breslow depth, 0.2 mm). Staged excision achieved clear margins, but after 8 months HRCM showed LM features. Histology confirmed the diagnosis and imiquimod was reapplied.

Comment

Diagnosis and choice of treatment modality for cases of facial LM is a challenge, and there are a number of factors that may create even more of a clinical dilemma. Surgical excision is the treatment of choice for LM/LMM, and better results are achieved when using histologically controlled surgical procedures such as Mohs micrographic surgery, staged excision, or the "spaghetti technique."^15-17 However, advanced patient age, multiple comorbidities (eg, coronary artery disease, deep vein thrombosis, other conditions requiring anticoagulation therapy), large lesion size in functionally or aesthetically sensitive areas, and indiscriminate borders on photodamaged skin may make surgical excision complicated or not feasible. Additionally, prior treatments to the affected area may further obscure clinical borders, complicating the diagnosis of recurrence/persistence when observed with the naked eye, dermoscopy, or Wood lamp. Because RCM can detect small amounts of melanin and has cellular resolution, it has been suggested as a great diagnostic tool to be combined with dermoscopy when evaluating lightly pigmented/amelanotic facial lesions arising on sun-damaged skin.^18,19 In this case series, we highlighted these difficulties and showed how HRCM can be useful in a variety of scenarios, both pretreatment and posttreatment in complex LM/LMM cases.

Pretreatment Evaluation

Blind mapping biopsies of LM are prone to sample bias and depend greatly on biopsy technique; however, HRCM can guide mapping biopsies by detecting features of LM in vivo with high sensitivity.¹¹ Due to the cosmetically sensitive nature of the lesions, many physicians are discouraged to do multiple mapping biopsies, making it difficult to assess the breadth of the lesion and occult invasion. Multiple studies have shown that occult invasion was not apparent until complete lesion excision was done.^15,20,21 Agarwal-Antal et al²⁰ reported 92 cases of LM, of which 16% (15/92) had unsuspected invasion on final excisional pathology. A long-standing disadvantage of treating LM with nonsurgical modalities has been the inability to detect occult invasion or multifocal invasion within the lesion. As described in patients 1, 4, and 5 in the current case series, utilizing real-time video imaging of the DEJ at the margins and within the lesion has allowed for the detection of deep atypical melanocytes suspicious for perifollicular infiltration and invasion. Knowing the depth of invasion before treatment is essential for not only counseling the patient about disease risk but also for choosing an appropriate treatment modality. Therefore, prospective studies evaluating the performance of RCM to identify invasion are crucial to improve sampling error and avoid unnecessary biopsies.

Surgical Treatment

Although surgery is the first-line treatment option for facial LM, it is not without associated morbidity, and LM is known to have histological subclinical extension, which makes margin assessment difficult. Wide surgical margins on the face are not always possible and become further complicated when trying to maintain adequate functional and cosmetic outcomes. Additionally, the margin for surgical clearance may not be straightforward for facial lesions. Hazan et al¹⁵ showed the mean total surgical margins required for excision of LM and LMM was 7.1 and 10.3 mm, respectively; of the 91 tumors initially diagnosed as LM on biopsy, 16% (15/91) had unsuspected invasion. Guitera et al² reported that the presence of atypical cells within the dermal papillae might be a sign of invasion, which occasionally is not detected histologically due to sampling bias. Handheld RCM offers the advantage of a rapid real-time assessment in areas that may not have been amenable to previous iterations of the device, and it also provides a larger field of view that would be time consuming if performed using conventional RCM. Compared to prior RCM devices that were not handheld, the use of the HRCM does not need to attach a ring to the skin and is less bulky, permitting its use at the bedside of the patient or even intraoperatively.13 In our experience, HRCM has helped to better characterize subclinical spread of LM during the initial consultation and better counsel patients about the extent of the lesion. Handheld RCM also has been used to guide the spaghetti technique in patients with LM/LMM with good correlation between HRCM and histology.²² In our case series, HRCM was used in complex LM/LMM to delineate surgical margins, though in some cases the histologic margins were too close or affected, suggesting HRCM underestimation. Lentigo maligna margin assessment with RCM uses an algorithm that evaluates confocal features in the center of the lesion.^1,2 Therefore, further studies using HRCM should evaluate minor confocal features in the margins as potential markers of positivity to accurately delineate surgical margins.

Nonsurgical Treatment Options

For patients unable or unwilling to pursue surgical treatment, therapies such as imiquimod or radiation have been suggested.^23,24 However, the lack of histological confirmation and possibility for invasive spread has limited these modalities. Lentigo malignas treated with radiation have a 5% recurrence rate, with a median follow-up time of 3 years.²³ Recurrence often can be difficult to detect clinically, as it may manifest as an amelanotic lesion, or postradiation changes can hinder detection. Handheld RCM allows for a cellular-level observation of the irradiated field and can identify radiation-induced changes in LM lesions, including superficial necrosis, apoptotic cells, dilated vessels, and increased inflammatory cells.²⁵ Handheld RCM has previously been used to assess LM treated with radiation and, as in patient 2, can help define the radiation field and detect treatment failure or recurrence.^12,25

Similarly, as described in patient 5, HRCM was utilized to monitor treatment with imiquimod. Many reports use imiquimod for treatment of LM, but application and response vary greatly. Reflectance confocal microscopy has been shown to be useful in monitoring LM treated with imiquimod,⁸ which is important because clinical findings such as inflammation and erythema do not correlate well with response to therapy. Thus, RCM is an appealing noninvasive modality to monitor response to treatment and assess the need for longer treatment duration. Moreover, similar to postradiation changes, treatment with imiquimod may cause an alteration of the clinically apparent pigment. Therefore, it is difficult to assess treatment success by clinical inspection alone. The use of RCM before, during, and after treatment provides a longitudinal assessment of the lesion and has augmented dermatologists' ability to determine treatment success or failure; however, prospective studies evaluating the usefulness of HRCM in the recurrent setting are needed to validate these results.

Limitations

Limitations of this technology include the time needed to image large areas; technology cost; and associated learning curve, which may take from 6 months to 1 year based on our experience. Others have reported the training required for accurate RCM interpretation to be less than that of dermoscopy.²⁶ It has been shown that key RCM diagnostic criteria for lesions including melanoma and basal cell carcinoma are reproducibly recognized among RCM users and that diagnostic accuracy increases with experience.²⁷ These limitations can be overcome with advances in videomosaicing that may streamline the imaging as well as an eventual decrease in cost with greater user adoption and the development of training platforms that enable a faster learning of RCM.²⁸

Conclusion

The use of HRCM can help in the diagnosis and management of facial LMs. Handheld RCM provides longitudinal assessment of LM/LMM that may help determine treatment success or failure and has proven to be useful in detecting the presence of recurrence/persistence in cases that were clinically poorly evident. Moreover, HRCM is a notable ancillary tool, as it can be performed at the bedside of the patient or even intraoperatively and provides a faster approach than conventional RCM in cases where large areas need to be mapped.

In summary, HRCM may eventually be a useful screening tool to guide scouting biopsies to diagnose de novo LM; guide surgical and nonsurgical therapies; and evaluate the presence of recurrence/persistence, especially in large, complex, amelanotic or poorly pigmented lesions. A more standardized use of HRCM in mapping surgical and nonsurgical approaches needs to be evaluated in further studies to provide a fast and reliable complement to histology in such complex cases; therefore, larger studies need to be performed to validate this technique in such complex cases.

Lentigo maligna (LM) and LM melanoma (LMM) represent diagnostic and therapeutic challenges due to their heterogeneous nature and location on cosmetically sensitive areas. Newer ancillary technologies such as reflectance confocal microscopy (RCM) have helped improve diagnosis and management of these challenging lesions.^1,2

Reflectance confocal microscopy is a noninvasive laser system that provides real-time imaging of the epidermis and dermis with cellular resolution and improves diagnostic accuracy of melanocytic lesions.^2,3 Normal melanocytes appear as round bright structures on RCM that are similar in size to surrounding keratinocytes located in the basal layer and regularly distributed around the dermal papillae (junctional nevi) or form regular dense nests in the dermis (intradermal nevi).^4,5 In LM/LMM, there may be widespread infiltration of atypical melanocytes invading hair follicles; large, round, pagetoid melanocytes (larger than surrounding keratinocytes); sheets of large atypical cells at the dermoepidermal junction (DEJ); loss of contour in the dermal papillae; and atypical melanocytes invading the dermal papillae.² Indeed, RCM has good correlation with the degree of histologic atypia and is useful to distinguish between benign nevi, atypical nevi, and melanoma.⁶ By combining lateral mosaics with vertical stacks, RCM allows 3-dimensional approximation of tumor margins and monitoring of nonsurgical therapies.^7,8 The advent of handheld RCM (HRCM) has allowed assessment of large lesions as well as those presenting in difficult locations.⁹ Furthermore, the generation of videomosaics overcomes the limited field of view of traditional RCM and allows for accurate assessment of large lesions.¹⁰

Traditional and handheld RCM have been used to diagnose and map primary LM.^1,2,11 Guitera et al² developed an algorithm using traditional RCM to distinguish benign facial macules and LM. In their training set, they found that when their score resulted in 2 or more points, the sensitivity and specificity to diagnose LM was 85% and 76%, respectively, with an odds ratio of 18.6 for LM. They later applied the algorithm in a test set of 44 benign facial macules and 29 LM and obtained an odds ratio of 60.7 for LM, with sensitivity and specificity rates of 93% and 82%, respectively.² This algorithm also was tested by Menge et al11 using the HRCM. They found 100% sensitivity and 71% specificity for LM when evaluating 63 equivocal facial lesions. Although these results suggest that RCM can accurately distinguish LM from benign lesions in the primary setting, few reports have studied the impact of HRCM in the recurrent setting and its impact in monitoring treatment of LM.^12,13

Herein, we present 5 cases in which HRCM was used to manage complex facial LM/LMM, highlighting its versatility and potential for use in the clinical setting (eTable).

Case Series

Following institutional review board approval, cases of facial LM/LMM presenting for assessment and treatment from January 2014 to December 2015 were retrospectively reviewed. Initially, the clinical margins of the lesions were determined using Wood lamp and/or dermoscopy. Using HRCM, vertical stacks were taken at the 12-, 3-, 6-, and 9-o'clock positions, and videos were captured along the peripheral margins at the DEJ. To create videomosaics, HRCM video frames were extracted and later stitched using a computer algorithm written in a fourth-generation programming language based on prior studies.^10,14 An example HRCM video that was captured and turned into a videomosaic accompanies this article online (http://bit.ly/2oDYS6k). Additional stacks were taken in suspicious areas. We considered an area positive for LM under HRCM when the LM score developed by Guitera et al² was 2 or more. The algorithm scoring includes 2 major criteria--nonedged papillae and round large pagetoid cells--which score 2 points, and 4 minor criteria, including 3 positive criteria--atypical cells at the DEJ, follicular invasion, nucleated cells in the papillae--which each score 1 point, and 1 negative criterion--broadened honeycomb pattern--which scores -1 point.²

RELATED VIDEO: RCM Videomosaic of Melanoma In Situ

Patient 1

An 82-year-old woman was referred to us for management of an LMM on the left side of the forehead (Figure 1A). Handheld RCM from the biopsy site showed large atypical cells in the epidermis, DEJ, and papillary dermis. Superiorly, HRCM showed large dendritic processes but did not reveal LM features in 3 additional clinically worrisome areas. Biopsies showed LMM at the prior biopsy site, LM superiorly, and actinic keratosis in the remaining 3 areas, supporting the HRCM findings. Due to upstaging, the patient was referred for head and neck surgery. To aid in resection, HRCM was performed intraoperatively in a multidisciplinary approach (Figure 1B). Due to the large size of the lesion, surgical margins were taken right outside the HRCM border. Pathology showed LMM extending focally into the margins that were reexcised, achieving clearance.

Patient 2

An 88-year-old woman presented with a slightly pigmented, 2.5×2.3-cm LMM on the left cheek. Because of her age and comorbidities (eg, osteoporosis, deep vein thrombosis in both lower legs requiring anticoagulation therapy, presence of an inferior vena cava filter, bilateral lymphedema of the legs, irritable bowel syndrome, hyperparathyroidism), she was treated with imiquimod cream 5% achieving partial response. The lesion was subsequently excised showing LMM extending to the margins. Not wanting to undergo further surgery, she opted for radiation therapy. Handheld RCM was performed to guide the radiation field, showing pagetoid cells within 1 cm of the scar and clear margins beyond 2 cm. She underwent radiation therapy followed by treatment with imiquimod. On 6-month follow-up, no clinical lesion was apparent, but HRCM showed atypical cells. Biopsies revealed an atypical intraepidermal melanocytic proliferation, but due to patient's comorbidities, close observation was decided.

Patient 3

A 78-year-old man presented with an LMM on the right preauricular area. Handheld RCM demonstrated pleomorphic pagetoid cells along and beyond the clinical margins. Wide excision with sentinel lymph node biopsy was planned, and to aid surgery a confocal map was created (Figure 2). Margins were clear at 1 cm, except inferiorly where they extended to 1.5 cm. Using this preoperative HRCM map, all intraoperative sections were clear. Final pathology confirmed clear margins throughout.

Patient 4

A 62-year-old man presented with hyperpigmentation and bleeding on the left cheek where an LMM was previously removed 8 times over 18 years. Handheld RCM showed pleomorphic cells along the graft border and interestingly within the graft. Ten biopsies were taken, 8 at sites with confocal features that were worrisome for LM (Figures 3A and 3B) and 2 at clinically suspicious sites. The former revealed melanomas (2 that were invasive to 0.3 mm), and the latter revealed solar lentigines. The patient underwent staged excision guided by HRCM (Figure 3C), achieving clear histologic margins except for a focus in the helix. This area was RCM positive but was intentionally not resected due to reconstructive difficulties; imiquimod was indicated in this area.

Patient 5

An 85-year-old woman with 6 prior melanomas over 15 years presented with ill-defined light brown patches on the left cheek at the site where an LM was previously excised 15 years prior. Biopsies showed LM, and due to the patient's age, health, and personal preference to avoid extensive surgery, treatment with imiquimod cream 5% was decided. Over a period of 6 to 12 months, she developed multiple erythematous macules with 2 faintly pigmented areas. Handheld RCM demonstrated atypical cells within the papillae in previously biopsied sites that were rebiopsied, revealing LMM (Breslow depth, 0.2 mm). Staged excision achieved clear margins, but after 8 months HRCM showed LM features. Histology confirmed the diagnosis and imiquimod was reapplied.

Comment

Diagnosis and choice of treatment modality for cases of facial LM is a challenge, and there are a number of factors that may create even more of a clinical dilemma. Surgical excision is the treatment of choice for LM/LMM, and better results are achieved when using histologically controlled surgical procedures such as Mohs micrographic surgery, staged excision, or the "spaghetti technique."^15-17 However, advanced patient age, multiple comorbidities (eg, coronary artery disease, deep vein thrombosis, other conditions requiring anticoagulation therapy), large lesion size in functionally or aesthetically sensitive areas, and indiscriminate borders on photodamaged skin may make surgical excision complicated or not feasible. Additionally, prior treatments to the affected area may further obscure clinical borders, complicating the diagnosis of recurrence/persistence when observed with the naked eye, dermoscopy, or Wood lamp. Because RCM can detect small amounts of melanin and has cellular resolution, it has been suggested as a great diagnostic tool to be combined with dermoscopy when evaluating lightly pigmented/amelanotic facial lesions arising on sun-damaged skin.^18,19 In this case series, we highlighted these difficulties and showed how HRCM can be useful in a variety of scenarios, both pretreatment and posttreatment in complex LM/LMM cases.

Pretreatment Evaluation

Blind mapping biopsies of LM are prone to sample bias and depend greatly on biopsy technique; however, HRCM can guide mapping biopsies by detecting features of LM in vivo with high sensitivity.¹¹ Due to the cosmetically sensitive nature of the lesions, many physicians are discouraged to do multiple mapping biopsies, making it difficult to assess the breadth of the lesion and occult invasion. Multiple studies have shown that occult invasion was not apparent until complete lesion excision was done.^15,20,21 Agarwal-Antal et al²⁰ reported 92 cases of LM, of which 16% (15/92) had unsuspected invasion on final excisional pathology. A long-standing disadvantage of treating LM with nonsurgical modalities has been the inability to detect occult invasion or multifocal invasion within the lesion. As described in patients 1, 4, and 5 in the current case series, utilizing real-time video imaging of the DEJ at the margins and within the lesion has allowed for the detection of deep atypical melanocytes suspicious for perifollicular infiltration and invasion. Knowing the depth of invasion before treatment is essential for not only counseling the patient about disease risk but also for choosing an appropriate treatment modality. Therefore, prospective studies evaluating the performance of RCM to identify invasion are crucial to improve sampling error and avoid unnecessary biopsies.

Surgical Treatment

Although surgery is the first-line treatment option for facial LM, it is not without associated morbidity, and LM is known to have histological subclinical extension, which makes margin assessment difficult. Wide surgical margins on the face are not always possible and become further complicated when trying to maintain adequate functional and cosmetic outcomes. Additionally, the margin for surgical clearance may not be straightforward for facial lesions. Hazan et al¹⁵ showed the mean total surgical margins required for excision of LM and LMM was 7.1 and 10.3 mm, respectively; of the 91 tumors initially diagnosed as LM on biopsy, 16% (15/91) had unsuspected invasion. Guitera et al² reported that the presence of atypical cells within the dermal papillae might be a sign of invasion, which occasionally is not detected histologically due to sampling bias. Handheld RCM offers the advantage of a rapid real-time assessment in areas that may not have been amenable to previous iterations of the device, and it also provides a larger field of view that would be time consuming if performed using conventional RCM. Compared to prior RCM devices that were not handheld, the use of the HRCM does not need to attach a ring to the skin and is less bulky, permitting its use at the bedside of the patient or even intraoperatively.13 In our experience, HRCM has helped to better characterize subclinical spread of LM during the initial consultation and better counsel patients about the extent of the lesion. Handheld RCM also has been used to guide the spaghetti technique in patients with LM/LMM with good correlation between HRCM and histology.²² In our case series, HRCM was used in complex LM/LMM to delineate surgical margins, though in some cases the histologic margins were too close or affected, suggesting HRCM underestimation. Lentigo maligna margin assessment with RCM uses an algorithm that evaluates confocal features in the center of the lesion.^1,2 Therefore, further studies using HRCM should evaluate minor confocal features in the margins as potential markers of positivity to accurately delineate surgical margins.

Nonsurgical Treatment Options

For patients unable or unwilling to pursue surgical treatment, therapies such as imiquimod or radiation have been suggested.^23,24 However, the lack of histological confirmation and possibility for invasive spread has limited these modalities. Lentigo malignas treated with radiation have a 5% recurrence rate, with a median follow-up time of 3 years.²³ Recurrence often can be difficult to detect clinically, as it may manifest as an amelanotic lesion, or postradiation changes can hinder detection. Handheld RCM allows for a cellular-level observation of the irradiated field and can identify radiation-induced changes in LM lesions, including superficial necrosis, apoptotic cells, dilated vessels, and increased inflammatory cells.²⁵ Handheld RCM has previously been used to assess LM treated with radiation and, as in patient 2, can help define the radiation field and detect treatment failure or recurrence.^12,25

Similarly, as described in patient 5, HRCM was utilized to monitor treatment with imiquimod. Many reports use imiquimod for treatment of LM, but application and response vary greatly. Reflectance confocal microscopy has been shown to be useful in monitoring LM treated with imiquimod,⁸ which is important because clinical findings such as inflammation and erythema do not correlate well with response to therapy. Thus, RCM is an appealing noninvasive modality to monitor response to treatment and assess the need for longer treatment duration. Moreover, similar to postradiation changes, treatment with imiquimod may cause an alteration of the clinically apparent pigment. Therefore, it is difficult to assess treatment success by clinical inspection alone. The use of RCM before, during, and after treatment provides a longitudinal assessment of the lesion and has augmented dermatologists' ability to determine treatment success or failure; however, prospective studies evaluating the usefulness of HRCM in the recurrent setting are needed to validate these results.

Limitations

Limitations of this technology include the time needed to image large areas; technology cost; and associated learning curve, which may take from 6 months to 1 year based on our experience. Others have reported the training required for accurate RCM interpretation to be less than that of dermoscopy.²⁶ It has been shown that key RCM diagnostic criteria for lesions including melanoma and basal cell carcinoma are reproducibly recognized among RCM users and that diagnostic accuracy increases with experience.²⁷ These limitations can be overcome with advances in videomosaicing that may streamline the imaging as well as an eventual decrease in cost with greater user adoption and the development of training platforms that enable a faster learning of RCM.²⁸

Conclusion

The use of HRCM can help in the diagnosis and management of facial LMs. Handheld RCM provides longitudinal assessment of LM/LMM that may help determine treatment success or failure and has proven to be useful in detecting the presence of recurrence/persistence in cases that were clinically poorly evident. Moreover, HRCM is a notable ancillary tool, as it can be performed at the bedside of the patient or even intraoperatively and provides a faster approach than conventional RCM in cases where large areas need to be mapped.

In summary, HRCM may eventually be a useful screening tool to guide scouting biopsies to diagnose de novo LM; guide surgical and nonsurgical therapies; and evaluate the presence of recurrence/persistence, especially in large, complex, amelanotic or poorly pigmented lesions. A more standardized use of HRCM in mapping surgical and nonsurgical approaches needs to be evaluated in further studies to provide a fast and reliable complement to histology in such complex cases; therefore, larger studies need to be performed to validate this technique in such complex cases.

Patients with psoriasis may be at a greater risk of melanoma and hematologic cancers, compared with the general population, but treatments do not appear to increase risk, according to Shivani P. Reddy of the University of Illinois at Chicago, and associates.

In a retrospective cohort study, they identified 815,765 patients at Kaiser Permanente Southern California who had at least one medical encounter from January 2004 through December 2013. Of these patients, 8,161 (1%) met the diagnostic and inclusion criteria for psoriasis, and there were 7,167 (0.89%) cases of melanoma and 5,399 (0.66%) cases of lymphoma or leukemia.

Among the patients with psoriasis, there were 62 (0.87%) melanoma cases and 47 (0.87%) cases of lymphoma or leukemia.

Of the 109 patients with psoriasis who went on to develop melanoma or lymphoma, the time to diagnosis of melanoma or hematologic cancers was significantly less for patients with psoriasis than for patients without psoriasis (P = .01). The patients with psoriasis had a 1.53 times higher risk of developing a malignancy compared with patients without psoriasis (P less than .01) in the multivariable Cox proportional hazards model.

“There were no differences between patients with melanoma and hematologic cancer by treatment type,” which were phototherapy, tumor necrosis factor inhibitor therapy, and topical medications, they wrote.

“Our study demonstrates that the risk of hematologic cancer and melanoma is increased in patients with psoriasis over time, although this risk is not impacted by psoriasis therapies,” the researchers concluded. “Defining the risk of malignancy in these patients is important for proper workup and management.”

Read the study in the Journal of the American Academy of Dermatology (doi: 10.1016/j.jaad.2016.09.047).
 

llaubach@frontlinemedcom.com

Patients with psoriasis may be at a greater risk of melanoma and hematologic cancers, compared with the general population, but treatments do not appear to increase risk, according to Shivani P. Reddy of the University of Illinois at Chicago, and associates.

In a retrospective cohort study, they identified 815,765 patients at Kaiser Permanente Southern California who had at least one medical encounter from January 2004 through December 2013. Of these patients, 8,161 (1%) met the diagnostic and inclusion criteria for psoriasis, and there were 7,167 (0.89%) cases of melanoma and 5,399 (0.66%) cases of lymphoma or leukemia.

Among the patients with psoriasis, there were 62 (0.87%) melanoma cases and 47 (0.87%) cases of lymphoma or leukemia.

Of the 109 patients with psoriasis who went on to develop melanoma or lymphoma, the time to diagnosis of melanoma or hematologic cancers was significantly less for patients with psoriasis than for patients without psoriasis (P = .01). The patients with psoriasis had a 1.53 times higher risk of developing a malignancy compared with patients without psoriasis (P less than .01) in the multivariable Cox proportional hazards model.

“There were no differences between patients with melanoma and hematologic cancer by treatment type,” which were phototherapy, tumor necrosis factor inhibitor therapy, and topical medications, they wrote.

“Our study demonstrates that the risk of hematologic cancer and melanoma is increased in patients with psoriasis over time, although this risk is not impacted by psoriasis therapies,” the researchers concluded. “Defining the risk of malignancy in these patients is important for proper workup and management.”

Read the study in the Journal of the American Academy of Dermatology (doi: 10.1016/j.jaad.2016.09.047).
 

llaubach@frontlinemedcom.com

Patients with psoriasis may be at a greater risk of melanoma and hematologic cancers, compared with the general population, but treatments do not appear to increase risk, according to Shivani P. Reddy of the University of Illinois at Chicago, and associates.

In a retrospective cohort study, they identified 815,765 patients at Kaiser Permanente Southern California who had at least one medical encounter from January 2004 through December 2013. Of these patients, 8,161 (1%) met the diagnostic and inclusion criteria for psoriasis, and there were 7,167 (0.89%) cases of melanoma and 5,399 (0.66%) cases of lymphoma or leukemia.

Among the patients with psoriasis, there were 62 (0.87%) melanoma cases and 47 (0.87%) cases of lymphoma or leukemia.

Of the 109 patients with psoriasis who went on to develop melanoma or lymphoma, the time to diagnosis of melanoma or hematologic cancers was significantly less for patients with psoriasis than for patients without psoriasis (P = .01). The patients with psoriasis had a 1.53 times higher risk of developing a malignancy compared with patients without psoriasis (P less than .01) in the multivariable Cox proportional hazards model.

“There were no differences between patients with melanoma and hematologic cancer by treatment type,” which were phototherapy, tumor necrosis factor inhibitor therapy, and topical medications, they wrote.

“Our study demonstrates that the risk of hematologic cancer and melanoma is increased in patients with psoriasis over time, although this risk is not impacted by psoriasis therapies,” the researchers concluded. “Defining the risk of malignancy in these patients is important for proper workup and management.”

Read the study in the Journal of the American Academy of Dermatology (doi: 10.1016/j.jaad.2016.09.047).
 

llaubach@frontlinemedcom.com

Histopathology findings of cytologic atypia, architectural disorder, and pagetoid spread are common in congenital melanocytic nevi (CMN) of all sizes in children aged 0-35 months, and tend to have benign outcomes, according to a retrospective study.

Emily A. Simons, MPH, and her associates at Boston Children’s Hospital studied 197 nevi in 179 patients with an average age of 14 months (range, 4 days to 35 months); 51% were female. Of those, 80% had skin types I-II, and 90% were white. The majority of the lesions involved the head or trunk and were predominantly medium in size, and 58% had a projected adult size of 1.5-10 cm. The study was retrospective; cases had been diagnosed between 1993 and 2013.

Cytologic atypia, architectural disorder, and pagetoid spread were the most frequent features – they were present in 73% of nevi and were closely associated. Combined histologic patterns of a blue nevus, spindle and Spitz nevus, or a deep penetrating nevus were identified in 40% of CMN. Proliferative nodules occurred in 5% of nevi.

Clinical outcomes were available for 130 patients, including 26 with large CMN and 8 with proliferative nodules. The children were alive and had not been diagnosed with melanoma at a mean follow-up of a mean of 8.4 years (range, 7 months to 21.3 years), even though margins of the last excision were positive in 41% of all CMN and in 77% of large CMN.

Malignant transformation of CMN certainly should be recognized, but the morbidity of overdiagnosis also needs to be considered. “Excision of larger CMN might require serial excisions under general anesthesia, the use of tissue expanders, and grafts,” Dr. Simons and her associates said.

Among the limitations of this study were that the majority of patients were white, so the results may not translate to children with darker skin types, they noted.

“The diagnosis of malignant melanoma should be made with great caution in this population,” they concluded, pointing out that the histopathologic features alone (cytologic atypia, architectural disorder, and pagetoid spread) “should not be interpreted as evidence for potential malignant behavior or serve as grounds for further excision.”

Read more in the Journal of the American Academy of Dermatology (2017 May;76[5]941-7).

The authors had no relevant financial disorders.

Histopathology findings of cytologic atypia, architectural disorder, and pagetoid spread are common in congenital melanocytic nevi (CMN) of all sizes in children aged 0-35 months, and tend to have benign outcomes, according to a retrospective study.

Emily A. Simons, MPH, and her associates at Boston Children’s Hospital studied 197 nevi in 179 patients with an average age of 14 months (range, 4 days to 35 months); 51% were female. Of those, 80% had skin types I-II, and 90% were white. The majority of the lesions involved the head or trunk and were predominantly medium in size, and 58% had a projected adult size of 1.5-10 cm. The study was retrospective; cases had been diagnosed between 1993 and 2013.

Cytologic atypia, architectural disorder, and pagetoid spread were the most frequent features – they were present in 73% of nevi and were closely associated. Combined histologic patterns of a blue nevus, spindle and Spitz nevus, or a deep penetrating nevus were identified in 40% of CMN. Proliferative nodules occurred in 5% of nevi.

Clinical outcomes were available for 130 patients, including 26 with large CMN and 8 with proliferative nodules. The children were alive and had not been diagnosed with melanoma at a mean follow-up of a mean of 8.4 years (range, 7 months to 21.3 years), even though margins of the last excision were positive in 41% of all CMN and in 77% of large CMN.

Malignant transformation of CMN certainly should be recognized, but the morbidity of overdiagnosis also needs to be considered. “Excision of larger CMN might require serial excisions under general anesthesia, the use of tissue expanders, and grafts,” Dr. Simons and her associates said.

Among the limitations of this study were that the majority of patients were white, so the results may not translate to children with darker skin types, they noted.

“The diagnosis of malignant melanoma should be made with great caution in this population,” they concluded, pointing out that the histopathologic features alone (cytologic atypia, architectural disorder, and pagetoid spread) “should not be interpreted as evidence for potential malignant behavior or serve as grounds for further excision.”

Read more in the Journal of the American Academy of Dermatology (2017 May;76[5]941-7).

The authors had no relevant financial disorders.

Histopathology findings of cytologic atypia, architectural disorder, and pagetoid spread are common in congenital melanocytic nevi (CMN) of all sizes in children aged 0-35 months, and tend to have benign outcomes, according to a retrospective study.

Emily A. Simons, MPH, and her associates at Boston Children’s Hospital studied 197 nevi in 179 patients with an average age of 14 months (range, 4 days to 35 months); 51% were female. Of those, 80% had skin types I-II, and 90% were white. The majority of the lesions involved the head or trunk and were predominantly medium in size, and 58% had a projected adult size of 1.5-10 cm. The study was retrospective; cases had been diagnosed between 1993 and 2013.

Cytologic atypia, architectural disorder, and pagetoid spread were the most frequent features – they were present in 73% of nevi and were closely associated. Combined histologic patterns of a blue nevus, spindle and Spitz nevus, or a deep penetrating nevus were identified in 40% of CMN. Proliferative nodules occurred in 5% of nevi.

Clinical outcomes were available for 130 patients, including 26 with large CMN and 8 with proliferative nodules. The children were alive and had not been diagnosed with melanoma at a mean follow-up of a mean of 8.4 years (range, 7 months to 21.3 years), even though margins of the last excision were positive in 41% of all CMN and in 77% of large CMN.

Malignant transformation of CMN certainly should be recognized, but the morbidity of overdiagnosis also needs to be considered. “Excision of larger CMN might require serial excisions under general anesthesia, the use of tissue expanders, and grafts,” Dr. Simons and her associates said.

Among the limitations of this study were that the majority of patients were white, so the results may not translate to children with darker skin types, they noted.

“The diagnosis of malignant melanoma should be made with great caution in this population,” they concluded, pointing out that the histopathologic features alone (cytologic atypia, architectural disorder, and pagetoid spread) “should not be interpreted as evidence for potential malignant behavior or serve as grounds for further excision.”

Read more in the Journal of the American Academy of Dermatology (2017 May;76[5]941-7).

The authors had no relevant financial disorders.

The last decade has been a period of advancement for the lesbian, gay, bisexual, and transgender (LGBT) community for legal protections and visibility. Although the journey to acceptance and equality is far from over, this progress has appropriately extended to medical academia as physicians search for ways to become more inclusive and effective care providers for their LGBT patients.¹ In a recent cross-sectional study, Ginsberg et al² examined the role for dermatologists in the care of transgender patients. The investigators concluded that dermatologists should play a larger role in a transgender patient’s physical transformation.² It is our opinion that dermatologists need to be comfortable building rapport with LGBT patients and to become attuned to their specific needs to provide effective care.

When forging a relationship with an LGBT patient, assumptions can damage rapport. Two assumptions that should be avoided include presuming heterosexuality or, on the other hand, assuming risk for disease based on known LGBT status. A dermatologist who takes a cursory sexual history, or none at all, assuming his/her patient is heterosexual creates an environment in which a nonheterosexual patient feels uncomfortable being honest and open. Although there is enough literature to support the claim that some sexual minority groups have increased risk for sexually transmitted infections (STIs),³ it is dangerous to assume a patient’s risk based solely on sexual orientation. An abstinent patient or a patient in a long-term, monogamous, same-sex relationship, for instance, may feel stereotyped by a dermatologist who wants to screen him/her for an STI. The best step in building a therapeutic relationship is to cast out these assumptions and allow LGBT patients to be open about themselves and their sexual practices. Sexual histories should be asked in nonjudgmental ways that are related to the health of the patient, leading to relevant and useful information for their care. For example, ask patients, “Do you have sex with men, women, or both?” This question should be delivered in a matter-of-fact tone, which conveys to the patient that the provider merely wants an answer to guide patient care.

Dermatologists can tailor their encounters to the specific needs of sexual minority patients. The medical literature is rich with examples of conditions that occur at greater frequency in specific sexual minority groups. Sexually transmitted infections, particularly human immunodeficiency virus, are important causes of morbidity and mortality among sexual minorities, especially men who have sex with men (MSM).^3,4 Anal and penile human papillomavirus (HPV) infection and HPV-associated anal carcinoma risk are increased in MSM.^5,6 The literature has remained inconclusive on the use of anal Papanicolaou tests for diagnosis; however, dermatologists have a duty to at least examine the perianal and genital area of any patient at risk for HPV-related disease or STIs.^7,8 For younger patients, the HPV vaccine can help prevent certain types of HPV infection and likely reduce a patient’s risk for condyloma acuminatum and other sequelae of the virus. Guidelines have been expanded to include men aged 13 to 21 years and up to 26 years.⁹ More research is needed to determine if detection and prevention of these types of HPV infection using the vaccine in MSM actually leads to a decreased incidence of anal carcinoma.

Certain LGBT groups may benefit from a dermatologist’s care outside the realm of infectious diseases. One study found that increased indoor tanning use in MSM correlated with increased risk for nonmelanoma skin cancer.¹⁰ Lesbians have been found to be less likely to pursue preventative health examinations in general, including skin checks.¹¹ Finally, transgender patients can utilize dermatologists for help with transformative procedures and side effects of hormonal treatment such as androgenic acne.^1,4

Cutaneous and beyond, the future of LGBT health care in the United States is affected by the institutions that train future physicians. There is a trend toward incorporating formal LGBT curricula into medical schools and academic centers.¹² The Penn Medicine Program for LGBT Health (Philadelphia, Pennsylvania) is a pilot program geared toward both educating future clinicians and providing equal and unbiased care to LGBT patients.¹² Programs such as this one give rise to a new generation of physicians who feel comfortable and aware of the needs of their LGBT patients.

In a time when LGBT patients are becoming more comfortable claiming their sexual and gender identities openly, there is a need for dermatologists to provide individualized unbiased care, which can best be achieved by building rapport through assumption-free history taking, performing thorough physical examinations that include the genital and perianal area, and passing these good practices on to trainees.

The last decade has been a period of advancement for the lesbian, gay, bisexual, and transgender (LGBT) community for legal protections and visibility. Although the journey to acceptance and equality is far from over, this progress has appropriately extended to medical academia as physicians search for ways to become more inclusive and effective care providers for their LGBT patients.¹ In a recent cross-sectional study, Ginsberg et al² examined the role for dermatologists in the care of transgender patients. The investigators concluded that dermatologists should play a larger role in a transgender patient’s physical transformation.² It is our opinion that dermatologists need to be comfortable building rapport with LGBT patients and to become attuned to their specific needs to provide effective care.

When forging a relationship with an LGBT patient, assumptions can damage rapport. Two assumptions that should be avoided include presuming heterosexuality or, on the other hand, assuming risk for disease based on known LGBT status. A dermatologist who takes a cursory sexual history, or none at all, assuming his/her patient is heterosexual creates an environment in which a nonheterosexual patient feels uncomfortable being honest and open. Although there is enough literature to support the claim that some sexual minority groups have increased risk for sexually transmitted infections (STIs),³ it is dangerous to assume a patient’s risk based solely on sexual orientation. An abstinent patient or a patient in a long-term, monogamous, same-sex relationship, for instance, may feel stereotyped by a dermatologist who wants to screen him/her for an STI. The best step in building a therapeutic relationship is to cast out these assumptions and allow LGBT patients to be open about themselves and their sexual practices. Sexual histories should be asked in nonjudgmental ways that are related to the health of the patient, leading to relevant and useful information for their care. For example, ask patients, “Do you have sex with men, women, or both?” This question should be delivered in a matter-of-fact tone, which conveys to the patient that the provider merely wants an answer to guide patient care.

Dermatologists can tailor their encounters to the specific needs of sexual minority patients. The medical literature is rich with examples of conditions that occur at greater frequency in specific sexual minority groups. Sexually transmitted infections, particularly human immunodeficiency virus, are important causes of morbidity and mortality among sexual minorities, especially men who have sex with men (MSM).^3,4 Anal and penile human papillomavirus (HPV) infection and HPV-associated anal carcinoma risk are increased in MSM.^5,6 The literature has remained inconclusive on the use of anal Papanicolaou tests for diagnosis; however, dermatologists have a duty to at least examine the perianal and genital area of any patient at risk for HPV-related disease or STIs.^7,8 For younger patients, the HPV vaccine can help prevent certain types of HPV infection and likely reduce a patient’s risk for condyloma acuminatum and other sequelae of the virus. Guidelines have been expanded to include men aged 13 to 21 years and up to 26 years.⁹ More research is needed to determine if detection and prevention of these types of HPV infection using the vaccine in MSM actually leads to a decreased incidence of anal carcinoma.

Certain LGBT groups may benefit from a dermatologist’s care outside the realm of infectious diseases. One study found that increased indoor tanning use in MSM correlated with increased risk for nonmelanoma skin cancer.¹⁰ Lesbians have been found to be less likely to pursue preventative health examinations in general, including skin checks.¹¹ Finally, transgender patients can utilize dermatologists for help with transformative procedures and side effects of hormonal treatment such as androgenic acne.^1,4

Cutaneous and beyond, the future of LGBT health care in the United States is affected by the institutions that train future physicians. There is a trend toward incorporating formal LGBT curricula into medical schools and academic centers.¹² The Penn Medicine Program for LGBT Health (Philadelphia, Pennsylvania) is a pilot program geared toward both educating future clinicians and providing equal and unbiased care to LGBT patients.¹² Programs such as this one give rise to a new generation of physicians who feel comfortable and aware of the needs of their LGBT patients.

In a time when LGBT patients are becoming more comfortable claiming their sexual and gender identities openly, there is a need for dermatologists to provide individualized unbiased care, which can best be achieved by building rapport through assumption-free history taking, performing thorough physical examinations that include the genital and perianal area, and passing these good practices on to trainees.

The last decade has been a period of advancement for the lesbian, gay, bisexual, and transgender (LGBT) community for legal protections and visibility. Although the journey to acceptance and equality is far from over, this progress has appropriately extended to medical academia as physicians search for ways to become more inclusive and effective care providers for their LGBT patients.¹ In a recent cross-sectional study, Ginsberg et al² examined the role for dermatologists in the care of transgender patients. The investigators concluded that dermatologists should play a larger role in a transgender patient’s physical transformation.² It is our opinion that dermatologists need to be comfortable building rapport with LGBT patients and to become attuned to their specific needs to provide effective care.

When forging a relationship with an LGBT patient, assumptions can damage rapport. Two assumptions that should be avoided include presuming heterosexuality or, on the other hand, assuming risk for disease based on known LGBT status. A dermatologist who takes a cursory sexual history, or none at all, assuming his/her patient is heterosexual creates an environment in which a nonheterosexual patient feels uncomfortable being honest and open. Although there is enough literature to support the claim that some sexual minority groups have increased risk for sexually transmitted infections (STIs),³ it is dangerous to assume a patient’s risk based solely on sexual orientation. An abstinent patient or a patient in a long-term, monogamous, same-sex relationship, for instance, may feel stereotyped by a dermatologist who wants to screen him/her for an STI. The best step in building a therapeutic relationship is to cast out these assumptions and allow LGBT patients to be open about themselves and their sexual practices. Sexual histories should be asked in nonjudgmental ways that are related to the health of the patient, leading to relevant and useful information for their care. For example, ask patients, “Do you have sex with men, women, or both?” This question should be delivered in a matter-of-fact tone, which conveys to the patient that the provider merely wants an answer to guide patient care.

Dermatologists can tailor their encounters to the specific needs of sexual minority patients. The medical literature is rich with examples of conditions that occur at greater frequency in specific sexual minority groups. Sexually transmitted infections, particularly human immunodeficiency virus, are important causes of morbidity and mortality among sexual minorities, especially men who have sex with men (MSM).^3,4 Anal and penile human papillomavirus (HPV) infection and HPV-associated anal carcinoma risk are increased in MSM.^5,6 The literature has remained inconclusive on the use of anal Papanicolaou tests for diagnosis; however, dermatologists have a duty to at least examine the perianal and genital area of any patient at risk for HPV-related disease or STIs.^7,8 For younger patients, the HPV vaccine can help prevent certain types of HPV infection and likely reduce a patient’s risk for condyloma acuminatum and other sequelae of the virus. Guidelines have been expanded to include men aged 13 to 21 years and up to 26 years.⁹ More research is needed to determine if detection and prevention of these types of HPV infection using the vaccine in MSM actually leads to a decreased incidence of anal carcinoma.

Certain LGBT groups may benefit from a dermatologist’s care outside the realm of infectious diseases. One study found that increased indoor tanning use in MSM correlated with increased risk for nonmelanoma skin cancer.¹⁰ Lesbians have been found to be less likely to pursue preventative health examinations in general, including skin checks.¹¹ Finally, transgender patients can utilize dermatologists for help with transformative procedures and side effects of hormonal treatment such as androgenic acne.^1,4

Cutaneous and beyond, the future of LGBT health care in the United States is affected by the institutions that train future physicians. There is a trend toward incorporating formal LGBT curricula into medical schools and academic centers.¹² The Penn Medicine Program for LGBT Health (Philadelphia, Pennsylvania) is a pilot program geared toward both educating future clinicians and providing equal and unbiased care to LGBT patients.¹² Programs such as this one give rise to a new generation of physicians who feel comfortable and aware of the needs of their LGBT patients.

In a time when LGBT patients are becoming more comfortable claiming their sexual and gender identities openly, there is a need for dermatologists to provide individualized unbiased care, which can best be achieved by building rapport through assumption-free history taking, performing thorough physical examinations that include the genital and perianal area, and passing these good practices on to trainees.

SNOWMASS, COLO. – Physicians can expect to encounter more and more patients with inflammatory arthritis and other rheumatic adverse events induced by immune checkpoint inhibitors as a result of anticipated exponential growth in the use of these drugs to treat an expanding list of cancers, Clifton O. Bingham III, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

These cancer immunotherapy–induced rheumatic diseases may superficially look like the classic forms of familiar autoimmune diseases, but they have highly atypical features that will affect treatment decisions.

Rheumatologic IRAE presentations

Inflammatory arthritis is the most common form of rheumatologic IRAE, followed by sicca syndrome. At the Johns Hopkins Arthritis Center, Dr. Bingham and his coworkers have 25 well-characterized patients with inflammatory arthritis resulting from an ICI, only 1 of whom is HLA-B27-positive.

“Also, just one is autoantibody-positive, even though they all look for all the world as though they have rheumatoid arthritis,” the rheumatologist observed.

This ICI-induced inflammatory arthritis initially presents most commonly in the midsize and large joints – knees, ankles, elbows – then expands to include small joints such as the wrists, proximal interphalangeal joints, and the metacarpophalangeal joints.

Notably, the Hopkins group also has three patients with classic reactive arthritis marked by conjunctivitis, urethritis, arthritis, and dactylitis.

“I don’t know about you, but, in our general rheumatology practice, we see maybe one case of reactive arthritis in several years, so this is something that has struck us as really quite interesting,” said Dr. Bingham, who is also director of research in the division of rheumatology at Johns Hopkins.

The arthritis center is also managing a group of patients with ICI-induced sicca syndrome, which is uniformly extremely severe and treatment resistant, as well as a couple of patients with myositis IRAE, one with polymyalgia rheumatica, and two with crystal disease that is highly inflammatory in nature, difficult to treat, and includes an inflammatory polyarthritis component not typical in patients with crystal arthritis.
 

Why physicians will see more rheumatologic IRAEs

ICIs have dramatically transformed the treatment of selected advanced-stage cancers. For example, whereas patients with metastatic melanoma historically had a 2-year survival rate of 5%, combination therapy with the ICIs ipilimumab (Yervoy) and nivolumab (Opdivo) resulted in a 60% rate of partial or complete remission in a landmark clinical trial.

The basis of cancer immunotherapy is the discovery that, in order for cancer cells to thrive, they emit blocking signals that downregulate the native ability of T cells to recognize and kill them. This is true for both solid tumors and hematologic malignancies. The ICIs inhibit these blocking signals, which include cytotoxic T-lymphocyte–associated protein 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PDL-1), thereby freeing up the T cells for tumor fighting.

Because of the nonspecific mechanism of this T-cell activation, however, ICIs have, as their main toxicities, T-cell–mediated autoimmune inflammatory tissue damage, which gets lumped under the umbrella term IRAEs. It can affect almost every organ system. Skin rashes are the most common, colitis second. Other commonly encountered IRAEs include thyroiditis, hypophysitis, hepatitis, peripheral neuropathy, and pneumonitis.

In addition to the four currently approved ICIs – ipilimumab, nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) – investigational ICIs targeting CTLA4, PD-1, and/or PDL-1 are in development. Plus, new ICIs targeting other blocking signals, including lymphocyte activation gene-3, CD137, and T-cell immunoglobulin and mucin domain-3, are now in clinical trials.

Clinical trials aimed at expanding the indications of existing ICIs and using ICIs in earlier-stage cancers in an effort to improve rates of lasting remission are also underway.

All told, probably at least 400 clinical trials of ICIs are ongoing worldwide, the rheumatologist estimated.

“More people will be exposed to these drugs, and we’ll see more and more of these rheumatologic IRAEs,” Dr. Bingham predicted.
 

Rheumatologic IRAEs are seriously underdiagnosed

Back in the pre-ICI days, Dr. Bingham was coauthor of a major study which concluded that clinical trialists in oncology consistently downgrade the severity of rheumatologic adverse events, often by 1 or 2 grades (J Rheumatol. 2007 Jun;34[6]:1401-14).

Unpublished details of ICI clinical trials in melanoma that he obtained from Bristol-Myers Squibb suggest that the true rate of rheumatologic IRAEs is about 20%, or roughly double that reported in the studies. That’s because the adverse events–grading system used in oncology undercalls the severity of arthritis and autoimmune disorders.

Indeed, the National Cancer Institute’s Common Terminology Criteria for Adverse Events, used in oncology clinical trials, is confusing on the topic of musculoskeletal and connective tissue disorders as treatment-emergent adverse events, according to Dr. Bingham. He noted that an oncologist can code a swollen joint in three different ways – joint effusion, arthritis, or arthralgia – and it takes disabling interference with self-care in activities of daily living for that swollen joint to rise to the level of a Grade 3 adverse event. From a rheumatology trialist’s perspective, that would be a Grade 4 disability.

Plus, neither the product labeling nor the patient information guides for the approved immunotherapy drugs mention the importance of monitoring for rheumatologic IRAEs or their management.

“There is poor awareness of musculoskeletal and rheumatic IRAEs in the general oncology community,” Dr. Bingham asserted. “But, if you talk with any oncology nurses who work in a clinical trial, they will tell you they’re seeing these events with significant frequency and severity.”
 

Treatment and response

It’s critical to gain control of rheumatologic IRAEs quickly so that patients can get on with their cancer immunotherapy. Dr. Bingham uses intra-articular steroid injections for patients with oligoarthritis and high-dose oral prednisone for polyarticular disease. He starts methotrexate and/or leflunomide early because the conventional disease-modifying antirheumatic drugs have roughly a 2-month delay in onset of action. He has had several patients who are unable to taper steroids despite background methotrexate.

In the most severely affected patients, he has turned to biologic agents in consultation with their oncologists. Tumor necrosis factor (TNF) inhibitors are the ones he and other rheumatologists have used most often.

“Notably, we have not been able to taper down very well. We have patients who are out more than 2 years now who still require their TNF inhibitor to treat their inflammatory arthritis, and these are patients on conventional disease–modifying antirheumatic drugs as well. As soon as it’s tapered, the arthritis begins to come back,” according to Dr. Bingham.

In marked contrast, colitis as an IRAE typically clears in response to just one or two doses of a TNF inhibitor.

One audience member related that she’d encountered a roadblock in trying to get authorization for a TNF inhibitor for a patient with a rheumatologic IRAE secondary to ICI treatment for metastatic melanoma because the labeling states these agents are relatively contraindicated in melanoma patients. Dr. Bingham offered a tip: Collaborate with the patient’s oncologist.

“In most cases, oncologists can get infliximab for these patients and administer it in their infusion centers. They are able to get things authorized with very little trouble,” he said.

Besides, most of these patients with severe inflammatory arthritis meet conventional criteria for TNF inhibitor therapy, based on their number of infected joints and elevated acute phase reactants for longer than 6 weeks, Dr. Bingham noted.

“We’ve had some very interesting conversations with patients. It’s impressive to see the impact arthritis can have on people. A lot of patients have said, ‘I don’t care if I die. Get me functional right now.’ That’s pretty profound. Quality of life is still very important for people, even when dealing with life-threatening diseases,” he observed.

Oncologists are actually eager for their patients to get on steroid-sparing therapy because of concern that high doses of steroids may reduce the efficacy of cancer immunotherapy. That’s not an issue with the TNF inhibitors, the rheumatologist continued.

Turning to the utility of other classes of biologic agents, Dr. Bingham advised avoiding abatacept (Orencia) because its mechanism of action is likely to cause interference with the cancer immunotherapy. Rituximab (Rituxan) takes too long to act. Anakinra (Kineret), tofacitinib (Xeljanz), and tocilizumab (Actemra), on the other hand, are agents he is interested in using as alternatives to TNF inhibitors, although he hasn’t done so yet.
 

Use of ICIs in patients with preexisting autoimmune disease

The experience here is entirely anecdotal, since such patients have been excluded from ICI clinical trials, but the available evidence suggests physicians should be prepared for higher rheumatologic IRAE rates in this setting. Investigators at Vanderbilt University reported that 8 of 30 cancer patients with known preexisting autoimmune disease experienced flares of that disease when treated with ipilimumab, and 10 developed a new IRAE (Therap Adv Gastroenterol. 2016 Jul;9[4]:457-62).

The Hopkins group has three patients with preexisting rheumatoid arthritis and two with preexisting scleroderma who have received ICIs. All three rheumatoid arthritis patients flared. Rheumatologists are trying to manage these flares so the patients can continue on their ICI. One of the scleroderma patients experienced no change in that disease while on an ICI, while the other showed a definite improvement in scleroderma symptoms.

“I think the jury’s still out in terms of what you do about ICI therapy in patients with preexisting autoimmunity. The data would say that there’s maybe a 50-50 chance of the autoimmune disease becoming worse, but, if patients have an otherwise fatal cancer, I think it’s probably worth the chance,” Dr. Bingham said.

Anecdotal reports suggest that more severe IRAEs may be a favorable prognostic sign in terms of cancer eradication, but a lot more patient experience will be needed in order to be sure, the rheumatologist said.

Dr. Bingham reported serving as a consultant to Bristol-Myers Squibb.

bjancin@frontlinemedcom.com
 

SNOWMASS, COLO. – Physicians can expect to encounter more and more patients with inflammatory arthritis and other rheumatic adverse events induced by immune checkpoint inhibitors as a result of anticipated exponential growth in the use of these drugs to treat an expanding list of cancers, Clifton O. Bingham III, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

These cancer immunotherapy–induced rheumatic diseases may superficially look like the classic forms of familiar autoimmune diseases, but they have highly atypical features that will affect treatment decisions.

Rheumatologic IRAE presentations

Inflammatory arthritis is the most common form of rheumatologic IRAE, followed by sicca syndrome. At the Johns Hopkins Arthritis Center, Dr. Bingham and his coworkers have 25 well-characterized patients with inflammatory arthritis resulting from an ICI, only 1 of whom is HLA-B27-positive.

“Also, just one is autoantibody-positive, even though they all look for all the world as though they have rheumatoid arthritis,” the rheumatologist observed.

This ICI-induced inflammatory arthritis initially presents most commonly in the midsize and large joints – knees, ankles, elbows – then expands to include small joints such as the wrists, proximal interphalangeal joints, and the metacarpophalangeal joints.

Notably, the Hopkins group also has three patients with classic reactive arthritis marked by conjunctivitis, urethritis, arthritis, and dactylitis.

“I don’t know about you, but, in our general rheumatology practice, we see maybe one case of reactive arthritis in several years, so this is something that has struck us as really quite interesting,” said Dr. Bingham, who is also director of research in the division of rheumatology at Johns Hopkins.

The arthritis center is also managing a group of patients with ICI-induced sicca syndrome, which is uniformly extremely severe and treatment resistant, as well as a couple of patients with myositis IRAE, one with polymyalgia rheumatica, and two with crystal disease that is highly inflammatory in nature, difficult to treat, and includes an inflammatory polyarthritis component not typical in patients with crystal arthritis.
 

Why physicians will see more rheumatologic IRAEs

ICIs have dramatically transformed the treatment of selected advanced-stage cancers. For example, whereas patients with metastatic melanoma historically had a 2-year survival rate of 5%, combination therapy with the ICIs ipilimumab (Yervoy) and nivolumab (Opdivo) resulted in a 60% rate of partial or complete remission in a landmark clinical trial.

The basis of cancer immunotherapy is the discovery that, in order for cancer cells to thrive, they emit blocking signals that downregulate the native ability of T cells to recognize and kill them. This is true for both solid tumors and hematologic malignancies. The ICIs inhibit these blocking signals, which include cytotoxic T-lymphocyte–associated protein 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PDL-1), thereby freeing up the T cells for tumor fighting.

Because of the nonspecific mechanism of this T-cell activation, however, ICIs have, as their main toxicities, T-cell–mediated autoimmune inflammatory tissue damage, which gets lumped under the umbrella term IRAEs. It can affect almost every organ system. Skin rashes are the most common, colitis second. Other commonly encountered IRAEs include thyroiditis, hypophysitis, hepatitis, peripheral neuropathy, and pneumonitis.

In addition to the four currently approved ICIs – ipilimumab, nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) – investigational ICIs targeting CTLA4, PD-1, and/or PDL-1 are in development. Plus, new ICIs targeting other blocking signals, including lymphocyte activation gene-3, CD137, and T-cell immunoglobulin and mucin domain-3, are now in clinical trials.

Clinical trials aimed at expanding the indications of existing ICIs and using ICIs in earlier-stage cancers in an effort to improve rates of lasting remission are also underway.

All told, probably at least 400 clinical trials of ICIs are ongoing worldwide, the rheumatologist estimated.

“More people will be exposed to these drugs, and we’ll see more and more of these rheumatologic IRAEs,” Dr. Bingham predicted.
 

Rheumatologic IRAEs are seriously underdiagnosed

Back in the pre-ICI days, Dr. Bingham was coauthor of a major study which concluded that clinical trialists in oncology consistently downgrade the severity of rheumatologic adverse events, often by 1 or 2 grades (J Rheumatol. 2007 Jun;34[6]:1401-14).

Unpublished details of ICI clinical trials in melanoma that he obtained from Bristol-Myers Squibb suggest that the true rate of rheumatologic IRAEs is about 20%, or roughly double that reported in the studies. That’s because the adverse events–grading system used in oncology undercalls the severity of arthritis and autoimmune disorders.

Indeed, the National Cancer Institute’s Common Terminology Criteria for Adverse Events, used in oncology clinical trials, is confusing on the topic of musculoskeletal and connective tissue disorders as treatment-emergent adverse events, according to Dr. Bingham. He noted that an oncologist can code a swollen joint in three different ways – joint effusion, arthritis, or arthralgia – and it takes disabling interference with self-care in activities of daily living for that swollen joint to rise to the level of a Grade 3 adverse event. From a rheumatology trialist’s perspective, that would be a Grade 4 disability.

Plus, neither the product labeling nor the patient information guides for the approved immunotherapy drugs mention the importance of monitoring for rheumatologic IRAEs or their management.

“There is poor awareness of musculoskeletal and rheumatic IRAEs in the general oncology community,” Dr. Bingham asserted. “But, if you talk with any oncology nurses who work in a clinical trial, they will tell you they’re seeing these events with significant frequency and severity.”
 

Treatment and response

It’s critical to gain control of rheumatologic IRAEs quickly so that patients can get on with their cancer immunotherapy. Dr. Bingham uses intra-articular steroid injections for patients with oligoarthritis and high-dose oral prednisone for polyarticular disease. He starts methotrexate and/or leflunomide early because the conventional disease-modifying antirheumatic drugs have roughly a 2-month delay in onset of action. He has had several patients who are unable to taper steroids despite background methotrexate.

In the most severely affected patients, he has turned to biologic agents in consultation with their oncologists. Tumor necrosis factor (TNF) inhibitors are the ones he and other rheumatologists have used most often.

“Notably, we have not been able to taper down very well. We have patients who are out more than 2 years now who still require their TNF inhibitor to treat their inflammatory arthritis, and these are patients on conventional disease–modifying antirheumatic drugs as well. As soon as it’s tapered, the arthritis begins to come back,” according to Dr. Bingham.

In marked contrast, colitis as an IRAE typically clears in response to just one or two doses of a TNF inhibitor.

One audience member related that she’d encountered a roadblock in trying to get authorization for a TNF inhibitor for a patient with a rheumatologic IRAE secondary to ICI treatment for metastatic melanoma because the labeling states these agents are relatively contraindicated in melanoma patients. Dr. Bingham offered a tip: Collaborate with the patient’s oncologist.

“In most cases, oncologists can get infliximab for these patients and administer it in their infusion centers. They are able to get things authorized with very little trouble,” he said.

Besides, most of these patients with severe inflammatory arthritis meet conventional criteria for TNF inhibitor therapy, based on their number of infected joints and elevated acute phase reactants for longer than 6 weeks, Dr. Bingham noted.

“We’ve had some very interesting conversations with patients. It’s impressive to see the impact arthritis can have on people. A lot of patients have said, ‘I don’t care if I die. Get me functional right now.’ That’s pretty profound. Quality of life is still very important for people, even when dealing with life-threatening diseases,” he observed.

Oncologists are actually eager for their patients to get on steroid-sparing therapy because of concern that high doses of steroids may reduce the efficacy of cancer immunotherapy. That’s not an issue with the TNF inhibitors, the rheumatologist continued.

Turning to the utility of other classes of biologic agents, Dr. Bingham advised avoiding abatacept (Orencia) because its mechanism of action is likely to cause interference with the cancer immunotherapy. Rituximab (Rituxan) takes too long to act. Anakinra (Kineret), tofacitinib (Xeljanz), and tocilizumab (Actemra), on the other hand, are agents he is interested in using as alternatives to TNF inhibitors, although he hasn’t done so yet.
 

Use of ICIs in patients with preexisting autoimmune disease

The experience here is entirely anecdotal, since such patients have been excluded from ICI clinical trials, but the available evidence suggests physicians should be prepared for higher rheumatologic IRAE rates in this setting. Investigators at Vanderbilt University reported that 8 of 30 cancer patients with known preexisting autoimmune disease experienced flares of that disease when treated with ipilimumab, and 10 developed a new IRAE (Therap Adv Gastroenterol. 2016 Jul;9[4]:457-62).

The Hopkins group has three patients with preexisting rheumatoid arthritis and two with preexisting scleroderma who have received ICIs. All three rheumatoid arthritis patients flared. Rheumatologists are trying to manage these flares so the patients can continue on their ICI. One of the scleroderma patients experienced no change in that disease while on an ICI, while the other showed a definite improvement in scleroderma symptoms.

“I think the jury’s still out in terms of what you do about ICI therapy in patients with preexisting autoimmunity. The data would say that there’s maybe a 50-50 chance of the autoimmune disease becoming worse, but, if patients have an otherwise fatal cancer, I think it’s probably worth the chance,” Dr. Bingham said.

Anecdotal reports suggest that more severe IRAEs may be a favorable prognostic sign in terms of cancer eradication, but a lot more patient experience will be needed in order to be sure, the rheumatologist said.

Dr. Bingham reported serving as a consultant to Bristol-Myers Squibb.

bjancin@frontlinemedcom.com
 

SNOWMASS, COLO. – Physicians can expect to encounter more and more patients with inflammatory arthritis and other rheumatic adverse events induced by immune checkpoint inhibitors as a result of anticipated exponential growth in the use of these drugs to treat an expanding list of cancers, Clifton O. Bingham III, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

These cancer immunotherapy–induced rheumatic diseases may superficially look like the classic forms of familiar autoimmune diseases, but they have highly atypical features that will affect treatment decisions.

Rheumatologic IRAE presentations

Inflammatory arthritis is the most common form of rheumatologic IRAE, followed by sicca syndrome. At the Johns Hopkins Arthritis Center, Dr. Bingham and his coworkers have 25 well-characterized patients with inflammatory arthritis resulting from an ICI, only 1 of whom is HLA-B27-positive.

“Also, just one is autoantibody-positive, even though they all look for all the world as though they have rheumatoid arthritis,” the rheumatologist observed.

This ICI-induced inflammatory arthritis initially presents most commonly in the midsize and large joints – knees, ankles, elbows – then expands to include small joints such as the wrists, proximal interphalangeal joints, and the metacarpophalangeal joints.

Notably, the Hopkins group also has three patients with classic reactive arthritis marked by conjunctivitis, urethritis, arthritis, and dactylitis.

“I don’t know about you, but, in our general rheumatology practice, we see maybe one case of reactive arthritis in several years, so this is something that has struck us as really quite interesting,” said Dr. Bingham, who is also director of research in the division of rheumatology at Johns Hopkins.

The arthritis center is also managing a group of patients with ICI-induced sicca syndrome, which is uniformly extremely severe and treatment resistant, as well as a couple of patients with myositis IRAE, one with polymyalgia rheumatica, and two with crystal disease that is highly inflammatory in nature, difficult to treat, and includes an inflammatory polyarthritis component not typical in patients with crystal arthritis.
 

Why physicians will see more rheumatologic IRAEs

ICIs have dramatically transformed the treatment of selected advanced-stage cancers. For example, whereas patients with metastatic melanoma historically had a 2-year survival rate of 5%, combination therapy with the ICIs ipilimumab (Yervoy) and nivolumab (Opdivo) resulted in a 60% rate of partial or complete remission in a landmark clinical trial.

The basis of cancer immunotherapy is the discovery that, in order for cancer cells to thrive, they emit blocking signals that downregulate the native ability of T cells to recognize and kill them. This is true for both solid tumors and hematologic malignancies. The ICIs inhibit these blocking signals, which include cytotoxic T-lymphocyte–associated protein 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PDL-1), thereby freeing up the T cells for tumor fighting.

Because of the nonspecific mechanism of this T-cell activation, however, ICIs have, as their main toxicities, T-cell–mediated autoimmune inflammatory tissue damage, which gets lumped under the umbrella term IRAEs. It can affect almost every organ system. Skin rashes are the most common, colitis second. Other commonly encountered IRAEs include thyroiditis, hypophysitis, hepatitis, peripheral neuropathy, and pneumonitis.

In addition to the four currently approved ICIs – ipilimumab, nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) – investigational ICIs targeting CTLA4, PD-1, and/or PDL-1 are in development. Plus, new ICIs targeting other blocking signals, including lymphocyte activation gene-3, CD137, and T-cell immunoglobulin and mucin domain-3, are now in clinical trials.

Clinical trials aimed at expanding the indications of existing ICIs and using ICIs in earlier-stage cancers in an effort to improve rates of lasting remission are also underway.

All told, probably at least 400 clinical trials of ICIs are ongoing worldwide, the rheumatologist estimated.

“More people will be exposed to these drugs, and we’ll see more and more of these rheumatologic IRAEs,” Dr. Bingham predicted.
 

Rheumatologic IRAEs are seriously underdiagnosed

Back in the pre-ICI days, Dr. Bingham was coauthor of a major study which concluded that clinical trialists in oncology consistently downgrade the severity of rheumatologic adverse events, often by 1 or 2 grades (J Rheumatol. 2007 Jun;34[6]:1401-14).

Unpublished details of ICI clinical trials in melanoma that he obtained from Bristol-Myers Squibb suggest that the true rate of rheumatologic IRAEs is about 20%, or roughly double that reported in the studies. That’s because the adverse events–grading system used in oncology undercalls the severity of arthritis and autoimmune disorders.

Indeed, the National Cancer Institute’s Common Terminology Criteria for Adverse Events, used in oncology clinical trials, is confusing on the topic of musculoskeletal and connective tissue disorders as treatment-emergent adverse events, according to Dr. Bingham. He noted that an oncologist can code a swollen joint in three different ways – joint effusion, arthritis, or arthralgia – and it takes disabling interference with self-care in activities of daily living for that swollen joint to rise to the level of a Grade 3 adverse event. From a rheumatology trialist’s perspective, that would be a Grade 4 disability.

Plus, neither the product labeling nor the patient information guides for the approved immunotherapy drugs mention the importance of monitoring for rheumatologic IRAEs or their management.

“There is poor awareness of musculoskeletal and rheumatic IRAEs in the general oncology community,” Dr. Bingham asserted. “But, if you talk with any oncology nurses who work in a clinical trial, they will tell you they’re seeing these events with significant frequency and severity.”
 

Treatment and response

It’s critical to gain control of rheumatologic IRAEs quickly so that patients can get on with their cancer immunotherapy. Dr. Bingham uses intra-articular steroid injections for patients with oligoarthritis and high-dose oral prednisone for polyarticular disease. He starts methotrexate and/or leflunomide early because the conventional disease-modifying antirheumatic drugs have roughly a 2-month delay in onset of action. He has had several patients who are unable to taper steroids despite background methotrexate.

In the most severely affected patients, he has turned to biologic agents in consultation with their oncologists. Tumor necrosis factor (TNF) inhibitors are the ones he and other rheumatologists have used most often.

“Notably, we have not been able to taper down very well. We have patients who are out more than 2 years now who still require their TNF inhibitor to treat their inflammatory arthritis, and these are patients on conventional disease–modifying antirheumatic drugs as well. As soon as it’s tapered, the arthritis begins to come back,” according to Dr. Bingham.

In marked contrast, colitis as an IRAE typically clears in response to just one or two doses of a TNF inhibitor.

One audience member related that she’d encountered a roadblock in trying to get authorization for a TNF inhibitor for a patient with a rheumatologic IRAE secondary to ICI treatment for metastatic melanoma because the labeling states these agents are relatively contraindicated in melanoma patients. Dr. Bingham offered a tip: Collaborate with the patient’s oncologist.

“In most cases, oncologists can get infliximab for these patients and administer it in their infusion centers. They are able to get things authorized with very little trouble,” he said.

Besides, most of these patients with severe inflammatory arthritis meet conventional criteria for TNF inhibitor therapy, based on their number of infected joints and elevated acute phase reactants for longer than 6 weeks, Dr. Bingham noted.

“We’ve had some very interesting conversations with patients. It’s impressive to see the impact arthritis can have on people. A lot of patients have said, ‘I don’t care if I die. Get me functional right now.’ That’s pretty profound. Quality of life is still very important for people, even when dealing with life-threatening diseases,” he observed.

Oncologists are actually eager for their patients to get on steroid-sparing therapy because of concern that high doses of steroids may reduce the efficacy of cancer immunotherapy. That’s not an issue with the TNF inhibitors, the rheumatologist continued.

Turning to the utility of other classes of biologic agents, Dr. Bingham advised avoiding abatacept (Orencia) because its mechanism of action is likely to cause interference with the cancer immunotherapy. Rituximab (Rituxan) takes too long to act. Anakinra (Kineret), tofacitinib (Xeljanz), and tocilizumab (Actemra), on the other hand, are agents he is interested in using as alternatives to TNF inhibitors, although he hasn’t done so yet.
 

Use of ICIs in patients with preexisting autoimmune disease

The experience here is entirely anecdotal, since such patients have been excluded from ICI clinical trials, but the available evidence suggests physicians should be prepared for higher rheumatologic IRAE rates in this setting. Investigators at Vanderbilt University reported that 8 of 30 cancer patients with known preexisting autoimmune disease experienced flares of that disease when treated with ipilimumab, and 10 developed a new IRAE (Therap Adv Gastroenterol. 2016 Jul;9[4]:457-62).

The Hopkins group has three patients with preexisting rheumatoid arthritis and two with preexisting scleroderma who have received ICIs. All three rheumatoid arthritis patients flared. Rheumatologists are trying to manage these flares so the patients can continue on their ICI. One of the scleroderma patients experienced no change in that disease while on an ICI, while the other showed a definite improvement in scleroderma symptoms.

“I think the jury’s still out in terms of what you do about ICI therapy in patients with preexisting autoimmunity. The data would say that there’s maybe a 50-50 chance of the autoimmune disease becoming worse, but, if patients have an otherwise fatal cancer, I think it’s probably worth the chance,” Dr. Bingham said.

Anecdotal reports suggest that more severe IRAEs may be a favorable prognostic sign in terms of cancer eradication, but a lot more patient experience will be needed in order to be sure, the rheumatologist said.

Dr. Bingham reported serving as a consultant to Bristol-Myers Squibb.

bjancin@frontlinemedcom.com