Cutis

The Diagnosis: Pagetoid Reticulosis

Histopathologic examination demonstrated a dense infiltrate and psoriasiform pattern epidermal hyperplasia (Figure, A). There was conspicuous epidermotropism of moderately enlarged, hyperchromatic lymphocytes. Intraepidermal lymphocytes were slightly larger, darker, and more convoluted than those in the subjacent dermis (Figure, B). These cells exhibited CD3⁺ T-cell differentiation with an abnormal CD4-CD7-CD8- phenotype (Figure, C). The histopathologic finding of atypical epidermotropic T-cell infiltrate was compatible with a rare variant of mycosis fungoides known as pagetoid reticulosis (PR). After discussing the diagnosis and treatment options, the patient elected to begin with a conservative approach to therapy. We prescribed fluocinonide ointment 0.05% twice daily under occlusion. At 1 month follow-up, the patient experienced marked improvement of the erythema and scaling of the lesion.

Pagetoid reticulosis is a primary cutaneous T-cell lymphoma that has been categorized as an indolent localized variant of mycosis fungoides. This rare skin disorder was originally described by Woringer and Kolopp in 1939¹ and was further renamed in 1973 by Braun-Falco et al.² At that time the term pagetoid reticulosis was introduced due to similarities in histopathologic findings seen in Paget disease of the nipple. Two variants of the disease have been described since then: the localized type and the disseminated type. The localized type, also known as Woringer-Kolopp disease (WKD), typically presents as a persistent, sharply localized, scaly patch that slowly expands over several years. The lesion is classically located on the extensor surface of the hand or foot and often is asymptomatic. Due to the benign presentation, WKD can easily be confused with much more common diseases, such as psoriasis or fungal infections, resulting in a substantial delay in the diagnosis. The patient will often report a medical history notable for frequent office visits and numerous failed therapies. Even though it is exceedingly uncommon, these findings should prompt the practitioner to add WKD to their differential. The disseminated type of PR (also known as Ketron-Goodman disease) is characterized by diffuse cutaneous involvement, carries a much more progressive course, and often leads to a poor outcome.³ The histopathologic features of WKD and Ketron-Goodman disease are identical, and the 2 types are distinguished on clinical grounds alone.

Histopathologic features of PR are unique and often distinct in comparison to mycosis fungoides. Pagetoid reticulosis often is described as epidermal hyperplasia with parakeratosis, prominent acanthosis, and excessive epidermotropism of atypical lymphocytes scattered throughout the epidermis.³ The distinct pattern of epidermotropism seen in PR is the characteristic finding. Review of immunocytochemistry from reported cases has shown that CD marker expression of neoplastic T cells in PR can be variable in nature.⁴ Although it is known that immunophenotyping can be useful in diagnosing and distinguishing PR from other types of primary cutaneous T-cell lymphoma, the clinical significance of the observed phenotypic variation remains a mystery. As of now, it appears to be prognostically irrelevant.⁵

There are numerous therapeutic options available for PR. Depending on the size and extent of the disease, surgical excision and radiotherapy may be an option and are the most effective.⁶ For patients who are not good candidates or opt out of these options, there are various pharmacotherapies that also have proven to work. Traditional therapies include topical corticosteroids, corticosteroid injections, and phototherapy. However, more recent trials with retinoids, such as alitretinoin or bexarotene, appear to offer a promising therapeutic approach.⁷

Pagetoid reticulosis is a true malignant lymphoma of T-cell lineage, but it typically carries an excellent prognosis. Rare cases have been reported to progress to disseminated lymphoma.⁸ Therefore, long-term follow-up for a patient diagnosed with PR is recommended.

The Diagnosis: Pagetoid Reticulosis

Histopathologic examination demonstrated a dense infiltrate and psoriasiform pattern epidermal hyperplasia (Figure, A). There was conspicuous epidermotropism of moderately enlarged, hyperchromatic lymphocytes. Intraepidermal lymphocytes were slightly larger, darker, and more convoluted than those in the subjacent dermis (Figure, B). These cells exhibited CD3⁺ T-cell differentiation with an abnormal CD4-CD7-CD8- phenotype (Figure, C). The histopathologic finding of atypical epidermotropic T-cell infiltrate was compatible with a rare variant of mycosis fungoides known as pagetoid reticulosis (PR). After discussing the diagnosis and treatment options, the patient elected to begin with a conservative approach to therapy. We prescribed fluocinonide ointment 0.05% twice daily under occlusion. At 1 month follow-up, the patient experienced marked improvement of the erythema and scaling of the lesion.

Pagetoid reticulosis is a primary cutaneous T-cell lymphoma that has been categorized as an indolent localized variant of mycosis fungoides. This rare skin disorder was originally described by Woringer and Kolopp in 1939¹ and was further renamed in 1973 by Braun-Falco et al.² At that time the term pagetoid reticulosis was introduced due to similarities in histopathologic findings seen in Paget disease of the nipple. Two variants of the disease have been described since then: the localized type and the disseminated type. The localized type, also known as Woringer-Kolopp disease (WKD), typically presents as a persistent, sharply localized, scaly patch that slowly expands over several years. The lesion is classically located on the extensor surface of the hand or foot and often is asymptomatic. Due to the benign presentation, WKD can easily be confused with much more common diseases, such as psoriasis or fungal infections, resulting in a substantial delay in the diagnosis. The patient will often report a medical history notable for frequent office visits and numerous failed therapies. Even though it is exceedingly uncommon, these findings should prompt the practitioner to add WKD to their differential. The disseminated type of PR (also known as Ketron-Goodman disease) is characterized by diffuse cutaneous involvement, carries a much more progressive course, and often leads to a poor outcome.³ The histopathologic features of WKD and Ketron-Goodman disease are identical, and the 2 types are distinguished on clinical grounds alone.

Histopathologic features of PR are unique and often distinct in comparison to mycosis fungoides. Pagetoid reticulosis often is described as epidermal hyperplasia with parakeratosis, prominent acanthosis, and excessive epidermotropism of atypical lymphocytes scattered throughout the epidermis.³ The distinct pattern of epidermotropism seen in PR is the characteristic finding. Review of immunocytochemistry from reported cases has shown that CD marker expression of neoplastic T cells in PR can be variable in nature.⁴ Although it is known that immunophenotyping can be useful in diagnosing and distinguishing PR from other types of primary cutaneous T-cell lymphoma, the clinical significance of the observed phenotypic variation remains a mystery. As of now, it appears to be prognostically irrelevant.⁵

There are numerous therapeutic options available for PR. Depending on the size and extent of the disease, surgical excision and radiotherapy may be an option and are the most effective.⁶ For patients who are not good candidates or opt out of these options, there are various pharmacotherapies that also have proven to work. Traditional therapies include topical corticosteroids, corticosteroid injections, and phototherapy. However, more recent trials with retinoids, such as alitretinoin or bexarotene, appear to offer a promising therapeutic approach.⁷

Pagetoid reticulosis is a true malignant lymphoma of T-cell lineage, but it typically carries an excellent prognosis. Rare cases have been reported to progress to disseminated lymphoma.⁸ Therefore, long-term follow-up for a patient diagnosed with PR is recommended.

The Diagnosis: Pagetoid Reticulosis

Histopathologic examination demonstrated a dense infiltrate and psoriasiform pattern epidermal hyperplasia (Figure, A). There was conspicuous epidermotropism of moderately enlarged, hyperchromatic lymphocytes. Intraepidermal lymphocytes were slightly larger, darker, and more convoluted than those in the subjacent dermis (Figure, B). These cells exhibited CD3⁺ T-cell differentiation with an abnormal CD4-CD7-CD8- phenotype (Figure, C). The histopathologic finding of atypical epidermotropic T-cell infiltrate was compatible with a rare variant of mycosis fungoides known as pagetoid reticulosis (PR). After discussing the diagnosis and treatment options, the patient elected to begin with a conservative approach to therapy. We prescribed fluocinonide ointment 0.05% twice daily under occlusion. At 1 month follow-up, the patient experienced marked improvement of the erythema and scaling of the lesion.

Pagetoid reticulosis is a primary cutaneous T-cell lymphoma that has been categorized as an indolent localized variant of mycosis fungoides. This rare skin disorder was originally described by Woringer and Kolopp in 1939¹ and was further renamed in 1973 by Braun-Falco et al.² At that time the term pagetoid reticulosis was introduced due to similarities in histopathologic findings seen in Paget disease of the nipple. Two variants of the disease have been described since then: the localized type and the disseminated type. The localized type, also known as Woringer-Kolopp disease (WKD), typically presents as a persistent, sharply localized, scaly patch that slowly expands over several years. The lesion is classically located on the extensor surface of the hand or foot and often is asymptomatic. Due to the benign presentation, WKD can easily be confused with much more common diseases, such as psoriasis or fungal infections, resulting in a substantial delay in the diagnosis. The patient will often report a medical history notable for frequent office visits and numerous failed therapies. Even though it is exceedingly uncommon, these findings should prompt the practitioner to add WKD to their differential. The disseminated type of PR (also known as Ketron-Goodman disease) is characterized by diffuse cutaneous involvement, carries a much more progressive course, and often leads to a poor outcome.³ The histopathologic features of WKD and Ketron-Goodman disease are identical, and the 2 types are distinguished on clinical grounds alone.

Histopathologic features of PR are unique and often distinct in comparison to mycosis fungoides. Pagetoid reticulosis often is described as epidermal hyperplasia with parakeratosis, prominent acanthosis, and excessive epidermotropism of atypical lymphocytes scattered throughout the epidermis.³ The distinct pattern of epidermotropism seen in PR is the characteristic finding. Review of immunocytochemistry from reported cases has shown that CD marker expression of neoplastic T cells in PR can be variable in nature.⁴ Although it is known that immunophenotyping can be useful in diagnosing and distinguishing PR from other types of primary cutaneous T-cell lymphoma, the clinical significance of the observed phenotypic variation remains a mystery. As of now, it appears to be prognostically irrelevant.⁵

There are numerous therapeutic options available for PR. Depending on the size and extent of the disease, surgical excision and radiotherapy may be an option and are the most effective.⁶ For patients who are not good candidates or opt out of these options, there are various pharmacotherapies that also have proven to work. Traditional therapies include topical corticosteroids, corticosteroid injections, and phototherapy. However, more recent trials with retinoids, such as alitretinoin or bexarotene, appear to offer a promising therapeutic approach.⁷

Pagetoid reticulosis is a true malignant lymphoma of T-cell lineage, but it typically carries an excellent prognosis. Rare cases have been reported to progress to disseminated lymphoma.⁸ Therefore, long-term follow-up for a patient diagnosed with PR is recommended.

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.^5,6Five 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.^5,6Five 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.^5,6Five 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.

The first Skin of Color column, "Diversity in Dermatology: A Society Devoted to Skin of Color," produced in collaboration with the Skin of Color Society appears on page 322. This column will be published quarterly and will serve to increase the knowledge available to dermatologists to help improve delivery of care to this underserved population.

Look for Skin of Color columns in upcoming issues of Cutis.

The first Skin of Color column, "Diversity in Dermatology: A Society Devoted to Skin of Color," produced in collaboration with the Skin of Color Society appears on page 322. This column will be published quarterly and will serve to increase the knowledge available to dermatologists to help improve delivery of care to this underserved population.

Look for Skin of Color columns in upcoming issues of Cutis.

The first Skin of Color column, "Diversity in Dermatology: A Society Devoted to Skin of Color," produced in collaboration with the Skin of Color Society appears on page 322. This column will be published quarterly and will serve to increase the knowledge available to dermatologists to help improve delivery of care to this underserved population.

Look for Skin of Color columns in upcoming issues of Cutis.

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.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

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.

Sun exposure and sunburns sustained during childhood are linked to an increased risk for development of skin cancers in adulthood. In infants, the skin is particularly vulnerable and is considered to be at increased risk for UV radiation damage,¹ even as early as the first 6 months of life.² Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ To effectively teach parents proper sun-safe practices, it is essential to understand their existing perceptions and behaviors. This study sought to examine differences in infant sun-safety practices during the first 6 months of life among black, Hispanic, and non-Hispanic white (NHW) parents in Miami, Florida.

Methods

Parents presenting to the University of Miami general pediatrics clinic from February 2015 through April 2015 with a child younger than 5 years were administered a 15-item questionnaire that included items on demographics, sun-safety strategies, sunburns and tanning, beliefs and limitations regarding sunscreen, and primary information source regarding sun safety (eg, physician, Internet, media, instincts). Parents were approached by the investigators consecutively for participation in scheduled blocks, with the exception of those who were otherwise engaged in appointment-related tasks (eg, paperwork). The study was approved by the University of Miami Miller School of Medicine institutional review board. The primary objective of this study was to determine the sun protection behaviors that black and Hispanic parents in Miami, Florida, employ in infants younger than 6 months. Secondary objectives included determining if this patient population is at risk for infant sunburns and tanning, beliefs among parents regarding sunscreen's efficacy in the prevention of skin cancers, and limitations of sunscreen use.

All data were analyzed using SAS software version 9.3. Wilcoxon signed rank test, Kruskal-Wallis test, Fisher exact test, and proportional-odds cumulative logit model were used to compare nonparametric data. Parents reporting on the full first 6 months of life (ie, the child was older than 6 months at the time of study completion) were included for analysis of sun-safety strategies. All survey respondents were included for analysis of secondary objectives. Responses from parents of infants of mixed racial and ethnic backgrounds were excluded from applicable subgroup analyses.

Results

Ninety-eight parents were approached for participation in the study; 97 consented to participate and 95 completed the survey. Seventy parents had children who were at least 6 months of age and were included for analysis of the primary objectives (ie, sun-protection strategies in the first 6 months of life). The cohort included 49 Hispanic parents, 26 black parents, and 9 NHW parents; 5 parents indicated their child was of mixed racial and ethnic background. Six respondents indicated another minority group (eg, Native American, Pacific Islander). Eighty-three respondents were mothers, 72 were educated beyond high school, and 14 were Spanish-speaking only. Four reported a known family history of skin cancer.

There were notable differences in application of sunscreen, belief in the efficacy of sunscreen, and primary source of information between parents (Tables 1 and 2). Hispanic parents reported applying sunscreen more consistently than black parents (odds ratio, 4.656; 95% confidence interval, 1.154-18.782; P<.01). Hispanic parents also were more likely than black parents to believe sunscreen is effective in the prevention of skin cancers (odds ratio, 7.499; 95% confidence interval, 1.535-36.620; P<.01). Hispanic parents were more likely to report receiving information regarding sun-safety practices for infants from their pediatrician, whereas NHW parents were more likely to follow their instincts regarding how and if infants should be exposed to the sun (P<.05). No significant differences were found in the reported primary source of information in black versus Hispanic parents or in black versus NHW parents. Three percent (3/95) of respondents reported a sunburn in the infant's first 6 months of life, and 12% (11/95) reported tanning of infants' skin from sun exposure. Tanning was associated with inconsistent shade (P<.01), inconsistent clothing coverage (P<.01), and consistently allowing infants to "develop tolerance to the sun's rays by slowly increasing sun exposure each day" (P<.05).

Comment

The survey results indicated suboptimal sun-protection practices among parents of black and Hispanic infants in Miami. Although the majority of respondents (83% [58/70]) reported keeping their infants in the shade, less than half of parents consistently covered their infants adequately with clothing and hats (40% [28/70] and 43% [30/70], respectively). More alarmingly, one-third of parents reported intentionally increasing their infant's level of sun exposure to develop his/her tolerance to the sun. A minority of parents reported sunburns (3%) and tanning (12%) within the first 6 months of life. Twenty-nine percent of parents (20/70) reported consistently applying sunscreen to their infants who were younger than 6 months despite limited safety data available for this age group.

Although our study included a limited sample size and represents a narrow geographic distribution, these results suggest that shortcomings in current practices in sun protection for black and Hispanic infants younger than 6 months may be a widespread problem. Black and Hispanic patients have a lower incidence of skin cancer, but the diagnosis often is delayed and the mortality is higher when skin cancer does occur.⁴ The common perception among laypeople as well as many health care providers that black and Hispanic individuals are not at risk for skin cancer may limit sun-safety counseling as well as the overall knowledge base of this patient demographic. As demonstrated by the results of this study, there is a need for counseling on sun-safe behaviors from a young age among this population.

Conclusion

This study highlights potential shortcomings in current sun-protection practices for black and Hispanic infants younger than 6 months. Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ Additional studies are needed to further define sun-safety behaviors in black and Hispanic children across the United States. Further, additional studies should focus on developing interventions that positively influence sun-safety behaviors in this patient population. 

Sun exposure and sunburns sustained during childhood are linked to an increased risk for development of skin cancers in adulthood. In infants, the skin is particularly vulnerable and is considered to be at increased risk for UV radiation damage,¹ even as early as the first 6 months of life.² Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ To effectively teach parents proper sun-safe practices, it is essential to understand their existing perceptions and behaviors. This study sought to examine differences in infant sun-safety practices during the first 6 months of life among black, Hispanic, and non-Hispanic white (NHW) parents in Miami, Florida.

Methods

Parents presenting to the University of Miami general pediatrics clinic from February 2015 through April 2015 with a child younger than 5 years were administered a 15-item questionnaire that included items on demographics, sun-safety strategies, sunburns and tanning, beliefs and limitations regarding sunscreen, and primary information source regarding sun safety (eg, physician, Internet, media, instincts). Parents were approached by the investigators consecutively for participation in scheduled blocks, with the exception of those who were otherwise engaged in appointment-related tasks (eg, paperwork). The study was approved by the University of Miami Miller School of Medicine institutional review board. The primary objective of this study was to determine the sun protection behaviors that black and Hispanic parents in Miami, Florida, employ in infants younger than 6 months. Secondary objectives included determining if this patient population is at risk for infant sunburns and tanning, beliefs among parents regarding sunscreen's efficacy in the prevention of skin cancers, and limitations of sunscreen use.

All data were analyzed using SAS software version 9.3. Wilcoxon signed rank test, Kruskal-Wallis test, Fisher exact test, and proportional-odds cumulative logit model were used to compare nonparametric data. Parents reporting on the full first 6 months of life (ie, the child was older than 6 months at the time of study completion) were included for analysis of sun-safety strategies. All survey respondents were included for analysis of secondary objectives. Responses from parents of infants of mixed racial and ethnic backgrounds were excluded from applicable subgroup analyses.

Results

Ninety-eight parents were approached for participation in the study; 97 consented to participate and 95 completed the survey. Seventy parents had children who were at least 6 months of age and were included for analysis of the primary objectives (ie, sun-protection strategies in the first 6 months of life). The cohort included 49 Hispanic parents, 26 black parents, and 9 NHW parents; 5 parents indicated their child was of mixed racial and ethnic background. Six respondents indicated another minority group (eg, Native American, Pacific Islander). Eighty-three respondents were mothers, 72 were educated beyond high school, and 14 were Spanish-speaking only. Four reported a known family history of skin cancer.

There were notable differences in application of sunscreen, belief in the efficacy of sunscreen, and primary source of information between parents (Tables 1 and 2). Hispanic parents reported applying sunscreen more consistently than black parents (odds ratio, 4.656; 95% confidence interval, 1.154-18.782; P<.01). Hispanic parents also were more likely than black parents to believe sunscreen is effective in the prevention of skin cancers (odds ratio, 7.499; 95% confidence interval, 1.535-36.620; P<.01). Hispanic parents were more likely to report receiving information regarding sun-safety practices for infants from their pediatrician, whereas NHW parents were more likely to follow their instincts regarding how and if infants should be exposed to the sun (P<.05). No significant differences were found in the reported primary source of information in black versus Hispanic parents or in black versus NHW parents. Three percent (3/95) of respondents reported a sunburn in the infant's first 6 months of life, and 12% (11/95) reported tanning of infants' skin from sun exposure. Tanning was associated with inconsistent shade (P<.01), inconsistent clothing coverage (P<.01), and consistently allowing infants to "develop tolerance to the sun's rays by slowly increasing sun exposure each day" (P<.05).

Comment

The survey results indicated suboptimal sun-protection practices among parents of black and Hispanic infants in Miami. Although the majority of respondents (83% [58/70]) reported keeping their infants in the shade, less than half of parents consistently covered their infants adequately with clothing and hats (40% [28/70] and 43% [30/70], respectively). More alarmingly, one-third of parents reported intentionally increasing their infant's level of sun exposure to develop his/her tolerance to the sun. A minority of parents reported sunburns (3%) and tanning (12%) within the first 6 months of life. Twenty-nine percent of parents (20/70) reported consistently applying sunscreen to their infants who were younger than 6 months despite limited safety data available for this age group.

Although our study included a limited sample size and represents a narrow geographic distribution, these results suggest that shortcomings in current practices in sun protection for black and Hispanic infants younger than 6 months may be a widespread problem. Black and Hispanic patients have a lower incidence of skin cancer, but the diagnosis often is delayed and the mortality is higher when skin cancer does occur.⁴ The common perception among laypeople as well as many health care providers that black and Hispanic individuals are not at risk for skin cancer may limit sun-safety counseling as well as the overall knowledge base of this patient demographic. As demonstrated by the results of this study, there is a need for counseling on sun-safe behaviors from a young age among this population.

Conclusion

This study highlights potential shortcomings in current sun-protection practices for black and Hispanic infants younger than 6 months. Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ Additional studies are needed to further define sun-safety behaviors in black and Hispanic children across the United States. Further, additional studies should focus on developing interventions that positively influence sun-safety behaviors in this patient population. 

Sun exposure and sunburns sustained during childhood are linked to an increased risk for development of skin cancers in adulthood. In infants, the skin is particularly vulnerable and is considered to be at increased risk for UV radiation damage,¹ even as early as the first 6 months of life.² Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ To effectively teach parents proper sun-safe practices, it is essential to understand their existing perceptions and behaviors. This study sought to examine differences in infant sun-safety practices during the first 6 months of life among black, Hispanic, and non-Hispanic white (NHW) parents in Miami, Florida.

Methods

Parents presenting to the University of Miami general pediatrics clinic from February 2015 through April 2015 with a child younger than 5 years were administered a 15-item questionnaire that included items on demographics, sun-safety strategies, sunburns and tanning, beliefs and limitations regarding sunscreen, and primary information source regarding sun safety (eg, physician, Internet, media, instincts). Parents were approached by the investigators consecutively for participation in scheduled blocks, with the exception of those who were otherwise engaged in appointment-related tasks (eg, paperwork). The study was approved by the University of Miami Miller School of Medicine institutional review board. The primary objective of this study was to determine the sun protection behaviors that black and Hispanic parents in Miami, Florida, employ in infants younger than 6 months. Secondary objectives included determining if this patient population is at risk for infant sunburns and tanning, beliefs among parents regarding sunscreen's efficacy in the prevention of skin cancers, and limitations of sunscreen use.

All data were analyzed using SAS software version 9.3. Wilcoxon signed rank test, Kruskal-Wallis test, Fisher exact test, and proportional-odds cumulative logit model were used to compare nonparametric data. Parents reporting on the full first 6 months of life (ie, the child was older than 6 months at the time of study completion) were included for analysis of sun-safety strategies. All survey respondents were included for analysis of secondary objectives. Responses from parents of infants of mixed racial and ethnic backgrounds were excluded from applicable subgroup analyses.

Results

Ninety-eight parents were approached for participation in the study; 97 consented to participate and 95 completed the survey. Seventy parents had children who were at least 6 months of age and were included for analysis of the primary objectives (ie, sun-protection strategies in the first 6 months of life). The cohort included 49 Hispanic parents, 26 black parents, and 9 NHW parents; 5 parents indicated their child was of mixed racial and ethnic background. Six respondents indicated another minority group (eg, Native American, Pacific Islander). Eighty-three respondents were mothers, 72 were educated beyond high school, and 14 were Spanish-speaking only. Four reported a known family history of skin cancer.

There were notable differences in application of sunscreen, belief in the efficacy of sunscreen, and primary source of information between parents (Tables 1 and 2). Hispanic parents reported applying sunscreen more consistently than black parents (odds ratio, 4.656; 95% confidence interval, 1.154-18.782; P<.01). Hispanic parents also were more likely than black parents to believe sunscreen is effective in the prevention of skin cancers (odds ratio, 7.499; 95% confidence interval, 1.535-36.620; P<.01). Hispanic parents were more likely to report receiving information regarding sun-safety practices for infants from their pediatrician, whereas NHW parents were more likely to follow their instincts regarding how and if infants should be exposed to the sun (P<.05). No significant differences were found in the reported primary source of information in black versus Hispanic parents or in black versus NHW parents. Three percent (3/95) of respondents reported a sunburn in the infant's first 6 months of life, and 12% (11/95) reported tanning of infants' skin from sun exposure. Tanning was associated with inconsistent shade (P<.01), inconsistent clothing coverage (P<.01), and consistently allowing infants to "develop tolerance to the sun's rays by slowly increasing sun exposure each day" (P<.05).

Comment

The survey results indicated suboptimal sun-protection practices among parents of black and Hispanic infants in Miami. Although the majority of respondents (83% [58/70]) reported keeping their infants in the shade, less than half of parents consistently covered their infants adequately with clothing and hats (40% [28/70] and 43% [30/70], respectively). More alarmingly, one-third of parents reported intentionally increasing their infant's level of sun exposure to develop his/her tolerance to the sun. A minority of parents reported sunburns (3%) and tanning (12%) within the first 6 months of life. Twenty-nine percent of parents (20/70) reported consistently applying sunscreen to their infants who were younger than 6 months despite limited safety data available for this age group.

Although our study included a limited sample size and represents a narrow geographic distribution, these results suggest that shortcomings in current practices in sun protection for black and Hispanic infants younger than 6 months may be a widespread problem. Black and Hispanic patients have a lower incidence of skin cancer, but the diagnosis often is delayed and the mortality is higher when skin cancer does occur.⁴ The common perception among laypeople as well as many health care providers that black and Hispanic individuals are not at risk for skin cancer may limit sun-safety counseling as well as the overall knowledge base of this patient demographic. As demonstrated by the results of this study, there is a need for counseling on sun-safe behaviors from a young age among this population.

Conclusion

This study highlights potential shortcomings in current sun-protection practices for black and Hispanic infants younger than 6 months. Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ Additional studies are needed to further define sun-safety behaviors in black and Hispanic children across the United States. Further, additional studies should focus on developing interventions that positively influence sun-safety behaviors in this patient population. 

To the Editor:

Serpentine supravenous hyperpigmentation (SSH) is a rare phenomenon characterized by linear hyperpigmentation of the skin overlying veins secondary to intravenous antineoplastic therapy. The term was first suggested by Hrushesky¹ in 1976 as an uncommon side effect of administering intravenous 5-fluorouracil (5-FU). Although 5-FU is the most frequent offending agent, cases involving treatment with actinomycin, cyclophosphamide, docetaxel, fotemustine, nitrogen mustard, nitrosoureas, taxanes, and triazinate, as well as various combinations of chemotherapeutic agents, also have been observed.^2,3 We present the case of SSH following a cisplatin and pemetrexed chemotherapy regimen.

A 52-year-old man with newly diagnosed inoperable adenocarcinoma in the left upper lung lobe received 2 cycles of treatment with cisplatin 138 mg and pemetrexed 920 mg 21 days apart. The first cycle of chemotherapy was delivered intravenously through the left forearm and the second cycle through the right forearm. Each infusion was followed by a 20-cc 0.9% saline flush. The patient developed nausea, vomiting, diarrhea, and hyperpigmentation tracing the path of infusion on the right arm as well as a slight darkness on the left arm that were noted by medical staff. At that time, cisplatin was discontinued from the chemotherapeutic regimen.

A port-a-cath was inserted into the patient’s right upper chest 4 weeks later and was used for subsequent infusions. Carboplatin 450 mg was initiated with pemetrexed thereafter. The patient was seen in the dermatology clinic 3 weeks after the insertion of the port-a-cath for evaluation of diffuse tinea versicolor of the trunk. Further examination of the arms revealed asymptomatic serpiginous hyperpigmentation overlying the superficial venous network tracing from the prior intravenous access points in the bilateral forearms to the upper arms (Figure). There was no evidence of extravasation or phlebitis prior to the hyperpigmentation. The patient was continued on pemetrexed and was subsequently lost to follow-up.

Cisplatin was the first member of the platinum-based chemotherapeutic agent class and is now one of the most potent and widely used in the treatment of solid malignancies. The cytotoxic mode of action is primarily mediated through interaction with DNA to form intrastrand cross-link adducts leading to aberrant mitosis and culminating in the activation of apoptosis. A variety of dermatologic complications have been reported with cisplatin chemotherapy including melanonychia, oral mucosal hyperpigmentation, hypersensitivity reactions, extravasation,⁴ Raynaud phenomenon, and flushing.⁵

Two cases of SSH have been reported following combination chemotherapy with cisplatin included in the regimen. A 61-year-old man with inoperable esophageal squamous cell carcinoma received cisplatin and 5-FU in addition to concurrent radiotherapy.⁶ After worsening renal function, cisplatin promptly was replaced with leucovorin. The patient developed SSH after the eighth infusion of 5-FU–leucovorin delivered through a peripheral catheter over a 24-hour period. The cutaneous side effect was attributed to the use of intravenous 5-FU.⁶ The second case involved a 48-year-old woman diagnosed with Paget disease of the breast who received adjuvant therapy with 12 courses of once-daily 5-FU and docetaxel for 5 years as well as 2 courses of vinorelbine and 1 course of cisplatin and etoposide for lung metastases.⁷ Serpentine supravenous hyperpigmentation lesions slowly developed over approximately 6 months. Based on the literature, the authors speculated that 5-FU and vinorelbine were most likely to be responsible. They noted, however, the inability to clarify the relationship between the onset of skin lesions and the time course of the chemotherapy.⁷ Although these cases do not directly implicate cisplatin as the cause of SSH, the possibility of a delayed reaction or augmentation of another drug’s effect cannot be excluded.

Pemetrexed, on the other hand, has not been associated with SSH. Several cutaneous adverse reactions have been reported, including acute generalized exanthematous pustulosis, alopecia, pityriasis lichenoides, radiation recall dermatitis, toxic epidermal necrolysis, and urticarial vasculitis.⁸ Three cases of pemetrexed-induced skin hyperpigmentation including the palms of the hands and soles of the feet as well as diffuse hyperpigmentation sparing only the palms and soles have been reported.^8-10

Similar cases of SSH have demonstrated histopathologic findings with increased basal melanin synthesis and occasional melanophages in the papillary dermis without inflammatory changes.^7,11 Although the unique serpentine pattern of hyperpigmentation is instantly recognizable, clinical differential diagnosis may include thrombophlebitis, cutis marmorata, erythema ab igne, livedo reticularis, and lichen planus.^2,12

The exact mechanism of SSH has not been conclusively elucidated. Several studies postulate that direct cytotoxic damage causes loss of endothelial integrity permitting the extravasation of the agent to the overlying epidermis and interfering with melanogenesis.^2,6,11 Other hypotheses include direct stimulation of melanocytes, depletion of reduced thioredoxin leading to tyrosinase stimulation, hyperthermia-related changes including reduced cytokine production and/or increased expression of melanocyte-stimulating hormone receptor, subclinical phlebitis leading to postinflammatory hyperpigmentation, or hyperpigmentation secondary to increased blood flow in certain areas and therefore increased drug deposition.^12,13

Currently, there is no specific therapy recommended for SSH and the pigment may persist anywhere from a few months to more than a year after completing chemotherapy.^2,7 Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.¹² Several authors have suggested avoiding peripheral infusions of chemotherapeutic agents known to cause SSH or have recommended using a permanent central venous catheter.^6,7 Another option, which needs further investigation, is the administration of an abundant flush following chemotherapy. This technique was described in a case report of a 47-year-old man who developed persistent SSH in the right forearm following docetaxel injection.¹³ Copious venous washing with 1000 mL of isotonic saline solution following the second infusion in the unaffected arm prevented discoloration. The lack of subsequent reaction may support the theory that direct toxic effect on the vascular endothelium results in hyperpigmentation of the supravenous skin.¹³

Serpentine supravenous hyperpigmentation is an uncommon cutaneous reaction secondary to antineoplastic therapies. Given the widespread use of chemotherapeutic regimens, dermatologists should be aware of the reaction. Additional studies are warranted to better elucidate the pathogenesis and investigate how infusion techniques might aid in the prevention of skin discoloration. Although this side effect originally was described in relation to 5-FU, subsequent observations have included other chemotherapeutic agents. In light of the findings presented in this report, cisplatin and pemetrexed should be considered on the list of offending agents. Ultimately, patients should be reassured that the lesions are benign, self-limiting, and gradually resolve on their own in most cases.¹²

To the Editor:

Serpentine supravenous hyperpigmentation (SSH) is a rare phenomenon characterized by linear hyperpigmentation of the skin overlying veins secondary to intravenous antineoplastic therapy. The term was first suggested by Hrushesky¹ in 1976 as an uncommon side effect of administering intravenous 5-fluorouracil (5-FU). Although 5-FU is the most frequent offending agent, cases involving treatment with actinomycin, cyclophosphamide, docetaxel, fotemustine, nitrogen mustard, nitrosoureas, taxanes, and triazinate, as well as various combinations of chemotherapeutic agents, also have been observed.^2,3 We present the case of SSH following a cisplatin and pemetrexed chemotherapy regimen.

A 52-year-old man with newly diagnosed inoperable adenocarcinoma in the left upper lung lobe received 2 cycles of treatment with cisplatin 138 mg and pemetrexed 920 mg 21 days apart. The first cycle of chemotherapy was delivered intravenously through the left forearm and the second cycle through the right forearm. Each infusion was followed by a 20-cc 0.9% saline flush. The patient developed nausea, vomiting, diarrhea, and hyperpigmentation tracing the path of infusion on the right arm as well as a slight darkness on the left arm that were noted by medical staff. At that time, cisplatin was discontinued from the chemotherapeutic regimen.

A port-a-cath was inserted into the patient’s right upper chest 4 weeks later and was used for subsequent infusions. Carboplatin 450 mg was initiated with pemetrexed thereafter. The patient was seen in the dermatology clinic 3 weeks after the insertion of the port-a-cath for evaluation of diffuse tinea versicolor of the trunk. Further examination of the arms revealed asymptomatic serpiginous hyperpigmentation overlying the superficial venous network tracing from the prior intravenous access points in the bilateral forearms to the upper arms (Figure). There was no evidence of extravasation or phlebitis prior to the hyperpigmentation. The patient was continued on pemetrexed and was subsequently lost to follow-up.

Cisplatin was the first member of the platinum-based chemotherapeutic agent class and is now one of the most potent and widely used in the treatment of solid malignancies. The cytotoxic mode of action is primarily mediated through interaction with DNA to form intrastrand cross-link adducts leading to aberrant mitosis and culminating in the activation of apoptosis. A variety of dermatologic complications have been reported with cisplatin chemotherapy including melanonychia, oral mucosal hyperpigmentation, hypersensitivity reactions, extravasation,⁴ Raynaud phenomenon, and flushing.⁵

Two cases of SSH have been reported following combination chemotherapy with cisplatin included in the regimen. A 61-year-old man with inoperable esophageal squamous cell carcinoma received cisplatin and 5-FU in addition to concurrent radiotherapy.⁶ After worsening renal function, cisplatin promptly was replaced with leucovorin. The patient developed SSH after the eighth infusion of 5-FU–leucovorin delivered through a peripheral catheter over a 24-hour period. The cutaneous side effect was attributed to the use of intravenous 5-FU.⁶ The second case involved a 48-year-old woman diagnosed with Paget disease of the breast who received adjuvant therapy with 12 courses of once-daily 5-FU and docetaxel for 5 years as well as 2 courses of vinorelbine and 1 course of cisplatin and etoposide for lung metastases.⁷ Serpentine supravenous hyperpigmentation lesions slowly developed over approximately 6 months. Based on the literature, the authors speculated that 5-FU and vinorelbine were most likely to be responsible. They noted, however, the inability to clarify the relationship between the onset of skin lesions and the time course of the chemotherapy.⁷ Although these cases do not directly implicate cisplatin as the cause of SSH, the possibility of a delayed reaction or augmentation of another drug’s effect cannot be excluded.

Pemetrexed, on the other hand, has not been associated with SSH. Several cutaneous adverse reactions have been reported, including acute generalized exanthematous pustulosis, alopecia, pityriasis lichenoides, radiation recall dermatitis, toxic epidermal necrolysis, and urticarial vasculitis.⁸ Three cases of pemetrexed-induced skin hyperpigmentation including the palms of the hands and soles of the feet as well as diffuse hyperpigmentation sparing only the palms and soles have been reported.^8-10

Similar cases of SSH have demonstrated histopathologic findings with increased basal melanin synthesis and occasional melanophages in the papillary dermis without inflammatory changes.^7,11 Although the unique serpentine pattern of hyperpigmentation is instantly recognizable, clinical differential diagnosis may include thrombophlebitis, cutis marmorata, erythema ab igne, livedo reticularis, and lichen planus.^2,12

The exact mechanism of SSH has not been conclusively elucidated. Several studies postulate that direct cytotoxic damage causes loss of endothelial integrity permitting the extravasation of the agent to the overlying epidermis and interfering with melanogenesis.^2,6,11 Other hypotheses include direct stimulation of melanocytes, depletion of reduced thioredoxin leading to tyrosinase stimulation, hyperthermia-related changes including reduced cytokine production and/or increased expression of melanocyte-stimulating hormone receptor, subclinical phlebitis leading to postinflammatory hyperpigmentation, or hyperpigmentation secondary to increased blood flow in certain areas and therefore increased drug deposition.^12,13

Currently, there is no specific therapy recommended for SSH and the pigment may persist anywhere from a few months to more than a year after completing chemotherapy.^2,7 Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.¹² Several authors have suggested avoiding peripheral infusions of chemotherapeutic agents known to cause SSH or have recommended using a permanent central venous catheter.^6,7 Another option, which needs further investigation, is the administration of an abundant flush following chemotherapy. This technique was described in a case report of a 47-year-old man who developed persistent SSH in the right forearm following docetaxel injection.¹³ Copious venous washing with 1000 mL of isotonic saline solution following the second infusion in the unaffected arm prevented discoloration. The lack of subsequent reaction may support the theory that direct toxic effect on the vascular endothelium results in hyperpigmentation of the supravenous skin.¹³

Serpentine supravenous hyperpigmentation is an uncommon cutaneous reaction secondary to antineoplastic therapies. Given the widespread use of chemotherapeutic regimens, dermatologists should be aware of the reaction. Additional studies are warranted to better elucidate the pathogenesis and investigate how infusion techniques might aid in the prevention of skin discoloration. Although this side effect originally was described in relation to 5-FU, subsequent observations have included other chemotherapeutic agents. In light of the findings presented in this report, cisplatin and pemetrexed should be considered on the list of offending agents. Ultimately, patients should be reassured that the lesions are benign, self-limiting, and gradually resolve on their own in most cases.¹²

To the Editor:

Serpentine supravenous hyperpigmentation (SSH) is a rare phenomenon characterized by linear hyperpigmentation of the skin overlying veins secondary to intravenous antineoplastic therapy. The term was first suggested by Hrushesky¹ in 1976 as an uncommon side effect of administering intravenous 5-fluorouracil (5-FU). Although 5-FU is the most frequent offending agent, cases involving treatment with actinomycin, cyclophosphamide, docetaxel, fotemustine, nitrogen mustard, nitrosoureas, taxanes, and triazinate, as well as various combinations of chemotherapeutic agents, also have been observed.^2,3 We present the case of SSH following a cisplatin and pemetrexed chemotherapy regimen.

A 52-year-old man with newly diagnosed inoperable adenocarcinoma in the left upper lung lobe received 2 cycles of treatment with cisplatin 138 mg and pemetrexed 920 mg 21 days apart. The first cycle of chemotherapy was delivered intravenously through the left forearm and the second cycle through the right forearm. Each infusion was followed by a 20-cc 0.9% saline flush. The patient developed nausea, vomiting, diarrhea, and hyperpigmentation tracing the path of infusion on the right arm as well as a slight darkness on the left arm that were noted by medical staff. At that time, cisplatin was discontinued from the chemotherapeutic regimen.

A port-a-cath was inserted into the patient’s right upper chest 4 weeks later and was used for subsequent infusions. Carboplatin 450 mg was initiated with pemetrexed thereafter. The patient was seen in the dermatology clinic 3 weeks after the insertion of the port-a-cath for evaluation of diffuse tinea versicolor of the trunk. Further examination of the arms revealed asymptomatic serpiginous hyperpigmentation overlying the superficial venous network tracing from the prior intravenous access points in the bilateral forearms to the upper arms (Figure). There was no evidence of extravasation or phlebitis prior to the hyperpigmentation. The patient was continued on pemetrexed and was subsequently lost to follow-up.

Cisplatin was the first member of the platinum-based chemotherapeutic agent class and is now one of the most potent and widely used in the treatment of solid malignancies. The cytotoxic mode of action is primarily mediated through interaction with DNA to form intrastrand cross-link adducts leading to aberrant mitosis and culminating in the activation of apoptosis. A variety of dermatologic complications have been reported with cisplatin chemotherapy including melanonychia, oral mucosal hyperpigmentation, hypersensitivity reactions, extravasation,⁴ Raynaud phenomenon, and flushing.⁵

Two cases of SSH have been reported following combination chemotherapy with cisplatin included in the regimen. A 61-year-old man with inoperable esophageal squamous cell carcinoma received cisplatin and 5-FU in addition to concurrent radiotherapy.⁶ After worsening renal function, cisplatin promptly was replaced with leucovorin. The patient developed SSH after the eighth infusion of 5-FU–leucovorin delivered through a peripheral catheter over a 24-hour period. The cutaneous side effect was attributed to the use of intravenous 5-FU.⁶ The second case involved a 48-year-old woman diagnosed with Paget disease of the breast who received adjuvant therapy with 12 courses of once-daily 5-FU and docetaxel for 5 years as well as 2 courses of vinorelbine and 1 course of cisplatin and etoposide for lung metastases.⁷ Serpentine supravenous hyperpigmentation lesions slowly developed over approximately 6 months. Based on the literature, the authors speculated that 5-FU and vinorelbine were most likely to be responsible. They noted, however, the inability to clarify the relationship between the onset of skin lesions and the time course of the chemotherapy.⁷ Although these cases do not directly implicate cisplatin as the cause of SSH, the possibility of a delayed reaction or augmentation of another drug’s effect cannot be excluded.

Pemetrexed, on the other hand, has not been associated with SSH. Several cutaneous adverse reactions have been reported, including acute generalized exanthematous pustulosis, alopecia, pityriasis lichenoides, radiation recall dermatitis, toxic epidermal necrolysis, and urticarial vasculitis.⁸ Three cases of pemetrexed-induced skin hyperpigmentation including the palms of the hands and soles of the feet as well as diffuse hyperpigmentation sparing only the palms and soles have been reported.^8-10

Similar cases of SSH have demonstrated histopathologic findings with increased basal melanin synthesis and occasional melanophages in the papillary dermis without inflammatory changes.^7,11 Although the unique serpentine pattern of hyperpigmentation is instantly recognizable, clinical differential diagnosis may include thrombophlebitis, cutis marmorata, erythema ab igne, livedo reticularis, and lichen planus.^2,12

The exact mechanism of SSH has not been conclusively elucidated. Several studies postulate that direct cytotoxic damage causes loss of endothelial integrity permitting the extravasation of the agent to the overlying epidermis and interfering with melanogenesis.^2,6,11 Other hypotheses include direct stimulation of melanocytes, depletion of reduced thioredoxin leading to tyrosinase stimulation, hyperthermia-related changes including reduced cytokine production and/or increased expression of melanocyte-stimulating hormone receptor, subclinical phlebitis leading to postinflammatory hyperpigmentation, or hyperpigmentation secondary to increased blood flow in certain areas and therefore increased drug deposition.^12,13

Currently, there is no specific therapy recommended for SSH and the pigment may persist anywhere from a few months to more than a year after completing chemotherapy.^2,7 Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.¹² Several authors have suggested avoiding peripheral infusions of chemotherapeutic agents known to cause SSH or have recommended using a permanent central venous catheter.^6,7 Another option, which needs further investigation, is the administration of an abundant flush following chemotherapy. This technique was described in a case report of a 47-year-old man who developed persistent SSH in the right forearm following docetaxel injection.¹³ Copious venous washing with 1000 mL of isotonic saline solution following the second infusion in the unaffected arm prevented discoloration. The lack of subsequent reaction may support the theory that direct toxic effect on the vascular endothelium results in hyperpigmentation of the supravenous skin.¹³

Serpentine supravenous hyperpigmentation is an uncommon cutaneous reaction secondary to antineoplastic therapies. Given the widespread use of chemotherapeutic regimens, dermatologists should be aware of the reaction. Additional studies are warranted to better elucidate the pathogenesis and investigate how infusion techniques might aid in the prevention of skin discoloration. Although this side effect originally was described in relation to 5-FU, subsequent observations have included other chemotherapeutic agents. In light of the findings presented in this report, cisplatin and pemetrexed should be considered on the list of offending agents. Ultimately, patients should be reassured that the lesions are benign, self-limiting, and gradually resolve on their own in most cases.¹²

Since the serendipitous discovery of expedited involution of infantile hemangiomas (IHs) with propranolol in 2008,¹ current research has proliferated to discern the mechanism of action of beta-blockers in the care of IHs. Propranolol is a nonselective beta-blocker with a structure similar to catecholamines and thus competes for β-adrenergic receptors. Blocking β₁-receptors is cardioselective, leading to decreased heart rate and myocardial contractility, while blocking β₂-receptors leads to inhibition of smooth muscle relaxation and decreased glycogenolysis. The endothelial cells of IH express β₂-adrenergic receptors; the mechanistic role of propranolol in these lesions is surmised to be due to vasoconstriction, decreased angiogenesis through inhibition of vascular endothelial growth factor, and subsequent endothelial cell apoptosis.²

After this breakthrough finding, a subsequent novel development was made when an ophthalmologist demonstrated that timolol, a topical beta-blocker, could be utilized to expedite IH involution and prevent ocular complications such as amblyopia secondary to the mass effect of the lesion. Guo and Ni³ prescribed the commercially available ophthalmologic solution of timolol maleate 0.5% for twice-daily use for 5 weeks. Remarkable reduction in the periorbital IH without rebound phenomenon was observed.³ A recent multicenter retrospective cohort of more than 700 patients with IH were treated with topical timolol with a 70% success rate, corresponding to 10% improvement from baseline; this study highlights the efficacy of timolol while confirming the safety of the medication.⁴

Systemic beta-blockers for IH have been used predominately for critical sites such as the nasal tip, lip, ear, perineum, and periocular area; ulcerated lesions or those that may be prone to leave a fibrofatty tissue residue after involution also have been targeted. Contraindications for use include premature infants younger than 5 weeks, infants weighing less than 2 kg, history of asthma or bronchospasm, heart rate less than 80 beats per minute, blood pressure less than 50/30 mm Hg, or hypersensitivity to the medication.⁵ Current guidelines for propranolol initiation vary; some dermatologists consult cardiology prior to initiation, while others perform routine vitals and an indication-driven electrocardiogram as needed based on family history of cardiac disease, maternal history of connective tissue disease, congenital heart block, or abnormal vital signs.

Given the demonstrated long-term safety of propranolol and the acceptable side-effect profile, the use of beta-blockers for IH has become increasingly mainstream. Three randomized controlled trials (RCTs) have evaluated the efficacy and minimal adverse effects of propranolol for IH. The first RCT evaluated 40 patients who received either placebo or propranolol 2 mg/kg daily (divided into 3 doses) for 6 months; IH growth stopped by week 4 in the treatment group and the largest volume difference in IH was seen at week 12.⁶ Léauté-Labrèze et al⁷ demonstrated that propranolol could be given earlier to patients and at higher doses; the treatment group included 7 patients at 3 mg/kg daily of propranolol for 15 days, followed by 15 additional days of 4 mg/kg daily of propranolol. A statistically significant (P=.004) decrease in IH volume, quantified by use of ultrasonography, was exhibited by the propranolol group.⁷ Lastly, the largest RCT (N=456) established the efficacy of propranolol 3 mg/kg daily for 6 months with a 60% successful treatment rate compared to 4% for patients receiving placebo.⁸

Given the efficacy of propranolol for IH, other investigators have experimented with nonselective beta-blockers for other dermatologic conditions. In addition to second-line use for flushing, hyperhidrosis, and adrenergic urticaria, the future of propranolol is expanding for vascular lesions in particular.⁹ Chow et al¹⁰ highlighted a case of progressive angiosarcoma of the scalp that responded to propranolol hydrochloride therapy at 40 mg 3 times daily with extensive regression; propranolol was given in addition to chemotherapy and radiation. The tumor was biopsied before and after propranolol therapy and exhibited a 34% decrease in the proliferative index (Ki-67).¹⁰ Interestingly, Chisholm et al¹¹ evaluated the expression of β-adrenergic expression in 141 vascular lesions; endothelial cell expression of β₂-adrenergic receptors was found positive in 100% of IHs, 67% of kaposiform hemangioendotheliomas, 41% of angiosarcomas, 50% of pyogenic granulomas, and 75% of Kaposi sarcomas, to name merely a few studied lesions.

These data have spurred physicians to further seek beta-blocker dermatologic use in specific patient populations. For example, Meseguer-Yebra et al¹² employed timolol solution 0.5% twice daily for 12 weeks for 2 human immunodeficiency virus–negative patients with limited Kaposi sarcoma of the right thigh and foot; no clinical evidence of recurrence was seen at 20 months, and one of the patients had a subsequent biopsy performed with negative human herpesvirus 8 staining after therapy. In the pediatric arena, topical timolol has been used for both port-wine stains and pyogenic granulomas.^13-15 Two lesions of pyogenic granulomas on the scalp of a child were treated with timolol ophthalmic solution 0.5% under occlusion for 4 weeks with resolution.¹⁵ Propranolol also has been utilized as adjunctive therapy for aggressive pediatric vascular lesions such as kaposiform hemangioendothelioma with promising results and additionally reducing the duration of therapy needed with vincristine.²

In summary, propranolol and timolol have made an indelible impression on the field of pediatric dermatology and have demonstrated a burgeoning role in the dermatologic arena. The use of nonselective beta-blockers for the management of vascular lesions can serve as adjunctive or monotherapy for certain patient populations. The relatively low adverse risk profile of propranolol makes it a versatile tool to use both systemically and topically. Although the authors of the study assessing the β₂-adrenergic expression in vascular lesions admittedly stated that the positivity of the receptors does not necessarily correlate with therapeutic management, it is an interesting subject area with much potential in the future.¹¹ This review serves to illuminate the expanding role of beta-blockers in dermatology.

Since the serendipitous discovery of expedited involution of infantile hemangiomas (IHs) with propranolol in 2008,¹ current research has proliferated to discern the mechanism of action of beta-blockers in the care of IHs. Propranolol is a nonselective beta-blocker with a structure similar to catecholamines and thus competes for β-adrenergic receptors. Blocking β₁-receptors is cardioselective, leading to decreased heart rate and myocardial contractility, while blocking β₂-receptors leads to inhibition of smooth muscle relaxation and decreased glycogenolysis. The endothelial cells of IH express β₂-adrenergic receptors; the mechanistic role of propranolol in these lesions is surmised to be due to vasoconstriction, decreased angiogenesis through inhibition of vascular endothelial growth factor, and subsequent endothelial cell apoptosis.²

After this breakthrough finding, a subsequent novel development was made when an ophthalmologist demonstrated that timolol, a topical beta-blocker, could be utilized to expedite IH involution and prevent ocular complications such as amblyopia secondary to the mass effect of the lesion. Guo and Ni³ prescribed the commercially available ophthalmologic solution of timolol maleate 0.5% for twice-daily use for 5 weeks. Remarkable reduction in the periorbital IH without rebound phenomenon was observed.³ A recent multicenter retrospective cohort of more than 700 patients with IH were treated with topical timolol with a 70% success rate, corresponding to 10% improvement from baseline; this study highlights the efficacy of timolol while confirming the safety of the medication.⁴

Systemic beta-blockers for IH have been used predominately for critical sites such as the nasal tip, lip, ear, perineum, and periocular area; ulcerated lesions or those that may be prone to leave a fibrofatty tissue residue after involution also have been targeted. Contraindications for use include premature infants younger than 5 weeks, infants weighing less than 2 kg, history of asthma or bronchospasm, heart rate less than 80 beats per minute, blood pressure less than 50/30 mm Hg, or hypersensitivity to the medication.⁵ Current guidelines for propranolol initiation vary; some dermatologists consult cardiology prior to initiation, while others perform routine vitals and an indication-driven electrocardiogram as needed based on family history of cardiac disease, maternal history of connective tissue disease, congenital heart block, or abnormal vital signs.

Given the demonstrated long-term safety of propranolol and the acceptable side-effect profile, the use of beta-blockers for IH has become increasingly mainstream. Three randomized controlled trials (RCTs) have evaluated the efficacy and minimal adverse effects of propranolol for IH. The first RCT evaluated 40 patients who received either placebo or propranolol 2 mg/kg daily (divided into 3 doses) for 6 months; IH growth stopped by week 4 in the treatment group and the largest volume difference in IH was seen at week 12.⁶ Léauté-Labrèze et al⁷ demonstrated that propranolol could be given earlier to patients and at higher doses; the treatment group included 7 patients at 3 mg/kg daily of propranolol for 15 days, followed by 15 additional days of 4 mg/kg daily of propranolol. A statistically significant (P=.004) decrease in IH volume, quantified by use of ultrasonography, was exhibited by the propranolol group.⁷ Lastly, the largest RCT (N=456) established the efficacy of propranolol 3 mg/kg daily for 6 months with a 60% successful treatment rate compared to 4% for patients receiving placebo.⁸

Given the efficacy of propranolol for IH, other investigators have experimented with nonselective beta-blockers for other dermatologic conditions. In addition to second-line use for flushing, hyperhidrosis, and adrenergic urticaria, the future of propranolol is expanding for vascular lesions in particular.⁹ Chow et al¹⁰ highlighted a case of progressive angiosarcoma of the scalp that responded to propranolol hydrochloride therapy at 40 mg 3 times daily with extensive regression; propranolol was given in addition to chemotherapy and radiation. The tumor was biopsied before and after propranolol therapy and exhibited a 34% decrease in the proliferative index (Ki-67).¹⁰ Interestingly, Chisholm et al¹¹ evaluated the expression of β-adrenergic expression in 141 vascular lesions; endothelial cell expression of β₂-adrenergic receptors was found positive in 100% of IHs, 67% of kaposiform hemangioendotheliomas, 41% of angiosarcomas, 50% of pyogenic granulomas, and 75% of Kaposi sarcomas, to name merely a few studied lesions.

These data have spurred physicians to further seek beta-blocker dermatologic use in specific patient populations. For example, Meseguer-Yebra et al¹² employed timolol solution 0.5% twice daily for 12 weeks for 2 human immunodeficiency virus–negative patients with limited Kaposi sarcoma of the right thigh and foot; no clinical evidence of recurrence was seen at 20 months, and one of the patients had a subsequent biopsy performed with negative human herpesvirus 8 staining after therapy. In the pediatric arena, topical timolol has been used for both port-wine stains and pyogenic granulomas.^13-15 Two lesions of pyogenic granulomas on the scalp of a child were treated with timolol ophthalmic solution 0.5% under occlusion for 4 weeks with resolution.¹⁵ Propranolol also has been utilized as adjunctive therapy for aggressive pediatric vascular lesions such as kaposiform hemangioendothelioma with promising results and additionally reducing the duration of therapy needed with vincristine.²

In summary, propranolol and timolol have made an indelible impression on the field of pediatric dermatology and have demonstrated a burgeoning role in the dermatologic arena. The use of nonselective beta-blockers for the management of vascular lesions can serve as adjunctive or monotherapy for certain patient populations. The relatively low adverse risk profile of propranolol makes it a versatile tool to use both systemically and topically. Although the authors of the study assessing the β₂-adrenergic expression in vascular lesions admittedly stated that the positivity of the receptors does not necessarily correlate with therapeutic management, it is an interesting subject area with much potential in the future.¹¹ This review serves to illuminate the expanding role of beta-blockers in dermatology.

Since the serendipitous discovery of expedited involution of infantile hemangiomas (IHs) with propranolol in 2008,¹ current research has proliferated to discern the mechanism of action of beta-blockers in the care of IHs. Propranolol is a nonselective beta-blocker with a structure similar to catecholamines and thus competes for β-adrenergic receptors. Blocking β₁-receptors is cardioselective, leading to decreased heart rate and myocardial contractility, while blocking β₂-receptors leads to inhibition of smooth muscle relaxation and decreased glycogenolysis. The endothelial cells of IH express β₂-adrenergic receptors; the mechanistic role of propranolol in these lesions is surmised to be due to vasoconstriction, decreased angiogenesis through inhibition of vascular endothelial growth factor, and subsequent endothelial cell apoptosis.²

After this breakthrough finding, a subsequent novel development was made when an ophthalmologist demonstrated that timolol, a topical beta-blocker, could be utilized to expedite IH involution and prevent ocular complications such as amblyopia secondary to the mass effect of the lesion. Guo and Ni³ prescribed the commercially available ophthalmologic solution of timolol maleate 0.5% for twice-daily use for 5 weeks. Remarkable reduction in the periorbital IH without rebound phenomenon was observed.³ A recent multicenter retrospective cohort of more than 700 patients with IH were treated with topical timolol with a 70% success rate, corresponding to 10% improvement from baseline; this study highlights the efficacy of timolol while confirming the safety of the medication.⁴

Systemic beta-blockers for IH have been used predominately for critical sites such as the nasal tip, lip, ear, perineum, and periocular area; ulcerated lesions or those that may be prone to leave a fibrofatty tissue residue after involution also have been targeted. Contraindications for use include premature infants younger than 5 weeks, infants weighing less than 2 kg, history of asthma or bronchospasm, heart rate less than 80 beats per minute, blood pressure less than 50/30 mm Hg, or hypersensitivity to the medication.⁵ Current guidelines for propranolol initiation vary; some dermatologists consult cardiology prior to initiation, while others perform routine vitals and an indication-driven electrocardiogram as needed based on family history of cardiac disease, maternal history of connective tissue disease, congenital heart block, or abnormal vital signs.

Given the demonstrated long-term safety of propranolol and the acceptable side-effect profile, the use of beta-blockers for IH has become increasingly mainstream. Three randomized controlled trials (RCTs) have evaluated the efficacy and minimal adverse effects of propranolol for IH. The first RCT evaluated 40 patients who received either placebo or propranolol 2 mg/kg daily (divided into 3 doses) for 6 months; IH growth stopped by week 4 in the treatment group and the largest volume difference in IH was seen at week 12.⁶ Léauté-Labrèze et al⁷ demonstrated that propranolol could be given earlier to patients and at higher doses; the treatment group included 7 patients at 3 mg/kg daily of propranolol for 15 days, followed by 15 additional days of 4 mg/kg daily of propranolol. A statistically significant (P=.004) decrease in IH volume, quantified by use of ultrasonography, was exhibited by the propranolol group.⁷ Lastly, the largest RCT (N=456) established the efficacy of propranolol 3 mg/kg daily for 6 months with a 60% successful treatment rate compared to 4% for patients receiving placebo.⁸

Given the efficacy of propranolol for IH, other investigators have experimented with nonselective beta-blockers for other dermatologic conditions. In addition to second-line use for flushing, hyperhidrosis, and adrenergic urticaria, the future of propranolol is expanding for vascular lesions in particular.⁹ Chow et al¹⁰ highlighted a case of progressive angiosarcoma of the scalp that responded to propranolol hydrochloride therapy at 40 mg 3 times daily with extensive regression; propranolol was given in addition to chemotherapy and radiation. The tumor was biopsied before and after propranolol therapy and exhibited a 34% decrease in the proliferative index (Ki-67).¹⁰ Interestingly, Chisholm et al¹¹ evaluated the expression of β-adrenergic expression in 141 vascular lesions; endothelial cell expression of β₂-adrenergic receptors was found positive in 100% of IHs, 67% of kaposiform hemangioendotheliomas, 41% of angiosarcomas, 50% of pyogenic granulomas, and 75% of Kaposi sarcomas, to name merely a few studied lesions.

These data have spurred physicians to further seek beta-blocker dermatologic use in specific patient populations. For example, Meseguer-Yebra et al¹² employed timolol solution 0.5% twice daily for 12 weeks for 2 human immunodeficiency virus–negative patients with limited Kaposi sarcoma of the right thigh and foot; no clinical evidence of recurrence was seen at 20 months, and one of the patients had a subsequent biopsy performed with negative human herpesvirus 8 staining after therapy. In the pediatric arena, topical timolol has been used for both port-wine stains and pyogenic granulomas.^13-15 Two lesions of pyogenic granulomas on the scalp of a child were treated with timolol ophthalmic solution 0.5% under occlusion for 4 weeks with resolution.¹⁵ Propranolol also has been utilized as adjunctive therapy for aggressive pediatric vascular lesions such as kaposiform hemangioendothelioma with promising results and additionally reducing the duration of therapy needed with vincristine.²

In summary, propranolol and timolol have made an indelible impression on the field of pediatric dermatology and have demonstrated a burgeoning role in the dermatologic arena. The use of nonselective beta-blockers for the management of vascular lesions can serve as adjunctive or monotherapy for certain patient populations. The relatively low adverse risk profile of propranolol makes it a versatile tool to use both systemically and topically. Although the authors of the study assessing the β₂-adrenergic expression in vascular lesions admittedly stated that the positivity of the receptors does not necessarily correlate with therapeutic management, it is an interesting subject area with much potential in the future.¹¹ This review serves to illuminate the expanding role of beta-blockers in dermatology.

To improve patient care and outcomes, leading dermatologists offered their recommendations on products for sensitive skin. Consideration must be given to:

• Avène Cicalfate Restorative Skin Cream
  Pierre Fabre Dermo-Cosmetique USA
  “Sucralfate for speeding up skin repair and the soothing thermal spring waters found in this product make it perfect postprocedure for immediately cooling and calming the skin.”—Jeannette Graf, MD, New York, New York

• Cetaphil RestoraDerm Eczema Calming Body Moisturizer
  Galderma Laboratories, LP
  “This product is formulated for atopic skin. I personally use it on my face as a moisturizer during the cold New York City winter.”—Anthony M. Rossi, MD, New York, New York

• Vanicream
  Pharmaceutical Specialties, Inc
  “I recommend Vanicream brand products to patients with sensitive skin or eczema. These products are fragrance free and have minimal ingredients.”— Gary Goldenberg, MD, New York, New York

Cutis invites readers to send us their recommendations. Athlete's foot treatments, cleansing devices, redness-reducing products, and face scrubs will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on products for sensitive skin. Consideration must be given to:

• Avène Cicalfate Restorative Skin Cream
  Pierre Fabre Dermo-Cosmetique USA
  “Sucralfate for speeding up skin repair and the soothing thermal spring waters found in this product make it perfect postprocedure for immediately cooling and calming the skin.”—Jeannette Graf, MD, New York, New York

• Cetaphil RestoraDerm Eczema Calming Body Moisturizer
  Galderma Laboratories, LP
  “This product is formulated for atopic skin. I personally use it on my face as a moisturizer during the cold New York City winter.”—Anthony M. Rossi, MD, New York, New York

• Vanicream
  Pharmaceutical Specialties, Inc
  “I recommend Vanicream brand products to patients with sensitive skin or eczema. These products are fragrance free and have minimal ingredients.”— Gary Goldenberg, MD, New York, New York

Cutis invites readers to send us their recommendations. Athlete's foot treatments, cleansing devices, redness-reducing products, and face scrubs will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on products for sensitive skin. Consideration must be given to:

• Avène Cicalfate Restorative Skin Cream
  Pierre Fabre Dermo-Cosmetique USA
  “Sucralfate for speeding up skin repair and the soothing thermal spring waters found in this product make it perfect postprocedure for immediately cooling and calming the skin.”—Jeannette Graf, MD, New York, New York

• Cetaphil RestoraDerm Eczema Calming Body Moisturizer
  Galderma Laboratories, LP
  “This product is formulated for atopic skin. I personally use it on my face as a moisturizer during the cold New York City winter.”—Anthony M. Rossi, MD, New York, New York

• Vanicream
  Pharmaceutical Specialties, Inc
  “I recommend Vanicream brand products to patients with sensitive skin or eczema. These products are fragrance free and have minimal ingredients.”— Gary Goldenberg, MD, New York, New York

Cutis invites readers to send us their recommendations. Athlete's foot treatments, cleansing devices, redness-reducing products, and face scrubs will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.