Nonmelanoma Skin Cancer

Dermoscopic examination has been proven to increase diagnostic accuracy and decrease unnecessary biopsies of both melanoma and nonmelanoma skin cancers.^1,2 Digital dermoscopy refers to acquiring and storing digital dermoscopic photographs via digital camera, smart image capture devices such as smartphones and tablets, or any other devices used for image acquisition. The stored images may then be used in a variety of ways, including sequential digital monitoring, teledermoscopy, and machine learning.

Sequential Digital Monitoring

Sequential digital dermoscopy imaging (SDDI) is the capture and storage of dermoscopic images of suspicious lesions that are then monitored over time for changes. Studies have shown that SDDI allows for early detection of melanomas and leads to a decrease in the number of unnecessary excisions.^3,4 A meta-analysis of SDDI found that the chance of detecting melanoma increased with the length of monitoring, which suggests that continued follow-up, especially in high-risk groups, is crucial.⁴

Teledermoscopy

Teledermatology (telederm) is on the rise in the United States, with the number of programs and consultations increasing yearly. One study showed a 48% increase in telederm programs in the last 5 years.⁵ Studies have shown the addition of digital dermoscopic images improved the diagnostic accuracy in telederm skin cancer screenings versus clinical images alone.^6,7

Telederm currently is practiced in 2 main models: live-interactive video consultation and storage of images for future consultation (store and forward). Medicare currently only reimburses live-interactive telederm for patients in nonmetropolitan areas and store-and-forward telederm pilot programs in Alaska and Hawaii; however, Medicaid does reimburse for store and forward in a handful of states.8 Similar to dermatoscope use during clinical examination, there currently is no additional reimbursement for teledermoscopy. Of note, a willingness-to-pay survey of 214 students from a southwestern university health center showed that participants were willing to pay an average (SD) of $55.27 ($39.11) out of pocket for a teledermoscopy/telederm evaluation, citing factors such as convenience.⁹

Direct-to-consumer telederm offers a new way for patients to receive care.¹⁰ Some dermatoscopes (eg, DermLite HÜD [3Gen], Molescope/Molescope II [Metaoptima Technology Inc]) currently are marketed directly to consumers along with telederm services to facilitate direct-to-patient teledermoscopy.^11,12

Machine Learning

Big data and machine learning has been hailed as the future of medicine and dermatology alike.¹³ Machine learning is a type of artificial intelligence that uses computational algorithms (eg, neural networks) that allow computer programs to automatically improve their accuracy (learn) by analyzing large data sets. In dermatology, machine learning has been most notably used to train computers to identify images of skin cancer by way of large image databases.^14-17 One algorithm, a convolutional neural network (CNN), made headlines in 2017 when it was able to identify dermoscopic and clinical images of skin cancer with comparable accuracy to a group of 21 dermatologists.¹⁴ In 2018, the International Skin Imaging Collaboration (ISIC) published results of a study of the diagnostic accuracy of 25 computer algorithms compared to 8 dermatologists using a set of 100 dermoscopic images of melanoma and benign nevi.¹⁵ Using the average sensitivity of the dermatologists (82%), the top fusion algorithm in the study had a sensitivity of 76% versus 59% for the dermatologists (P=.02). These results compared the mean sensitivity of the dermatologists, as some individual dermatologists outperformed the algorithm.¹⁵ More recently, another CNN was compared to 58 international dermatologists in the classification of a set of 100 dermoscopic images (20 melanoma and 80 melanocytic nevi).¹⁶ Using the mean sensitivity of the dermatologists (86.6%), the CNN had a specificity of 92.5% versus 71.3% for dermatologists (P<.01). In the second part of the study, the dermatologists were given some clinical information and close-up photographs of the lesions, which improved their average (SD) sensitivity and specificity to 88.9% (9.6%)(P=.19) and 75.7% (11.7%)(P<.05), respectively. When compared to the CNN at this higher sensitivity, the CNN still had a higher specificity than the dermatologists (82.5% vs 75.7% [P<.01]).¹⁶ However, in real-life clinical practice dermatologists perform better, not only because they can collect more in-person clinical information but also because humans gather more information during live examination than when they are interpreting close-up clinical and/or dermoscopic images. In a sense, we currently are limited to comparing data that is incommensurable.

Machine learning studies have other notable limitations, such as data sets that do not contain a full spectrum of skin lesions or less common lesions (eg, pigmented seborrheic keratoses, amelanotic melanomas) and variation in image databases used.^15,16 For machine algorithms to improve, they require access to high-quality and ideally standardized digital dermoscopic image databases. The ISIC and other organizations currently have databases specifically for this purpose, but more images are needed.¹⁸ As additional practitioners incorporate digital dermoscopy in their clinical practice, the potential for larger databases and more accurate algorithms becomes a possibility. 

Image Acquisition

Many devices are available for digital dermoscopic image acquisition, including dermatoscopes that attach to smartphones and/or digital cameras and all-in-one systems (eTable). The exact system employed will depend on the practitioner's requirements for price, portability, speed, image quality, and software. Digital single-lens reflex (DSLR) cameras boast the highest image quality, while video dermoscopy traditionally yields stored images with poor resolution.¹⁹ Macroscopic images obtained by other imaging devices, including spectral imaging devices and reflectance confocal microscopy, usually are yielded via video dermoscopy or a video camera to capture images; thus, stored images generally are not as high quality. 

Smartphones are increasingly used for clinical imaging in dermatology.²⁰ Although DSLR cameras still take the highest-quality images, current smartphone image quality is comparable to digital cameras.^21,22 Computational photography uses computer processing power to enhance image quality and may bring smartphone image quality closer to DSLR cameras.^22,23 Smartphones with newer dual-lens cameras have been reported to further improve image quality.²¹ Current smartphones have the option of enabling high-dynamic-range imaging, which combines multiple images taken with different exposures to create a single image with improved dynamic range of luminosity. It has been reported that high-dynamic-range imaging may even enhance dermoscopic features of more challenging hypopigmented skin cancers.²⁴

Standardizing Imaging

There has been a concerted effort to standardize digital dermatologic image acquisition.^25,26 Standardization promises to facilitate data analysis, improve collaboration, protect patient privacy, and improve patient care.^13,26,27 At the forefront of image standardization is the ISIC organization, which recently published its Delphi consensus guidelines on standards for lesion imaging, including dermoscopy.²⁶

The true holy grail of image standardization is the Digital Imaging and Communications in Medicine (DICOM) standard.^26-28 The DICOM is a comprehensive imaging standard for storage, annotation, transfer, and display of images, and it is most notable for its use in radiology. The DICOM also could be applied to new imaging modalities in dermatology (eg, optical coherence tomography, reflectance confocal microscopy). Past efforts to develop a DICOM standard for dermatology were undertaken by a working group that has since disbanded.²⁷ Work by the ISIC and many others will hopefully lead to adoption of the DICOM standard by dermatology at some point in the future. 

Protected Health Information

The Health Insurance Portability and Accountability Act (HIPAA) requires protected health information (PHI) to be stored in a secure manner with limited access that sufficiently protects identifiable patient information. Although dermoscopic images generally are deidentified, they often are stored alongside clinical photographs and data that contains PHI in clinical practice.

Image storage can take 2 forms: (1) physical local storage on internal and external hard drives or (2) remote storage (eg, cloud-based storage). Encryption is essential regardless of the method of storage. It is required by law that loss of nonencrypted PHI be reported to all potentially affected patients, the US Department of Health & Human Services, and local/state media depending on the number of patients affected. Loss of PHI can result in fines of up to $1.5 million.²⁹ On the contrary, loss of properly encrypted data would not be required to be reported.³⁰

As smart image acquisition devices begin to dominate the clinical setting, practitioners need to be vigilant in securing patient PHI. There are multiple applications (apps) that allow for secure encrypted digital dermoscopic image acquisition and storage on smartphones. Additionally, it is important to secure smartphones with complex passcodes (eg, a mix of special characters, numbers, uppercase and lowercase letters). Most dermatoscope manufacturers have apps for image acquisition and storage that can be tied into other platforms or storage systems (eg, DermLite app [3Gen], Handyscope [FotoFinder Systems GmbH], VEOS app [Canfield Scientific, Inc]).²⁸ Other options include syncing images with current electronic medical record technologies, transferring photographs to HIPAA-compliant cloud storage, or transferring photographs to an encrypted computer and/or external hard drive. Some tips for securing data based on HIPAA and other guidelines are listed in the Table.^30,31

Conclusion

The expansion of teledermoscopy alongside direct-to-patient services may create additional incentives for clinicians to incorporate digital dermoscopy into their practice. As more practitioners adopt digital dermoscopy, machine learning driven by technological advancements and larger image data sets could influence the future practice of dermatology. With the rise in digital dermoscopy by way of smartphones, additional steps must be taken to ensure patients' PHI is safeguarded. Digital dermoscopy is a dynamic field that will likely see continued growth in the coming years.

Dermoscopic examination has been proven to increase diagnostic accuracy and decrease unnecessary biopsies of both melanoma and nonmelanoma skin cancers.^1,2 Digital dermoscopy refers to acquiring and storing digital dermoscopic photographs via digital camera, smart image capture devices such as smartphones and tablets, or any other devices used for image acquisition. The stored images may then be used in a variety of ways, including sequential digital monitoring, teledermoscopy, and machine learning.

Sequential Digital Monitoring

Sequential digital dermoscopy imaging (SDDI) is the capture and storage of dermoscopic images of suspicious lesions that are then monitored over time for changes. Studies have shown that SDDI allows for early detection of melanomas and leads to a decrease in the number of unnecessary excisions.^3,4 A meta-analysis of SDDI found that the chance of detecting melanoma increased with the length of monitoring, which suggests that continued follow-up, especially in high-risk groups, is crucial.⁴

Teledermoscopy

Teledermatology (telederm) is on the rise in the United States, with the number of programs and consultations increasing yearly. One study showed a 48% increase in telederm programs in the last 5 years.⁵ Studies have shown the addition of digital dermoscopic images improved the diagnostic accuracy in telederm skin cancer screenings versus clinical images alone.^6,7

Telederm currently is practiced in 2 main models: live-interactive video consultation and storage of images for future consultation (store and forward). Medicare currently only reimburses live-interactive telederm for patients in nonmetropolitan areas and store-and-forward telederm pilot programs in Alaska and Hawaii; however, Medicaid does reimburse for store and forward in a handful of states.8 Similar to dermatoscope use during clinical examination, there currently is no additional reimbursement for teledermoscopy. Of note, a willingness-to-pay survey of 214 students from a southwestern university health center showed that participants were willing to pay an average (SD) of $55.27 ($39.11) out of pocket for a teledermoscopy/telederm evaluation, citing factors such as convenience.⁹

Direct-to-consumer telederm offers a new way for patients to receive care.¹⁰ Some dermatoscopes (eg, DermLite HÜD [3Gen], Molescope/Molescope II [Metaoptima Technology Inc]) currently are marketed directly to consumers along with telederm services to facilitate direct-to-patient teledermoscopy.^11,12

Machine Learning

Big data and machine learning has been hailed as the future of medicine and dermatology alike.¹³ Machine learning is a type of artificial intelligence that uses computational algorithms (eg, neural networks) that allow computer programs to automatically improve their accuracy (learn) by analyzing large data sets. In dermatology, machine learning has been most notably used to train computers to identify images of skin cancer by way of large image databases.^14-17 One algorithm, a convolutional neural network (CNN), made headlines in 2017 when it was able to identify dermoscopic and clinical images of skin cancer with comparable accuracy to a group of 21 dermatologists.¹⁴ In 2018, the International Skin Imaging Collaboration (ISIC) published results of a study of the diagnostic accuracy of 25 computer algorithms compared to 8 dermatologists using a set of 100 dermoscopic images of melanoma and benign nevi.¹⁵ Using the average sensitivity of the dermatologists (82%), the top fusion algorithm in the study had a sensitivity of 76% versus 59% for the dermatologists (P=.02). These results compared the mean sensitivity of the dermatologists, as some individual dermatologists outperformed the algorithm.¹⁵ More recently, another CNN was compared to 58 international dermatologists in the classification of a set of 100 dermoscopic images (20 melanoma and 80 melanocytic nevi).¹⁶ Using the mean sensitivity of the dermatologists (86.6%), the CNN had a specificity of 92.5% versus 71.3% for dermatologists (P<.01). In the second part of the study, the dermatologists were given some clinical information and close-up photographs of the lesions, which improved their average (SD) sensitivity and specificity to 88.9% (9.6%)(P=.19) and 75.7% (11.7%)(P<.05), respectively. When compared to the CNN at this higher sensitivity, the CNN still had a higher specificity than the dermatologists (82.5% vs 75.7% [P<.01]).¹⁶ However, in real-life clinical practice dermatologists perform better, not only because they can collect more in-person clinical information but also because humans gather more information during live examination than when they are interpreting close-up clinical and/or dermoscopic images. In a sense, we currently are limited to comparing data that is incommensurable.

Machine learning studies have other notable limitations, such as data sets that do not contain a full spectrum of skin lesions or less common lesions (eg, pigmented seborrheic keratoses, amelanotic melanomas) and variation in image databases used.^15,16 For machine algorithms to improve, they require access to high-quality and ideally standardized digital dermoscopic image databases. The ISIC and other organizations currently have databases specifically for this purpose, but more images are needed.¹⁸ As additional practitioners incorporate digital dermoscopy in their clinical practice, the potential for larger databases and more accurate algorithms becomes a possibility. 

Image Acquisition

Many devices are available for digital dermoscopic image acquisition, including dermatoscopes that attach to smartphones and/or digital cameras and all-in-one systems (eTable). The exact system employed will depend on the practitioner's requirements for price, portability, speed, image quality, and software. Digital single-lens reflex (DSLR) cameras boast the highest image quality, while video dermoscopy traditionally yields stored images with poor resolution.¹⁹ Macroscopic images obtained by other imaging devices, including spectral imaging devices and reflectance confocal microscopy, usually are yielded via video dermoscopy or a video camera to capture images; thus, stored images generally are not as high quality. 

Smartphones are increasingly used for clinical imaging in dermatology.²⁰ Although DSLR cameras still take the highest-quality images, current smartphone image quality is comparable to digital cameras.^21,22 Computational photography uses computer processing power to enhance image quality and may bring smartphone image quality closer to DSLR cameras.^22,23 Smartphones with newer dual-lens cameras have been reported to further improve image quality.²¹ Current smartphones have the option of enabling high-dynamic-range imaging, which combines multiple images taken with different exposures to create a single image with improved dynamic range of luminosity. It has been reported that high-dynamic-range imaging may even enhance dermoscopic features of more challenging hypopigmented skin cancers.²⁴

Standardizing Imaging

There has been a concerted effort to standardize digital dermatologic image acquisition.^25,26 Standardization promises to facilitate data analysis, improve collaboration, protect patient privacy, and improve patient care.^13,26,27 At the forefront of image standardization is the ISIC organization, which recently published its Delphi consensus guidelines on standards for lesion imaging, including dermoscopy.²⁶

The true holy grail of image standardization is the Digital Imaging and Communications in Medicine (DICOM) standard.^26-28 The DICOM is a comprehensive imaging standard for storage, annotation, transfer, and display of images, and it is most notable for its use in radiology. The DICOM also could be applied to new imaging modalities in dermatology (eg, optical coherence tomography, reflectance confocal microscopy). Past efforts to develop a DICOM standard for dermatology were undertaken by a working group that has since disbanded.²⁷ Work by the ISIC and many others will hopefully lead to adoption of the DICOM standard by dermatology at some point in the future. 

Protected Health Information

The Health Insurance Portability and Accountability Act (HIPAA) requires protected health information (PHI) to be stored in a secure manner with limited access that sufficiently protects identifiable patient information. Although dermoscopic images generally are deidentified, they often are stored alongside clinical photographs and data that contains PHI in clinical practice.

Image storage can take 2 forms: (1) physical local storage on internal and external hard drives or (2) remote storage (eg, cloud-based storage). Encryption is essential regardless of the method of storage. It is required by law that loss of nonencrypted PHI be reported to all potentially affected patients, the US Department of Health & Human Services, and local/state media depending on the number of patients affected. Loss of PHI can result in fines of up to $1.5 million.²⁹ On the contrary, loss of properly encrypted data would not be required to be reported.³⁰

As smart image acquisition devices begin to dominate the clinical setting, practitioners need to be vigilant in securing patient PHI. There are multiple applications (apps) that allow for secure encrypted digital dermoscopic image acquisition and storage on smartphones. Additionally, it is important to secure smartphones with complex passcodes (eg, a mix of special characters, numbers, uppercase and lowercase letters). Most dermatoscope manufacturers have apps for image acquisition and storage that can be tied into other platforms or storage systems (eg, DermLite app [3Gen], Handyscope [FotoFinder Systems GmbH], VEOS app [Canfield Scientific, Inc]).²⁸ Other options include syncing images with current electronic medical record technologies, transferring photographs to HIPAA-compliant cloud storage, or transferring photographs to an encrypted computer and/or external hard drive. Some tips for securing data based on HIPAA and other guidelines are listed in the Table.^30,31

Conclusion

The expansion of teledermoscopy alongside direct-to-patient services may create additional incentives for clinicians to incorporate digital dermoscopy into their practice. As more practitioners adopt digital dermoscopy, machine learning driven by technological advancements and larger image data sets could influence the future practice of dermatology. With the rise in digital dermoscopy by way of smartphones, additional steps must be taken to ensure patients' PHI is safeguarded. Digital dermoscopy is a dynamic field that will likely see continued growth in the coming years.

Dermoscopic examination has been proven to increase diagnostic accuracy and decrease unnecessary biopsies of both melanoma and nonmelanoma skin cancers.^1,2 Digital dermoscopy refers to acquiring and storing digital dermoscopic photographs via digital camera, smart image capture devices such as smartphones and tablets, or any other devices used for image acquisition. The stored images may then be used in a variety of ways, including sequential digital monitoring, teledermoscopy, and machine learning.

Sequential Digital Monitoring

Sequential digital dermoscopy imaging (SDDI) is the capture and storage of dermoscopic images of suspicious lesions that are then monitored over time for changes. Studies have shown that SDDI allows for early detection of melanomas and leads to a decrease in the number of unnecessary excisions.^3,4 A meta-analysis of SDDI found that the chance of detecting melanoma increased with the length of monitoring, which suggests that continued follow-up, especially in high-risk groups, is crucial.⁴

Teledermoscopy

Teledermatology (telederm) is on the rise in the United States, with the number of programs and consultations increasing yearly. One study showed a 48% increase in telederm programs in the last 5 years.⁵ Studies have shown the addition of digital dermoscopic images improved the diagnostic accuracy in telederm skin cancer screenings versus clinical images alone.^6,7

Telederm currently is practiced in 2 main models: live-interactive video consultation and storage of images for future consultation (store and forward). Medicare currently only reimburses live-interactive telederm for patients in nonmetropolitan areas and store-and-forward telederm pilot programs in Alaska and Hawaii; however, Medicaid does reimburse for store and forward in a handful of states.8 Similar to dermatoscope use during clinical examination, there currently is no additional reimbursement for teledermoscopy. Of note, a willingness-to-pay survey of 214 students from a southwestern university health center showed that participants were willing to pay an average (SD) of $55.27 ($39.11) out of pocket for a teledermoscopy/telederm evaluation, citing factors such as convenience.⁹

Direct-to-consumer telederm offers a new way for patients to receive care.¹⁰ Some dermatoscopes (eg, DermLite HÜD [3Gen], Molescope/Molescope II [Metaoptima Technology Inc]) currently are marketed directly to consumers along with telederm services to facilitate direct-to-patient teledermoscopy.^11,12

Machine Learning

Big data and machine learning has been hailed as the future of medicine and dermatology alike.¹³ Machine learning is a type of artificial intelligence that uses computational algorithms (eg, neural networks) that allow computer programs to automatically improve their accuracy (learn) by analyzing large data sets. In dermatology, machine learning has been most notably used to train computers to identify images of skin cancer by way of large image databases.^14-17 One algorithm, a convolutional neural network (CNN), made headlines in 2017 when it was able to identify dermoscopic and clinical images of skin cancer with comparable accuracy to a group of 21 dermatologists.¹⁴ In 2018, the International Skin Imaging Collaboration (ISIC) published results of a study of the diagnostic accuracy of 25 computer algorithms compared to 8 dermatologists using a set of 100 dermoscopic images of melanoma and benign nevi.¹⁵ Using the average sensitivity of the dermatologists (82%), the top fusion algorithm in the study had a sensitivity of 76% versus 59% for the dermatologists (P=.02). These results compared the mean sensitivity of the dermatologists, as some individual dermatologists outperformed the algorithm.¹⁵ More recently, another CNN was compared to 58 international dermatologists in the classification of a set of 100 dermoscopic images (20 melanoma and 80 melanocytic nevi).¹⁶ Using the mean sensitivity of the dermatologists (86.6%), the CNN had a specificity of 92.5% versus 71.3% for dermatologists (P<.01). In the second part of the study, the dermatologists were given some clinical information and close-up photographs of the lesions, which improved their average (SD) sensitivity and specificity to 88.9% (9.6%)(P=.19) and 75.7% (11.7%)(P<.05), respectively. When compared to the CNN at this higher sensitivity, the CNN still had a higher specificity than the dermatologists (82.5% vs 75.7% [P<.01]).¹⁶ However, in real-life clinical practice dermatologists perform better, not only because they can collect more in-person clinical information but also because humans gather more information during live examination than when they are interpreting close-up clinical and/or dermoscopic images. In a sense, we currently are limited to comparing data that is incommensurable.

Machine learning studies have other notable limitations, such as data sets that do not contain a full spectrum of skin lesions or less common lesions (eg, pigmented seborrheic keratoses, amelanotic melanomas) and variation in image databases used.^15,16 For machine algorithms to improve, they require access to high-quality and ideally standardized digital dermoscopic image databases. The ISIC and other organizations currently have databases specifically for this purpose, but more images are needed.¹⁸ As additional practitioners incorporate digital dermoscopy in their clinical practice, the potential for larger databases and more accurate algorithms becomes a possibility. 

Image Acquisition

Many devices are available for digital dermoscopic image acquisition, including dermatoscopes that attach to smartphones and/or digital cameras and all-in-one systems (eTable). The exact system employed will depend on the practitioner's requirements for price, portability, speed, image quality, and software. Digital single-lens reflex (DSLR) cameras boast the highest image quality, while video dermoscopy traditionally yields stored images with poor resolution.¹⁹ Macroscopic images obtained by other imaging devices, including spectral imaging devices and reflectance confocal microscopy, usually are yielded via video dermoscopy or a video camera to capture images; thus, stored images generally are not as high quality. 

Smartphones are increasingly used for clinical imaging in dermatology.²⁰ Although DSLR cameras still take the highest-quality images, current smartphone image quality is comparable to digital cameras.^21,22 Computational photography uses computer processing power to enhance image quality and may bring smartphone image quality closer to DSLR cameras.^22,23 Smartphones with newer dual-lens cameras have been reported to further improve image quality.²¹ Current smartphones have the option of enabling high-dynamic-range imaging, which combines multiple images taken with different exposures to create a single image with improved dynamic range of luminosity. It has been reported that high-dynamic-range imaging may even enhance dermoscopic features of more challenging hypopigmented skin cancers.²⁴

Standardizing Imaging

There has been a concerted effort to standardize digital dermatologic image acquisition.^25,26 Standardization promises to facilitate data analysis, improve collaboration, protect patient privacy, and improve patient care.^13,26,27 At the forefront of image standardization is the ISIC organization, which recently published its Delphi consensus guidelines on standards for lesion imaging, including dermoscopy.²⁶

The true holy grail of image standardization is the Digital Imaging and Communications in Medicine (DICOM) standard.^26-28 The DICOM is a comprehensive imaging standard for storage, annotation, transfer, and display of images, and it is most notable for its use in radiology. The DICOM also could be applied to new imaging modalities in dermatology (eg, optical coherence tomography, reflectance confocal microscopy). Past efforts to develop a DICOM standard for dermatology were undertaken by a working group that has since disbanded.²⁷ Work by the ISIC and many others will hopefully lead to adoption of the DICOM standard by dermatology at some point in the future. 

Protected Health Information

The Health Insurance Portability and Accountability Act (HIPAA) requires protected health information (PHI) to be stored in a secure manner with limited access that sufficiently protects identifiable patient information. Although dermoscopic images generally are deidentified, they often are stored alongside clinical photographs and data that contains PHI in clinical practice.

Image storage can take 2 forms: (1) physical local storage on internal and external hard drives or (2) remote storage (eg, cloud-based storage). Encryption is essential regardless of the method of storage. It is required by law that loss of nonencrypted PHI be reported to all potentially affected patients, the US Department of Health & Human Services, and local/state media depending on the number of patients affected. Loss of PHI can result in fines of up to $1.5 million.²⁹ On the contrary, loss of properly encrypted data would not be required to be reported.³⁰

As smart image acquisition devices begin to dominate the clinical setting, practitioners need to be vigilant in securing patient PHI. There are multiple applications (apps) that allow for secure encrypted digital dermoscopic image acquisition and storage on smartphones. Additionally, it is important to secure smartphones with complex passcodes (eg, a mix of special characters, numbers, uppercase and lowercase letters). Most dermatoscope manufacturers have apps for image acquisition and storage that can be tied into other platforms or storage systems (eg, DermLite app [3Gen], Handyscope [FotoFinder Systems GmbH], VEOS app [Canfield Scientific, Inc]).²⁸ Other options include syncing images with current electronic medical record technologies, transferring photographs to HIPAA-compliant cloud storage, or transferring photographs to an encrypted computer and/or external hard drive. Some tips for securing data based on HIPAA and other guidelines are listed in the Table.^30,31

Conclusion

The expansion of teledermoscopy alongside direct-to-patient services may create additional incentives for clinicians to incorporate digital dermoscopy into their practice. As more practitioners adopt digital dermoscopy, machine learning driven by technological advancements and larger image data sets could influence the future practice of dermatology. With the rise in digital dermoscopy by way of smartphones, additional steps must be taken to ensure patients' PHI is safeguarded. Digital dermoscopy is a dynamic field that will likely see continued growth in the coming years.

Almost half of the individuals diagnosed with melanoma in a free skin cancer screening program otherwise would not have gone to a doctor to have their skin examined, according to an analysis of the American Academy of Dermatology’s national skin cancer screening program, during 1986-2014.

Courtesy AAD

The SPOTme program, a national skin cancer screening and education program conducted by volunteer dermatologists, was launched in 1985. More than 2 million free screenings have been provided by the program in a “predominantly high-risk population, rendering important clinical diagnoses for hundreds of thousands of participants,” according to first authors Jean-Phillip Okhovat, MD, of Beth Israel Deaconess Medical Center, and Derek Beaulieu, MD, of Tufts University, both in Boston, and their colleagues.

The analysis was published online in the Journal of the American Academy of Dermatology on July 26.

Their study analyzed data on almost 2 million people screened through the program from 1986-2014. About 62% were women; 90% were white, about 2% were black, and almost 4% were Hispanic. Almost 80% had no regular dermatologist, almost 73% had not been screened previously, almost 45% had never had a skin cancer check, and 9% were uninsured. Almost 31% reported a mole that had recently change in size, color, or shape; almost 34% said they had a family history of skin cancer, and about 14% said they had a personal history of skin cancer.

Participants were asked about demographics and risk factors, although some questions changed from year to year (for example, in 2009 and 2010, participants were asked about melanoma risk factors, and from 1992 through 2010, participants were asked about their access to dermatologic care).

During 1991-2014 (which did not include data for 1995, 1996, and 2000, which were not available), the screening program resulted in 20,628 clinical melanoma diagnoses, 156,087 clinical dysplastic nevi diagnoses, 32,893 clinical squamous cell carcinoma diagnoses, and 129,848 clinical basal cell carcinoma diagnoses.

Of those clinically diagnosed with melanoma during 1992-2010, 83% said they did not have a regular dermatologist, 77% said they had not been screened previously, and 47% said they would not have seen a doctor for a skin exam if the SPOTme program had not been available.

Of those screened in 2009 and 2010 , 72% were considered at high risk for melanoma (older than age 65 years, having a history of sunburns, a family history of skin cancer, and/or more than 50 moles or unusual moles).

Among the other findings was that from 1992 to 2010, about 12% of those with a clinical melanoma diagnosis were not insured, which increased over time, from almost 11% during 1992-1999 to almost 16% during 2007-2010.

The “consistently high rates” of multiple skin cancer risk factors among those newly screened in the study are consistent with previously reported data, “suggesting that there is an untapped pool of at-risk Americans who have yet to be screened for skin cancer,” the authors wrote. “While the SPOTme program cannot be expected to meet the demands of this larger at-risk population, increased publicity and educational campaigns led by the AAD and assistance to primary care physicians in triaging of patients who should be seen by dermatologists could decrease the number of Americans who need to be screened,” they added.

Limitations of the study included the inability to confirm the clinical diagnoses with histopathology, and no data from the providers were available.

The authors had no disclosures. SPOTme, part of the AAD’s SPOT Skin Cancer initiative, is supported by a grant from Bristol-Myers Squibb.

[email protected]

SOURCE: Okhovat JP et al. J Am Acad Dermatol. https://doi./org/10.1016.j.jaad.2018.05.1242.

Almost half of the individuals diagnosed with melanoma in a free skin cancer screening program otherwise would not have gone to a doctor to have their skin examined, according to an analysis of the American Academy of Dermatology’s national skin cancer screening program, during 1986-2014.

Courtesy AAD

The SPOTme program, a national skin cancer screening and education program conducted by volunteer dermatologists, was launched in 1985. More than 2 million free screenings have been provided by the program in a “predominantly high-risk population, rendering important clinical diagnoses for hundreds of thousands of participants,” according to first authors Jean-Phillip Okhovat, MD, of Beth Israel Deaconess Medical Center, and Derek Beaulieu, MD, of Tufts University, both in Boston, and their colleagues.

The analysis was published online in the Journal of the American Academy of Dermatology on July 26.

Their study analyzed data on almost 2 million people screened through the program from 1986-2014. About 62% were women; 90% were white, about 2% were black, and almost 4% were Hispanic. Almost 80% had no regular dermatologist, almost 73% had not been screened previously, almost 45% had never had a skin cancer check, and 9% were uninsured. Almost 31% reported a mole that had recently change in size, color, or shape; almost 34% said they had a family history of skin cancer, and about 14% said they had a personal history of skin cancer.

Participants were asked about demographics and risk factors, although some questions changed from year to year (for example, in 2009 and 2010, participants were asked about melanoma risk factors, and from 1992 through 2010, participants were asked about their access to dermatologic care).

During 1991-2014 (which did not include data for 1995, 1996, and 2000, which were not available), the screening program resulted in 20,628 clinical melanoma diagnoses, 156,087 clinical dysplastic nevi diagnoses, 32,893 clinical squamous cell carcinoma diagnoses, and 129,848 clinical basal cell carcinoma diagnoses.

Of those clinically diagnosed with melanoma during 1992-2010, 83% said they did not have a regular dermatologist, 77% said they had not been screened previously, and 47% said they would not have seen a doctor for a skin exam if the SPOTme program had not been available.

Of those screened in 2009 and 2010 , 72% were considered at high risk for melanoma (older than age 65 years, having a history of sunburns, a family history of skin cancer, and/or more than 50 moles or unusual moles).

Among the other findings was that from 1992 to 2010, about 12% of those with a clinical melanoma diagnosis were not insured, which increased over time, from almost 11% during 1992-1999 to almost 16% during 2007-2010.

The “consistently high rates” of multiple skin cancer risk factors among those newly screened in the study are consistent with previously reported data, “suggesting that there is an untapped pool of at-risk Americans who have yet to be screened for skin cancer,” the authors wrote. “While the SPOTme program cannot be expected to meet the demands of this larger at-risk population, increased publicity and educational campaigns led by the AAD and assistance to primary care physicians in triaging of patients who should be seen by dermatologists could decrease the number of Americans who need to be screened,” they added.

Limitations of the study included the inability to confirm the clinical diagnoses with histopathology, and no data from the providers were available.

The authors had no disclosures. SPOTme, part of the AAD’s SPOT Skin Cancer initiative, is supported by a grant from Bristol-Myers Squibb.

[email protected]

SOURCE: Okhovat JP et al. J Am Acad Dermatol. https://doi./org/10.1016.j.jaad.2018.05.1242.

Almost half of the individuals diagnosed with melanoma in a free skin cancer screening program otherwise would not have gone to a doctor to have their skin examined, according to an analysis of the American Academy of Dermatology’s national skin cancer screening program, during 1986-2014.

Courtesy AAD

The SPOTme program, a national skin cancer screening and education program conducted by volunteer dermatologists, was launched in 1985. More than 2 million free screenings have been provided by the program in a “predominantly high-risk population, rendering important clinical diagnoses for hundreds of thousands of participants,” according to first authors Jean-Phillip Okhovat, MD, of Beth Israel Deaconess Medical Center, and Derek Beaulieu, MD, of Tufts University, both in Boston, and their colleagues.

The analysis was published online in the Journal of the American Academy of Dermatology on July 26.

Their study analyzed data on almost 2 million people screened through the program from 1986-2014. About 62% were women; 90% were white, about 2% were black, and almost 4% were Hispanic. Almost 80% had no regular dermatologist, almost 73% had not been screened previously, almost 45% had never had a skin cancer check, and 9% were uninsured. Almost 31% reported a mole that had recently change in size, color, or shape; almost 34% said they had a family history of skin cancer, and about 14% said they had a personal history of skin cancer.

Participants were asked about demographics and risk factors, although some questions changed from year to year (for example, in 2009 and 2010, participants were asked about melanoma risk factors, and from 1992 through 2010, participants were asked about their access to dermatologic care).

During 1991-2014 (which did not include data for 1995, 1996, and 2000, which were not available), the screening program resulted in 20,628 clinical melanoma diagnoses, 156,087 clinical dysplastic nevi diagnoses, 32,893 clinical squamous cell carcinoma diagnoses, and 129,848 clinical basal cell carcinoma diagnoses.

Of those clinically diagnosed with melanoma during 1992-2010, 83% said they did not have a regular dermatologist, 77% said they had not been screened previously, and 47% said they would not have seen a doctor for a skin exam if the SPOTme program had not been available.

Of those screened in 2009 and 2010 , 72% were considered at high risk for melanoma (older than age 65 years, having a history of sunburns, a family history of skin cancer, and/or more than 50 moles or unusual moles).

Among the other findings was that from 1992 to 2010, about 12% of those with a clinical melanoma diagnosis were not insured, which increased over time, from almost 11% during 1992-1999 to almost 16% during 2007-2010.

The “consistently high rates” of multiple skin cancer risk factors among those newly screened in the study are consistent with previously reported data, “suggesting that there is an untapped pool of at-risk Americans who have yet to be screened for skin cancer,” the authors wrote. “While the SPOTme program cannot be expected to meet the demands of this larger at-risk population, increased publicity and educational campaigns led by the AAD and assistance to primary care physicians in triaging of patients who should be seen by dermatologists could decrease the number of Americans who need to be screened,” they added.

Limitations of the study included the inability to confirm the clinical diagnoses with histopathology, and no data from the providers were available.

The authors had no disclosures. SPOTme, part of the AAD’s SPOT Skin Cancer initiative, is supported by a grant from Bristol-Myers Squibb.

[email protected]

SOURCE: Okhovat JP et al. J Am Acad Dermatol. https://doi./org/10.1016.j.jaad.2018.05.1242.

Adult T-cell leukemia/lymphoma (ATLL) is an uncommon neoplasm of mature T lymphocytes associated with infection by human T-lymphotropic virus 1 (HTLV-1),^1-3 which is increasing in incidence in areas of the United States with large immigrant populations.⁴ Human T-lymphotrophic virus 1 infection is asymptomatic in most patients and has been associated with ATLL as well as tropical spastic paraparesis.⁵ We present a case of rapid-onset ATLL in an 82-year-old Japanese man who had immigrated to the United States.

Case Report

An 82-year-old Japanese man who had immigrated to the United States presented with papules and nodules on the neck, trunk, and arms of 4 weeks’ duration. Minimal pruritus was associated with the lesions, which were otherwise asymptomatic. The patient reported that he was generally healthy, and a review of systems was negative.

Physical examination revealed numerous erythematous and violaceous papules and nodules on the right side of the neck (Figure 1A), chest, back, abdomen, groin, left arm (Figure 1B), and medial thighs. Bilateral axillary and inguinal lymphadenopathy also was noted.

A biopsy from the abdomen revealed a dense, atypical, pandermal lymphoid infiltrate comprised of medium-sized lymphocytes with oval nuclei, fine chromatin, and pale cytoplasm (Figure 2). Mitotic figures and apoptotic cells also were observed. Immunostaining was strongly and diffusely positive for CD4 (Figure 3A), B-cell lymphoma 2 (Bcl-2)(Figure 3B), CD3, and programmed death 1, and was negative for CD8, CD10, CD20, CD30, and myeloperoxidase.

A bone marrow biopsy revealed an atypical T-cell population on flow cytometry. Western blot analysis for HTLV-1 antibodies was positive. Complete blood cell count and complete metabolic panel were within reference range.

Clinical and histopathologic findings fit the diagnosis of ATLL. The patient was referred to hematology/oncology, but the rapid progression of lesions continued, and the patient died within 4 months of initial presentation.

Comment

Etiology
First described in 1977, ATLL is an uncommon neoplasm of mature T cells.⁶ The etiology is associated with infection by the retrovirus HTLV-1, which is endemic in Southern Japan, the Caribbean, Central and West Africa, and Central and South America, with increasing incidence in areas of the United States with large immigrant populations.⁷ The incidence of ATLL among all registered lymphoma cases from 2003 to 2008 in Japan was 8.3% compared to 0.2% in the United States.⁷

Transmission of HTLV-1
Human T-lymphotropic virus 1 is a retrovirus most commonly found in CD4⁺T cells and can be transmitted through breast milk, sexual intercourse, and blood exposure (eg, blood transfusion), with breastfeeding and blood exposure being the most common.^8-10 Human T-lymphotrophic virus 1 has been described as the causative agent for 3 entities: (1) ATLL, (2) a nervous system degenerative disorder known as HTLV-1–associated myelopathy or tropical spastic paraparesis, and (3) HTLV-1 uveitis.^5,11 It is thought that 10 to 20 million individuals worldwide are infected with HTLV-1.¹²

The evolution from infection with HTLV-1 to ATLL is thought to involve multiple steps.^13,14 Those who contract the virus later in life rarely, if ever, develop ATLL, suggesting that this progression requires considerable time to evolve to carcinogenesis. More than 90% of those infected with HTLV-1 remain asymptomatic, while only 2% to 3% of women and 6% to 7% of men develop ATLL with a median incubation period greater than 15 to 20 years.⁷

Subtypes
Adult T-cell leukemia/lymphoma has been divided into 4 clinical subtypes based on clinical presentation and prognosis.¹⁵ The acute type is more aggressive and has a poorer prognosis, while the chronic and smoldering types have a more indolent course. The smoldering variant largely has only cutaneous involvement with less than 1% of the peripheral leukocytes being atypical lymphocytes.¹⁶ A cutaneous subtype in which few to no leukemic cells are present also has been described and may overlap with the smoldering variant.The cutaneous variant has been further classified into 2 subtypes, tumoral and erythematopapular, with the tumoral subtype carrying a worse prognosis.^17,18 Clinically, 39% to 57% of ATLL cases have skin involvement, with nearly one-third reporting skin manifestations as the first symptom.^19,20 The cutaneous manifestations vary greatly and may include papules, plaques, nodules, tumors, erythematous patches, or erythroderma.^4,21 In addition to skin manifestations, most patients with acute ATLL demonstrate leukemia, lymphadenopathy, organomegaly, and hypercalcemia.²²

Histopathology
Histologically, both the smoldering and chronic forms of tumoral or erythematopapular ATLL demonstrate a cutaneous, dermal, or subcutaneous infiltrate of small- to medium-sized CD4⁺ T cells with histiocytes and admixed granulomas.⁴ Epidermotropism and Pautrier microabscesses often are limited or absent but can be seen. The neoplastic T cells involved in ATLL commonly express CD3, CD4, CD25, CD30, and programmed death 1, and T-cell clonality frequently is present.^11,22 Even with staining, diagnosis of ATLL is difficult, as it requires positive testing for HTLV-1 antibody as well as monoclonal integration of HTLV-1 proviral DNA into tumor cells.¹¹ Clinical information is vital in coming to this diagnosis, as there is such great histopathologic overlap with other cutaneous T-cell lymphomas.²³

Differential Diagnosis
The differential diagnosis includes other small- or medium-sized T-cell lymphomas. The chronic and smoldering types can be difficult to distinguish from mycosis fungoides. Primary cutaneous CD4⁺ small- or medium-sized pleomorphic T-cell lymphoma also must be considered, though it often is confined to the skin and can be differentiated from ATLL, as systemic involvement is commonly present in the latter.

Treatment
Treatment decisions should be made based on the subclassification and prognostic factors at the time of diagnosis. High doses of interferon alfa and zidovudine may show some benefit, but many cases require multiagent chemotherapy.²² The only possible curative treatment is allogeneic stem cell transplant. Mogamulizumab, an antichemokine receptor 4 monoclonal antibody, has demonstrated some ATLL antitumor activity.²⁴

Adult T-cell leukemia/lymphoma (ATLL) is an uncommon neoplasm of mature T lymphocytes associated with infection by human T-lymphotropic virus 1 (HTLV-1),^1-3 which is increasing in incidence in areas of the United States with large immigrant populations.⁴ Human T-lymphotrophic virus 1 infection is asymptomatic in most patients and has been associated with ATLL as well as tropical spastic paraparesis.⁵ We present a case of rapid-onset ATLL in an 82-year-old Japanese man who had immigrated to the United States.

Case Report

An 82-year-old Japanese man who had immigrated to the United States presented with papules and nodules on the neck, trunk, and arms of 4 weeks’ duration. Minimal pruritus was associated with the lesions, which were otherwise asymptomatic. The patient reported that he was generally healthy, and a review of systems was negative.

Physical examination revealed numerous erythematous and violaceous papules and nodules on the right side of the neck (Figure 1A), chest, back, abdomen, groin, left arm (Figure 1B), and medial thighs. Bilateral axillary and inguinal lymphadenopathy also was noted.

A biopsy from the abdomen revealed a dense, atypical, pandermal lymphoid infiltrate comprised of medium-sized lymphocytes with oval nuclei, fine chromatin, and pale cytoplasm (Figure 2). Mitotic figures and apoptotic cells also were observed. Immunostaining was strongly and diffusely positive for CD4 (Figure 3A), B-cell lymphoma 2 (Bcl-2)(Figure 3B), CD3, and programmed death 1, and was negative for CD8, CD10, CD20, CD30, and myeloperoxidase.

A bone marrow biopsy revealed an atypical T-cell population on flow cytometry. Western blot analysis for HTLV-1 antibodies was positive. Complete blood cell count and complete metabolic panel were within reference range.

Clinical and histopathologic findings fit the diagnosis of ATLL. The patient was referred to hematology/oncology, but the rapid progression of lesions continued, and the patient died within 4 months of initial presentation.

Comment

Etiology
First described in 1977, ATLL is an uncommon neoplasm of mature T cells.⁶ The etiology is associated with infection by the retrovirus HTLV-1, which is endemic in Southern Japan, the Caribbean, Central and West Africa, and Central and South America, with increasing incidence in areas of the United States with large immigrant populations.⁷ The incidence of ATLL among all registered lymphoma cases from 2003 to 2008 in Japan was 8.3% compared to 0.2% in the United States.⁷

Transmission of HTLV-1
Human T-lymphotropic virus 1 is a retrovirus most commonly found in CD4⁺T cells and can be transmitted through breast milk, sexual intercourse, and blood exposure (eg, blood transfusion), with breastfeeding and blood exposure being the most common.^8-10 Human T-lymphotrophic virus 1 has been described as the causative agent for 3 entities: (1) ATLL, (2) a nervous system degenerative disorder known as HTLV-1–associated myelopathy or tropical spastic paraparesis, and (3) HTLV-1 uveitis.^5,11 It is thought that 10 to 20 million individuals worldwide are infected with HTLV-1.¹²

The evolution from infection with HTLV-1 to ATLL is thought to involve multiple steps.^13,14 Those who contract the virus later in life rarely, if ever, develop ATLL, suggesting that this progression requires considerable time to evolve to carcinogenesis. More than 90% of those infected with HTLV-1 remain asymptomatic, while only 2% to 3% of women and 6% to 7% of men develop ATLL with a median incubation period greater than 15 to 20 years.⁷

Subtypes
Adult T-cell leukemia/lymphoma has been divided into 4 clinical subtypes based on clinical presentation and prognosis.¹⁵ The acute type is more aggressive and has a poorer prognosis, while the chronic and smoldering types have a more indolent course. The smoldering variant largely has only cutaneous involvement with less than 1% of the peripheral leukocytes being atypical lymphocytes.¹⁶ A cutaneous subtype in which few to no leukemic cells are present also has been described and may overlap with the smoldering variant.The cutaneous variant has been further classified into 2 subtypes, tumoral and erythematopapular, with the tumoral subtype carrying a worse prognosis.^17,18 Clinically, 39% to 57% of ATLL cases have skin involvement, with nearly one-third reporting skin manifestations as the first symptom.^19,20 The cutaneous manifestations vary greatly and may include papules, plaques, nodules, tumors, erythematous patches, or erythroderma.^4,21 In addition to skin manifestations, most patients with acute ATLL demonstrate leukemia, lymphadenopathy, organomegaly, and hypercalcemia.²²

Histopathology
Histologically, both the smoldering and chronic forms of tumoral or erythematopapular ATLL demonstrate a cutaneous, dermal, or subcutaneous infiltrate of small- to medium-sized CD4⁺ T cells with histiocytes and admixed granulomas.⁴ Epidermotropism and Pautrier microabscesses often are limited or absent but can be seen. The neoplastic T cells involved in ATLL commonly express CD3, CD4, CD25, CD30, and programmed death 1, and T-cell clonality frequently is present.^11,22 Even with staining, diagnosis of ATLL is difficult, as it requires positive testing for HTLV-1 antibody as well as monoclonal integration of HTLV-1 proviral DNA into tumor cells.¹¹ Clinical information is vital in coming to this diagnosis, as there is such great histopathologic overlap with other cutaneous T-cell lymphomas.²³

Differential Diagnosis
The differential diagnosis includes other small- or medium-sized T-cell lymphomas. The chronic and smoldering types can be difficult to distinguish from mycosis fungoides. Primary cutaneous CD4⁺ small- or medium-sized pleomorphic T-cell lymphoma also must be considered, though it often is confined to the skin and can be differentiated from ATLL, as systemic involvement is commonly present in the latter.

Treatment
Treatment decisions should be made based on the subclassification and prognostic factors at the time of diagnosis. High doses of interferon alfa and zidovudine may show some benefit, but many cases require multiagent chemotherapy.²² The only possible curative treatment is allogeneic stem cell transplant. Mogamulizumab, an antichemokine receptor 4 monoclonal antibody, has demonstrated some ATLL antitumor activity.²⁴

Adult T-cell leukemia/lymphoma (ATLL) is an uncommon neoplasm of mature T lymphocytes associated with infection by human T-lymphotropic virus 1 (HTLV-1),^1-3 which is increasing in incidence in areas of the United States with large immigrant populations.⁴ Human T-lymphotrophic virus 1 infection is asymptomatic in most patients and has been associated with ATLL as well as tropical spastic paraparesis.⁵ We present a case of rapid-onset ATLL in an 82-year-old Japanese man who had immigrated to the United States.

Case Report

An 82-year-old Japanese man who had immigrated to the United States presented with papules and nodules on the neck, trunk, and arms of 4 weeks’ duration. Minimal pruritus was associated with the lesions, which were otherwise asymptomatic. The patient reported that he was generally healthy, and a review of systems was negative.

Physical examination revealed numerous erythematous and violaceous papules and nodules on the right side of the neck (Figure 1A), chest, back, abdomen, groin, left arm (Figure 1B), and medial thighs. Bilateral axillary and inguinal lymphadenopathy also was noted.

A biopsy from the abdomen revealed a dense, atypical, pandermal lymphoid infiltrate comprised of medium-sized lymphocytes with oval nuclei, fine chromatin, and pale cytoplasm (Figure 2). Mitotic figures and apoptotic cells also were observed. Immunostaining was strongly and diffusely positive for CD4 (Figure 3A), B-cell lymphoma 2 (Bcl-2)(Figure 3B), CD3, and programmed death 1, and was negative for CD8, CD10, CD20, CD30, and myeloperoxidase.

A bone marrow biopsy revealed an atypical T-cell population on flow cytometry. Western blot analysis for HTLV-1 antibodies was positive. Complete blood cell count and complete metabolic panel were within reference range.

Clinical and histopathologic findings fit the diagnosis of ATLL. The patient was referred to hematology/oncology, but the rapid progression of lesions continued, and the patient died within 4 months of initial presentation.

Comment

Etiology
First described in 1977, ATLL is an uncommon neoplasm of mature T cells.⁶ The etiology is associated with infection by the retrovirus HTLV-1, which is endemic in Southern Japan, the Caribbean, Central and West Africa, and Central and South America, with increasing incidence in areas of the United States with large immigrant populations.⁷ The incidence of ATLL among all registered lymphoma cases from 2003 to 2008 in Japan was 8.3% compared to 0.2% in the United States.⁷

Transmission of HTLV-1
Human T-lymphotropic virus 1 is a retrovirus most commonly found in CD4⁺T cells and can be transmitted through breast milk, sexual intercourse, and blood exposure (eg, blood transfusion), with breastfeeding and blood exposure being the most common.^8-10 Human T-lymphotrophic virus 1 has been described as the causative agent for 3 entities: (1) ATLL, (2) a nervous system degenerative disorder known as HTLV-1–associated myelopathy or tropical spastic paraparesis, and (3) HTLV-1 uveitis.^5,11 It is thought that 10 to 20 million individuals worldwide are infected with HTLV-1.¹²

The evolution from infection with HTLV-1 to ATLL is thought to involve multiple steps.^13,14 Those who contract the virus later in life rarely, if ever, develop ATLL, suggesting that this progression requires considerable time to evolve to carcinogenesis. More than 90% of those infected with HTLV-1 remain asymptomatic, while only 2% to 3% of women and 6% to 7% of men develop ATLL with a median incubation period greater than 15 to 20 years.⁷

Subtypes
Adult T-cell leukemia/lymphoma has been divided into 4 clinical subtypes based on clinical presentation and prognosis.¹⁵ The acute type is more aggressive and has a poorer prognosis, while the chronic and smoldering types have a more indolent course. The smoldering variant largely has only cutaneous involvement with less than 1% of the peripheral leukocytes being atypical lymphocytes.¹⁶ A cutaneous subtype in which few to no leukemic cells are present also has been described and may overlap with the smoldering variant.The cutaneous variant has been further classified into 2 subtypes, tumoral and erythematopapular, with the tumoral subtype carrying a worse prognosis.^17,18 Clinically, 39% to 57% of ATLL cases have skin involvement, with nearly one-third reporting skin manifestations as the first symptom.^19,20 The cutaneous manifestations vary greatly and may include papules, plaques, nodules, tumors, erythematous patches, or erythroderma.^4,21 In addition to skin manifestations, most patients with acute ATLL demonstrate leukemia, lymphadenopathy, organomegaly, and hypercalcemia.²²

Histopathology
Histologically, both the smoldering and chronic forms of tumoral or erythematopapular ATLL demonstrate a cutaneous, dermal, or subcutaneous infiltrate of small- to medium-sized CD4⁺ T cells with histiocytes and admixed granulomas.⁴ Epidermotropism and Pautrier microabscesses often are limited or absent but can be seen. The neoplastic T cells involved in ATLL commonly express CD3, CD4, CD25, CD30, and programmed death 1, and T-cell clonality frequently is present.^11,22 Even with staining, diagnosis of ATLL is difficult, as it requires positive testing for HTLV-1 antibody as well as monoclonal integration of HTLV-1 proviral DNA into tumor cells.¹¹ Clinical information is vital in coming to this diagnosis, as there is such great histopathologic overlap with other cutaneous T-cell lymphomas.²³

Differential Diagnosis
The differential diagnosis includes other small- or medium-sized T-cell lymphomas. The chronic and smoldering types can be difficult to distinguish from mycosis fungoides. Primary cutaneous CD4⁺ small- or medium-sized pleomorphic T-cell lymphoma also must be considered, though it often is confined to the skin and can be differentiated from ATLL, as systemic involvement is commonly present in the latter.

Treatment
Treatment decisions should be made based on the subclassification and prognostic factors at the time of diagnosis. High doses of interferon alfa and zidovudine may show some benefit, but many cases require multiagent chemotherapy.²² The only possible curative treatment is allogeneic stem cell transplant. Mogamulizumab, an antichemokine receptor 4 monoclonal antibody, has demonstrated some ATLL antitumor activity.²⁴

Stress balls and hand-holding failed to lower patient anxiety during head and neck skin cancer removals under local anesthesia, according to a randomized trial of 135 patients at Northwestern University, Chicago.

TommL/E+/Getty Images

[email protected]

SOURCE: Yanes AF et al. JAMA Dermatol. 2018 Jul 18. doi:10.1001/jamadermatol.2018.1783.

Stress balls and hand-holding failed to lower patient anxiety during head and neck skin cancer removals under local anesthesia, according to a randomized trial of 135 patients at Northwestern University, Chicago.

TommL/E+/Getty Images

[email protected]

SOURCE: Yanes AF et al. JAMA Dermatol. 2018 Jul 18. doi:10.1001/jamadermatol.2018.1783.

Stress balls and hand-holding failed to lower patient anxiety during head and neck skin cancer removals under local anesthesia, according to a randomized trial of 135 patients at Northwestern University, Chicago.

TommL/E+/Getty Images

[email protected]

SOURCE: Yanes AF et al. JAMA Dermatol. 2018 Jul 18. doi:10.1001/jamadermatol.2018.1783.

A 17-year-old girl seen in a Portuguese dermatology clinic was found to have a nodular basal cell carcinoma on the parietal region of her scalp. The nodule appeared 6 years after she had received a kidney transplant, according to João Borges-Costa, MD, PhD, who submitted the case report.

Since the transplant, the girl had been maintained on immunosuppressive medication of tacrolimus 1 mg twice daily, mycophenolate sodium 360 mg twice daily, and prednisolone 10 mg every other day. The 1-cm nodule was pigmented; dermatoscopy did not yield clarity about whether the lesion was melanocytic. An excisional biopsy with 0.5-cm margins was performed, and histology confirmed that the lesion was a nodular pigmented basal cell carcinoma that had been excised completely.

The case, said Dr. Borges-Costa, shows that skin cancers can develop earlier than the typical 12-18 years after pediatric transplantation. Most reported cases have been squamous cell cancers and melanomas, and often are associated with lack of appropriate sun protection behavior.

The patient, a Caucasian, was a sailor who used sunscreen but did not typically wear a hat while sailing, reported Dr. Borges-Costa, a dermatologist at the University of Lisbon. Her family history was significant for a grandparent with melanoma.

Dr. Borges noted that the parents and patient were given advice regarding the importance of the lifelong use of sun-protective clothing and headgear. “Education of pediatric organ recipients and their parents about sun protection is important because, as occurred with our patient, protective clothing and hats are frequently forgotten.”

Because of the ongoing potential for skin malignancies, early referral “after transplantation to specialized dermatology outpatient clinics, similar to what is now advocated for transplanted adults, could help in surveillance and improve adherence to sun-protective measures,” he added.

SOURCE: Borges-Costa J et al. Pediatr Dermatol. 2018. doi: 10.1111/pde.13537..

A 17-year-old girl seen in a Portuguese dermatology clinic was found to have a nodular basal cell carcinoma on the parietal region of her scalp. The nodule appeared 6 years after she had received a kidney transplant, according to João Borges-Costa, MD, PhD, who submitted the case report.

Since the transplant, the girl had been maintained on immunosuppressive medication of tacrolimus 1 mg twice daily, mycophenolate sodium 360 mg twice daily, and prednisolone 10 mg every other day. The 1-cm nodule was pigmented; dermatoscopy did not yield clarity about whether the lesion was melanocytic. An excisional biopsy with 0.5-cm margins was performed, and histology confirmed that the lesion was a nodular pigmented basal cell carcinoma that had been excised completely.

The case, said Dr. Borges-Costa, shows that skin cancers can develop earlier than the typical 12-18 years after pediatric transplantation. Most reported cases have been squamous cell cancers and melanomas, and often are associated with lack of appropriate sun protection behavior.

The patient, a Caucasian, was a sailor who used sunscreen but did not typically wear a hat while sailing, reported Dr. Borges-Costa, a dermatologist at the University of Lisbon. Her family history was significant for a grandparent with melanoma.

Dr. Borges noted that the parents and patient were given advice regarding the importance of the lifelong use of sun-protective clothing and headgear. “Education of pediatric organ recipients and their parents about sun protection is important because, as occurred with our patient, protective clothing and hats are frequently forgotten.”

Because of the ongoing potential for skin malignancies, early referral “after transplantation to specialized dermatology outpatient clinics, similar to what is now advocated for transplanted adults, could help in surveillance and improve adherence to sun-protective measures,” he added.

SOURCE: Borges-Costa J et al. Pediatr Dermatol. 2018. doi: 10.1111/pde.13537..

A 17-year-old girl seen in a Portuguese dermatology clinic was found to have a nodular basal cell carcinoma on the parietal region of her scalp. The nodule appeared 6 years after she had received a kidney transplant, according to João Borges-Costa, MD, PhD, who submitted the case report.

Since the transplant, the girl had been maintained on immunosuppressive medication of tacrolimus 1 mg twice daily, mycophenolate sodium 360 mg twice daily, and prednisolone 10 mg every other day. The 1-cm nodule was pigmented; dermatoscopy did not yield clarity about whether the lesion was melanocytic. An excisional biopsy with 0.5-cm margins was performed, and histology confirmed that the lesion was a nodular pigmented basal cell carcinoma that had been excised completely.

The case, said Dr. Borges-Costa, shows that skin cancers can develop earlier than the typical 12-18 years after pediatric transplantation. Most reported cases have been squamous cell cancers and melanomas, and often are associated with lack of appropriate sun protection behavior.

The patient, a Caucasian, was a sailor who used sunscreen but did not typically wear a hat while sailing, reported Dr. Borges-Costa, a dermatologist at the University of Lisbon. Her family history was significant for a grandparent with melanoma.

Dr. Borges noted that the parents and patient were given advice regarding the importance of the lifelong use of sun-protective clothing and headgear. “Education of pediatric organ recipients and their parents about sun protection is important because, as occurred with our patient, protective clothing and hats are frequently forgotten.”

Because of the ongoing potential for skin malignancies, early referral “after transplantation to specialized dermatology outpatient clinics, similar to what is now advocated for transplanted adults, could help in surveillance and improve adherence to sun-protective measures,” he added.

SOURCE: Borges-Costa J et al. Pediatr Dermatol. 2018. doi: 10.1111/pde.13537..

Case Report

A 60-year-old man with a history of Hodgkin lymphoma that had been treated with chemotherapy 6 years prior presented to our dermatology clinic with a persistent pruritic rash on the back, abdomen, and bilateral arms and legs. The eruption initially began as localized discrete lesions on the lower back 1 year prior to the current presentation; at that time a diagnosis of psoriasis was made at an outside dermatology clinic, and treatment with mometasone furoate cream was initiated. Despite the patient’s compliance with this treatment, the lesions did not resolve and began spreading to the arms, legs, chest, and abdomen. His current medications included lisinopril, escitalopram, aspirin, and omeprazole.

On presentation to our clinic, physical examination revealed round, scaly, pink plaques and tumors of variable sizes (3–10 cm) distributed asymmetrically on the chest, back, abdomen, arms, and legs (Figure 1). The lesions were grouped in well-defined areas encompassing approximately 30% of the body surface area. No lymphadenopathy was appreciated. In vivo reflectance confocal microscopy (RCM) performed on one of the lesions revealed disarray of the epidermis with small, weakly refractile, round to oval cells scattered within the spinous layer and dermoepidermal junction (Figure 2). Additionally, these weakly refractile, round to oval cells also were seen in vesiclelike dark spaces, and hyporefractile basal cells were appreciated surrounding the dermal papillae. Mycosis fungoides (MF) was diagnosed following correlation of the RCM findings with the clinical picture.

A biopsy was performed, with pathologic examination confirming the diagnosis of tumor-stage MF. Parakeratosis with epidermotropism of lymphocytes was noted along the basal layer and into the spinous layer of the epidermis (Figure 3). Underlying the epidermis there was a dense mononuclear infiltrate and conspicuous eosinophils extending to the deeper reticular dermis. The infiltrating cells had cerebriform nuclei and large pale cytoplasm. On immunostaining, the lymphocytes were positive for CD3 and CD4, and negative for CD5, CD7, and CD8. The patient was referred to the oncology department for disease management. Staging workup including computed tomography, flow cytometry, and T-cell receptor gene rearrangement were consistent with tumor-stage MF (T3N0M0B0).

Comment

Clinical Presentation of MF
Mycosis fungoides, a non-Hodgkin lymphoma of T-cell origin, is the most commonly diagnosed cutaneous lymphoma worldwide.¹ It has an annual incidence of approximately 0.36 per 100,000 persons, and this number continues to rise.^2,3 The median age of diagnosis is 55 to 60 years, and MF occurs twice as often in men versus women.⁴

The clinical presentation of MF varies and is classified by stages including patches, plaques, tumors, and erythroderma.⁵ Classically, MF is slowly progressive and begins as pruritic erythematous patches that have a predilection for non–sun-exposed areas of the skin. Over time, these patches may evolve into plaques and tumors. Early or patch-stage MF often presents as well-demarcated lesions of various sizes and shapes that tend to enlarge.⁶ These lesions may resemble eczema or psoriasis if there is scaling, such as in our patient. At the tumor stage, flat or dome-shaped nodules that may vary in color and are deeper than plaques begin to appear. Ulcerations, which were absent in our case, may often be seen.

Because of the diverse clinical manifestations of MF, which can mimic other common dermatoses, diagnosis often is challenging for clinicians. Furthermore, histology can yield nonspecific diagnostic results and may even resemble chronic inflammatory dermatoses.⁷ As a result, patients frequently are subjected to multiple skin biopsies to establish the diagnosis,⁸ and diagnosis may be delayed, with the median time from onset of skin symptoms to diagnosis being approximately 6 years.⁹

Reflectance Confocal Microscopy
In vivo RCM is a noninvasive technique that allows visualization of the skin at a cellular level and recently has been evaluated as a diagnostic tool for many skin conditions.^10,11 Reflectance confocal microscopy findings have been well established for many cutaneous malignancies as well as inflammatory conditions such as psoriasis and atopic dermatitis.^12,13 Specifically, 2 preliminary descriptive studies utilized RCM to visualize the characteristic features of MF in vivo.^14,15 These studies reported the histopathologic correlation of RCM findings in biopsy-proven MF lesions. Consistent in all stages of MF is the presence of small, weakly refractile, round to oval cells within the spinous layer that correlate with atypical lymphocytes, in addition to hyporefractile basal cells surrounding the dermal papillae. Patch-stage MF lesions have more subtle epidermal findings compared to plaque-stage lesions, which tend to have more prominent vesiclelike dark spaces filled with collections of monomorphous, weakly refractile, round to oval cells corresponding with Pautrier microabscesses and evidence of spongiosis.^14,15 The first descriptive study of RCM in the diagnosis of MF failed to identify features of tumor-stage MF that would distinguish it from patch- or plaque-stage disease. The investigators also stated that deep nodular collections of atypical lymphocytes seen on histopathology in tumor-stage MF were missed on RCM evaluation.¹⁴ Furthermore, the second descriptive study of RCM and MF, which included 2 patients with tumor-stage disease, also failed to differentiate tumor-stage MF from the patch or plaque stages.¹⁵

Because of these 2 descriptive studies, a pilot study was conducted to determine the applicability and reproducibility of RCM findings for MF diagnosis.¹⁶ Two blinded confocalists were asked to diagnose RCM images as MF when compared to either normal skin or a variety of lymphoproliferative disorders. Of 15 patients, the confocalists correctly diagnosed MF in 84% and 90% of cases, respectively. Additionally, they reported the specificity and sensitivity of the following RCM features in the diagnosis of MF: spongiosis, 88.9% and 94.7%; loss of demarcation, 88.9% and 94.7%; disarray of the epidermis, 77.8% and 89.5%; hyporefractile rings, 88.9% and 78.9%; junctional atypical lymphocytes, 100% and 73.7%; and vesiclelike structures (Pautrier microabscesses), 100% and 73.7%. Importantly, this study did not evaluate the specificity and sensitivity of MF diagnosis compared to other eczematous or inflammatory conditions that may share similar RCM findings; therefore, these results are not generalizable, and many of the RCM findings characteristically seen in MF are not specific to its diagnosis.¹⁶

One study assessed the diagnostic accuracy of RCM in evaluating erythematosquamous diseases including MF, psoriasis, contact dermatitis, discoid lupus, and subacute cutaneous lupus.¹⁷ In this study, 3 blinded confocalists achieved a 95.41% and 92.89% specificity and 89.13% and 63.33% sensitivity for psoriasis and MF, respectively. Typical features of psoriasis on RCM included parakeratosis, reduction or absence of the granular layer, papillomatosis, acanthosis with normal honeycomb pattern of the epidermis, and dilated vessels in the upper dermis. Features that were more specific to MF included epidermotropic atypical lymphocytes, interface dermatitis, pleomorphic tumor cells, and dendritic cells.¹⁷ However, atypical lymphocytes and interface dermatitis also may be seen in cutaneous lupus; therefore, additional studies are still needed to validate RCM’s utility in differentiating between erythematosquamous skin diseases, including psoriasis, cutaneous lupus, and MF. Currently, RCM findings must be interpreted in conjunction with the clinical and histologic picture.

Importantly, RCM also is limited when evaluating MF due to its limited depth of visualization, as it allows imaging only to the superficial papillary dermis. Furthermore, any infiltrative process such as epidermal hyperplasia, spongiosis, or scaling, which can be seen in MF, may further impair the imaging quality of the deeper dermis.

Conclusion

Despite its limitations, RCM has the potential to be advantageous in evaluating skin lesions suspicious for MF in real time and is a promising technology for a quick noninvasive bedside adjunct tool. Its utility in selecting the optimal site for biopsy for better yield of histopathologic results in suspected MF cases has been demonstrated.¹⁶ However, large-scale studies still are needed to evaluate RCM in the diagnosis of the wide diversity of MF lesions as well as its efficacy in selecting optimal biopsy sites.

Case Report

A 60-year-old man with a history of Hodgkin lymphoma that had been treated with chemotherapy 6 years prior presented to our dermatology clinic with a persistent pruritic rash on the back, abdomen, and bilateral arms and legs. The eruption initially began as localized discrete lesions on the lower back 1 year prior to the current presentation; at that time a diagnosis of psoriasis was made at an outside dermatology clinic, and treatment with mometasone furoate cream was initiated. Despite the patient’s compliance with this treatment, the lesions did not resolve and began spreading to the arms, legs, chest, and abdomen. His current medications included lisinopril, escitalopram, aspirin, and omeprazole.

On presentation to our clinic, physical examination revealed round, scaly, pink plaques and tumors of variable sizes (3–10 cm) distributed asymmetrically on the chest, back, abdomen, arms, and legs (Figure 1). The lesions were grouped in well-defined areas encompassing approximately 30% of the body surface area. No lymphadenopathy was appreciated. In vivo reflectance confocal microscopy (RCM) performed on one of the lesions revealed disarray of the epidermis with small, weakly refractile, round to oval cells scattered within the spinous layer and dermoepidermal junction (Figure 2). Additionally, these weakly refractile, round to oval cells also were seen in vesiclelike dark spaces, and hyporefractile basal cells were appreciated surrounding the dermal papillae. Mycosis fungoides (MF) was diagnosed following correlation of the RCM findings with the clinical picture.

A biopsy was performed, with pathologic examination confirming the diagnosis of tumor-stage MF. Parakeratosis with epidermotropism of lymphocytes was noted along the basal layer and into the spinous layer of the epidermis (Figure 3). Underlying the epidermis there was a dense mononuclear infiltrate and conspicuous eosinophils extending to the deeper reticular dermis. The infiltrating cells had cerebriform nuclei and large pale cytoplasm. On immunostaining, the lymphocytes were positive for CD3 and CD4, and negative for CD5, CD7, and CD8. The patient was referred to the oncology department for disease management. Staging workup including computed tomography, flow cytometry, and T-cell receptor gene rearrangement were consistent with tumor-stage MF (T3N0M0B0).

Comment

Clinical Presentation of MF
Mycosis fungoides, a non-Hodgkin lymphoma of T-cell origin, is the most commonly diagnosed cutaneous lymphoma worldwide.¹ It has an annual incidence of approximately 0.36 per 100,000 persons, and this number continues to rise.^2,3 The median age of diagnosis is 55 to 60 years, and MF occurs twice as often in men versus women.⁴

The clinical presentation of MF varies and is classified by stages including patches, plaques, tumors, and erythroderma.⁵ Classically, MF is slowly progressive and begins as pruritic erythematous patches that have a predilection for non–sun-exposed areas of the skin. Over time, these patches may evolve into plaques and tumors. Early or patch-stage MF often presents as well-demarcated lesions of various sizes and shapes that tend to enlarge.⁶ These lesions may resemble eczema or psoriasis if there is scaling, such as in our patient. At the tumor stage, flat or dome-shaped nodules that may vary in color and are deeper than plaques begin to appear. Ulcerations, which were absent in our case, may often be seen.

Because of the diverse clinical manifestations of MF, which can mimic other common dermatoses, diagnosis often is challenging for clinicians. Furthermore, histology can yield nonspecific diagnostic results and may even resemble chronic inflammatory dermatoses.⁷ As a result, patients frequently are subjected to multiple skin biopsies to establish the diagnosis,⁸ and diagnosis may be delayed, with the median time from onset of skin symptoms to diagnosis being approximately 6 years.⁹

Reflectance Confocal Microscopy
In vivo RCM is a noninvasive technique that allows visualization of the skin at a cellular level and recently has been evaluated as a diagnostic tool for many skin conditions.^10,11 Reflectance confocal microscopy findings have been well established for many cutaneous malignancies as well as inflammatory conditions such as psoriasis and atopic dermatitis.^12,13 Specifically, 2 preliminary descriptive studies utilized RCM to visualize the characteristic features of MF in vivo.^14,15 These studies reported the histopathologic correlation of RCM findings in biopsy-proven MF lesions. Consistent in all stages of MF is the presence of small, weakly refractile, round to oval cells within the spinous layer that correlate with atypical lymphocytes, in addition to hyporefractile basal cells surrounding the dermal papillae. Patch-stage MF lesions have more subtle epidermal findings compared to plaque-stage lesions, which tend to have more prominent vesiclelike dark spaces filled with collections of monomorphous, weakly refractile, round to oval cells corresponding with Pautrier microabscesses and evidence of spongiosis.^14,15 The first descriptive study of RCM in the diagnosis of MF failed to identify features of tumor-stage MF that would distinguish it from patch- or plaque-stage disease. The investigators also stated that deep nodular collections of atypical lymphocytes seen on histopathology in tumor-stage MF were missed on RCM evaluation.¹⁴ Furthermore, the second descriptive study of RCM and MF, which included 2 patients with tumor-stage disease, also failed to differentiate tumor-stage MF from the patch or plaque stages.¹⁵

Because of these 2 descriptive studies, a pilot study was conducted to determine the applicability and reproducibility of RCM findings for MF diagnosis.¹⁶ Two blinded confocalists were asked to diagnose RCM images as MF when compared to either normal skin or a variety of lymphoproliferative disorders. Of 15 patients, the confocalists correctly diagnosed MF in 84% and 90% of cases, respectively. Additionally, they reported the specificity and sensitivity of the following RCM features in the diagnosis of MF: spongiosis, 88.9% and 94.7%; loss of demarcation, 88.9% and 94.7%; disarray of the epidermis, 77.8% and 89.5%; hyporefractile rings, 88.9% and 78.9%; junctional atypical lymphocytes, 100% and 73.7%; and vesiclelike structures (Pautrier microabscesses), 100% and 73.7%. Importantly, this study did not evaluate the specificity and sensitivity of MF diagnosis compared to other eczematous or inflammatory conditions that may share similar RCM findings; therefore, these results are not generalizable, and many of the RCM findings characteristically seen in MF are not specific to its diagnosis.¹⁶

One study assessed the diagnostic accuracy of RCM in evaluating erythematosquamous diseases including MF, psoriasis, contact dermatitis, discoid lupus, and subacute cutaneous lupus.¹⁷ In this study, 3 blinded confocalists achieved a 95.41% and 92.89% specificity and 89.13% and 63.33% sensitivity for psoriasis and MF, respectively. Typical features of psoriasis on RCM included parakeratosis, reduction or absence of the granular layer, papillomatosis, acanthosis with normal honeycomb pattern of the epidermis, and dilated vessels in the upper dermis. Features that were more specific to MF included epidermotropic atypical lymphocytes, interface dermatitis, pleomorphic tumor cells, and dendritic cells.¹⁷ However, atypical lymphocytes and interface dermatitis also may be seen in cutaneous lupus; therefore, additional studies are still needed to validate RCM’s utility in differentiating between erythematosquamous skin diseases, including psoriasis, cutaneous lupus, and MF. Currently, RCM findings must be interpreted in conjunction with the clinical and histologic picture.

Importantly, RCM also is limited when evaluating MF due to its limited depth of visualization, as it allows imaging only to the superficial papillary dermis. Furthermore, any infiltrative process such as epidermal hyperplasia, spongiosis, or scaling, which can be seen in MF, may further impair the imaging quality of the deeper dermis.

Conclusion

Despite its limitations, RCM has the potential to be advantageous in evaluating skin lesions suspicious for MF in real time and is a promising technology for a quick noninvasive bedside adjunct tool. Its utility in selecting the optimal site for biopsy for better yield of histopathologic results in suspected MF cases has been demonstrated.¹⁶ However, large-scale studies still are needed to evaluate RCM in the diagnosis of the wide diversity of MF lesions as well as its efficacy in selecting optimal biopsy sites.

Case Report

A 60-year-old man with a history of Hodgkin lymphoma that had been treated with chemotherapy 6 years prior presented to our dermatology clinic with a persistent pruritic rash on the back, abdomen, and bilateral arms and legs. The eruption initially began as localized discrete lesions on the lower back 1 year prior to the current presentation; at that time a diagnosis of psoriasis was made at an outside dermatology clinic, and treatment with mometasone furoate cream was initiated. Despite the patient’s compliance with this treatment, the lesions did not resolve and began spreading to the arms, legs, chest, and abdomen. His current medications included lisinopril, escitalopram, aspirin, and omeprazole.

On presentation to our clinic, physical examination revealed round, scaly, pink plaques and tumors of variable sizes (3–10 cm) distributed asymmetrically on the chest, back, abdomen, arms, and legs (Figure 1). The lesions were grouped in well-defined areas encompassing approximately 30% of the body surface area. No lymphadenopathy was appreciated. In vivo reflectance confocal microscopy (RCM) performed on one of the lesions revealed disarray of the epidermis with small, weakly refractile, round to oval cells scattered within the spinous layer and dermoepidermal junction (Figure 2). Additionally, these weakly refractile, round to oval cells also were seen in vesiclelike dark spaces, and hyporefractile basal cells were appreciated surrounding the dermal papillae. Mycosis fungoides (MF) was diagnosed following correlation of the RCM findings with the clinical picture.

A biopsy was performed, with pathologic examination confirming the diagnosis of tumor-stage MF. Parakeratosis with epidermotropism of lymphocytes was noted along the basal layer and into the spinous layer of the epidermis (Figure 3). Underlying the epidermis there was a dense mononuclear infiltrate and conspicuous eosinophils extending to the deeper reticular dermis. The infiltrating cells had cerebriform nuclei and large pale cytoplasm. On immunostaining, the lymphocytes were positive for CD3 and CD4, and negative for CD5, CD7, and CD8. The patient was referred to the oncology department for disease management. Staging workup including computed tomography, flow cytometry, and T-cell receptor gene rearrangement were consistent with tumor-stage MF (T3N0M0B0).

Comment

Clinical Presentation of MF
Mycosis fungoides, a non-Hodgkin lymphoma of T-cell origin, is the most commonly diagnosed cutaneous lymphoma worldwide.¹ It has an annual incidence of approximately 0.36 per 100,000 persons, and this number continues to rise.^2,3 The median age of diagnosis is 55 to 60 years, and MF occurs twice as often in men versus women.⁴

The clinical presentation of MF varies and is classified by stages including patches, plaques, tumors, and erythroderma.⁵ Classically, MF is slowly progressive and begins as pruritic erythematous patches that have a predilection for non–sun-exposed areas of the skin. Over time, these patches may evolve into plaques and tumors. Early or patch-stage MF often presents as well-demarcated lesions of various sizes and shapes that tend to enlarge.⁶ These lesions may resemble eczema or psoriasis if there is scaling, such as in our patient. At the tumor stage, flat or dome-shaped nodules that may vary in color and are deeper than plaques begin to appear. Ulcerations, which were absent in our case, may often be seen.

Because of the diverse clinical manifestations of MF, which can mimic other common dermatoses, diagnosis often is challenging for clinicians. Furthermore, histology can yield nonspecific diagnostic results and may even resemble chronic inflammatory dermatoses.⁷ As a result, patients frequently are subjected to multiple skin biopsies to establish the diagnosis,⁸ and diagnosis may be delayed, with the median time from onset of skin symptoms to diagnosis being approximately 6 years.⁹

Reflectance Confocal Microscopy
In vivo RCM is a noninvasive technique that allows visualization of the skin at a cellular level and recently has been evaluated as a diagnostic tool for many skin conditions.^10,11 Reflectance confocal microscopy findings have been well established for many cutaneous malignancies as well as inflammatory conditions such as psoriasis and atopic dermatitis.^12,13 Specifically, 2 preliminary descriptive studies utilized RCM to visualize the characteristic features of MF in vivo.^14,15 These studies reported the histopathologic correlation of RCM findings in biopsy-proven MF lesions. Consistent in all stages of MF is the presence of small, weakly refractile, round to oval cells within the spinous layer that correlate with atypical lymphocytes, in addition to hyporefractile basal cells surrounding the dermal papillae. Patch-stage MF lesions have more subtle epidermal findings compared to plaque-stage lesions, which tend to have more prominent vesiclelike dark spaces filled with collections of monomorphous, weakly refractile, round to oval cells corresponding with Pautrier microabscesses and evidence of spongiosis.^14,15 The first descriptive study of RCM in the diagnosis of MF failed to identify features of tumor-stage MF that would distinguish it from patch- or plaque-stage disease. The investigators also stated that deep nodular collections of atypical lymphocytes seen on histopathology in tumor-stage MF were missed on RCM evaluation.¹⁴ Furthermore, the second descriptive study of RCM and MF, which included 2 patients with tumor-stage disease, also failed to differentiate tumor-stage MF from the patch or plaque stages.¹⁵

Because of these 2 descriptive studies, a pilot study was conducted to determine the applicability and reproducibility of RCM findings for MF diagnosis.¹⁶ Two blinded confocalists were asked to diagnose RCM images as MF when compared to either normal skin or a variety of lymphoproliferative disorders. Of 15 patients, the confocalists correctly diagnosed MF in 84% and 90% of cases, respectively. Additionally, they reported the specificity and sensitivity of the following RCM features in the diagnosis of MF: spongiosis, 88.9% and 94.7%; loss of demarcation, 88.9% and 94.7%; disarray of the epidermis, 77.8% and 89.5%; hyporefractile rings, 88.9% and 78.9%; junctional atypical lymphocytes, 100% and 73.7%; and vesiclelike structures (Pautrier microabscesses), 100% and 73.7%. Importantly, this study did not evaluate the specificity and sensitivity of MF diagnosis compared to other eczematous or inflammatory conditions that may share similar RCM findings; therefore, these results are not generalizable, and many of the RCM findings characteristically seen in MF are not specific to its diagnosis.¹⁶

One study assessed the diagnostic accuracy of RCM in evaluating erythematosquamous diseases including MF, psoriasis, contact dermatitis, discoid lupus, and subacute cutaneous lupus.¹⁷ In this study, 3 blinded confocalists achieved a 95.41% and 92.89% specificity and 89.13% and 63.33% sensitivity for psoriasis and MF, respectively. Typical features of psoriasis on RCM included parakeratosis, reduction or absence of the granular layer, papillomatosis, acanthosis with normal honeycomb pattern of the epidermis, and dilated vessels in the upper dermis. Features that were more specific to MF included epidermotropic atypical lymphocytes, interface dermatitis, pleomorphic tumor cells, and dendritic cells.¹⁷ However, atypical lymphocytes and interface dermatitis also may be seen in cutaneous lupus; therefore, additional studies are still needed to validate RCM’s utility in differentiating between erythematosquamous skin diseases, including psoriasis, cutaneous lupus, and MF. Currently, RCM findings must be interpreted in conjunction with the clinical and histologic picture.

Importantly, RCM also is limited when evaluating MF due to its limited depth of visualization, as it allows imaging only to the superficial papillary dermis. Furthermore, any infiltrative process such as epidermal hyperplasia, spongiosis, or scaling, which can be seen in MF, may further impair the imaging quality of the deeper dermis.

Conclusion

Despite its limitations, RCM has the potential to be advantageous in evaluating skin lesions suspicious for MF in real time and is a promising technology for a quick noninvasive bedside adjunct tool. Its utility in selecting the optimal site for biopsy for better yield of histopathologic results in suspected MF cases has been demonstrated.¹⁶ However, large-scale studies still are needed to evaluate RCM in the diagnosis of the wide diversity of MF lesions as well as its efficacy in selecting optimal biopsy sites.

Practice Gap

Mohs micrographic surgery (MMS) is a highly curative tissue-sparing skin cancer treatment¹ and is a required component of dermatology residency training. According to the Accreditation Council for Graduate Medical Education, residents must have exposure “either through direct observation or as an assistant in Mohs micrographic surgery, and reconstruction of these defects, to include flaps and grafts.”² The MMS technique allows for complete circumferential peripheral and deep margin assessment of excised specimens; however, the conformation of a 3-dimensional gross tissue specimen into a 2-dimensional specimen as represented on a microscope slide is challenging to conceptualize.

Behavioral science research has shown that analogies and metaphors help integrate topics into a memorable format and produce deeper comprehension.³ As such, analogies can aid in the visualization of these complex spatial concepts. The MMS tissue-processing technique has been compared to flattening a pie pan.⁴ More recently, a peanut butter cup analogy was described as a visualization tool for explaining the various steps of MMS to patients.⁵ Although these analogies may help elucidate certain aspects of the MMS technique, none adequately account for the multilayered anatomy of the skin.

The Technique

To address this need, we developed the cantaloupe analogy, which provides visual representation of the 3 basic skin layers: (1) the rind represents the epidermis; (2) the flesh represents the dermis, and (3) the seed cavity represents the subcutaneous layer (Figures 1 and 2).

Image courtesy of Janna M. Vassantachart, MD.

Image courtesy of Janna M. Vassantachart, MD.

In MMS tissue processing, the peripheral margin of the ovoid excised skin specimen is pressed down into the same plane as the deepest layer through a process called relaxation.⁴ The cantaloupe represents the dome shape of the relaxed tissue, which is then serially sectioned in horizontal layers from deep to superficial (Figure 2). The first slice represents the deepest subcutaneous layer and most peripheral dermal and epidermal layers of the specimen (Figure 3). Using the cantaloupe analogy, subsequent stages (if warranted) would be guided by the location of the residual skin cancer. If the skin cancer is in the epidermis (rind) or dermis (flesh), then a skin specimen from the perimeter of the defect would be indicated. Residual skin cancer extending into the subcutaneous layer (seed cavity) would require a deeper resection.

Image courtesy of Janna M. Vassantachart, MD.

Practice Implications

The cantaloupe provides a simple analogy to conceptualize the transition from the multilayered 3-dimensional skin tissue specimen to the 2-dimensional histologic slide specimen. Use of this cantaloupe analogy will aid dermatology residents and others interested in gaining a clearer understanding of MMS.

Practice Gap

Mohs micrographic surgery (MMS) is a highly curative tissue-sparing skin cancer treatment¹ and is a required component of dermatology residency training. According to the Accreditation Council for Graduate Medical Education, residents must have exposure “either through direct observation or as an assistant in Mohs micrographic surgery, and reconstruction of these defects, to include flaps and grafts.”² The MMS technique allows for complete circumferential peripheral and deep margin assessment of excised specimens; however, the conformation of a 3-dimensional gross tissue specimen into a 2-dimensional specimen as represented on a microscope slide is challenging to conceptualize.

Behavioral science research has shown that analogies and metaphors help integrate topics into a memorable format and produce deeper comprehension.³ As such, analogies can aid in the visualization of these complex spatial concepts. The MMS tissue-processing technique has been compared to flattening a pie pan.⁴ More recently, a peanut butter cup analogy was described as a visualization tool for explaining the various steps of MMS to patients.⁵ Although these analogies may help elucidate certain aspects of the MMS technique, none adequately account for the multilayered anatomy of the skin.

The Technique

To address this need, we developed the cantaloupe analogy, which provides visual representation of the 3 basic skin layers: (1) the rind represents the epidermis; (2) the flesh represents the dermis, and (3) the seed cavity represents the subcutaneous layer (Figures 1 and 2).

Image courtesy of Janna M. Vassantachart, MD.

Image courtesy of Janna M. Vassantachart, MD.

In MMS tissue processing, the peripheral margin of the ovoid excised skin specimen is pressed down into the same plane as the deepest layer through a process called relaxation.⁴ The cantaloupe represents the dome shape of the relaxed tissue, which is then serially sectioned in horizontal layers from deep to superficial (Figure 2). The first slice represents the deepest subcutaneous layer and most peripheral dermal and epidermal layers of the specimen (Figure 3). Using the cantaloupe analogy, subsequent stages (if warranted) would be guided by the location of the residual skin cancer. If the skin cancer is in the epidermis (rind) or dermis (flesh), then a skin specimen from the perimeter of the defect would be indicated. Residual skin cancer extending into the subcutaneous layer (seed cavity) would require a deeper resection.

Image courtesy of Janna M. Vassantachart, MD.

Practice Implications

The cantaloupe provides a simple analogy to conceptualize the transition from the multilayered 3-dimensional skin tissue specimen to the 2-dimensional histologic slide specimen. Use of this cantaloupe analogy will aid dermatology residents and others interested in gaining a clearer understanding of MMS.

Practice Gap

Mohs micrographic surgery (MMS) is a highly curative tissue-sparing skin cancer treatment¹ and is a required component of dermatology residency training. According to the Accreditation Council for Graduate Medical Education, residents must have exposure “either through direct observation or as an assistant in Mohs micrographic surgery, and reconstruction of these defects, to include flaps and grafts.”² The MMS technique allows for complete circumferential peripheral and deep margin assessment of excised specimens; however, the conformation of a 3-dimensional gross tissue specimen into a 2-dimensional specimen as represented on a microscope slide is challenging to conceptualize.

Behavioral science research has shown that analogies and metaphors help integrate topics into a memorable format and produce deeper comprehension.³ As such, analogies can aid in the visualization of these complex spatial concepts. The MMS tissue-processing technique has been compared to flattening a pie pan.⁴ More recently, a peanut butter cup analogy was described as a visualization tool for explaining the various steps of MMS to patients.⁵ Although these analogies may help elucidate certain aspects of the MMS technique, none adequately account for the multilayered anatomy of the skin.

The Technique

To address this need, we developed the cantaloupe analogy, which provides visual representation of the 3 basic skin layers: (1) the rind represents the epidermis; (2) the flesh represents the dermis, and (3) the seed cavity represents the subcutaneous layer (Figures 1 and 2).

Image courtesy of Janna M. Vassantachart, MD.

Image courtesy of Janna M. Vassantachart, MD.

In MMS tissue processing, the peripheral margin of the ovoid excised skin specimen is pressed down into the same plane as the deepest layer through a process called relaxation.⁴ The cantaloupe represents the dome shape of the relaxed tissue, which is then serially sectioned in horizontal layers from deep to superficial (Figure 2). The first slice represents the deepest subcutaneous layer and most peripheral dermal and epidermal layers of the specimen (Figure 3). Using the cantaloupe analogy, subsequent stages (if warranted) would be guided by the location of the residual skin cancer. If the skin cancer is in the epidermis (rind) or dermis (flesh), then a skin specimen from the perimeter of the defect would be indicated. Residual skin cancer extending into the subcutaneous layer (seed cavity) would require a deeper resection.

Image courtesy of Janna M. Vassantachart, MD.

Practice Implications

The cantaloupe provides a simple analogy to conceptualize the transition from the multilayered 3-dimensional skin tissue specimen to the 2-dimensional histologic slide specimen. Use of this cantaloupe analogy will aid dermatology residents and others interested in gaining a clearer understanding of MMS.

A patient with an aggressive form of squamous cell carcinoma (SCC) experienced complete resolution of tumors following administration of human papillomavirus (HPV) vaccine, a recent case report shows.

The patient, an immunocompetent woman, aged in her 90s, with multiple inoperable cutaneous basaloid SCCs, was treated with a combination of systemic and intratumoral delivery of 9-valent HPV vaccine, authors of the case report wrote in JAMA Dermatology.

All tumors resolved within 11 months of the first intratumoral injection, according to Anna J. Nichols, MD, PhD, department of dermatology and cutaneous surgery, University of Miami, and her coauthors.

‘These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection,” they wrote.

Previously, Dr. Nichols and her coinvestigators reported a reduction in SCCs and basal cell carcinoma in 2 immunocompetent patients who had received quadrivalent HPV vaccine. Those results suggested development of these keratinocyte carcinomas in immunocompetent patients may be driven in part by HPV, the investigators said at the time.

The patient in the current report was treated with 9-valent HPV vaccine in a university-based outpatient clinic between March 2016 and February 2017.

She initially received two doses of intramuscular vaccine 6 weeks apart; 3 weeks later, she received intratumoral administration of the vaccine diluted with sterile saline, followed by three additional intratumoral doses over the next 8 months.

“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” Dr. Nichols and her coauthors said in the report.

A reduction in tumor size and number was seen 2 weeks after the second intratumoral dose of the 9-valent HPV vaccine, and within 11 months of the first intratumoral dose, there was no clinical or histologic evidence of SCC, they said.

The patient was left with small, violet-colored scars, along with a small pink papule, histopathologic analysis of which showed mild cellular atypia of basal keratinocytes with hyperkeratosis, according to published details of the case report.

The patient experienced mild pain in some of the tumors on days of intratumoral treatment, but no other side effects were seen, according to the authors.

The patient remained tumor free at the end of follow-up in May 2018, and there was no clinical evidence of SCC recurrence at the patient’s most recent follow-up visit, 24 months after the first intratumoral HPV dose, the researchers wrote.

It’s not clear what role the systemic vaccine doses played in the therapeutic benefit the patient experienced, authors said, noting that tumors not injected directly may have regressed because of either local vaccine dispersion or systemic, immune-mediated mechanisms.

“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they concluded.

Dr. Nichols had no disclosures. Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.

SOURCE: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.

A patient with an aggressive form of squamous cell carcinoma (SCC) experienced complete resolution of tumors following administration of human papillomavirus (HPV) vaccine, a recent case report shows.

The patient, an immunocompetent woman, aged in her 90s, with multiple inoperable cutaneous basaloid SCCs, was treated with a combination of systemic and intratumoral delivery of 9-valent HPV vaccine, authors of the case report wrote in JAMA Dermatology.

All tumors resolved within 11 months of the first intratumoral injection, according to Anna J. Nichols, MD, PhD, department of dermatology and cutaneous surgery, University of Miami, and her coauthors.

‘These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection,” they wrote.

Previously, Dr. Nichols and her coinvestigators reported a reduction in SCCs and basal cell carcinoma in 2 immunocompetent patients who had received quadrivalent HPV vaccine. Those results suggested development of these keratinocyte carcinomas in immunocompetent patients may be driven in part by HPV, the investigators said at the time.

The patient in the current report was treated with 9-valent HPV vaccine in a university-based outpatient clinic between March 2016 and February 2017.

She initially received two doses of intramuscular vaccine 6 weeks apart; 3 weeks later, she received intratumoral administration of the vaccine diluted with sterile saline, followed by three additional intratumoral doses over the next 8 months.

“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” Dr. Nichols and her coauthors said in the report.

A reduction in tumor size and number was seen 2 weeks after the second intratumoral dose of the 9-valent HPV vaccine, and within 11 months of the first intratumoral dose, there was no clinical or histologic evidence of SCC, they said.

The patient was left with small, violet-colored scars, along with a small pink papule, histopathologic analysis of which showed mild cellular atypia of basal keratinocytes with hyperkeratosis, according to published details of the case report.

The patient experienced mild pain in some of the tumors on days of intratumoral treatment, but no other side effects were seen, according to the authors.

The patient remained tumor free at the end of follow-up in May 2018, and there was no clinical evidence of SCC recurrence at the patient’s most recent follow-up visit, 24 months after the first intratumoral HPV dose, the researchers wrote.

It’s not clear what role the systemic vaccine doses played in the therapeutic benefit the patient experienced, authors said, noting that tumors not injected directly may have regressed because of either local vaccine dispersion or systemic, immune-mediated mechanisms.

“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they concluded.

Dr. Nichols had no disclosures. Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.

SOURCE: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.

A patient with an aggressive form of squamous cell carcinoma (SCC) experienced complete resolution of tumors following administration of human papillomavirus (HPV) vaccine, a recent case report shows.

The patient, an immunocompetent woman, aged in her 90s, with multiple inoperable cutaneous basaloid SCCs, was treated with a combination of systemic and intratumoral delivery of 9-valent HPV vaccine, authors of the case report wrote in JAMA Dermatology.

All tumors resolved within 11 months of the first intratumoral injection, according to Anna J. Nichols, MD, PhD, department of dermatology and cutaneous surgery, University of Miami, and her coauthors.

‘These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection,” they wrote.

Previously, Dr. Nichols and her coinvestigators reported a reduction in SCCs and basal cell carcinoma in 2 immunocompetent patients who had received quadrivalent HPV vaccine. Those results suggested development of these keratinocyte carcinomas in immunocompetent patients may be driven in part by HPV, the investigators said at the time.

The patient in the current report was treated with 9-valent HPV vaccine in a university-based outpatient clinic between March 2016 and February 2017.

She initially received two doses of intramuscular vaccine 6 weeks apart; 3 weeks later, she received intratumoral administration of the vaccine diluted with sterile saline, followed by three additional intratumoral doses over the next 8 months.

“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” Dr. Nichols and her coauthors said in the report.

A reduction in tumor size and number was seen 2 weeks after the second intratumoral dose of the 9-valent HPV vaccine, and within 11 months of the first intratumoral dose, there was no clinical or histologic evidence of SCC, they said.

The patient was left with small, violet-colored scars, along with a small pink papule, histopathologic analysis of which showed mild cellular atypia of basal keratinocytes with hyperkeratosis, according to published details of the case report.

The patient experienced mild pain in some of the tumors on days of intratumoral treatment, but no other side effects were seen, according to the authors.

The patient remained tumor free at the end of follow-up in May 2018, and there was no clinical evidence of SCC recurrence at the patient’s most recent follow-up visit, 24 months after the first intratumoral HPV dose, the researchers wrote.

It’s not clear what role the systemic vaccine doses played in the therapeutic benefit the patient experienced, authors said, noting that tumors not injected directly may have regressed because of either local vaccine dispersion or systemic, immune-mediated mechanisms.

“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they concluded.

Dr. Nichols had no disclosures. Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.

SOURCE: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer after basal cell carcinoma.¹ With an estimated 700,000 cases reported annually in the United States, the incidence of cSCC continues to increase.² Most patients with cSCC have an excellent prognosis after surgical clearance, with Mohs micrographic surgery (MMS) being the most successful treatment, followed by excision and electrodesiccation and curettage. A subset of patients with cSCC carry an increased risk of local recurrence, lymph node metastasis, and disease-specific death. A meta-analysis of 36 studies found that statistically significant risk factors for recurrence of cSCC included thickness greater than 2 mm (risk ratio [RR], 9.64; 95% CI, 1.30-1.52), invasion beyond the subcutaneous fat (RR, 7.61; 95% CI, 4.17-13.88), perineural invasion (RR, 4.30; 95% CI, 2.80-6.60), diameter greater than 20 mm (RR, 3.22; 95% CI, 1.91-5.45), location on temple (RR, 3.20; 95% CI, 1.12-9.15), and poor differentiation (RR, 2.66; 95% CI, 1.72-4.14).³ Additional risk factors for cSCC metastasis included location on the temple, ear, or lip, as well as a history of immunosuppression. Factors for disease-specific death were diameter greater than 20 mm, poor differentiation, location on the ear or lip, invasion beyond the subcutaneous fat, and perineural invasion.³ Perineural and/or lymphovascular invasion is considered high risk, but despite being linked to negative outcomes, there are no treatment guidelines based on lymphovascular (intravascular) invasion.⁴ We present a case of intravascular involvement found during MMS and treated with adjuvant radiotherapy after surgery. We share this case with the goal of discussing management in such cases and highlighting the need for improved definitive guidelines for high-risk cSCCs.

Case Report

A 72-year-old man presented with a rapidly growing lesion on the left side of the forehead of 1 year’s duration. His medical history was remarkable for B-cell lymphoma, which was currently in remission following chemotherapy 10 years prior. The lesion started as a small, red, dry patch that the patient initially thought was eczema. The site progressively enlarged to a red tumor measuring 2.4×2.0 cm (Figure 1), and the patient presented to the dermatology department for further evaluation. There was no clinical evidence of lymphadenopathy. A skin biopsy confirmed a moderately differentiated cSCC with a positive deep margin (Figure 2). Due to the tumor’s location, histology, size, and poorly defined borders, the patient was referred for treatment with MMS. The lesion was removed in a total of 2 stages and 4 sections. In addition to a proliferation of spindled tumor cells seen during surgery, which was consistent with cSCC, an intravascular component was noted despite clear margins after the surgery (Figure 3). The aggressive histology of intravascular involvement was subsequently confirmed by the academic dermatopathologist at our institution. With the evidence of an intravascular component of this patient’s cSCC, there was concern about further metastatic disease. After discussing the more aggressive histology type and size of the cSCC with the patient, he underwent subsequent computed tomography of the head, neck, and chest. Fortunately, this imaging did not show evidence of metastatic disease; thus, final staging of the cSCC was cT2N0M0. After interdisciplinary discussion and consultation with radiation oncology, the site of the cSCC was treated with adjuvant radiotherapy. The patient received a total of 6600 cGy delivered in 33 fractions of 200 cGy, each using an en face technique and 6 eV over a total treatment course of 48 days.

One year after undergoing MMS and adjuvant radiotherapy, the patient remains free of cSCC recurrence or metastases and still undergoes regular interdisciplinary monitoring. Without clear guidelines on the treatment of patients with intravascular involvement of cSCC, we relied on prior experience with similar cases.

Comment

This case highlights the challenge in managing patients with high-risk cSCC, as the current guidelines provided by the American Joint Committee on Cancer (AJCC) and the National Comprehensive Cancer Network (NCCN) vary on the inclusion of intravascular involvement of cSCC as high risk and treatment is at the discretion of the provider in such circumstances.^5-7 Both the AJCC and the NCCN have defined high-risk factors and staging for cSCC. The AJCC 8th edition (AJCC-8) revised guidelines include several high-risk factors of cSCC, including tumor diameter of 4 cm or larger leading to upstaging of a tumor from T2 to T3, invasion into or beyond the level of the subcutaneous tissue, depth of invasion greater than 6 mm, and large-caliber perineural invasion, and removed poorly differentiated histology from the AJCC-8 guidelines compared to the AJCC-7 guidelines. According to the AJCC-8 guidelines, location on the ear or lip, desmoplastic or spindle cell features, lymphovascular invasion, and immunosuppression do not affect tumor staging. The AJCC’s criteria for its TNM staging system strictly focus on features of the primary tumor and do not include clinical risk factors such as recurrence or immunosuppression. In contrast, the NCCN does include lymphovascular invasion as a high-risk factor of cSCC.

Intravascular invasion plays a considerable role in patient survival in certain cancers (eg, breast, gastric, prostate). In cutaneous malignancies, such as melanoma and SCC, metastasis more commonly occurs via lymphatic spread. When present, vascular invasion typically coexists with lymphatic involvement. The presence of microscopic lymphovascular invasion in cSCCs has not been definitively proven to increase the risk of metastases.⁸ However, multivariate analysis has shown that lymphovascular invasion independently predicts nodal metastasis and disease-specific death.⁹ As such, there are no guidelines on sentinel lymph node biopsy or adjuvant therapy in the setting of lymphovascular involvement of cSCCs. A survey-based study of 117 Mohs surgeons found a lack of consistency in their approaches to evaluation and management of high-risk SCCs. Most respondents noted perineural invasion and in-transit metastasis as the main findings that would lead to radiologic nodal staging, sentinel lymph node biopsy, or adjuvant radiotherapy, but they highlighted the lack of evidence-based treatment guidelines.⁴ High-risk cSCC can be treated via MMS or conventional surgery with safe excision margins. Adjuvant radiotherapy can reduce tumor recurrence and improve survival and therefore should be considered in cases of advanced or high-risk cSCCs, such as in our case.

The lack of consensus over the definition of high-risk cSCCs, a lack of high-quality therapeutic studies, and the absence of a prognostic model that integrates multiple risk factors all have made the prediction of outcomes and the formation of definitive management of cSCCs challenging. Multidisciplinary teams and vigilant monitoring are crucial in the successful management of high-risk cSCC, but further studies and reports are needed to develop definitive treatment algorithms.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer after basal cell carcinoma.¹ With an estimated 700,000 cases reported annually in the United States, the incidence of cSCC continues to increase.² Most patients with cSCC have an excellent prognosis after surgical clearance, with Mohs micrographic surgery (MMS) being the most successful treatment, followed by excision and electrodesiccation and curettage. A subset of patients with cSCC carry an increased risk of local recurrence, lymph node metastasis, and disease-specific death. A meta-analysis of 36 studies found that statistically significant risk factors for recurrence of cSCC included thickness greater than 2 mm (risk ratio [RR], 9.64; 95% CI, 1.30-1.52), invasion beyond the subcutaneous fat (RR, 7.61; 95% CI, 4.17-13.88), perineural invasion (RR, 4.30; 95% CI, 2.80-6.60), diameter greater than 20 mm (RR, 3.22; 95% CI, 1.91-5.45), location on temple (RR, 3.20; 95% CI, 1.12-9.15), and poor differentiation (RR, 2.66; 95% CI, 1.72-4.14).³ Additional risk factors for cSCC metastasis included location on the temple, ear, or lip, as well as a history of immunosuppression. Factors for disease-specific death were diameter greater than 20 mm, poor differentiation, location on the ear or lip, invasion beyond the subcutaneous fat, and perineural invasion.³ Perineural and/or lymphovascular invasion is considered high risk, but despite being linked to negative outcomes, there are no treatment guidelines based on lymphovascular (intravascular) invasion.⁴ We present a case of intravascular involvement found during MMS and treated with adjuvant radiotherapy after surgery. We share this case with the goal of discussing management in such cases and highlighting the need for improved definitive guidelines for high-risk cSCCs.

Case Report

A 72-year-old man presented with a rapidly growing lesion on the left side of the forehead of 1 year’s duration. His medical history was remarkable for B-cell lymphoma, which was currently in remission following chemotherapy 10 years prior. The lesion started as a small, red, dry patch that the patient initially thought was eczema. The site progressively enlarged to a red tumor measuring 2.4×2.0 cm (Figure 1), and the patient presented to the dermatology department for further evaluation. There was no clinical evidence of lymphadenopathy. A skin biopsy confirmed a moderately differentiated cSCC with a positive deep margin (Figure 2). Due to the tumor’s location, histology, size, and poorly defined borders, the patient was referred for treatment with MMS. The lesion was removed in a total of 2 stages and 4 sections. In addition to a proliferation of spindled tumor cells seen during surgery, which was consistent with cSCC, an intravascular component was noted despite clear margins after the surgery (Figure 3). The aggressive histology of intravascular involvement was subsequently confirmed by the academic dermatopathologist at our institution. With the evidence of an intravascular component of this patient’s cSCC, there was concern about further metastatic disease. After discussing the more aggressive histology type and size of the cSCC with the patient, he underwent subsequent computed tomography of the head, neck, and chest. Fortunately, this imaging did not show evidence of metastatic disease; thus, final staging of the cSCC was cT2N0M0. After interdisciplinary discussion and consultation with radiation oncology, the site of the cSCC was treated with adjuvant radiotherapy. The patient received a total of 6600 cGy delivered in 33 fractions of 200 cGy, each using an en face technique and 6 eV over a total treatment course of 48 days.

One year after undergoing MMS and adjuvant radiotherapy, the patient remains free of cSCC recurrence or metastases and still undergoes regular interdisciplinary monitoring. Without clear guidelines on the treatment of patients with intravascular involvement of cSCC, we relied on prior experience with similar cases.

Comment

This case highlights the challenge in managing patients with high-risk cSCC, as the current guidelines provided by the American Joint Committee on Cancer (AJCC) and the National Comprehensive Cancer Network (NCCN) vary on the inclusion of intravascular involvement of cSCC as high risk and treatment is at the discretion of the provider in such circumstances.^5-7 Both the AJCC and the NCCN have defined high-risk factors and staging for cSCC. The AJCC 8th edition (AJCC-8) revised guidelines include several high-risk factors of cSCC, including tumor diameter of 4 cm or larger leading to upstaging of a tumor from T2 to T3, invasion into or beyond the level of the subcutaneous tissue, depth of invasion greater than 6 mm, and large-caliber perineural invasion, and removed poorly differentiated histology from the AJCC-8 guidelines compared to the AJCC-7 guidelines. According to the AJCC-8 guidelines, location on the ear or lip, desmoplastic or spindle cell features, lymphovascular invasion, and immunosuppression do not affect tumor staging. The AJCC’s criteria for its TNM staging system strictly focus on features of the primary tumor and do not include clinical risk factors such as recurrence or immunosuppression. In contrast, the NCCN does include lymphovascular invasion as a high-risk factor of cSCC.

Intravascular invasion plays a considerable role in patient survival in certain cancers (eg, breast, gastric, prostate). In cutaneous malignancies, such as melanoma and SCC, metastasis more commonly occurs via lymphatic spread. When present, vascular invasion typically coexists with lymphatic involvement. The presence of microscopic lymphovascular invasion in cSCCs has not been definitively proven to increase the risk of metastases.⁸ However, multivariate analysis has shown that lymphovascular invasion independently predicts nodal metastasis and disease-specific death.⁹ As such, there are no guidelines on sentinel lymph node biopsy or adjuvant therapy in the setting of lymphovascular involvement of cSCCs. A survey-based study of 117 Mohs surgeons found a lack of consistency in their approaches to evaluation and management of high-risk SCCs. Most respondents noted perineural invasion and in-transit metastasis as the main findings that would lead to radiologic nodal staging, sentinel lymph node biopsy, or adjuvant radiotherapy, but they highlighted the lack of evidence-based treatment guidelines.⁴ High-risk cSCC can be treated via MMS or conventional surgery with safe excision margins. Adjuvant radiotherapy can reduce tumor recurrence and improve survival and therefore should be considered in cases of advanced or high-risk cSCCs, such as in our case.

The lack of consensus over the definition of high-risk cSCCs, a lack of high-quality therapeutic studies, and the absence of a prognostic model that integrates multiple risk factors all have made the prediction of outcomes and the formation of definitive management of cSCCs challenging. Multidisciplinary teams and vigilant monitoring are crucial in the successful management of high-risk cSCC, but further studies and reports are needed to develop definitive treatment algorithms.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer after basal cell carcinoma.¹ With an estimated 700,000 cases reported annually in the United States, the incidence of cSCC continues to increase.² Most patients with cSCC have an excellent prognosis after surgical clearance, with Mohs micrographic surgery (MMS) being the most successful treatment, followed by excision and electrodesiccation and curettage. A subset of patients with cSCC carry an increased risk of local recurrence, lymph node metastasis, and disease-specific death. A meta-analysis of 36 studies found that statistically significant risk factors for recurrence of cSCC included thickness greater than 2 mm (risk ratio [RR], 9.64; 95% CI, 1.30-1.52), invasion beyond the subcutaneous fat (RR, 7.61; 95% CI, 4.17-13.88), perineural invasion (RR, 4.30; 95% CI, 2.80-6.60), diameter greater than 20 mm (RR, 3.22; 95% CI, 1.91-5.45), location on temple (RR, 3.20; 95% CI, 1.12-9.15), and poor differentiation (RR, 2.66; 95% CI, 1.72-4.14).³ Additional risk factors for cSCC metastasis included location on the temple, ear, or lip, as well as a history of immunosuppression. Factors for disease-specific death were diameter greater than 20 mm, poor differentiation, location on the ear or lip, invasion beyond the subcutaneous fat, and perineural invasion.³ Perineural and/or lymphovascular invasion is considered high risk, but despite being linked to negative outcomes, there are no treatment guidelines based on lymphovascular (intravascular) invasion.⁴ We present a case of intravascular involvement found during MMS and treated with adjuvant radiotherapy after surgery. We share this case with the goal of discussing management in such cases and highlighting the need for improved definitive guidelines for high-risk cSCCs.

Case Report

A 72-year-old man presented with a rapidly growing lesion on the left side of the forehead of 1 year’s duration. His medical history was remarkable for B-cell lymphoma, which was currently in remission following chemotherapy 10 years prior. The lesion started as a small, red, dry patch that the patient initially thought was eczema. The site progressively enlarged to a red tumor measuring 2.4×2.0 cm (Figure 1), and the patient presented to the dermatology department for further evaluation. There was no clinical evidence of lymphadenopathy. A skin biopsy confirmed a moderately differentiated cSCC with a positive deep margin (Figure 2). Due to the tumor’s location, histology, size, and poorly defined borders, the patient was referred for treatment with MMS. The lesion was removed in a total of 2 stages and 4 sections. In addition to a proliferation of spindled tumor cells seen during surgery, which was consistent with cSCC, an intravascular component was noted despite clear margins after the surgery (Figure 3). The aggressive histology of intravascular involvement was subsequently confirmed by the academic dermatopathologist at our institution. With the evidence of an intravascular component of this patient’s cSCC, there was concern about further metastatic disease. After discussing the more aggressive histology type and size of the cSCC with the patient, he underwent subsequent computed tomography of the head, neck, and chest. Fortunately, this imaging did not show evidence of metastatic disease; thus, final staging of the cSCC was cT2N0M0. After interdisciplinary discussion and consultation with radiation oncology, the site of the cSCC was treated with adjuvant radiotherapy. The patient received a total of 6600 cGy delivered in 33 fractions of 200 cGy, each using an en face technique and 6 eV over a total treatment course of 48 days.

One year after undergoing MMS and adjuvant radiotherapy, the patient remains free of cSCC recurrence or metastases and still undergoes regular interdisciplinary monitoring. Without clear guidelines on the treatment of patients with intravascular involvement of cSCC, we relied on prior experience with similar cases.

Comment

This case highlights the challenge in managing patients with high-risk cSCC, as the current guidelines provided by the American Joint Committee on Cancer (AJCC) and the National Comprehensive Cancer Network (NCCN) vary on the inclusion of intravascular involvement of cSCC as high risk and treatment is at the discretion of the provider in such circumstances.^5-7 Both the AJCC and the NCCN have defined high-risk factors and staging for cSCC. The AJCC 8th edition (AJCC-8) revised guidelines include several high-risk factors of cSCC, including tumor diameter of 4 cm or larger leading to upstaging of a tumor from T2 to T3, invasion into or beyond the level of the subcutaneous tissue, depth of invasion greater than 6 mm, and large-caliber perineural invasion, and removed poorly differentiated histology from the AJCC-8 guidelines compared to the AJCC-7 guidelines. According to the AJCC-8 guidelines, location on the ear or lip, desmoplastic or spindle cell features, lymphovascular invasion, and immunosuppression do not affect tumor staging. The AJCC’s criteria for its TNM staging system strictly focus on features of the primary tumor and do not include clinical risk factors such as recurrence or immunosuppression. In contrast, the NCCN does include lymphovascular invasion as a high-risk factor of cSCC.

Intravascular invasion plays a considerable role in patient survival in certain cancers (eg, breast, gastric, prostate). In cutaneous malignancies, such as melanoma and SCC, metastasis more commonly occurs via lymphatic spread. When present, vascular invasion typically coexists with lymphatic involvement. The presence of microscopic lymphovascular invasion in cSCCs has not been definitively proven to increase the risk of metastases.⁸ However, multivariate analysis has shown that lymphovascular invasion independently predicts nodal metastasis and disease-specific death.⁹ As such, there are no guidelines on sentinel lymph node biopsy or adjuvant therapy in the setting of lymphovascular involvement of cSCCs. A survey-based study of 117 Mohs surgeons found a lack of consistency in their approaches to evaluation and management of high-risk SCCs. Most respondents noted perineural invasion and in-transit metastasis as the main findings that would lead to radiologic nodal staging, sentinel lymph node biopsy, or adjuvant radiotherapy, but they highlighted the lack of evidence-based treatment guidelines.⁴ High-risk cSCC can be treated via MMS or conventional surgery with safe excision margins. Adjuvant radiotherapy can reduce tumor recurrence and improve survival and therefore should be considered in cases of advanced or high-risk cSCCs, such as in our case.

The lack of consensus over the definition of high-risk cSCCs, a lack of high-quality therapeutic studies, and the absence of a prognostic model that integrates multiple risk factors all have made the prediction of outcomes and the formation of definitive management of cSCCs challenging. Multidisciplinary teams and vigilant monitoring are crucial in the successful management of high-risk cSCC, but further studies and reports are needed to develop definitive treatment algorithms.

The parvovirus known as cutavirus appears unlikely to play a pathogenic role in primary cutaneous B- and T-cell lymphoma, based on data from 189 biopsies.

Although researchers have long suspected viruses of a role in primary cutaneous lymphomas, “all of the so-far-suspected viruses including retroviruses, herpesviruses, and polyomaviruses have failed to reveal a consistent association with both cutaneous B-cell lymphoma [CBCL] and cutaneous T-cell lymphoma [CTCL],” wrote Alexander Kreuter, MD, of the department of dermatology, venereology, and allergology at Helios St. Elisabeth Hospital Oberhausen, Germany, and his colleagues.

In a research letter published in JAMA Dermatology, the researchers analyzed 189 paraffin-embedded biopsy specimens from 130 adults with CBCL or CTCL.

Overall, cutavirus DNA was identified in 6 (3.2%) of the 189 lymphoma biopsies and in 6 (4.6%) of 130 patients. Cutavirus was identified only in male patients with mycosis fungoides, and no cutavirus was identified in patients or biopsies without mycosis fungoides, the researchers noted. Viral DNA loads in the cutavirus-positive biopsies ranged from 1.3 to 85.0 cutavirus DNA copies per beta globin gene copy.

The findings were limited by several factors, such as the lack of biopsy samples for some lymphoma subtypes and the availability of a single specimen from most patients, the researchers noted. However, the analysis of a large number of samples suggested that cutavirus is not associated with the development of most primary cutaneous lymphomas, they said.

The study was funded by the German National Reference Center for Papilloma- and Polyomaviruses. The researchers had no financial conflicts to disclose.

SOURCE: Kreuter A et al. JAMA Dermatol. 2018 Jun 27. doi:10.1001/jamadermatol.2018.1628.

The parvovirus known as cutavirus appears unlikely to play a pathogenic role in primary cutaneous B- and T-cell lymphoma, based on data from 189 biopsies.

Although researchers have long suspected viruses of a role in primary cutaneous lymphomas, “all of the so-far-suspected viruses including retroviruses, herpesviruses, and polyomaviruses have failed to reveal a consistent association with both cutaneous B-cell lymphoma [CBCL] and cutaneous T-cell lymphoma [CTCL],” wrote Alexander Kreuter, MD, of the department of dermatology, venereology, and allergology at Helios St. Elisabeth Hospital Oberhausen, Germany, and his colleagues.

In a research letter published in JAMA Dermatology, the researchers analyzed 189 paraffin-embedded biopsy specimens from 130 adults with CBCL or CTCL.

Overall, cutavirus DNA was identified in 6 (3.2%) of the 189 lymphoma biopsies and in 6 (4.6%) of 130 patients. Cutavirus was identified only in male patients with mycosis fungoides, and no cutavirus was identified in patients or biopsies without mycosis fungoides, the researchers noted. Viral DNA loads in the cutavirus-positive biopsies ranged from 1.3 to 85.0 cutavirus DNA copies per beta globin gene copy.

The findings were limited by several factors, such as the lack of biopsy samples for some lymphoma subtypes and the availability of a single specimen from most patients, the researchers noted. However, the analysis of a large number of samples suggested that cutavirus is not associated with the development of most primary cutaneous lymphomas, they said.

The study was funded by the German National Reference Center for Papilloma- and Polyomaviruses. The researchers had no financial conflicts to disclose.

SOURCE: Kreuter A et al. JAMA Dermatol. 2018 Jun 27. doi:10.1001/jamadermatol.2018.1628.

The parvovirus known as cutavirus appears unlikely to play a pathogenic role in primary cutaneous B- and T-cell lymphoma, based on data from 189 biopsies.

Although researchers have long suspected viruses of a role in primary cutaneous lymphomas, “all of the so-far-suspected viruses including retroviruses, herpesviruses, and polyomaviruses have failed to reveal a consistent association with both cutaneous B-cell lymphoma [CBCL] and cutaneous T-cell lymphoma [CTCL],” wrote Alexander Kreuter, MD, of the department of dermatology, venereology, and allergology at Helios St. Elisabeth Hospital Oberhausen, Germany, and his colleagues.

In a research letter published in JAMA Dermatology, the researchers analyzed 189 paraffin-embedded biopsy specimens from 130 adults with CBCL or CTCL.

Overall, cutavirus DNA was identified in 6 (3.2%) of the 189 lymphoma biopsies and in 6 (4.6%) of 130 patients. Cutavirus was identified only in male patients with mycosis fungoides, and no cutavirus was identified in patients or biopsies without mycosis fungoides, the researchers noted. Viral DNA loads in the cutavirus-positive biopsies ranged from 1.3 to 85.0 cutavirus DNA copies per beta globin gene copy.

The findings were limited by several factors, such as the lack of biopsy samples for some lymphoma subtypes and the availability of a single specimen from most patients, the researchers noted. However, the analysis of a large number of samples suggested that cutavirus is not associated with the development of most primary cutaneous lymphomas, they said.

The study was funded by the German National Reference Center for Papilloma- and Polyomaviruses. The researchers had no financial conflicts to disclose.

SOURCE: Kreuter A et al. JAMA Dermatol. 2018 Jun 27. doi:10.1001/jamadermatol.2018.1628.