Clinical Review

Advances in technology, including ubiquitous access to the internet and the capacity to transfer high-resolution representative images, have facilitated the adoption of telepathology by laboratories worldwide.^1-5 Telepathology includes the use of telecommunication links that enable transmission of digital pathology images for primary diagnosis, quality assurance (QA), education, research, or second opinion diagnoses.³ This improvement has culminated in approvals by the US Food and Drug Administration (FDA) of whole slide imaging (WSI) systems for surgical pathology slides: specifically, the Philips IntelliSite Digital Pathology Solution in 2017 and the Leica Aperio AT2 DX in 2020.^6-8 However, the approvals do not include telecytology due to lack of whole slide multiplanar scanning at different planes of focus or z-stacking capabilities.⁷

Long-term trends in pathology, specifically the slow reduction in the number of practicing pathologists available in the workforce compared with the total served population, along with the social distancing imperatives and disruptions brought about by the COVID-19 pandemic have made telepathology implementation pertinent to continue and improve pathology practice.^8-10

Description and Definitions

The primary modes of telepathology (static image telepathology, robotic telepathology, video microscopy, WSI, and multimodality telepathology) have been defined by the American Telemedicine Association (ATA).² WSI has been particularly suited for telepathology due to the ability to view digital slides in high resolution at various magnifications. These image files can also be viewed and shared with ease with other observers. Also, they take a shorter time to view compared with the use of a robotic microscope.³

Selection, Validation, and Implementation

WSI platforms vary in their characteristics and have several parameters, including but not limited to batch scanning vs continuous or random-access processing, throughput volume capacities, scan speed, cost, manual vs automatic loading of slides, image quality, slide capacity, flexibility for different slide sizes/features, telepathology capabilities once slide scanned, z-stacking, and regulatory approval status.⁸ Selection of the WSI device is dependent on need and cost considerations. For example, use for frozen section requires faster scanning speed and does not generally require a high throughput scanner.

Validation of telepathology by the testing site demonstrates that the new system performs as expected for its intended clinical use before being put into service and that the digital slides produced are acceptable for clinical diagnostic interpretation.¹¹ The College of American Pathologists (CAP) established WSI validation guidelines are part of the published laboratory standard of care.^11-13 An appropriate validation enables the benefits of telepathology while mitigating the risks.

There are 3 major CAP recommendations for validation. First, ≥ 60 cases should be included for each use case being validated with 20 additional cases for relevant ancillary applications not included in the 60 cases. Second, diagnostic concordance (ideally ≥ 95%) should be established between digital and glass slides for the same observer. Third, there should be a 2-week washout period between the viewing of digital and glass slides (Table 2).^12,13

Guidelines from the ATA establish that telepathology systems should be validated for clinical use, including non-WSI platforms.² Published validations of other non-WSI platforms (such as by robotic or multimodality telepathology) have followed the structure proposed in the guidelines by CAP for validating WSI.^14,15

Ensuring that all relevant responsibilities (clinical, facility, technical, training, documentation/archiving, quality management, and operations related) for the use of telepathology are met is another aspect of validation and implementation.² Clinical responsibilities include an agreement between the sending (referring) and receiving (consulting) parties on the information to accompany the digital material.² From ATA clinical guidelines, this includes identification information, provision to the consulting pathologist of all relevant clinical data, provision to retrieve for access any needed and/or relevant diagnostic material, and responsibility by referrer that the correct image/metadata was sent.² Involved parties should be trained to manage the materials being transmitted.²

Facility responsibilities include maintaining the standard of care defined by the facility and regulatory agencies.² The maintenance of accreditation, adherence to licensure requirements, and proper management of privileges to practice telepathology are also important.² Technical responsibilities include ensuring a proper validation that meets the standard of care and covers use cases.^2,11-13

All processes, training, and competencies should be followed and documented per standard facility operating procedures.² ATA recommends that telepathology should result in a formal report for diagnostic consultations, maintain logs of telepathology interactions or disclaimer statements, and have an appropriate retention policy.² The CAP recommends digital images used for primary diagnosis should be kept for 10 years if the original glass slides are not available.¹⁶ Once implemented, telepathology reports must be incorporated into the pathology and laboratory medicine department’s quality management plan for both the technical performance of the telepathology system and diagnostic performance of the pathologists using the system.² Operations responsibilities include ensuring that the telepathology system is maintained according to vendor recommendations and regulatory standards. Appropriate provisions for space and associated needs should be developed in conjunction with the information technology team of the facility to ensure appropriate security, privacy, and regulatory compliance.²

Applications and Uses

Telecytology. Rapid real-time telecytology has been documented to be useful in rapid on-site evaluations (ROSE) of the adequacy of fine needle aspirations (FNA).^17-21 Nevertheless, current Medicare reimbursement is limited given that ROSE is cost prohibitive, time consuming, and affects productivity in cytology laboratories.^17,22,23 Estimates of the time to provide ROSE for 1 procedure without telecytology range from 48.7 to 56.2 minutes.^17,23 The use of telecytology significantly reduces pathologist ROSE time without losing quality to about 12 minutes, of which only an average of 7.5 minutes was spent by the cytopathologist for the ROSE diagnosis.^17-21 ROSE also can be used for distant and remote locations to improve patient care.^17-21 Multiple vendors provide real-time telecytology service. Innovations using smartphone adapters, digital cameras that could work as their own IP addresses, and connection with high-speed dedicated connections with viewing platforms on high-sensitivity monitors can facilitate ROSE to improve patient management.^24,25 The successful accurate use of ROSE has been described; however, there are currently no FDA-approved telepathology ROSE platforms.^17-19,21-25

To date, the FDA has not approved any telecytology whole slide scanner due to a lack of z-stacking capability in submitted scanners.^7,21 Not all whole slide scanners offer z-stacking, though even in those that do offer it, the time necessary to scan the entire slide with adequate z-stacking takes too long to be clinically acceptable for many situations involving ROSE.²¹ WSI has also been used to develop international consensus for cytologic samples.²⁶ Published recommendations for the validation of these other modalities before usage follow the spirit of the CAP guidelines (as far as multiple cases with high concordance rates) for validation of WSI for diagnostic purposes but vary on the exact number of slides and acceptable concordance rate.^21,27 For ROSE with a robotic microscope without any on-site cytology personnel, documented standardized training of nonpathology staff members, such as the radiologist or other physician performing the FNA procedure, may be needed to enable the performance of ROSE telecytology and ensure compliance with regulations.^2,21 Besides ROSE, there are published validations for telecytology in primary diagnosis and QA, indicating a role for telecytology for diagnosis for laboratories that have properly validated and implemented the laboratory-developed test.^28-30

Frozen section. Telepathology has significant potential to improve access to frozen section consultation.^5,31-33 Benefits to improving access to frozen section include providing frozen section consultation at remote or off-site locations, increasing access to subspecialty consultation, improving workflow by eliminating the need to travel off-site to the frozen section case, cost savings in staff work time, and providing educational opportunities for pathology trainees.^5,31-33 In our experience, WSI with real-time viewing of frozen section allows for the assessment of transplant tissues, which is an evaluation that generally occurs at night. Discrepancies from frozen section telepathology using WSI to the final diagnosis may occur and those specific to WSI could result from slide or image quality, internet connectivity, and lack of training in using the telepathology system.³² Other issues that may lead to discrepancies between the frozen section diagnosis and the final diagnosis may occur with the review of glass slides by light microscopy.³⁴ Appropriate performance of validation, training, implementation, and quality control for telepathology can help in reaping the benefits while mitigating the risks.² In a large study comparing frozen section evaluation by telepathology with light microscopy, the sensitivity and specificity of frozen section were comparable between telepathology and light microscopy with a trend toward greater sensitivity by telepathology (0.92 and 0.99 for telepathology vs 0.90 and 0.99 by light microscopy alone, sensitivity and specificity, respectively).³³

Other applications. Evidence for efficacy in surgical pathology diagnosis led to FDA approval of the Philips IntelliSite Digital Pathology in 2017 and the Leica Aperio AT2 DX in 2020 WSI platforms.^6-8 The use of WSI in surgical pathology has been successfully validated or used in clinical practice at several pathology laboratory settings with documented benefits in the literature for primary and secondary diagnoses, QA, research, and education.^6-8,35-45 Benefits of telepathology include improved ergonomics and access to real-time pathologic services in remote areas or during on-site pathologist absence and expert second opinions. Telepathology also may reduce risk of slide loss during transport, shortened turnaround time, reduced costs of operation through workflow efficiencies, better load balancing, improve virtual collaboration, and digital storage of slides that may be irreplaceable.^3-8,35-45 Telepathology also has been shown to be useful for education, improving access to learning materials and increasing quality instructional materials at a lower cost.⁴⁵ The increased ease of collaboration with remote experts and access to slide material for other pathologists improves QA capabilities.^3-8,35-45 The availability of virtual slides is expected to promote further research in telepathology and pathology due to the increased availability of virtual material to researchers.^1,5,46

Telehematology. Published validations have shown effectiveness for hematopathology specimens, such as the peripheral smear. Telehematology also has demonstrated potential in a laboratory after proper validation and implementation as a laboratory-developed test.^37,47-49

Telemicrobiology and Computer-Assisted Pathologic Diagnosis. Telemicrobiology also has been successfully used for clinical, educational, and QA purposes.⁵⁰ The digitalization of slides involved with telepathology enables further innovation in machine learning for computer-assisted pathologic diagnosis (CAPD), which is already being used clinically for cervical Pap smears.²⁰ An artificial intelligence (AI)–based algorithm analyzes the slides to identify cells of interest, which are presented to the cytopathologist for confirmation.²⁰ However, the expansion of CAPD to include a variety of specimen types or diagnostic situations as well as safely and effectively take initiative in completing an accurate automated diagnosis requires additional development.^20,51,52 One of the key factors for machine learning to develop AI is the provision of a corpus of data.^51,52 Public, open-source data sources have been limited in size while private proprietary sources have highly restricted and expensive access; to address this, there is a current effort to build the world’s largest public open-source digital pathology corpus at Temple University Hospital, which may help enable innovations in the future.⁵²

Long-Term Trends/Applications

The COVID-19 pandemic has been unprecedented not only in its widespread morbidity and mortality, but also for the significant socioeconomic, health, lifestyle, societal, and workspace changes.^53-57 Specifically, the pandemic has introduced not only a need for social distancing and staff quarantines to prevent the spread of infection, but also a reduction in the workforce due to the stresses of COVID-19 (also known as the Great Resignation).⁵⁵ Before the pandemic, there was an existing downtrend in the number of pathologists in the US workforce.^9-10,58,59 From 2007 to 2017, the number of active pathologists in the US declined by 17.5% despite the increasing national population, resulting in not only an absolute decrease in the number of pathologists, but also an increasing population served per pathologist ratio.⁵⁹ Since 2017, this downtrend has continued; given the increasing loss of active pathologists from the workforce and the decreasing training of new pathologists, this decrease shows no signs of reversing even as the impact of the COVID-19 pandemic has begun to wane.^9,10,58-60

The advantages of telepathology in enabling social distancing and reducing travel to remote sites are known.^3-7,17 Given these advantages, some medical centers in the US have previously successfully validated and implemented telepathology operations earlier during the COVID-19 pandemic to ease workflow and ensure continued operations.^56,57 The use of telepathology also helps in balancing workload and continuing pathology operations even in light of the workforce reduction as cases no longer need to be signed out on site with glass slides but instead can be signed out at a remote laboratory. Although the impact of the COVID-19 pandemic on operations is decreasing, the capabilities for social distancing and reducing travel remain important to both improve operations and ensure resiliency in response to similar potential events.^3-7,17,60

Considering the long-term trends, the lessons of the COVID-19 pandemic, and the potential for future pandemics or other disasters, telepathology’s validation and implementation remains a reasonable choice for pathology practices looking to improve. A variety of practices not just in the general population, but also among US Department of Veterans Affairs medical centers (VAMCs) and the US Department of Defense Military Health System treating a veteran population can benefit from telepathology where it has previously been reported to have been reliable or successfully implemented.^61-63 Although the veteran population differs from the general population in several characteristics, such as the severity of disease, coexisting morbidities, and other history, given proper validation and implementation, telepathology’s usefulness extends across different pathology practice settings.^35-43,61-66

Limitations of Telepathology

In telepathology’s current state, there are limitations despite its immense promise.^6,35 These include initial capital costs, the additional training requirement, the additional time necessary to scan slides, technical challenges (ie, laboratory information system integration, color calibration, display artifacts, potential for small particle scanner omissions, and information technology dependence), the potential for slower evaluation per slide compared with optical microscopes, limitations of slide imaging (ie, z-stacking or lack of polarization on digital pathology), and occupational concerns regarding eye strain with increased computer monitor usage (ie, computer vision syndrome).^6,35 In addition, there are few telepathology scanners with FDA approval for WSI.^6-8

The improving technology of telepathology has made these limitations surmountable, including faster slide scanning and increasing digital storage capacity for large WSI files. Due to this improvement in technology, an increasing number of laboratory settings, have adopted telepathology as its advantages have begun to outweigh the limitations.^2-5 Additionally, the proper validation performed before implementing telepathology can help laboratories identify their unique challenges, troubleshoot, and resolve the limitations before use in clinical care.^11-13 Continuing QA during its use and implementation is important to ensure that telepathology performs as expected for clinical purposes despite its limitations.²

Conclusions

Telepathology is a promising technology that may improve pathology practice once properly validated and implemented.^1-8 Though there are barriers to this validation and implementation, particularly the capital costs and training, there are several potential benefits, including increased productivity, cost savings, improvement in the workflow, enhanced access to pathologic consultation, and adaptability of the pathology laboratory in an era of a decreased workforce and social distancing due to the COVID-19 pandemic.^1-8,55-56 This potential applies across the wide spectrum of potential telepathology uses from frozen section, telecytology (including ROSE) to primary and second opinion diagnoses.^1-8,17-33 The benefits also extends to QA, education, and research, as diagnoses can not only be rereviewed by specialty or second opinion consultation with ease, but also digital slides can be produced for educational and research purposes.^3-8,35-45 Settings that treat the general population and those focused on the care of veterans or members of the armed forces have reported similar reliability or successful implementation.^35-44,61-63 All in all, the use of telepathology represents an innovation that may transform the practice of pathology tomorrow.

Advances in technology, including ubiquitous access to the internet and the capacity to transfer high-resolution representative images, have facilitated the adoption of telepathology by laboratories worldwide.^1-5 Telepathology includes the use of telecommunication links that enable transmission of digital pathology images for primary diagnosis, quality assurance (QA), education, research, or second opinion diagnoses.³ This improvement has culminated in approvals by the US Food and Drug Administration (FDA) of whole slide imaging (WSI) systems for surgical pathology slides: specifically, the Philips IntelliSite Digital Pathology Solution in 2017 and the Leica Aperio AT2 DX in 2020.^6-8 However, the approvals do not include telecytology due to lack of whole slide multiplanar scanning at different planes of focus or z-stacking capabilities.⁷

Long-term trends in pathology, specifically the slow reduction in the number of practicing pathologists available in the workforce compared with the total served population, along with the social distancing imperatives and disruptions brought about by the COVID-19 pandemic have made telepathology implementation pertinent to continue and improve pathology practice.^8-10

Description and Definitions

The primary modes of telepathology (static image telepathology, robotic telepathology, video microscopy, WSI, and multimodality telepathology) have been defined by the American Telemedicine Association (ATA).² WSI has been particularly suited for telepathology due to the ability to view digital slides in high resolution at various magnifications. These image files can also be viewed and shared with ease with other observers. Also, they take a shorter time to view compared with the use of a robotic microscope.³

Selection, Validation, and Implementation

WSI platforms vary in their characteristics and have several parameters, including but not limited to batch scanning vs continuous or random-access processing, throughput volume capacities, scan speed, cost, manual vs automatic loading of slides, image quality, slide capacity, flexibility for different slide sizes/features, telepathology capabilities once slide scanned, z-stacking, and regulatory approval status.⁸ Selection of the WSI device is dependent on need and cost considerations. For example, use for frozen section requires faster scanning speed and does not generally require a high throughput scanner.

Validation of telepathology by the testing site demonstrates that the new system performs as expected for its intended clinical use before being put into service and that the digital slides produced are acceptable for clinical diagnostic interpretation.¹¹ The College of American Pathologists (CAP) established WSI validation guidelines are part of the published laboratory standard of care.^11-13 An appropriate validation enables the benefits of telepathology while mitigating the risks.

There are 3 major CAP recommendations for validation. First, ≥ 60 cases should be included for each use case being validated with 20 additional cases for relevant ancillary applications not included in the 60 cases. Second, diagnostic concordance (ideally ≥ 95%) should be established between digital and glass slides for the same observer. Third, there should be a 2-week washout period between the viewing of digital and glass slides (Table 2).^12,13

Guidelines from the ATA establish that telepathology systems should be validated for clinical use, including non-WSI platforms.² Published validations of other non-WSI platforms (such as by robotic or multimodality telepathology) have followed the structure proposed in the guidelines by CAP for validating WSI.^14,15

Ensuring that all relevant responsibilities (clinical, facility, technical, training, documentation/archiving, quality management, and operations related) for the use of telepathology are met is another aspect of validation and implementation.² Clinical responsibilities include an agreement between the sending (referring) and receiving (consulting) parties on the information to accompany the digital material.² From ATA clinical guidelines, this includes identification information, provision to the consulting pathologist of all relevant clinical data, provision to retrieve for access any needed and/or relevant diagnostic material, and responsibility by referrer that the correct image/metadata was sent.² Involved parties should be trained to manage the materials being transmitted.²

Facility responsibilities include maintaining the standard of care defined by the facility and regulatory agencies.² The maintenance of accreditation, adherence to licensure requirements, and proper management of privileges to practice telepathology are also important.² Technical responsibilities include ensuring a proper validation that meets the standard of care and covers use cases.^2,11-13

All processes, training, and competencies should be followed and documented per standard facility operating procedures.² ATA recommends that telepathology should result in a formal report for diagnostic consultations, maintain logs of telepathology interactions or disclaimer statements, and have an appropriate retention policy.² The CAP recommends digital images used for primary diagnosis should be kept for 10 years if the original glass slides are not available.¹⁶ Once implemented, telepathology reports must be incorporated into the pathology and laboratory medicine department’s quality management plan for both the technical performance of the telepathology system and diagnostic performance of the pathologists using the system.² Operations responsibilities include ensuring that the telepathology system is maintained according to vendor recommendations and regulatory standards. Appropriate provisions for space and associated needs should be developed in conjunction with the information technology team of the facility to ensure appropriate security, privacy, and regulatory compliance.²

Applications and Uses

Telecytology. Rapid real-time telecytology has been documented to be useful in rapid on-site evaluations (ROSE) of the adequacy of fine needle aspirations (FNA).^17-21 Nevertheless, current Medicare reimbursement is limited given that ROSE is cost prohibitive, time consuming, and affects productivity in cytology laboratories.^17,22,23 Estimates of the time to provide ROSE for 1 procedure without telecytology range from 48.7 to 56.2 minutes.^17,23 The use of telecytology significantly reduces pathologist ROSE time without losing quality to about 12 minutes, of which only an average of 7.5 minutes was spent by the cytopathologist for the ROSE diagnosis.^17-21 ROSE also can be used for distant and remote locations to improve patient care.^17-21 Multiple vendors provide real-time telecytology service. Innovations using smartphone adapters, digital cameras that could work as their own IP addresses, and connection with high-speed dedicated connections with viewing platforms on high-sensitivity monitors can facilitate ROSE to improve patient management.^24,25 The successful accurate use of ROSE has been described; however, there are currently no FDA-approved telepathology ROSE platforms.^17-19,21-25

To date, the FDA has not approved any telecytology whole slide scanner due to a lack of z-stacking capability in submitted scanners.^7,21 Not all whole slide scanners offer z-stacking, though even in those that do offer it, the time necessary to scan the entire slide with adequate z-stacking takes too long to be clinically acceptable for many situations involving ROSE.²¹ WSI has also been used to develop international consensus for cytologic samples.²⁶ Published recommendations for the validation of these other modalities before usage follow the spirit of the CAP guidelines (as far as multiple cases with high concordance rates) for validation of WSI for diagnostic purposes but vary on the exact number of slides and acceptable concordance rate.^21,27 For ROSE with a robotic microscope without any on-site cytology personnel, documented standardized training of nonpathology staff members, such as the radiologist or other physician performing the FNA procedure, may be needed to enable the performance of ROSE telecytology and ensure compliance with regulations.^2,21 Besides ROSE, there are published validations for telecytology in primary diagnosis and QA, indicating a role for telecytology for diagnosis for laboratories that have properly validated and implemented the laboratory-developed test.^28-30

Frozen section. Telepathology has significant potential to improve access to frozen section consultation.^5,31-33 Benefits to improving access to frozen section include providing frozen section consultation at remote or off-site locations, increasing access to subspecialty consultation, improving workflow by eliminating the need to travel off-site to the frozen section case, cost savings in staff work time, and providing educational opportunities for pathology trainees.^5,31-33 In our experience, WSI with real-time viewing of frozen section allows for the assessment of transplant tissues, which is an evaluation that generally occurs at night. Discrepancies from frozen section telepathology using WSI to the final diagnosis may occur and those specific to WSI could result from slide or image quality, internet connectivity, and lack of training in using the telepathology system.³² Other issues that may lead to discrepancies between the frozen section diagnosis and the final diagnosis may occur with the review of glass slides by light microscopy.³⁴ Appropriate performance of validation, training, implementation, and quality control for telepathology can help in reaping the benefits while mitigating the risks.² In a large study comparing frozen section evaluation by telepathology with light microscopy, the sensitivity and specificity of frozen section were comparable between telepathology and light microscopy with a trend toward greater sensitivity by telepathology (0.92 and 0.99 for telepathology vs 0.90 and 0.99 by light microscopy alone, sensitivity and specificity, respectively).³³

Other applications. Evidence for efficacy in surgical pathology diagnosis led to FDA approval of the Philips IntelliSite Digital Pathology in 2017 and the Leica Aperio AT2 DX in 2020 WSI platforms.^6-8 The use of WSI in surgical pathology has been successfully validated or used in clinical practice at several pathology laboratory settings with documented benefits in the literature for primary and secondary diagnoses, QA, research, and education.^6-8,35-45 Benefits of telepathology include improved ergonomics and access to real-time pathologic services in remote areas or during on-site pathologist absence and expert second opinions. Telepathology also may reduce risk of slide loss during transport, shortened turnaround time, reduced costs of operation through workflow efficiencies, better load balancing, improve virtual collaboration, and digital storage of slides that may be irreplaceable.^3-8,35-45 Telepathology also has been shown to be useful for education, improving access to learning materials and increasing quality instructional materials at a lower cost.⁴⁵ The increased ease of collaboration with remote experts and access to slide material for other pathologists improves QA capabilities.^3-8,35-45 The availability of virtual slides is expected to promote further research in telepathology and pathology due to the increased availability of virtual material to researchers.^1,5,46

Telehematology. Published validations have shown effectiveness for hematopathology specimens, such as the peripheral smear. Telehematology also has demonstrated potential in a laboratory after proper validation and implementation as a laboratory-developed test.^37,47-49

Telemicrobiology and Computer-Assisted Pathologic Diagnosis. Telemicrobiology also has been successfully used for clinical, educational, and QA purposes.⁵⁰ The digitalization of slides involved with telepathology enables further innovation in machine learning for computer-assisted pathologic diagnosis (CAPD), which is already being used clinically for cervical Pap smears.²⁰ An artificial intelligence (AI)–based algorithm analyzes the slides to identify cells of interest, which are presented to the cytopathologist for confirmation.²⁰ However, the expansion of CAPD to include a variety of specimen types or diagnostic situations as well as safely and effectively take initiative in completing an accurate automated diagnosis requires additional development.^20,51,52 One of the key factors for machine learning to develop AI is the provision of a corpus of data.^51,52 Public, open-source data sources have been limited in size while private proprietary sources have highly restricted and expensive access; to address this, there is a current effort to build the world’s largest public open-source digital pathology corpus at Temple University Hospital, which may help enable innovations in the future.⁵²

Long-Term Trends/Applications

The COVID-19 pandemic has been unprecedented not only in its widespread morbidity and mortality, but also for the significant socioeconomic, health, lifestyle, societal, and workspace changes.^53-57 Specifically, the pandemic has introduced not only a need for social distancing and staff quarantines to prevent the spread of infection, but also a reduction in the workforce due to the stresses of COVID-19 (also known as the Great Resignation).⁵⁵ Before the pandemic, there was an existing downtrend in the number of pathologists in the US workforce.^9-10,58,59 From 2007 to 2017, the number of active pathologists in the US declined by 17.5% despite the increasing national population, resulting in not only an absolute decrease in the number of pathologists, but also an increasing population served per pathologist ratio.⁵⁹ Since 2017, this downtrend has continued; given the increasing loss of active pathologists from the workforce and the decreasing training of new pathologists, this decrease shows no signs of reversing even as the impact of the COVID-19 pandemic has begun to wane.^9,10,58-60

The advantages of telepathology in enabling social distancing and reducing travel to remote sites are known.^3-7,17 Given these advantages, some medical centers in the US have previously successfully validated and implemented telepathology operations earlier during the COVID-19 pandemic to ease workflow and ensure continued operations.^56,57 The use of telepathology also helps in balancing workload and continuing pathology operations even in light of the workforce reduction as cases no longer need to be signed out on site with glass slides but instead can be signed out at a remote laboratory. Although the impact of the COVID-19 pandemic on operations is decreasing, the capabilities for social distancing and reducing travel remain important to both improve operations and ensure resiliency in response to similar potential events.^3-7,17,60

Considering the long-term trends, the lessons of the COVID-19 pandemic, and the potential for future pandemics or other disasters, telepathology’s validation and implementation remains a reasonable choice for pathology practices looking to improve. A variety of practices not just in the general population, but also among US Department of Veterans Affairs medical centers (VAMCs) and the US Department of Defense Military Health System treating a veteran population can benefit from telepathology where it has previously been reported to have been reliable or successfully implemented.^61-63 Although the veteran population differs from the general population in several characteristics, such as the severity of disease, coexisting morbidities, and other history, given proper validation and implementation, telepathology’s usefulness extends across different pathology practice settings.^35-43,61-66

Limitations of Telepathology

In telepathology’s current state, there are limitations despite its immense promise.^6,35 These include initial capital costs, the additional training requirement, the additional time necessary to scan slides, technical challenges (ie, laboratory information system integration, color calibration, display artifacts, potential for small particle scanner omissions, and information technology dependence), the potential for slower evaluation per slide compared with optical microscopes, limitations of slide imaging (ie, z-stacking or lack of polarization on digital pathology), and occupational concerns regarding eye strain with increased computer monitor usage (ie, computer vision syndrome).^6,35 In addition, there are few telepathology scanners with FDA approval for WSI.^6-8

The improving technology of telepathology has made these limitations surmountable, including faster slide scanning and increasing digital storage capacity for large WSI files. Due to this improvement in technology, an increasing number of laboratory settings, have adopted telepathology as its advantages have begun to outweigh the limitations.^2-5 Additionally, the proper validation performed before implementing telepathology can help laboratories identify their unique challenges, troubleshoot, and resolve the limitations before use in clinical care.^11-13 Continuing QA during its use and implementation is important to ensure that telepathology performs as expected for clinical purposes despite its limitations.²

Conclusions

Telepathology is a promising technology that may improve pathology practice once properly validated and implemented.^1-8 Though there are barriers to this validation and implementation, particularly the capital costs and training, there are several potential benefits, including increased productivity, cost savings, improvement in the workflow, enhanced access to pathologic consultation, and adaptability of the pathology laboratory in an era of a decreased workforce and social distancing due to the COVID-19 pandemic.^1-8,55-56 This potential applies across the wide spectrum of potential telepathology uses from frozen section, telecytology (including ROSE) to primary and second opinion diagnoses.^1-8,17-33 The benefits also extends to QA, education, and research, as diagnoses can not only be rereviewed by specialty or second opinion consultation with ease, but also digital slides can be produced for educational and research purposes.^3-8,35-45 Settings that treat the general population and those focused on the care of veterans or members of the armed forces have reported similar reliability or successful implementation.^35-44,61-63 All in all, the use of telepathology represents an innovation that may transform the practice of pathology tomorrow.

Advances in technology, including ubiquitous access to the internet and the capacity to transfer high-resolution representative images, have facilitated the adoption of telepathology by laboratories worldwide.^1-5 Telepathology includes the use of telecommunication links that enable transmission of digital pathology images for primary diagnosis, quality assurance (QA), education, research, or second opinion diagnoses.³ This improvement has culminated in approvals by the US Food and Drug Administration (FDA) of whole slide imaging (WSI) systems for surgical pathology slides: specifically, the Philips IntelliSite Digital Pathology Solution in 2017 and the Leica Aperio AT2 DX in 2020.^6-8 However, the approvals do not include telecytology due to lack of whole slide multiplanar scanning at different planes of focus or z-stacking capabilities.⁷

Long-term trends in pathology, specifically the slow reduction in the number of practicing pathologists available in the workforce compared with the total served population, along with the social distancing imperatives and disruptions brought about by the COVID-19 pandemic have made telepathology implementation pertinent to continue and improve pathology practice.^8-10

Description and Definitions

The primary modes of telepathology (static image telepathology, robotic telepathology, video microscopy, WSI, and multimodality telepathology) have been defined by the American Telemedicine Association (ATA).² WSI has been particularly suited for telepathology due to the ability to view digital slides in high resolution at various magnifications. These image files can also be viewed and shared with ease with other observers. Also, they take a shorter time to view compared with the use of a robotic microscope.³

Selection, Validation, and Implementation

WSI platforms vary in their characteristics and have several parameters, including but not limited to batch scanning vs continuous or random-access processing, throughput volume capacities, scan speed, cost, manual vs automatic loading of slides, image quality, slide capacity, flexibility for different slide sizes/features, telepathology capabilities once slide scanned, z-stacking, and regulatory approval status.⁸ Selection of the WSI device is dependent on need and cost considerations. For example, use for frozen section requires faster scanning speed and does not generally require a high throughput scanner.

Validation of telepathology by the testing site demonstrates that the new system performs as expected for its intended clinical use before being put into service and that the digital slides produced are acceptable for clinical diagnostic interpretation.¹¹ The College of American Pathologists (CAP) established WSI validation guidelines are part of the published laboratory standard of care.^11-13 An appropriate validation enables the benefits of telepathology while mitigating the risks.

There are 3 major CAP recommendations for validation. First, ≥ 60 cases should be included for each use case being validated with 20 additional cases for relevant ancillary applications not included in the 60 cases. Second, diagnostic concordance (ideally ≥ 95%) should be established between digital and glass slides for the same observer. Third, there should be a 2-week washout period between the viewing of digital and glass slides (Table 2).^12,13

Guidelines from the ATA establish that telepathology systems should be validated for clinical use, including non-WSI platforms.² Published validations of other non-WSI platforms (such as by robotic or multimodality telepathology) have followed the structure proposed in the guidelines by CAP for validating WSI.^14,15

Ensuring that all relevant responsibilities (clinical, facility, technical, training, documentation/archiving, quality management, and operations related) for the use of telepathology are met is another aspect of validation and implementation.² Clinical responsibilities include an agreement between the sending (referring) and receiving (consulting) parties on the information to accompany the digital material.² From ATA clinical guidelines, this includes identification information, provision to the consulting pathologist of all relevant clinical data, provision to retrieve for access any needed and/or relevant diagnostic material, and responsibility by referrer that the correct image/metadata was sent.² Involved parties should be trained to manage the materials being transmitted.²

Facility responsibilities include maintaining the standard of care defined by the facility and regulatory agencies.² The maintenance of accreditation, adherence to licensure requirements, and proper management of privileges to practice telepathology are also important.² Technical responsibilities include ensuring a proper validation that meets the standard of care and covers use cases.^2,11-13

All processes, training, and competencies should be followed and documented per standard facility operating procedures.² ATA recommends that telepathology should result in a formal report for diagnostic consultations, maintain logs of telepathology interactions or disclaimer statements, and have an appropriate retention policy.² The CAP recommends digital images used for primary diagnosis should be kept for 10 years if the original glass slides are not available.¹⁶ Once implemented, telepathology reports must be incorporated into the pathology and laboratory medicine department’s quality management plan for both the technical performance of the telepathology system and diagnostic performance of the pathologists using the system.² Operations responsibilities include ensuring that the telepathology system is maintained according to vendor recommendations and regulatory standards. Appropriate provisions for space and associated needs should be developed in conjunction with the information technology team of the facility to ensure appropriate security, privacy, and regulatory compliance.²

Applications and Uses

Telecytology. Rapid real-time telecytology has been documented to be useful in rapid on-site evaluations (ROSE) of the adequacy of fine needle aspirations (FNA).^17-21 Nevertheless, current Medicare reimbursement is limited given that ROSE is cost prohibitive, time consuming, and affects productivity in cytology laboratories.^17,22,23 Estimates of the time to provide ROSE for 1 procedure without telecytology range from 48.7 to 56.2 minutes.^17,23 The use of telecytology significantly reduces pathologist ROSE time without losing quality to about 12 minutes, of which only an average of 7.5 minutes was spent by the cytopathologist for the ROSE diagnosis.^17-21 ROSE also can be used for distant and remote locations to improve patient care.^17-21 Multiple vendors provide real-time telecytology service. Innovations using smartphone adapters, digital cameras that could work as their own IP addresses, and connection with high-speed dedicated connections with viewing platforms on high-sensitivity monitors can facilitate ROSE to improve patient management.^24,25 The successful accurate use of ROSE has been described; however, there are currently no FDA-approved telepathology ROSE platforms.^17-19,21-25

To date, the FDA has not approved any telecytology whole slide scanner due to a lack of z-stacking capability in submitted scanners.^7,21 Not all whole slide scanners offer z-stacking, though even in those that do offer it, the time necessary to scan the entire slide with adequate z-stacking takes too long to be clinically acceptable for many situations involving ROSE.²¹ WSI has also been used to develop international consensus for cytologic samples.²⁶ Published recommendations for the validation of these other modalities before usage follow the spirit of the CAP guidelines (as far as multiple cases with high concordance rates) for validation of WSI for diagnostic purposes but vary on the exact number of slides and acceptable concordance rate.^21,27 For ROSE with a robotic microscope without any on-site cytology personnel, documented standardized training of nonpathology staff members, such as the radiologist or other physician performing the FNA procedure, may be needed to enable the performance of ROSE telecytology and ensure compliance with regulations.^2,21 Besides ROSE, there are published validations for telecytology in primary diagnosis and QA, indicating a role for telecytology for diagnosis for laboratories that have properly validated and implemented the laboratory-developed test.^28-30

Frozen section. Telepathology has significant potential to improve access to frozen section consultation.^5,31-33 Benefits to improving access to frozen section include providing frozen section consultation at remote or off-site locations, increasing access to subspecialty consultation, improving workflow by eliminating the need to travel off-site to the frozen section case, cost savings in staff work time, and providing educational opportunities for pathology trainees.^5,31-33 In our experience, WSI with real-time viewing of frozen section allows for the assessment of transplant tissues, which is an evaluation that generally occurs at night. Discrepancies from frozen section telepathology using WSI to the final diagnosis may occur and those specific to WSI could result from slide or image quality, internet connectivity, and lack of training in using the telepathology system.³² Other issues that may lead to discrepancies between the frozen section diagnosis and the final diagnosis may occur with the review of glass slides by light microscopy.³⁴ Appropriate performance of validation, training, implementation, and quality control for telepathology can help in reaping the benefits while mitigating the risks.² In a large study comparing frozen section evaluation by telepathology with light microscopy, the sensitivity and specificity of frozen section were comparable between telepathology and light microscopy with a trend toward greater sensitivity by telepathology (0.92 and 0.99 for telepathology vs 0.90 and 0.99 by light microscopy alone, sensitivity and specificity, respectively).³³

Other applications. Evidence for efficacy in surgical pathology diagnosis led to FDA approval of the Philips IntelliSite Digital Pathology in 2017 and the Leica Aperio AT2 DX in 2020 WSI platforms.^6-8 The use of WSI in surgical pathology has been successfully validated or used in clinical practice at several pathology laboratory settings with documented benefits in the literature for primary and secondary diagnoses, QA, research, and education.^6-8,35-45 Benefits of telepathology include improved ergonomics and access to real-time pathologic services in remote areas or during on-site pathologist absence and expert second opinions. Telepathology also may reduce risk of slide loss during transport, shortened turnaround time, reduced costs of operation through workflow efficiencies, better load balancing, improve virtual collaboration, and digital storage of slides that may be irreplaceable.^3-8,35-45 Telepathology also has been shown to be useful for education, improving access to learning materials and increasing quality instructional materials at a lower cost.⁴⁵ The increased ease of collaboration with remote experts and access to slide material for other pathologists improves QA capabilities.^3-8,35-45 The availability of virtual slides is expected to promote further research in telepathology and pathology due to the increased availability of virtual material to researchers.^1,5,46

Telehematology. Published validations have shown effectiveness for hematopathology specimens, such as the peripheral smear. Telehematology also has demonstrated potential in a laboratory after proper validation and implementation as a laboratory-developed test.^37,47-49

Telemicrobiology and Computer-Assisted Pathologic Diagnosis. Telemicrobiology also has been successfully used for clinical, educational, and QA purposes.⁵⁰ The digitalization of slides involved with telepathology enables further innovation in machine learning for computer-assisted pathologic diagnosis (CAPD), which is already being used clinically for cervical Pap smears.²⁰ An artificial intelligence (AI)–based algorithm analyzes the slides to identify cells of interest, which are presented to the cytopathologist for confirmation.²⁰ However, the expansion of CAPD to include a variety of specimen types or diagnostic situations as well as safely and effectively take initiative in completing an accurate automated diagnosis requires additional development.^20,51,52 One of the key factors for machine learning to develop AI is the provision of a corpus of data.^51,52 Public, open-source data sources have been limited in size while private proprietary sources have highly restricted and expensive access; to address this, there is a current effort to build the world’s largest public open-source digital pathology corpus at Temple University Hospital, which may help enable innovations in the future.⁵²

Long-Term Trends/Applications

The COVID-19 pandemic has been unprecedented not only in its widespread morbidity and mortality, but also for the significant socioeconomic, health, lifestyle, societal, and workspace changes.^53-57 Specifically, the pandemic has introduced not only a need for social distancing and staff quarantines to prevent the spread of infection, but also a reduction in the workforce due to the stresses of COVID-19 (also known as the Great Resignation).⁵⁵ Before the pandemic, there was an existing downtrend in the number of pathologists in the US workforce.^9-10,58,59 From 2007 to 2017, the number of active pathologists in the US declined by 17.5% despite the increasing national population, resulting in not only an absolute decrease in the number of pathologists, but also an increasing population served per pathologist ratio.⁵⁹ Since 2017, this downtrend has continued; given the increasing loss of active pathologists from the workforce and the decreasing training of new pathologists, this decrease shows no signs of reversing even as the impact of the COVID-19 pandemic has begun to wane.^9,10,58-60

The advantages of telepathology in enabling social distancing and reducing travel to remote sites are known.^3-7,17 Given these advantages, some medical centers in the US have previously successfully validated and implemented telepathology operations earlier during the COVID-19 pandemic to ease workflow and ensure continued operations.^56,57 The use of telepathology also helps in balancing workload and continuing pathology operations even in light of the workforce reduction as cases no longer need to be signed out on site with glass slides but instead can be signed out at a remote laboratory. Although the impact of the COVID-19 pandemic on operations is decreasing, the capabilities for social distancing and reducing travel remain important to both improve operations and ensure resiliency in response to similar potential events.^3-7,17,60

Considering the long-term trends, the lessons of the COVID-19 pandemic, and the potential for future pandemics or other disasters, telepathology’s validation and implementation remains a reasonable choice for pathology practices looking to improve. A variety of practices not just in the general population, but also among US Department of Veterans Affairs medical centers (VAMCs) and the US Department of Defense Military Health System treating a veteran population can benefit from telepathology where it has previously been reported to have been reliable or successfully implemented.^61-63 Although the veteran population differs from the general population in several characteristics, such as the severity of disease, coexisting morbidities, and other history, given proper validation and implementation, telepathology’s usefulness extends across different pathology practice settings.^35-43,61-66

Limitations of Telepathology

In telepathology’s current state, there are limitations despite its immense promise.^6,35 These include initial capital costs, the additional training requirement, the additional time necessary to scan slides, technical challenges (ie, laboratory information system integration, color calibration, display artifacts, potential for small particle scanner omissions, and information technology dependence), the potential for slower evaluation per slide compared with optical microscopes, limitations of slide imaging (ie, z-stacking or lack of polarization on digital pathology), and occupational concerns regarding eye strain with increased computer monitor usage (ie, computer vision syndrome).^6,35 In addition, there are few telepathology scanners with FDA approval for WSI.^6-8

The improving technology of telepathology has made these limitations surmountable, including faster slide scanning and increasing digital storage capacity for large WSI files. Due to this improvement in technology, an increasing number of laboratory settings, have adopted telepathology as its advantages have begun to outweigh the limitations.^2-5 Additionally, the proper validation performed before implementing telepathology can help laboratories identify their unique challenges, troubleshoot, and resolve the limitations before use in clinical care.^11-13 Continuing QA during its use and implementation is important to ensure that telepathology performs as expected for clinical purposes despite its limitations.²

Conclusions

Telepathology is a promising technology that may improve pathology practice once properly validated and implemented.^1-8 Though there are barriers to this validation and implementation, particularly the capital costs and training, there are several potential benefits, including increased productivity, cost savings, improvement in the workflow, enhanced access to pathologic consultation, and adaptability of the pathology laboratory in an era of a decreased workforce and social distancing due to the COVID-19 pandemic.^1-8,55-56 This potential applies across the wide spectrum of potential telepathology uses from frozen section, telecytology (including ROSE) to primary and second opinion diagnoses.^1-8,17-33 The benefits also extends to QA, education, and research, as diagnoses can not only be rereviewed by specialty or second opinion consultation with ease, but also digital slides can be produced for educational and research purposes.^3-8,35-45 Settings that treat the general population and those focused on the care of veterans or members of the armed forces have reported similar reliability or successful implementation.^35-44,61-63 All in all, the use of telepathology represents an innovation that may transform the practice of pathology tomorrow.

Pain and pruritus are the most common complaints in patients who present to vulvar clinics.¹ These symptoms can be related to a variety of conditions, including vulvar lesions. There are both common and uncommon vulvar lesions. Vulvar lesions can be skin colored, yellow, and red. Certain lesions can be diagnosed with history and physical examination alone. Some more common lesions include acrochordons (skin tags), benign growths that are common in patients with diabetes, obesity, and pregnancy.^2,3 Other common vulvar lesions are papillomatosis, lichen simplex chronicus, and epidermoid cysts. Other lesions include low- and high-grade squamous intraepithelial lesions (HSIL).⁴ These lesions require biopsy for diagnosis as high-grade lesions require treatment. HSIL of the vulva is considered a premalignancy that necessitates treatment.⁵ Other lesions that can present with vulvar complaints are molluscum contagiosum, Bartholin gland duct cyst, intradermal melanocytic nevus, and squamous cell carcinoma. 

Rarely, other less common conditions can present as vulvar lesions. Syringomas are benign eccrine sweat gland neoplasms. They are more commonly found on the face, neck, or chest.⁶ On the vulva they are generally small subcutaneous skin-colored papules.⁷ They may be asymptomatic and noted only on routine examination. 

Vulvar syringomas also may present with symptoms. On the vulva, syringomas often present as pruritic papules that can be isolated or multifocal. Often on the labia majora they range in size from 2 to 20 mm.⁸

They can coalesce to form a larger lesion. They also may be described as painful. When  syringomas are pruritic, the overlying skin may appear thickened from rubbing or scratching, and excoriations may be present. 

Since vulvar syringomas are rare, there is no standard treatment. Biopsy is necessary for definitive diagnosis. For asymptomatic cases, expectant management is warranted. In symptomatic cases treatment can be considered. Treatment options include cryotherapy, laser ablation, and intralesional electrodissection.⁸ Intralesional electrodissection and curettage also has been described as treatment.⁹ Other treatment options include surgical excision of individual lesions or larger excisions if multifocal. 

The case study described in "Case letter: Vulvar syringoma" highlights the diagnostic and therapeutic challenges associated with rare lesions of the vulva. Referral to a specialty clinic may be warranted in these challenging cases. ●

Pain and pruritus are the most common complaints in patients who present to vulvar clinics.¹ These symptoms can be related to a variety of conditions, including vulvar lesions. There are both common and uncommon vulvar lesions. Vulvar lesions can be skin colored, yellow, and red. Certain lesions can be diagnosed with history and physical examination alone. Some more common lesions include acrochordons (skin tags), benign growths that are common in patients with diabetes, obesity, and pregnancy.^2,3 Other common vulvar lesions are papillomatosis, lichen simplex chronicus, and epidermoid cysts. Other lesions include low- and high-grade squamous intraepithelial lesions (HSIL).⁴ These lesions require biopsy for diagnosis as high-grade lesions require treatment. HSIL of the vulva is considered a premalignancy that necessitates treatment.⁵ Other lesions that can present with vulvar complaints are molluscum contagiosum, Bartholin gland duct cyst, intradermal melanocytic nevus, and squamous cell carcinoma. 

Rarely, other less common conditions can present as vulvar lesions. Syringomas are benign eccrine sweat gland neoplasms. They are more commonly found on the face, neck, or chest.⁶ On the vulva they are generally small subcutaneous skin-colored papules.⁷ They may be asymptomatic and noted only on routine examination. 

Vulvar syringomas also may present with symptoms. On the vulva, syringomas often present as pruritic papules that can be isolated or multifocal. Often on the labia majora they range in size from 2 to 20 mm.⁸

They can coalesce to form a larger lesion. They also may be described as painful. When  syringomas are pruritic, the overlying skin may appear thickened from rubbing or scratching, and excoriations may be present. 

Since vulvar syringomas are rare, there is no standard treatment. Biopsy is necessary for definitive diagnosis. For asymptomatic cases, expectant management is warranted. In symptomatic cases treatment can be considered. Treatment options include cryotherapy, laser ablation, and intralesional electrodissection.⁸ Intralesional electrodissection and curettage also has been described as treatment.⁹ Other treatment options include surgical excision of individual lesions or larger excisions if multifocal. 

The case study described in "Case letter: Vulvar syringoma" highlights the diagnostic and therapeutic challenges associated with rare lesions of the vulva. Referral to a specialty clinic may be warranted in these challenging cases. ●

Pain and pruritus are the most common complaints in patients who present to vulvar clinics.¹ These symptoms can be related to a variety of conditions, including vulvar lesions. There are both common and uncommon vulvar lesions. Vulvar lesions can be skin colored, yellow, and red. Certain lesions can be diagnosed with history and physical examination alone. Some more common lesions include acrochordons (skin tags), benign growths that are common in patients with diabetes, obesity, and pregnancy.^2,3 Other common vulvar lesions are papillomatosis, lichen simplex chronicus, and epidermoid cysts. Other lesions include low- and high-grade squamous intraepithelial lesions (HSIL).⁴ These lesions require biopsy for diagnosis as high-grade lesions require treatment. HSIL of the vulva is considered a premalignancy that necessitates treatment.⁵ Other lesions that can present with vulvar complaints are molluscum contagiosum, Bartholin gland duct cyst, intradermal melanocytic nevus, and squamous cell carcinoma. 

Rarely, other less common conditions can present as vulvar lesions. Syringomas are benign eccrine sweat gland neoplasms. They are more commonly found on the face, neck, or chest.⁶ On the vulva they are generally small subcutaneous skin-colored papules.⁷ They may be asymptomatic and noted only on routine examination. 

Vulvar syringomas also may present with symptoms. On the vulva, syringomas often present as pruritic papules that can be isolated or multifocal. Often on the labia majora they range in size from 2 to 20 mm.⁸

They can coalesce to form a larger lesion. They also may be described as painful. When  syringomas are pruritic, the overlying skin may appear thickened from rubbing or scratching, and excoriations may be present. 

Since vulvar syringomas are rare, there is no standard treatment. Biopsy is necessary for definitive diagnosis. For asymptomatic cases, expectant management is warranted. In symptomatic cases treatment can be considered. Treatment options include cryotherapy, laser ablation, and intralesional electrodissection.⁸ Intralesional electrodissection and curettage also has been described as treatment.⁹ Other treatment options include surgical excision of individual lesions or larger excisions if multifocal. 

The case study described in "Case letter: Vulvar syringoma" highlights the diagnostic and therapeutic challenges associated with rare lesions of the vulva. Referral to a specialty clinic may be warranted in these challenging cases. ●

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVD by ascertaining LDL-C

• The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL),estimation of LDL-C is invalid.
• The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC–HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴
• National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵
• Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

• Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴
• Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Continue to: Applying the estimate of 10-year ASCVD risk...

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

• Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

• Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention: Stratification by age

• 40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force (USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

• 20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴
• > 75 years, without ASCVD. In this group, the benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy...

• Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

• Ezetimibe, a selective cholesterol-absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴
• PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23
• Inclisiran, an injectable small-interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴
• Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28
• Bempedoic acid is a small-molecule inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-intolerant patients, bempedoicacid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰
• Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL)and TG (42 mg/dL).^31,32
• Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; HDL-C< 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴ ●

CORRESPONDENCE

Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; [email protected]

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVD by ascertaining LDL-C

• The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL),estimation of LDL-C is invalid.
• The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC–HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴
• National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵
• Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

• Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴
• Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Continue to: Applying the estimate of 10-year ASCVD risk...

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

• Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

• Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention: Stratification by age

• 40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force (USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

• 20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴
• > 75 years, without ASCVD. In this group, the benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy...

• Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

• Ezetimibe, a selective cholesterol-absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴
• PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23
• Inclisiran, an injectable small-interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴
• Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28
• Bempedoic acid is a small-molecule inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-intolerant patients, bempedoicacid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰
• Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL)and TG (42 mg/dL).^31,32
• Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; HDL-C< 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴ ●

CORRESPONDENCE

Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; [email protected]

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVD by ascertaining LDL-C

• The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL),estimation of LDL-C is invalid.
• The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC–HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴
• National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵
• Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

• Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴
• Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Continue to: Applying the estimate of 10-year ASCVD risk...

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

• Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

• Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention: Stratification by age

• 40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force (USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

• 20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴
• > 75 years, without ASCVD. In this group, the benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy...

• Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

• Ezetimibe, a selective cholesterol-absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴
• PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23
• Inclisiran, an injectable small-interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴
• Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28
• Bempedoic acid is a small-molecule inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-intolerant patients, bempedoicacid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰
• Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL)and TG (42 mg/dL).^31,32
• Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; HDL-C< 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴ ●

CORRESPONDENCE

Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; [email protected]

Whole exome sequencing’s role in diagnosing genetic causes of FGR with and without associated anomalies

Mone F, Mellis R, Gabriel H, et al. Should we offer prenatal exome sequencing for intrauterine growth restriction or short long bones? A systematic review and meta-analysis. Am J Obstet Gynecol. Published online October 7, 2022. doi:10.1016/j.ajog.2022.09.045

Multiple factors can play a role in FGR, including inherent maternal, placental, or fetal factors; the environment; and/or nutrition. However, prenatal diagnosis is an important consideration when exploring the underlying etiology for a growth-restricted fetus, especially in severe or early-onset cases. Many genetic conditions do not result in structural anomalies but can disrupt overall growth. Additionally, phenotyping in the prenatal period is limited and can miss more subtle physical differences that could point to a genetic cause. 

When compared with karyotype, chromosomal microarray (CMA) has been shown to increase the diagnostic yield in cases of isolated early FGR by 5%,^1,2 and the incidence of chromosomal abnormalities has been reported to be as high as 19% in this population. Let’s explore the data on exome sequencing for prenatal diagnosis in cases of isolated FGR. 

Meta-analysis details

In this meta-analysis, the authors reviewed 19 cohort studies or case series that investigated the yield of prenatal sequencing in fetuses with intrauterine growth restriction (IUGR) or short long bones, both in association with and without additional anomalies. All cases had nondiagnostic cytogenetic results. Fetal DNA in most cases was obtained through amniocentesis. Variants classified as likely pathogenic and pathogenic were considered diagnostic. The authors then calculated the incremental yield of prenatal sequencing over cytogenetic studies as a pooled value, comparing the following groups:

• isolated FGR
• growth restriction with associated anomalies
• isolated short long bones
• short long bones with additional skeletal features.  

Study outcomes 

The total number of cases were as follows: isolated IUGR (n = 71), IUGR associated with additional anomalies (n = 45), isolated short long bones (n = 84), and short long bones associated with additional skeletal findings (n = 252). Causative pathogenic or likely pathogenic variants were identified in 224 (50%) cases. Apparent incremental yields with prenatal sequencing were as follows for the 4 groups (as illustrated in the FIGURE):

• 4% in isolated IUGR (95% confidence interval [CI], -5%–12%)
• 30% in IUGR with additional anomalies (95% CI, 13%–47%)
• 48% in isolated short long bones (95% CI, 26%–70%)
• 68% in short long bones with additional skeletal changes (95% CI, 58%–77%).

Overall, the authors concluded that prenatal sequencing does not improve prenatal diagnosis in cases of isolated IUGR. The majority of these cases were thought to be related to placental insufficiency.

Strengths and limitations 

The main limitation of this study with regard to our discussion is the small study populationof isolated growth restriction. The authors indicate that the number of cases of isolated IUGR were too small to draw firm conclusions. Another limitation was the heterogeneity of the isolated FGR population, which was not limited to severe or early-onset cases. However, the authors did demonstrate that growth restriction in association with fetal anomalies has very high genetic yield rates with prenatal sequencing. 

Continue to: Can whole exome sequencing diagnose genetic causes in cases of severe isolated FGR?...

Zhou H, Fu F, Wang Y, et al. Genetic causes of isolated and severe fetal growth restriction in normal chromosomal microarray analysis. Int J Gynaecol Obstet. Published online December 10, 2022. doi:10.1002/ijgo.14620

Severe FGR is diagnosed based on an estimated fetal weight (EFW) or abdominal circumference (AC) below the third percentile. As we discussed in the above study by Mone and colleagues, it does not appear that prenatal sequencing significantly improves the diagnostic yield in all isolated FGR cases. However, this has not been previously explored in isolated severe FGR or cases of early-onset FGR (<32 weeks’ gestation). We know that several monogenic conditions are associated with severe and early-onset isolated fetal growth impairment, including but not limited to Cornelia de Lange syndrome, Smith-Lemli-Opitz syndrome, and Meier-Gorlin syndrome. Often, these syndromes can present in the prenatal period without other phenotypic findings. Therefore, this study explored the possibility that prenatal sequencing plays an important role for severe cases of FGR with nondiagnostic CMA and/or karyotype. 

Retrospective study details 

Zhou and colleagues retrospectively analyzed 51 cases of severe (EFW or AC below the third percentile) isolated FGR with negative CMA who underwent trio whole exome sequencing, which includes submitting fetal cells as well as both parental samples for testing. Patients with abnormal toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (TORCH) tests; structural anomalies; and multiple gestation were excluded from the analysis. As in the study by Mone et al, variants classified as likely pathogenic and pathogenic were categorized as diagnostic. 

Results

Eight of 51 cases (15.7%) with severe isolated FGR had diagnostic findings on trio whole exome sequencing as shown in the TABLE. Another 8 cases (15.7%) were found to have variants of unknown significance, of which 2 were later determined to be novel pathogenic variants. Genetic conditions uncovered in this cohort include Cornelia de Lange syndrome, pyruvate dehydrogenase deficiency, Dent disease, trichohepaticenteric syndrome, achondroplasia, osteogenesis imperfecta, Pendred syndrome, and both autosomal dominant type 3A and autosomal recessive type 1A deafness. All 10 cases with diagnostic whole exome sequencing or identified novel pathogenic variants were affected by early-onset FGR (<32 weeks’ gestation). Of these 10 cases, 7 patients underwent pregnancy termination.

To summarize, a total of 10 cases (19.6%) of severe isolated early-onset FGR with negative cytogenetic studies were subsequently diagnosed with an underlying genetic condition using prenatal trio whole exome sequencing. 

Strengths and limitations 

This study is retrospective and has a small sample size (n = 51) that was mostly limited to early-onset isolated severe FGR. However, the diagnostic yield (19.6%) of whole exome sequencing after negative CMA testing was noteworthy and shows that monogenic conditions are an important consideration in the evaluation of severe early-onset FGR, even in the absence of structural abnormalities. 

Could epigenetic mechanisms of placental dysregulation explain low birthweight and future cardiometabolic disease?  

Tekola-Ayele F, Zeng X, Chatterjee S, et al. Placental multi-omics integration identifies candidate functional genes for birthweight. Nat Commun. 2022;13:2384.

FGR has been linked to greater mortality in childhood and increased risk for cardiometabolic disease in adulthood. While genomewide associations studies (GWAS) have defined areas of interest linking genetic variants to low birthweight, their relationship to epigenetic changes in the placenta as well as biologic and functional mechanisms are not yet well understood.  

Multiomics used to identify candidate functional genes for birthweight 

This study analyzed the methylation and gene expression patterns of 291 placental samples, integrating findings into pathways of previously defined GWAS variants. Patient samples were obtained from participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies–Singleton cohort. The cohort is ethnically diverse, with 97 Hispanic, 74 White, 71 Black, and 49 Asian participants. Of 286 single nucleotide polymorphisms (SNPs) found to be associated with birthweight, 273 were analyzed as part of the authors’ data set. These were found to have 7,901 unique protein-coding mRNAs (expression quantitative trait loci [eQTL]) and more than 100,000 nearby (within 1 Mb) CpG islands thought to be involved in changes in DNA methylation (methylation quantitative trait loci [mQTL]). Each functionally connected GWAS-eQTL-mQTL association is referred to as a triplet.

The next arm of the study investigatedthe connections and pathways within each triplet. Three possible scenarios were explored for birthweight GWAS SNPs using a causal interference test (CIT):

1. the SNP alters placental DNA methylation, which then influences gene expression
2. the SNP first alters placental DNA expression, which then influences methylation
3. the SNP influences placental DNA expression and methylation independently, with no notable crossover between their pathways.

Triplets were investigated using the Mendelian randomization (MR) Steiger directionality test to validate the directionality of the pathways found by CIT. Lastly, the possibility of linkage disequilibrium was also studied using the moloc test. 

Results

Using CIT, a causal relationship was predicted in 88 of 197 triplets, in which 84 (95.5%) indicated DNA methylation influences gene expression, and 4 (4.5%) indicated gene expression influences DNA methylation. The authors also used the MR Steiger test to investigate triplets to identify possible causal pathways. Using the MR Steiger test, only 3 of 45 (7%) triplets were found to have independent gene expression and methylation pathways. Thirty-eight of 45 (84%) triplets indicated that gene expression influences DNA methylation, and 7 (15%)triplets demonstrated that DNA methylation influences gene expression. Consistent predictions between CIT and the MR Steiger test revealed 3 triplets in which DNA methylation influences gene expression for the following genes: WNT3A, CTDNEP1, and RANBP2. Additionally, a strong colocalization signal was found among birthweight, DNA methylation, and gene expression for the following genes: PLEKHA1, FES, PRMT7, and CTDNEP1. Gene set enrichment analysis was performed as well and found that low birthweight is associated in substantial upregulation of genes associated with oxidative stress, immune response, adipogenesis, myogenesis, and the production of pancreatic ß cells.  

Study strengths and limitations

The study is one of the first to identify regulatory targets for placental DNA methylation and gene expression in previously identified GWAS loci associated with low birthweight. For example, DNA methylation was found to influence gene expression of WNT3A, CTDNEP1, and RANBP2, which have previously been shown in animal studies to impact the vascularization and development of the placenta, embryogenesis, and fetal growth. The study also identified 4 genes (PLEKHA1, FES, PRMT7, and CTDNEP1) thought to have direct regulatory influence on placental DNA methylation and gene expression.

A limitation of the study is that it could not distinguish between whether the epigenetic changes we outlined have a maternal or fetal origin. Another limitation is that tissue used by the authors for analysis was a small placental biopsy, which does not accurately reflect the genetic heterogeneity of the placenta. Finally, this study does not establish causality between the identified epigenetic pathways and low birthweight. ●

Whole exome sequencing’s role in diagnosing genetic causes of FGR with and without associated anomalies

Mone F, Mellis R, Gabriel H, et al. Should we offer prenatal exome sequencing for intrauterine growth restriction or short long bones? A systematic review and meta-analysis. Am J Obstet Gynecol. Published online October 7, 2022. doi:10.1016/j.ajog.2022.09.045

Multiple factors can play a role in FGR, including inherent maternal, placental, or fetal factors; the environment; and/or nutrition. However, prenatal diagnosis is an important consideration when exploring the underlying etiology for a growth-restricted fetus, especially in severe or early-onset cases. Many genetic conditions do not result in structural anomalies but can disrupt overall growth. Additionally, phenotyping in the prenatal period is limited and can miss more subtle physical differences that could point to a genetic cause. 

When compared with karyotype, chromosomal microarray (CMA) has been shown to increase the diagnostic yield in cases of isolated early FGR by 5%,^1,2 and the incidence of chromosomal abnormalities has been reported to be as high as 19% in this population. Let’s explore the data on exome sequencing for prenatal diagnosis in cases of isolated FGR. 

Meta-analysis details

In this meta-analysis, the authors reviewed 19 cohort studies or case series that investigated the yield of prenatal sequencing in fetuses with intrauterine growth restriction (IUGR) or short long bones, both in association with and without additional anomalies. All cases had nondiagnostic cytogenetic results. Fetal DNA in most cases was obtained through amniocentesis. Variants classified as likely pathogenic and pathogenic were considered diagnostic. The authors then calculated the incremental yield of prenatal sequencing over cytogenetic studies as a pooled value, comparing the following groups:

• isolated FGR
• growth restriction with associated anomalies
• isolated short long bones
• short long bones with additional skeletal features.  

Study outcomes 

The total number of cases were as follows: isolated IUGR (n = 71), IUGR associated with additional anomalies (n = 45), isolated short long bones (n = 84), and short long bones associated with additional skeletal findings (n = 252). Causative pathogenic or likely pathogenic variants were identified in 224 (50%) cases. Apparent incremental yields with prenatal sequencing were as follows for the 4 groups (as illustrated in the FIGURE):

• 4% in isolated IUGR (95% confidence interval [CI], -5%–12%)
• 30% in IUGR with additional anomalies (95% CI, 13%–47%)
• 48% in isolated short long bones (95% CI, 26%–70%)
• 68% in short long bones with additional skeletal changes (95% CI, 58%–77%).

Overall, the authors concluded that prenatal sequencing does not improve prenatal diagnosis in cases of isolated IUGR. The majority of these cases were thought to be related to placental insufficiency.

Strengths and limitations 

The main limitation of this study with regard to our discussion is the small study populationof isolated growth restriction. The authors indicate that the number of cases of isolated IUGR were too small to draw firm conclusions. Another limitation was the heterogeneity of the isolated FGR population, which was not limited to severe or early-onset cases. However, the authors did demonstrate that growth restriction in association with fetal anomalies has very high genetic yield rates with prenatal sequencing. 

Continue to: Can whole exome sequencing diagnose genetic causes in cases of severe isolated FGR?...

Zhou H, Fu F, Wang Y, et al. Genetic causes of isolated and severe fetal growth restriction in normal chromosomal microarray analysis. Int J Gynaecol Obstet. Published online December 10, 2022. doi:10.1002/ijgo.14620

Severe FGR is diagnosed based on an estimated fetal weight (EFW) or abdominal circumference (AC) below the third percentile. As we discussed in the above study by Mone and colleagues, it does not appear that prenatal sequencing significantly improves the diagnostic yield in all isolated FGR cases. However, this has not been previously explored in isolated severe FGR or cases of early-onset FGR (<32 weeks’ gestation). We know that several monogenic conditions are associated with severe and early-onset isolated fetal growth impairment, including but not limited to Cornelia de Lange syndrome, Smith-Lemli-Opitz syndrome, and Meier-Gorlin syndrome. Often, these syndromes can present in the prenatal period without other phenotypic findings. Therefore, this study explored the possibility that prenatal sequencing plays an important role for severe cases of FGR with nondiagnostic CMA and/or karyotype. 

Retrospective study details 

Zhou and colleagues retrospectively analyzed 51 cases of severe (EFW or AC below the third percentile) isolated FGR with negative CMA who underwent trio whole exome sequencing, which includes submitting fetal cells as well as both parental samples for testing. Patients with abnormal toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (TORCH) tests; structural anomalies; and multiple gestation were excluded from the analysis. As in the study by Mone et al, variants classified as likely pathogenic and pathogenic were categorized as diagnostic. 

Results

Eight of 51 cases (15.7%) with severe isolated FGR had diagnostic findings on trio whole exome sequencing as shown in the TABLE. Another 8 cases (15.7%) were found to have variants of unknown significance, of which 2 were later determined to be novel pathogenic variants. Genetic conditions uncovered in this cohort include Cornelia de Lange syndrome, pyruvate dehydrogenase deficiency, Dent disease, trichohepaticenteric syndrome, achondroplasia, osteogenesis imperfecta, Pendred syndrome, and both autosomal dominant type 3A and autosomal recessive type 1A deafness. All 10 cases with diagnostic whole exome sequencing or identified novel pathogenic variants were affected by early-onset FGR (<32 weeks’ gestation). Of these 10 cases, 7 patients underwent pregnancy termination.

To summarize, a total of 10 cases (19.6%) of severe isolated early-onset FGR with negative cytogenetic studies were subsequently diagnosed with an underlying genetic condition using prenatal trio whole exome sequencing. 

Strengths and limitations 

This study is retrospective and has a small sample size (n = 51) that was mostly limited to early-onset isolated severe FGR. However, the diagnostic yield (19.6%) of whole exome sequencing after negative CMA testing was noteworthy and shows that monogenic conditions are an important consideration in the evaluation of severe early-onset FGR, even in the absence of structural abnormalities. 

Could epigenetic mechanisms of placental dysregulation explain low birthweight and future cardiometabolic disease?  

Tekola-Ayele F, Zeng X, Chatterjee S, et al. Placental multi-omics integration identifies candidate functional genes for birthweight. Nat Commun. 2022;13:2384.

FGR has been linked to greater mortality in childhood and increased risk for cardiometabolic disease in adulthood. While genomewide associations studies (GWAS) have defined areas of interest linking genetic variants to low birthweight, their relationship to epigenetic changes in the placenta as well as biologic and functional mechanisms are not yet well understood.  

Multiomics used to identify candidate functional genes for birthweight 

This study analyzed the methylation and gene expression patterns of 291 placental samples, integrating findings into pathways of previously defined GWAS variants. Patient samples were obtained from participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies–Singleton cohort. The cohort is ethnically diverse, with 97 Hispanic, 74 White, 71 Black, and 49 Asian participants. Of 286 single nucleotide polymorphisms (SNPs) found to be associated with birthweight, 273 were analyzed as part of the authors’ data set. These were found to have 7,901 unique protein-coding mRNAs (expression quantitative trait loci [eQTL]) and more than 100,000 nearby (within 1 Mb) CpG islands thought to be involved in changes in DNA methylation (methylation quantitative trait loci [mQTL]). Each functionally connected GWAS-eQTL-mQTL association is referred to as a triplet.

The next arm of the study investigatedthe connections and pathways within each triplet. Three possible scenarios were explored for birthweight GWAS SNPs using a causal interference test (CIT):

1. the SNP alters placental DNA methylation, which then influences gene expression
2. the SNP first alters placental DNA expression, which then influences methylation
3. the SNP influences placental DNA expression and methylation independently, with no notable crossover between their pathways.

Triplets were investigated using the Mendelian randomization (MR) Steiger directionality test to validate the directionality of the pathways found by CIT. Lastly, the possibility of linkage disequilibrium was also studied using the moloc test. 

Results

Using CIT, a causal relationship was predicted in 88 of 197 triplets, in which 84 (95.5%) indicated DNA methylation influences gene expression, and 4 (4.5%) indicated gene expression influences DNA methylation. The authors also used the MR Steiger test to investigate triplets to identify possible causal pathways. Using the MR Steiger test, only 3 of 45 (7%) triplets were found to have independent gene expression and methylation pathways. Thirty-eight of 45 (84%) triplets indicated that gene expression influences DNA methylation, and 7 (15%)triplets demonstrated that DNA methylation influences gene expression. Consistent predictions between CIT and the MR Steiger test revealed 3 triplets in which DNA methylation influences gene expression for the following genes: WNT3A, CTDNEP1, and RANBP2. Additionally, a strong colocalization signal was found among birthweight, DNA methylation, and gene expression for the following genes: PLEKHA1, FES, PRMT7, and CTDNEP1. Gene set enrichment analysis was performed as well and found that low birthweight is associated in substantial upregulation of genes associated with oxidative stress, immune response, adipogenesis, myogenesis, and the production of pancreatic ß cells.  

Study strengths and limitations

The study is one of the first to identify regulatory targets for placental DNA methylation and gene expression in previously identified GWAS loci associated with low birthweight. For example, DNA methylation was found to influence gene expression of WNT3A, CTDNEP1, and RANBP2, which have previously been shown in animal studies to impact the vascularization and development of the placenta, embryogenesis, and fetal growth. The study also identified 4 genes (PLEKHA1, FES, PRMT7, and CTDNEP1) thought to have direct regulatory influence on placental DNA methylation and gene expression.

A limitation of the study is that it could not distinguish between whether the epigenetic changes we outlined have a maternal or fetal origin. Another limitation is that tissue used by the authors for analysis was a small placental biopsy, which does not accurately reflect the genetic heterogeneity of the placenta. Finally, this study does not establish causality between the identified epigenetic pathways and low birthweight. ●

Whole exome sequencing’s role in diagnosing genetic causes of FGR with and without associated anomalies

Mone F, Mellis R, Gabriel H, et al. Should we offer prenatal exome sequencing for intrauterine growth restriction or short long bones? A systematic review and meta-analysis. Am J Obstet Gynecol. Published online October 7, 2022. doi:10.1016/j.ajog.2022.09.045

Multiple factors can play a role in FGR, including inherent maternal, placental, or fetal factors; the environment; and/or nutrition. However, prenatal diagnosis is an important consideration when exploring the underlying etiology for a growth-restricted fetus, especially in severe or early-onset cases. Many genetic conditions do not result in structural anomalies but can disrupt overall growth. Additionally, phenotyping in the prenatal period is limited and can miss more subtle physical differences that could point to a genetic cause. 

When compared with karyotype, chromosomal microarray (CMA) has been shown to increase the diagnostic yield in cases of isolated early FGR by 5%,^1,2 and the incidence of chromosomal abnormalities has been reported to be as high as 19% in this population. Let’s explore the data on exome sequencing for prenatal diagnosis in cases of isolated FGR. 

Meta-analysis details

In this meta-analysis, the authors reviewed 19 cohort studies or case series that investigated the yield of prenatal sequencing in fetuses with intrauterine growth restriction (IUGR) or short long bones, both in association with and without additional anomalies. All cases had nondiagnostic cytogenetic results. Fetal DNA in most cases was obtained through amniocentesis. Variants classified as likely pathogenic and pathogenic were considered diagnostic. The authors then calculated the incremental yield of prenatal sequencing over cytogenetic studies as a pooled value, comparing the following groups:

• isolated FGR
• growth restriction with associated anomalies
• isolated short long bones
• short long bones with additional skeletal features.  

Study outcomes 

The total number of cases were as follows: isolated IUGR (n = 71), IUGR associated with additional anomalies (n = 45), isolated short long bones (n = 84), and short long bones associated with additional skeletal findings (n = 252). Causative pathogenic or likely pathogenic variants were identified in 224 (50%) cases. Apparent incremental yields with prenatal sequencing were as follows for the 4 groups (as illustrated in the FIGURE):

• 4% in isolated IUGR (95% confidence interval [CI], -5%–12%)
• 30% in IUGR with additional anomalies (95% CI, 13%–47%)
• 48% in isolated short long bones (95% CI, 26%–70%)
• 68% in short long bones with additional skeletal changes (95% CI, 58%–77%).

Overall, the authors concluded that prenatal sequencing does not improve prenatal diagnosis in cases of isolated IUGR. The majority of these cases were thought to be related to placental insufficiency.

Strengths and limitations 

The main limitation of this study with regard to our discussion is the small study populationof isolated growth restriction. The authors indicate that the number of cases of isolated IUGR were too small to draw firm conclusions. Another limitation was the heterogeneity of the isolated FGR population, which was not limited to severe or early-onset cases. However, the authors did demonstrate that growth restriction in association with fetal anomalies has very high genetic yield rates with prenatal sequencing. 

Continue to: Can whole exome sequencing diagnose genetic causes in cases of severe isolated FGR?...

Zhou H, Fu F, Wang Y, et al. Genetic causes of isolated and severe fetal growth restriction in normal chromosomal microarray analysis. Int J Gynaecol Obstet. Published online December 10, 2022. doi:10.1002/ijgo.14620

Severe FGR is diagnosed based on an estimated fetal weight (EFW) or abdominal circumference (AC) below the third percentile. As we discussed in the above study by Mone and colleagues, it does not appear that prenatal sequencing significantly improves the diagnostic yield in all isolated FGR cases. However, this has not been previously explored in isolated severe FGR or cases of early-onset FGR (<32 weeks’ gestation). We know that several monogenic conditions are associated with severe and early-onset isolated fetal growth impairment, including but not limited to Cornelia de Lange syndrome, Smith-Lemli-Opitz syndrome, and Meier-Gorlin syndrome. Often, these syndromes can present in the prenatal period without other phenotypic findings. Therefore, this study explored the possibility that prenatal sequencing plays an important role for severe cases of FGR with nondiagnostic CMA and/or karyotype. 

Retrospective study details 

Zhou and colleagues retrospectively analyzed 51 cases of severe (EFW or AC below the third percentile) isolated FGR with negative CMA who underwent trio whole exome sequencing, which includes submitting fetal cells as well as both parental samples for testing. Patients with abnormal toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (TORCH) tests; structural anomalies; and multiple gestation were excluded from the analysis. As in the study by Mone et al, variants classified as likely pathogenic and pathogenic were categorized as diagnostic. 

Results

Eight of 51 cases (15.7%) with severe isolated FGR had diagnostic findings on trio whole exome sequencing as shown in the TABLE. Another 8 cases (15.7%) were found to have variants of unknown significance, of which 2 were later determined to be novel pathogenic variants. Genetic conditions uncovered in this cohort include Cornelia de Lange syndrome, pyruvate dehydrogenase deficiency, Dent disease, trichohepaticenteric syndrome, achondroplasia, osteogenesis imperfecta, Pendred syndrome, and both autosomal dominant type 3A and autosomal recessive type 1A deafness. All 10 cases with diagnostic whole exome sequencing or identified novel pathogenic variants were affected by early-onset FGR (<32 weeks’ gestation). Of these 10 cases, 7 patients underwent pregnancy termination.

To summarize, a total of 10 cases (19.6%) of severe isolated early-onset FGR with negative cytogenetic studies were subsequently diagnosed with an underlying genetic condition using prenatal trio whole exome sequencing. 

Strengths and limitations 

This study is retrospective and has a small sample size (n = 51) that was mostly limited to early-onset isolated severe FGR. However, the diagnostic yield (19.6%) of whole exome sequencing after negative CMA testing was noteworthy and shows that monogenic conditions are an important consideration in the evaluation of severe early-onset FGR, even in the absence of structural abnormalities. 

Could epigenetic mechanisms of placental dysregulation explain low birthweight and future cardiometabolic disease?  

Tekola-Ayele F, Zeng X, Chatterjee S, et al. Placental multi-omics integration identifies candidate functional genes for birthweight. Nat Commun. 2022;13:2384.

FGR has been linked to greater mortality in childhood and increased risk for cardiometabolic disease in adulthood. While genomewide associations studies (GWAS) have defined areas of interest linking genetic variants to low birthweight, their relationship to epigenetic changes in the placenta as well as biologic and functional mechanisms are not yet well understood.  

Multiomics used to identify candidate functional genes for birthweight 

This study analyzed the methylation and gene expression patterns of 291 placental samples, integrating findings into pathways of previously defined GWAS variants. Patient samples were obtained from participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies–Singleton cohort. The cohort is ethnically diverse, with 97 Hispanic, 74 White, 71 Black, and 49 Asian participants. Of 286 single nucleotide polymorphisms (SNPs) found to be associated with birthweight, 273 were analyzed as part of the authors’ data set. These were found to have 7,901 unique protein-coding mRNAs (expression quantitative trait loci [eQTL]) and more than 100,000 nearby (within 1 Mb) CpG islands thought to be involved in changes in DNA methylation (methylation quantitative trait loci [mQTL]). Each functionally connected GWAS-eQTL-mQTL association is referred to as a triplet.

The next arm of the study investigatedthe connections and pathways within each triplet. Three possible scenarios were explored for birthweight GWAS SNPs using a causal interference test (CIT):

1. the SNP alters placental DNA methylation, which then influences gene expression
2. the SNP first alters placental DNA expression, which then influences methylation
3. the SNP influences placental DNA expression and methylation independently, with no notable crossover between their pathways.

Triplets were investigated using the Mendelian randomization (MR) Steiger directionality test to validate the directionality of the pathways found by CIT. Lastly, the possibility of linkage disequilibrium was also studied using the moloc test. 

Results

Using CIT, a causal relationship was predicted in 88 of 197 triplets, in which 84 (95.5%) indicated DNA methylation influences gene expression, and 4 (4.5%) indicated gene expression influences DNA methylation. The authors also used the MR Steiger test to investigate triplets to identify possible causal pathways. Using the MR Steiger test, only 3 of 45 (7%) triplets were found to have independent gene expression and methylation pathways. Thirty-eight of 45 (84%) triplets indicated that gene expression influences DNA methylation, and 7 (15%)triplets demonstrated that DNA methylation influences gene expression. Consistent predictions between CIT and the MR Steiger test revealed 3 triplets in which DNA methylation influences gene expression for the following genes: WNT3A, CTDNEP1, and RANBP2. Additionally, a strong colocalization signal was found among birthweight, DNA methylation, and gene expression for the following genes: PLEKHA1, FES, PRMT7, and CTDNEP1. Gene set enrichment analysis was performed as well and found that low birthweight is associated in substantial upregulation of genes associated with oxidative stress, immune response, adipogenesis, myogenesis, and the production of pancreatic ß cells.  

Study strengths and limitations

The study is one of the first to identify regulatory targets for placental DNA methylation and gene expression in previously identified GWAS loci associated with low birthweight. For example, DNA methylation was found to influence gene expression of WNT3A, CTDNEP1, and RANBP2, which have previously been shown in animal studies to impact the vascularization and development of the placenta, embryogenesis, and fetal growth. The study also identified 4 genes (PLEKHA1, FES, PRMT7, and CTDNEP1) thought to have direct regulatory influence on placental DNA methylation and gene expression.

A limitation of the study is that it could not distinguish between whether the epigenetic changes we outlined have a maternal or fetal origin. Another limitation is that tissue used by the authors for analysis was a small placental biopsy, which does not accurately reflect the genetic heterogeneity of the placenta. Finally, this study does not establish causality between the identified epigenetic pathways and low birthweight. ●

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

Cutaneous angiosarcoma (cAS) is a rare malignancy arising from vascular or lymphatic tissue. It classically presents during the sixth or seventh decades of life as a raised purple papule or plaque on the head and neck areas.¹ Primary cAS frequently mimics benign conditions, leading to delays in care. Such delays coupled with the aggressive nature of angiosarcomas leads to a poor prognosis. Five-year survival rates range from 11% to 50%, and more than half of patients die within 1 year of diagnosis.^2-7

Currently, there is no consensus on the most effective treatments, as the rare nature of cAS has made the development of controlled clinical trials difficult. Wide local excision (WLE) is most frequently employed; however, the tumor’s infiltrative growth makes complete resection and negative surgical margins difficult to achieve.⁸ Recently, Mohs micrographic surgery (MMS) has been postulated as a treatment option. The tissue-sparing nature and intraoperative margin control of MMS may provide tumor eradication and cosmesis benefits reported with other cutaneous malignancies.⁹

Nearly all localized cASs are treated with surgical excision with or without adjuvant treatment modalities; however, it is unclear which of these modalities provide a survival benefit. We conducted a systematic review of the literature to compare treatment modalities for localized cAS of the head and neck regions and to compare treatments based on tumor stage.

METHODS

A literature search was performed to identify published studies indexed by MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and PubMed from January 1, 1977, to May 8, 2020, reporting on cAS and treatment modalities used. The search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.⁵ Data extracted included patient demographics, tumor characteristics (including T1 [≤5 cm] and T2 [>5 cm and ≤10 cm] based on the American Joint Committee on Cancer soft tissue sarcoma staging criteria), treatments used, follow-up time, overall survival (OS) rates, and complications.^10,11

Studies were required to (1) include participants with head and neck cAS; (2) report original patient data following cAS treatment with surgical (WLE or MMS) and/or nonsurgical modalities (chemotherapy [CT], radiotherapy [RT], immunotherapy [IT]); (3) report outcome data related to OS rates following treatment; and (4) have articles published in English. Given the rare nature of cAS, there was no limitation on the number of participants needed.

The Newcastle-Ottawa scale for observational studies was used to assess the quality of studies.¹² Higher scores indicate low risk of bias, while lower scores represent high risk of bias.

Continuous data were reported with means and SDs, while categorical variables were reported as percentages. Overall survival means and SDs were compared between treatment modalities using an independent sample t test with P<.05 considered statistically significant. Due to the heterogeneity of the data, a meta-analysis was not reported.

RESULTS

Literature Search and Risk of Bias Assessment

There were 283 manuscripts identified, 56 articles read in full, and 40 articles included in the review (Figure). Among the 16 studies not meeting inclusion criteria, 7 did not provide enough data to isolate head and neck cAS cases,^1,13-18 6 did not report outcomes related to the current review,^19-24 and 3 did not provide enough data to isolate different treatment outcomes.^25-27 Among the included studies, 32 reported use of WLE: WLE alone (n=21)^2,7,11,28-45; WLE with RT (n=24)^{2,3,11,28-31,33-36,38-41,43-51}; WLE with CT (n=7)^{2,31,35,39,41,48,52}; WLE with RT and CT (n=11)^{2,29,31,33-35,39,40,48,52,53}; WLE with RT and IT (n=3)^35,54,55; and WLE with RT, CT, and IT (n=1).⁵³ Nine studies reported MMS: MMS alone (n=5)^39,56-59; MMS with RT (n=3)^32,50,60,61; and MMS with RT and CT (n=1).⁵¹

Risk of bias assessment identified low risk in 3 articles. High risk was identified in 5 case reports,^57-61 and 1 study did not describe patient selection.⁴³ Clayton et al⁵⁶ showed intermediate risk, given the study controlled for 1 factor.

Patient Demographics

A total of 1295 patients were included. The pooled mean age of the patients was 67.5 years (range, 3–88 years), and 64.7% were male. There were 79 cases identified as T1 and 105 as T2. A total of 825 cases were treated using WLE with or without adjuvant therapy, while a total of 9 cases were treated using MMS with and without adjuvant therapies (Table). There were 461 cases treated without surgical excision: RT alone (n=261), CT alone (n=38), IT alone (n=35), RT with CT (n=81), RT with IT (n=34), and RT with CT and IT (n=12)(Table). The median follow-up period across all studies was 23.5 months (range, 1–228 months).

Comparison Between Surgical and Nonsurgical Modalities

Wide Local Excision—Wide local excision (n=825; 63.7%) alone or in combination with other therapies was the most frequently used treatment modality. The mean (SD) OS was longest for WLE with RT, CT, and IT (n=3; 39.3 [24.1]), followed by WLE with RT (n=447; 35.9 [34.3] months), WLE with CT (n=13; 32.4 [30.2] months), WLE alone (n=324; 29.6 [34.1] months), WLE with RT and IT (n=11; 23.5 [4.9] months), and WLE with RT and CT (n=27; 20.7 [13.1] months).

Nonsurgical Modalities—Nonsurgical methods were used less frequently than surgical methods (n=461; 35.6%). The mean (SD) OS time in descending order was as follows: RT with CT and IT (n=12; 34.9 [1.2] months), RT with CT (n=81; 30.4 [37.8] months), IT alone (n=35; 25.7 [no SD reported] months), RT with IT (n=34; 20.5 [8.6] months), CT alone (n=38; 20.1 [15.9] months), and RT alone (n=261; 12.8 [8.3] months).

When comparing mean (SD) OS outcomes between surgical and nonsurgical treatment modalities, only the addition of WLE to RT significantly increased OS when compared with RT alone (WLE, 35.9 [34.3] months; RT alone, 12.8 [8.3] months; P=.001). When WLE was added to CT or both RT and CT, there was no significant difference with OS when compared with CT alone (WLE with CT, 32.4 [30.2] months; CT alone, 20.1 [15.9] months; P=.065); or both RT and CT in combination (WLE with RT and CT, 20.7 [13.1] months; RT and CT, 30.4 [37.8] months; P=.204).

Comparison Between T1 and T2 cAS

T1 Angiosarcoma—There were 79 patients identified as having T1 tumors across 16 studies.^{2,31,32,34,39-41,46,48-50,53,58-60,62} The mean (SD) OS was longest for WLE with RT, CT, and IT (n=2; 56.0 [6.0] months), followed by WLE with CT (n=4; 54.5 [41.0] months); WLE with RT (n=30; 39.7 [41.2] months); WLE alone (n=22; 37.2 [37.3] months); WLE with both RT and CT (n=7; 25.5 [18.7] months); RT with IT (n=2; 20.0 [11.0] months); RT with CT (n=6; 15.7 [6.8] months); and RT alone (n=1; 13 [no SD]) months)(eTable).

T2 Angiosarcoma—There were 105 patients with T2 tumors in 15 studies.^{2,31,32,34,39-41,46,48-50,52,53,57,62} The mean (SD) OS for each treatment modality in descending order was as follows: RT with CT and IT (n=1; 36 [no SD reported] months); RT with CT (n=23; 34.3 [46.3] months); WLE with RT (n=21; 26.3 [23.8] months); WLE with CT (n=8; 21.5 [16.6] months); WLE alone (n=16; 19.8 [15.6] months); WLE with RT and CT (n=14; 19.2 [10.5] months); RT alone (n=17; 10.1 [5.5] months); CT alone (n=2; 6.7 [3.7] months); and WLE with RT, CT, and IT (n=1; 6.0 [no SD] months)(eTable).

Mohs Micrographic Surgery—The use of MMS was only identified in case reports or small observational studies for a total of 9 patients. Five cASs were treated with MMS alone for a mean (SD) OS of 37 (21.5) months, with 4 reporting cAS staging: 2 were T1^58,59 (mean [SD] OS, 37.0 [17.0] months) and 2 were T2 tumors^39,57 (mean [SD] OS, 44.5 [26.5] months). Mohs micrographic surgery with RT was used for 3 tumors (mean [SD] OS, 34.0 [26.9] months); 2 were T1^50,60 (mean [SD] OS, 42.0 [30.0] months) and 1 unreported staging (eTable).⁵⁶ Mohs micrographic surgery with both RT and CT was used in 1 patient (unreported staging; OS, 82 months).⁵¹

Complications

Complications were rare and mainly associated with CT and RT. Four studies reported radiation dermatitis with RT.^53,55,62,63 Two studies reported peripheral neuropathy and myelotoxicity with CT.^35,51 Only 1 study reported poor wound healing due to surgical complications.²⁹

COMMENT

Cutaneous angiosarcomas are rare and have limited treatment guidelines. Surgical excision does appear to be an effective adjunct to nonsurgical treatments, particularly WLE combined with RT, CT, and IT. Although MMS ultimately may be useful for cAS, the limited number and substantial heterogeneity of reported cases precludes definitive conclusions at this time.

Achieving margin control during WLE is associated with higher OS when treating angiosarcoma,^36,46 which is particularly true for T1 tumors where margin control is imperative, and many cases are treated with a combination of WLE and RT. Overall survival times are lower for T2 tumors, as these tumors are larger and most likely have spread; therefore, more aggressive combination treatments were more prevalent. In these cases, complete margin control may be difficult to achieve and may not be as critical to the outcome if another form of adjuvant therapy can be administered promptly.^24,64

When surgery is contraindicated, RT with or without CT was the most commonly reported treatment modality. However, these treatments were notably less effective than when used in combination with surgical resection. The use of RT alone has a recurrence rate reported up to 100% in certain studies, suggesting the need to utilize RT in combination with other modalities.^23,39 It is important to note that RT often is used as monotherapy in palliative treatment, which may indirectly skew survival rates.²

Limitations of the study include a lack of randomized controlled trials. Most reports were retrospective reviews or case series, and tumor staging was sparsely reported. Finally, although MMS may provide utility in the treatment of cAS, the sample size of 9 precluded definitive conclusions from being formed about its efficacy.

CONCLUSION

Cutaneous angiosarcoma is rare and has limited data comparing different treatment modalities. The paucity of data currently limits definitive recommendations; however, both surgical and nonsurgical modalities have demonstrated potential efficacy in the treatment of cAS and may benefit from additional research. Clinicians should consider a multidisciplinary approach for patients with a diagnosis of cAS to tailor treatments on a case-by-case basis.

Cutaneous angiosarcoma (cAS) is a rare malignancy arising from vascular or lymphatic tissue. It classically presents during the sixth or seventh decades of life as a raised purple papule or plaque on the head and neck areas.¹ Primary cAS frequently mimics benign conditions, leading to delays in care. Such delays coupled with the aggressive nature of angiosarcomas leads to a poor prognosis. Five-year survival rates range from 11% to 50%, and more than half of patients die within 1 year of diagnosis.^2-7

Currently, there is no consensus on the most effective treatments, as the rare nature of cAS has made the development of controlled clinical trials difficult. Wide local excision (WLE) is most frequently employed; however, the tumor’s infiltrative growth makes complete resection and negative surgical margins difficult to achieve.⁸ Recently, Mohs micrographic surgery (MMS) has been postulated as a treatment option. The tissue-sparing nature and intraoperative margin control of MMS may provide tumor eradication and cosmesis benefits reported with other cutaneous malignancies.⁹

Nearly all localized cASs are treated with surgical excision with or without adjuvant treatment modalities; however, it is unclear which of these modalities provide a survival benefit. We conducted a systematic review of the literature to compare treatment modalities for localized cAS of the head and neck regions and to compare treatments based on tumor stage.

METHODS

A literature search was performed to identify published studies indexed by MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and PubMed from January 1, 1977, to May 8, 2020, reporting on cAS and treatment modalities used. The search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.⁵ Data extracted included patient demographics, tumor characteristics (including T1 [≤5 cm] and T2 [>5 cm and ≤10 cm] based on the American Joint Committee on Cancer soft tissue sarcoma staging criteria), treatments used, follow-up time, overall survival (OS) rates, and complications.^10,11

Studies were required to (1) include participants with head and neck cAS; (2) report original patient data following cAS treatment with surgical (WLE or MMS) and/or nonsurgical modalities (chemotherapy [CT], radiotherapy [RT], immunotherapy [IT]); (3) report outcome data related to OS rates following treatment; and (4) have articles published in English. Given the rare nature of cAS, there was no limitation on the number of participants needed.

The Newcastle-Ottawa scale for observational studies was used to assess the quality of studies.¹² Higher scores indicate low risk of bias, while lower scores represent high risk of bias.

Continuous data were reported with means and SDs, while categorical variables were reported as percentages. Overall survival means and SDs were compared between treatment modalities using an independent sample t test with P<.05 considered statistically significant. Due to the heterogeneity of the data, a meta-analysis was not reported.

RESULTS

Literature Search and Risk of Bias Assessment

There were 283 manuscripts identified, 56 articles read in full, and 40 articles included in the review (Figure). Among the 16 studies not meeting inclusion criteria, 7 did not provide enough data to isolate head and neck cAS cases,^1,13-18 6 did not report outcomes related to the current review,^19-24 and 3 did not provide enough data to isolate different treatment outcomes.^25-27 Among the included studies, 32 reported use of WLE: WLE alone (n=21)^2,7,11,28-45; WLE with RT (n=24)^{2,3,11,28-31,33-36,38-41,43-51}; WLE with CT (n=7)^{2,31,35,39,41,48,52}; WLE with RT and CT (n=11)^{2,29,31,33-35,39,40,48,52,53}; WLE with RT and IT (n=3)^35,54,55; and WLE with RT, CT, and IT (n=1).⁵³ Nine studies reported MMS: MMS alone (n=5)^39,56-59; MMS with RT (n=3)^32,50,60,61; and MMS with RT and CT (n=1).⁵¹

Risk of bias assessment identified low risk in 3 articles. High risk was identified in 5 case reports,^57-61 and 1 study did not describe patient selection.⁴³ Clayton et al⁵⁶ showed intermediate risk, given the study controlled for 1 factor.

Patient Demographics

A total of 1295 patients were included. The pooled mean age of the patients was 67.5 years (range, 3–88 years), and 64.7% were male. There were 79 cases identified as T1 and 105 as T2. A total of 825 cases were treated using WLE with or without adjuvant therapy, while a total of 9 cases were treated using MMS with and without adjuvant therapies (Table). There were 461 cases treated without surgical excision: RT alone (n=261), CT alone (n=38), IT alone (n=35), RT with CT (n=81), RT with IT (n=34), and RT with CT and IT (n=12)(Table). The median follow-up period across all studies was 23.5 months (range, 1–228 months).

Comparison Between Surgical and Nonsurgical Modalities

Wide Local Excision—Wide local excision (n=825; 63.7%) alone or in combination with other therapies was the most frequently used treatment modality. The mean (SD) OS was longest for WLE with RT, CT, and IT (n=3; 39.3 [24.1]), followed by WLE with RT (n=447; 35.9 [34.3] months), WLE with CT (n=13; 32.4 [30.2] months), WLE alone (n=324; 29.6 [34.1] months), WLE with RT and IT (n=11; 23.5 [4.9] months), and WLE with RT and CT (n=27; 20.7 [13.1] months).

Nonsurgical Modalities—Nonsurgical methods were used less frequently than surgical methods (n=461; 35.6%). The mean (SD) OS time in descending order was as follows: RT with CT and IT (n=12; 34.9 [1.2] months), RT with CT (n=81; 30.4 [37.8] months), IT alone (n=35; 25.7 [no SD reported] months), RT with IT (n=34; 20.5 [8.6] months), CT alone (n=38; 20.1 [15.9] months), and RT alone (n=261; 12.8 [8.3] months).

When comparing mean (SD) OS outcomes between surgical and nonsurgical treatment modalities, only the addition of WLE to RT significantly increased OS when compared with RT alone (WLE, 35.9 [34.3] months; RT alone, 12.8 [8.3] months; P=.001). When WLE was added to CT or both RT and CT, there was no significant difference with OS when compared with CT alone (WLE with CT, 32.4 [30.2] months; CT alone, 20.1 [15.9] months; P=.065); or both RT and CT in combination (WLE with RT and CT, 20.7 [13.1] months; RT and CT, 30.4 [37.8] months; P=.204).

Comparison Between T1 and T2 cAS

T1 Angiosarcoma—There were 79 patients identified as having T1 tumors across 16 studies.^{2,31,32,34,39-41,46,48-50,53,58-60,62} The mean (SD) OS was longest for WLE with RT, CT, and IT (n=2; 56.0 [6.0] months), followed by WLE with CT (n=4; 54.5 [41.0] months); WLE with RT (n=30; 39.7 [41.2] months); WLE alone (n=22; 37.2 [37.3] months); WLE with both RT and CT (n=7; 25.5 [18.7] months); RT with IT (n=2; 20.0 [11.0] months); RT with CT (n=6; 15.7 [6.8] months); and RT alone (n=1; 13 [no SD]) months)(eTable).

T2 Angiosarcoma—There were 105 patients with T2 tumors in 15 studies.^{2,31,32,34,39-41,46,48-50,52,53,57,62} The mean (SD) OS for each treatment modality in descending order was as follows: RT with CT and IT (n=1; 36 [no SD reported] months); RT with CT (n=23; 34.3 [46.3] months); WLE with RT (n=21; 26.3 [23.8] months); WLE with CT (n=8; 21.5 [16.6] months); WLE alone (n=16; 19.8 [15.6] months); WLE with RT and CT (n=14; 19.2 [10.5] months); RT alone (n=17; 10.1 [5.5] months); CT alone (n=2; 6.7 [3.7] months); and WLE with RT, CT, and IT (n=1; 6.0 [no SD] months)(eTable).

Mohs Micrographic Surgery—The use of MMS was only identified in case reports or small observational studies for a total of 9 patients. Five cASs were treated with MMS alone for a mean (SD) OS of 37 (21.5) months, with 4 reporting cAS staging: 2 were T1^58,59 (mean [SD] OS, 37.0 [17.0] months) and 2 were T2 tumors^39,57 (mean [SD] OS, 44.5 [26.5] months). Mohs micrographic surgery with RT was used for 3 tumors (mean [SD] OS, 34.0 [26.9] months); 2 were T1^50,60 (mean [SD] OS, 42.0 [30.0] months) and 1 unreported staging (eTable).⁵⁶ Mohs micrographic surgery with both RT and CT was used in 1 patient (unreported staging; OS, 82 months).⁵¹

Complications

Complications were rare and mainly associated with CT and RT. Four studies reported radiation dermatitis with RT.^53,55,62,63 Two studies reported peripheral neuropathy and myelotoxicity with CT.^35,51 Only 1 study reported poor wound healing due to surgical complications.²⁹

COMMENT

Cutaneous angiosarcomas are rare and have limited treatment guidelines. Surgical excision does appear to be an effective adjunct to nonsurgical treatments, particularly WLE combined with RT, CT, and IT. Although MMS ultimately may be useful for cAS, the limited number and substantial heterogeneity of reported cases precludes definitive conclusions at this time.

Achieving margin control during WLE is associated with higher OS when treating angiosarcoma,^36,46 which is particularly true for T1 tumors where margin control is imperative, and many cases are treated with a combination of WLE and RT. Overall survival times are lower for T2 tumors, as these tumors are larger and most likely have spread; therefore, more aggressive combination treatments were more prevalent. In these cases, complete margin control may be difficult to achieve and may not be as critical to the outcome if another form of adjuvant therapy can be administered promptly.^24,64

When surgery is contraindicated, RT with or without CT was the most commonly reported treatment modality. However, these treatments were notably less effective than when used in combination with surgical resection. The use of RT alone has a recurrence rate reported up to 100% in certain studies, suggesting the need to utilize RT in combination with other modalities.^23,39 It is important to note that RT often is used as monotherapy in palliative treatment, which may indirectly skew survival rates.²

Limitations of the study include a lack of randomized controlled trials. Most reports were retrospective reviews or case series, and tumor staging was sparsely reported. Finally, although MMS may provide utility in the treatment of cAS, the sample size of 9 precluded definitive conclusions from being formed about its efficacy.

CONCLUSION

Cutaneous angiosarcoma is rare and has limited data comparing different treatment modalities. The paucity of data currently limits definitive recommendations; however, both surgical and nonsurgical modalities have demonstrated potential efficacy in the treatment of cAS and may benefit from additional research. Clinicians should consider a multidisciplinary approach for patients with a diagnosis of cAS to tailor treatments on a case-by-case basis.

Cutaneous angiosarcoma (cAS) is a rare malignancy arising from vascular or lymphatic tissue. It classically presents during the sixth or seventh decades of life as a raised purple papule or plaque on the head and neck areas.¹ Primary cAS frequently mimics benign conditions, leading to delays in care. Such delays coupled with the aggressive nature of angiosarcomas leads to a poor prognosis. Five-year survival rates range from 11% to 50%, and more than half of patients die within 1 year of diagnosis.^2-7

Currently, there is no consensus on the most effective treatments, as the rare nature of cAS has made the development of controlled clinical trials difficult. Wide local excision (WLE) is most frequently employed; however, the tumor’s infiltrative growth makes complete resection and negative surgical margins difficult to achieve.⁸ Recently, Mohs micrographic surgery (MMS) has been postulated as a treatment option. The tissue-sparing nature and intraoperative margin control of MMS may provide tumor eradication and cosmesis benefits reported with other cutaneous malignancies.⁹

Nearly all localized cASs are treated with surgical excision with or without adjuvant treatment modalities; however, it is unclear which of these modalities provide a survival benefit. We conducted a systematic review of the literature to compare treatment modalities for localized cAS of the head and neck regions and to compare treatments based on tumor stage.

METHODS

A literature search was performed to identify published studies indexed by MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and PubMed from January 1, 1977, to May 8, 2020, reporting on cAS and treatment modalities used. The search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.⁵ Data extracted included patient demographics, tumor characteristics (including T1 [≤5 cm] and T2 [>5 cm and ≤10 cm] based on the American Joint Committee on Cancer soft tissue sarcoma staging criteria), treatments used, follow-up time, overall survival (OS) rates, and complications.^10,11

Studies were required to (1) include participants with head and neck cAS; (2) report original patient data following cAS treatment with surgical (WLE or MMS) and/or nonsurgical modalities (chemotherapy [CT], radiotherapy [RT], immunotherapy [IT]); (3) report outcome data related to OS rates following treatment; and (4) have articles published in English. Given the rare nature of cAS, there was no limitation on the number of participants needed.

The Newcastle-Ottawa scale for observational studies was used to assess the quality of studies.¹² Higher scores indicate low risk of bias, while lower scores represent high risk of bias.

Continuous data were reported with means and SDs, while categorical variables were reported as percentages. Overall survival means and SDs were compared between treatment modalities using an independent sample t test with P<.05 considered statistically significant. Due to the heterogeneity of the data, a meta-analysis was not reported.

RESULTS

Literature Search and Risk of Bias Assessment

There were 283 manuscripts identified, 56 articles read in full, and 40 articles included in the review (Figure). Among the 16 studies not meeting inclusion criteria, 7 did not provide enough data to isolate head and neck cAS cases,^1,13-18 6 did not report outcomes related to the current review,^19-24 and 3 did not provide enough data to isolate different treatment outcomes.^25-27 Among the included studies, 32 reported use of WLE: WLE alone (n=21)^2,7,11,28-45; WLE with RT (n=24)^{2,3,11,28-31,33-36,38-41,43-51}; WLE with CT (n=7)^{2,31,35,39,41,48,52}; WLE with RT and CT (n=11)^{2,29,31,33-35,39,40,48,52,53}; WLE with RT and IT (n=3)^35,54,55; and WLE with RT, CT, and IT (n=1).⁵³ Nine studies reported MMS: MMS alone (n=5)^39,56-59; MMS with RT (n=3)^32,50,60,61; and MMS with RT and CT (n=1).⁵¹

Risk of bias assessment identified low risk in 3 articles. High risk was identified in 5 case reports,^57-61 and 1 study did not describe patient selection.⁴³ Clayton et al⁵⁶ showed intermediate risk, given the study controlled for 1 factor.

Patient Demographics

A total of 1295 patients were included. The pooled mean age of the patients was 67.5 years (range, 3–88 years), and 64.7% were male. There were 79 cases identified as T1 and 105 as T2. A total of 825 cases were treated using WLE with or without adjuvant therapy, while a total of 9 cases were treated using MMS with and without adjuvant therapies (Table). There were 461 cases treated without surgical excision: RT alone (n=261), CT alone (n=38), IT alone (n=35), RT with CT (n=81), RT with IT (n=34), and RT with CT and IT (n=12)(Table). The median follow-up period across all studies was 23.5 months (range, 1–228 months).

Comparison Between Surgical and Nonsurgical Modalities

Wide Local Excision—Wide local excision (n=825; 63.7%) alone or in combination with other therapies was the most frequently used treatment modality. The mean (SD) OS was longest for WLE with RT, CT, and IT (n=3; 39.3 [24.1]), followed by WLE with RT (n=447; 35.9 [34.3] months), WLE with CT (n=13; 32.4 [30.2] months), WLE alone (n=324; 29.6 [34.1] months), WLE with RT and IT (n=11; 23.5 [4.9] months), and WLE with RT and CT (n=27; 20.7 [13.1] months).

Nonsurgical Modalities—Nonsurgical methods were used less frequently than surgical methods (n=461; 35.6%). The mean (SD) OS time in descending order was as follows: RT with CT and IT (n=12; 34.9 [1.2] months), RT with CT (n=81; 30.4 [37.8] months), IT alone (n=35; 25.7 [no SD reported] months), RT with IT (n=34; 20.5 [8.6] months), CT alone (n=38; 20.1 [15.9] months), and RT alone (n=261; 12.8 [8.3] months).

When comparing mean (SD) OS outcomes between surgical and nonsurgical treatment modalities, only the addition of WLE to RT significantly increased OS when compared with RT alone (WLE, 35.9 [34.3] months; RT alone, 12.8 [8.3] months; P=.001). When WLE was added to CT or both RT and CT, there was no significant difference with OS when compared with CT alone (WLE with CT, 32.4 [30.2] months; CT alone, 20.1 [15.9] months; P=.065); or both RT and CT in combination (WLE with RT and CT, 20.7 [13.1] months; RT and CT, 30.4 [37.8] months; P=.204).

Comparison Between T1 and T2 cAS

T1 Angiosarcoma—There were 79 patients identified as having T1 tumors across 16 studies.^{2,31,32,34,39-41,46,48-50,53,58-60,62} The mean (SD) OS was longest for WLE with RT, CT, and IT (n=2; 56.0 [6.0] months), followed by WLE with CT (n=4; 54.5 [41.0] months); WLE with RT (n=30; 39.7 [41.2] months); WLE alone (n=22; 37.2 [37.3] months); WLE with both RT and CT (n=7; 25.5 [18.7] months); RT with IT (n=2; 20.0 [11.0] months); RT with CT (n=6; 15.7 [6.8] months); and RT alone (n=1; 13 [no SD]) months)(eTable).

T2 Angiosarcoma—There were 105 patients with T2 tumors in 15 studies.^{2,31,32,34,39-41,46,48-50,52,53,57,62} The mean (SD) OS for each treatment modality in descending order was as follows: RT with CT and IT (n=1; 36 [no SD reported] months); RT with CT (n=23; 34.3 [46.3] months); WLE with RT (n=21; 26.3 [23.8] months); WLE with CT (n=8; 21.5 [16.6] months); WLE alone (n=16; 19.8 [15.6] months); WLE with RT and CT (n=14; 19.2 [10.5] months); RT alone (n=17; 10.1 [5.5] months); CT alone (n=2; 6.7 [3.7] months); and WLE with RT, CT, and IT (n=1; 6.0 [no SD] months)(eTable).

Mohs Micrographic Surgery—The use of MMS was only identified in case reports or small observational studies for a total of 9 patients. Five cASs were treated with MMS alone for a mean (SD) OS of 37 (21.5) months, with 4 reporting cAS staging: 2 were T1^58,59 (mean [SD] OS, 37.0 [17.0] months) and 2 were T2 tumors^39,57 (mean [SD] OS, 44.5 [26.5] months). Mohs micrographic surgery with RT was used for 3 tumors (mean [SD] OS, 34.0 [26.9] months); 2 were T1^50,60 (mean [SD] OS, 42.0 [30.0] months) and 1 unreported staging (eTable).⁵⁶ Mohs micrographic surgery with both RT and CT was used in 1 patient (unreported staging; OS, 82 months).⁵¹

Complications

Complications were rare and mainly associated with CT and RT. Four studies reported radiation dermatitis with RT.^53,55,62,63 Two studies reported peripheral neuropathy and myelotoxicity with CT.^35,51 Only 1 study reported poor wound healing due to surgical complications.²⁹

COMMENT

Cutaneous angiosarcomas are rare and have limited treatment guidelines. Surgical excision does appear to be an effective adjunct to nonsurgical treatments, particularly WLE combined with RT, CT, and IT. Although MMS ultimately may be useful for cAS, the limited number and substantial heterogeneity of reported cases precludes definitive conclusions at this time.

Achieving margin control during WLE is associated with higher OS when treating angiosarcoma,^36,46 which is particularly true for T1 tumors where margin control is imperative, and many cases are treated with a combination of WLE and RT. Overall survival times are lower for T2 tumors, as these tumors are larger and most likely have spread; therefore, more aggressive combination treatments were more prevalent. In these cases, complete margin control may be difficult to achieve and may not be as critical to the outcome if another form of adjuvant therapy can be administered promptly.^24,64

When surgery is contraindicated, RT with or without CT was the most commonly reported treatment modality. However, these treatments were notably less effective than when used in combination with surgical resection. The use of RT alone has a recurrence rate reported up to 100% in certain studies, suggesting the need to utilize RT in combination with other modalities.^23,39 It is important to note that RT often is used as monotherapy in palliative treatment, which may indirectly skew survival rates.²

Limitations of the study include a lack of randomized controlled trials. Most reports were retrospective reviews or case series, and tumor staging was sparsely reported. Finally, although MMS may provide utility in the treatment of cAS, the sample size of 9 precluded definitive conclusions from being formed about its efficacy.

CONCLUSION

Cutaneous angiosarcoma is rare and has limited data comparing different treatment modalities. The paucity of data currently limits definitive recommendations; however, both surgical and nonsurgical modalities have demonstrated potential efficacy in the treatment of cAS and may benefit from additional research. Clinicians should consider a multidisciplinary approach for patients with a diagnosis of cAS to tailor treatments on a case-by-case basis.

Have you ever looked at the operating room (OR) trash bin at the end of a case and wondered if all that waste is necessary? Since I started my residency, not a day goes by that I have not asked myself this question.

In the mid-1990s, John Elkington introduced the concept of the triple bottom line—that is, people, planet, and profit—for implementation and measurement of sustainability in businesses.¹ The health care sector is no exception when it comes to the bottom line! However, “people” remain the priority. What is our role, as ObGyns, in protecting the “planet” while keeping the “people” safe?

According to the World Health Organization (WHO), climate change remains the single biggest health threat to humanity.² The health care system is both the victim and the culprit. Studies suggest that the health care system, second to the food industry, is the biggest contributor to waste production in the United States. This sector generates more than 6,000 metric tons of waste each day and nearly 4 million tons (3.6 million metric tons) of solid waste each year.³ The health care system is responsible for an estimated 8% to 10% of total greenhouse gas emissions in the United States; the US health care system alone contributes to more than one-fourth of the global health care carbon footprint. If it were a country, the US health care system would rank 13th among all countries in emissions.⁴In turn, pollution produced by the health sector negatively impacts population health, further burdening the health care system. According to 2013 study data, the annual health damage caused by health care pollution was comparable to that of the deaths caused by preventable medical error.⁴

Aside from the environmental aspects, hospital waste disposal is expensive; reducing this cost is a potential area of interest for institutions.

As ObGyns, what is our role in reducing our waste generation and carbon footprint while keeping patients safe?

Defining health care waste, and disposal considerations

The WHO defines health care waste as including “the waste generated by health-care establishments, research facilities, and laboratories” as well as waste from scattered sources such as home dialysis and insulin injections.⁵ Despite representing a relatively small physical area of hospitals, labor and delivery units combined with ORs account for approximately 70% of all hospital waste.³ Operating room waste consists of disposable surgical supplies, personal protective equipment, drapes, plastic wrappers, sterile blue wraps, glass, cardboard, packaging material, medications, fluids, and other materials (FIGURE 1).

Photo: Courtesy of Golnaz Namazi, MD

The WHO also notes that of all the waste generated by health care activities, about 85% is general, nonhazardous waste that is comparable to domestic waste.⁶ Hazardous waste is any material that poses a health risk, including potentially infectious materials, such as blood-soaked gauze, sharps, pharmaceuticals, or radioactive materials.⁶

Disposal of hazardous waste is expensiveand energy consuming as it is typically incinerated rather than disposed of in a landfill. This process produces substantial greenhouse gases, about 3 kg of carbon dioxide for every 1 kg of hazardous waste.⁷

Red bags are used for hazardous waste disposal, while clear bags are used for general waste. Operating rooms produce about two-thirds of the hospital red-bag waste.⁸ Waste segregation unfortunately is not accurate, and as much as 90% of OR general waste is improperly designated as hazardous waste.³ Drapes and uncontaminated, needleless syringes, for example, should be disposed of in clear bags, but often they are instead directed to the red-bag and sharps container (FIGURE 2).

Photo: Courtesy of Golnaz Namazi, MD

Recycling in the OR

Recycling has become an established practice in many health care facilities and ORs. Studies suggest that introducing recycling programs in ORs not only reduces carbon footprints but also reduces costs.³ One study reported that US academic medical centers consume 2 million lb ($15 million) each year of recoverable medical supplies.⁹

Single-stream recycling, a system in which all recyclable material—including plastics, paper, metal, and glass—are placed in a single bin without segregation at the collection site, has gained in popularity. Recycling can be implemented both in ORs and in other perioperative areas where regular trash bins are located.

In a study done at Oxford University Hospitals in the United Kingdom, introducing recycling bins in every OR, as well as in recovery and staff rest areas, helped improve waste segregation such that approximately 22% of OR waste was recycled.¹⁰ Studies show that recycling programs not only decrease the health care carbon footprint but also have a considerable financial impact. Albert and colleagues demonstrated that introducing a single-stream recycling program to a 9-OR day (or ambulatory) surgery center could redirect more than 4 tons of waste each month and saved thousands of dollars.¹¹

Despite continued improvement in recycling programs, the segregation process is still far from optimal. In a survey done at the Mayo Clinic by Azouz and colleagues, more than half of the staff reported being unclear about which OR items are recyclable and nearly half reported that lack of knowledge was the barrier to proper recycling.¹² That study also showed that after implementation of a recycling education program, costs decreased 10% relative to the same time period in prior years.¹²

Blue wraps. One example of recycling optimization is blue wraps, the polypropylene (No. 5 plastic) material used for wrapping surgical instruments. Blue wraps account for approximately 19% of OR waste and 5% of all hospital waste.¹¹ Blue wraps are not biodegradable and also are not widely recycled. In recent years, a resale market has emerged for blue wraps, as they can be used for production of other No. 5 plastic items.⁹ By reselling blue wraps, revenue can be generated by recycling a necessary packing material that would otherwise require payment for disposal.

Sterility considerations. While recycling in ORs may raise concern due to the absolute sterility required in procedural settings, technologic developments have been promising in advancing safe recycling to reduce carbon footprints and health care costs without compromising patients’ safety. Segregation of waste from recyclable packaging material prior to the case, as well as directing trash to the correct bin (regular vs red bin), is one example. Moreover, because about 80% of all OR waste is generated during the set up before the patient arrives in the OR, it is not contaminated and can be safely recycled.¹³

Continue to: Packaging material...

A substantial part of OR waste consists of packaging material; of all OR waste, 26% consists of plastics and 7%, paper and cartons.¹⁴ Increasing use of disposable or “single use” medical products in ORs, along with the intention to safeguard sterility, contributes significantly to the generation of medical waste in operating units. Containers, wraps and overwraps, cardboard, and plastic packaging are all composed of materials that when clean, can be recycled; however, these items often end up in the landfill (FIGURE 3).

Photo: Courtesy of Golnaz Namazi, MD

Although the segregation of packaging material to recycling versus regular trash versus red bin is of paramount importance, packaging design plays a significant role as well. In 2018, Boston Scientific introduced a new packaging design for ureteral stents that reduced plastic use in packaging by 120,000 lb each year.¹⁵ Despite the advances in the medical packaging industry to increase sustainability while safeguarding sterility for medical devices, there is still room for innovation in this area.

Reducing overage by judicious selection of surgical devices, instruments, and supplies

Overage is the term used to describe surgical inventory that is opened and prepared for surgery but ultimately not used and therefore discarded. Design of surgical carts and instrument and supply selection requires direct input from ObGyns. Opening only the needed instruments while ensuring ready availability of potentially needed supplies can significantly reduce OR waste generation as well as decrease chemical pollution generated by instrument sterilization. Decreasing OR overage reduces overall costs as well (FIGURE 4).

Photo: Courtesy of Golnaz Namazi, MD

In a pilot study at the University of Massachusetts, Albert and colleagues examined the sets of disposable items and instruments designated for common plastic and hand surgery procedures.¹¹ They identified the supplies and instruments that are routinely opened and wasted, based on surgeons’ interview responses, and redesigned the sets. Fifteen items were removed from disposable plastic surgery packs and 7 items from hand surgery packs. The authors reported saving thousands of dollars per year with these changes alone, as well as reducing waste.¹¹ This same concept easily could be implemented in obstetrics and gynecology. We must ask ourselves: Do we always need, for example, a complete dilation and curettage kit to place the uterine manipulator prior to a minimally invasive hysterectomy?

In another pilot study, Greenberg and colleagues investigated whether cesarean deliveries consistently could be performed in a safe manner with only 20 instruments in the surgical kit.¹⁶ Obstetricians rated the 20-instrument kit an 8.7 out of 10 for performing cesarean deliveries safely.¹⁶

In addition to instrument selection, surgeons have a role in other supply use and waste generation: for instance, opening multiple pairs of surgical gloves and surgical gowns in advance when most of them will not be used during the case. Furthermore, many ObGyn surgeons routinely change gloves or even gowns during gynecologic procedures when they go back and forth between the vaginal and abdominal fields. Is the perineum “dirty” after application of a surgical prep solution?

In an observational study, Shockley and colleagues investigated the type and quantity of bacteria found intraoperatively on the abdomen, vagina, surgical gloves, instrument tips, and uterus at distinct time points during total laparoscopic hysterectomy.¹⁷ They showed that in 98.9% of cultures, the overall bacterial concentrations did not exceed the threshold for infection. There was no bacterial growth from vaginal cultures, and the only samples with some bacterial growth belonged to the surgeon’s gloves after specimen extraction; about one-third of samples showed growth after specimen extraction, but only 1 sample had a bacterial load above the infectious threshold of 5,000 colony-forming units per mL. The authors therefore suggested that if a surgeon changes gloves, doing so after specimen extraction and before turning attention back to the abdomen for vaginal cuff closure may be most effective in reducing bacterial load.¹⁷

Surgical site infection contributes to medical cost and likely medical waste as well. For example, surgical site infection may require prolonged treatments, tests, and medical instruments. In severe cases with abscesses, treatment entails hospitalization with prolonged antibiotic therapy with or without procedures to drain the collections. Further research therefore is warranted to investigate safe and environmentally friendly practices.

Myriad products are introduced to the medical system each day, some of which replace conventional tools. For instance, low-density polyethylene, or LDPE, transfer sheet is advertised for lateral patient transfer from the OR table to the bed or stretcher. This No. 4–coded plastic, while recyclable, is routinely discarded as trash in ORs. One ergonomic study found that reusable slide boards are as effective for reducing friction and staff muscle activities and are noninferior to the plastic sheets.¹⁸

Steps to making an impact

Operating rooms and labor and delivery units are responsible for a large proportion of hospital waste, and therefore they are of paramount importance in reducing waste and carbon footprint at the individual and institutional level. Reduction of OR waste not only is environmentally conscious but also decreases cost. Steps as small as individual practices to as big as changing infrastructures can make an impact. For instance:

• redesigning surgical carts
• reformulating surgeon-specific supply lists
• raising awareness about surgical overage
• encouraging recycling through education and audit
• optimizing surgical waste segregation through educational posters.

These are all simple steps that could significantly reduce waste and carbon footprint.

Bottom line

Although waste reduction is the responsibility of all health care providers, as leaders in their workplace physicians can serve as role models by implementing “green” practices in procedural units. Raising awareness and using a team approach is critical to succeed in our endeavors to move toward an environmentally friendly future. ●

Have you ever looked at the operating room (OR) trash bin at the end of a case and wondered if all that waste is necessary? Since I started my residency, not a day goes by that I have not asked myself this question.

In the mid-1990s, John Elkington introduced the concept of the triple bottom line—that is, people, planet, and profit—for implementation and measurement of sustainability in businesses.¹ The health care sector is no exception when it comes to the bottom line! However, “people” remain the priority. What is our role, as ObGyns, in protecting the “planet” while keeping the “people” safe?

According to the World Health Organization (WHO), climate change remains the single biggest health threat to humanity.² The health care system is both the victim and the culprit. Studies suggest that the health care system, second to the food industry, is the biggest contributor to waste production in the United States. This sector generates more than 6,000 metric tons of waste each day and nearly 4 million tons (3.6 million metric tons) of solid waste each year.³ The health care system is responsible for an estimated 8% to 10% of total greenhouse gas emissions in the United States; the US health care system alone contributes to more than one-fourth of the global health care carbon footprint. If it were a country, the US health care system would rank 13th among all countries in emissions.⁴In turn, pollution produced by the health sector negatively impacts population health, further burdening the health care system. According to 2013 study data, the annual health damage caused by health care pollution was comparable to that of the deaths caused by preventable medical error.⁴

Aside from the environmental aspects, hospital waste disposal is expensive; reducing this cost is a potential area of interest for institutions.

As ObGyns, what is our role in reducing our waste generation and carbon footprint while keeping patients safe?

Defining health care waste, and disposal considerations

The WHO defines health care waste as including “the waste generated by health-care establishments, research facilities, and laboratories” as well as waste from scattered sources such as home dialysis and insulin injections.⁵ Despite representing a relatively small physical area of hospitals, labor and delivery units combined with ORs account for approximately 70% of all hospital waste.³ Operating room waste consists of disposable surgical supplies, personal protective equipment, drapes, plastic wrappers, sterile blue wraps, glass, cardboard, packaging material, medications, fluids, and other materials (FIGURE 1).

Photo: Courtesy of Golnaz Namazi, MD

The WHO also notes that of all the waste generated by health care activities, about 85% is general, nonhazardous waste that is comparable to domestic waste.⁶ Hazardous waste is any material that poses a health risk, including potentially infectious materials, such as blood-soaked gauze, sharps, pharmaceuticals, or radioactive materials.⁶

Disposal of hazardous waste is expensiveand energy consuming as it is typically incinerated rather than disposed of in a landfill. This process produces substantial greenhouse gases, about 3 kg of carbon dioxide for every 1 kg of hazardous waste.⁷

Red bags are used for hazardous waste disposal, while clear bags are used for general waste. Operating rooms produce about two-thirds of the hospital red-bag waste.⁸ Waste segregation unfortunately is not accurate, and as much as 90% of OR general waste is improperly designated as hazardous waste.³ Drapes and uncontaminated, needleless syringes, for example, should be disposed of in clear bags, but often they are instead directed to the red-bag and sharps container (FIGURE 2).

Photo: Courtesy of Golnaz Namazi, MD

Recycling in the OR

Recycling has become an established practice in many health care facilities and ORs. Studies suggest that introducing recycling programs in ORs not only reduces carbon footprints but also reduces costs.³ One study reported that US academic medical centers consume 2 million lb ($15 million) each year of recoverable medical supplies.⁹

Single-stream recycling, a system in which all recyclable material—including plastics, paper, metal, and glass—are placed in a single bin without segregation at the collection site, has gained in popularity. Recycling can be implemented both in ORs and in other perioperative areas where regular trash bins are located.

In a study done at Oxford University Hospitals in the United Kingdom, introducing recycling bins in every OR, as well as in recovery and staff rest areas, helped improve waste segregation such that approximately 22% of OR waste was recycled.¹⁰ Studies show that recycling programs not only decrease the health care carbon footprint but also have a considerable financial impact. Albert and colleagues demonstrated that introducing a single-stream recycling program to a 9-OR day (or ambulatory) surgery center could redirect more than 4 tons of waste each month and saved thousands of dollars.¹¹

Despite continued improvement in recycling programs, the segregation process is still far from optimal. In a survey done at the Mayo Clinic by Azouz and colleagues, more than half of the staff reported being unclear about which OR items are recyclable and nearly half reported that lack of knowledge was the barrier to proper recycling.¹² That study also showed that after implementation of a recycling education program, costs decreased 10% relative to the same time period in prior years.¹²

Blue wraps. One example of recycling optimization is blue wraps, the polypropylene (No. 5 plastic) material used for wrapping surgical instruments. Blue wraps account for approximately 19% of OR waste and 5% of all hospital waste.¹¹ Blue wraps are not biodegradable and also are not widely recycled. In recent years, a resale market has emerged for blue wraps, as they can be used for production of other No. 5 plastic items.⁹ By reselling blue wraps, revenue can be generated by recycling a necessary packing material that would otherwise require payment for disposal.

Sterility considerations. While recycling in ORs may raise concern due to the absolute sterility required in procedural settings, technologic developments have been promising in advancing safe recycling to reduce carbon footprints and health care costs without compromising patients’ safety. Segregation of waste from recyclable packaging material prior to the case, as well as directing trash to the correct bin (regular vs red bin), is one example. Moreover, because about 80% of all OR waste is generated during the set up before the patient arrives in the OR, it is not contaminated and can be safely recycled.¹³

Continue to: Packaging material...

A substantial part of OR waste consists of packaging material; of all OR waste, 26% consists of plastics and 7%, paper and cartons.¹⁴ Increasing use of disposable or “single use” medical products in ORs, along with the intention to safeguard sterility, contributes significantly to the generation of medical waste in operating units. Containers, wraps and overwraps, cardboard, and plastic packaging are all composed of materials that when clean, can be recycled; however, these items often end up in the landfill (FIGURE 3).

Photo: Courtesy of Golnaz Namazi, MD

Although the segregation of packaging material to recycling versus regular trash versus red bin is of paramount importance, packaging design plays a significant role as well. In 2018, Boston Scientific introduced a new packaging design for ureteral stents that reduced plastic use in packaging by 120,000 lb each year.¹⁵ Despite the advances in the medical packaging industry to increase sustainability while safeguarding sterility for medical devices, there is still room for innovation in this area.

Reducing overage by judicious selection of surgical devices, instruments, and supplies

Overage is the term used to describe surgical inventory that is opened and prepared for surgery but ultimately not used and therefore discarded. Design of surgical carts and instrument and supply selection requires direct input from ObGyns. Opening only the needed instruments while ensuring ready availability of potentially needed supplies can significantly reduce OR waste generation as well as decrease chemical pollution generated by instrument sterilization. Decreasing OR overage reduces overall costs as well (FIGURE 4).

Photo: Courtesy of Golnaz Namazi, MD

In a pilot study at the University of Massachusetts, Albert and colleagues examined the sets of disposable items and instruments designated for common plastic and hand surgery procedures.¹¹ They identified the supplies and instruments that are routinely opened and wasted, based on surgeons’ interview responses, and redesigned the sets. Fifteen items were removed from disposable plastic surgery packs and 7 items from hand surgery packs. The authors reported saving thousands of dollars per year with these changes alone, as well as reducing waste.¹¹ This same concept easily could be implemented in obstetrics and gynecology. We must ask ourselves: Do we always need, for example, a complete dilation and curettage kit to place the uterine manipulator prior to a minimally invasive hysterectomy?

In another pilot study, Greenberg and colleagues investigated whether cesarean deliveries consistently could be performed in a safe manner with only 20 instruments in the surgical kit.¹⁶ Obstetricians rated the 20-instrument kit an 8.7 out of 10 for performing cesarean deliveries safely.¹⁶

In addition to instrument selection, surgeons have a role in other supply use and waste generation: for instance, opening multiple pairs of surgical gloves and surgical gowns in advance when most of them will not be used during the case. Furthermore, many ObGyn surgeons routinely change gloves or even gowns during gynecologic procedures when they go back and forth between the vaginal and abdominal fields. Is the perineum “dirty” after application of a surgical prep solution?

In an observational study, Shockley and colleagues investigated the type and quantity of bacteria found intraoperatively on the abdomen, vagina, surgical gloves, instrument tips, and uterus at distinct time points during total laparoscopic hysterectomy.¹⁷ They showed that in 98.9% of cultures, the overall bacterial concentrations did not exceed the threshold for infection. There was no bacterial growth from vaginal cultures, and the only samples with some bacterial growth belonged to the surgeon’s gloves after specimen extraction; about one-third of samples showed growth after specimen extraction, but only 1 sample had a bacterial load above the infectious threshold of 5,000 colony-forming units per mL. The authors therefore suggested that if a surgeon changes gloves, doing so after specimen extraction and before turning attention back to the abdomen for vaginal cuff closure may be most effective in reducing bacterial load.¹⁷

Surgical site infection contributes to medical cost and likely medical waste as well. For example, surgical site infection may require prolonged treatments, tests, and medical instruments. In severe cases with abscesses, treatment entails hospitalization with prolonged antibiotic therapy with or without procedures to drain the collections. Further research therefore is warranted to investigate safe and environmentally friendly practices.

Myriad products are introduced to the medical system each day, some of which replace conventional tools. For instance, low-density polyethylene, or LDPE, transfer sheet is advertised for lateral patient transfer from the OR table to the bed or stretcher. This No. 4–coded plastic, while recyclable, is routinely discarded as trash in ORs. One ergonomic study found that reusable slide boards are as effective for reducing friction and staff muscle activities and are noninferior to the plastic sheets.¹⁸

Steps to making an impact

Operating rooms and labor and delivery units are responsible for a large proportion of hospital waste, and therefore they are of paramount importance in reducing waste and carbon footprint at the individual and institutional level. Reduction of OR waste not only is environmentally conscious but also decreases cost. Steps as small as individual practices to as big as changing infrastructures can make an impact. For instance:

• redesigning surgical carts
• reformulating surgeon-specific supply lists
• raising awareness about surgical overage
• encouraging recycling through education and audit
• optimizing surgical waste segregation through educational posters.

These are all simple steps that could significantly reduce waste and carbon footprint.

Bottom line

Although waste reduction is the responsibility of all health care providers, as leaders in their workplace physicians can serve as role models by implementing “green” practices in procedural units. Raising awareness and using a team approach is critical to succeed in our endeavors to move toward an environmentally friendly future. ●

Have you ever looked at the operating room (OR) trash bin at the end of a case and wondered if all that waste is necessary? Since I started my residency, not a day goes by that I have not asked myself this question.

In the mid-1990s, John Elkington introduced the concept of the triple bottom line—that is, people, planet, and profit—for implementation and measurement of sustainability in businesses.¹ The health care sector is no exception when it comes to the bottom line! However, “people” remain the priority. What is our role, as ObGyns, in protecting the “planet” while keeping the “people” safe?

According to the World Health Organization (WHO), climate change remains the single biggest health threat to humanity.² The health care system is both the victim and the culprit. Studies suggest that the health care system, second to the food industry, is the biggest contributor to waste production in the United States. This sector generates more than 6,000 metric tons of waste each day and nearly 4 million tons (3.6 million metric tons) of solid waste each year.³ The health care system is responsible for an estimated 8% to 10% of total greenhouse gas emissions in the United States; the US health care system alone contributes to more than one-fourth of the global health care carbon footprint. If it were a country, the US health care system would rank 13th among all countries in emissions.⁴In turn, pollution produced by the health sector negatively impacts population health, further burdening the health care system. According to 2013 study data, the annual health damage caused by health care pollution was comparable to that of the deaths caused by preventable medical error.⁴

Aside from the environmental aspects, hospital waste disposal is expensive; reducing this cost is a potential area of interest for institutions.

As ObGyns, what is our role in reducing our waste generation and carbon footprint while keeping patients safe?

Defining health care waste, and disposal considerations

The WHO defines health care waste as including “the waste generated by health-care establishments, research facilities, and laboratories” as well as waste from scattered sources such as home dialysis and insulin injections.⁵ Despite representing a relatively small physical area of hospitals, labor and delivery units combined with ORs account for approximately 70% of all hospital waste.³ Operating room waste consists of disposable surgical supplies, personal protective equipment, drapes, plastic wrappers, sterile blue wraps, glass, cardboard, packaging material, medications, fluids, and other materials (FIGURE 1).

Photo: Courtesy of Golnaz Namazi, MD

The WHO also notes that of all the waste generated by health care activities, about 85% is general, nonhazardous waste that is comparable to domestic waste.⁶ Hazardous waste is any material that poses a health risk, including potentially infectious materials, such as blood-soaked gauze, sharps, pharmaceuticals, or radioactive materials.⁶

Disposal of hazardous waste is expensiveand energy consuming as it is typically incinerated rather than disposed of in a landfill. This process produces substantial greenhouse gases, about 3 kg of carbon dioxide for every 1 kg of hazardous waste.⁷

Red bags are used for hazardous waste disposal, while clear bags are used for general waste. Operating rooms produce about two-thirds of the hospital red-bag waste.⁸ Waste segregation unfortunately is not accurate, and as much as 90% of OR general waste is improperly designated as hazardous waste.³ Drapes and uncontaminated, needleless syringes, for example, should be disposed of in clear bags, but often they are instead directed to the red-bag and sharps container (FIGURE 2).

Photo: Courtesy of Golnaz Namazi, MD

Recycling in the OR

Recycling has become an established practice in many health care facilities and ORs. Studies suggest that introducing recycling programs in ORs not only reduces carbon footprints but also reduces costs.³ One study reported that US academic medical centers consume 2 million lb ($15 million) each year of recoverable medical supplies.⁹

Single-stream recycling, a system in which all recyclable material—including plastics, paper, metal, and glass—are placed in a single bin without segregation at the collection site, has gained in popularity. Recycling can be implemented both in ORs and in other perioperative areas where regular trash bins are located.

In a study done at Oxford University Hospitals in the United Kingdom, introducing recycling bins in every OR, as well as in recovery and staff rest areas, helped improve waste segregation such that approximately 22% of OR waste was recycled.¹⁰ Studies show that recycling programs not only decrease the health care carbon footprint but also have a considerable financial impact. Albert and colleagues demonstrated that introducing a single-stream recycling program to a 9-OR day (or ambulatory) surgery center could redirect more than 4 tons of waste each month and saved thousands of dollars.¹¹

Despite continued improvement in recycling programs, the segregation process is still far from optimal. In a survey done at the Mayo Clinic by Azouz and colleagues, more than half of the staff reported being unclear about which OR items are recyclable and nearly half reported that lack of knowledge was the barrier to proper recycling.¹² That study also showed that after implementation of a recycling education program, costs decreased 10% relative to the same time period in prior years.¹²

Blue wraps. One example of recycling optimization is blue wraps, the polypropylene (No. 5 plastic) material used for wrapping surgical instruments. Blue wraps account for approximately 19% of OR waste and 5% of all hospital waste.¹¹ Blue wraps are not biodegradable and also are not widely recycled. In recent years, a resale market has emerged for blue wraps, as they can be used for production of other No. 5 plastic items.⁹ By reselling blue wraps, revenue can be generated by recycling a necessary packing material that would otherwise require payment for disposal.

Sterility considerations. While recycling in ORs may raise concern due to the absolute sterility required in procedural settings, technologic developments have been promising in advancing safe recycling to reduce carbon footprints and health care costs without compromising patients’ safety. Segregation of waste from recyclable packaging material prior to the case, as well as directing trash to the correct bin (regular vs red bin), is one example. Moreover, because about 80% of all OR waste is generated during the set up before the patient arrives in the OR, it is not contaminated and can be safely recycled.¹³

Continue to: Packaging material...

A substantial part of OR waste consists of packaging material; of all OR waste, 26% consists of plastics and 7%, paper and cartons.¹⁴ Increasing use of disposable or “single use” medical products in ORs, along with the intention to safeguard sterility, contributes significantly to the generation of medical waste in operating units. Containers, wraps and overwraps, cardboard, and plastic packaging are all composed of materials that when clean, can be recycled; however, these items often end up in the landfill (FIGURE 3).

Photo: Courtesy of Golnaz Namazi, MD

Although the segregation of packaging material to recycling versus regular trash versus red bin is of paramount importance, packaging design plays a significant role as well. In 2018, Boston Scientific introduced a new packaging design for ureteral stents that reduced plastic use in packaging by 120,000 lb each year.¹⁵ Despite the advances in the medical packaging industry to increase sustainability while safeguarding sterility for medical devices, there is still room for innovation in this area.

Reducing overage by judicious selection of surgical devices, instruments, and supplies

Overage is the term used to describe surgical inventory that is opened and prepared for surgery but ultimately not used and therefore discarded. Design of surgical carts and instrument and supply selection requires direct input from ObGyns. Opening only the needed instruments while ensuring ready availability of potentially needed supplies can significantly reduce OR waste generation as well as decrease chemical pollution generated by instrument sterilization. Decreasing OR overage reduces overall costs as well (FIGURE 4).

Photo: Courtesy of Golnaz Namazi, MD

In a pilot study at the University of Massachusetts, Albert and colleagues examined the sets of disposable items and instruments designated for common plastic and hand surgery procedures.¹¹ They identified the supplies and instruments that are routinely opened and wasted, based on surgeons’ interview responses, and redesigned the sets. Fifteen items were removed from disposable plastic surgery packs and 7 items from hand surgery packs. The authors reported saving thousands of dollars per year with these changes alone, as well as reducing waste.¹¹ This same concept easily could be implemented in obstetrics and gynecology. We must ask ourselves: Do we always need, for example, a complete dilation and curettage kit to place the uterine manipulator prior to a minimally invasive hysterectomy?

In another pilot study, Greenberg and colleagues investigated whether cesarean deliveries consistently could be performed in a safe manner with only 20 instruments in the surgical kit.¹⁶ Obstetricians rated the 20-instrument kit an 8.7 out of 10 for performing cesarean deliveries safely.¹⁶

In addition to instrument selection, surgeons have a role in other supply use and waste generation: for instance, opening multiple pairs of surgical gloves and surgical gowns in advance when most of them will not be used during the case. Furthermore, many ObGyn surgeons routinely change gloves or even gowns during gynecologic procedures when they go back and forth between the vaginal and abdominal fields. Is the perineum “dirty” after application of a surgical prep solution?

In an observational study, Shockley and colleagues investigated the type and quantity of bacteria found intraoperatively on the abdomen, vagina, surgical gloves, instrument tips, and uterus at distinct time points during total laparoscopic hysterectomy.¹⁷ They showed that in 98.9% of cultures, the overall bacterial concentrations did not exceed the threshold for infection. There was no bacterial growth from vaginal cultures, and the only samples with some bacterial growth belonged to the surgeon’s gloves after specimen extraction; about one-third of samples showed growth after specimen extraction, but only 1 sample had a bacterial load above the infectious threshold of 5,000 colony-forming units per mL. The authors therefore suggested that if a surgeon changes gloves, doing so after specimen extraction and before turning attention back to the abdomen for vaginal cuff closure may be most effective in reducing bacterial load.¹⁷

Surgical site infection contributes to medical cost and likely medical waste as well. For example, surgical site infection may require prolonged treatments, tests, and medical instruments. In severe cases with abscesses, treatment entails hospitalization with prolonged antibiotic therapy with or without procedures to drain the collections. Further research therefore is warranted to investigate safe and environmentally friendly practices.

Myriad products are introduced to the medical system each day, some of which replace conventional tools. For instance, low-density polyethylene, or LDPE, transfer sheet is advertised for lateral patient transfer from the OR table to the bed or stretcher. This No. 4–coded plastic, while recyclable, is routinely discarded as trash in ORs. One ergonomic study found that reusable slide boards are as effective for reducing friction and staff muscle activities and are noninferior to the plastic sheets.¹⁸

Steps to making an impact

Operating rooms and labor and delivery units are responsible for a large proportion of hospital waste, and therefore they are of paramount importance in reducing waste and carbon footprint at the individual and institutional level. Reduction of OR waste not only is environmentally conscious but also decreases cost. Steps as small as individual practices to as big as changing infrastructures can make an impact. For instance:

• redesigning surgical carts
• reformulating surgeon-specific supply lists
• raising awareness about surgical overage
• encouraging recycling through education and audit
• optimizing surgical waste segregation through educational posters.

These are all simple steps that could significantly reduce waste and carbon footprint.

Bottom line

Although waste reduction is the responsibility of all health care providers, as leaders in their workplace physicians can serve as role models by implementing “green” practices in procedural units. Raising awareness and using a team approach is critical to succeed in our endeavors to move toward an environmentally friendly future. ●

Erythema ab igne (EAI)(also known as toasted skin syndrome) was first described in the British Journal of Dermatology in the 20th century, ¹ though it was known by physicians long before. Reticular netlike skin changes were seen in association with patients who spent extended time directly next to a heat source. This association led to the name of this condition, which literally means “redness by fire.” Indeed, EAI induced by chronic heat exposure has been described across the world for centuries. For example, in the cold regions of northern China, people used to sleep on beds of hot bricks called kang to stay warm at night. The people of India’s Kashmir district carried pots of hot coals called kangri next to the skin under large woven shawls to stay warm. In the past, Irish women often spent much time by a turf- or peat-burning fire. Chronic heat exposure in these cases can lead not only to EAI but also to aggressive types of cancer, often with a latency of 30 years or more. ²

More recently, the invention of home central heating led to a stark decrease in the number of cases associated with combustion-based heat, with a transition to etiologies such as use of hot water bottles, electric blankets, and electric space heaters. Over time, technological advances led to ever-increasing potential causes for EAI, such as laptops or cell phones, car heaters and heated seats, heated blankets,^3,4 infrared lamps for food, and even medical devices such as ultrasound-based heating products and convective temperature management systems for hospitalized patients. As technology evolves, so do the potential causes of EAI, requiring clinicians to diagnose and deduce the cause through a thorough social and medical history as well as a workup on the present illness with considerations for the anatomical location.^5-7 Herein, we describe the etiology of EAI, diagnosis, and treatment options.

Clinical Characteristics

Erythema ab igne begins as mild, transient, and erythematous macules and patches in a reticular pattern that resolve minutes to hours after removal of the heat source. With weeks to months of continued or repeated application of the heat source, the affected area eventually becomes hyperpigmented where there once was erythema (Figures 1 and 2). Sometimes papules, bullae, telangiectasia, and hyperkeratosis also form. The rash usually is asymptomatic, though pain, pruritus, and dysesthesia have been reported.⁷ Dermoscopy of EAI in the hyperpigmented stage can reveal diffuse superficial dark pigmentation, telangiectasia, and mild whitish scaling.⁸ Although the pathogenesis has remained elusive over the years, lesions do seem to be mostly associated with cumulative exposure to heat rather than length of exposure.⁷

Etiology of EAI

Anatomic Location—The affected site depends on the source of heat (Table). Classic examples of this condition include a patient with EAI presenting on the anterior thighs after working in front of a hot oven or a patient with chronic back pain presenting with lower-back EAI secondary to frequent use of a hot water bottle or heating pad.⁷ With evolving technology over the last few decades, new etiologies have become more common—teenagers are presenting with anterior thigh EAI secondary to frequent laptop use^2-29; patients are holding warm cell phones in their pant pockets, leading to unilateral geometric EAI on the anterior thigh (front pocket) or buttock (back pocket)³⁰; plug-in radiators under computer desks are causing EAI on the lower legs^31-34; and automobile seat heaters have been shown to cause EAI on the posterior legs.^5,35-37 Clinicians should consider anatomic location a critical clue for etiology.

Social History—There are rarer and more highly specific causes of EAI than simple heat exposure that can be parsed from a patient’s social history. Occupational exposure has been documented, such as bakers with exposure to ovens, foundry workers with exposure to heated metals, or fast-food workers with chronic exposure to infrared food lamps.^6,7 There also are cultural practices that can cause EAI. For example, the practice of cupping with moxibustion was shown to create a specific pattern in the shape of the cultural tool used.³⁸ When footbaths with Chinese herbal remedies are performed frequently with high heat, they can lead to EAI on the feet with a linear border at the ankles. There also have been reports of kotatsu (heated tables in Japan) leading to lower-body EAI.^39,40 These cultural practices also are more common in patients with darker skin types, which can lead to hyperpigmentation that is difficult to treat, making early diagnosis important.⁷

Medical History—Case reports have shown EAI caused by patients attempting to use heat-based methods for pain relief of an underlying serious disease such as cancer, bowel pathology (abdominal EAI), spinal disc prolapse (midline back EAI),⁴¹ sickle cell anemia, and renal pathology (posterior upper flank EAI).^6,7,40-49 Patients with hypothyroidism or anorexia have been noted to have generalized EAI sparing the face secondary to repeated and extended hot baths or showers.^50-53 One patient with schizophrenia was shown to have associated thermophilia due to a delusion that led the patient to soak in hot baths for long periods of time, leading to EAI.⁵⁴ Finally, all physicians should be aware of iatrogenic causes of EAI, such as use of warming devices, ultrasound-based warming techniques, and laser therapy for lipolysis. Inquire about the patient’s surgical history or intensive care unit stays as well as alternative medicine or chiropractic visits. Obtaining a history of medical procedures can be enlightening when an etiology is not immediately clear.^7,55,56

Diagnosis

Erythema ab igne is a clinical diagnosis based on recognizable cutaneous findings and a clear history of moderate heat exposure. However, when a clinical diagnosis of EAI is not certain (eg, when unable to obtain a clear history from the patient) or when malignant transformation is suspected, a biopsy can be performed. Pathologically, hematoxylin and eosin staining of EAI classically reveals dilated small vascular channels in the superficial dermis, hence a clinically reticular rash; interface dermatitis clinically manifesting as erythema; and pigment incontinence with melanin-laden macrophages consistent with clinical hyperpigmentation. Finally, for unclear reasons, increased numbers of elastic fibers classically are seen in biopsies of EAI.⁷

The differential diagnosis for a reticular patch includes livedo reticularis (Figure 3), which usually manifests as a more generalized rash in patients with chronic disease or coagulopathy such as systemic lupus erythematosus, cryoglobulinemia, or Raynaud phenomenon. When differentiating EAI from livedo reticularis or cutis marmorata, consider that both alternative diagnoses are more vascular appearing and are associated with cold exposure rather than heat exposure. In cases that are less reticular, livedo racemosa can be considered in the differential diagnosis. Finally, poikiloderma of Civatte can be reticular, particularly on dermoscopy, but the distribution on the neck with submental sparing should help to distinguish it from EAI unless a heat source around the neck is identified while taking the patient’s history.⁷

In babies, a reticular generalized rash is most likely to be cutis marmorata (Figure 4), which is a physiologic response to cold exposure that resolves with rewarming of the skin. A more serious condition—cutis marmorata telangiectatica congenita (Figure 5)—usually is present at birth, most frequently involves a single extremity, and notably does not resolve with rewarming. This is an important differential for EAI in children because it can be associated with vascular and neurologic anomalies as well as limb asymmetry. Finally, port-wine stains can sometimes be reticular in appearance and can mimic the early erythematous stages of EAI. However, unlike the erythematous stage of EAI, the port-wine stains will be present at birth.⁷

Emerging in 2020, an important differential diagnosis to consider is a cutaneous manifestation of COVID-19 infection. An erythematous, reticular, chilblainlike or transient livedo reticularis–like rash has been described as a cutaneous manifestation of COVID-19. Although the pathophysiology is still being elucidated, it is suspected that this is caused by a major vaso-occlusive crisis secondary to COVID-19–induced thrombotic vasculopathy. Interestingly, the majority of patients with this COVID-related exanthem also displayed symptoms of COVID-19 (eg, fever, cough) at the time of presentation,^57-60 but there also have been cases in patients who were asymptomatic or mildly symptomatic.⁶⁰

In some cases, EAI is an indication to screen for an underlying disease. For example, uncontrolled pain is an opportunity to improve interventions such as modifying the patient’s pain-control regimen, placing a palliative care pain consultation, or checking if the patient has had age-appropriate screenings for malignancy. New focal pain in a patient with a prior diagnosis of cancer may be a sign of a new metastasis. A thermophilic patient leaves opportunity to assess for underlying medical causes such as thyroid abnormalities or social/psychological issues. Geriatric patients who are diagnosed with EAI may need to be assessed for dementia or home safety issues. Patients with a history of diabetes mellitus can unknowingly develop EAI on the lower extremities, which may signal a need to assess the patient for peripheral neuropathy. Patients with gastroparesis secondary to diabetes also may develop EAI on the abdomen secondary to heating pad use for discomfort. These examples are a reminder to consider possible secondary comorbidities in all diagnoses of EAI.⁷ 

Prognosis

Although the prognosis of EAI is excellent if caught early, failure to diagnose this condition can lead to permanent discoloration of the skin and even malignancy.⁶ A rare sequela includes squamous cell carcinoma, most commonly seen in chronic cases of the lower leg, which is likely related to chronic inflammation of the skin.^61-65 Rare cases of poorly differentiated carcinoma,⁶⁶ cutaneous marginal zone lymphoma,⁶⁷ and Merkel cell carcinoma⁶⁸ have been reported. Patients diagnosed with EAI should receive normal periodic surveillance of the skin based on their medical history, though the physician should have an increased suspicion and plan for biopsy of any nodules or ulcerations found on the skin of the affected area.⁷

Treatments

Once the diagnosis of EAI is made, treatment starts with removal of the heat source causing the rash. Because the rash usually is asymptomatic, further treatment typically is not required. The discoloration can resolve over months or years, but permanent hyperpigmentation is not uncommon. If hyperpigmentation persists despite removal of the heat source and the patient desires further treatment for discoloration, there are few treatment options, none of which are approved by the US Food and Drug Administration for this condition.⁷ There is some evidence for the use of Nd:YAG lasers to reduce hyperpigmentation in EAI.⁶⁹ There have been some reports of treatment using topical hydroquinone and topical tretinoin in an attempt to lighten the skin. If associated hyperkeratosis or other epithelial atypia is present, the use of 5-fluorouracil may show some improvement.⁷⁰ One case report has been published of successful treatment with systemic mesoglycan and topical bioflavonoids.⁷¹ It also is conceivable that medications used to treat postinflammatory hyperpigmentation may be helpful in this condition (eg, kojic acid, arbutin, mild topical steroids, azelaic acid). Patients with darker skin may experience permanent discoloration and may not be good candidates for alternative treatments such as laser therapy due to the risk for inducible hyperpigmentation.⁷

Conclusion

No matter the etiology, EAI usually is a benign skin condition that is treated by removal of the causative heat source. Once a diagnosis is made, the clinician must work with the patient to determine the etiology. Care must be taken to ensure that there are no underlying signs, such as chronic pain or psychiatric illness, that could point to associated conditions. Rarely, sequalae such as cancers have been documented in areas of chronic EAI. Once the heat source is identified and removed, any remaining hyperpigmentation usually will self-resolve over months to years, though this may take longer in patients with darker skin types. If more aggressive treatment is preferred by the patient, laser therapy, topical medications, and oral over-the-counter vitamins have been tried with minimal responses. 

Erythema ab igne (EAI)(also known as toasted skin syndrome) was first described in the British Journal of Dermatology in the 20th century, ¹ though it was known by physicians long before. Reticular netlike skin changes were seen in association with patients who spent extended time directly next to a heat source. This association led to the name of this condition, which literally means “redness by fire.” Indeed, EAI induced by chronic heat exposure has been described across the world for centuries. For example, in the cold regions of northern China, people used to sleep on beds of hot bricks called kang to stay warm at night. The people of India’s Kashmir district carried pots of hot coals called kangri next to the skin under large woven shawls to stay warm. In the past, Irish women often spent much time by a turf- or peat-burning fire. Chronic heat exposure in these cases can lead not only to EAI but also to aggressive types of cancer, often with a latency of 30 years or more. ²

More recently, the invention of home central heating led to a stark decrease in the number of cases associated with combustion-based heat, with a transition to etiologies such as use of hot water bottles, electric blankets, and electric space heaters. Over time, technological advances led to ever-increasing potential causes for EAI, such as laptops or cell phones, car heaters and heated seats, heated blankets,^3,4 infrared lamps for food, and even medical devices such as ultrasound-based heating products and convective temperature management systems for hospitalized patients. As technology evolves, so do the potential causes of EAI, requiring clinicians to diagnose and deduce the cause through a thorough social and medical history as well as a workup on the present illness with considerations for the anatomical location.^5-7 Herein, we describe the etiology of EAI, diagnosis, and treatment options.

Clinical Characteristics

Erythema ab igne begins as mild, transient, and erythematous macules and patches in a reticular pattern that resolve minutes to hours after removal of the heat source. With weeks to months of continued or repeated application of the heat source, the affected area eventually becomes hyperpigmented where there once was erythema (Figures 1 and 2). Sometimes papules, bullae, telangiectasia, and hyperkeratosis also form. The rash usually is asymptomatic, though pain, pruritus, and dysesthesia have been reported.⁷ Dermoscopy of EAI in the hyperpigmented stage can reveal diffuse superficial dark pigmentation, telangiectasia, and mild whitish scaling.⁸ Although the pathogenesis has remained elusive over the years, lesions do seem to be mostly associated with cumulative exposure to heat rather than length of exposure.⁷

Etiology of EAI

Anatomic Location—The affected site depends on the source of heat (Table). Classic examples of this condition include a patient with EAI presenting on the anterior thighs after working in front of a hot oven or a patient with chronic back pain presenting with lower-back EAI secondary to frequent use of a hot water bottle or heating pad.⁷ With evolving technology over the last few decades, new etiologies have become more common—teenagers are presenting with anterior thigh EAI secondary to frequent laptop use^2-29; patients are holding warm cell phones in their pant pockets, leading to unilateral geometric EAI on the anterior thigh (front pocket) or buttock (back pocket)³⁰; plug-in radiators under computer desks are causing EAI on the lower legs^31-34; and automobile seat heaters have been shown to cause EAI on the posterior legs.^5,35-37 Clinicians should consider anatomic location a critical clue for etiology.

Social History—There are rarer and more highly specific causes of EAI than simple heat exposure that can be parsed from a patient’s social history. Occupational exposure has been documented, such as bakers with exposure to ovens, foundry workers with exposure to heated metals, or fast-food workers with chronic exposure to infrared food lamps.^6,7 There also are cultural practices that can cause EAI. For example, the practice of cupping with moxibustion was shown to create a specific pattern in the shape of the cultural tool used.³⁸ When footbaths with Chinese herbal remedies are performed frequently with high heat, they can lead to EAI on the feet with a linear border at the ankles. There also have been reports of kotatsu (heated tables in Japan) leading to lower-body EAI.^39,40 These cultural practices also are more common in patients with darker skin types, which can lead to hyperpigmentation that is difficult to treat, making early diagnosis important.⁷

Medical History—Case reports have shown EAI caused by patients attempting to use heat-based methods for pain relief of an underlying serious disease such as cancer, bowel pathology (abdominal EAI), spinal disc prolapse (midline back EAI),⁴¹ sickle cell anemia, and renal pathology (posterior upper flank EAI).^6,7,40-49 Patients with hypothyroidism or anorexia have been noted to have generalized EAI sparing the face secondary to repeated and extended hot baths or showers.^50-53 One patient with schizophrenia was shown to have associated thermophilia due to a delusion that led the patient to soak in hot baths for long periods of time, leading to EAI.⁵⁴ Finally, all physicians should be aware of iatrogenic causes of EAI, such as use of warming devices, ultrasound-based warming techniques, and laser therapy for lipolysis. Inquire about the patient’s surgical history or intensive care unit stays as well as alternative medicine or chiropractic visits. Obtaining a history of medical procedures can be enlightening when an etiology is not immediately clear.^7,55,56

Diagnosis

Erythema ab igne is a clinical diagnosis based on recognizable cutaneous findings and a clear history of moderate heat exposure. However, when a clinical diagnosis of EAI is not certain (eg, when unable to obtain a clear history from the patient) or when malignant transformation is suspected, a biopsy can be performed. Pathologically, hematoxylin and eosin staining of EAI classically reveals dilated small vascular channels in the superficial dermis, hence a clinically reticular rash; interface dermatitis clinically manifesting as erythema; and pigment incontinence with melanin-laden macrophages consistent with clinical hyperpigmentation. Finally, for unclear reasons, increased numbers of elastic fibers classically are seen in biopsies of EAI.⁷

The differential diagnosis for a reticular patch includes livedo reticularis (Figure 3), which usually manifests as a more generalized rash in patients with chronic disease or coagulopathy such as systemic lupus erythematosus, cryoglobulinemia, or Raynaud phenomenon. When differentiating EAI from livedo reticularis or cutis marmorata, consider that both alternative diagnoses are more vascular appearing and are associated with cold exposure rather than heat exposure. In cases that are less reticular, livedo racemosa can be considered in the differential diagnosis. Finally, poikiloderma of Civatte can be reticular, particularly on dermoscopy, but the distribution on the neck with submental sparing should help to distinguish it from EAI unless a heat source around the neck is identified while taking the patient’s history.⁷

In babies, a reticular generalized rash is most likely to be cutis marmorata (Figure 4), which is a physiologic response to cold exposure that resolves with rewarming of the skin. A more serious condition—cutis marmorata telangiectatica congenita (Figure 5)—usually is present at birth, most frequently involves a single extremity, and notably does not resolve with rewarming. This is an important differential for EAI in children because it can be associated with vascular and neurologic anomalies as well as limb asymmetry. Finally, port-wine stains can sometimes be reticular in appearance and can mimic the early erythematous stages of EAI. However, unlike the erythematous stage of EAI, the port-wine stains will be present at birth.⁷

Emerging in 2020, an important differential diagnosis to consider is a cutaneous manifestation of COVID-19 infection. An erythematous, reticular, chilblainlike or transient livedo reticularis–like rash has been described as a cutaneous manifestation of COVID-19. Although the pathophysiology is still being elucidated, it is suspected that this is caused by a major vaso-occlusive crisis secondary to COVID-19–induced thrombotic vasculopathy. Interestingly, the majority of patients with this COVID-related exanthem also displayed symptoms of COVID-19 (eg, fever, cough) at the time of presentation,^57-60 but there also have been cases in patients who were asymptomatic or mildly symptomatic.⁶⁰

In some cases, EAI is an indication to screen for an underlying disease. For example, uncontrolled pain is an opportunity to improve interventions such as modifying the patient’s pain-control regimen, placing a palliative care pain consultation, or checking if the patient has had age-appropriate screenings for malignancy. New focal pain in a patient with a prior diagnosis of cancer may be a sign of a new metastasis. A thermophilic patient leaves opportunity to assess for underlying medical causes such as thyroid abnormalities or social/psychological issues. Geriatric patients who are diagnosed with EAI may need to be assessed for dementia or home safety issues. Patients with a history of diabetes mellitus can unknowingly develop EAI on the lower extremities, which may signal a need to assess the patient for peripheral neuropathy. Patients with gastroparesis secondary to diabetes also may develop EAI on the abdomen secondary to heating pad use for discomfort. These examples are a reminder to consider possible secondary comorbidities in all diagnoses of EAI.⁷ 

Prognosis

Although the prognosis of EAI is excellent if caught early, failure to diagnose this condition can lead to permanent discoloration of the skin and even malignancy.⁶ A rare sequela includes squamous cell carcinoma, most commonly seen in chronic cases of the lower leg, which is likely related to chronic inflammation of the skin.^61-65 Rare cases of poorly differentiated carcinoma,⁶⁶ cutaneous marginal zone lymphoma,⁶⁷ and Merkel cell carcinoma⁶⁸ have been reported. Patients diagnosed with EAI should receive normal periodic surveillance of the skin based on their medical history, though the physician should have an increased suspicion and plan for biopsy of any nodules or ulcerations found on the skin of the affected area.⁷

Treatments

Once the diagnosis of EAI is made, treatment starts with removal of the heat source causing the rash. Because the rash usually is asymptomatic, further treatment typically is not required. The discoloration can resolve over months or years, but permanent hyperpigmentation is not uncommon. If hyperpigmentation persists despite removal of the heat source and the patient desires further treatment for discoloration, there are few treatment options, none of which are approved by the US Food and Drug Administration for this condition.⁷ There is some evidence for the use of Nd:YAG lasers to reduce hyperpigmentation in EAI.⁶⁹ There have been some reports of treatment using topical hydroquinone and topical tretinoin in an attempt to lighten the skin. If associated hyperkeratosis or other epithelial atypia is present, the use of 5-fluorouracil may show some improvement.⁷⁰ One case report has been published of successful treatment with systemic mesoglycan and topical bioflavonoids.⁷¹ It also is conceivable that medications used to treat postinflammatory hyperpigmentation may be helpful in this condition (eg, kojic acid, arbutin, mild topical steroids, azelaic acid). Patients with darker skin may experience permanent discoloration and may not be good candidates for alternative treatments such as laser therapy due to the risk for inducible hyperpigmentation.⁷

Conclusion

No matter the etiology, EAI usually is a benign skin condition that is treated by removal of the causative heat source. Once a diagnosis is made, the clinician must work with the patient to determine the etiology. Care must be taken to ensure that there are no underlying signs, such as chronic pain or psychiatric illness, that could point to associated conditions. Rarely, sequalae such as cancers have been documented in areas of chronic EAI. Once the heat source is identified and removed, any remaining hyperpigmentation usually will self-resolve over months to years, though this may take longer in patients with darker skin types. If more aggressive treatment is preferred by the patient, laser therapy, topical medications, and oral over-the-counter vitamins have been tried with minimal responses. 

Erythema ab igne (EAI)(also known as toasted skin syndrome) was first described in the British Journal of Dermatology in the 20th century, ¹ though it was known by physicians long before. Reticular netlike skin changes were seen in association with patients who spent extended time directly next to a heat source. This association led to the name of this condition, which literally means “redness by fire.” Indeed, EAI induced by chronic heat exposure has been described across the world for centuries. For example, in the cold regions of northern China, people used to sleep on beds of hot bricks called kang to stay warm at night. The people of India’s Kashmir district carried pots of hot coals called kangri next to the skin under large woven shawls to stay warm. In the past, Irish women often spent much time by a turf- or peat-burning fire. Chronic heat exposure in these cases can lead not only to EAI but also to aggressive types of cancer, often with a latency of 30 years or more. ²

More recently, the invention of home central heating led to a stark decrease in the number of cases associated with combustion-based heat, with a transition to etiologies such as use of hot water bottles, electric blankets, and electric space heaters. Over time, technological advances led to ever-increasing potential causes for EAI, such as laptops or cell phones, car heaters and heated seats, heated blankets,^3,4 infrared lamps for food, and even medical devices such as ultrasound-based heating products and convective temperature management systems for hospitalized patients. As technology evolves, so do the potential causes of EAI, requiring clinicians to diagnose and deduce the cause through a thorough social and medical history as well as a workup on the present illness with considerations for the anatomical location.^5-7 Herein, we describe the etiology of EAI, diagnosis, and treatment options.

Clinical Characteristics

Erythema ab igne begins as mild, transient, and erythematous macules and patches in a reticular pattern that resolve minutes to hours after removal of the heat source. With weeks to months of continued or repeated application of the heat source, the affected area eventually becomes hyperpigmented where there once was erythema (Figures 1 and 2). Sometimes papules, bullae, telangiectasia, and hyperkeratosis also form. The rash usually is asymptomatic, though pain, pruritus, and dysesthesia have been reported.⁷ Dermoscopy of EAI in the hyperpigmented stage can reveal diffuse superficial dark pigmentation, telangiectasia, and mild whitish scaling.⁸ Although the pathogenesis has remained elusive over the years, lesions do seem to be mostly associated with cumulative exposure to heat rather than length of exposure.⁷

Etiology of EAI

Anatomic Location—The affected site depends on the source of heat (Table). Classic examples of this condition include a patient with EAI presenting on the anterior thighs after working in front of a hot oven or a patient with chronic back pain presenting with lower-back EAI secondary to frequent use of a hot water bottle or heating pad.⁷ With evolving technology over the last few decades, new etiologies have become more common—teenagers are presenting with anterior thigh EAI secondary to frequent laptop use^2-29; patients are holding warm cell phones in their pant pockets, leading to unilateral geometric EAI on the anterior thigh (front pocket) or buttock (back pocket)³⁰; plug-in radiators under computer desks are causing EAI on the lower legs^31-34; and automobile seat heaters have been shown to cause EAI on the posterior legs.^5,35-37 Clinicians should consider anatomic location a critical clue for etiology.

Social History—There are rarer and more highly specific causes of EAI than simple heat exposure that can be parsed from a patient’s social history. Occupational exposure has been documented, such as bakers with exposure to ovens, foundry workers with exposure to heated metals, or fast-food workers with chronic exposure to infrared food lamps.^6,7 There also are cultural practices that can cause EAI. For example, the practice of cupping with moxibustion was shown to create a specific pattern in the shape of the cultural tool used.³⁸ When footbaths with Chinese herbal remedies are performed frequently with high heat, they can lead to EAI on the feet with a linear border at the ankles. There also have been reports of kotatsu (heated tables in Japan) leading to lower-body EAI.^39,40 These cultural practices also are more common in patients with darker skin types, which can lead to hyperpigmentation that is difficult to treat, making early diagnosis important.⁷

Medical History—Case reports have shown EAI caused by patients attempting to use heat-based methods for pain relief of an underlying serious disease such as cancer, bowel pathology (abdominal EAI), spinal disc prolapse (midline back EAI),⁴¹ sickle cell anemia, and renal pathology (posterior upper flank EAI).^6,7,40-49 Patients with hypothyroidism or anorexia have been noted to have generalized EAI sparing the face secondary to repeated and extended hot baths or showers.^50-53 One patient with schizophrenia was shown to have associated thermophilia due to a delusion that led the patient to soak in hot baths for long periods of time, leading to EAI.⁵⁴ Finally, all physicians should be aware of iatrogenic causes of EAI, such as use of warming devices, ultrasound-based warming techniques, and laser therapy for lipolysis. Inquire about the patient’s surgical history or intensive care unit stays as well as alternative medicine or chiropractic visits. Obtaining a history of medical procedures can be enlightening when an etiology is not immediately clear.^7,55,56

Diagnosis

Erythema ab igne is a clinical diagnosis based on recognizable cutaneous findings and a clear history of moderate heat exposure. However, when a clinical diagnosis of EAI is not certain (eg, when unable to obtain a clear history from the patient) or when malignant transformation is suspected, a biopsy can be performed. Pathologically, hematoxylin and eosin staining of EAI classically reveals dilated small vascular channels in the superficial dermis, hence a clinically reticular rash; interface dermatitis clinically manifesting as erythema; and pigment incontinence with melanin-laden macrophages consistent with clinical hyperpigmentation. Finally, for unclear reasons, increased numbers of elastic fibers classically are seen in biopsies of EAI.⁷

The differential diagnosis for a reticular patch includes livedo reticularis (Figure 3), which usually manifests as a more generalized rash in patients with chronic disease or coagulopathy such as systemic lupus erythematosus, cryoglobulinemia, or Raynaud phenomenon. When differentiating EAI from livedo reticularis or cutis marmorata, consider that both alternative diagnoses are more vascular appearing and are associated with cold exposure rather than heat exposure. In cases that are less reticular, livedo racemosa can be considered in the differential diagnosis. Finally, poikiloderma of Civatte can be reticular, particularly on dermoscopy, but the distribution on the neck with submental sparing should help to distinguish it from EAI unless a heat source around the neck is identified while taking the patient’s history.⁷

In babies, a reticular generalized rash is most likely to be cutis marmorata (Figure 4), which is a physiologic response to cold exposure that resolves with rewarming of the skin. A more serious condition—cutis marmorata telangiectatica congenita (Figure 5)—usually is present at birth, most frequently involves a single extremity, and notably does not resolve with rewarming. This is an important differential for EAI in children because it can be associated with vascular and neurologic anomalies as well as limb asymmetry. Finally, port-wine stains can sometimes be reticular in appearance and can mimic the early erythematous stages of EAI. However, unlike the erythematous stage of EAI, the port-wine stains will be present at birth.⁷

Emerging in 2020, an important differential diagnosis to consider is a cutaneous manifestation of COVID-19 infection. An erythematous, reticular, chilblainlike or transient livedo reticularis–like rash has been described as a cutaneous manifestation of COVID-19. Although the pathophysiology is still being elucidated, it is suspected that this is caused by a major vaso-occlusive crisis secondary to COVID-19–induced thrombotic vasculopathy. Interestingly, the majority of patients with this COVID-related exanthem also displayed symptoms of COVID-19 (eg, fever, cough) at the time of presentation,^57-60 but there also have been cases in patients who were asymptomatic or mildly symptomatic.⁶⁰

In some cases, EAI is an indication to screen for an underlying disease. For example, uncontrolled pain is an opportunity to improve interventions such as modifying the patient’s pain-control regimen, placing a palliative care pain consultation, or checking if the patient has had age-appropriate screenings for malignancy. New focal pain in a patient with a prior diagnosis of cancer may be a sign of a new metastasis. A thermophilic patient leaves opportunity to assess for underlying medical causes such as thyroid abnormalities or social/psychological issues. Geriatric patients who are diagnosed with EAI may need to be assessed for dementia or home safety issues. Patients with a history of diabetes mellitus can unknowingly develop EAI on the lower extremities, which may signal a need to assess the patient for peripheral neuropathy. Patients with gastroparesis secondary to diabetes also may develop EAI on the abdomen secondary to heating pad use for discomfort. These examples are a reminder to consider possible secondary comorbidities in all diagnoses of EAI.⁷ 

Prognosis

Although the prognosis of EAI is excellent if caught early, failure to diagnose this condition can lead to permanent discoloration of the skin and even malignancy.⁶ A rare sequela includes squamous cell carcinoma, most commonly seen in chronic cases of the lower leg, which is likely related to chronic inflammation of the skin.^61-65 Rare cases of poorly differentiated carcinoma,⁶⁶ cutaneous marginal zone lymphoma,⁶⁷ and Merkel cell carcinoma⁶⁸ have been reported. Patients diagnosed with EAI should receive normal periodic surveillance of the skin based on their medical history, though the physician should have an increased suspicion and plan for biopsy of any nodules or ulcerations found on the skin of the affected area.⁷

Treatments

Once the diagnosis of EAI is made, treatment starts with removal of the heat source causing the rash. Because the rash usually is asymptomatic, further treatment typically is not required. The discoloration can resolve over months or years, but permanent hyperpigmentation is not uncommon. If hyperpigmentation persists despite removal of the heat source and the patient desires further treatment for discoloration, there are few treatment options, none of which are approved by the US Food and Drug Administration for this condition.⁷ There is some evidence for the use of Nd:YAG lasers to reduce hyperpigmentation in EAI.⁶⁹ There have been some reports of treatment using topical hydroquinone and topical tretinoin in an attempt to lighten the skin. If associated hyperkeratosis or other epithelial atypia is present, the use of 5-fluorouracil may show some improvement.⁷⁰ One case report has been published of successful treatment with systemic mesoglycan and topical bioflavonoids.⁷¹ It also is conceivable that medications used to treat postinflammatory hyperpigmentation may be helpful in this condition (eg, kojic acid, arbutin, mild topical steroids, azelaic acid). Patients with darker skin may experience permanent discoloration and may not be good candidates for alternative treatments such as laser therapy due to the risk for inducible hyperpigmentation.⁷

Conclusion

No matter the etiology, EAI usually is a benign skin condition that is treated by removal of the causative heat source. Once a diagnosis is made, the clinician must work with the patient to determine the etiology. Care must be taken to ensure that there are no underlying signs, such as chronic pain or psychiatric illness, that could point to associated conditions. Rarely, sequalae such as cancers have been documented in areas of chronic EAI. Once the heat source is identified and removed, any remaining hyperpigmentation usually will self-resolve over months to years, though this may take longer in patients with darker skin types. If more aggressive treatment is preferred by the patient, laser therapy, topical medications, and oral over-the-counter vitamins have been tried with minimal responses. 

COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.^1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.³ As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.⁴

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.⁵ Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,⁶ an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,^7,8 the COVIDSKIN registry of the French Dermatology Society,⁹ and the Italian registry.¹⁰ Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)⁵ and Japan (0.56%),¹¹ compared with Europe (up to 20%).⁶ Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.¹² They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.^13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-19¹³ and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).^16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,¹⁹ which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.^20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.^17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.^26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.³⁰

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.^31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.³³

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.³⁴

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).³⁵ Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance³⁶; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported^37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.³⁹ It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.⁴⁰ Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.⁴¹ Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.⁴²

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children⁴³ and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).⁴⁴ Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).⁴⁵

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.^9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.⁴⁶

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.⁴⁷ This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,³ a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.⁴⁸ In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.^49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals⁵¹; 54.4% of 879 health care professionals in one study reported such events.⁵² These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).^53,54

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.⁵⁵ Psoriasis and acrodermatitis continua of Hallopeau,⁵⁶ which may progress into generalized, pustular, or erythrodermic forms,⁵⁷ have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.⁵⁷ Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.⁵⁸ The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.⁵⁹ Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,⁶⁰ possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.⁶¹ Lupus erythematosus, which may relapse in the form of Rowell syndrome,⁶² and livedoid vasculopathy⁶³ also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,⁴ an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.^64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.⁶⁵ Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.⁷⁰ Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.⁷⁰
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.⁷⁰

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.⁷⁰

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.⁷⁰

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.⁷⁰

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.⁷¹

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.⁷²

• Chilblainlike lesions: several such cases have been reported so far⁷³; they constitute 0.03% of postvaccination reactions.⁷⁰ Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.^73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.⁷⁶

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).⁷⁰

• Severe reactions: these include acute generalized exanthematous pustulosis⁷⁷ and Stevens-Johnson syndrome.⁷⁸ One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,^79,80 leukocytoclastic vasculitis,^81,82 lymphocytic⁸³ or urticarial⁸⁴ vasculitis, Sweet syndrome,⁸⁵ lupus erythematosus, dermatomyositis,^86,87 alopecia,^37,88 infection with Trichophyton rubrum,⁸⁹ Grover disease,⁹⁰ and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30⁺], and de novo development of lymphomatoid papulosis).⁹¹

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.⁹² Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.