This retrospective observational study investigates skin cancer prevalence and care patterns within the Military Health System (MHS) from 2017 to 2022. Utilizing the MHS Management Analysis and Reporting Tool (most commonly called M2), we analyzed more than 5 million patient encounters and documented skin cancer prevalence in the MHS beneficiary population utilizing available demographic data. Notable findings included an increased prevalence of skin cancer in the military population compared with the civilian population, a substantial decline in direct care (DC) visits at military treatment facilities compared with civilian purchased care (PC) visits, and a decreased total number of visits during COVID-19 restrictions.

The Military Health System (MHS) is a worldwide health care delivery system that serves 9.6 million beneficiaries, including military service members, retirees, and their families.¹ Its mission is 2-fold: provide a medically ready force, and provide a medical benefit in keeping with the service and sacrifice of active-duty personnel, military retirees, and their families. For fiscal year (FY) 2022, active-duty service members and their families comprised 16.7% and 19.9% of beneficiaries, respectively, while retired service members and their families comprised 27% and 32% of beneficiaries, respectively.

The MHS operates under the authority of the Department of Defense (DoD) and is supported by an annual budget of approximately $50 billion.¹ Health care provision within the MHS is managed by TRICARE regional networks.² Within these networks, MHS beneficiaries may receive health care in 2 categories: direct care (DC) and purchased care (PC). Direct care is rendered in military treatment facilities by military or civilian providers contracted by the DoD, and PC is administered by civilian providers at civilian health care facilities within the TRICARE network, which is comprised of individual providers, clinics, and hospitals that have agreed to accept TRICARE beneficiaries.¹ Purchased care is fee-for-service and paid for by the MHS. Of note, the MHS differs from the Veterans Affairs health care system in that the MHS through DC and PC sees only active-duty service members, active-duty dependents, retirees, and retirees’ dependents (primarily spouses), whereas Veterans Affairs sees only veterans (not necessarily retirees) discharged from military service with compensable medical conditions or disabilities.

Skin cancer presents a notable concern for the US Military, as the risk for skin cancer is thought to be higher than in the general population.^3,4 This elevated risk is attributed to numerous factors inherent to active-duty service, including time spent in tropical environments, increased exposure to UV radiation, time spent at high altitudes, and decreased rates of sun-protective behaviors.³ Although numerous studies have explored the mechanisms that contribute to service members’ increased skin cancer risk, there are few (if any) that discuss the burden of skin cancer on the MHS and where its beneficiaries receive their skin cancer care. This study evaluated the burden of skin cancer within the MHS, as demonstrated by the period prevalence of skin cancer among its beneficiaries and the number and distribution of patient visits for skin cancer across both DC and PC from 2017 to 2022.

Methods

Data Collection—This retrospective observational study was designed to describe trends in outpatient visits with a skin cancer diagnosis and annual prevalence of skin cancer types in the MHS. Data are from all MHS beneficiaries who were eligible or enrolled in the analysis year. Our data source was the MHS Management Analysis and Reporting Tool (most commonly called M2), a query tool that contains the current and most recent 5 full FYs of Defense Health Agency corporate health care data including aggregated FY and calendar-year counts of MHS beneficiaries from 2017 to 2022 using encounter and claims data tables from both DC and PC. Data in M2 are coded using a pseudo-person identification number, and queries performed for this study were limited to de-identified visit and patient counts.

Skin cancer diagnoses were defined by relevant International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes recorded from outpatient visits in DC and PC. The M2 database was queried to find aggregate counts of visits and unique MHS beneficiaries with one or more diagnoses of a skin cancer type of interest (defined by relevant ICD-10-CM code) over the study period stratified by year and by patient demographic characteristics. Skin cancer types by ICD-10-CM code group included basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), and other (including Merkel cell carcinoma and sebaceous carcinoma). Demographic strata included age, sex, military status (active duty, dependents of active duty, retired, or all others), sponsor military rank, and sponsor branch (army, air force, marine corps, or navy). Visit counts included diagnoses from any ICD position (for encounters that contained multiple ICD codes) to describe the total volume of care that addressed a diagnosed skin cancer. Counts of unique patients in prevalence analyses included relevant diagnoses in the primary ICD position only to increase the specificity of prevalence estimates.

Data Analysis—Descriptive analyses included the total number of outpatient visits with a skin cancer diagnosis in DC and PC over the study period, with percentages of total visits by year and by demographic strata. Separate analyses estimated annual prevalences of skin cancer types in the MHS by study year and within 2022 by demographic strata. Numerators in prevalence analyses were defined as the number of unique individuals with one or more relevant ICD codes in the analysis year. Denominators were defined as the total number of MHS beneficiaries in the analysis year and resulting period prevalences reported. Observed prevalences were qualitatively described, and trends were compared with prevalences in nonmilitary populations reported in the literature.

Ethics—This study was conducted as part of a study using secondary analyses of de-identified data from the M2 database. The study was reviewed and approved by the Walter Reed National Military Medical Center institutional review board.

Results

Encounter data were analyzed from a total of 5,374,348 visits between DC and PC over the study period for each cancer type of interest. Figures 1 and 2 show temporal trends in DC visits compared with PC visits in each beneficiary category. The percentage of total DC visits subsequently declined each year throughout the study period, with percentage decreases from 2017 to 2022 of 1.45% or 8200 fewer visits for MM, 3.41% or 7280 fewer visits for BCC, and 2.26% or 3673 fewer visits for SCC.

When stratified by beneficiary category, this trend remained consistent among dependents and retirees, with the most notable annual percentage decrease from 2019 to 2020. A higher proportion of younger adults and active-duty beneficiaries was seen in DC relative to PC, in which most visits were among retirees and others (primarily dependents of retirees, survivors, and Guard/Reserve on active duty, as well as inactive Guard/Reserve). No linear trends over time were apparent for active duty in DC and for dependents and retirees in PC. eTable 1 summarizes the demographic characteristics of MHS beneficiaries being seen in DC and PC over the study period for each cancer type of interest.

The Table shows the period prevalence of skin cancer diagnoses within the MHS beneficiary population from 2017 to 2022. These data were further analyzed by MM, BCC, and SCC (eTable 2) and demographics of interest for the year 2022. By beneficiary category, the period prevalence of MM was 0.08% in active duty, 0.06% in dependents, 0.48% in others, and 1.10% in retirees; the period prevalence of BCC was 0.12% in active duty, 0.07% in dependents, 0.91% in others, and 2.50% in retirees; and the period prevalence of SCC was 0.02% in active duty, 0.01% in dependents, 0.63% in others, and 1.87% in retirees. By sponsor branch, the period prevalence of MM was 0.35% in the army, 0.62% in the air force, 0.35% in the marine corps, and 0.65% in the navy; the period prevalence of BCC was 0.74% in the army, 1.30% in the air force, 0.74% in the marine corps, and 1.36% in the navy; and the period prevalence of SCC was 0.52% in the army, 0.92% in the air force, 0.51% in the marine corps, and 0.97% in the navy.

Comment

This study aimed to provide insight into the burden of skin cancer within the MHS beneficiary population and to identify temporal trends in where these beneficiaries receive their care. We examined patient encounter data from more than 9.6 million MHS beneficiaries.

The utilization of ICD codes from patient encounters to estimate the prevalence of nonmelanoma skin cancer (NMSC) has demonstrated a high positive predictive value. In one study, NMSC cases were confirmed in 96.5% of ICD code–identified patients.⁵ We presented an extensive collection of epidemiologic data on BCC and SCC, which posed unique challenges for tracking, as they are not reported to or monitored by cancer registries such as the Surveillance, Epidemiology, and End Results (SEER) Program.⁶

MHS Compared to the US Population—A study using the Global Burden of Disease 2019 database revealed an increasing trend in the incidence and prevalence of NMSC and melanoma since 1990. The same study found the period prevalence in 2019 of MM, SCC, and BCC in the general US population to be 0.13%, 0.31%, and 0.05%, respectively.⁷ In contrast, among MHS beneficiaries, we observed a higher prevalence in the same year, with figures of 0.66% for MM, 0.72% for SCC, and 1.02% for BCC. According to the SEER database, the period prevalence of MM within the general US population in 2020 was 0.4%.⁸ That same year, we identified a higher period prevalence of MM—0.54%—within the MHS beneficiary population. Specifically, within the MHS retiree population, the prevalence in 2022 was double that of the general MHS population, with a rate of 1.10%, underscoring the importance of skin cancer screening in older, at-risk adult populations. Prior studies similarly found increased rates of skin cancer within the military beneficiary population. Further studies are needed to compare age-adjusted rates in the MHS vs US population.^9-11

COVID-19 Trends—Our data showed an overall decreasing prevalence of skin cancer in the MHS from 2019 to 2021. We suspect that the apparent decrease in skin cancer prevalence may be attributed to underdiagnosis from COVID-19 pandemic restrictions. During that time, many dermatology clinics at military treatment facilities underwent temporary closures, and some dermatologists were sent on nondermatologic utilization tours. Likewise, a US multi-institutional study described declining rates of new melanomas from 2020 to 2021, with an increased proportion of patient presentations with advanced melanoma, suggesting an underdiagnosis of melanoma cases during pandemic restrictions. That study also noted an increased rate of patient-identified melanomas and a decreased rate of provider-identified melanomas during that time.¹² Contributing factors may include excess hospital demand, increased patient complexity and acute care needs, and long outpatient clinic backlogs during this time.¹³Financial Burden—Over our 5-year study period, there were 5,374,348 patient encounters addressing skin cancer, both in DC and PC (Figures 1 and 2; eTable 1). In 2016 to 2018, the average annual cost of treating skin cancer in the US civilian, noninstitutionalized population was $1243 for NMSC (BCC and SCC) and $2430 for melanoma.⁶ Using this metric, the estimated total cost of care rendered in the MHS in 2018 for NMSC and melanoma was $202,510,803 and $156,516,300, respectively.

Trends in DC vs PC—In the years examined, we found a notable decrease in the number of beneficiaries receiving treatment for MM, BCC, and SCC in DC. Simultaneously, there has been an increase in the number of beneficiaries receiving PC for BCC and SCC, though this trend was not apparent for MM.

Our data provided interesting insights into the percentage of PC compared with DC offered within the MHS. Importantly, our findings suggested that the majority of skin cancer in active-duty service members is managed with DC within the military treatment facility setting (61% DC management over the period analyzed). This finding was true across all years of data analyzed, suggesting that the COVID-19 pandemic did not result in a quantifiable shift in care of skin cancer within the active-duty component to outside providers. One of the critical roles of dermatologists in the MHS is to diagnose and treat skin cancer, and our study suggested that the current global manning and staffing for MHS dermatologists may not be sufficient to meet the burden of skin cancers encountered within our active-duty troops, as only 61% are managed with DC. In particular, service members in more austere and/or overseas locations may not have ready access to a dermatologist.

The burden of skin cancer shifts dramatically when analyzing care of all other populations included in these data, including dependents of active-duty service members, retirees, and the category of “other” (ie, principally dependents of retirees). Within these populations, the rate of DC falls to 30%, with 70% of active-duty dependent care being deferred to network. The findings are even more noticeable for retirees and others within these 2 cohorts in all types of skin cancer analyzed, where DC only accounted for 5.2% of those skin cancers encountered and managed across TRICARE-eligible beneficiaries. For MM, BCC, and SCC, percentages of DC were 5.4%, 5.8%, and 3.5%, respectively. Although it is interesting to note the lower percentage of SCC managed via DC, our data did not allow for extrapolation as to why more SCC cases may be deferred to network. The shift to PC may align with DoD initiatives to increase the private sector’s involvement in military medicine and transition to civilianizing the MHS.¹⁴ In the end, the findings are remarkable, with approximately 95% of skin cancer care and management provided overall via PC.

These findings differ from previously published data regarding DC and PC from other specialty areas. Results from an analysis of DC vs PC for plastic surgery for the entire MHS from 2016 to 2019 found 83.2% of cases were deferred to network.¹⁵ A similar publication in the orthopedics literature examined TRICARE claims for patients who underwent total hip or knee arthroplasties between 2006 and 2019 and found 84.6% of cases were referred for PC. Notably, the authors utilized generalized linear models for cost analysis and found that DC was more expensive than PC, though this likely was a result of higher rates of hospital readmission within DC cases.¹⁶ Lastly, an article on the DC vs PC disposition of MHS patients with breast cancer from 2003 to 2008 found 46% of cases managed with DC vs 26.% with PC and 27.8% receiving a combination. In this case, the authors found a reduced cost associated with DC vs PC.¹⁷

Little additional literature exists regarding the costs of DC vs PC. An article published in 2016 designed to assess costs of DC vs PC showed that almost all military treatment facilities have higher costs than their private sector counterparts, with a few exceptions.¹⁸ This does not assess the costs of specific procedures, however, and only the overall cost to maintain a treatment facility. Importantly, this study was based on data from FY 2014 and has not been updated to reflect complex changes within the MHS system and the private health care system. Indeed, a US Government Accountability Office FY 2023 study highlighted staffing and efficiency issues within this transition to civilian medicine; subsequently, the 2024 President’s Budget suspended all planned clinical medical military end strength divestitures, underscoring the potential ineffectiveness of a civilianized MHS at meeting the health care needs of its beneficiaries.^19,20 Future research on a national scale will be necessary to see if there is a reversal of this trend to PC and if doing so has any impact on access to DC for active-duty troops or active-duty dependents.

In addition to PC vs DC trends, we also can get a sense of the impact of the COVID pandemic restrictions on access to DC vs PC by assessing the change in rates seen in the data from the pre-COVID years (2017-2019) to the “post-COVID” years (2020-2022) included. Overall, rates of DC decreased uniformly from their already low percentages. In our study, rates of DC decreased from 5.8% in 2019 to 4.8% in 2022 for MM, from 6.6% to 4.3% for BCC, and from 4.2% to 2.9% for SCC. Although these changes seem small at first, they represent a 30.6% overall decrease in DC for BCC and an overall decrease of 55.4% in DC for SCC. Although our data do not allow us to extrapolate the real cost of this reduction across a nationwide health care system and more than 5 million care encounters, the financial and personal (ie, lost man-hours) costs of this decrease in DC likely are substantial.

In addition to costs, qualitative aspects that contribute to the burden of skin cancer include treatment-related morbidity, such as scarring, pain, and time spent away from family, work, and hobbies, as well as overall patient satisfaction with the quality of care they receive.²¹ Future work is critical to assess the real cost of this immense burden of PC for the treatment and management of skin cancers within the DoD beneficiary population.

Limitations—This study is limited by its observational nature. Given the mechanism of our data collection, we may have underestimated disease prevalence, as not all patients are seen for their diagnosis annually. Furthermore, reported demographic strata (eg, age, sex) were limited to those available and valid in the M2 reporting system. Finally, our study only collected data from those service members or former service members seen within the MHS and does not reflect any care rendered to those who are no longer active duty but did not officially retire from the military (ie, nonretired service members receiving care in the Veterans Affairs system for skin cancer).

Conclusion

We describe the annual burden of care for skin cancer in the MHS beneficiary population. Noteworthy findings observed were an overall decrease in beneficiaries being treated for skin cancer through DC; a decreasing annual prevalence of skin cancer diagnosis between 2019 and 2021, which may represent underdiagnosis or decreased follow-up in the setting of the COVID-19 pandemic; and a higher rate of skin cancer in the military beneficiary population compared to the civilian population.

This retrospective observational study investigates skin cancer prevalence and care patterns within the Military Health System (MHS) from 2017 to 2022. Utilizing the MHS Management Analysis and Reporting Tool (most commonly called M2), we analyzed more than 5 million patient encounters and documented skin cancer prevalence in the MHS beneficiary population utilizing available demographic data. Notable findings included an increased prevalence of skin cancer in the military population compared with the civilian population, a substantial decline in direct care (DC) visits at military treatment facilities compared with civilian purchased care (PC) visits, and a decreased total number of visits during COVID-19 restrictions.

The Military Health System (MHS) is a worldwide health care delivery system that serves 9.6 million beneficiaries, including military service members, retirees, and their families.¹ Its mission is 2-fold: provide a medically ready force, and provide a medical benefit in keeping with the service and sacrifice of active-duty personnel, military retirees, and their families. For fiscal year (FY) 2022, active-duty service members and their families comprised 16.7% and 19.9% of beneficiaries, respectively, while retired service members and their families comprised 27% and 32% of beneficiaries, respectively.

The MHS operates under the authority of the Department of Defense (DoD) and is supported by an annual budget of approximately $50 billion.¹ Health care provision within the MHS is managed by TRICARE regional networks.² Within these networks, MHS beneficiaries may receive health care in 2 categories: direct care (DC) and purchased care (PC). Direct care is rendered in military treatment facilities by military or civilian providers contracted by the DoD, and PC is administered by civilian providers at civilian health care facilities within the TRICARE network, which is comprised of individual providers, clinics, and hospitals that have agreed to accept TRICARE beneficiaries.¹ Purchased care is fee-for-service and paid for by the MHS. Of note, the MHS differs from the Veterans Affairs health care system in that the MHS through DC and PC sees only active-duty service members, active-duty dependents, retirees, and retirees’ dependents (primarily spouses), whereas Veterans Affairs sees only veterans (not necessarily retirees) discharged from military service with compensable medical conditions or disabilities.

Skin cancer presents a notable concern for the US Military, as the risk for skin cancer is thought to be higher than in the general population.^3,4 This elevated risk is attributed to numerous factors inherent to active-duty service, including time spent in tropical environments, increased exposure to UV radiation, time spent at high altitudes, and decreased rates of sun-protective behaviors.³ Although numerous studies have explored the mechanisms that contribute to service members’ increased skin cancer risk, there are few (if any) that discuss the burden of skin cancer on the MHS and where its beneficiaries receive their skin cancer care. This study evaluated the burden of skin cancer within the MHS, as demonstrated by the period prevalence of skin cancer among its beneficiaries and the number and distribution of patient visits for skin cancer across both DC and PC from 2017 to 2022.

Methods

Data Collection—This retrospective observational study was designed to describe trends in outpatient visits with a skin cancer diagnosis and annual prevalence of skin cancer types in the MHS. Data are from all MHS beneficiaries who were eligible or enrolled in the analysis year. Our data source was the MHS Management Analysis and Reporting Tool (most commonly called M2), a query tool that contains the current and most recent 5 full FYs of Defense Health Agency corporate health care data including aggregated FY and calendar-year counts of MHS beneficiaries from 2017 to 2022 using encounter and claims data tables from both DC and PC. Data in M2 are coded using a pseudo-person identification number, and queries performed for this study were limited to de-identified visit and patient counts.

Skin cancer diagnoses were defined by relevant International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes recorded from outpatient visits in DC and PC. The M2 database was queried to find aggregate counts of visits and unique MHS beneficiaries with one or more diagnoses of a skin cancer type of interest (defined by relevant ICD-10-CM code) over the study period stratified by year and by patient demographic characteristics. Skin cancer types by ICD-10-CM code group included basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), and other (including Merkel cell carcinoma and sebaceous carcinoma). Demographic strata included age, sex, military status (active duty, dependents of active duty, retired, or all others), sponsor military rank, and sponsor branch (army, air force, marine corps, or navy). Visit counts included diagnoses from any ICD position (for encounters that contained multiple ICD codes) to describe the total volume of care that addressed a diagnosed skin cancer. Counts of unique patients in prevalence analyses included relevant diagnoses in the primary ICD position only to increase the specificity of prevalence estimates.

Data Analysis—Descriptive analyses included the total number of outpatient visits with a skin cancer diagnosis in DC and PC over the study period, with percentages of total visits by year and by demographic strata. Separate analyses estimated annual prevalences of skin cancer types in the MHS by study year and within 2022 by demographic strata. Numerators in prevalence analyses were defined as the number of unique individuals with one or more relevant ICD codes in the analysis year. Denominators were defined as the total number of MHS beneficiaries in the analysis year and resulting period prevalences reported. Observed prevalences were qualitatively described, and trends were compared with prevalences in nonmilitary populations reported in the literature.

Ethics—This study was conducted as part of a study using secondary analyses of de-identified data from the M2 database. The study was reviewed and approved by the Walter Reed National Military Medical Center institutional review board.

Results

Encounter data were analyzed from a total of 5,374,348 visits between DC and PC over the study period for each cancer type of interest. Figures 1 and 2 show temporal trends in DC visits compared with PC visits in each beneficiary category. The percentage of total DC visits subsequently declined each year throughout the study period, with percentage decreases from 2017 to 2022 of 1.45% or 8200 fewer visits for MM, 3.41% or 7280 fewer visits for BCC, and 2.26% or 3673 fewer visits for SCC.

When stratified by beneficiary category, this trend remained consistent among dependents and retirees, with the most notable annual percentage decrease from 2019 to 2020. A higher proportion of younger adults and active-duty beneficiaries was seen in DC relative to PC, in which most visits were among retirees and others (primarily dependents of retirees, survivors, and Guard/Reserve on active duty, as well as inactive Guard/Reserve). No linear trends over time were apparent for active duty in DC and for dependents and retirees in PC. eTable 1 summarizes the demographic characteristics of MHS beneficiaries being seen in DC and PC over the study period for each cancer type of interest.

The Table shows the period prevalence of skin cancer diagnoses within the MHS beneficiary population from 2017 to 2022. These data were further analyzed by MM, BCC, and SCC (eTable 2) and demographics of interest for the year 2022. By beneficiary category, the period prevalence of MM was 0.08% in active duty, 0.06% in dependents, 0.48% in others, and 1.10% in retirees; the period prevalence of BCC was 0.12% in active duty, 0.07% in dependents, 0.91% in others, and 2.50% in retirees; and the period prevalence of SCC was 0.02% in active duty, 0.01% in dependents, 0.63% in others, and 1.87% in retirees. By sponsor branch, the period prevalence of MM was 0.35% in the army, 0.62% in the air force, 0.35% in the marine corps, and 0.65% in the navy; the period prevalence of BCC was 0.74% in the army, 1.30% in the air force, 0.74% in the marine corps, and 1.36% in the navy; and the period prevalence of SCC was 0.52% in the army, 0.92% in the air force, 0.51% in the marine corps, and 0.97% in the navy.

Comment

This study aimed to provide insight into the burden of skin cancer within the MHS beneficiary population and to identify temporal trends in where these beneficiaries receive their care. We examined patient encounter data from more than 9.6 million MHS beneficiaries.

The utilization of ICD codes from patient encounters to estimate the prevalence of nonmelanoma skin cancer (NMSC) has demonstrated a high positive predictive value. In one study, NMSC cases were confirmed in 96.5% of ICD code–identified patients.⁵ We presented an extensive collection of epidemiologic data on BCC and SCC, which posed unique challenges for tracking, as they are not reported to or monitored by cancer registries such as the Surveillance, Epidemiology, and End Results (SEER) Program.⁶

MHS Compared to the US Population—A study using the Global Burden of Disease 2019 database revealed an increasing trend in the incidence and prevalence of NMSC and melanoma since 1990. The same study found the period prevalence in 2019 of MM, SCC, and BCC in the general US population to be 0.13%, 0.31%, and 0.05%, respectively.⁷ In contrast, among MHS beneficiaries, we observed a higher prevalence in the same year, with figures of 0.66% for MM, 0.72% for SCC, and 1.02% for BCC. According to the SEER database, the period prevalence of MM within the general US population in 2020 was 0.4%.⁸ That same year, we identified a higher period prevalence of MM—0.54%—within the MHS beneficiary population. Specifically, within the MHS retiree population, the prevalence in 2022 was double that of the general MHS population, with a rate of 1.10%, underscoring the importance of skin cancer screening in older, at-risk adult populations. Prior studies similarly found increased rates of skin cancer within the military beneficiary population. Further studies are needed to compare age-adjusted rates in the MHS vs US population.^9-11

COVID-19 Trends—Our data showed an overall decreasing prevalence of skin cancer in the MHS from 2019 to 2021. We suspect that the apparent decrease in skin cancer prevalence may be attributed to underdiagnosis from COVID-19 pandemic restrictions. During that time, many dermatology clinics at military treatment facilities underwent temporary closures, and some dermatologists were sent on nondermatologic utilization tours. Likewise, a US multi-institutional study described declining rates of new melanomas from 2020 to 2021, with an increased proportion of patient presentations with advanced melanoma, suggesting an underdiagnosis of melanoma cases during pandemic restrictions. That study also noted an increased rate of patient-identified melanomas and a decreased rate of provider-identified melanomas during that time.¹² Contributing factors may include excess hospital demand, increased patient complexity and acute care needs, and long outpatient clinic backlogs during this time.¹³Financial Burden—Over our 5-year study period, there were 5,374,348 patient encounters addressing skin cancer, both in DC and PC (Figures 1 and 2; eTable 1). In 2016 to 2018, the average annual cost of treating skin cancer in the US civilian, noninstitutionalized population was $1243 for NMSC (BCC and SCC) and $2430 for melanoma.⁶ Using this metric, the estimated total cost of care rendered in the MHS in 2018 for NMSC and melanoma was $202,510,803 and $156,516,300, respectively.

Trends in DC vs PC—In the years examined, we found a notable decrease in the number of beneficiaries receiving treatment for MM, BCC, and SCC in DC. Simultaneously, there has been an increase in the number of beneficiaries receiving PC for BCC and SCC, though this trend was not apparent for MM.

Our data provided interesting insights into the percentage of PC compared with DC offered within the MHS. Importantly, our findings suggested that the majority of skin cancer in active-duty service members is managed with DC within the military treatment facility setting (61% DC management over the period analyzed). This finding was true across all years of data analyzed, suggesting that the COVID-19 pandemic did not result in a quantifiable shift in care of skin cancer within the active-duty component to outside providers. One of the critical roles of dermatologists in the MHS is to diagnose and treat skin cancer, and our study suggested that the current global manning and staffing for MHS dermatologists may not be sufficient to meet the burden of skin cancers encountered within our active-duty troops, as only 61% are managed with DC. In particular, service members in more austere and/or overseas locations may not have ready access to a dermatologist.

The burden of skin cancer shifts dramatically when analyzing care of all other populations included in these data, including dependents of active-duty service members, retirees, and the category of “other” (ie, principally dependents of retirees). Within these populations, the rate of DC falls to 30%, with 70% of active-duty dependent care being deferred to network. The findings are even more noticeable for retirees and others within these 2 cohorts in all types of skin cancer analyzed, where DC only accounted for 5.2% of those skin cancers encountered and managed across TRICARE-eligible beneficiaries. For MM, BCC, and SCC, percentages of DC were 5.4%, 5.8%, and 3.5%, respectively. Although it is interesting to note the lower percentage of SCC managed via DC, our data did not allow for extrapolation as to why more SCC cases may be deferred to network. The shift to PC may align with DoD initiatives to increase the private sector’s involvement in military medicine and transition to civilianizing the MHS.¹⁴ In the end, the findings are remarkable, with approximately 95% of skin cancer care and management provided overall via PC.

These findings differ from previously published data regarding DC and PC from other specialty areas. Results from an analysis of DC vs PC for plastic surgery for the entire MHS from 2016 to 2019 found 83.2% of cases were deferred to network.¹⁵ A similar publication in the orthopedics literature examined TRICARE claims for patients who underwent total hip or knee arthroplasties between 2006 and 2019 and found 84.6% of cases were referred for PC. Notably, the authors utilized generalized linear models for cost analysis and found that DC was more expensive than PC, though this likely was a result of higher rates of hospital readmission within DC cases.¹⁶ Lastly, an article on the DC vs PC disposition of MHS patients with breast cancer from 2003 to 2008 found 46% of cases managed with DC vs 26.% with PC and 27.8% receiving a combination. In this case, the authors found a reduced cost associated with DC vs PC.¹⁷

Little additional literature exists regarding the costs of DC vs PC. An article published in 2016 designed to assess costs of DC vs PC showed that almost all military treatment facilities have higher costs than their private sector counterparts, with a few exceptions.¹⁸ This does not assess the costs of specific procedures, however, and only the overall cost to maintain a treatment facility. Importantly, this study was based on data from FY 2014 and has not been updated to reflect complex changes within the MHS system and the private health care system. Indeed, a US Government Accountability Office FY 2023 study highlighted staffing and efficiency issues within this transition to civilian medicine; subsequently, the 2024 President’s Budget suspended all planned clinical medical military end strength divestitures, underscoring the potential ineffectiveness of a civilianized MHS at meeting the health care needs of its beneficiaries.^19,20 Future research on a national scale will be necessary to see if there is a reversal of this trend to PC and if doing so has any impact on access to DC for active-duty troops or active-duty dependents.

In addition to PC vs DC trends, we also can get a sense of the impact of the COVID pandemic restrictions on access to DC vs PC by assessing the change in rates seen in the data from the pre-COVID years (2017-2019) to the “post-COVID” years (2020-2022) included. Overall, rates of DC decreased uniformly from their already low percentages. In our study, rates of DC decreased from 5.8% in 2019 to 4.8% in 2022 for MM, from 6.6% to 4.3% for BCC, and from 4.2% to 2.9% for SCC. Although these changes seem small at first, they represent a 30.6% overall decrease in DC for BCC and an overall decrease of 55.4% in DC for SCC. Although our data do not allow us to extrapolate the real cost of this reduction across a nationwide health care system and more than 5 million care encounters, the financial and personal (ie, lost man-hours) costs of this decrease in DC likely are substantial.

In addition to costs, qualitative aspects that contribute to the burden of skin cancer include treatment-related morbidity, such as scarring, pain, and time spent away from family, work, and hobbies, as well as overall patient satisfaction with the quality of care they receive.²¹ Future work is critical to assess the real cost of this immense burden of PC for the treatment and management of skin cancers within the DoD beneficiary population.

Limitations—This study is limited by its observational nature. Given the mechanism of our data collection, we may have underestimated disease prevalence, as not all patients are seen for their diagnosis annually. Furthermore, reported demographic strata (eg, age, sex) were limited to those available and valid in the M2 reporting system. Finally, our study only collected data from those service members or former service members seen within the MHS and does not reflect any care rendered to those who are no longer active duty but did not officially retire from the military (ie, nonretired service members receiving care in the Veterans Affairs system for skin cancer).

Conclusion

We describe the annual burden of care for skin cancer in the MHS beneficiary population. Noteworthy findings observed were an overall decrease in beneficiaries being treated for skin cancer through DC; a decreasing annual prevalence of skin cancer diagnosis between 2019 and 2021, which may represent underdiagnosis or decreased follow-up in the setting of the COVID-19 pandemic; and a higher rate of skin cancer in the military beneficiary population compared to the civilian population.

This retrospective observational study investigates skin cancer prevalence and care patterns within the Military Health System (MHS) from 2017 to 2022. Utilizing the MHS Management Analysis and Reporting Tool (most commonly called M2), we analyzed more than 5 million patient encounters and documented skin cancer prevalence in the MHS beneficiary population utilizing available demographic data. Notable findings included an increased prevalence of skin cancer in the military population compared with the civilian population, a substantial decline in direct care (DC) visits at military treatment facilities compared with civilian purchased care (PC) visits, and a decreased total number of visits during COVID-19 restrictions.

The Military Health System (MHS) is a worldwide health care delivery system that serves 9.6 million beneficiaries, including military service members, retirees, and their families.¹ Its mission is 2-fold: provide a medically ready force, and provide a medical benefit in keeping with the service and sacrifice of active-duty personnel, military retirees, and their families. For fiscal year (FY) 2022, active-duty service members and their families comprised 16.7% and 19.9% of beneficiaries, respectively, while retired service members and their families comprised 27% and 32% of beneficiaries, respectively.

The MHS operates under the authority of the Department of Defense (DoD) and is supported by an annual budget of approximately $50 billion.¹ Health care provision within the MHS is managed by TRICARE regional networks.² Within these networks, MHS beneficiaries may receive health care in 2 categories: direct care (DC) and purchased care (PC). Direct care is rendered in military treatment facilities by military or civilian providers contracted by the DoD, and PC is administered by civilian providers at civilian health care facilities within the TRICARE network, which is comprised of individual providers, clinics, and hospitals that have agreed to accept TRICARE beneficiaries.¹ Purchased care is fee-for-service and paid for by the MHS. Of note, the MHS differs from the Veterans Affairs health care system in that the MHS through DC and PC sees only active-duty service members, active-duty dependents, retirees, and retirees’ dependents (primarily spouses), whereas Veterans Affairs sees only veterans (not necessarily retirees) discharged from military service with compensable medical conditions or disabilities.

Skin cancer presents a notable concern for the US Military, as the risk for skin cancer is thought to be higher than in the general population.^3,4 This elevated risk is attributed to numerous factors inherent to active-duty service, including time spent in tropical environments, increased exposure to UV radiation, time spent at high altitudes, and decreased rates of sun-protective behaviors.³ Although numerous studies have explored the mechanisms that contribute to service members’ increased skin cancer risk, there are few (if any) that discuss the burden of skin cancer on the MHS and where its beneficiaries receive their skin cancer care. This study evaluated the burden of skin cancer within the MHS, as demonstrated by the period prevalence of skin cancer among its beneficiaries and the number and distribution of patient visits for skin cancer across both DC and PC from 2017 to 2022.

Methods

Data Collection—This retrospective observational study was designed to describe trends in outpatient visits with a skin cancer diagnosis and annual prevalence of skin cancer types in the MHS. Data are from all MHS beneficiaries who were eligible or enrolled in the analysis year. Our data source was the MHS Management Analysis and Reporting Tool (most commonly called M2), a query tool that contains the current and most recent 5 full FYs of Defense Health Agency corporate health care data including aggregated FY and calendar-year counts of MHS beneficiaries from 2017 to 2022 using encounter and claims data tables from both DC and PC. Data in M2 are coded using a pseudo-person identification number, and queries performed for this study were limited to de-identified visit and patient counts.

Skin cancer diagnoses were defined by relevant International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes recorded from outpatient visits in DC and PC. The M2 database was queried to find aggregate counts of visits and unique MHS beneficiaries with one or more diagnoses of a skin cancer type of interest (defined by relevant ICD-10-CM code) over the study period stratified by year and by patient demographic characteristics. Skin cancer types by ICD-10-CM code group included basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), and other (including Merkel cell carcinoma and sebaceous carcinoma). Demographic strata included age, sex, military status (active duty, dependents of active duty, retired, or all others), sponsor military rank, and sponsor branch (army, air force, marine corps, or navy). Visit counts included diagnoses from any ICD position (for encounters that contained multiple ICD codes) to describe the total volume of care that addressed a diagnosed skin cancer. Counts of unique patients in prevalence analyses included relevant diagnoses in the primary ICD position only to increase the specificity of prevalence estimates.

Data Analysis—Descriptive analyses included the total number of outpatient visits with a skin cancer diagnosis in DC and PC over the study period, with percentages of total visits by year and by demographic strata. Separate analyses estimated annual prevalences of skin cancer types in the MHS by study year and within 2022 by demographic strata. Numerators in prevalence analyses were defined as the number of unique individuals with one or more relevant ICD codes in the analysis year. Denominators were defined as the total number of MHS beneficiaries in the analysis year and resulting period prevalences reported. Observed prevalences were qualitatively described, and trends were compared with prevalences in nonmilitary populations reported in the literature.

Ethics—This study was conducted as part of a study using secondary analyses of de-identified data from the M2 database. The study was reviewed and approved by the Walter Reed National Military Medical Center institutional review board.

Results

Encounter data were analyzed from a total of 5,374,348 visits between DC and PC over the study period for each cancer type of interest. Figures 1 and 2 show temporal trends in DC visits compared with PC visits in each beneficiary category. The percentage of total DC visits subsequently declined each year throughout the study period, with percentage decreases from 2017 to 2022 of 1.45% or 8200 fewer visits for MM, 3.41% or 7280 fewer visits for BCC, and 2.26% or 3673 fewer visits for SCC.

When stratified by beneficiary category, this trend remained consistent among dependents and retirees, with the most notable annual percentage decrease from 2019 to 2020. A higher proportion of younger adults and active-duty beneficiaries was seen in DC relative to PC, in which most visits were among retirees and others (primarily dependents of retirees, survivors, and Guard/Reserve on active duty, as well as inactive Guard/Reserve). No linear trends over time were apparent for active duty in DC and for dependents and retirees in PC. eTable 1 summarizes the demographic characteristics of MHS beneficiaries being seen in DC and PC over the study period for each cancer type of interest.

The Table shows the period prevalence of skin cancer diagnoses within the MHS beneficiary population from 2017 to 2022. These data were further analyzed by MM, BCC, and SCC (eTable 2) and demographics of interest for the year 2022. By beneficiary category, the period prevalence of MM was 0.08% in active duty, 0.06% in dependents, 0.48% in others, and 1.10% in retirees; the period prevalence of BCC was 0.12% in active duty, 0.07% in dependents, 0.91% in others, and 2.50% in retirees; and the period prevalence of SCC was 0.02% in active duty, 0.01% in dependents, 0.63% in others, and 1.87% in retirees. By sponsor branch, the period prevalence of MM was 0.35% in the army, 0.62% in the air force, 0.35% in the marine corps, and 0.65% in the navy; the period prevalence of BCC was 0.74% in the army, 1.30% in the air force, 0.74% in the marine corps, and 1.36% in the navy; and the period prevalence of SCC was 0.52% in the army, 0.92% in the air force, 0.51% in the marine corps, and 0.97% in the navy.

Comment

This study aimed to provide insight into the burden of skin cancer within the MHS beneficiary population and to identify temporal trends in where these beneficiaries receive their care. We examined patient encounter data from more than 9.6 million MHS beneficiaries.

The utilization of ICD codes from patient encounters to estimate the prevalence of nonmelanoma skin cancer (NMSC) has demonstrated a high positive predictive value. In one study, NMSC cases were confirmed in 96.5% of ICD code–identified patients.⁵ We presented an extensive collection of epidemiologic data on BCC and SCC, which posed unique challenges for tracking, as they are not reported to or monitored by cancer registries such as the Surveillance, Epidemiology, and End Results (SEER) Program.⁶

MHS Compared to the US Population—A study using the Global Burden of Disease 2019 database revealed an increasing trend in the incidence and prevalence of NMSC and melanoma since 1990. The same study found the period prevalence in 2019 of MM, SCC, and BCC in the general US population to be 0.13%, 0.31%, and 0.05%, respectively.⁷ In contrast, among MHS beneficiaries, we observed a higher prevalence in the same year, with figures of 0.66% for MM, 0.72% for SCC, and 1.02% for BCC. According to the SEER database, the period prevalence of MM within the general US population in 2020 was 0.4%.⁸ That same year, we identified a higher period prevalence of MM—0.54%—within the MHS beneficiary population. Specifically, within the MHS retiree population, the prevalence in 2022 was double that of the general MHS population, with a rate of 1.10%, underscoring the importance of skin cancer screening in older, at-risk adult populations. Prior studies similarly found increased rates of skin cancer within the military beneficiary population. Further studies are needed to compare age-adjusted rates in the MHS vs US population.^9-11

COVID-19 Trends—Our data showed an overall decreasing prevalence of skin cancer in the MHS from 2019 to 2021. We suspect that the apparent decrease in skin cancer prevalence may be attributed to underdiagnosis from COVID-19 pandemic restrictions. During that time, many dermatology clinics at military treatment facilities underwent temporary closures, and some dermatologists were sent on nondermatologic utilization tours. Likewise, a US multi-institutional study described declining rates of new melanomas from 2020 to 2021, with an increased proportion of patient presentations with advanced melanoma, suggesting an underdiagnosis of melanoma cases during pandemic restrictions. That study also noted an increased rate of patient-identified melanomas and a decreased rate of provider-identified melanomas during that time.¹² Contributing factors may include excess hospital demand, increased patient complexity and acute care needs, and long outpatient clinic backlogs during this time.¹³Financial Burden—Over our 5-year study period, there were 5,374,348 patient encounters addressing skin cancer, both in DC and PC (Figures 1 and 2; eTable 1). In 2016 to 2018, the average annual cost of treating skin cancer in the US civilian, noninstitutionalized population was $1243 for NMSC (BCC and SCC) and $2430 for melanoma.⁶ Using this metric, the estimated total cost of care rendered in the MHS in 2018 for NMSC and melanoma was $202,510,803 and $156,516,300, respectively.

Trends in DC vs PC—In the years examined, we found a notable decrease in the number of beneficiaries receiving treatment for MM, BCC, and SCC in DC. Simultaneously, there has been an increase in the number of beneficiaries receiving PC for BCC and SCC, though this trend was not apparent for MM.

Our data provided interesting insights into the percentage of PC compared with DC offered within the MHS. Importantly, our findings suggested that the majority of skin cancer in active-duty service members is managed with DC within the military treatment facility setting (61% DC management over the period analyzed). This finding was true across all years of data analyzed, suggesting that the COVID-19 pandemic did not result in a quantifiable shift in care of skin cancer within the active-duty component to outside providers. One of the critical roles of dermatologists in the MHS is to diagnose and treat skin cancer, and our study suggested that the current global manning and staffing for MHS dermatologists may not be sufficient to meet the burden of skin cancers encountered within our active-duty troops, as only 61% are managed with DC. In particular, service members in more austere and/or overseas locations may not have ready access to a dermatologist.

The burden of skin cancer shifts dramatically when analyzing care of all other populations included in these data, including dependents of active-duty service members, retirees, and the category of “other” (ie, principally dependents of retirees). Within these populations, the rate of DC falls to 30%, with 70% of active-duty dependent care being deferred to network. The findings are even more noticeable for retirees and others within these 2 cohorts in all types of skin cancer analyzed, where DC only accounted for 5.2% of those skin cancers encountered and managed across TRICARE-eligible beneficiaries. For MM, BCC, and SCC, percentages of DC were 5.4%, 5.8%, and 3.5%, respectively. Although it is interesting to note the lower percentage of SCC managed via DC, our data did not allow for extrapolation as to why more SCC cases may be deferred to network. The shift to PC may align with DoD initiatives to increase the private sector’s involvement in military medicine and transition to civilianizing the MHS.¹⁴ In the end, the findings are remarkable, with approximately 95% of skin cancer care and management provided overall via PC.

These findings differ from previously published data regarding DC and PC from other specialty areas. Results from an analysis of DC vs PC for plastic surgery for the entire MHS from 2016 to 2019 found 83.2% of cases were deferred to network.¹⁵ A similar publication in the orthopedics literature examined TRICARE claims for patients who underwent total hip or knee arthroplasties between 2006 and 2019 and found 84.6% of cases were referred for PC. Notably, the authors utilized generalized linear models for cost analysis and found that DC was more expensive than PC, though this likely was a result of higher rates of hospital readmission within DC cases.¹⁶ Lastly, an article on the DC vs PC disposition of MHS patients with breast cancer from 2003 to 2008 found 46% of cases managed with DC vs 26.% with PC and 27.8% receiving a combination. In this case, the authors found a reduced cost associated with DC vs PC.¹⁷

Little additional literature exists regarding the costs of DC vs PC. An article published in 2016 designed to assess costs of DC vs PC showed that almost all military treatment facilities have higher costs than their private sector counterparts, with a few exceptions.¹⁸ This does not assess the costs of specific procedures, however, and only the overall cost to maintain a treatment facility. Importantly, this study was based on data from FY 2014 and has not been updated to reflect complex changes within the MHS system and the private health care system. Indeed, a US Government Accountability Office FY 2023 study highlighted staffing and efficiency issues within this transition to civilian medicine; subsequently, the 2024 President’s Budget suspended all planned clinical medical military end strength divestitures, underscoring the potential ineffectiveness of a civilianized MHS at meeting the health care needs of its beneficiaries.^19,20 Future research on a national scale will be necessary to see if there is a reversal of this trend to PC and if doing so has any impact on access to DC for active-duty troops or active-duty dependents.

In addition to PC vs DC trends, we also can get a sense of the impact of the COVID pandemic restrictions on access to DC vs PC by assessing the change in rates seen in the data from the pre-COVID years (2017-2019) to the “post-COVID” years (2020-2022) included. Overall, rates of DC decreased uniformly from their already low percentages. In our study, rates of DC decreased from 5.8% in 2019 to 4.8% in 2022 for MM, from 6.6% to 4.3% for BCC, and from 4.2% to 2.9% for SCC. Although these changes seem small at first, they represent a 30.6% overall decrease in DC for BCC and an overall decrease of 55.4% in DC for SCC. Although our data do not allow us to extrapolate the real cost of this reduction across a nationwide health care system and more than 5 million care encounters, the financial and personal (ie, lost man-hours) costs of this decrease in DC likely are substantial.

In addition to costs, qualitative aspects that contribute to the burden of skin cancer include treatment-related morbidity, such as scarring, pain, and time spent away from family, work, and hobbies, as well as overall patient satisfaction with the quality of care they receive.²¹ Future work is critical to assess the real cost of this immense burden of PC for the treatment and management of skin cancers within the DoD beneficiary population.

Limitations—This study is limited by its observational nature. Given the mechanism of our data collection, we may have underestimated disease prevalence, as not all patients are seen for their diagnosis annually. Furthermore, reported demographic strata (eg, age, sex) were limited to those available and valid in the M2 reporting system. Finally, our study only collected data from those service members or former service members seen within the MHS and does not reflect any care rendered to those who are no longer active duty but did not officially retire from the military (ie, nonretired service members receiving care in the Veterans Affairs system for skin cancer).

Conclusion

We describe the annual burden of care for skin cancer in the MHS beneficiary population. Noteworthy findings observed were an overall decrease in beneficiaries being treated for skin cancer through DC; a decreasing annual prevalence of skin cancer diagnosis between 2019 and 2021, which may represent underdiagnosis or decreased follow-up in the setting of the COVID-19 pandemic; and a higher rate of skin cancer in the military beneficiary population compared to the civilian population.

Angiosarcomas are aggressive endothelial cell tumors of vascular origin that account for 1% to 2% of all soft tissue sarcomas in the United States.^1,2 They can affect any organ in the body but most commonly affect the skin and soft tissue. Cutaneous angiosarcoma (CAS) is a rare type of skin cancer that can present in 2 forms: primary and secondary. The primary form lacks a known underlying cause, but secondary CAS commonly is linked to prior radiation therapy of the breast as well as lymphedema of the breast and arm. Secondary CAS may require different treatment than primary CAS, as radiation therapy poses risks to patients with radiation-induced CAS.³ The prognosis of CAS is poor due to delayed diagnosis. Current treatment modalities have a high rate of local recurrence and/or distant metastasis, but recent advances in surgery and other therapies such as radiation and immunotherapy provide hope for more successful disease control.

Dermatologists may be responsible for the initial diagnosis and management of CAS. They must be familiar with its presentation, as this condition can be difficult to diagnose and mimics other diseases. Additionally, dermatologists must understand the role of varying treatment modalities including Mohs micrographic surgery (MMS) in the management of CAS. This review will provide an overview of the epidemiology, presentation, and pathologic features of CAS and will discuss both emerging and existing treatments.

Epidemiology

Cutaneous angiosarcoma may present in various locations in the body, predominantly on the head and neck.^4,5 Approximately 85% of cases arise in patients older than 60 years, and most of these patients are White men.^1,4,5 The risk factors for the development of CAS include prior radiation exposure; chronic lymphedema (ie, Stewart-Treves syndrome); and familial syndromes including neurofibromatosis 1, BRCA1 or BRCA2 mutations, Maffucci syndrome, and Klippel-Trenaunay syndrome. Exogenous exposure to toxins such as vinyl chloride, thorium dioxide, or anabolic steroids also is associated with angiosarcoma, primarily in the form of visceral disease such as hepatic angiosarcoma.⁶

The average tumor size is approximately 4 to 5 cm; however, some tumors may grow larger than 10 cm.^7,8 Metastasis through hematogenous or lymphatic spread is fairly common, occurring in approximately 16% to 35% of patients. The lungs and liver are the most common sites of metastasis.^9,10 The age-adjusted incidence rate of CAS is decreasing for patients younger than 50 years, from 1.30 in 1995 to 2004 to 1.10 in 2005 to 2014, but increasing for individuals older than 70 years, from 2.53 in 1995 to 2004 to 2.87 in 2005 to 2014.⁴ The incidence of angiosarcoma also has grown in the female population, likely due to the increasing use of radiotherapy for the treatment of breast cancer.¹¹

The high rates of CAS on the head and neck may be explained by the increased vascularity and UV exposure in these locations.¹² In a Surveillance, Epidemiology, and End Results population-based study (N=811), 43% of patients with CAS had a history of other malignancies such as breast, prostate, genitourinary, gastrointestinal tract, and respiratory tract cancers.⁴ Cutaneous angiosarcoma can develop secondary to the primary cancer treatment, as seen in patients who develop CAS following radiation therapy.¹¹

The underlying mechanism of CAS is believed to involve dysregulation of angiogenesis due to the vascular origin of these tumors. Studies have identified overexpression of vascular endothelial growth factor (VEGF), TP53 mutations, and RAS pathway mutations as potential contributing factors to the pathogenesis of angiosarcoma.⁶ Molecular differences between primary and secondary angiosarcomas are not well documented; however, radiation-associated CAS has been found to have higher expression of LYN and PRKCΘ, while non–radiation-induced lesions express FTL1 and AKT3.² Chromosomal abnormalities have been identified in a small set of primary CAS patients, but the specific role of these abnormalities in the pathogenesis of CAS remains unclear.⁷

Prognosis

Cutaneous angiosarcoma has a poor prognosis, with 3-year disease-specific survival rates as low as 40% and 5-year rates as low as 17%.^4,5,13,14 Survival rates increased from 1985 to 2014, likely due to earlier diagnoses and more effective treatments.⁴ Several factors are associated with worse prognosis, including metastatic disease, increasing age, scalp and neck tumor location, tumor size greater than 5 cm, necrosis, multiple skin lesions, and nodular and epithelioid morphology.^4,5,10,13-16 Factors including sex, race, and presence of another malignancy do not affect survival.^4,5 Prognosis in CAS may be evaluated by TNM tumor staging. The American Joint Committee on Cancer Staging Manual (8th edition) for soft tissue sarcoma (STS) commonly is used; however, CAS is not included in this staging system because it does not share the same behavior and natural history as other types of STS. This staging system provides separate guidelines for STS of the head and neck and STS of the extremities and trunk because of the smaller size but paradoxically higher risk for head and neck tumors.¹⁷ Given that there is no agreed-upon staging system for CAS, prognosis and communication among providers may be complicated.

Early CAS typically presents as single or multifocal ill-defined, enlarging, violaceous or dusky red macules or patches (Figure 1). Lesions often rapidly develop into raised nodules and plaques that may bleed and ulcerate. Other common symptoms include pain, edema, neuropathy, anemia, and weight loss; however, it is not uncommon for lesions to be asymptomatic.^8,18-20 Nodular lesions are more common on the scalp, and patches are more common on the face and neck.¹⁶ Tumors typically extend into the dermis, and aggressive cancers may invade the subcutaneous tissue and fascia.²

Cutaneous angiosarcoma may mimic ecchymosis, hemangioma, lymphangioma, edema, cellulitis, or scarring alopecia. Its nonspecific features make it difficult to recognize without dermoscopy or ultrasonography, which often results in delayed diagnosis and treatment. The median delay typically is 5 to 7 months and up to 1 year for some patients.^7,16 Cutaneous angiosarcoma of the scalp tends to have a longer diagnostic delay than other areas of the body, which may be attributable to challenges in tumor identification and visualization by patients.¹⁶

Dermoscopy and ultrasonography can aid in the diagnosis of CAS. Dermoscopy may demonstrate a range of colors with yellow, brown, or red areas in a violaceous background. Other reported features include white veils and lines, purple ovals, pink-purple “steamlike” areas, and atypical vessels (Figure 2).^21-23 Dermoscopic findings may appear similar to other vascular tumors, such as hemangioma and Kaposi sarcoma, or nonvascular tumors, including amelanotic melanoma, Merkel cell carcinoma, and primary cutaneous B-cell lymphoma. Ultrasonography may show ill-defined, hypoechoic areas with anechoic reticular channels and a hypoechoic subepidermal layer.²¹ Other radiologic modalities, such as computed tomography, magnetic resonance imaging, or positron emission tomography, are nonspecific and are more useful in evaluating the extent of tumor spread in visceral angiosarcoma. Magnetic resonance imaging in CAS may indicate malignancy with the presence of high T2 and T1 signal intensity and high-flow serpentine vessels.²⁴

Histopathology

Histologically, angiosarcoma is characterized by anastomosing irregular vascular channels lined by a single layer of endothelial cells displaying slight to moderate atypia.²⁵ These vascular channels dissect between collagen bundles and adipocytes. Monocyte infiltration may be observed.⁶ The neoplastic endothelial cells may present as spindle-shaped, round, polygonal, or epithelioid with eosinophilic cytoplasm. Histologic features differ based on the type of clinical lesion (Figure 3). In a study of CAS in Asian populations, nodular tumors showed solid sheets of pleomorphic spindle cells, many mitotic figures, and widely hemorrhagic spaces, whereas nonnodular tumors showed irregular vascular spaces dissecting collagen.¹⁶ Poorly differentiated tumors may present with hyperchromatic nuclei and prominent nucleoli, papillary endothelial formations, mitoses, and possible hemorrhage or necrosis.^2,6,8 Histologic specimens also may reveal calcified bodies and hemosiderin particles.¹⁹ Angiosarcomas typically are invasive without a clear capsule or border.⁶

Photograph courtesy of Kim HooKim, MD (Camden, New Jersey).

Secondary CAS in the setting of lymphedema and radiation therapy has MYC amplification and is positive for MYC via immunohistochemistry, which is uncommon in primary angiosarcoma.²⁶ Immunohistochemical staining of tumor specimens is helpful to confirm the diagnosis of CAS. These markers include CD31, CD34, CD117, cytokeratin, vimentin, epithelial membrane antigen, factor VIII–related antigen, Ulex europaeus agglutinin-1, von Willebrand factor, and VEGF.^6,19,27,28 Notably, advanced angiosarcomas with progressive dedifferentiation often lose these markers.

Treatment

Surgery—The majority of patients treated for CAS undergo surgical resection, as surgery has been shown to have the best prognosis for patients.^5,9,10,13,15 Achieving R0 resection (microscopically negative margins) is the most important factor in determining the success of treatment, with incomplete surgical resection resulting in higher rates of systemic and local spread.²⁹ Abraham et al⁸ found that the median disease-specific survival of patients with microscopically negative margins was 83.7 months; patients with microscopically positive and grossly positive margins had median disease-specific survival of 63.4 and 18.1 months, respectively. In a case series of patients undergoing resection with negative surgical margins, 4 patients demonstrated no evidence of local recurrence or systemic disease at an average of 4.3 years after therapy, and the other 4 patients each had 1 local recurrence but were disease free an average of 4.8 years after removal of the recurrent lesion. In a series of 27 patients with positive surgical margins, there was local recurrence within 2 years for most patients.¹²

Large tumors invading nearby structures may not be amenable to surgical resection because of extensive local growth, propensity for skip lesions, and localization near vital organs of the head and neck.^5,7 The extended delay in diagnosis often seen in CAS allows for advanced local progression, resulting in large areas of resection. In a case series (N=8), the average surgical defect measured 14.3×11.8 cm, necessitating reconstruction with either a tissue flap or split-thickness skin graft in every case because primary closure was not possible. More than 80% of patients in this study still had positive margins after surgery, necessitating the use of additional chemotherapy or radiation to eradicate remaining disease.⁷ In several studies, multimodality therapy was associated with improved overall survival.^7,14,30

Mohs Micrographic Surgery—Mohs micrographic surgery is the standard of care for many aggressive cutaneous malignancies on the head, but its utility for the treatment of CAS is uncertain. Only a few studies have compared the efficacy of MMS vs wide local excision (WLE). There have been reports of recurrence-free follow-up at 12, 16, 18, 20, and 72 months after MMS.^31-36 The latter case showed a patient who underwent MMS with a 72-month relapse-free survival, whereas other patients who underwent WLE only survived 5 to 7 months without recurrence.³⁶ In another study, there was a local recurrence rate of 42.9% after a median follow-up of 4 years in 7 patients with CAS treated with complete circumferential peripheral and deep margin assessment, which is less than the reported recurrence rates of 72% to 84% after standard excisional procedures.^28,37

Houpe et al³⁸ conducted a systematic review of the use of WLE vs MMS; the median overall survival was longest for WLE in conjunction with chemotherapy, radiotherapy, and immunotherapy at 39.3 months, followed by MMS alone at 37 months. Mohs micrographic surgery in conjunction with chemotherapy and radiotherapy was used in 1 patient, with a median overall survival of 82 months. Wide local excision alone resulted in a median overall survival of 19.8 months. Although these data are promising and suggest that the combination of surgery with adjuvant therapy may be more beneficial than surgery alone, it is important to note that there were only 9 cases treated with MMS compared with 825 cases treated with WLE.³⁸

Several studies have documented that paraffin-embedded sections may be more useful than frozen sections in the determination of margin positivity from a surgical specimen, as frozen sections showed a poor negative predictive value of 33.3%.^7,35 Mohs micrographic surgery has been proposed for tumors measuring less than 5 cm; however, the most recent appropriate use criteria for MMS of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery deemed the use of MMS for angiosarcoma uncertain.^32,33,37 Further research is necessary to elucidate the role of MMS in the management of CAS.

Radiotherapy—Radiotherapy is a common adjuvant to surgical resection but has been used palliatively in patients with tumors that are unresectable. Improved local control and disease-free survival have been observed with the combination of radiation and surgery. A dose response to radiotherapy has been demonstrated,^18,30 with 1 study showing that patients who received more than 5000 cGy of radiotherapy achieved better local control than patients who received 4500 cGy or less.¹⁸ Pawlik et al⁷ showed a decreased chance of death with the addition of adjunctive radiotherapy, and patients who underwent postoperative radiotherapy demonstrated a median survival almost 4-times longer than patients who did not receive radiation. Morrison et al³⁹ reported that radiation therapy administered to patients with no clinically evident disease after surgical resection resulted in improved local control and overall survival vs patients who were irradiated with clinically evident disease.

Complications of radiotherapy for angiosarcoma have been reported, including xerostomia, nonfunctionally significant fibrosis, chronic ulceration/cellulitis of the scalp, necrosis requiring debridement, severe ocular complications, and fibrosis of the eyelids requiring surgical intervention.¹⁴ Radiation therapy also poses unique risks to patients with radiation-induced angiosarcoma of the breast, as many of these patients have already received the maximum recommended dose of radiation in the affected areas and additional radiation could exacerbate their CAS.

Chemotherapy—Chemotherapy occasionally is used as an adjunct to surgical resection with positive margins or as palliative care when surgical resection is not possible. Unfortunately, STSs have a response rate of less than 40% to standard chemotherapy.⁴⁰ Studies in which the use of chemotherapy is evaluated for CAS have mixed results. Mark et al¹⁸ reported no significant overall survival benefit when comparing CAS treated with surgery plus radiotherapy with or without chemotherapy. Torres et al⁴¹ evaluated radiation-induced angiosarcoma of the breast and found a reduced risk for local recurrence in patients receiving chemotherapy in addition to surgery, indicating that chemotherapy may be useful in this subset of patients when radiation is not recommended.

Cytotoxic chemotherapy agents such as paclitaxel, doxorubicin, or doxorubicin in combination with mesna and ifosfamide (MAI) are common.³⁹ Median progression-free survival is 5.4 months, 4 to 5.6 months, and 3.9 months for MAI, paclitaxel, and doxorubicin, respectively.^8,9,42-46 Improved prognosis with MAI may indicate that combination chemotherapy regimens are more effective than single-agent regimens. Cutaneous angiosarcomas may respond better to paclitaxel than doxorubicin, and angiosarcomas of the scalp and face have shown a better response to paclitaxel.^47,48

Other Therapies—Although there have not been large-scale studies performed on alternative treatments, there are several case reports on the use of immune modulators, biologics, β-blockers, and various other therapies in the treatment of CAS. The following studies include small sample sizes of patients with metastatic or locally aggressive disease not amenable to surgical resection, which may affect reported outcomes and survival times.^49-57 In addition, several studies include patients with visceral angiosarcoma, which may not be generalizable to the CAS population. Even so, these treatment alternatives should not be overlooked because there are few agents that are truly efficacious in the treatment of CAS.

Results on the use of VEGF and tyrosine kinase inhibitors have been disappointing. There have been reports of median progression-free survival of only 3.8 months with sorafenib treatment, 3 months with pazopanib, and 6 months with bevacizumab.^49-51 However, one study of patients who were treated with bevacizumab combined with radiation and surgery resulted in a complete response in 2 patients, with no evidence of residual disease at the last follow-up of 8.5 months and 2.1 years.⁵²

Studies on the utility of β-blockers in the treatment of CAS have shown mixed results. Pasquier et al⁵³ evaluated the use of adjunctive therapy with propranolol and vinblastine-based chemotherapy, with a promising median progression-free survival of 11 months compared with an average of 3 to 6 months with conventional chemotherapy regimens. However, in vitro studies reported by Pasquier et al⁵³ indicated that the addition of propranolol to doxorubicin or paclitaxel did not result in increased efficacy. Chow et al⁵⁴ demonstrated that propranolol monotherapy resulted in a reduction of the proliferative index of scalp angiosarcoma by 34% after only 1 week of treatment. This was followed by combination therapy of propranolol, paclitaxel, and radiation, which resulted in substantial tumor regression and no evidence of metastasis after 8 months of therapy.⁵⁴

Immune checkpoint inhibitors have been a recent subject of interest in the treatment of angiosarcoma. Two case reports showed improvement in CAS of the face and primary pleural angiosarcoma with a course of pembrolizumab.^55,56 In another case series, investigators used immune checkpoint inhibitors in 7 patients with cutaneous, breast, or radiation-associated angiosarcoma and found partial response in several patients treated with pembrolizumab and ipilimumab-nivolumab and complete response in 1 patient treated with anti–cytotoxic T-lymphocyte–associated protein 4 antibodies. The authors of this study hypothesized that treatment response was associated with the mutational profile of tumors, including mutational signatures of UV radiation with a large number of C-to-T substitutions similar to melanomas.⁵⁷

Conclusion

Cutaneous angiosarcoma is a rare and aggressive tumor with a poor prognosis due to delayed detection. A thorough skin examination and heightened awareness of CAS by dermatologists may result in early biopsy and shortened time to a definitive diagnosis. Until quality evidence allows for the creation of consensus guidelines, care at a cancer center that specializes in rare and difficult-to-treat tumors and employs a multidisciplinary approach is essential to optimizing patient outcomes. Current knowledge supports surgery with negative margins as the mainstay of treatment, with adjuvant radiation, chemotherapy, and targeted therapies as possible additions for extensive disease. The role of MMS is uncertain, and because of the lack of contiguity in CAS, it may not be an optimal treatment.

Angiosarcomas are aggressive endothelial cell tumors of vascular origin that account for 1% to 2% of all soft tissue sarcomas in the United States.^1,2 They can affect any organ in the body but most commonly affect the skin and soft tissue. Cutaneous angiosarcoma (CAS) is a rare type of skin cancer that can present in 2 forms: primary and secondary. The primary form lacks a known underlying cause, but secondary CAS commonly is linked to prior radiation therapy of the breast as well as lymphedema of the breast and arm. Secondary CAS may require different treatment than primary CAS, as radiation therapy poses risks to patients with radiation-induced CAS.³ The prognosis of CAS is poor due to delayed diagnosis. Current treatment modalities have a high rate of local recurrence and/or distant metastasis, but recent advances in surgery and other therapies such as radiation and immunotherapy provide hope for more successful disease control.

Dermatologists may be responsible for the initial diagnosis and management of CAS. They must be familiar with its presentation, as this condition can be difficult to diagnose and mimics other diseases. Additionally, dermatologists must understand the role of varying treatment modalities including Mohs micrographic surgery (MMS) in the management of CAS. This review will provide an overview of the epidemiology, presentation, and pathologic features of CAS and will discuss both emerging and existing treatments.

Epidemiology

Cutaneous angiosarcoma may present in various locations in the body, predominantly on the head and neck.^4,5 Approximately 85% of cases arise in patients older than 60 years, and most of these patients are White men.^1,4,5 The risk factors for the development of CAS include prior radiation exposure; chronic lymphedema (ie, Stewart-Treves syndrome); and familial syndromes including neurofibromatosis 1, BRCA1 or BRCA2 mutations, Maffucci syndrome, and Klippel-Trenaunay syndrome. Exogenous exposure to toxins such as vinyl chloride, thorium dioxide, or anabolic steroids also is associated with angiosarcoma, primarily in the form of visceral disease such as hepatic angiosarcoma.⁶

The average tumor size is approximately 4 to 5 cm; however, some tumors may grow larger than 10 cm.^7,8 Metastasis through hematogenous or lymphatic spread is fairly common, occurring in approximately 16% to 35% of patients. The lungs and liver are the most common sites of metastasis.^9,10 The age-adjusted incidence rate of CAS is decreasing for patients younger than 50 years, from 1.30 in 1995 to 2004 to 1.10 in 2005 to 2014, but increasing for individuals older than 70 years, from 2.53 in 1995 to 2004 to 2.87 in 2005 to 2014.⁴ The incidence of angiosarcoma also has grown in the female population, likely due to the increasing use of radiotherapy for the treatment of breast cancer.¹¹

The high rates of CAS on the head and neck may be explained by the increased vascularity and UV exposure in these locations.¹² In a Surveillance, Epidemiology, and End Results population-based study (N=811), 43% of patients with CAS had a history of other malignancies such as breast, prostate, genitourinary, gastrointestinal tract, and respiratory tract cancers.⁴ Cutaneous angiosarcoma can develop secondary to the primary cancer treatment, as seen in patients who develop CAS following radiation therapy.¹¹

The underlying mechanism of CAS is believed to involve dysregulation of angiogenesis due to the vascular origin of these tumors. Studies have identified overexpression of vascular endothelial growth factor (VEGF), TP53 mutations, and RAS pathway mutations as potential contributing factors to the pathogenesis of angiosarcoma.⁶ Molecular differences between primary and secondary angiosarcomas are not well documented; however, radiation-associated CAS has been found to have higher expression of LYN and PRKCΘ, while non–radiation-induced lesions express FTL1 and AKT3.² Chromosomal abnormalities have been identified in a small set of primary CAS patients, but the specific role of these abnormalities in the pathogenesis of CAS remains unclear.⁷

Prognosis

Cutaneous angiosarcoma has a poor prognosis, with 3-year disease-specific survival rates as low as 40% and 5-year rates as low as 17%.^4,5,13,14 Survival rates increased from 1985 to 2014, likely due to earlier diagnoses and more effective treatments.⁴ Several factors are associated with worse prognosis, including metastatic disease, increasing age, scalp and neck tumor location, tumor size greater than 5 cm, necrosis, multiple skin lesions, and nodular and epithelioid morphology.^4,5,10,13-16 Factors including sex, race, and presence of another malignancy do not affect survival.^4,5 Prognosis in CAS may be evaluated by TNM tumor staging. The American Joint Committee on Cancer Staging Manual (8th edition) for soft tissue sarcoma (STS) commonly is used; however, CAS is not included in this staging system because it does not share the same behavior and natural history as other types of STS. This staging system provides separate guidelines for STS of the head and neck and STS of the extremities and trunk because of the smaller size but paradoxically higher risk for head and neck tumors.¹⁷ Given that there is no agreed-upon staging system for CAS, prognosis and communication among providers may be complicated.

Early CAS typically presents as single or multifocal ill-defined, enlarging, violaceous or dusky red macules or patches (Figure 1). Lesions often rapidly develop into raised nodules and plaques that may bleed and ulcerate. Other common symptoms include pain, edema, neuropathy, anemia, and weight loss; however, it is not uncommon for lesions to be asymptomatic.^8,18-20 Nodular lesions are more common on the scalp, and patches are more common on the face and neck.¹⁶ Tumors typically extend into the dermis, and aggressive cancers may invade the subcutaneous tissue and fascia.²

Cutaneous angiosarcoma may mimic ecchymosis, hemangioma, lymphangioma, edema, cellulitis, or scarring alopecia. Its nonspecific features make it difficult to recognize without dermoscopy or ultrasonography, which often results in delayed diagnosis and treatment. The median delay typically is 5 to 7 months and up to 1 year for some patients.^7,16 Cutaneous angiosarcoma of the scalp tends to have a longer diagnostic delay than other areas of the body, which may be attributable to challenges in tumor identification and visualization by patients.¹⁶

Dermoscopy and ultrasonography can aid in the diagnosis of CAS. Dermoscopy may demonstrate a range of colors with yellow, brown, or red areas in a violaceous background. Other reported features include white veils and lines, purple ovals, pink-purple “steamlike” areas, and atypical vessels (Figure 2).^21-23 Dermoscopic findings may appear similar to other vascular tumors, such as hemangioma and Kaposi sarcoma, or nonvascular tumors, including amelanotic melanoma, Merkel cell carcinoma, and primary cutaneous B-cell lymphoma. Ultrasonography may show ill-defined, hypoechoic areas with anechoic reticular channels and a hypoechoic subepidermal layer.²¹ Other radiologic modalities, such as computed tomography, magnetic resonance imaging, or positron emission tomography, are nonspecific and are more useful in evaluating the extent of tumor spread in visceral angiosarcoma. Magnetic resonance imaging in CAS may indicate malignancy with the presence of high T2 and T1 signal intensity and high-flow serpentine vessels.²⁴

Histopathology

Histologically, angiosarcoma is characterized by anastomosing irregular vascular channels lined by a single layer of endothelial cells displaying slight to moderate atypia.²⁵ These vascular channels dissect between collagen bundles and adipocytes. Monocyte infiltration may be observed.⁶ The neoplastic endothelial cells may present as spindle-shaped, round, polygonal, or epithelioid with eosinophilic cytoplasm. Histologic features differ based on the type of clinical lesion (Figure 3). In a study of CAS in Asian populations, nodular tumors showed solid sheets of pleomorphic spindle cells, many mitotic figures, and widely hemorrhagic spaces, whereas nonnodular tumors showed irregular vascular spaces dissecting collagen.¹⁶ Poorly differentiated tumors may present with hyperchromatic nuclei and prominent nucleoli, papillary endothelial formations, mitoses, and possible hemorrhage or necrosis.^2,6,8 Histologic specimens also may reveal calcified bodies and hemosiderin particles.¹⁹ Angiosarcomas typically are invasive without a clear capsule or border.⁶

Photograph courtesy of Kim HooKim, MD (Camden, New Jersey).

Secondary CAS in the setting of lymphedema and radiation therapy has MYC amplification and is positive for MYC via immunohistochemistry, which is uncommon in primary angiosarcoma.²⁶ Immunohistochemical staining of tumor specimens is helpful to confirm the diagnosis of CAS. These markers include CD31, CD34, CD117, cytokeratin, vimentin, epithelial membrane antigen, factor VIII–related antigen, Ulex europaeus agglutinin-1, von Willebrand factor, and VEGF.^6,19,27,28 Notably, advanced angiosarcomas with progressive dedifferentiation often lose these markers.

Treatment

Surgery—The majority of patients treated for CAS undergo surgical resection, as surgery has been shown to have the best prognosis for patients.^5,9,10,13,15 Achieving R0 resection (microscopically negative margins) is the most important factor in determining the success of treatment, with incomplete surgical resection resulting in higher rates of systemic and local spread.²⁹ Abraham et al⁸ found that the median disease-specific survival of patients with microscopically negative margins was 83.7 months; patients with microscopically positive and grossly positive margins had median disease-specific survival of 63.4 and 18.1 months, respectively. In a case series of patients undergoing resection with negative surgical margins, 4 patients demonstrated no evidence of local recurrence or systemic disease at an average of 4.3 years after therapy, and the other 4 patients each had 1 local recurrence but were disease free an average of 4.8 years after removal of the recurrent lesion. In a series of 27 patients with positive surgical margins, there was local recurrence within 2 years for most patients.¹²

Large tumors invading nearby structures may not be amenable to surgical resection because of extensive local growth, propensity for skip lesions, and localization near vital organs of the head and neck.^5,7 The extended delay in diagnosis often seen in CAS allows for advanced local progression, resulting in large areas of resection. In a case series (N=8), the average surgical defect measured 14.3×11.8 cm, necessitating reconstruction with either a tissue flap or split-thickness skin graft in every case because primary closure was not possible. More than 80% of patients in this study still had positive margins after surgery, necessitating the use of additional chemotherapy or radiation to eradicate remaining disease.⁷ In several studies, multimodality therapy was associated with improved overall survival.^7,14,30

Mohs Micrographic Surgery—Mohs micrographic surgery is the standard of care for many aggressive cutaneous malignancies on the head, but its utility for the treatment of CAS is uncertain. Only a few studies have compared the efficacy of MMS vs wide local excision (WLE). There have been reports of recurrence-free follow-up at 12, 16, 18, 20, and 72 months after MMS.^31-36 The latter case showed a patient who underwent MMS with a 72-month relapse-free survival, whereas other patients who underwent WLE only survived 5 to 7 months without recurrence.³⁶ In another study, there was a local recurrence rate of 42.9% after a median follow-up of 4 years in 7 patients with CAS treated with complete circumferential peripheral and deep margin assessment, which is less than the reported recurrence rates of 72% to 84% after standard excisional procedures.^28,37

Houpe et al³⁸ conducted a systematic review of the use of WLE vs MMS; the median overall survival was longest for WLE in conjunction with chemotherapy, radiotherapy, and immunotherapy at 39.3 months, followed by MMS alone at 37 months. Mohs micrographic surgery in conjunction with chemotherapy and radiotherapy was used in 1 patient, with a median overall survival of 82 months. Wide local excision alone resulted in a median overall survival of 19.8 months. Although these data are promising and suggest that the combination of surgery with adjuvant therapy may be more beneficial than surgery alone, it is important to note that there were only 9 cases treated with MMS compared with 825 cases treated with WLE.³⁸

Several studies have documented that paraffin-embedded sections may be more useful than frozen sections in the determination of margin positivity from a surgical specimen, as frozen sections showed a poor negative predictive value of 33.3%.^7,35 Mohs micrographic surgery has been proposed for tumors measuring less than 5 cm; however, the most recent appropriate use criteria for MMS of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery deemed the use of MMS for angiosarcoma uncertain.^32,33,37 Further research is necessary to elucidate the role of MMS in the management of CAS.

Radiotherapy—Radiotherapy is a common adjuvant to surgical resection but has been used palliatively in patients with tumors that are unresectable. Improved local control and disease-free survival have been observed with the combination of radiation and surgery. A dose response to radiotherapy has been demonstrated,^18,30 with 1 study showing that patients who received more than 5000 cGy of radiotherapy achieved better local control than patients who received 4500 cGy or less.¹⁸ Pawlik et al⁷ showed a decreased chance of death with the addition of adjunctive radiotherapy, and patients who underwent postoperative radiotherapy demonstrated a median survival almost 4-times longer than patients who did not receive radiation. Morrison et al³⁹ reported that radiation therapy administered to patients with no clinically evident disease after surgical resection resulted in improved local control and overall survival vs patients who were irradiated with clinically evident disease.

Complications of radiotherapy for angiosarcoma have been reported, including xerostomia, nonfunctionally significant fibrosis, chronic ulceration/cellulitis of the scalp, necrosis requiring debridement, severe ocular complications, and fibrosis of the eyelids requiring surgical intervention.¹⁴ Radiation therapy also poses unique risks to patients with radiation-induced angiosarcoma of the breast, as many of these patients have already received the maximum recommended dose of radiation in the affected areas and additional radiation could exacerbate their CAS.

Chemotherapy—Chemotherapy occasionally is used as an adjunct to surgical resection with positive margins or as palliative care when surgical resection is not possible. Unfortunately, STSs have a response rate of less than 40% to standard chemotherapy.⁴⁰ Studies in which the use of chemotherapy is evaluated for CAS have mixed results. Mark et al¹⁸ reported no significant overall survival benefit when comparing CAS treated with surgery plus radiotherapy with or without chemotherapy. Torres et al⁴¹ evaluated radiation-induced angiosarcoma of the breast and found a reduced risk for local recurrence in patients receiving chemotherapy in addition to surgery, indicating that chemotherapy may be useful in this subset of patients when radiation is not recommended.

Cytotoxic chemotherapy agents such as paclitaxel, doxorubicin, or doxorubicin in combination with mesna and ifosfamide (MAI) are common.³⁹ Median progression-free survival is 5.4 months, 4 to 5.6 months, and 3.9 months for MAI, paclitaxel, and doxorubicin, respectively.^8,9,42-46 Improved prognosis with MAI may indicate that combination chemotherapy regimens are more effective than single-agent regimens. Cutaneous angiosarcomas may respond better to paclitaxel than doxorubicin, and angiosarcomas of the scalp and face have shown a better response to paclitaxel.^47,48

Other Therapies—Although there have not been large-scale studies performed on alternative treatments, there are several case reports on the use of immune modulators, biologics, β-blockers, and various other therapies in the treatment of CAS. The following studies include small sample sizes of patients with metastatic or locally aggressive disease not amenable to surgical resection, which may affect reported outcomes and survival times.^49-57 In addition, several studies include patients with visceral angiosarcoma, which may not be generalizable to the CAS population. Even so, these treatment alternatives should not be overlooked because there are few agents that are truly efficacious in the treatment of CAS.

Results on the use of VEGF and tyrosine kinase inhibitors have been disappointing. There have been reports of median progression-free survival of only 3.8 months with sorafenib treatment, 3 months with pazopanib, and 6 months with bevacizumab.^49-51 However, one study of patients who were treated with bevacizumab combined with radiation and surgery resulted in a complete response in 2 patients, with no evidence of residual disease at the last follow-up of 8.5 months and 2.1 years.⁵²

Studies on the utility of β-blockers in the treatment of CAS have shown mixed results. Pasquier et al⁵³ evaluated the use of adjunctive therapy with propranolol and vinblastine-based chemotherapy, with a promising median progression-free survival of 11 months compared with an average of 3 to 6 months with conventional chemotherapy regimens. However, in vitro studies reported by Pasquier et al⁵³ indicated that the addition of propranolol to doxorubicin or paclitaxel did not result in increased efficacy. Chow et al⁵⁴ demonstrated that propranolol monotherapy resulted in a reduction of the proliferative index of scalp angiosarcoma by 34% after only 1 week of treatment. This was followed by combination therapy of propranolol, paclitaxel, and radiation, which resulted in substantial tumor regression and no evidence of metastasis after 8 months of therapy.⁵⁴

Immune checkpoint inhibitors have been a recent subject of interest in the treatment of angiosarcoma. Two case reports showed improvement in CAS of the face and primary pleural angiosarcoma with a course of pembrolizumab.^55,56 In another case series, investigators used immune checkpoint inhibitors in 7 patients with cutaneous, breast, or radiation-associated angiosarcoma and found partial response in several patients treated with pembrolizumab and ipilimumab-nivolumab and complete response in 1 patient treated with anti–cytotoxic T-lymphocyte–associated protein 4 antibodies. The authors of this study hypothesized that treatment response was associated with the mutational profile of tumors, including mutational signatures of UV radiation with a large number of C-to-T substitutions similar to melanomas.⁵⁷

Conclusion

Cutaneous angiosarcoma is a rare and aggressive tumor with a poor prognosis due to delayed detection. A thorough skin examination and heightened awareness of CAS by dermatologists may result in early biopsy and shortened time to a definitive diagnosis. Until quality evidence allows for the creation of consensus guidelines, care at a cancer center that specializes in rare and difficult-to-treat tumors and employs a multidisciplinary approach is essential to optimizing patient outcomes. Current knowledge supports surgery with negative margins as the mainstay of treatment, with adjuvant radiation, chemotherapy, and targeted therapies as possible additions for extensive disease. The role of MMS is uncertain, and because of the lack of contiguity in CAS, it may not be an optimal treatment.

Angiosarcomas are aggressive endothelial cell tumors of vascular origin that account for 1% to 2% of all soft tissue sarcomas in the United States.^1,2 They can affect any organ in the body but most commonly affect the skin and soft tissue. Cutaneous angiosarcoma (CAS) is a rare type of skin cancer that can present in 2 forms: primary and secondary. The primary form lacks a known underlying cause, but secondary CAS commonly is linked to prior radiation therapy of the breast as well as lymphedema of the breast and arm. Secondary CAS may require different treatment than primary CAS, as radiation therapy poses risks to patients with radiation-induced CAS.³ The prognosis of CAS is poor due to delayed diagnosis. Current treatment modalities have a high rate of local recurrence and/or distant metastasis, but recent advances in surgery and other therapies such as radiation and immunotherapy provide hope for more successful disease control.

Dermatologists may be responsible for the initial diagnosis and management of CAS. They must be familiar with its presentation, as this condition can be difficult to diagnose and mimics other diseases. Additionally, dermatologists must understand the role of varying treatment modalities including Mohs micrographic surgery (MMS) in the management of CAS. This review will provide an overview of the epidemiology, presentation, and pathologic features of CAS and will discuss both emerging and existing treatments.

Epidemiology

Cutaneous angiosarcoma may present in various locations in the body, predominantly on the head and neck.^4,5 Approximately 85% of cases arise in patients older than 60 years, and most of these patients are White men.^1,4,5 The risk factors for the development of CAS include prior radiation exposure; chronic lymphedema (ie, Stewart-Treves syndrome); and familial syndromes including neurofibromatosis 1, BRCA1 or BRCA2 mutations, Maffucci syndrome, and Klippel-Trenaunay syndrome. Exogenous exposure to toxins such as vinyl chloride, thorium dioxide, or anabolic steroids also is associated with angiosarcoma, primarily in the form of visceral disease such as hepatic angiosarcoma.⁶

The average tumor size is approximately 4 to 5 cm; however, some tumors may grow larger than 10 cm.^7,8 Metastasis through hematogenous or lymphatic spread is fairly common, occurring in approximately 16% to 35% of patients. The lungs and liver are the most common sites of metastasis.^9,10 The age-adjusted incidence rate of CAS is decreasing for patients younger than 50 years, from 1.30 in 1995 to 2004 to 1.10 in 2005 to 2014, but increasing for individuals older than 70 years, from 2.53 in 1995 to 2004 to 2.87 in 2005 to 2014.⁴ The incidence of angiosarcoma also has grown in the female population, likely due to the increasing use of radiotherapy for the treatment of breast cancer.¹¹

The high rates of CAS on the head and neck may be explained by the increased vascularity and UV exposure in these locations.¹² In a Surveillance, Epidemiology, and End Results population-based study (N=811), 43% of patients with CAS had a history of other malignancies such as breast, prostate, genitourinary, gastrointestinal tract, and respiratory tract cancers.⁴ Cutaneous angiosarcoma can develop secondary to the primary cancer treatment, as seen in patients who develop CAS following radiation therapy.¹¹

The underlying mechanism of CAS is believed to involve dysregulation of angiogenesis due to the vascular origin of these tumors. Studies have identified overexpression of vascular endothelial growth factor (VEGF), TP53 mutations, and RAS pathway mutations as potential contributing factors to the pathogenesis of angiosarcoma.⁶ Molecular differences between primary and secondary angiosarcomas are not well documented; however, radiation-associated CAS has been found to have higher expression of LYN and PRKCΘ, while non–radiation-induced lesions express FTL1 and AKT3.² Chromosomal abnormalities have been identified in a small set of primary CAS patients, but the specific role of these abnormalities in the pathogenesis of CAS remains unclear.⁷

Prognosis

Cutaneous angiosarcoma has a poor prognosis, with 3-year disease-specific survival rates as low as 40% and 5-year rates as low as 17%.^4,5,13,14 Survival rates increased from 1985 to 2014, likely due to earlier diagnoses and more effective treatments.⁴ Several factors are associated with worse prognosis, including metastatic disease, increasing age, scalp and neck tumor location, tumor size greater than 5 cm, necrosis, multiple skin lesions, and nodular and epithelioid morphology.^4,5,10,13-16 Factors including sex, race, and presence of another malignancy do not affect survival.^4,5 Prognosis in CAS may be evaluated by TNM tumor staging. The American Joint Committee on Cancer Staging Manual (8th edition) for soft tissue sarcoma (STS) commonly is used; however, CAS is not included in this staging system because it does not share the same behavior and natural history as other types of STS. This staging system provides separate guidelines for STS of the head and neck and STS of the extremities and trunk because of the smaller size but paradoxically higher risk for head and neck tumors.¹⁷ Given that there is no agreed-upon staging system for CAS, prognosis and communication among providers may be complicated.

Early CAS typically presents as single or multifocal ill-defined, enlarging, violaceous or dusky red macules or patches (Figure 1). Lesions often rapidly develop into raised nodules and plaques that may bleed and ulcerate. Other common symptoms include pain, edema, neuropathy, anemia, and weight loss; however, it is not uncommon for lesions to be asymptomatic.^8,18-20 Nodular lesions are more common on the scalp, and patches are more common on the face and neck.¹⁶ Tumors typically extend into the dermis, and aggressive cancers may invade the subcutaneous tissue and fascia.²

Cutaneous angiosarcoma may mimic ecchymosis, hemangioma, lymphangioma, edema, cellulitis, or scarring alopecia. Its nonspecific features make it difficult to recognize without dermoscopy or ultrasonography, which often results in delayed diagnosis and treatment. The median delay typically is 5 to 7 months and up to 1 year for some patients.^7,16 Cutaneous angiosarcoma of the scalp tends to have a longer diagnostic delay than other areas of the body, which may be attributable to challenges in tumor identification and visualization by patients.¹⁶

Dermoscopy and ultrasonography can aid in the diagnosis of CAS. Dermoscopy may demonstrate a range of colors with yellow, brown, or red areas in a violaceous background. Other reported features include white veils and lines, purple ovals, pink-purple “steamlike” areas, and atypical vessels (Figure 2).^21-23 Dermoscopic findings may appear similar to other vascular tumors, such as hemangioma and Kaposi sarcoma, or nonvascular tumors, including amelanotic melanoma, Merkel cell carcinoma, and primary cutaneous B-cell lymphoma. Ultrasonography may show ill-defined, hypoechoic areas with anechoic reticular channels and a hypoechoic subepidermal layer.²¹ Other radiologic modalities, such as computed tomography, magnetic resonance imaging, or positron emission tomography, are nonspecific and are more useful in evaluating the extent of tumor spread in visceral angiosarcoma. Magnetic resonance imaging in CAS may indicate malignancy with the presence of high T2 and T1 signal intensity and high-flow serpentine vessels.²⁴

Histopathology

Histologically, angiosarcoma is characterized by anastomosing irregular vascular channels lined by a single layer of endothelial cells displaying slight to moderate atypia.²⁵ These vascular channels dissect between collagen bundles and adipocytes. Monocyte infiltration may be observed.⁶ The neoplastic endothelial cells may present as spindle-shaped, round, polygonal, or epithelioid with eosinophilic cytoplasm. Histologic features differ based on the type of clinical lesion (Figure 3). In a study of CAS in Asian populations, nodular tumors showed solid sheets of pleomorphic spindle cells, many mitotic figures, and widely hemorrhagic spaces, whereas nonnodular tumors showed irregular vascular spaces dissecting collagen.¹⁶ Poorly differentiated tumors may present with hyperchromatic nuclei and prominent nucleoli, papillary endothelial formations, mitoses, and possible hemorrhage or necrosis.^2,6,8 Histologic specimens also may reveal calcified bodies and hemosiderin particles.¹⁹ Angiosarcomas typically are invasive without a clear capsule or border.⁶

Photograph courtesy of Kim HooKim, MD (Camden, New Jersey).

Secondary CAS in the setting of lymphedema and radiation therapy has MYC amplification and is positive for MYC via immunohistochemistry, which is uncommon in primary angiosarcoma.²⁶ Immunohistochemical staining of tumor specimens is helpful to confirm the diagnosis of CAS. These markers include CD31, CD34, CD117, cytokeratin, vimentin, epithelial membrane antigen, factor VIII–related antigen, Ulex europaeus agglutinin-1, von Willebrand factor, and VEGF.^6,19,27,28 Notably, advanced angiosarcomas with progressive dedifferentiation often lose these markers.

Treatment

Surgery—The majority of patients treated for CAS undergo surgical resection, as surgery has been shown to have the best prognosis for patients.^5,9,10,13,15 Achieving R0 resection (microscopically negative margins) is the most important factor in determining the success of treatment, with incomplete surgical resection resulting in higher rates of systemic and local spread.²⁹ Abraham et al⁸ found that the median disease-specific survival of patients with microscopically negative margins was 83.7 months; patients with microscopically positive and grossly positive margins had median disease-specific survival of 63.4 and 18.1 months, respectively. In a case series of patients undergoing resection with negative surgical margins, 4 patients demonstrated no evidence of local recurrence or systemic disease at an average of 4.3 years after therapy, and the other 4 patients each had 1 local recurrence but were disease free an average of 4.8 years after removal of the recurrent lesion. In a series of 27 patients with positive surgical margins, there was local recurrence within 2 years for most patients.¹²

Large tumors invading nearby structures may not be amenable to surgical resection because of extensive local growth, propensity for skip lesions, and localization near vital organs of the head and neck.^5,7 The extended delay in diagnosis often seen in CAS allows for advanced local progression, resulting in large areas of resection. In a case series (N=8), the average surgical defect measured 14.3×11.8 cm, necessitating reconstruction with either a tissue flap or split-thickness skin graft in every case because primary closure was not possible. More than 80% of patients in this study still had positive margins after surgery, necessitating the use of additional chemotherapy or radiation to eradicate remaining disease.⁷ In several studies, multimodality therapy was associated with improved overall survival.^7,14,30

Mohs Micrographic Surgery—Mohs micrographic surgery is the standard of care for many aggressive cutaneous malignancies on the head, but its utility for the treatment of CAS is uncertain. Only a few studies have compared the efficacy of MMS vs wide local excision (WLE). There have been reports of recurrence-free follow-up at 12, 16, 18, 20, and 72 months after MMS.^31-36 The latter case showed a patient who underwent MMS with a 72-month relapse-free survival, whereas other patients who underwent WLE only survived 5 to 7 months without recurrence.³⁶ In another study, there was a local recurrence rate of 42.9% after a median follow-up of 4 years in 7 patients with CAS treated with complete circumferential peripheral and deep margin assessment, which is less than the reported recurrence rates of 72% to 84% after standard excisional procedures.^28,37

Houpe et al³⁸ conducted a systematic review of the use of WLE vs MMS; the median overall survival was longest for WLE in conjunction with chemotherapy, radiotherapy, and immunotherapy at 39.3 months, followed by MMS alone at 37 months. Mohs micrographic surgery in conjunction with chemotherapy and radiotherapy was used in 1 patient, with a median overall survival of 82 months. Wide local excision alone resulted in a median overall survival of 19.8 months. Although these data are promising and suggest that the combination of surgery with adjuvant therapy may be more beneficial than surgery alone, it is important to note that there were only 9 cases treated with MMS compared with 825 cases treated with WLE.³⁸

Several studies have documented that paraffin-embedded sections may be more useful than frozen sections in the determination of margin positivity from a surgical specimen, as frozen sections showed a poor negative predictive value of 33.3%.^7,35 Mohs micrographic surgery has been proposed for tumors measuring less than 5 cm; however, the most recent appropriate use criteria for MMS of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery deemed the use of MMS for angiosarcoma uncertain.^32,33,37 Further research is necessary to elucidate the role of MMS in the management of CAS.

Radiotherapy—Radiotherapy is a common adjuvant to surgical resection but has been used palliatively in patients with tumors that are unresectable. Improved local control and disease-free survival have been observed with the combination of radiation and surgery. A dose response to radiotherapy has been demonstrated,^18,30 with 1 study showing that patients who received more than 5000 cGy of radiotherapy achieved better local control than patients who received 4500 cGy or less.¹⁸ Pawlik et al⁷ showed a decreased chance of death with the addition of adjunctive radiotherapy, and patients who underwent postoperative radiotherapy demonstrated a median survival almost 4-times longer than patients who did not receive radiation. Morrison et al³⁹ reported that radiation therapy administered to patients with no clinically evident disease after surgical resection resulted in improved local control and overall survival vs patients who were irradiated with clinically evident disease.

Complications of radiotherapy for angiosarcoma have been reported, including xerostomia, nonfunctionally significant fibrosis, chronic ulceration/cellulitis of the scalp, necrosis requiring debridement, severe ocular complications, and fibrosis of the eyelids requiring surgical intervention.¹⁴ Radiation therapy also poses unique risks to patients with radiation-induced angiosarcoma of the breast, as many of these patients have already received the maximum recommended dose of radiation in the affected areas and additional radiation could exacerbate their CAS.

Chemotherapy—Chemotherapy occasionally is used as an adjunct to surgical resection with positive margins or as palliative care when surgical resection is not possible. Unfortunately, STSs have a response rate of less than 40% to standard chemotherapy.⁴⁰ Studies in which the use of chemotherapy is evaluated for CAS have mixed results. Mark et al¹⁸ reported no significant overall survival benefit when comparing CAS treated with surgery plus radiotherapy with or without chemotherapy. Torres et al⁴¹ evaluated radiation-induced angiosarcoma of the breast and found a reduced risk for local recurrence in patients receiving chemotherapy in addition to surgery, indicating that chemotherapy may be useful in this subset of patients when radiation is not recommended.

Cytotoxic chemotherapy agents such as paclitaxel, doxorubicin, or doxorubicin in combination with mesna and ifosfamide (MAI) are common.³⁹ Median progression-free survival is 5.4 months, 4 to 5.6 months, and 3.9 months for MAI, paclitaxel, and doxorubicin, respectively.^8,9,42-46 Improved prognosis with MAI may indicate that combination chemotherapy regimens are more effective than single-agent regimens. Cutaneous angiosarcomas may respond better to paclitaxel than doxorubicin, and angiosarcomas of the scalp and face have shown a better response to paclitaxel.^47,48

Other Therapies—Although there have not been large-scale studies performed on alternative treatments, there are several case reports on the use of immune modulators, biologics, β-blockers, and various other therapies in the treatment of CAS. The following studies include small sample sizes of patients with metastatic or locally aggressive disease not amenable to surgical resection, which may affect reported outcomes and survival times.^49-57 In addition, several studies include patients with visceral angiosarcoma, which may not be generalizable to the CAS population. Even so, these treatment alternatives should not be overlooked because there are few agents that are truly efficacious in the treatment of CAS.

Results on the use of VEGF and tyrosine kinase inhibitors have been disappointing. There have been reports of median progression-free survival of only 3.8 months with sorafenib treatment, 3 months with pazopanib, and 6 months with bevacizumab.^49-51 However, one study of patients who were treated with bevacizumab combined with radiation and surgery resulted in a complete response in 2 patients, with no evidence of residual disease at the last follow-up of 8.5 months and 2.1 years.⁵²

Studies on the utility of β-blockers in the treatment of CAS have shown mixed results. Pasquier et al⁵³ evaluated the use of adjunctive therapy with propranolol and vinblastine-based chemotherapy, with a promising median progression-free survival of 11 months compared with an average of 3 to 6 months with conventional chemotherapy regimens. However, in vitro studies reported by Pasquier et al⁵³ indicated that the addition of propranolol to doxorubicin or paclitaxel did not result in increased efficacy. Chow et al⁵⁴ demonstrated that propranolol monotherapy resulted in a reduction of the proliferative index of scalp angiosarcoma by 34% after only 1 week of treatment. This was followed by combination therapy of propranolol, paclitaxel, and radiation, which resulted in substantial tumor regression and no evidence of metastasis after 8 months of therapy.⁵⁴

Immune checkpoint inhibitors have been a recent subject of interest in the treatment of angiosarcoma. Two case reports showed improvement in CAS of the face and primary pleural angiosarcoma with a course of pembrolizumab.^55,56 In another case series, investigators used immune checkpoint inhibitors in 7 patients with cutaneous, breast, or radiation-associated angiosarcoma and found partial response in several patients treated with pembrolizumab and ipilimumab-nivolumab and complete response in 1 patient treated with anti–cytotoxic T-lymphocyte–associated protein 4 antibodies. The authors of this study hypothesized that treatment response was associated with the mutational profile of tumors, including mutational signatures of UV radiation with a large number of C-to-T substitutions similar to melanomas.⁵⁷

Conclusion

Cutaneous angiosarcoma is a rare and aggressive tumor with a poor prognosis due to delayed detection. A thorough skin examination and heightened awareness of CAS by dermatologists may result in early biopsy and shortened time to a definitive diagnosis. Until quality evidence allows for the creation of consensus guidelines, care at a cancer center that specializes in rare and difficult-to-treat tumors and employs a multidisciplinary approach is essential to optimizing patient outcomes. Current knowledge supports surgery with negative margins as the mainstay of treatment, with adjuvant radiation, chemotherapy, and targeted therapies as possible additions for extensive disease. The role of MMS is uncertain, and because of the lack of contiguity in CAS, it may not be an optimal treatment.

Basal cell carcinoma (BCC) of the ear may have aggressive histologic subtypes and a greater propensity for subclinical spread than BCC in other anatomic locations. In this retrospective analysis, we evaluated recurrence rates of BCC of the ear in 102 patients who underwent treatment with Mohs micrographic surgery (MMS) or radiation therapy (RT) at a single institution between January 2017 and December 2019. Data on patient demographics, tumor characteristics, treatment modality, and recurrence rates were collected from medical records. Recurrence rates were assessed over a mean follow-up time of 2.8 years. Although MMS is the gold standard for treatment of BCC of the ear, RT may be a suitable alternative for nonsurgical candidates.

Basal cell carcinoma (BCC) of the ear may have aggressive histologic subtypes and a greater propensity for subclinical spread than BCC in other anatomic locations. Given that these aggressive histologic subtypes—defined as morpheaform, basosquamous, sclerosing, infiltrative, or micronodular in any portion of the tumor—have been reported as independent predictors of recurrence,^1,2 BCC of the ear may be more likely to recur.

Mohs micrographic surgery (MMS) is the gold standard for the treatment of BCC of the ear. For nonsurgical candidates—those with high bleeding risk, low life expectancy, or other medical or social factors—definitive radiation therapy (RT) may be an option. Our study sought to examine recurrence rates in patients with BCC of the ear treated with MMS vs RT.

Methods

A retrospective review of patients undergoing treatment of BCC of the ear at Bighorn Mohs Surgery and Dermatology Center (San Diego, California) between January 2017 and December 2019 was conducted. A total of 507 medical records were reviewed, and 102 patients were included in the study. Inclusion criteria consisted of biopsy-confirmed BCC of the ear that was treated with MMS, RT, or both. Data on patient demographics, tumor characteristics, treatment modality, and recurrence rates were collected from medical records. This retrospective review of medical records was exempt from institutional review board approval, as it did not involve direct human research subjects, solely entailing a retrospective examination of existing data.

Results

Of the 102 patients included, 82 were male and 20 were female, with an average age of 71 years. All patients were White with the exception of 1 patient whose race was unknown. Two patients were immunocompromised. The helix was identified as the most frequently involved site on the ear (Table). Most of the tumors (56/102) exhibited aggressive histologic subtypes; 36 tumors had nonaggressive histology, and 10 had no subtype listed. Two of the BCCs demonstrated perineural invasion on biopsy. Mohs micrographic surgery was used to treat 96 BCCs, definitive RT was used to treat 5 BCCs (all of which occurred in nonsurgical candidates), and MMS and adjuvant RT were used in 1 patient given multifocal perineural involvement. All 5 patients treated with definitive RT received electron beam radiation therapy; the total dose ranged from 5100 to 6000 cGy divided into 17 to 24 fractions. The final MMS defects ranged from 6 to 55 mm in size. The average follow-up time was 2.8 years. One of the BCCs on the helix that was treated with MMS recurred after 1.3 years. The overall recurrence rate was 0.98%. None of the patients treated with definitive RT experienced recurrence after the mean follow-up time of 2.8 years.

Comment

Basal cell carcinoma is the most commonly diagnosed cancer in the United States, with approximately 2 million new cases each year.¹ Treatment modalities for localized BCC include MMS, surgical excision, electrodesiccation and curettage, topical and intralesional medications, laser therapy, and RT. For high-risk BCCs, MMS is associated with the lowest recurrence rates⁴ and remains the gold standard for treatment. For patients with contraindications to surgery, definitive RT is an alternative treatment for high-risk BCC.¹

Definitive RT can be employed for patients who are poor surgical candidates or when surgery would result in substantial morbidity, impaired function, and/or poor cosmesis.³ Radiation therapy for skin cancers of the ear commonly is administered using high-energy electrons that produce double-strand breaks in the DNA of malignant cells, leading to cell death.⁴ Disadvantages of RT compared to MMS include a longer treatment course (3 to 6 weeks), possible minimal long-term cosmetic sequelae (eg, color or texture mismatch), lack of pathologic confirmation of margin control, and small risk for secondary malignancy in the treatment field over 2 to 3 decades. For patients with incurable or metastatic disease, palliative RT can provide local control and/or symptomatic relief to improve quality of life.⁴ Adjuvant RT may be indicated if there is substantial perineural involvement or positive margins after MMS when margins are unable to be achieved or in patients who may not tolerate prolonged or extensive surgical procedures.³

Basal cell carcinoma of the ear is considered a high-risk anatomic location independent of other prognostic factors. Basal cell carcinomas of the ear have a higher propensity for more aggressive histologic subtypes and subclinical spread.⁵ Our study demonstrated a higher proportion of aggressive histologic subtypes (56/102 [54.9%]) compared with nonaggressive subtypes (36/102 [35.3%]). There was 1 recurrence of a nodular, sclerosing, and infiltrative BCC on the helix treated with MMS after 1.3 years.

Limitations of our study include that it was conducted at a single institution with a homogenous study population and with relatively short follow-up.

Conclusion

Our study further validates the well-known utility of MMS for the treatment of BCC of the ears. Definitive RT is a suitable alternative for patients who are not surgical candidates. Adjuvant RT may be considered for substantial perineural involvement or positive margins after MMS.³

Basal cell carcinoma (BCC) of the ear may have aggressive histologic subtypes and a greater propensity for subclinical spread than BCC in other anatomic locations. In this retrospective analysis, we evaluated recurrence rates of BCC of the ear in 102 patients who underwent treatment with Mohs micrographic surgery (MMS) or radiation therapy (RT) at a single institution between January 2017 and December 2019. Data on patient demographics, tumor characteristics, treatment modality, and recurrence rates were collected from medical records. Recurrence rates were assessed over a mean follow-up time of 2.8 years. Although MMS is the gold standard for treatment of BCC of the ear, RT may be a suitable alternative for nonsurgical candidates.

Basal cell carcinoma (BCC) of the ear may have aggressive histologic subtypes and a greater propensity for subclinical spread than BCC in other anatomic locations. Given that these aggressive histologic subtypes—defined as morpheaform, basosquamous, sclerosing, infiltrative, or micronodular in any portion of the tumor—have been reported as independent predictors of recurrence,^1,2 BCC of the ear may be more likely to recur.

Mohs micrographic surgery (MMS) is the gold standard for the treatment of BCC of the ear. For nonsurgical candidates—those with high bleeding risk, low life expectancy, or other medical or social factors—definitive radiation therapy (RT) may be an option. Our study sought to examine recurrence rates in patients with BCC of the ear treated with MMS vs RT.

Methods

A retrospective review of patients undergoing treatment of BCC of the ear at Bighorn Mohs Surgery and Dermatology Center (San Diego, California) between January 2017 and December 2019 was conducted. A total of 507 medical records were reviewed, and 102 patients were included in the study. Inclusion criteria consisted of biopsy-confirmed BCC of the ear that was treated with MMS, RT, or both. Data on patient demographics, tumor characteristics, treatment modality, and recurrence rates were collected from medical records. This retrospective review of medical records was exempt from institutional review board approval, as it did not involve direct human research subjects, solely entailing a retrospective examination of existing data.

Results

Of the 102 patients included, 82 were male and 20 were female, with an average age of 71 years. All patients were White with the exception of 1 patient whose race was unknown. Two patients were immunocompromised. The helix was identified as the most frequently involved site on the ear (Table). Most of the tumors (56/102) exhibited aggressive histologic subtypes; 36 tumors had nonaggressive histology, and 10 had no subtype listed. Two of the BCCs demonstrated perineural invasion on biopsy. Mohs micrographic surgery was used to treat 96 BCCs, definitive RT was used to treat 5 BCCs (all of which occurred in nonsurgical candidates), and MMS and adjuvant RT were used in 1 patient given multifocal perineural involvement. All 5 patients treated with definitive RT received electron beam radiation therapy; the total dose ranged from 5100 to 6000 cGy divided into 17 to 24 fractions. The final MMS defects ranged from 6 to 55 mm in size. The average follow-up time was 2.8 years. One of the BCCs on the helix that was treated with MMS recurred after 1.3 years. The overall recurrence rate was 0.98%. None of the patients treated with definitive RT experienced recurrence after the mean follow-up time of 2.8 years.

Comment

Basal cell carcinoma is the most commonly diagnosed cancer in the United States, with approximately 2 million new cases each year.¹ Treatment modalities for localized BCC include MMS, surgical excision, electrodesiccation and curettage, topical and intralesional medications, laser therapy, and RT. For high-risk BCCs, MMS is associated with the lowest recurrence rates⁴ and remains the gold standard for treatment. For patients with contraindications to surgery, definitive RT is an alternative treatment for high-risk BCC.¹

Definitive RT can be employed for patients who are poor surgical candidates or when surgery would result in substantial morbidity, impaired function, and/or poor cosmesis.³ Radiation therapy for skin cancers of the ear commonly is administered using high-energy electrons that produce double-strand breaks in the DNA of malignant cells, leading to cell death.⁴ Disadvantages of RT compared to MMS include a longer treatment course (3 to 6 weeks), possible minimal long-term cosmetic sequelae (eg, color or texture mismatch), lack of pathologic confirmation of margin control, and small risk for secondary malignancy in the treatment field over 2 to 3 decades. For patients with incurable or metastatic disease, palliative RT can provide local control and/or symptomatic relief to improve quality of life.⁴ Adjuvant RT may be indicated if there is substantial perineural involvement or positive margins after MMS when margins are unable to be achieved or in patients who may not tolerate prolonged or extensive surgical procedures.³

Basal cell carcinoma of the ear is considered a high-risk anatomic location independent of other prognostic factors. Basal cell carcinomas of the ear have a higher propensity for more aggressive histologic subtypes and subclinical spread.⁵ Our study demonstrated a higher proportion of aggressive histologic subtypes (56/102 [54.9%]) compared with nonaggressive subtypes (36/102 [35.3%]). There was 1 recurrence of a nodular, sclerosing, and infiltrative BCC on the helix treated with MMS after 1.3 years.

Limitations of our study include that it was conducted at a single institution with a homogenous study population and with relatively short follow-up.

Conclusion

Our study further validates the well-known utility of MMS for the treatment of BCC of the ears. Definitive RT is a suitable alternative for patients who are not surgical candidates. Adjuvant RT may be considered for substantial perineural involvement or positive margins after MMS.³

Basal cell carcinoma (BCC) of the ear may have aggressive histologic subtypes and a greater propensity for subclinical spread than BCC in other anatomic locations. In this retrospective analysis, we evaluated recurrence rates of BCC of the ear in 102 patients who underwent treatment with Mohs micrographic surgery (MMS) or radiation therapy (RT) at a single institution between January 2017 and December 2019. Data on patient demographics, tumor characteristics, treatment modality, and recurrence rates were collected from medical records. Recurrence rates were assessed over a mean follow-up time of 2.8 years. Although MMS is the gold standard for treatment of BCC of the ear, RT may be a suitable alternative for nonsurgical candidates.

Basal cell carcinoma (BCC) of the ear may have aggressive histologic subtypes and a greater propensity for subclinical spread than BCC in other anatomic locations. Given that these aggressive histologic subtypes—defined as morpheaform, basosquamous, sclerosing, infiltrative, or micronodular in any portion of the tumor—have been reported as independent predictors of recurrence,^1,2 BCC of the ear may be more likely to recur.

Mohs micrographic surgery (MMS) is the gold standard for the treatment of BCC of the ear. For nonsurgical candidates—those with high bleeding risk, low life expectancy, or other medical or social factors—definitive radiation therapy (RT) may be an option. Our study sought to examine recurrence rates in patients with BCC of the ear treated with MMS vs RT.

Methods

A retrospective review of patients undergoing treatment of BCC of the ear at Bighorn Mohs Surgery and Dermatology Center (San Diego, California) between January 2017 and December 2019 was conducted. A total of 507 medical records were reviewed, and 102 patients were included in the study. Inclusion criteria consisted of biopsy-confirmed BCC of the ear that was treated with MMS, RT, or both. Data on patient demographics, tumor characteristics, treatment modality, and recurrence rates were collected from medical records. This retrospective review of medical records was exempt from institutional review board approval, as it did not involve direct human research subjects, solely entailing a retrospective examination of existing data.

Results

Of the 102 patients included, 82 were male and 20 were female, with an average age of 71 years. All patients were White with the exception of 1 patient whose race was unknown. Two patients were immunocompromised. The helix was identified as the most frequently involved site on the ear (Table). Most of the tumors (56/102) exhibited aggressive histologic subtypes; 36 tumors had nonaggressive histology, and 10 had no subtype listed. Two of the BCCs demonstrated perineural invasion on biopsy. Mohs micrographic surgery was used to treat 96 BCCs, definitive RT was used to treat 5 BCCs (all of which occurred in nonsurgical candidates), and MMS and adjuvant RT were used in 1 patient given multifocal perineural involvement. All 5 patients treated with definitive RT received electron beam radiation therapy; the total dose ranged from 5100 to 6000 cGy divided into 17 to 24 fractions. The final MMS defects ranged from 6 to 55 mm in size. The average follow-up time was 2.8 years. One of the BCCs on the helix that was treated with MMS recurred after 1.3 years. The overall recurrence rate was 0.98%. None of the patients treated with definitive RT experienced recurrence after the mean follow-up time of 2.8 years.

Comment

Basal cell carcinoma is the most commonly diagnosed cancer in the United States, with approximately 2 million new cases each year.¹ Treatment modalities for localized BCC include MMS, surgical excision, electrodesiccation and curettage, topical and intralesional medications, laser therapy, and RT. For high-risk BCCs, MMS is associated with the lowest recurrence rates⁴ and remains the gold standard for treatment. For patients with contraindications to surgery, definitive RT is an alternative treatment for high-risk BCC.¹

Definitive RT can be employed for patients who are poor surgical candidates or when surgery would result in substantial morbidity, impaired function, and/or poor cosmesis.³ Radiation therapy for skin cancers of the ear commonly is administered using high-energy electrons that produce double-strand breaks in the DNA of malignant cells, leading to cell death.⁴ Disadvantages of RT compared to MMS include a longer treatment course (3 to 6 weeks), possible minimal long-term cosmetic sequelae (eg, color or texture mismatch), lack of pathologic confirmation of margin control, and small risk for secondary malignancy in the treatment field over 2 to 3 decades. For patients with incurable or metastatic disease, palliative RT can provide local control and/or symptomatic relief to improve quality of life.⁴ Adjuvant RT may be indicated if there is substantial perineural involvement or positive margins after MMS when margins are unable to be achieved or in patients who may not tolerate prolonged or extensive surgical procedures.³

Basal cell carcinoma of the ear is considered a high-risk anatomic location independent of other prognostic factors. Basal cell carcinomas of the ear have a higher propensity for more aggressive histologic subtypes and subclinical spread.⁵ Our study demonstrated a higher proportion of aggressive histologic subtypes (56/102 [54.9%]) compared with nonaggressive subtypes (36/102 [35.3%]). There was 1 recurrence of a nodular, sclerosing, and infiltrative BCC on the helix treated with MMS after 1.3 years.

Limitations of our study include that it was conducted at a single institution with a homogenous study population and with relatively short follow-up.

Conclusion

Our study further validates the well-known utility of MMS for the treatment of BCC of the ears. Definitive RT is a suitable alternative for patients who are not surgical candidates. Adjuvant RT may be considered for substantial perineural involvement or positive margins after MMS.³

With the increasing utilization of telemedicine since the COVID-19 pandemic, it is critical that clinicians have an appropriate understanding of the application of virtual care resources, including teledermatology. We present a case series of 3 patients to demonstrate the clinical utility of teledermatology in reducing the time to diagnosis of various rare and/or aggressive cutaneous malignancies, including Merkel cell carcinoma, malignant melanoma, and atypical fibroxanthoma. Cases were obtained from one large Midwestern medical center during the month of July 2021. Each case presented includes a description of the initial teledermatology presentation and reviews the clinical timeline from initial consultation submission to in-person clinic visit with lesion biopsy. This case series demonstrates real-world examples of how teledermatology can be utilized to expedite the care of specific vulnerable patient populations.

Teledermatology is a rapidly growing digital resource with specific utility in triaging patients to determine those requiring in-person evaluation for early and accurate detection of skin malignancies. Approximately one-third of teledermatology consultations result in face-to-face clinical encounters, with malignant neoplasms being the leading cause for biopsy.^1,2 For specific populations, such as geriatric and immunocompromised patients, teledermatology may serve as a valuable tool, particularly in the wake of the COVID-19 pandemic. Furthermore, telemedicine may aid in addressing health disparities within the field of medicine and ultimately may improve access to care for vulnerable populations.³ Along with increasing access to specific subspecialty expertise, the use of teledermatology may reduce health care costs and improve the overall quality of care delivered to patients.^4,5

We describe the clinical utility of teledermatology in triaging and diagnosing skin malignancies through a series of 3 cases obtained from digital image review at one large Midwestern medical center during the month of July 2021. Three unique cases with a final diagnosis of a rare or aggressive skin cancer were selected as examples, including a 75-year-old man with Merkle cell carcinoma, a 55-year-old man with aggressive pT3b malignant melanoma, and a 72-year-old man with an atypical fibroxanthoma. A clinical timeline of each case is presented, including the time intervals from initial image submission to image review, image submission to face-to-face clinical encounter, and image submission to final diagnosis. In all cases, the primary care provider submitted an order for teledermatology, and the teledermatology team obtained the images.

Case Series

Patient 1—Images of the right hand of a 75-year-old man with a medical history of basal cell carcinoma were submitted for teledermatology consultation utilizing store-and-forward image-capturing technology (day 1). The patient history provided with image submission indicated that the lesion had been present for 6 months and there were no associated symptoms. Clinical imaging demonstrated a pink-red pearly papule located on the proximal fourth digit of the dorsal aspect of the right hand (Figure 1). One day following the teledermatology request (day 2), the patient’s case was reviewed and triaged for an in-person visit. The patient was brought to clinic on day 34, and a biopsy was performed. On day 36, dermatopathology results indicated a diagnosis of Merkel cell carcinoma. On day 37, the patient was referred to surgical oncology, and on day 44, the patient underwent an initial surgical oncology visit with a plan for wide local excision of the right fourth digit with right axillary sentinel lymph node biopsy.

Patient 2—Images of the left flank of a 55-year-old man were submitted for teledermatology consultation via store-and-forward technology (day 1). A patient history provided with the image indicated that the lesion had been present for months to years and there were no associated symptoms, but the lesion recently had changed in color and size. Teledermatology images were reviewed on day 3 and demonstrated a 2- to 3-cm brown plaque on the left flank with color variegation and a prominent red papule protruding centrally (Figure 2). The patient was scheduled for an urgent in-person visit with biopsy. On day 6, the patient presented to clinic and an excision biopsy was performed. Dermatopathology was ordered with a RUSH indication, with results on day 7 revealing a pT3b malignant melanoma. An urgent consultation to surgical oncology was placed on the same day, and the patient underwent an initial surgical oncology visit on day 24 with a plan for wide local excision with left axillary and inguinal sentinel lymph node biopsy.

Patient 3—Images of the left ear of a 72-year-old man were submitted for teledermatology consultation utilizing review via store-and-forward technology (day 1). A patient history indicated that the lesion had been present for 3 months with associated bleeding. Image review demonstrated a solitary pearly pink papule located on the crura of the antihelix (Figure 3). Initial teledermatology consultation was reviewed on day 2 with notification of the need for in-person evaluation. The patient presented to clinic on day 33 for a biopsy, with dermatopathology results on day 36 consistent with an atypical fibroxanthoma. The patient was scheduled for Mohs micrographic surgery on day 37 and underwent surgical treatment on day 64.

Comment

Teledermatology consultations from all patients demonstrated adequate image quality to be able to evaluate the lesion of concern and yielded a request for in-person evaluation with possible biopsy (Table). In this case series, the average time interval from teledermatology consultation placement to teledermatology image report was 2 days (range, 1–3 days). The average time from teledermatology consultation placement to face-to-face encounter with biopsy was 24.3 days for the 3 cases presented in this series (range, 6–34 days). The initial surgical oncology visits took place an average of 34 days after the initial teledermatology consultation was placed for the 2 patients requiring referral (44 days for patient 1; 24 days for patient 2). For patient 3, Mohs micrographic surgery was required for treatment, which was scheduled by day 37 and subsequently performed on day 64.

When specifically looking at the diagnosis of cutaneous malignancies, studies have found that the incidence of skin cancer detection is similar for teledermatology compared to in-person clinic visits.^6,7 Creighton-Smith et al⁶ performed a retrospective cohort study comparing prebiopsy and postbiopsy diagnostic accuracy and detection rates of skin cancer between store-and-forward technology and face-to-face consultation. When adjusting for possible compounding factors including personal and family history of skin cancer, there was no notable difference in detection rates of any skin cancer, including melanoma and nonmelanoma skin cancers. Furthermore, the 2 cohorts of patients were found to have similar prebiopsy and postbiopsy diagnostic concordance, with similar times from consultation being placed to requested biopsy and time from biopsy to final treatment.⁶

Clarke et al⁷ similarly analyzed the accuracy of store-and-forward teledermatology and found that there was overall concordance in diagnosis when comparing clinical dermatologists to teledermatologists. Moreover, when melanocytic lesions were excluded from the study, the decision to biopsy did not differ substantially.⁷

Areas of further study include determining what percentage of teledermatology lesions of concern for malignancy were proven to be skin cancer after in-person evaluation and biopsy, as well as investigating the effectiveness of teledermatology for melanocytic lesions, which frequently are removed from analysis in large-scale teledermatology studies.

Although teledermatology has substantial clinical utility and may serve as a great resource for specific populations, including geriatric patients and those who are immunocompromised, it is important to recognize notable limitations. Specifically, brief history and image review should not serve as replacements for a face-to-face visit with physical examination in cases where the diagnosis remains uncertain or when high-risk skin malignancies are suspected or included in the differential. Certain aggressive cutaneous malignancies such as Merkel cell carcinoma may appear as less aggressive via teledermatology due to restrictions of technology.

Conclusion

Teledermatology has had a major impact on the way health care is delivered to patients and may increase access to care, reducing unnecessary in-person visits and decreasing the number of in-person visit no-shows. With the appropriate use of a brief clinical history and image review, teledermatology can be effective to evaluate specific lesions of concern. We report 3 unique cases identified during a 1-month period at a large Midwestern medical center. These cases serve as important examples of the application of teledermatology in reducing the time to diagnosis of aggressive skin malignancies. Further research on the clinical utility of teledermatology is warranted.

Acknowledgments—The authors thank the additional providers from the University of Wisconsin and William S. Middleton Memorial Veterans Hospital (both in Madison, Wisconsin) involved in the medical care of the patients included in this case series.

With the increasing utilization of telemedicine since the COVID-19 pandemic, it is critical that clinicians have an appropriate understanding of the application of virtual care resources, including teledermatology. We present a case series of 3 patients to demonstrate the clinical utility of teledermatology in reducing the time to diagnosis of various rare and/or aggressive cutaneous malignancies, including Merkel cell carcinoma, malignant melanoma, and atypical fibroxanthoma. Cases were obtained from one large Midwestern medical center during the month of July 2021. Each case presented includes a description of the initial teledermatology presentation and reviews the clinical timeline from initial consultation submission to in-person clinic visit with lesion biopsy. This case series demonstrates real-world examples of how teledermatology can be utilized to expedite the care of specific vulnerable patient populations.

Teledermatology is a rapidly growing digital resource with specific utility in triaging patients to determine those requiring in-person evaluation for early and accurate detection of skin malignancies. Approximately one-third of teledermatology consultations result in face-to-face clinical encounters, with malignant neoplasms being the leading cause for biopsy.^1,2 For specific populations, such as geriatric and immunocompromised patients, teledermatology may serve as a valuable tool, particularly in the wake of the COVID-19 pandemic. Furthermore, telemedicine may aid in addressing health disparities within the field of medicine and ultimately may improve access to care for vulnerable populations.³ Along with increasing access to specific subspecialty expertise, the use of teledermatology may reduce health care costs and improve the overall quality of care delivered to patients.^4,5

We describe the clinical utility of teledermatology in triaging and diagnosing skin malignancies through a series of 3 cases obtained from digital image review at one large Midwestern medical center during the month of July 2021. Three unique cases with a final diagnosis of a rare or aggressive skin cancer were selected as examples, including a 75-year-old man with Merkle cell carcinoma, a 55-year-old man with aggressive pT3b malignant melanoma, and a 72-year-old man with an atypical fibroxanthoma. A clinical timeline of each case is presented, including the time intervals from initial image submission to image review, image submission to face-to-face clinical encounter, and image submission to final diagnosis. In all cases, the primary care provider submitted an order for teledermatology, and the teledermatology team obtained the images.

Case Series

Patient 1—Images of the right hand of a 75-year-old man with a medical history of basal cell carcinoma were submitted for teledermatology consultation utilizing store-and-forward image-capturing technology (day 1). The patient history provided with image submission indicated that the lesion had been present for 6 months and there were no associated symptoms. Clinical imaging demonstrated a pink-red pearly papule located on the proximal fourth digit of the dorsal aspect of the right hand (Figure 1). One day following the teledermatology request (day 2), the patient’s case was reviewed and triaged for an in-person visit. The patient was brought to clinic on day 34, and a biopsy was performed. On day 36, dermatopathology results indicated a diagnosis of Merkel cell carcinoma. On day 37, the patient was referred to surgical oncology, and on day 44, the patient underwent an initial surgical oncology visit with a plan for wide local excision of the right fourth digit with right axillary sentinel lymph node biopsy.

Patient 2—Images of the left flank of a 55-year-old man were submitted for teledermatology consultation via store-and-forward technology (day 1). A patient history provided with the image indicated that the lesion had been present for months to years and there were no associated symptoms, but the lesion recently had changed in color and size. Teledermatology images were reviewed on day 3 and demonstrated a 2- to 3-cm brown plaque on the left flank with color variegation and a prominent red papule protruding centrally (Figure 2). The patient was scheduled for an urgent in-person visit with biopsy. On day 6, the patient presented to clinic and an excision biopsy was performed. Dermatopathology was ordered with a RUSH indication, with results on day 7 revealing a pT3b malignant melanoma. An urgent consultation to surgical oncology was placed on the same day, and the patient underwent an initial surgical oncology visit on day 24 with a plan for wide local excision with left axillary and inguinal sentinel lymph node biopsy.

Patient 3—Images of the left ear of a 72-year-old man were submitted for teledermatology consultation utilizing review via store-and-forward technology (day 1). A patient history indicated that the lesion had been present for 3 months with associated bleeding. Image review demonstrated a solitary pearly pink papule located on the crura of the antihelix (Figure 3). Initial teledermatology consultation was reviewed on day 2 with notification of the need for in-person evaluation. The patient presented to clinic on day 33 for a biopsy, with dermatopathology results on day 36 consistent with an atypical fibroxanthoma. The patient was scheduled for Mohs micrographic surgery on day 37 and underwent surgical treatment on day 64.

Comment

Teledermatology consultations from all patients demonstrated adequate image quality to be able to evaluate the lesion of concern and yielded a request for in-person evaluation with possible biopsy (Table). In this case series, the average time interval from teledermatology consultation placement to teledermatology image report was 2 days (range, 1–3 days). The average time from teledermatology consultation placement to face-to-face encounter with biopsy was 24.3 days for the 3 cases presented in this series (range, 6–34 days). The initial surgical oncology visits took place an average of 34 days after the initial teledermatology consultation was placed for the 2 patients requiring referral (44 days for patient 1; 24 days for patient 2). For patient 3, Mohs micrographic surgery was required for treatment, which was scheduled by day 37 and subsequently performed on day 64.

When specifically looking at the diagnosis of cutaneous malignancies, studies have found that the incidence of skin cancer detection is similar for teledermatology compared to in-person clinic visits.^6,7 Creighton-Smith et al⁶ performed a retrospective cohort study comparing prebiopsy and postbiopsy diagnostic accuracy and detection rates of skin cancer between store-and-forward technology and face-to-face consultation. When adjusting for possible compounding factors including personal and family history of skin cancer, there was no notable difference in detection rates of any skin cancer, including melanoma and nonmelanoma skin cancers. Furthermore, the 2 cohorts of patients were found to have similar prebiopsy and postbiopsy diagnostic concordance, with similar times from consultation being placed to requested biopsy and time from biopsy to final treatment.⁶

Clarke et al⁷ similarly analyzed the accuracy of store-and-forward teledermatology and found that there was overall concordance in diagnosis when comparing clinical dermatologists to teledermatologists. Moreover, when melanocytic lesions were excluded from the study, the decision to biopsy did not differ substantially.⁷

Areas of further study include determining what percentage of teledermatology lesions of concern for malignancy were proven to be skin cancer after in-person evaluation and biopsy, as well as investigating the effectiveness of teledermatology for melanocytic lesions, which frequently are removed from analysis in large-scale teledermatology studies.

Although teledermatology has substantial clinical utility and may serve as a great resource for specific populations, including geriatric patients and those who are immunocompromised, it is important to recognize notable limitations. Specifically, brief history and image review should not serve as replacements for a face-to-face visit with physical examination in cases where the diagnosis remains uncertain or when high-risk skin malignancies are suspected or included in the differential. Certain aggressive cutaneous malignancies such as Merkel cell carcinoma may appear as less aggressive via teledermatology due to restrictions of technology.

Conclusion

Teledermatology has had a major impact on the way health care is delivered to patients and may increase access to care, reducing unnecessary in-person visits and decreasing the number of in-person visit no-shows. With the appropriate use of a brief clinical history and image review, teledermatology can be effective to evaluate specific lesions of concern. We report 3 unique cases identified during a 1-month period at a large Midwestern medical center. These cases serve as important examples of the application of teledermatology in reducing the time to diagnosis of aggressive skin malignancies. Further research on the clinical utility of teledermatology is warranted.

Acknowledgments—The authors thank the additional providers from the University of Wisconsin and William S. Middleton Memorial Veterans Hospital (both in Madison, Wisconsin) involved in the medical care of the patients included in this case series.

With the increasing utilization of telemedicine since the COVID-19 pandemic, it is critical that clinicians have an appropriate understanding of the application of virtual care resources, including teledermatology. We present a case series of 3 patients to demonstrate the clinical utility of teledermatology in reducing the time to diagnosis of various rare and/or aggressive cutaneous malignancies, including Merkel cell carcinoma, malignant melanoma, and atypical fibroxanthoma. Cases were obtained from one large Midwestern medical center during the month of July 2021. Each case presented includes a description of the initial teledermatology presentation and reviews the clinical timeline from initial consultation submission to in-person clinic visit with lesion biopsy. This case series demonstrates real-world examples of how teledermatology can be utilized to expedite the care of specific vulnerable patient populations.

Teledermatology is a rapidly growing digital resource with specific utility in triaging patients to determine those requiring in-person evaluation for early and accurate detection of skin malignancies. Approximately one-third of teledermatology consultations result in face-to-face clinical encounters, with malignant neoplasms being the leading cause for biopsy.^1,2 For specific populations, such as geriatric and immunocompromised patients, teledermatology may serve as a valuable tool, particularly in the wake of the COVID-19 pandemic. Furthermore, telemedicine may aid in addressing health disparities within the field of medicine and ultimately may improve access to care for vulnerable populations.³ Along with increasing access to specific subspecialty expertise, the use of teledermatology may reduce health care costs and improve the overall quality of care delivered to patients.^4,5

We describe the clinical utility of teledermatology in triaging and diagnosing skin malignancies through a series of 3 cases obtained from digital image review at one large Midwestern medical center during the month of July 2021. Three unique cases with a final diagnosis of a rare or aggressive skin cancer were selected as examples, including a 75-year-old man with Merkle cell carcinoma, a 55-year-old man with aggressive pT3b malignant melanoma, and a 72-year-old man with an atypical fibroxanthoma. A clinical timeline of each case is presented, including the time intervals from initial image submission to image review, image submission to face-to-face clinical encounter, and image submission to final diagnosis. In all cases, the primary care provider submitted an order for teledermatology, and the teledermatology team obtained the images.

Case Series

Patient 1—Images of the right hand of a 75-year-old man with a medical history of basal cell carcinoma were submitted for teledermatology consultation utilizing store-and-forward image-capturing technology (day 1). The patient history provided with image submission indicated that the lesion had been present for 6 months and there were no associated symptoms. Clinical imaging demonstrated a pink-red pearly papule located on the proximal fourth digit of the dorsal aspect of the right hand (Figure 1). One day following the teledermatology request (day 2), the patient’s case was reviewed and triaged for an in-person visit. The patient was brought to clinic on day 34, and a biopsy was performed. On day 36, dermatopathology results indicated a diagnosis of Merkel cell carcinoma. On day 37, the patient was referred to surgical oncology, and on day 44, the patient underwent an initial surgical oncology visit with a plan for wide local excision of the right fourth digit with right axillary sentinel lymph node biopsy.

Patient 2—Images of the left flank of a 55-year-old man were submitted for teledermatology consultation via store-and-forward technology (day 1). A patient history provided with the image indicated that the lesion had been present for months to years and there were no associated symptoms, but the lesion recently had changed in color and size. Teledermatology images were reviewed on day 3 and demonstrated a 2- to 3-cm brown plaque on the left flank with color variegation and a prominent red papule protruding centrally (Figure 2). The patient was scheduled for an urgent in-person visit with biopsy. On day 6, the patient presented to clinic and an excision biopsy was performed. Dermatopathology was ordered with a RUSH indication, with results on day 7 revealing a pT3b malignant melanoma. An urgent consultation to surgical oncology was placed on the same day, and the patient underwent an initial surgical oncology visit on day 24 with a plan for wide local excision with left axillary and inguinal sentinel lymph node biopsy.

Patient 3—Images of the left ear of a 72-year-old man were submitted for teledermatology consultation utilizing review via store-and-forward technology (day 1). A patient history indicated that the lesion had been present for 3 months with associated bleeding. Image review demonstrated a solitary pearly pink papule located on the crura of the antihelix (Figure 3). Initial teledermatology consultation was reviewed on day 2 with notification of the need for in-person evaluation. The patient presented to clinic on day 33 for a biopsy, with dermatopathology results on day 36 consistent with an atypical fibroxanthoma. The patient was scheduled for Mohs micrographic surgery on day 37 and underwent surgical treatment on day 64.

Comment

Teledermatology consultations from all patients demonstrated adequate image quality to be able to evaluate the lesion of concern and yielded a request for in-person evaluation with possible biopsy (Table). In this case series, the average time interval from teledermatology consultation placement to teledermatology image report was 2 days (range, 1–3 days). The average time from teledermatology consultation placement to face-to-face encounter with biopsy was 24.3 days for the 3 cases presented in this series (range, 6–34 days). The initial surgical oncology visits took place an average of 34 days after the initial teledermatology consultation was placed for the 2 patients requiring referral (44 days for patient 1; 24 days for patient 2). For patient 3, Mohs micrographic surgery was required for treatment, which was scheduled by day 37 and subsequently performed on day 64.

When specifically looking at the diagnosis of cutaneous malignancies, studies have found that the incidence of skin cancer detection is similar for teledermatology compared to in-person clinic visits.^6,7 Creighton-Smith et al⁶ performed a retrospective cohort study comparing prebiopsy and postbiopsy diagnostic accuracy and detection rates of skin cancer between store-and-forward technology and face-to-face consultation. When adjusting for possible compounding factors including personal and family history of skin cancer, there was no notable difference in detection rates of any skin cancer, including melanoma and nonmelanoma skin cancers. Furthermore, the 2 cohorts of patients were found to have similar prebiopsy and postbiopsy diagnostic concordance, with similar times from consultation being placed to requested biopsy and time from biopsy to final treatment.⁶

Clarke et al⁷ similarly analyzed the accuracy of store-and-forward teledermatology and found that there was overall concordance in diagnosis when comparing clinical dermatologists to teledermatologists. Moreover, when melanocytic lesions were excluded from the study, the decision to biopsy did not differ substantially.⁷

Areas of further study include determining what percentage of teledermatology lesions of concern for malignancy were proven to be skin cancer after in-person evaluation and biopsy, as well as investigating the effectiveness of teledermatology for melanocytic lesions, which frequently are removed from analysis in large-scale teledermatology studies.

Although teledermatology has substantial clinical utility and may serve as a great resource for specific populations, including geriatric patients and those who are immunocompromised, it is important to recognize notable limitations. Specifically, brief history and image review should not serve as replacements for a face-to-face visit with physical examination in cases where the diagnosis remains uncertain or when high-risk skin malignancies are suspected or included in the differential. Certain aggressive cutaneous malignancies such as Merkel cell carcinoma may appear as less aggressive via teledermatology due to restrictions of technology.

Conclusion

Teledermatology has had a major impact on the way health care is delivered to patients and may increase access to care, reducing unnecessary in-person visits and decreasing the number of in-person visit no-shows. With the appropriate use of a brief clinical history and image review, teledermatology can be effective to evaluate specific lesions of concern. We report 3 unique cases identified during a 1-month period at a large Midwestern medical center. These cases serve as important examples of the application of teledermatology in reducing the time to diagnosis of aggressive skin malignancies. Further research on the clinical utility of teledermatology is warranted.

Acknowledgments—The authors thank the additional providers from the University of Wisconsin and William S. Middleton Memorial Veterans Hospital (both in Madison, Wisconsin) involved in the medical care of the patients included in this case series.

Introduction

Barrett’s esophagus (BE) is characterized by the replacement of squamous epithelium by columnar metaplasia of the distal esophagus (>1 cm length). It is a precancerous condition, with 3%-5% of patients with BE developing esophageal adenocarcinoma (EAC) in their lifetime. EAC is one of the cancers with high morbidity and mortality (5-year survival < 20%), and its incidence has been on the rise. Studies examining the natural history of BE have demonstrated that the progression happens through a metaplasia-dysplasia-neoplasia sequence. Therefore, early detection of BE and timely management to prevent progression to EAC is crucial.

Grades of Dysplasia

The current gold standard for the diagnosis of BE neoplasia includes a high-quality endoscopic evaluation and biopsies. Biopsies should be obtained from any visible lesions (nodules, ulcers) followed by a random 4-quadrant fashion (Seattle protocol) interval of the entire length of the BE segment. It is essential to pay attention to the results of the biopsy that have been obtained since it will not only determine the surveillance interval but is crucial in planning any necessary endoscopic therapy. The possible results of the biopsy and its implications are:

• No intestinal metaplasia (IM): This would rule out Barrett’s esophagus and no further surveillance would be necessary. A recent population-based study of over 1 million patients showed a 55% and 61% reduced risk of upper gastrointestinal (UGI) cancer and deaths respectively after a negative endoscopy.¹
• Intestinal metaplasia with no dysplasia (non-dysplastic BE): Biopsies confirm presence of intestinal metaplasia in the biopsies without any evidence of dysplasia. While the rate of progression to EAC is low (0.07%-0.25%), it is not absent and thus surveillance would be indicated. Current guidelines suggest repeating an endoscopy with biopsy in 5 years if the length of BE is < 3 cm or 3 years if length of BE ≥ 3 cm.²
• Indeterminate for dysplasia (BE-IND): Biopsies confirm IM but are not able to definitively rule out dysplasia. This can be seen in about 4%-8% of the biopsies obtained. The progression rates to EAC are reported to be comparable or lower to low-grade dysplasia (LGD), so the current recommendation is to intensify acid reduction therapy and repeat endoscopy in 6 months. If repeat endoscopy downgrades to non-dysplastic, then can follow surveillance according to NDBE protocol; otherwise recommend continuing surveillance every 12 months.
• Low-grade dysplasia (BE-LGD): Biopsies confirm IM but also show tightly packed overlapping basal nuclei with hyperchromasia and irregular contours, basal stratification of nuclei, and diminished goblet and columnar cell mucus. There is significant inter-observer variability reported,³ and thus the slides must be reviewed by a second pathologist with experience in BE to confirm the findings. Once confirmed, based on risk factors such as presence of multifocal LGD, persistence of LGD, presence of visible lesions, etc., the patient can be offered Barrett’s endoscopic therapy (BET) or undergo continued surveillance. The decision of pursuing one or the other would be dependent on patient preference and shared decision-making between the patient and the provider.
• High-grade dysplasia (BE-HGD): Biopsies confirm IM with cells showing greater degree of cytologic and architectural alterations of dysplasia than LGD but without overt neoplastic features. Over 40% of the patients would progress to EAC and thus the current recommendations would be to recommend BET in these patients.⁴
• Esophageal adenocarcinoma (EAC): Biopsies demonstrate neoplasia. If the neoplastic changes are limited to the mucosa (T1a) on endoscopic ultrasound or cross-sectional imaging, then BET is suggested. If there is involvement of submucosa, then depending on the depth of invasion, absence of high-risk features (poor differentiation, lymphovascular invasion), BET can be considered as an alternative to esophagectomy.

Lesion Detection on Endoscopy

Data from large population-based studies with at least 3 years of follow-up reported that 58%-66% of EAC detected during endoscopy were diagnosed within 1 year of an index Barrett’s esophagus screening endoscopy, or post-endoscopy Barrett’s neoplasia, and were considered likely to have been missed during index endoscopy.⁵ This underscores the importance of careful and systematic endoscopic examination during an upper endoscopy.

Studies have also demonstrated that longer examination time was associated with significantly higher detection of HGD/EAC.^6,7 Careful examination of the tubular esophagus and gastroesophageal junction (GEJ) should be performed in forward and retroflexed views looking for any subtle areas of nodularity, loop distortion, variability in vascular patterns, mucosal changes concerning for dysplasia or neoplasia. Use of high-definition white light endoscopy (HD-WLE) and virtual chromoendoscopy techniques such as narrow banding imaging (NBI) or blue laser imaging (BLI) are currently recommended in the guidelines.² Spray chromoendoscopy using acetic acid can also be utilized. Another exciting development is the use of artificial intelligence (AI) in detecting and diagnosing BE associated lesions and neoplasia.
 

Barrett’s Endoscopic Therapy (BET)

Patients with visible lesions, dysplasia, or early EAC are candidates for BET (Table 1).

BET involves resective and ablative modalities. The resective modalities include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) and are the modalities of choice for nodular or raised lesions.

EMR involves endoscopic resection of abnormal mucosa using either lift-assisted technique or multi-band ligation (Figure 1).

ESD, on the other hand, involves submucosal dissection and perimeter resection of the lesion, thus providing the advantage of an en-bloc resection. In a recent randomized controlled trial (RCT) of 40 patients undergoing ESD vs EMR for HGD/EAC, ESD was better for curative resection (R0) (58%) compared with EMR (12%); however, the remission rates at 3 months were comparable with two perforations reported in the ESD group while there were no complications in the EMR group.⁸

There is an apparent learning curve when it comes to these advanced techniques, and with more experience, we are seeing comparable results for both these modalities. However, given the complexity and time required for the procedure, current practices typically involve preserving ESD for lesions > 2 cm, those having a likelihood of cancer in the superficial submucosa, or those that EMR cannot remove due to underlying fibrosis or post-EMR recurrence.

University of Kansas Health System

Barrett’s Refractory to Endoscopic Therapy

Failure of BET is defined as persistent columnar lined epithelium (intestinal metaplasia) with inadequate response, after adequate attempts at endoscopic ablation therapy (after resection) with at least four ablation sessions.¹³ If encountered, special attention must be given to check compliance with proton pump inhibitors (PPIs), previous incomplete resection, and presence of large hiatal hernia. If CE-IM is not achieved after multiple sessions, change of ablative modality is typically considered. In addition, careful examination for visible lesions should be performed and even if a small one is noted, this should be first resected prior to application of any ablative therapy.

University of Kansas Health System

Currently there are no guideline recommendations regarding the preference of one endoscopic modality over another or consideration of potential endoscopic or surgical fundoplication. These modalities primarily rely on technologies available at an institution and the preference of a provider based on their training and experience. Most studies indicate 1-3 sessions (~ 3 months apart) of ablative treatment before achieving CE-IM.
 

Success and Adverse Events of BET

In a recent real-world study of over 27,000 patients with dysplastic BE, 5295 underwent BET. Analysis showed that patients with HGD/EAC who had BET had a significantly lower 3-year mortality (HGD: RR, 0.59; 95%CI, 0.49-0.71; EAC: RR, 0.53; 95% CI, 0.44-0.65) compared with those who did not undergo BET. Esophageal strictures were the most common adverse event and were noted in 6.5%, followed by chest pain (1.8%), upper GI bleeding (0.47%), and esophageal perforation (0.2%).¹⁴

In general, adverse events can be divided into immediate and delayed adverse events. Immediate adverse events typically involve bleeding and perforation that can occur during or shortly after the procedure. These are reported at higher rates with resective modalities compared with ablative therapies. Standard endoscopic techniques involving coagulation grasper or clips can be used to achieve hemostasis. Endoscopic suturing devices offer the ability to contain any perforation. The need for surgical intervention is small and limited to adverse events not detected during the procedure.

Delayed adverse events such as stricture and stenosis are higher for resective modalities (up to 30%), especially when involving more significant than 75% of the esophageal circumference. Post-procedural pain/dysphagia is most common after ablative therapies. Dysphagia reported after any endoscopic therapy should be promptly evaluated, and sequential dilation until the goal esophageal lumen is achieved should be performed every 2-4 weeks.
 

Recurrences and Surveillance After BET

What is established is that recurrences can occur and may be subtle, therefore detailed endoscopic surveillance is required. In a prospective study, recurrence rates of 15%-16% for IM and 3%-5% for any dysplasia were reported, with the majority being in the first 2 years after achieving CE-IM.¹⁵ A systematic review of 21 studies looking at the location of recurrences suggested that the majority (56%) occur in the distal esophagus. Of those that occur in the esophagus, about 80% of them were in the distal 2 cm of the esophagus and only 50% of the recurrences were visible recurrences, thus reiterating the importance of meticulous examination and systematic biopsies.¹⁶

On the contrary, a recent single-center study of 217 patients who had achieved CE-IM with 5.5 years of follow-up demonstrated a 26% and 8% recurrence of IM and dysplasia, respectively. One hundred percent of the recurrence in the esophagus was reported as visible.¹⁷ Therefore, follow-up endoscopy surveillance protocol after CE-IM should still involve meticulous examination, biopsy of visible lesions, and systematic biopsies for non-visible lesions from the original BE segment, similar to those patients who have not needed BET.

Current guidelines based on expert consensus and evidence recommend surveillance after CE-IM based on original most advanced histology:²

1. LGD: 1 year, 3 years, and every 2 years after that.

2. HGD/EAC: 3 months, 6 months, 12 months, and annually after that.

There is no clear guideline on when to stop surveillance since the longest available follow-up is around 10 years, and recurrences are still detected. A potential surveillance endpoint may be based on age and comorbidities, especially those that would preclude a patient from being a candidate for BET.
 

When Should a Patient Be Referred?

BE patients with visible lesions and/or dysplastic changes in the biopsy who would require BET should be considered for referral to high-volume centers. Studies have shown higher success for CE-IM and lower rates of adverse events and recurrences in these patients managed at expert centers. The presence of a multidisciplinary team involving pathologists, surgeons, and oncologists is critical and offers a timely opportunity in case of need for a high-risk patient.

Conclusion

BE is a precursor to EAC, with rising incidence and poor 5-year survival. Endoscopic diagnosis is the gold standard and requires a high-quality examination and biopsies. Based on histopathology, a systematic surveillance and BET plan should be performed to achieve CE-IM in patients with dysplasia. Once CE-IM is achieved, regular surveillance should be performed with careful attention to recurrences and complications from the BET modalities.

Dr. Srinivasan and Dr. Sharma are based at the University of Kansas Medical Center, Kansas City, Kansas, and the Kansas City Veterans Affairs Medical Center, Kansas City, Missouri. Dr. Srinivasan has no relevant disclosures. Dr. Sharma disclosed research grants from ERBE, Ironwood Pharmaceuticals, Olympus, and Medtronic. He has served as a consultant for Takeda, Samsung Bioepis, Olympus, and Lumendi, and reports other funding from Medtronic, Fujifilm Medical Systems USA, and Salix.

References

1. Holmberg D, et al. Incidence and mortality in upper gastrointestinal cancer after negative endoscopy for gastroesophageal reflux disease. Gastroenterology. 2022;162(2):431-438.e4.

2. Shaheen NJ, et al. Diagnosis and management of Barrett’s esophagus: An updated ACG guideline. Am J Gastroenterol. 2022 Apr;117(4):559-587.

3. Pech O, et al. Inter-observer variability in the diagnosis of low-grade dysplasia in pathologists: A comparison between experienced and inexperienced pathologists. Gastrointest Endosc. 2006 Apr;63(5):AB130.

4. Krishnamoorthi R, et al. Factors associated with progression of Barrett’s esophagus: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018 Jul;16(7):1046-1055.e8.

5. Visrodia K, et al. Magnitude of missed esophageal adenocarcinoma after Barrett’s esophagus diagnosis: A systematic review and meta-analysis. Gastroenterology. 2016 Mar;150(3):599-607.e7; quiz e14-5.

6. Perisetti A, Sharma P. Tips for improving the identification of neoplastic visible lesions in Barrett’s esophagus. Gastrointest Endosc. 2023 Feb;97(2):248-250.

7. Gupta N, et al. Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett’s esophagus. Gastrointest Endosc. 2012 Sep;76(3):531-538.

8. Terheggen G, et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett’s neoplasia. Gut. 2017 May;66(5):783-793.

9. Wolfson P, et al. Endoscopic eradication therapy for Barrett’s esophagus-related neoplasia: A final 10-year report from the UK National HALO Radiofrequency Ablation Registry. Gastrointest Endosc. 2022 Aug;96(2):223-233.

10. Rösch T, et al. 1151 Multicenter feasibility study of combined injection and argon plasma coagulation (hybrid-APC) in the ablation therapy of neoplastic Barrett esophagus. Gastrointest Endosc. 2017;85(5):AB154.

11. Knabe M, et al. Radiofrequency ablation versus hybrid argon plasma coagulation in Barrett’s esophagus: A prospective randomised trial. Surg Endosc. 2023;37(10):7803-7811.

12. Van Munster SN, et al. Radiofrequency vapor ablation for Barrett’s esophagus: Feasibility, safety, and proof of concept in a stepwise study with in vitro, animal, and the first in-human application. Endoscopy. 2021 Nov;53(11):1162-1168.

13. Emura F, et al. Rio de Janeiro global consensus on landmarks, definitions, and classifications in Barrett’s esophagus: World Endoscopy Organization Delphi study. Gastroenterology. 2022 Jul;163(1):84-96.e2.

14. Singh RR, et al. Real-world evidence of safety and effectiveness of Barrett’s endoscopic therapy. Gastrointest Endosc. 2023 Aug;98(2):155-161.e1.

15. Wani S, et al. Recurrence Is rare following complete eradication of intestinal metaplasia in patients with Barrett’s esophagus and peaks at 18 months. Clin Gastroenterol Hepatol. 2020 Oct;18(11):2609-2617.e2.

16. Duvvuri A, et al. Mo1273 Location and pattern of recurrences in patients with Barrett’s esophagus after endoscopic therapy: A systematic review and critical analysis of the published literature. Gastrointest Endosc. 2020;91(6):AB410-1.

17. He T, et al. Location and appearance of dysplastic Barrett’s esophagus recurrence after endoscopic eradication therapy: No additional yield from random biopsy sampling neosquamous mucosa. Gastrointest Endosc. 2023 Nov;98(5):722-732.

Introduction

Barrett’s esophagus (BE) is characterized by the replacement of squamous epithelium by columnar metaplasia of the distal esophagus (>1 cm length). It is a precancerous condition, with 3%-5% of patients with BE developing esophageal adenocarcinoma (EAC) in their lifetime. EAC is one of the cancers with high morbidity and mortality (5-year survival < 20%), and its incidence has been on the rise. Studies examining the natural history of BE have demonstrated that the progression happens through a metaplasia-dysplasia-neoplasia sequence. Therefore, early detection of BE and timely management to prevent progression to EAC is crucial.

Grades of Dysplasia

The current gold standard for the diagnosis of BE neoplasia includes a high-quality endoscopic evaluation and biopsies. Biopsies should be obtained from any visible lesions (nodules, ulcers) followed by a random 4-quadrant fashion (Seattle protocol) interval of the entire length of the BE segment. It is essential to pay attention to the results of the biopsy that have been obtained since it will not only determine the surveillance interval but is crucial in planning any necessary endoscopic therapy. The possible results of the biopsy and its implications are:

• No intestinal metaplasia (IM): This would rule out Barrett’s esophagus and no further surveillance would be necessary. A recent population-based study of over 1 million patients showed a 55% and 61% reduced risk of upper gastrointestinal (UGI) cancer and deaths respectively after a negative endoscopy.¹
• Intestinal metaplasia with no dysplasia (non-dysplastic BE): Biopsies confirm presence of intestinal metaplasia in the biopsies without any evidence of dysplasia. While the rate of progression to EAC is low (0.07%-0.25%), it is not absent and thus surveillance would be indicated. Current guidelines suggest repeating an endoscopy with biopsy in 5 years if the length of BE is < 3 cm or 3 years if length of BE ≥ 3 cm.²
• Indeterminate for dysplasia (BE-IND): Biopsies confirm IM but are not able to definitively rule out dysplasia. This can be seen in about 4%-8% of the biopsies obtained. The progression rates to EAC are reported to be comparable or lower to low-grade dysplasia (LGD), so the current recommendation is to intensify acid reduction therapy and repeat endoscopy in 6 months. If repeat endoscopy downgrades to non-dysplastic, then can follow surveillance according to NDBE protocol; otherwise recommend continuing surveillance every 12 months.
• Low-grade dysplasia (BE-LGD): Biopsies confirm IM but also show tightly packed overlapping basal nuclei with hyperchromasia and irregular contours, basal stratification of nuclei, and diminished goblet and columnar cell mucus. There is significant inter-observer variability reported,³ and thus the slides must be reviewed by a second pathologist with experience in BE to confirm the findings. Once confirmed, based on risk factors such as presence of multifocal LGD, persistence of LGD, presence of visible lesions, etc., the patient can be offered Barrett’s endoscopic therapy (BET) or undergo continued surveillance. The decision of pursuing one or the other would be dependent on patient preference and shared decision-making between the patient and the provider.
• High-grade dysplasia (BE-HGD): Biopsies confirm IM with cells showing greater degree of cytologic and architectural alterations of dysplasia than LGD but without overt neoplastic features. Over 40% of the patients would progress to EAC and thus the current recommendations would be to recommend BET in these patients.⁴
• Esophageal adenocarcinoma (EAC): Biopsies demonstrate neoplasia. If the neoplastic changes are limited to the mucosa (T1a) on endoscopic ultrasound or cross-sectional imaging, then BET is suggested. If there is involvement of submucosa, then depending on the depth of invasion, absence of high-risk features (poor differentiation, lymphovascular invasion), BET can be considered as an alternative to esophagectomy.

Lesion Detection on Endoscopy

Data from large population-based studies with at least 3 years of follow-up reported that 58%-66% of EAC detected during endoscopy were diagnosed within 1 year of an index Barrett’s esophagus screening endoscopy, or post-endoscopy Barrett’s neoplasia, and were considered likely to have been missed during index endoscopy.⁵ This underscores the importance of careful and systematic endoscopic examination during an upper endoscopy.

Studies have also demonstrated that longer examination time was associated with significantly higher detection of HGD/EAC.^6,7 Careful examination of the tubular esophagus and gastroesophageal junction (GEJ) should be performed in forward and retroflexed views looking for any subtle areas of nodularity, loop distortion, variability in vascular patterns, mucosal changes concerning for dysplasia or neoplasia. Use of high-definition white light endoscopy (HD-WLE) and virtual chromoendoscopy techniques such as narrow banding imaging (NBI) or blue laser imaging (BLI) are currently recommended in the guidelines.² Spray chromoendoscopy using acetic acid can also be utilized. Another exciting development is the use of artificial intelligence (AI) in detecting and diagnosing BE associated lesions and neoplasia.
 

Barrett’s Endoscopic Therapy (BET)

Patients with visible lesions, dysplasia, or early EAC are candidates for BET (Table 1).

BET involves resective and ablative modalities. The resective modalities include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) and are the modalities of choice for nodular or raised lesions.

EMR involves endoscopic resection of abnormal mucosa using either lift-assisted technique or multi-band ligation (Figure 1).

ESD, on the other hand, involves submucosal dissection and perimeter resection of the lesion, thus providing the advantage of an en-bloc resection. In a recent randomized controlled trial (RCT) of 40 patients undergoing ESD vs EMR for HGD/EAC, ESD was better for curative resection (R0) (58%) compared with EMR (12%); however, the remission rates at 3 months were comparable with two perforations reported in the ESD group while there were no complications in the EMR group.⁸

There is an apparent learning curve when it comes to these advanced techniques, and with more experience, we are seeing comparable results for both these modalities. However, given the complexity and time required for the procedure, current practices typically involve preserving ESD for lesions > 2 cm, those having a likelihood of cancer in the superficial submucosa, or those that EMR cannot remove due to underlying fibrosis or post-EMR recurrence.

University of Kansas Health System

Barrett’s Refractory to Endoscopic Therapy

Failure of BET is defined as persistent columnar lined epithelium (intestinal metaplasia) with inadequate response, after adequate attempts at endoscopic ablation therapy (after resection) with at least four ablation sessions.¹³ If encountered, special attention must be given to check compliance with proton pump inhibitors (PPIs), previous incomplete resection, and presence of large hiatal hernia. If CE-IM is not achieved after multiple sessions, change of ablative modality is typically considered. In addition, careful examination for visible lesions should be performed and even if a small one is noted, this should be first resected prior to application of any ablative therapy.

University of Kansas Health System

Currently there are no guideline recommendations regarding the preference of one endoscopic modality over another or consideration of potential endoscopic or surgical fundoplication. These modalities primarily rely on technologies available at an institution and the preference of a provider based on their training and experience. Most studies indicate 1-3 sessions (~ 3 months apart) of ablative treatment before achieving CE-IM.
 

Success and Adverse Events of BET

In a recent real-world study of over 27,000 patients with dysplastic BE, 5295 underwent BET. Analysis showed that patients with HGD/EAC who had BET had a significantly lower 3-year mortality (HGD: RR, 0.59; 95%CI, 0.49-0.71; EAC: RR, 0.53; 95% CI, 0.44-0.65) compared with those who did not undergo BET. Esophageal strictures were the most common adverse event and were noted in 6.5%, followed by chest pain (1.8%), upper GI bleeding (0.47%), and esophageal perforation (0.2%).¹⁴

In general, adverse events can be divided into immediate and delayed adverse events. Immediate adverse events typically involve bleeding and perforation that can occur during or shortly after the procedure. These are reported at higher rates with resective modalities compared with ablative therapies. Standard endoscopic techniques involving coagulation grasper or clips can be used to achieve hemostasis. Endoscopic suturing devices offer the ability to contain any perforation. The need for surgical intervention is small and limited to adverse events not detected during the procedure.

Delayed adverse events such as stricture and stenosis are higher for resective modalities (up to 30%), especially when involving more significant than 75% of the esophageal circumference. Post-procedural pain/dysphagia is most common after ablative therapies. Dysphagia reported after any endoscopic therapy should be promptly evaluated, and sequential dilation until the goal esophageal lumen is achieved should be performed every 2-4 weeks.
 

Recurrences and Surveillance After BET

What is established is that recurrences can occur and may be subtle, therefore detailed endoscopic surveillance is required. In a prospective study, recurrence rates of 15%-16% for IM and 3%-5% for any dysplasia were reported, with the majority being in the first 2 years after achieving CE-IM.¹⁵ A systematic review of 21 studies looking at the location of recurrences suggested that the majority (56%) occur in the distal esophagus. Of those that occur in the esophagus, about 80% of them were in the distal 2 cm of the esophagus and only 50% of the recurrences were visible recurrences, thus reiterating the importance of meticulous examination and systematic biopsies.¹⁶

On the contrary, a recent single-center study of 217 patients who had achieved CE-IM with 5.5 years of follow-up demonstrated a 26% and 8% recurrence of IM and dysplasia, respectively. One hundred percent of the recurrence in the esophagus was reported as visible.¹⁷ Therefore, follow-up endoscopy surveillance protocol after CE-IM should still involve meticulous examination, biopsy of visible lesions, and systematic biopsies for non-visible lesions from the original BE segment, similar to those patients who have not needed BET.

Current guidelines based on expert consensus and evidence recommend surveillance after CE-IM based on original most advanced histology:²

1. LGD: 1 year, 3 years, and every 2 years after that.

2. HGD/EAC: 3 months, 6 months, 12 months, and annually after that.

There is no clear guideline on when to stop surveillance since the longest available follow-up is around 10 years, and recurrences are still detected. A potential surveillance endpoint may be based on age and comorbidities, especially those that would preclude a patient from being a candidate for BET.
 

When Should a Patient Be Referred?

BE patients with visible lesions and/or dysplastic changes in the biopsy who would require BET should be considered for referral to high-volume centers. Studies have shown higher success for CE-IM and lower rates of adverse events and recurrences in these patients managed at expert centers. The presence of a multidisciplinary team involving pathologists, surgeons, and oncologists is critical and offers a timely opportunity in case of need for a high-risk patient.

Conclusion

BE is a precursor to EAC, with rising incidence and poor 5-year survival. Endoscopic diagnosis is the gold standard and requires a high-quality examination and biopsies. Based on histopathology, a systematic surveillance and BET plan should be performed to achieve CE-IM in patients with dysplasia. Once CE-IM is achieved, regular surveillance should be performed with careful attention to recurrences and complications from the BET modalities.

Dr. Srinivasan and Dr. Sharma are based at the University of Kansas Medical Center, Kansas City, Kansas, and the Kansas City Veterans Affairs Medical Center, Kansas City, Missouri. Dr. Srinivasan has no relevant disclosures. Dr. Sharma disclosed research grants from ERBE, Ironwood Pharmaceuticals, Olympus, and Medtronic. He has served as a consultant for Takeda, Samsung Bioepis, Olympus, and Lumendi, and reports other funding from Medtronic, Fujifilm Medical Systems USA, and Salix.

References

1. Holmberg D, et al. Incidence and mortality in upper gastrointestinal cancer after negative endoscopy for gastroesophageal reflux disease. Gastroenterology. 2022;162(2):431-438.e4.

2. Shaheen NJ, et al. Diagnosis and management of Barrett’s esophagus: An updated ACG guideline. Am J Gastroenterol. 2022 Apr;117(4):559-587.

3. Pech O, et al. Inter-observer variability in the diagnosis of low-grade dysplasia in pathologists: A comparison between experienced and inexperienced pathologists. Gastrointest Endosc. 2006 Apr;63(5):AB130.

4. Krishnamoorthi R, et al. Factors associated with progression of Barrett’s esophagus: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018 Jul;16(7):1046-1055.e8.

5. Visrodia K, et al. Magnitude of missed esophageal adenocarcinoma after Barrett’s esophagus diagnosis: A systematic review and meta-analysis. Gastroenterology. 2016 Mar;150(3):599-607.e7; quiz e14-5.

6. Perisetti A, Sharma P. Tips for improving the identification of neoplastic visible lesions in Barrett’s esophagus. Gastrointest Endosc. 2023 Feb;97(2):248-250.

7. Gupta N, et al. Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett’s esophagus. Gastrointest Endosc. 2012 Sep;76(3):531-538.

8. Terheggen G, et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett’s neoplasia. Gut. 2017 May;66(5):783-793.

9. Wolfson P, et al. Endoscopic eradication therapy for Barrett’s esophagus-related neoplasia: A final 10-year report from the UK National HALO Radiofrequency Ablation Registry. Gastrointest Endosc. 2022 Aug;96(2):223-233.

10. Rösch T, et al. 1151 Multicenter feasibility study of combined injection and argon plasma coagulation (hybrid-APC) in the ablation therapy of neoplastic Barrett esophagus. Gastrointest Endosc. 2017;85(5):AB154.

11. Knabe M, et al. Radiofrequency ablation versus hybrid argon plasma coagulation in Barrett’s esophagus: A prospective randomised trial. Surg Endosc. 2023;37(10):7803-7811.

12. Van Munster SN, et al. Radiofrequency vapor ablation for Barrett’s esophagus: Feasibility, safety, and proof of concept in a stepwise study with in vitro, animal, and the first in-human application. Endoscopy. 2021 Nov;53(11):1162-1168.

13. Emura F, et al. Rio de Janeiro global consensus on landmarks, definitions, and classifications in Barrett’s esophagus: World Endoscopy Organization Delphi study. Gastroenterology. 2022 Jul;163(1):84-96.e2.

14. Singh RR, et al. Real-world evidence of safety and effectiveness of Barrett’s endoscopic therapy. Gastrointest Endosc. 2023 Aug;98(2):155-161.e1.

15. Wani S, et al. Recurrence Is rare following complete eradication of intestinal metaplasia in patients with Barrett’s esophagus and peaks at 18 months. Clin Gastroenterol Hepatol. 2020 Oct;18(11):2609-2617.e2.

16. Duvvuri A, et al. Mo1273 Location and pattern of recurrences in patients with Barrett’s esophagus after endoscopic therapy: A systematic review and critical analysis of the published literature. Gastrointest Endosc. 2020;91(6):AB410-1.

17. He T, et al. Location and appearance of dysplastic Barrett’s esophagus recurrence after endoscopic eradication therapy: No additional yield from random biopsy sampling neosquamous mucosa. Gastrointest Endosc. 2023 Nov;98(5):722-732.

Introduction

Barrett’s esophagus (BE) is characterized by the replacement of squamous epithelium by columnar metaplasia of the distal esophagus (>1 cm length). It is a precancerous condition, with 3%-5% of patients with BE developing esophageal adenocarcinoma (EAC) in their lifetime. EAC is one of the cancers with high morbidity and mortality (5-year survival < 20%), and its incidence has been on the rise. Studies examining the natural history of BE have demonstrated that the progression happens through a metaplasia-dysplasia-neoplasia sequence. Therefore, early detection of BE and timely management to prevent progression to EAC is crucial.

Grades of Dysplasia

The current gold standard for the diagnosis of BE neoplasia includes a high-quality endoscopic evaluation and biopsies. Biopsies should be obtained from any visible lesions (nodules, ulcers) followed by a random 4-quadrant fashion (Seattle protocol) interval of the entire length of the BE segment. It is essential to pay attention to the results of the biopsy that have been obtained since it will not only determine the surveillance interval but is crucial in planning any necessary endoscopic therapy. The possible results of the biopsy and its implications are:

• No intestinal metaplasia (IM): This would rule out Barrett’s esophagus and no further surveillance would be necessary. A recent population-based study of over 1 million patients showed a 55% and 61% reduced risk of upper gastrointestinal (UGI) cancer and deaths respectively after a negative endoscopy.¹
• Intestinal metaplasia with no dysplasia (non-dysplastic BE): Biopsies confirm presence of intestinal metaplasia in the biopsies without any evidence of dysplasia. While the rate of progression to EAC is low (0.07%-0.25%), it is not absent and thus surveillance would be indicated. Current guidelines suggest repeating an endoscopy with biopsy in 5 years if the length of BE is < 3 cm or 3 years if length of BE ≥ 3 cm.²
• Indeterminate for dysplasia (BE-IND): Biopsies confirm IM but are not able to definitively rule out dysplasia. This can be seen in about 4%-8% of the biopsies obtained. The progression rates to EAC are reported to be comparable or lower to low-grade dysplasia (LGD), so the current recommendation is to intensify acid reduction therapy and repeat endoscopy in 6 months. If repeat endoscopy downgrades to non-dysplastic, then can follow surveillance according to NDBE protocol; otherwise recommend continuing surveillance every 12 months.
• Low-grade dysplasia (BE-LGD): Biopsies confirm IM but also show tightly packed overlapping basal nuclei with hyperchromasia and irregular contours, basal stratification of nuclei, and diminished goblet and columnar cell mucus. There is significant inter-observer variability reported,³ and thus the slides must be reviewed by a second pathologist with experience in BE to confirm the findings. Once confirmed, based on risk factors such as presence of multifocal LGD, persistence of LGD, presence of visible lesions, etc., the patient can be offered Barrett’s endoscopic therapy (BET) or undergo continued surveillance. The decision of pursuing one or the other would be dependent on patient preference and shared decision-making between the patient and the provider.
• High-grade dysplasia (BE-HGD): Biopsies confirm IM with cells showing greater degree of cytologic and architectural alterations of dysplasia than LGD but without overt neoplastic features. Over 40% of the patients would progress to EAC and thus the current recommendations would be to recommend BET in these patients.⁴
• Esophageal adenocarcinoma (EAC): Biopsies demonstrate neoplasia. If the neoplastic changes are limited to the mucosa (T1a) on endoscopic ultrasound or cross-sectional imaging, then BET is suggested. If there is involvement of submucosa, then depending on the depth of invasion, absence of high-risk features (poor differentiation, lymphovascular invasion), BET can be considered as an alternative to esophagectomy.

Lesion Detection on Endoscopy

Data from large population-based studies with at least 3 years of follow-up reported that 58%-66% of EAC detected during endoscopy were diagnosed within 1 year of an index Barrett’s esophagus screening endoscopy, or post-endoscopy Barrett’s neoplasia, and were considered likely to have been missed during index endoscopy.⁵ This underscores the importance of careful and systematic endoscopic examination during an upper endoscopy.

Studies have also demonstrated that longer examination time was associated with significantly higher detection of HGD/EAC.^6,7 Careful examination of the tubular esophagus and gastroesophageal junction (GEJ) should be performed in forward and retroflexed views looking for any subtle areas of nodularity, loop distortion, variability in vascular patterns, mucosal changes concerning for dysplasia or neoplasia. Use of high-definition white light endoscopy (HD-WLE) and virtual chromoendoscopy techniques such as narrow banding imaging (NBI) or blue laser imaging (BLI) are currently recommended in the guidelines.² Spray chromoendoscopy using acetic acid can also be utilized. Another exciting development is the use of artificial intelligence (AI) in detecting and diagnosing BE associated lesions and neoplasia.
 

Barrett’s Endoscopic Therapy (BET)

Patients with visible lesions, dysplasia, or early EAC are candidates for BET (Table 1).

BET involves resective and ablative modalities. The resective modalities include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) and are the modalities of choice for nodular or raised lesions.

EMR involves endoscopic resection of abnormal mucosa using either lift-assisted technique or multi-band ligation (Figure 1).

ESD, on the other hand, involves submucosal dissection and perimeter resection of the lesion, thus providing the advantage of an en-bloc resection. In a recent randomized controlled trial (RCT) of 40 patients undergoing ESD vs EMR for HGD/EAC, ESD was better for curative resection (R0) (58%) compared with EMR (12%); however, the remission rates at 3 months were comparable with two perforations reported in the ESD group while there were no complications in the EMR group.⁸

There is an apparent learning curve when it comes to these advanced techniques, and with more experience, we are seeing comparable results for both these modalities. However, given the complexity and time required for the procedure, current practices typically involve preserving ESD for lesions > 2 cm, those having a likelihood of cancer in the superficial submucosa, or those that EMR cannot remove due to underlying fibrosis or post-EMR recurrence.

University of Kansas Health System

Barrett’s Refractory to Endoscopic Therapy

Failure of BET is defined as persistent columnar lined epithelium (intestinal metaplasia) with inadequate response, after adequate attempts at endoscopic ablation therapy (after resection) with at least four ablation sessions.¹³ If encountered, special attention must be given to check compliance with proton pump inhibitors (PPIs), previous incomplete resection, and presence of large hiatal hernia. If CE-IM is not achieved after multiple sessions, change of ablative modality is typically considered. In addition, careful examination for visible lesions should be performed and even if a small one is noted, this should be first resected prior to application of any ablative therapy.

University of Kansas Health System

Currently there are no guideline recommendations regarding the preference of one endoscopic modality over another or consideration of potential endoscopic or surgical fundoplication. These modalities primarily rely on technologies available at an institution and the preference of a provider based on their training and experience. Most studies indicate 1-3 sessions (~ 3 months apart) of ablative treatment before achieving CE-IM.
 

Success and Adverse Events of BET

In a recent real-world study of over 27,000 patients with dysplastic BE, 5295 underwent BET. Analysis showed that patients with HGD/EAC who had BET had a significantly lower 3-year mortality (HGD: RR, 0.59; 95%CI, 0.49-0.71; EAC: RR, 0.53; 95% CI, 0.44-0.65) compared with those who did not undergo BET. Esophageal strictures were the most common adverse event and were noted in 6.5%, followed by chest pain (1.8%), upper GI bleeding (0.47%), and esophageal perforation (0.2%).¹⁴

In general, adverse events can be divided into immediate and delayed adverse events. Immediate adverse events typically involve bleeding and perforation that can occur during or shortly after the procedure. These are reported at higher rates with resective modalities compared with ablative therapies. Standard endoscopic techniques involving coagulation grasper or clips can be used to achieve hemostasis. Endoscopic suturing devices offer the ability to contain any perforation. The need for surgical intervention is small and limited to adverse events not detected during the procedure.

Delayed adverse events such as stricture and stenosis are higher for resective modalities (up to 30%), especially when involving more significant than 75% of the esophageal circumference. Post-procedural pain/dysphagia is most common after ablative therapies. Dysphagia reported after any endoscopic therapy should be promptly evaluated, and sequential dilation until the goal esophageal lumen is achieved should be performed every 2-4 weeks.
 

Recurrences and Surveillance After BET

What is established is that recurrences can occur and may be subtle, therefore detailed endoscopic surveillance is required. In a prospective study, recurrence rates of 15%-16% for IM and 3%-5% for any dysplasia were reported, with the majority being in the first 2 years after achieving CE-IM.¹⁵ A systematic review of 21 studies looking at the location of recurrences suggested that the majority (56%) occur in the distal esophagus. Of those that occur in the esophagus, about 80% of them were in the distal 2 cm of the esophagus and only 50% of the recurrences were visible recurrences, thus reiterating the importance of meticulous examination and systematic biopsies.¹⁶

On the contrary, a recent single-center study of 217 patients who had achieved CE-IM with 5.5 years of follow-up demonstrated a 26% and 8% recurrence of IM and dysplasia, respectively. One hundred percent of the recurrence in the esophagus was reported as visible.¹⁷ Therefore, follow-up endoscopy surveillance protocol after CE-IM should still involve meticulous examination, biopsy of visible lesions, and systematic biopsies for non-visible lesions from the original BE segment, similar to those patients who have not needed BET.

Current guidelines based on expert consensus and evidence recommend surveillance after CE-IM based on original most advanced histology:²

1. LGD: 1 year, 3 years, and every 2 years after that.

2. HGD/EAC: 3 months, 6 months, 12 months, and annually after that.

There is no clear guideline on when to stop surveillance since the longest available follow-up is around 10 years, and recurrences are still detected. A potential surveillance endpoint may be based on age and comorbidities, especially those that would preclude a patient from being a candidate for BET.
 

When Should a Patient Be Referred?

BE patients with visible lesions and/or dysplastic changes in the biopsy who would require BET should be considered for referral to high-volume centers. Studies have shown higher success for CE-IM and lower rates of adverse events and recurrences in these patients managed at expert centers. The presence of a multidisciplinary team involving pathologists, surgeons, and oncologists is critical and offers a timely opportunity in case of need for a high-risk patient.

Conclusion

BE is a precursor to EAC, with rising incidence and poor 5-year survival. Endoscopic diagnosis is the gold standard and requires a high-quality examination and biopsies. Based on histopathology, a systematic surveillance and BET plan should be performed to achieve CE-IM in patients with dysplasia. Once CE-IM is achieved, regular surveillance should be performed with careful attention to recurrences and complications from the BET modalities.

Dr. Srinivasan and Dr. Sharma are based at the University of Kansas Medical Center, Kansas City, Kansas, and the Kansas City Veterans Affairs Medical Center, Kansas City, Missouri. Dr. Srinivasan has no relevant disclosures. Dr. Sharma disclosed research grants from ERBE, Ironwood Pharmaceuticals, Olympus, and Medtronic. He has served as a consultant for Takeda, Samsung Bioepis, Olympus, and Lumendi, and reports other funding from Medtronic, Fujifilm Medical Systems USA, and Salix.

References

1. Holmberg D, et al. Incidence and mortality in upper gastrointestinal cancer after negative endoscopy for gastroesophageal reflux disease. Gastroenterology. 2022;162(2):431-438.e4.

2. Shaheen NJ, et al. Diagnosis and management of Barrett’s esophagus: An updated ACG guideline. Am J Gastroenterol. 2022 Apr;117(4):559-587.

3. Pech O, et al. Inter-observer variability in the diagnosis of low-grade dysplasia in pathologists: A comparison between experienced and inexperienced pathologists. Gastrointest Endosc. 2006 Apr;63(5):AB130.

4. Krishnamoorthi R, et al. Factors associated with progression of Barrett’s esophagus: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018 Jul;16(7):1046-1055.e8.

5. Visrodia K, et al. Magnitude of missed esophageal adenocarcinoma after Barrett’s esophagus diagnosis: A systematic review and meta-analysis. Gastroenterology. 2016 Mar;150(3):599-607.e7; quiz e14-5.

6. Perisetti A, Sharma P. Tips for improving the identification of neoplastic visible lesions in Barrett’s esophagus. Gastrointest Endosc. 2023 Feb;97(2):248-250.

7. Gupta N, et al. Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett’s esophagus. Gastrointest Endosc. 2012 Sep;76(3):531-538.

8. Terheggen G, et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett’s neoplasia. Gut. 2017 May;66(5):783-793.

9. Wolfson P, et al. Endoscopic eradication therapy for Barrett’s esophagus-related neoplasia: A final 10-year report from the UK National HALO Radiofrequency Ablation Registry. Gastrointest Endosc. 2022 Aug;96(2):223-233.

10. Rösch T, et al. 1151 Multicenter feasibility study of combined injection and argon plasma coagulation (hybrid-APC) in the ablation therapy of neoplastic Barrett esophagus. Gastrointest Endosc. 2017;85(5):AB154.

11. Knabe M, et al. Radiofrequency ablation versus hybrid argon plasma coagulation in Barrett’s esophagus: A prospective randomised trial. Surg Endosc. 2023;37(10):7803-7811.

12. Van Munster SN, et al. Radiofrequency vapor ablation for Barrett’s esophagus: Feasibility, safety, and proof of concept in a stepwise study with in vitro, animal, and the first in-human application. Endoscopy. 2021 Nov;53(11):1162-1168.

13. Emura F, et al. Rio de Janeiro global consensus on landmarks, definitions, and classifications in Barrett’s esophagus: World Endoscopy Organization Delphi study. Gastroenterology. 2022 Jul;163(1):84-96.e2.

14. Singh RR, et al. Real-world evidence of safety and effectiveness of Barrett’s endoscopic therapy. Gastrointest Endosc. 2023 Aug;98(2):155-161.e1.

15. Wani S, et al. Recurrence Is rare following complete eradication of intestinal metaplasia in patients with Barrett’s esophagus and peaks at 18 months. Clin Gastroenterol Hepatol. 2020 Oct;18(11):2609-2617.e2.

16. Duvvuri A, et al. Mo1273 Location and pattern of recurrences in patients with Barrett’s esophagus after endoscopic therapy: A systematic review and critical analysis of the published literature. Gastrointest Endosc. 2020;91(6):AB410-1.

17. He T, et al. Location and appearance of dysplastic Barrett’s esophagus recurrence after endoscopic eradication therapy: No additional yield from random biopsy sampling neosquamous mucosa. Gastrointest Endosc. 2023 Nov;98(5):722-732.

Sunscreen is a cornerstone of skin cancer prevention. The first commercial sunscreen was developed nearly 100 years ago,¹ yet questions and concerns about the safety of these essential topical photoprotective agents continue to occupy our minds. This article serves as an update on some of the big sunscreen questions, as informed by the available evidence.

Are sunscreens safe?

The story of sunscreen regulation in the United States is long and dry. The major pain point is that sunscreens are regulated by the US Food and Drug Administration (FDA) as over-the-counter drugs rather than cosmetics (as in Europe).² Regulatory hurdles created a situation wherein no new active sunscreen ingredient has been approved by the FDA since 1999, except ecamsule for use in one product line. There is hope that changes enacted under the CARES Act will streamline and expedite the sunscreen approval process in the future.³

Amid the ongoing regulatory slog, the FDA became interested in learning more about sunscreen safety. Specifically, they sought to determine the GRASE (generally regarded as safe and effective) status of the active ingredients in sunscreens. In 2019, only the inorganic (physical/mineral) UV filters zinc oxide and titanium dioxide were considered GRASE.⁴ Trolamine salicylate and para-aminobenzoic acid were not GRASE, but they currently are not used in sunscreens in the United States. For all the remaining organic (chemical) filters, additional safety data were required to establish GRASE status.⁴ In 2024, the situation remains largely unchanged. Industry is working with the FDA on testing requirements.⁵

Why the focus on safety? After all, sunscreens have been used widely for decades without any major safety signals; their only well-established adverse effects are contact dermatitis and staining of clothing.⁶ Although preclinical studies raised concerns that chemical sunscreens could be associated with endocrine, reproductive, and neurologic toxicities, to date there are no high-quality human studies demonstrating negative effects.^7,8

However, exposure patterns have evolved. Sunscreen is recommended to be applied (and reapplied) daily. Also, chemical UV filters are used in many nonsunscreen products such as cosmetics, shampoos, fragrances, and plastics. In the United States, exposure to chemical sunscreens is ubiquitous; according to data from the National Health and Nutrition Examination Survey 2003-2004, oxybenzone was detected in 97% of more than 2500 urine samples, implying systemic absorption but not harm.⁹

The FDA confirmed the implication of systemic absorption via 2 maximal usage trials published in 2019 and 2020.^10,11 In both studies, several chemical sunscreens were applied at the recommended density of 2 mg/cm² to 75% of the body surface area multiple times over 4 days. For all tested organic UV filters, blood levels exceeded the predetermined FDA cutoff (0.5 ng/mL), even after one application.^10,11 What’s the takeaway? Simply that the FDA now requires additional safety data for chemical sunscreen filters⁵; the findings in no way imply any associated harm. Two potential mitigating factors are that no one applies sunscreen at 2 mg/cm², and the FDA’s blood level cutoff was a general estimate not specific to sunscreens.^4,12

Nevertheless, a good long-term safety record for sunscreens does not negate the need for enhanced safety data when there is clear evidence of systemic absorption. In the meantime, concerned patients should be counseled that the physical/mineral sunscreens containing zinc oxide and titanium dioxide are considered GRASE by the FDA; even in nanoparticle form, they generally have not been found to penetrate beneath the stratum corneum.^7,13

Dermatologists are confronting the conundrum of rising cases of frontal fibrosing alopecia (FFA). Several theories on the pathogenesis of this idiopathic scarring alopecia have been raised, one of which involves increased use of sunscreen. Proposed explanations for sunscreen’s role in FFA include a lichenoid reaction inducing hair follicle autoimmunity through an unclear mechanism; a T cell–mediated allergic reaction, which is unlikely according to contact dermatitis experts¹⁴; reactive oxygen species production by titanium nanoparticles, yet titanium has been detected in hair follicles of both patients with FFA and controls¹⁵; and endocrine disruption following systemic absorption, which has not been supported by any high-quality human studies.⁷

An association between facial sunscreen use and FFA has been reported in case-control studies¹⁶; however, they have been criticized due to methodologic issues and biases, and they provide no evidence of causality.^17,18 The jury remains out on the controversial association between sunscreen and FFA, with a need for more convincing data.

Does sunscreen impact coral reef health?

Coral reefs—crucial sources of aquatic biodiversity—are under attack from several different directions including climate change and pollution. As much as 14,000 tons of sunscreen enter coral reefs each year, and chemical sunscreen filters are detectable in waterways throughout the world—even in the Arctic.^19,20 Thus, sunscreen has come under scrutiny as a potential environmental threat, particularly with coral bleaching.

Bleaching is a process in which corals exposed to an environmental stressor expel their symbiotic photosynthetic algae and turn white; if conditions fail to improve, the corals are vulnerable to death. In a highly cited 2016 study, coral larvae exposed to oxybenzone in artificial laboratory conditions displayed concentration-dependent mortality and decreased chlorophyll fluorescence, which suggested bleaching.¹⁹ These findings influenced legislation in Hawaii and other localities banning sunscreens containing oxybenzone. Problematically, the study has been criticized for acutely exposing the most susceptible coral life-forms to unrealistic oxybenzone concentrations; more broadly, there is no standardized approach to coral toxicity testing.²¹

The bigger picture (and elephant in the room) is that the primary cause of coral bleaching is undoubtedly climate change/ocean warming.⁷ More recent studies suggest that oxybenzone probably adds insult to injury for corals already debilitated by ocean warming.^22,23

It has been posited that a narrow focus on sunscreens detracts attention from the climate issue.²⁴ Individuals can take a number of actions to reduce their carbon footprint in an effort to preserve our environment, specifically coral reefs.²⁵ Concerned patients should be counseled to use sunscreens containing the physical/mineral UV filters zinc oxide and titanium dioxide, which are unlikely to contribute to coral bleaching as commercially formulated.⁷

Ongoing Questions

A lot of unknowns about sunscreen safety remain, and much hubbub has been made over studies that often are preliminary at best. At the time of this writing, absent a crystal ball, this author continues to wear chemical sunscreens; spends a lot more time worrying about their carbon footprint than what type of sunscreen to use at the beach; and believes the association of FFA with sunscreen is unlikely to be causal. Hopefully much-needed rigorous evidence will guide our future approach to sunscreen formulation and use.

Sunscreen is a cornerstone of skin cancer prevention. The first commercial sunscreen was developed nearly 100 years ago,¹ yet questions and concerns about the safety of these essential topical photoprotective agents continue to occupy our minds. This article serves as an update on some of the big sunscreen questions, as informed by the available evidence.

Are sunscreens safe?

The story of sunscreen regulation in the United States is long and dry. The major pain point is that sunscreens are regulated by the US Food and Drug Administration (FDA) as over-the-counter drugs rather than cosmetics (as in Europe).² Regulatory hurdles created a situation wherein no new active sunscreen ingredient has been approved by the FDA since 1999, except ecamsule for use in one product line. There is hope that changes enacted under the CARES Act will streamline and expedite the sunscreen approval process in the future.³

Amid the ongoing regulatory slog, the FDA became interested in learning more about sunscreen safety. Specifically, they sought to determine the GRASE (generally regarded as safe and effective) status of the active ingredients in sunscreens. In 2019, only the inorganic (physical/mineral) UV filters zinc oxide and titanium dioxide were considered GRASE.⁴ Trolamine salicylate and para-aminobenzoic acid were not GRASE, but they currently are not used in sunscreens in the United States. For all the remaining organic (chemical) filters, additional safety data were required to establish GRASE status.⁴ In 2024, the situation remains largely unchanged. Industry is working with the FDA on testing requirements.⁵

Why the focus on safety? After all, sunscreens have been used widely for decades without any major safety signals; their only well-established adverse effects are contact dermatitis and staining of clothing.⁶ Although preclinical studies raised concerns that chemical sunscreens could be associated with endocrine, reproductive, and neurologic toxicities, to date there are no high-quality human studies demonstrating negative effects.^7,8

However, exposure patterns have evolved. Sunscreen is recommended to be applied (and reapplied) daily. Also, chemical UV filters are used in many nonsunscreen products such as cosmetics, shampoos, fragrances, and plastics. In the United States, exposure to chemical sunscreens is ubiquitous; according to data from the National Health and Nutrition Examination Survey 2003-2004, oxybenzone was detected in 97% of more than 2500 urine samples, implying systemic absorption but not harm.⁹

The FDA confirmed the implication of systemic absorption via 2 maximal usage trials published in 2019 and 2020.^10,11 In both studies, several chemical sunscreens were applied at the recommended density of 2 mg/cm² to 75% of the body surface area multiple times over 4 days. For all tested organic UV filters, blood levels exceeded the predetermined FDA cutoff (0.5 ng/mL), even after one application.^10,11 What’s the takeaway? Simply that the FDA now requires additional safety data for chemical sunscreen filters⁵; the findings in no way imply any associated harm. Two potential mitigating factors are that no one applies sunscreen at 2 mg/cm², and the FDA’s blood level cutoff was a general estimate not specific to sunscreens.^4,12

Nevertheless, a good long-term safety record for sunscreens does not negate the need for enhanced safety data when there is clear evidence of systemic absorption. In the meantime, concerned patients should be counseled that the physical/mineral sunscreens containing zinc oxide and titanium dioxide are considered GRASE by the FDA; even in nanoparticle form, they generally have not been found to penetrate beneath the stratum corneum.^7,13

Dermatologists are confronting the conundrum of rising cases of frontal fibrosing alopecia (FFA). Several theories on the pathogenesis of this idiopathic scarring alopecia have been raised, one of which involves increased use of sunscreen. Proposed explanations for sunscreen’s role in FFA include a lichenoid reaction inducing hair follicle autoimmunity through an unclear mechanism; a T cell–mediated allergic reaction, which is unlikely according to contact dermatitis experts¹⁴; reactive oxygen species production by titanium nanoparticles, yet titanium has been detected in hair follicles of both patients with FFA and controls¹⁵; and endocrine disruption following systemic absorption, which has not been supported by any high-quality human studies.⁷

An association between facial sunscreen use and FFA has been reported in case-control studies¹⁶; however, they have been criticized due to methodologic issues and biases, and they provide no evidence of causality.^17,18 The jury remains out on the controversial association between sunscreen and FFA, with a need for more convincing data.

Does sunscreen impact coral reef health?

Coral reefs—crucial sources of aquatic biodiversity—are under attack from several different directions including climate change and pollution. As much as 14,000 tons of sunscreen enter coral reefs each year, and chemical sunscreen filters are detectable in waterways throughout the world—even in the Arctic.^19,20 Thus, sunscreen has come under scrutiny as a potential environmental threat, particularly with coral bleaching.

Bleaching is a process in which corals exposed to an environmental stressor expel their symbiotic photosynthetic algae and turn white; if conditions fail to improve, the corals are vulnerable to death. In a highly cited 2016 study, coral larvae exposed to oxybenzone in artificial laboratory conditions displayed concentration-dependent mortality and decreased chlorophyll fluorescence, which suggested bleaching.¹⁹ These findings influenced legislation in Hawaii and other localities banning sunscreens containing oxybenzone. Problematically, the study has been criticized for acutely exposing the most susceptible coral life-forms to unrealistic oxybenzone concentrations; more broadly, there is no standardized approach to coral toxicity testing.²¹

The bigger picture (and elephant in the room) is that the primary cause of coral bleaching is undoubtedly climate change/ocean warming.⁷ More recent studies suggest that oxybenzone probably adds insult to injury for corals already debilitated by ocean warming.^22,23

It has been posited that a narrow focus on sunscreens detracts attention from the climate issue.²⁴ Individuals can take a number of actions to reduce their carbon footprint in an effort to preserve our environment, specifically coral reefs.²⁵ Concerned patients should be counseled to use sunscreens containing the physical/mineral UV filters zinc oxide and titanium dioxide, which are unlikely to contribute to coral bleaching as commercially formulated.⁷

Ongoing Questions

A lot of unknowns about sunscreen safety remain, and much hubbub has been made over studies that often are preliminary at best. At the time of this writing, absent a crystal ball, this author continues to wear chemical sunscreens; spends a lot more time worrying about their carbon footprint than what type of sunscreen to use at the beach; and believes the association of FFA with sunscreen is unlikely to be causal. Hopefully much-needed rigorous evidence will guide our future approach to sunscreen formulation and use.

Sunscreen is a cornerstone of skin cancer prevention. The first commercial sunscreen was developed nearly 100 years ago,¹ yet questions and concerns about the safety of these essential topical photoprotective agents continue to occupy our minds. This article serves as an update on some of the big sunscreen questions, as informed by the available evidence.

Are sunscreens safe?

The story of sunscreen regulation in the United States is long and dry. The major pain point is that sunscreens are regulated by the US Food and Drug Administration (FDA) as over-the-counter drugs rather than cosmetics (as in Europe).² Regulatory hurdles created a situation wherein no new active sunscreen ingredient has been approved by the FDA since 1999, except ecamsule for use in one product line. There is hope that changes enacted under the CARES Act will streamline and expedite the sunscreen approval process in the future.³

Amid the ongoing regulatory slog, the FDA became interested in learning more about sunscreen safety. Specifically, they sought to determine the GRASE (generally regarded as safe and effective) status of the active ingredients in sunscreens. In 2019, only the inorganic (physical/mineral) UV filters zinc oxide and titanium dioxide were considered GRASE.⁴ Trolamine salicylate and para-aminobenzoic acid were not GRASE, but they currently are not used in sunscreens in the United States. For all the remaining organic (chemical) filters, additional safety data were required to establish GRASE status.⁴ In 2024, the situation remains largely unchanged. Industry is working with the FDA on testing requirements.⁵

Why the focus on safety? After all, sunscreens have been used widely for decades without any major safety signals; their only well-established adverse effects are contact dermatitis and staining of clothing.⁶ Although preclinical studies raised concerns that chemical sunscreens could be associated with endocrine, reproductive, and neurologic toxicities, to date there are no high-quality human studies demonstrating negative effects.^7,8

However, exposure patterns have evolved. Sunscreen is recommended to be applied (and reapplied) daily. Also, chemical UV filters are used in many nonsunscreen products such as cosmetics, shampoos, fragrances, and plastics. In the United States, exposure to chemical sunscreens is ubiquitous; according to data from the National Health and Nutrition Examination Survey 2003-2004, oxybenzone was detected in 97% of more than 2500 urine samples, implying systemic absorption but not harm.⁹

The FDA confirmed the implication of systemic absorption via 2 maximal usage trials published in 2019 and 2020.^10,11 In both studies, several chemical sunscreens were applied at the recommended density of 2 mg/cm² to 75% of the body surface area multiple times over 4 days. For all tested organic UV filters, blood levels exceeded the predetermined FDA cutoff (0.5 ng/mL), even after one application.^10,11 What’s the takeaway? Simply that the FDA now requires additional safety data for chemical sunscreen filters⁵; the findings in no way imply any associated harm. Two potential mitigating factors are that no one applies sunscreen at 2 mg/cm², and the FDA’s blood level cutoff was a general estimate not specific to sunscreens.^4,12

Nevertheless, a good long-term safety record for sunscreens does not negate the need for enhanced safety data when there is clear evidence of systemic absorption. In the meantime, concerned patients should be counseled that the physical/mineral sunscreens containing zinc oxide and titanium dioxide are considered GRASE by the FDA; even in nanoparticle form, they generally have not been found to penetrate beneath the stratum corneum.^7,13

Dermatologists are confronting the conundrum of rising cases of frontal fibrosing alopecia (FFA). Several theories on the pathogenesis of this idiopathic scarring alopecia have been raised, one of which involves increased use of sunscreen. Proposed explanations for sunscreen’s role in FFA include a lichenoid reaction inducing hair follicle autoimmunity through an unclear mechanism; a T cell–mediated allergic reaction, which is unlikely according to contact dermatitis experts¹⁴; reactive oxygen species production by titanium nanoparticles, yet titanium has been detected in hair follicles of both patients with FFA and controls¹⁵; and endocrine disruption following systemic absorption, which has not been supported by any high-quality human studies.⁷

An association between facial sunscreen use and FFA has been reported in case-control studies¹⁶; however, they have been criticized due to methodologic issues and biases, and they provide no evidence of causality.^17,18 The jury remains out on the controversial association between sunscreen and FFA, with a need for more convincing data.

Does sunscreen impact coral reef health?

Coral reefs—crucial sources of aquatic biodiversity—are under attack from several different directions including climate change and pollution. As much as 14,000 tons of sunscreen enter coral reefs each year, and chemical sunscreen filters are detectable in waterways throughout the world—even in the Arctic.^19,20 Thus, sunscreen has come under scrutiny as a potential environmental threat, particularly with coral bleaching.

Bleaching is a process in which corals exposed to an environmental stressor expel their symbiotic photosynthetic algae and turn white; if conditions fail to improve, the corals are vulnerable to death. In a highly cited 2016 study, coral larvae exposed to oxybenzone in artificial laboratory conditions displayed concentration-dependent mortality and decreased chlorophyll fluorescence, which suggested bleaching.¹⁹ These findings influenced legislation in Hawaii and other localities banning sunscreens containing oxybenzone. Problematically, the study has been criticized for acutely exposing the most susceptible coral life-forms to unrealistic oxybenzone concentrations; more broadly, there is no standardized approach to coral toxicity testing.²¹

The bigger picture (and elephant in the room) is that the primary cause of coral bleaching is undoubtedly climate change/ocean warming.⁷ More recent studies suggest that oxybenzone probably adds insult to injury for corals already debilitated by ocean warming.^22,23

It has been posited that a narrow focus on sunscreens detracts attention from the climate issue.²⁴ Individuals can take a number of actions to reduce their carbon footprint in an effort to preserve our environment, specifically coral reefs.²⁵ Concerned patients should be counseled to use sunscreens containing the physical/mineral UV filters zinc oxide and titanium dioxide, which are unlikely to contribute to coral bleaching as commercially formulated.⁷

Ongoing Questions

A lot of unknowns about sunscreen safety remain, and much hubbub has been made over studies that often are preliminary at best. At the time of this writing, absent a crystal ball, this author continues to wear chemical sunscreens; spends a lot more time worrying about their carbon footprint than what type of sunscreen to use at the beach; and believes the association of FFA with sunscreen is unlikely to be causal. Hopefully much-needed rigorous evidence will guide our future approach to sunscreen formulation and use.

From India to Brazil, researchers around the world are experimenting with ways to simplify the complex production of chimeric antigen receptor (CAR) T cells and lower the treatment’s sky-high costs.

In the United States, a stand-alone device could greatly reduce the expense of producing modified immune cells. In India, researchers hope homegrown technology is the key to getting costs under control. In Latin America, a partnership between the Brazilian government and a US nonprofit may be just the ticket.

At stake is expanded access to CAR T-cell therapy, a form of immunotherapy that in just the past few years has revolutionized the care of hematologic cancers.

“Among patients with lymphoma, leukemia, and myeloma, anywhere between 30% to 50% reach long-term remission after one CAR T-cell infusion,” Mayo Clinic–Rochester hematologist/oncologist Saad J. Kenderian, MB, ChB, said in an interview. “It’s such an important therapy.”

However, only a small percentage of eligible patients in the United States — perhaps 20% or fewer — are receiving the treatment, he added.

A 2024 report suggested that many patients in the United States who may benefit aren’t being treated because of a range of possible reasons, including high prices, manufacturing logistics, and far distance from the limited number of institutions offering the therapy.

“Taken together, the real-world cost of CAR T-cell therapy can range from $700,000 to $1 million, which may make the treatment unaffordable to those patients without robust financial and/or social support,” the report authors noted.

Outside Western countries, access to the therapy is even more limited, because of its exorbitant price. The 2024 report noted that “there is a wide use of CAR T-cell therapy in Europe and China, but access is limited in developing countries in Southeast Asia, Africa, and Latin America.”
 

Harnessing the Power of T-Cells

Several types of CAR T-cell therapy have been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory blood cancers such as follicular lymphoma, large B-cell lymphoma, multiple myeloma, and B-cell precursor acute lymphoblastic leukemia. A 2023 review analyzed clinical trials and reported that complete response rates were 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B-cell lymphoma.

Pediatric hematologist/oncologist Kirsten Williams, MD, who specializes in pediatric blood and marrow transplant and cellular therapy at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, described CAR T-cell therapy as “a very unique form of immunotherapy” that harnesses the power of the immune system’s T-cells.

These cells are effective tumor killers, but they typically aren’t assigned to control cancer, she said in an interview. “We have very few of them, and most of our T cells are focused on killing various viruses,” she said. The therapy “allows us to take the T cell that would have killed the flu or mono and instead target leukemia, B-cell leukemia, or lymphoma.”

As she explained, “T cells are collected by a machine that reserves white blood cells and gives back the rest of the blood to the patient. We insert a gene into the T cells that encodes for a B-cell receptor. This receptor acts as a GPS signal, pulling T cells to the cancer so that they can kill it.”

In addition, “with this genetic change, we also add some things that allow the T cell to be stronger, to have a higher signal to kill the cancer cell once it locks on.”

The therapy is unique for each patient, Dr. Williams said. “We have collected and modified your specific T cells, and they can now only be infused into you. If we try to give your product to someone else, those cells would either cause harm by attacking the patient or would be immediately killed by that patient’s own immune system. This is very different than all the other kinds of therapies. When you take other medicines, it doesn’t matter who receives that pill.”
 

Treatment: Individual, Complex, and Costly

Why is CAR T-cell therapy so expensive? While only a single treatment is needed, the T cells have to go through an “individualized, bespoke manufacturing” process that’s “highly technical,” pediatric oncologist Stephan A. Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia, said in an interview. As he explained, the cells for a single patient have to go through the same testing as with a drug that might be given to 1,000 people.

“The first thing we need to do is collect the cells from a patient,” said Dr. Williams. “For adults, that process involves putting in two big IVs — one in each arm — and then pulling the blood through a machine. This typically involves an 8-hour collection in the hospital and very highly specialized people to oversee the collection process.”

Secondly, at some institutions, “the cells get sent to a company where they undergo the process where the gene is inserted,” she said. “This process needs to be done in a very sterile environment so there’s no infections, and it needs to have a lot of oversight.”

Finally, “after the cells are generated, they are typically frozen and shipped back to the site where the patient is at the hospital,” she said. “Then we give chemotherapy to the patient, which prepares the patient’s blood system. It removes some of the T-cells that are there, allowing for the T cells that we’re about to infuse to quickly be activated, find the cancer, and kill it.”

Side effects can boost costs even more. “Unfortunately, some significant toxicities can occur after we infuse these cells,” Dr. Williams noted. “Patients can have trouble breathing and sometimes need ventilatory support. They can have trouble maintaining their blood pressure and become swollen as fluid seeps into tissues. Or they can have high fevers and organ dysfunction. Many of those patients go to the intensive care unit, which is obviously expensive as well.”
 

Taking Gene Therapy In-House

As Dr. Williams explained, one way to reduce costs is to “perform the genetic manipulation and expansion of the cells outside of a company.” Several academic institutions in the United States are embracing this approach, including Children’s Hospital of Philadelphia, which is experimenting with an automated device developed by the German company Miltenyi Biotec and known as the CliniMACS Prodigy machine.

“The current manufacturing process is very manual and requires a lot of interaction with the product and highly trained personnel,” Dr. Grupp said. “If you have an automated device, you have those cells in the device over the 7 to 12 days that you actually need to grow the cells. There’s much less interaction, so you need fewer trained personnel.”

Children&#039;s Hospital of Philadelphia

India: Big Hopes for Homegrown Technology

In India, researchers are hoping that their homegrown approach to CAR T-cell therapy will expand access by greatly lowering treatment prices.

Last fall, India’s equivalent of the FDA-granted approval for actalycabtagene autoleucel (NexCAR19), which was developed by Indian scientists who worked closely with the US National Institutes of Health (NIH). The therapy’s developer is a company called ImmunoACT.

In an interview, ImmunoACT founder Rahul Purwar, PhD, MSc, associate professor at Indian Institute of Technology Bombay, said the treatment costs about $40,000. The price is much lower than in the United States because staffing, facility construction, and maintenance are less expensive in India, he said.

Results of small early clinical trials have been promising, with complete responses in 68% of 38 lymphoma patients and 72% of 15 leukemia patients. Updated data will be presented at the annual American Society of Hematology meeting in December 2024, Dr. Purwar said.

According to the NIH, at first ImmunoACT hopes to treat about 1,200 patients a year. The immediate goal is to “focus and stabilize our operation in India,” Dr. Purwar said. “Then, if opportunities come, we will try to bring CAR T to all who might benefit from these technologies. A majority of countries don’t have access to these technologies.”
 

A US-Brazil Partnership Holds Promise

Meanwhile, a US nonprofit known as Caring Cross announced this year that it has partnered with Fundação Oswaldo Cruz (Fiocruz), a Brazilian government foundation, to manufacture CAR T cells at point-of-care in South America.

“Our model is different than traditional biotech/pharma,” Boro Dropulic, PhD, MBA, cofounder and executive director of Caring Cross, said in an interview. “Our goal is to develop technologies and transfer them to organizations like Fiocruz to enable them to manufacture these transformative therapies for patients in their regions. We believe this model is an important solution for therapies that are priced so high that they are not accessible to many patients that need them, particularly underserved populations and those in low- and middle-income countries.”

According to Dr. Dropulic: “We have developed a production process where the material cost is about $20,000 per dose.” When labor and infrastructure costs are added, the total expense won’t be more than $37,000-$47,500, he said.

The research process for the CAR T-cell technology is at an earlier stage than in India. Scientists plan to start clinical trials of the technology in the United States by the end of 2024 and then begin them in Brazil in 2025, after safety and efficacy have been demonstrated. The first trial, a phase I/II study, will enroll about 20 patients, Dr. Dropulic said.

Dr. Kenderian reported ties with Novartis, Capstan Bio, Kite/Gilead, Juno/BMS, Humanigen, Tolero, Leah Labs, Lentigen, Luminary, Sunesis/Viracta, Morphosys, Troque, Carisma, Sendero, and LifEngine. Dr. Williams disclosed grants from National Institutes of Health and philanthropic organizations. Dr. Grupp reported relationships with Novartis, Kite, Vertex and Servier, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene, and Cabaletta. Dr. Purwar is the founder of ImmunoACT. Dr. Dropulic serves as executive director of Caring Cross and CEO of Vector BioMed, which provides vectors for gene therapy.

From India to Brazil, researchers around the world are experimenting with ways to simplify the complex production of chimeric antigen receptor (CAR) T cells and lower the treatment’s sky-high costs.

In the United States, a stand-alone device could greatly reduce the expense of producing modified immune cells. In India, researchers hope homegrown technology is the key to getting costs under control. In Latin America, a partnership between the Brazilian government and a US nonprofit may be just the ticket.

At stake is expanded access to CAR T-cell therapy, a form of immunotherapy that in just the past few years has revolutionized the care of hematologic cancers.

“Among patients with lymphoma, leukemia, and myeloma, anywhere between 30% to 50% reach long-term remission after one CAR T-cell infusion,” Mayo Clinic–Rochester hematologist/oncologist Saad J. Kenderian, MB, ChB, said in an interview. “It’s such an important therapy.”

However, only a small percentage of eligible patients in the United States — perhaps 20% or fewer — are receiving the treatment, he added.

A 2024 report suggested that many patients in the United States who may benefit aren’t being treated because of a range of possible reasons, including high prices, manufacturing logistics, and far distance from the limited number of institutions offering the therapy.

“Taken together, the real-world cost of CAR T-cell therapy can range from $700,000 to $1 million, which may make the treatment unaffordable to those patients without robust financial and/or social support,” the report authors noted.

Outside Western countries, access to the therapy is even more limited, because of its exorbitant price. The 2024 report noted that “there is a wide use of CAR T-cell therapy in Europe and China, but access is limited in developing countries in Southeast Asia, Africa, and Latin America.”
 

Harnessing the Power of T-Cells

Several types of CAR T-cell therapy have been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory blood cancers such as follicular lymphoma, large B-cell lymphoma, multiple myeloma, and B-cell precursor acute lymphoblastic leukemia. A 2023 review analyzed clinical trials and reported that complete response rates were 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B-cell lymphoma.

Pediatric hematologist/oncologist Kirsten Williams, MD, who specializes in pediatric blood and marrow transplant and cellular therapy at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, described CAR T-cell therapy as “a very unique form of immunotherapy” that harnesses the power of the immune system’s T-cells.

These cells are effective tumor killers, but they typically aren’t assigned to control cancer, she said in an interview. “We have very few of them, and most of our T cells are focused on killing various viruses,” she said. The therapy “allows us to take the T cell that would have killed the flu or mono and instead target leukemia, B-cell leukemia, or lymphoma.”

As she explained, “T cells are collected by a machine that reserves white blood cells and gives back the rest of the blood to the patient. We insert a gene into the T cells that encodes for a B-cell receptor. This receptor acts as a GPS signal, pulling T cells to the cancer so that they can kill it.”

In addition, “with this genetic change, we also add some things that allow the T cell to be stronger, to have a higher signal to kill the cancer cell once it locks on.”

The therapy is unique for each patient, Dr. Williams said. “We have collected and modified your specific T cells, and they can now only be infused into you. If we try to give your product to someone else, those cells would either cause harm by attacking the patient or would be immediately killed by that patient’s own immune system. This is very different than all the other kinds of therapies. When you take other medicines, it doesn’t matter who receives that pill.”
 

Treatment: Individual, Complex, and Costly

Why is CAR T-cell therapy so expensive? While only a single treatment is needed, the T cells have to go through an “individualized, bespoke manufacturing” process that’s “highly technical,” pediatric oncologist Stephan A. Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia, said in an interview. As he explained, the cells for a single patient have to go through the same testing as with a drug that might be given to 1,000 people.

“The first thing we need to do is collect the cells from a patient,” said Dr. Williams. “For adults, that process involves putting in two big IVs — one in each arm — and then pulling the blood through a machine. This typically involves an 8-hour collection in the hospital and very highly specialized people to oversee the collection process.”

Secondly, at some institutions, “the cells get sent to a company where they undergo the process where the gene is inserted,” she said. “This process needs to be done in a very sterile environment so there’s no infections, and it needs to have a lot of oversight.”

Finally, “after the cells are generated, they are typically frozen and shipped back to the site where the patient is at the hospital,” she said. “Then we give chemotherapy to the patient, which prepares the patient’s blood system. It removes some of the T-cells that are there, allowing for the T cells that we’re about to infuse to quickly be activated, find the cancer, and kill it.”

Side effects can boost costs even more. “Unfortunately, some significant toxicities can occur after we infuse these cells,” Dr. Williams noted. “Patients can have trouble breathing and sometimes need ventilatory support. They can have trouble maintaining their blood pressure and become swollen as fluid seeps into tissues. Or they can have high fevers and organ dysfunction. Many of those patients go to the intensive care unit, which is obviously expensive as well.”
 

Taking Gene Therapy In-House

As Dr. Williams explained, one way to reduce costs is to “perform the genetic manipulation and expansion of the cells outside of a company.” Several academic institutions in the United States are embracing this approach, including Children’s Hospital of Philadelphia, which is experimenting with an automated device developed by the German company Miltenyi Biotec and known as the CliniMACS Prodigy machine.

“The current manufacturing process is very manual and requires a lot of interaction with the product and highly trained personnel,” Dr. Grupp said. “If you have an automated device, you have those cells in the device over the 7 to 12 days that you actually need to grow the cells. There’s much less interaction, so you need fewer trained personnel.”

Children&#039;s Hospital of Philadelphia

India: Big Hopes for Homegrown Technology

In India, researchers are hoping that their homegrown approach to CAR T-cell therapy will expand access by greatly lowering treatment prices.

Last fall, India’s equivalent of the FDA-granted approval for actalycabtagene autoleucel (NexCAR19), which was developed by Indian scientists who worked closely with the US National Institutes of Health (NIH). The therapy’s developer is a company called ImmunoACT.

In an interview, ImmunoACT founder Rahul Purwar, PhD, MSc, associate professor at Indian Institute of Technology Bombay, said the treatment costs about $40,000. The price is much lower than in the United States because staffing, facility construction, and maintenance are less expensive in India, he said.

Results of small early clinical trials have been promising, with complete responses in 68% of 38 lymphoma patients and 72% of 15 leukemia patients. Updated data will be presented at the annual American Society of Hematology meeting in December 2024, Dr. Purwar said.

According to the NIH, at first ImmunoACT hopes to treat about 1,200 patients a year. The immediate goal is to “focus and stabilize our operation in India,” Dr. Purwar said. “Then, if opportunities come, we will try to bring CAR T to all who might benefit from these technologies. A majority of countries don’t have access to these technologies.”
 

A US-Brazil Partnership Holds Promise

Meanwhile, a US nonprofit known as Caring Cross announced this year that it has partnered with Fundação Oswaldo Cruz (Fiocruz), a Brazilian government foundation, to manufacture CAR T cells at point-of-care in South America.

“Our model is different than traditional biotech/pharma,” Boro Dropulic, PhD, MBA, cofounder and executive director of Caring Cross, said in an interview. “Our goal is to develop technologies and transfer them to organizations like Fiocruz to enable them to manufacture these transformative therapies for patients in their regions. We believe this model is an important solution for therapies that are priced so high that they are not accessible to many patients that need them, particularly underserved populations and those in low- and middle-income countries.”

According to Dr. Dropulic: “We have developed a production process where the material cost is about $20,000 per dose.” When labor and infrastructure costs are added, the total expense won’t be more than $37,000-$47,500, he said.

The research process for the CAR T-cell technology is at an earlier stage than in India. Scientists plan to start clinical trials of the technology in the United States by the end of 2024 and then begin them in Brazil in 2025, after safety and efficacy have been demonstrated. The first trial, a phase I/II study, will enroll about 20 patients, Dr. Dropulic said.

Dr. Kenderian reported ties with Novartis, Capstan Bio, Kite/Gilead, Juno/BMS, Humanigen, Tolero, Leah Labs, Lentigen, Luminary, Sunesis/Viracta, Morphosys, Troque, Carisma, Sendero, and LifEngine. Dr. Williams disclosed grants from National Institutes of Health and philanthropic organizations. Dr. Grupp reported relationships with Novartis, Kite, Vertex and Servier, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene, and Cabaletta. Dr. Purwar is the founder of ImmunoACT. Dr. Dropulic serves as executive director of Caring Cross and CEO of Vector BioMed, which provides vectors for gene therapy.

From India to Brazil, researchers around the world are experimenting with ways to simplify the complex production of chimeric antigen receptor (CAR) T cells and lower the treatment’s sky-high costs.

In the United States, a stand-alone device could greatly reduce the expense of producing modified immune cells. In India, researchers hope homegrown technology is the key to getting costs under control. In Latin America, a partnership between the Brazilian government and a US nonprofit may be just the ticket.

At stake is expanded access to CAR T-cell therapy, a form of immunotherapy that in just the past few years has revolutionized the care of hematologic cancers.

“Among patients with lymphoma, leukemia, and myeloma, anywhere between 30% to 50% reach long-term remission after one CAR T-cell infusion,” Mayo Clinic–Rochester hematologist/oncologist Saad J. Kenderian, MB, ChB, said in an interview. “It’s such an important therapy.”

However, only a small percentage of eligible patients in the United States — perhaps 20% or fewer — are receiving the treatment, he added.

A 2024 report suggested that many patients in the United States who may benefit aren’t being treated because of a range of possible reasons, including high prices, manufacturing logistics, and far distance from the limited number of institutions offering the therapy.

“Taken together, the real-world cost of CAR T-cell therapy can range from $700,000 to $1 million, which may make the treatment unaffordable to those patients without robust financial and/or social support,” the report authors noted.

Outside Western countries, access to the therapy is even more limited, because of its exorbitant price. The 2024 report noted that “there is a wide use of CAR T-cell therapy in Europe and China, but access is limited in developing countries in Southeast Asia, Africa, and Latin America.”
 

Harnessing the Power of T-Cells

Several types of CAR T-cell therapy have been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory blood cancers such as follicular lymphoma, large B-cell lymphoma, multiple myeloma, and B-cell precursor acute lymphoblastic leukemia. A 2023 review analyzed clinical trials and reported that complete response rates were 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B-cell lymphoma.

Pediatric hematologist/oncologist Kirsten Williams, MD, who specializes in pediatric blood and marrow transplant and cellular therapy at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, described CAR T-cell therapy as “a very unique form of immunotherapy” that harnesses the power of the immune system’s T-cells.

These cells are effective tumor killers, but they typically aren’t assigned to control cancer, she said in an interview. “We have very few of them, and most of our T cells are focused on killing various viruses,” she said. The therapy “allows us to take the T cell that would have killed the flu or mono and instead target leukemia, B-cell leukemia, or lymphoma.”

As she explained, “T cells are collected by a machine that reserves white blood cells and gives back the rest of the blood to the patient. We insert a gene into the T cells that encodes for a B-cell receptor. This receptor acts as a GPS signal, pulling T cells to the cancer so that they can kill it.”

In addition, “with this genetic change, we also add some things that allow the T cell to be stronger, to have a higher signal to kill the cancer cell once it locks on.”

The therapy is unique for each patient, Dr. Williams said. “We have collected and modified your specific T cells, and they can now only be infused into you. If we try to give your product to someone else, those cells would either cause harm by attacking the patient or would be immediately killed by that patient’s own immune system. This is very different than all the other kinds of therapies. When you take other medicines, it doesn’t matter who receives that pill.”
 

Treatment: Individual, Complex, and Costly

Why is CAR T-cell therapy so expensive? While only a single treatment is needed, the T cells have to go through an “individualized, bespoke manufacturing” process that’s “highly technical,” pediatric oncologist Stephan A. Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia, said in an interview. As he explained, the cells for a single patient have to go through the same testing as with a drug that might be given to 1,000 people.

“The first thing we need to do is collect the cells from a patient,” said Dr. Williams. “For adults, that process involves putting in two big IVs — one in each arm — and then pulling the blood through a machine. This typically involves an 8-hour collection in the hospital and very highly specialized people to oversee the collection process.”

Secondly, at some institutions, “the cells get sent to a company where they undergo the process where the gene is inserted,” she said. “This process needs to be done in a very sterile environment so there’s no infections, and it needs to have a lot of oversight.”

Finally, “after the cells are generated, they are typically frozen and shipped back to the site where the patient is at the hospital,” she said. “Then we give chemotherapy to the patient, which prepares the patient’s blood system. It removes some of the T-cells that are there, allowing for the T cells that we’re about to infuse to quickly be activated, find the cancer, and kill it.”

Side effects can boost costs even more. “Unfortunately, some significant toxicities can occur after we infuse these cells,” Dr. Williams noted. “Patients can have trouble breathing and sometimes need ventilatory support. They can have trouble maintaining their blood pressure and become swollen as fluid seeps into tissues. Or they can have high fevers and organ dysfunction. Many of those patients go to the intensive care unit, which is obviously expensive as well.”
 

Taking Gene Therapy In-House

As Dr. Williams explained, one way to reduce costs is to “perform the genetic manipulation and expansion of the cells outside of a company.” Several academic institutions in the United States are embracing this approach, including Children’s Hospital of Philadelphia, which is experimenting with an automated device developed by the German company Miltenyi Biotec and known as the CliniMACS Prodigy machine.

“The current manufacturing process is very manual and requires a lot of interaction with the product and highly trained personnel,” Dr. Grupp said. “If you have an automated device, you have those cells in the device over the 7 to 12 days that you actually need to grow the cells. There’s much less interaction, so you need fewer trained personnel.”

Children&#039;s Hospital of Philadelphia

India: Big Hopes for Homegrown Technology

In India, researchers are hoping that their homegrown approach to CAR T-cell therapy will expand access by greatly lowering treatment prices.

Last fall, India’s equivalent of the FDA-granted approval for actalycabtagene autoleucel (NexCAR19), which was developed by Indian scientists who worked closely with the US National Institutes of Health (NIH). The therapy’s developer is a company called ImmunoACT.

In an interview, ImmunoACT founder Rahul Purwar, PhD, MSc, associate professor at Indian Institute of Technology Bombay, said the treatment costs about $40,000. The price is much lower than in the United States because staffing, facility construction, and maintenance are less expensive in India, he said.

Results of small early clinical trials have been promising, with complete responses in 68% of 38 lymphoma patients and 72% of 15 leukemia patients. Updated data will be presented at the annual American Society of Hematology meeting in December 2024, Dr. Purwar said.

According to the NIH, at first ImmunoACT hopes to treat about 1,200 patients a year. The immediate goal is to “focus and stabilize our operation in India,” Dr. Purwar said. “Then, if opportunities come, we will try to bring CAR T to all who might benefit from these technologies. A majority of countries don’t have access to these technologies.”
 

A US-Brazil Partnership Holds Promise

Meanwhile, a US nonprofit known as Caring Cross announced this year that it has partnered with Fundação Oswaldo Cruz (Fiocruz), a Brazilian government foundation, to manufacture CAR T cells at point-of-care in South America.

“Our model is different than traditional biotech/pharma,” Boro Dropulic, PhD, MBA, cofounder and executive director of Caring Cross, said in an interview. “Our goal is to develop technologies and transfer them to organizations like Fiocruz to enable them to manufacture these transformative therapies for patients in their regions. We believe this model is an important solution for therapies that are priced so high that they are not accessible to many patients that need them, particularly underserved populations and those in low- and middle-income countries.”

According to Dr. Dropulic: “We have developed a production process where the material cost is about $20,000 per dose.” When labor and infrastructure costs are added, the total expense won’t be more than $37,000-$47,500, he said.

The research process for the CAR T-cell technology is at an earlier stage than in India. Scientists plan to start clinical trials of the technology in the United States by the end of 2024 and then begin them in Brazil in 2025, after safety and efficacy have been demonstrated. The first trial, a phase I/II study, will enroll about 20 patients, Dr. Dropulic said.

Dr. Kenderian reported ties with Novartis, Capstan Bio, Kite/Gilead, Juno/BMS, Humanigen, Tolero, Leah Labs, Lentigen, Luminary, Sunesis/Viracta, Morphosys, Troque, Carisma, Sendero, and LifEngine. Dr. Williams disclosed grants from National Institutes of Health and philanthropic organizations. Dr. Grupp reported relationships with Novartis, Kite, Vertex and Servier, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene, and Cabaletta. Dr. Purwar is the founder of ImmunoACT. Dr. Dropulic serves as executive director of Caring Cross and CEO of Vector BioMed, which provides vectors for gene therapy.

BOSTON — Patients with acute colonic diverticulitis are more likely to be seen by primary care providers than by emergency physicians, representing a shift in the way clinicians detect and treat the condition.

Acute colonic diverticulitis affects roughly 180 per 100,000 people per year in the United States.

CT of the abdomen and pelvis may not be a first-line method to detect diverticulitis in the primary care setting as it has been in emergent care, according to Kaveh Sharzehi, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland.

Indeed, clinical guidelines by multiple physician groups recommend that providers use a more individualized approach to detecting and treating the condition. 

“There is still great value in proper and thorough physical history and some adjunct testing,” Dr. Sharzehi told attendees during a presentation on April 20 at the American College of Physicians Internal Medicine Meeting 2024. These two methods can detect the disease up to 65% of the time, Dr. Sharzehi added.

An initial evaluation of a patient with suspected acute diverticulitis should first assess the patient’s history of abdominal pain, fever, and leukocytosis, Dr. Sharzehi said. 

A C-reactive protein level > 50 mg/L “almost doubles the odds of having diverticulitis,” Dr. Sharzehi said. Studies also suggest increased levels of procalcitonin and fecal calprotectin can indicate the presence of the condition.

The American Gastroenterological Association (AGA) and the American College of Physicians recommend abdominal CT if clinicians are uncertain of the diagnosis, and to evaluate potential complications in severe cases. Ultrasound and MRI can be useful alternatives, according to guidelines from the American Society of Colon and Rectal Surgeons.

The chances of developing diverticulitis increase with age. More than 60% of Americans aged 60 years or older have diverticulosis, a condition characterized by small pouches in the colon lining that can weaken the colon wall. Less than 5% of people with diverticulosis go on to develop diverticulitis. 

“Aspirin and opioid use are also risk factors, likely from their effect on the colonic transit time and causing constipation that might contribute to diverticulitis, but that›s not very well understood,” Dr. Sharzehi said. 

Medical management has shifted from predominantly inpatient to predominantly outpatient care, Dr. Sharzehi told attendees 

“Unfortunately, there are not that many supportive guidelines for what diet a patient should have in the acute setting of diverticulitis,” he said. 

Patients with a mild case may benefit from a clear liquid diet; for some patients, high-fiber diets, regular physical activity, and statins may protect against recurrence. 

Current guidelines recommend against prescribing antibiotics for most cases because evidence suggests that diverticulitis is primarily an inflammatory process that can result in small tears in the diverticulum, rather than the disease being a complication of existing tears. 

Patients should also not be treated with probiotics or 5-aminosalicylic acid agents, Dr. Sharzehi said.

“My practice is in the Pacific Northwest, where there’s a lot of belief in naturopathic remedies, so we get a lot of questions about supplements and probiotics in preventing diverticulitis,” he said. “We don’t think it does help, and this is unanimous among all the main [physician] societies.” 

The AGA recommends referring patients for a colonoscopy within a year after diverticulitis symptoms have resided. 

Severe or unresolved cases could require inpatient procedures such as percutaneous drainage or surgery. An estimated 15%-30% of patients admitted to hospital with acute diverticulitis require surgery, Dr. Sharzehi said. 

Surgery may become an option for patients who have recurrent cases of the disease, even if not severe, Dr. Sharzehi said.

Dr. Sharzehi reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

BOSTON — Patients with acute colonic diverticulitis are more likely to be seen by primary care providers than by emergency physicians, representing a shift in the way clinicians detect and treat the condition.

Acute colonic diverticulitis affects roughly 180 per 100,000 people per year in the United States.

CT of the abdomen and pelvis may not be a first-line method to detect diverticulitis in the primary care setting as it has been in emergent care, according to Kaveh Sharzehi, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland.

Indeed, clinical guidelines by multiple physician groups recommend that providers use a more individualized approach to detecting and treating the condition. 

“There is still great value in proper and thorough physical history and some adjunct testing,” Dr. Sharzehi told attendees during a presentation on April 20 at the American College of Physicians Internal Medicine Meeting 2024. These two methods can detect the disease up to 65% of the time, Dr. Sharzehi added.

An initial evaluation of a patient with suspected acute diverticulitis should first assess the patient’s history of abdominal pain, fever, and leukocytosis, Dr. Sharzehi said. 

A C-reactive protein level > 50 mg/L “almost doubles the odds of having diverticulitis,” Dr. Sharzehi said. Studies also suggest increased levels of procalcitonin and fecal calprotectin can indicate the presence of the condition.

The American Gastroenterological Association (AGA) and the American College of Physicians recommend abdominal CT if clinicians are uncertain of the diagnosis, and to evaluate potential complications in severe cases. Ultrasound and MRI can be useful alternatives, according to guidelines from the American Society of Colon and Rectal Surgeons.

The chances of developing diverticulitis increase with age. More than 60% of Americans aged 60 years or older have diverticulosis, a condition characterized by small pouches in the colon lining that can weaken the colon wall. Less than 5% of people with diverticulosis go on to develop diverticulitis. 

“Aspirin and opioid use are also risk factors, likely from their effect on the colonic transit time and causing constipation that might contribute to diverticulitis, but that›s not very well understood,” Dr. Sharzehi said. 

Medical management has shifted from predominantly inpatient to predominantly outpatient care, Dr. Sharzehi told attendees 

“Unfortunately, there are not that many supportive guidelines for what diet a patient should have in the acute setting of diverticulitis,” he said. 

Patients with a mild case may benefit from a clear liquid diet; for some patients, high-fiber diets, regular physical activity, and statins may protect against recurrence. 

Current guidelines recommend against prescribing antibiotics for most cases because evidence suggests that diverticulitis is primarily an inflammatory process that can result in small tears in the diverticulum, rather than the disease being a complication of existing tears. 

Patients should also not be treated with probiotics or 5-aminosalicylic acid agents, Dr. Sharzehi said.

“My practice is in the Pacific Northwest, where there’s a lot of belief in naturopathic remedies, so we get a lot of questions about supplements and probiotics in preventing diverticulitis,” he said. “We don’t think it does help, and this is unanimous among all the main [physician] societies.” 

The AGA recommends referring patients for a colonoscopy within a year after diverticulitis symptoms have resided. 

Severe or unresolved cases could require inpatient procedures such as percutaneous drainage or surgery. An estimated 15%-30% of patients admitted to hospital with acute diverticulitis require surgery, Dr. Sharzehi said. 

Surgery may become an option for patients who have recurrent cases of the disease, even if not severe, Dr. Sharzehi said.

Dr. Sharzehi reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

BOSTON — Patients with acute colonic diverticulitis are more likely to be seen by primary care providers than by emergency physicians, representing a shift in the way clinicians detect and treat the condition.

Acute colonic diverticulitis affects roughly 180 per 100,000 people per year in the United States.

CT of the abdomen and pelvis may not be a first-line method to detect diverticulitis in the primary care setting as it has been in emergent care, according to Kaveh Sharzehi, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland.

Indeed, clinical guidelines by multiple physician groups recommend that providers use a more individualized approach to detecting and treating the condition. 

“There is still great value in proper and thorough physical history and some adjunct testing,” Dr. Sharzehi told attendees during a presentation on April 20 at the American College of Physicians Internal Medicine Meeting 2024. These two methods can detect the disease up to 65% of the time, Dr. Sharzehi added.

An initial evaluation of a patient with suspected acute diverticulitis should first assess the patient’s history of abdominal pain, fever, and leukocytosis, Dr. Sharzehi said. 

A C-reactive protein level > 50 mg/L “almost doubles the odds of having diverticulitis,” Dr. Sharzehi said. Studies also suggest increased levels of procalcitonin and fecal calprotectin can indicate the presence of the condition.

The American Gastroenterological Association (AGA) and the American College of Physicians recommend abdominal CT if clinicians are uncertain of the diagnosis, and to evaluate potential complications in severe cases. Ultrasound and MRI can be useful alternatives, according to guidelines from the American Society of Colon and Rectal Surgeons.

The chances of developing diverticulitis increase with age. More than 60% of Americans aged 60 years or older have diverticulosis, a condition characterized by small pouches in the colon lining that can weaken the colon wall. Less than 5% of people with diverticulosis go on to develop diverticulitis. 

“Aspirin and opioid use are also risk factors, likely from their effect on the colonic transit time and causing constipation that might contribute to diverticulitis, but that›s not very well understood,” Dr. Sharzehi said. 

Medical management has shifted from predominantly inpatient to predominantly outpatient care, Dr. Sharzehi told attendees 

“Unfortunately, there are not that many supportive guidelines for what diet a patient should have in the acute setting of diverticulitis,” he said. 

Patients with a mild case may benefit from a clear liquid diet; for some patients, high-fiber diets, regular physical activity, and statins may protect against recurrence. 

Current guidelines recommend against prescribing antibiotics for most cases because evidence suggests that diverticulitis is primarily an inflammatory process that can result in small tears in the diverticulum, rather than the disease being a complication of existing tears. 

Patients should also not be treated with probiotics or 5-aminosalicylic acid agents, Dr. Sharzehi said.

“My practice is in the Pacific Northwest, where there’s a lot of belief in naturopathic remedies, so we get a lot of questions about supplements and probiotics in preventing diverticulitis,” he said. “We don’t think it does help, and this is unanimous among all the main [physician] societies.” 

The AGA recommends referring patients for a colonoscopy within a year after diverticulitis symptoms have resided. 

Severe or unresolved cases could require inpatient procedures such as percutaneous drainage or surgery. An estimated 15%-30% of patients admitted to hospital with acute diverticulitis require surgery, Dr. Sharzehi said. 

Surgery may become an option for patients who have recurrent cases of the disease, even if not severe, Dr. Sharzehi said.

Dr. Sharzehi reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

In addition to warmer weather, June will usher in changes in asthma and COPD inhaler costs for many patients, potentially reducing barriers to those seeing high prescription prices. Price ceilings have been set by some companies, likely following action earlier this year by a Senate Committee which pointed to higher costs of US inhalers compared with other countries.

Senator Sanders stated: “In my view, Americans who have asthma and COPD should not be forced to pay, in many cases, 10-70 times more for the same exact inhalers as patients in Europe and other parts of the world.”

Starting June 1, Boehringer Ingelheim will cap out-of-pocket costs for the company’s inhaler products for chronic lung disease and asthma at $35 per month, according to a March 7, 2024, press release from the German drugmaker’s US headquarters in Ridgefield, Conn. The reductions cover the full range of the company’s inhaler products for asthma and chronic obstructive pulmonary disease (COPD) including Atrovent, Combivent Respimat and Spiriva HandiHaler and Respimat, Stiolto Respimat and Striverdi Respimat. In the release, Boehringer Ingelheim USA Corporation’s President and CEO Jean-Michel Boers stated, “The US health care system is complex and often doesn’t work for patients, especially the most vulnerable. While we can’t fix the entire system alone, we are bringing forward a solution to make it fairer. We want to do our part to help patients living with COPD or asthma who struggle to pay for their medications.”

Similar announcements were made by AstraZeneca and GSK. GSK’s cap will go into effect on January 1, 2025, and includes Advair Diskus, Advair HFA, Anoro Ellipta, Arnuity Ellipta, Breo Ellipta, Incruse Ellipta, Serevent Diskus, Trelegy Ellipta, and Ventolin HFA. The AstraZeneca cap, which covers Airsupra, Bevespi Aerosphere, Breztri Aeroshpere, and Symbicort, goes into effect on June 1, 2024.
 

Senate statement on pricing

These companies plus Teva had received letters sent on January 8, 2024, by the members of the Senate Committee on Health, Education, Labor, and Pensions: senators Sanders, Baldwin, Luján and Markey. The letters cited enormous inhaler price discrepancies, for example $489 for Combivent Respimat in the United States but just $7 in France, and announced the conduct of an investigation into efforts by these companies to artificially inflate and manipulate prices of asthma inhalers that have been on the market for decades. A statement from Sen. Sanders’ office noted that AstraZeneca, GSK, and Teva made more than $25 billion in revenue from inhalers alone in the past 5 years (Boehringer Ingelheim does not provide public US inhaler revenue information).

Suit claims generic delay

A federal lawsuit filed in Boston on March 6, according to a Reuters brief from March 7, cited Boehringer for improperly submitting patents to the US Food and Drug Administration (FDA). The purpose of those patents, the suit charges, was to delay generic competition and inflate Combivent Respimat and Spiriva Respimat inhaler prices.

Inhaler prices soared in the United States, according to a March 10 U.S. News & World Report commentary by The Conversation, a nonprofit news organization, after the 2008 FDA ban on chlorofluorocarbon (CFC)-propellants led to the phase-out of CFC-containing inhalers and their replacement with hydrofluoroalkane-propellant inhalers. For the insured that meant an average out-of-pocket inhaler cost increase from $13.60 per prescription in 2004 to $25 in 2015. The current rate for the now nongeneric HFA-propelled but otherwise identical albuterol inhaler is $98. Competition from a more recently FDA-approved (2020) generic version has not been robust enough to effect meaningful price reductions, the report stated. While good insurance generally covers most of inhaler costs, the more than 25 million uninsured in 2023 faced steep market prices that put strain even on some insured, the CDC found, driving many in the United States to purchase from Mexican, Canadian, or other foreign pharmacies. The Teva QVAR REdiHaler corticosteroid inhaler, costing $9 in Germany, costs $286 in the US. Dosages, however, may not be identical. A first FDA-authorization of drug importing this past January applied only to agents for a limited number of disease states and pertained only to Florida, but may serve as a model for other states, according to the commentary.

“The announced price cap from Boehringer Ingelheim,” stated Kenneth Mendez, president and CEO of the Asthma and Allergy Foundation of America (AAFA) in a press release, “is a step toward improving access to essential asthma medicine and demonstrates that the voice of the asthma patient community is being heard.” The AAFA release noted further that asthma death rates, while declining overall, are triple in Blacks compared with Whites. Death rates, asthma rates, and rates of being uninsured or underinsured are much higher in Black and Puerto Rican populations than in Whites. The complex layers of the current US system, composed of pharmaceutical manufacturers, pharmacy benefit managers, insurance companies, employers, and federal policies often conspire against those people who need asthma drugs the most. AAFA research has shown that when drug prices become a barrier to treatment, people with asthma ration or simply discontinue their essential asthma medications. Beyond saved lives, access to asthma medications can reduce hospitalizations and lower the more than $82 billion in annual asthma costs to the US economy.

Sen. Sanders, on March 20, applauded the GSK announcement: “As Chairman of the Senate Health, Education, Labor, and Pensions Committee, I very much appreciate GlaxoSmithKline’s announcement today that Americans throughout the country with asthma and COPD will pay no more than $35 for the brand name inhalers they manufacture. I look forward to working with GSK to make sure that this decision reaches as many patients as possible.”

“Inhaled medications continue to be an essential part of the therapy for patients with asthma, COPD, and other respiratory conditions,” said Diego J. Maselli, professor and chief, Division of Pulmonary Diseases & Critical Care, UT Health at San Antonio, San Antonio, Texas, in an interview with CHEST Physician. He added, “Unfortunately, with increasing cost of these and other treatments, access has been challenging for many patients. Patients, families, and providers constantly experience frustration with the difficulties of obtaining these lifesaving medications, and cost is the main barrier. Even those with ample insurance coverage face difficult challenges, as the high prices of these medications motivate insurance carriers to constantly adjust what is the ‘preferred’ option among inhalers. Regrettably, noncompliance and nonadherence to inhaled therapies has been linked to poor patient outcomes and increased health care utilization in both asthma and COPD. Because of the high prevalence of these diseases in the US and worldwide, efforts to increase the access of these vital medications has been a priority. With the leveling of the prices of these medications across the world, we hope that there will be both improved access and, as a consequence, better patient outcomes.”

In addition to warmer weather, June will usher in changes in asthma and COPD inhaler costs for many patients, potentially reducing barriers to those seeing high prescription prices. Price ceilings have been set by some companies, likely following action earlier this year by a Senate Committee which pointed to higher costs of US inhalers compared with other countries.

Senator Sanders stated: “In my view, Americans who have asthma and COPD should not be forced to pay, in many cases, 10-70 times more for the same exact inhalers as patients in Europe and other parts of the world.”

Starting June 1, Boehringer Ingelheim will cap out-of-pocket costs for the company’s inhaler products for chronic lung disease and asthma at $35 per month, according to a March 7, 2024, press release from the German drugmaker’s US headquarters in Ridgefield, Conn. The reductions cover the full range of the company’s inhaler products for asthma and chronic obstructive pulmonary disease (COPD) including Atrovent, Combivent Respimat and Spiriva HandiHaler and Respimat, Stiolto Respimat and Striverdi Respimat. In the release, Boehringer Ingelheim USA Corporation’s President and CEO Jean-Michel Boers stated, “The US health care system is complex and often doesn’t work for patients, especially the most vulnerable. While we can’t fix the entire system alone, we are bringing forward a solution to make it fairer. We want to do our part to help patients living with COPD or asthma who struggle to pay for their medications.”

Similar announcements were made by AstraZeneca and GSK. GSK’s cap will go into effect on January 1, 2025, and includes Advair Diskus, Advair HFA, Anoro Ellipta, Arnuity Ellipta, Breo Ellipta, Incruse Ellipta, Serevent Diskus, Trelegy Ellipta, and Ventolin HFA. The AstraZeneca cap, which covers Airsupra, Bevespi Aerosphere, Breztri Aeroshpere, and Symbicort, goes into effect on June 1, 2024.
 

Senate statement on pricing

These companies plus Teva had received letters sent on January 8, 2024, by the members of the Senate Committee on Health, Education, Labor, and Pensions: senators Sanders, Baldwin, Luján and Markey. The letters cited enormous inhaler price discrepancies, for example $489 for Combivent Respimat in the United States but just $7 in France, and announced the conduct of an investigation into efforts by these companies to artificially inflate and manipulate prices of asthma inhalers that have been on the market for decades. A statement from Sen. Sanders’ office noted that AstraZeneca, GSK, and Teva made more than $25 billion in revenue from inhalers alone in the past 5 years (Boehringer Ingelheim does not provide public US inhaler revenue information).

Suit claims generic delay

A federal lawsuit filed in Boston on March 6, according to a Reuters brief from March 7, cited Boehringer for improperly submitting patents to the US Food and Drug Administration (FDA). The purpose of those patents, the suit charges, was to delay generic competition and inflate Combivent Respimat and Spiriva Respimat inhaler prices.

Inhaler prices soared in the United States, according to a March 10 U.S. News & World Report commentary by The Conversation, a nonprofit news organization, after the 2008 FDA ban on chlorofluorocarbon (CFC)-propellants led to the phase-out of CFC-containing inhalers and their replacement with hydrofluoroalkane-propellant inhalers. For the insured that meant an average out-of-pocket inhaler cost increase from $13.60 per prescription in 2004 to $25 in 2015. The current rate for the now nongeneric HFA-propelled but otherwise identical albuterol inhaler is $98. Competition from a more recently FDA-approved (2020) generic version has not been robust enough to effect meaningful price reductions, the report stated. While good insurance generally covers most of inhaler costs, the more than 25 million uninsured in 2023 faced steep market prices that put strain even on some insured, the CDC found, driving many in the United States to purchase from Mexican, Canadian, or other foreign pharmacies. The Teva QVAR REdiHaler corticosteroid inhaler, costing $9 in Germany, costs $286 in the US. Dosages, however, may not be identical. A first FDA-authorization of drug importing this past January applied only to agents for a limited number of disease states and pertained only to Florida, but may serve as a model for other states, according to the commentary.

“The announced price cap from Boehringer Ingelheim,” stated Kenneth Mendez, president and CEO of the Asthma and Allergy Foundation of America (AAFA) in a press release, “is a step toward improving access to essential asthma medicine and demonstrates that the voice of the asthma patient community is being heard.” The AAFA release noted further that asthma death rates, while declining overall, are triple in Blacks compared with Whites. Death rates, asthma rates, and rates of being uninsured or underinsured are much higher in Black and Puerto Rican populations than in Whites. The complex layers of the current US system, composed of pharmaceutical manufacturers, pharmacy benefit managers, insurance companies, employers, and federal policies often conspire against those people who need asthma drugs the most. AAFA research has shown that when drug prices become a barrier to treatment, people with asthma ration or simply discontinue their essential asthma medications. Beyond saved lives, access to asthma medications can reduce hospitalizations and lower the more than $82 billion in annual asthma costs to the US economy.

Sen. Sanders, on March 20, applauded the GSK announcement: “As Chairman of the Senate Health, Education, Labor, and Pensions Committee, I very much appreciate GlaxoSmithKline’s announcement today that Americans throughout the country with asthma and COPD will pay no more than $35 for the brand name inhalers they manufacture. I look forward to working with GSK to make sure that this decision reaches as many patients as possible.”

“Inhaled medications continue to be an essential part of the therapy for patients with asthma, COPD, and other respiratory conditions,” said Diego J. Maselli, professor and chief, Division of Pulmonary Diseases & Critical Care, UT Health at San Antonio, San Antonio, Texas, in an interview with CHEST Physician. He added, “Unfortunately, with increasing cost of these and other treatments, access has been challenging for many patients. Patients, families, and providers constantly experience frustration with the difficulties of obtaining these lifesaving medications, and cost is the main barrier. Even those with ample insurance coverage face difficult challenges, as the high prices of these medications motivate insurance carriers to constantly adjust what is the ‘preferred’ option among inhalers. Regrettably, noncompliance and nonadherence to inhaled therapies has been linked to poor patient outcomes and increased health care utilization in both asthma and COPD. Because of the high prevalence of these diseases in the US and worldwide, efforts to increase the access of these vital medications has been a priority. With the leveling of the prices of these medications across the world, we hope that there will be both improved access and, as a consequence, better patient outcomes.”

In addition to warmer weather, June will usher in changes in asthma and COPD inhaler costs for many patients, potentially reducing barriers to those seeing high prescription prices. Price ceilings have been set by some companies, likely following action earlier this year by a Senate Committee which pointed to higher costs of US inhalers compared with other countries.

Senator Sanders stated: “In my view, Americans who have asthma and COPD should not be forced to pay, in many cases, 10-70 times more for the same exact inhalers as patients in Europe and other parts of the world.”

Starting June 1, Boehringer Ingelheim will cap out-of-pocket costs for the company’s inhaler products for chronic lung disease and asthma at $35 per month, according to a March 7, 2024, press release from the German drugmaker’s US headquarters in Ridgefield, Conn. The reductions cover the full range of the company’s inhaler products for asthma and chronic obstructive pulmonary disease (COPD) including Atrovent, Combivent Respimat and Spiriva HandiHaler and Respimat, Stiolto Respimat and Striverdi Respimat. In the release, Boehringer Ingelheim USA Corporation’s President and CEO Jean-Michel Boers stated, “The US health care system is complex and often doesn’t work for patients, especially the most vulnerable. While we can’t fix the entire system alone, we are bringing forward a solution to make it fairer. We want to do our part to help patients living with COPD or asthma who struggle to pay for their medications.”

Similar announcements were made by AstraZeneca and GSK. GSK’s cap will go into effect on January 1, 2025, and includes Advair Diskus, Advair HFA, Anoro Ellipta, Arnuity Ellipta, Breo Ellipta, Incruse Ellipta, Serevent Diskus, Trelegy Ellipta, and Ventolin HFA. The AstraZeneca cap, which covers Airsupra, Bevespi Aerosphere, Breztri Aeroshpere, and Symbicort, goes into effect on June 1, 2024.
 

Senate statement on pricing

These companies plus Teva had received letters sent on January 8, 2024, by the members of the Senate Committee on Health, Education, Labor, and Pensions: senators Sanders, Baldwin, Luján and Markey. The letters cited enormous inhaler price discrepancies, for example $489 for Combivent Respimat in the United States but just $7 in France, and announced the conduct of an investigation into efforts by these companies to artificially inflate and manipulate prices of asthma inhalers that have been on the market for decades. A statement from Sen. Sanders’ office noted that AstraZeneca, GSK, and Teva made more than $25 billion in revenue from inhalers alone in the past 5 years (Boehringer Ingelheim does not provide public US inhaler revenue information).

Suit claims generic delay

A federal lawsuit filed in Boston on March 6, according to a Reuters brief from March 7, cited Boehringer for improperly submitting patents to the US Food and Drug Administration (FDA). The purpose of those patents, the suit charges, was to delay generic competition and inflate Combivent Respimat and Spiriva Respimat inhaler prices.

Inhaler prices soared in the United States, according to a March 10 U.S. News & World Report commentary by The Conversation, a nonprofit news organization, after the 2008 FDA ban on chlorofluorocarbon (CFC)-propellants led to the phase-out of CFC-containing inhalers and their replacement with hydrofluoroalkane-propellant inhalers. For the insured that meant an average out-of-pocket inhaler cost increase from $13.60 per prescription in 2004 to $25 in 2015. The current rate for the now nongeneric HFA-propelled but otherwise identical albuterol inhaler is $98. Competition from a more recently FDA-approved (2020) generic version has not been robust enough to effect meaningful price reductions, the report stated. While good insurance generally covers most of inhaler costs, the more than 25 million uninsured in 2023 faced steep market prices that put strain even on some insured, the CDC found, driving many in the United States to purchase from Mexican, Canadian, or other foreign pharmacies. The Teva QVAR REdiHaler corticosteroid inhaler, costing $9 in Germany, costs $286 in the US. Dosages, however, may not be identical. A first FDA-authorization of drug importing this past January applied only to agents for a limited number of disease states and pertained only to Florida, but may serve as a model for other states, according to the commentary.

“The announced price cap from Boehringer Ingelheim,” stated Kenneth Mendez, president and CEO of the Asthma and Allergy Foundation of America (AAFA) in a press release, “is a step toward improving access to essential asthma medicine and demonstrates that the voice of the asthma patient community is being heard.” The AAFA release noted further that asthma death rates, while declining overall, are triple in Blacks compared with Whites. Death rates, asthma rates, and rates of being uninsured or underinsured are much higher in Black and Puerto Rican populations than in Whites. The complex layers of the current US system, composed of pharmaceutical manufacturers, pharmacy benefit managers, insurance companies, employers, and federal policies often conspire against those people who need asthma drugs the most. AAFA research has shown that when drug prices become a barrier to treatment, people with asthma ration or simply discontinue their essential asthma medications. Beyond saved lives, access to asthma medications can reduce hospitalizations and lower the more than $82 billion in annual asthma costs to the US economy.

Sen. Sanders, on March 20, applauded the GSK announcement: “As Chairman of the Senate Health, Education, Labor, and Pensions Committee, I very much appreciate GlaxoSmithKline’s announcement today that Americans throughout the country with asthma and COPD will pay no more than $35 for the brand name inhalers they manufacture. I look forward to working with GSK to make sure that this decision reaches as many patients as possible.”

“Inhaled medications continue to be an essential part of the therapy for patients with asthma, COPD, and other respiratory conditions,” said Diego J. Maselli, professor and chief, Division of Pulmonary Diseases & Critical Care, UT Health at San Antonio, San Antonio, Texas, in an interview with CHEST Physician. He added, “Unfortunately, with increasing cost of these and other treatments, access has been challenging for many patients. Patients, families, and providers constantly experience frustration with the difficulties of obtaining these lifesaving medications, and cost is the main barrier. Even those with ample insurance coverage face difficult challenges, as the high prices of these medications motivate insurance carriers to constantly adjust what is the ‘preferred’ option among inhalers. Regrettably, noncompliance and nonadherence to inhaled therapies has been linked to poor patient outcomes and increased health care utilization in both asthma and COPD. Because of the high prevalence of these diseases in the US and worldwide, efforts to increase the access of these vital medications has been a priority. With the leveling of the prices of these medications across the world, we hope that there will be both improved access and, as a consequence, better patient outcomes.”

SAN DIEGO — Approximately 10 years ago in France, high throughput screening in a series of cases suggested that vaccine-derived rubella virus was the surprising cause of persistent cutaneous granulomas, but an update at the annual meeting of the American Academy of Dermatology suggests this phenomenon is not as rare as once supposed.

Based on accumulating evidence, the Centers for Disease Control and Prevention (CDC) through collaborations with others also recognized this in pediatric patients with inborn errors of immunity, and it is now appropriate for clinicians to consider this etiology when no other infectious agents can be identified, according to Karolyn A. Wanat, MD, professor of dermatology, Medical College of Wisconsin, Milwaukee, who spoke about rubella as a trigger in granulomatous disease at the meeting. “This is a huge evolving area of interest,” said Dr. Wanat, who has been the first author or coauthor on several published papers, including a review article published earlier this year.

In the earliest cases, including those reported in 2014, the cutaneous granulomas presumed to be causally related to vaccine-derived rubella virus were found only in those with a primary immunodeficiency. This is no longer the case. In a collaboration among US clinics, granulomas that had persisted for years in immunocompetent adults were identified, according to Dr. Wanat, the first author of a report on these findings in four adults in 2022. In addition, it now appears that wild-type rubella virus, like vaccine-derived rubella virus, can be the source of the antigenic response that underlies the development of rubella-associated cutaneous granulomas.

The phenotype of these granulomas is comparable to granulomas associated with other infectious agents. On dermatopathology, these commonly feature a robust granulomatous inflammation with multinucleated giant cells and lymphocytic infiltrate. Necrosis and fibrosis are also common.

“These are the types of granulomas that we would be thinking infection. If tissue cultures are negative, we would probably repeat them,” she said, suggesting that suspicion of an infectious etiology would probably remain high even after multiple negative tests.

Of the cases accruing in the United States and elsewhere, most but not all have been linked to inborn errors of immunity. In a 2020 CDC review, the risk of granulomas caused by compromised immunity, such as defects in T cell function, was estimated to be in the range of 0.6% to 2.5%, Dr. Wanat said.

It is now known that primary immunodeficiency is not a prerequisite, but this should not change the perception that the rubella vaccine, which was introduced in 1979, is effective and safe, according to Dr. Wanat. The vaccine is associated with few serious adverse events and is so effective that rubella was eliminated from the United States in 2004 and from the Americas in 2015.

This makes cases of granuloma associated with wild-type rubella virus surprising, but they appear to be exceedingly rare. Whether caused by vaccine exposure or another source, the mechanism of latent development of cutaneous granulomas is consistent with other infectious sources, and is not well understood.

“Rubella is a sneaky virus that can persist in some immunoprivileged sites indefinitely,” Dr. Wanat said. These sites include the eyes, joints, and placenta.

Many initial cases of rubella-associated granulomas occurred on the arms, presumably where the vaccine was administered, despite long intervals between exposure and lesion growth. This interval is often measured in years.

With more cases, it is now understood that involvement of other organs does occur even if the skin is the most common site of antigenic response in patients with immunodeficiency. The liver and lymph nodes represent other tissues that have been affected. Even lesions in the brain have been seen on autopsy.

Based on the benefit-to-risk ratio of a highly effective and successful vaccine, however, the association with a risk of granulomas “should not raise questions” about the value of the vaccine itself, Dr. Wanat noted.

“The proportion of patients who develop these granulomas is very, very low. Yet, the vaccine provides life-long immunity,” she said.

The discovery of granulomas associated with wild type rubella infection was “shocking” based on the supposition that the rubella virus had been eliminated, but this is just one of the unexpected discoveries as the still-evolving science has traced the story of rubella-associated granulomas over the past 10 years.

Cases now include children and adults through advanced ages.

Shedding of the virus and risk of infection to others has been studied but so far, the risk — if it exists — is very low. The evidence includes the many patients who have lived with the granulomas for years, even decades, without any known spread to others.

As for ongoing work in this area, Dr. Wanat said that a histopathological case definition for rubella-associated granulomas is being developed, and she and other investigators are actively seeking new cases to better characterize the disease.

So far, optimal treatment is not well defined. A number of strategies have had limited success or are considered impractical for routine use. One example is a stem cell transplant. In a case Dr. Wanat cited, complete resolution of the skin lesions was achieved with a transplant.

“I am not suggesting that those with localized disease in the skin should undergo a transplant, but it does support the role of the immune system and the potential for a reboot to clear the skin,” she said.

Other therapies associated with benefit in at least some patients include tumor necrosis factor (TNF) inhibitors with dapsone and ribavirin. The risk of adverse events for the latter might again limit its use, Dr. Wanat said.

With awareness, the number of granulomas found to be associated with rubella virus is expected to grow. Dr. Wanat speculated that those areas of the country that not yet have documented a case will do so over time. For idiopathic cases of cutaneous granulomas, rubella should be kept in mind, she said.

Characterizing rubella-associated cutaneous granulomas as “a public health concern,” Dr. Wanat urged clinicians to consider this etiology in lesions that match the phenotype, particularly when other more common infectious agents cannot be identified.

Asked for his perspective, Jeffrey P. North, MD, managing director of the UCSF Dermatopathology, and professor of dermatology and pathology at the University of California, San Francisco, agreed that rubella should be considered as a source of granulomas with a suspected infectious etiology when a pathogen cannot be found.

“It is likely much more common than we know as it has only been recently described and testing for it is limited. I suspected there are a lot of undiagnosed patients suffering from this disease,” Dr. North said in an interview.

“One of the important points for clinicians to consider is that while this has been reported mostly in patients with some form of immunodeficiency, there have also been patients reported to have this condition with no immunodeficiency,” he added. Even though the association between rubella and granulomas was made 10 years ago, awareness is only now spreading, which means the frequency with which rubella leads to granulomas remains uncertain.

“I think we will start to get a better idea of how common this is as more people learn about and testing for it expands,” Dr. North said.

Dr. Wanat reports no potential conflicts of interest. Dr. North reports financial relationships with AdviNow and Kiniksa Pharmaceuticals.

SAN DIEGO — Approximately 10 years ago in France, high throughput screening in a series of cases suggested that vaccine-derived rubella virus was the surprising cause of persistent cutaneous granulomas, but an update at the annual meeting of the American Academy of Dermatology suggests this phenomenon is not as rare as once supposed.

Based on accumulating evidence, the Centers for Disease Control and Prevention (CDC) through collaborations with others also recognized this in pediatric patients with inborn errors of immunity, and it is now appropriate for clinicians to consider this etiology when no other infectious agents can be identified, according to Karolyn A. Wanat, MD, professor of dermatology, Medical College of Wisconsin, Milwaukee, who spoke about rubella as a trigger in granulomatous disease at the meeting. “This is a huge evolving area of interest,” said Dr. Wanat, who has been the first author or coauthor on several published papers, including a review article published earlier this year.

In the earliest cases, including those reported in 2014, the cutaneous granulomas presumed to be causally related to vaccine-derived rubella virus were found only in those with a primary immunodeficiency. This is no longer the case. In a collaboration among US clinics, granulomas that had persisted for years in immunocompetent adults were identified, according to Dr. Wanat, the first author of a report on these findings in four adults in 2022. In addition, it now appears that wild-type rubella virus, like vaccine-derived rubella virus, can be the source of the antigenic response that underlies the development of rubella-associated cutaneous granulomas.

The phenotype of these granulomas is comparable to granulomas associated with other infectious agents. On dermatopathology, these commonly feature a robust granulomatous inflammation with multinucleated giant cells and lymphocytic infiltrate. Necrosis and fibrosis are also common.

“These are the types of granulomas that we would be thinking infection. If tissue cultures are negative, we would probably repeat them,” she said, suggesting that suspicion of an infectious etiology would probably remain high even after multiple negative tests.

Of the cases accruing in the United States and elsewhere, most but not all have been linked to inborn errors of immunity. In a 2020 CDC review, the risk of granulomas caused by compromised immunity, such as defects in T cell function, was estimated to be in the range of 0.6% to 2.5%, Dr. Wanat said.

It is now known that primary immunodeficiency is not a prerequisite, but this should not change the perception that the rubella vaccine, which was introduced in 1979, is effective and safe, according to Dr. Wanat. The vaccine is associated with few serious adverse events and is so effective that rubella was eliminated from the United States in 2004 and from the Americas in 2015.

This makes cases of granuloma associated with wild-type rubella virus surprising, but they appear to be exceedingly rare. Whether caused by vaccine exposure or another source, the mechanism of latent development of cutaneous granulomas is consistent with other infectious sources, and is not well understood.

“Rubella is a sneaky virus that can persist in some immunoprivileged sites indefinitely,” Dr. Wanat said. These sites include the eyes, joints, and placenta.

Many initial cases of rubella-associated granulomas occurred on the arms, presumably where the vaccine was administered, despite long intervals between exposure and lesion growth. This interval is often measured in years.

With more cases, it is now understood that involvement of other organs does occur even if the skin is the most common site of antigenic response in patients with immunodeficiency. The liver and lymph nodes represent other tissues that have been affected. Even lesions in the brain have been seen on autopsy.

Based on the benefit-to-risk ratio of a highly effective and successful vaccine, however, the association with a risk of granulomas “should not raise questions” about the value of the vaccine itself, Dr. Wanat noted.

“The proportion of patients who develop these granulomas is very, very low. Yet, the vaccine provides life-long immunity,” she said.

The discovery of granulomas associated with wild type rubella infection was “shocking” based on the supposition that the rubella virus had been eliminated, but this is just one of the unexpected discoveries as the still-evolving science has traced the story of rubella-associated granulomas over the past 10 years.

Cases now include children and adults through advanced ages.

Shedding of the virus and risk of infection to others has been studied but so far, the risk — if it exists — is very low. The evidence includes the many patients who have lived with the granulomas for years, even decades, without any known spread to others.

As for ongoing work in this area, Dr. Wanat said that a histopathological case definition for rubella-associated granulomas is being developed, and she and other investigators are actively seeking new cases to better characterize the disease.

So far, optimal treatment is not well defined. A number of strategies have had limited success or are considered impractical for routine use. One example is a stem cell transplant. In a case Dr. Wanat cited, complete resolution of the skin lesions was achieved with a transplant.

“I am not suggesting that those with localized disease in the skin should undergo a transplant, but it does support the role of the immune system and the potential for a reboot to clear the skin,” she said.

Other therapies associated with benefit in at least some patients include tumor necrosis factor (TNF) inhibitors with dapsone and ribavirin. The risk of adverse events for the latter might again limit its use, Dr. Wanat said.

With awareness, the number of granulomas found to be associated with rubella virus is expected to grow. Dr. Wanat speculated that those areas of the country that not yet have documented a case will do so over time. For idiopathic cases of cutaneous granulomas, rubella should be kept in mind, she said.

Characterizing rubella-associated cutaneous granulomas as “a public health concern,” Dr. Wanat urged clinicians to consider this etiology in lesions that match the phenotype, particularly when other more common infectious agents cannot be identified.

Asked for his perspective, Jeffrey P. North, MD, managing director of the UCSF Dermatopathology, and professor of dermatology and pathology at the University of California, San Francisco, agreed that rubella should be considered as a source of granulomas with a suspected infectious etiology when a pathogen cannot be found.

“It is likely much more common than we know as it has only been recently described and testing for it is limited. I suspected there are a lot of undiagnosed patients suffering from this disease,” Dr. North said in an interview.

“One of the important points for clinicians to consider is that while this has been reported mostly in patients with some form of immunodeficiency, there have also been patients reported to have this condition with no immunodeficiency,” he added. Even though the association between rubella and granulomas was made 10 years ago, awareness is only now spreading, which means the frequency with which rubella leads to granulomas remains uncertain.

“I think we will start to get a better idea of how common this is as more people learn about and testing for it expands,” Dr. North said.

Dr. Wanat reports no potential conflicts of interest. Dr. North reports financial relationships with AdviNow and Kiniksa Pharmaceuticals.

SAN DIEGO — Approximately 10 years ago in France, high throughput screening in a series of cases suggested that vaccine-derived rubella virus was the surprising cause of persistent cutaneous granulomas, but an update at the annual meeting of the American Academy of Dermatology suggests this phenomenon is not as rare as once supposed.

Based on accumulating evidence, the Centers for Disease Control and Prevention (CDC) through collaborations with others also recognized this in pediatric patients with inborn errors of immunity, and it is now appropriate for clinicians to consider this etiology when no other infectious agents can be identified, according to Karolyn A. Wanat, MD, professor of dermatology, Medical College of Wisconsin, Milwaukee, who spoke about rubella as a trigger in granulomatous disease at the meeting. “This is a huge evolving area of interest,” said Dr. Wanat, who has been the first author or coauthor on several published papers, including a review article published earlier this year.

In the earliest cases, including those reported in 2014, the cutaneous granulomas presumed to be causally related to vaccine-derived rubella virus were found only in those with a primary immunodeficiency. This is no longer the case. In a collaboration among US clinics, granulomas that had persisted for years in immunocompetent adults were identified, according to Dr. Wanat, the first author of a report on these findings in four adults in 2022. In addition, it now appears that wild-type rubella virus, like vaccine-derived rubella virus, can be the source of the antigenic response that underlies the development of rubella-associated cutaneous granulomas.

The phenotype of these granulomas is comparable to granulomas associated with other infectious agents. On dermatopathology, these commonly feature a robust granulomatous inflammation with multinucleated giant cells and lymphocytic infiltrate. Necrosis and fibrosis are also common.

“These are the types of granulomas that we would be thinking infection. If tissue cultures are negative, we would probably repeat them,” she said, suggesting that suspicion of an infectious etiology would probably remain high even after multiple negative tests.

Of the cases accruing in the United States and elsewhere, most but not all have been linked to inborn errors of immunity. In a 2020 CDC review, the risk of granulomas caused by compromised immunity, such as defects in T cell function, was estimated to be in the range of 0.6% to 2.5%, Dr. Wanat said.

It is now known that primary immunodeficiency is not a prerequisite, but this should not change the perception that the rubella vaccine, which was introduced in 1979, is effective and safe, according to Dr. Wanat. The vaccine is associated with few serious adverse events and is so effective that rubella was eliminated from the United States in 2004 and from the Americas in 2015.

This makes cases of granuloma associated with wild-type rubella virus surprising, but they appear to be exceedingly rare. Whether caused by vaccine exposure or another source, the mechanism of latent development of cutaneous granulomas is consistent with other infectious sources, and is not well understood.

“Rubella is a sneaky virus that can persist in some immunoprivileged sites indefinitely,” Dr. Wanat said. These sites include the eyes, joints, and placenta.

Many initial cases of rubella-associated granulomas occurred on the arms, presumably where the vaccine was administered, despite long intervals between exposure and lesion growth. This interval is often measured in years.

With more cases, it is now understood that involvement of other organs does occur even if the skin is the most common site of antigenic response in patients with immunodeficiency. The liver and lymph nodes represent other tissues that have been affected. Even lesions in the brain have been seen on autopsy.

Based on the benefit-to-risk ratio of a highly effective and successful vaccine, however, the association with a risk of granulomas “should not raise questions” about the value of the vaccine itself, Dr. Wanat noted.

“The proportion of patients who develop these granulomas is very, very low. Yet, the vaccine provides life-long immunity,” she said.

The discovery of granulomas associated with wild type rubella infection was “shocking” based on the supposition that the rubella virus had been eliminated, but this is just one of the unexpected discoveries as the still-evolving science has traced the story of rubella-associated granulomas over the past 10 years.

Cases now include children and adults through advanced ages.

Shedding of the virus and risk of infection to others has been studied but so far, the risk — if it exists — is very low. The evidence includes the many patients who have lived with the granulomas for years, even decades, without any known spread to others.

As for ongoing work in this area, Dr. Wanat said that a histopathological case definition for rubella-associated granulomas is being developed, and she and other investigators are actively seeking new cases to better characterize the disease.

So far, optimal treatment is not well defined. A number of strategies have had limited success or are considered impractical for routine use. One example is a stem cell transplant. In a case Dr. Wanat cited, complete resolution of the skin lesions was achieved with a transplant.

“I am not suggesting that those with localized disease in the skin should undergo a transplant, but it does support the role of the immune system and the potential for a reboot to clear the skin,” she said.

Other therapies associated with benefit in at least some patients include tumor necrosis factor (TNF) inhibitors with dapsone and ribavirin. The risk of adverse events for the latter might again limit its use, Dr. Wanat said.

With awareness, the number of granulomas found to be associated with rubella virus is expected to grow. Dr. Wanat speculated that those areas of the country that not yet have documented a case will do so over time. For idiopathic cases of cutaneous granulomas, rubella should be kept in mind, she said.

Characterizing rubella-associated cutaneous granulomas as “a public health concern,” Dr. Wanat urged clinicians to consider this etiology in lesions that match the phenotype, particularly when other more common infectious agents cannot be identified.

Asked for his perspective, Jeffrey P. North, MD, managing director of the UCSF Dermatopathology, and professor of dermatology and pathology at the University of California, San Francisco, agreed that rubella should be considered as a source of granulomas with a suspected infectious etiology when a pathogen cannot be found.

“It is likely much more common than we know as it has only been recently described and testing for it is limited. I suspected there are a lot of undiagnosed patients suffering from this disease,” Dr. North said in an interview.

“One of the important points for clinicians to consider is that while this has been reported mostly in patients with some form of immunodeficiency, there have also been patients reported to have this condition with no immunodeficiency,” he added. Even though the association between rubella and granulomas was made 10 years ago, awareness is only now spreading, which means the frequency with which rubella leads to granulomas remains uncertain.

“I think we will start to get a better idea of how common this is as more people learn about and testing for it expands,” Dr. North said.

Dr. Wanat reports no potential conflicts of interest. Dr. North reports financial relationships with AdviNow and Kiniksa Pharmaceuticals.