Nonmelanoma Skin Cancer

The Diagnosis: Purpuric Drug Eruption

Histopathology revealed interface dermatitis, spongiosis, and a perivascular lymphocytic infiltrate with extravasated red blood cells consistent with a purpuric drug eruption. Our patient achieved remission of hairy cell leukemia after receiving only 2 of 5 expected doses of cladribine. The rash resolved completely in 3 weeks following a prednisone taper (Figure).

Hairy cell leukemia is a rare indolent lymphoproliferative disorder of B cells that accounts for approximately 2% of adult leukemias in the United States. Cladribine, a purine nucleoside analog that impairs DNA synthesis and repair, has become the mainstay of therapy, demonstrating a 95% complete response rate.¹ Although few reports have addressed the cutaneous reactions seen with cladribine therapy, they can occur in more than 50% of patients.^1,2 The most common skin manifestation associated with cladribine therapy is a morbilliform rash, but Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) have been reported.¹

Few cases of purpuric eruption secondary to cladribine treatment have been described, and nearly all reports involve concomitant medications such as allopurinol, which our patient was taking, and antibiotics including trimethoprim-sulfamethoxazole and penicillins.^1,3,4 In a cohort of 35 patients receiving cladribine,1 only concomitant treatment with cladribine and allopurinol caused cutaneous reactions, further supporting the hypothesis of cladribine-induced drug sensitivity. Allopurinol often is prescribed during induction therapy for prophylaxis against tumor lysis syndrome; similarly, antibiotics frequently are given prophylactically and therapeutically for neutropenic fever. It is believed that T-cell imbalance and profound lymphopenia induced by cladribine increase susceptibility to drug hypersensitivity reactions.^1,3

The typical purpuric eruption develops within 2 days of starting cladribine therapy. Diascopy will reveal petechiae, and biopsy should be performed to rule out other serious drug-induced reactions, such as erythema multiforme, Stevens-Johnson syndrome, and TEN. A cladribine-induced purpuric eruption typically is self-resolving and carries a favorable prognosis, though high-dose corticosteroids often are prescribed to hasten recovery. The rare reports of serious cutaneous reactions secondary to cladribine therapy have been with maculopapular, not purpuric eruptions.² Based on limited available data, cladribine-induced purpura should not be a limitation to continued treatment in patients who need it.¹ Careful consideration of concomitant drug use is necessary, as the current literature demonstrates resolution of rash with withdrawal of other therapies, namely allopurinol.^2-4 Future studies are needed to examine the safety of withholding offending medications and to further elucidate the mechanisms contributing to drug hypersensitivity due to cladribine.

Widespread purpura and petechiae can pose a wide differential; the patient’s recent history of cladribine administration pointed to a classic purpuric eruption. Other diagnoses such as toxic erythema of chemotherapy (TEC) and TEN are not purpuric, though plaques can be violaceous. Lack of bullae, blisters, and facial or mucosal surface involvement suggest TEN.⁵ Thrombotic thrombocytopenic purpura and disseminated intravascular coagulation do manifest with petechiae and purpura, though such a robust eruption in the context of recent cladribine therapy is less likely. The classic retiform purpura and necrosis were not present to suggest purpura fulminans from disseminated intravascular coagulation.

Several of the proposed diagnoses as well as a purpuric drug eruption would demonstrate extravasated red blood cells on histopathology, but the presence of interface dermatitis narrows the differential to a purpuric drug eruption. Necrotic keratinocytes and full-thickness necrosis were not present on biopsy to support a diagnosis of TEN in our patient. Characteristic features of TEC—including eccrine squamous syringometaplasia, dermal edema, and keratinocyte atypia—were not present on biopsy.⁶ Finally, although TEN should resolve with steroid treatment, TEC is self-limited and thrombotic thrombocytopenic purpura and disseminated intravascular coagulation would not resolve with use of steroids alone. 

The Diagnosis: Purpuric Drug Eruption

Histopathology revealed interface dermatitis, spongiosis, and a perivascular lymphocytic infiltrate with extravasated red blood cells consistent with a purpuric drug eruption. Our patient achieved remission of hairy cell leukemia after receiving only 2 of 5 expected doses of cladribine. The rash resolved completely in 3 weeks following a prednisone taper (Figure).

Hairy cell leukemia is a rare indolent lymphoproliferative disorder of B cells that accounts for approximately 2% of adult leukemias in the United States. Cladribine, a purine nucleoside analog that impairs DNA synthesis and repair, has become the mainstay of therapy, demonstrating a 95% complete response rate.¹ Although few reports have addressed the cutaneous reactions seen with cladribine therapy, they can occur in more than 50% of patients.^1,2 The most common skin manifestation associated with cladribine therapy is a morbilliform rash, but Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) have been reported.¹

Few cases of purpuric eruption secondary to cladribine treatment have been described, and nearly all reports involve concomitant medications such as allopurinol, which our patient was taking, and antibiotics including trimethoprim-sulfamethoxazole and penicillins.^1,3,4 In a cohort of 35 patients receiving cladribine,1 only concomitant treatment with cladribine and allopurinol caused cutaneous reactions, further supporting the hypothesis of cladribine-induced drug sensitivity. Allopurinol often is prescribed during induction therapy for prophylaxis against tumor lysis syndrome; similarly, antibiotics frequently are given prophylactically and therapeutically for neutropenic fever. It is believed that T-cell imbalance and profound lymphopenia induced by cladribine increase susceptibility to drug hypersensitivity reactions.^1,3

The typical purpuric eruption develops within 2 days of starting cladribine therapy. Diascopy will reveal petechiae, and biopsy should be performed to rule out other serious drug-induced reactions, such as erythema multiforme, Stevens-Johnson syndrome, and TEN. A cladribine-induced purpuric eruption typically is self-resolving and carries a favorable prognosis, though high-dose corticosteroids often are prescribed to hasten recovery. The rare reports of serious cutaneous reactions secondary to cladribine therapy have been with maculopapular, not purpuric eruptions.² Based on limited available data, cladribine-induced purpura should not be a limitation to continued treatment in patients who need it.¹ Careful consideration of concomitant drug use is necessary, as the current literature demonstrates resolution of rash with withdrawal of other therapies, namely allopurinol.^2-4 Future studies are needed to examine the safety of withholding offending medications and to further elucidate the mechanisms contributing to drug hypersensitivity due to cladribine.

Widespread purpura and petechiae can pose a wide differential; the patient’s recent history of cladribine administration pointed to a classic purpuric eruption. Other diagnoses such as toxic erythema of chemotherapy (TEC) and TEN are not purpuric, though plaques can be violaceous. Lack of bullae, blisters, and facial or mucosal surface involvement suggest TEN.⁵ Thrombotic thrombocytopenic purpura and disseminated intravascular coagulation do manifest with petechiae and purpura, though such a robust eruption in the context of recent cladribine therapy is less likely. The classic retiform purpura and necrosis were not present to suggest purpura fulminans from disseminated intravascular coagulation.

Several of the proposed diagnoses as well as a purpuric drug eruption would demonstrate extravasated red blood cells on histopathology, but the presence of interface dermatitis narrows the differential to a purpuric drug eruption. Necrotic keratinocytes and full-thickness necrosis were not present on biopsy to support a diagnosis of TEN in our patient. Characteristic features of TEC—including eccrine squamous syringometaplasia, dermal edema, and keratinocyte atypia—were not present on biopsy.⁶ Finally, although TEN should resolve with steroid treatment, TEC is self-limited and thrombotic thrombocytopenic purpura and disseminated intravascular coagulation would not resolve with use of steroids alone. 

The Diagnosis: Purpuric Drug Eruption

Histopathology revealed interface dermatitis, spongiosis, and a perivascular lymphocytic infiltrate with extravasated red blood cells consistent with a purpuric drug eruption. Our patient achieved remission of hairy cell leukemia after receiving only 2 of 5 expected doses of cladribine. The rash resolved completely in 3 weeks following a prednisone taper (Figure).

Hairy cell leukemia is a rare indolent lymphoproliferative disorder of B cells that accounts for approximately 2% of adult leukemias in the United States. Cladribine, a purine nucleoside analog that impairs DNA synthesis and repair, has become the mainstay of therapy, demonstrating a 95% complete response rate.¹ Although few reports have addressed the cutaneous reactions seen with cladribine therapy, they can occur in more than 50% of patients.^1,2 The most common skin manifestation associated with cladribine therapy is a morbilliform rash, but Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) have been reported.¹

Few cases of purpuric eruption secondary to cladribine treatment have been described, and nearly all reports involve concomitant medications such as allopurinol, which our patient was taking, and antibiotics including trimethoprim-sulfamethoxazole and penicillins.^1,3,4 In a cohort of 35 patients receiving cladribine,1 only concomitant treatment with cladribine and allopurinol caused cutaneous reactions, further supporting the hypothesis of cladribine-induced drug sensitivity. Allopurinol often is prescribed during induction therapy for prophylaxis against tumor lysis syndrome; similarly, antibiotics frequently are given prophylactically and therapeutically for neutropenic fever. It is believed that T-cell imbalance and profound lymphopenia induced by cladribine increase susceptibility to drug hypersensitivity reactions.^1,3

The typical purpuric eruption develops within 2 days of starting cladribine therapy. Diascopy will reveal petechiae, and biopsy should be performed to rule out other serious drug-induced reactions, such as erythema multiforme, Stevens-Johnson syndrome, and TEN. A cladribine-induced purpuric eruption typically is self-resolving and carries a favorable prognosis, though high-dose corticosteroids often are prescribed to hasten recovery. The rare reports of serious cutaneous reactions secondary to cladribine therapy have been with maculopapular, not purpuric eruptions.² Based on limited available data, cladribine-induced purpura should not be a limitation to continued treatment in patients who need it.¹ Careful consideration of concomitant drug use is necessary, as the current literature demonstrates resolution of rash with withdrawal of other therapies, namely allopurinol.^2-4 Future studies are needed to examine the safety of withholding offending medications and to further elucidate the mechanisms contributing to drug hypersensitivity due to cladribine.

Widespread purpura and petechiae can pose a wide differential; the patient’s recent history of cladribine administration pointed to a classic purpuric eruption. Other diagnoses such as toxic erythema of chemotherapy (TEC) and TEN are not purpuric, though plaques can be violaceous. Lack of bullae, blisters, and facial or mucosal surface involvement suggest TEN.⁵ Thrombotic thrombocytopenic purpura and disseminated intravascular coagulation do manifest with petechiae and purpura, though such a robust eruption in the context of recent cladribine therapy is less likely. The classic retiform purpura and necrosis were not present to suggest purpura fulminans from disseminated intravascular coagulation.

Several of the proposed diagnoses as well as a purpuric drug eruption would demonstrate extravasated red blood cells on histopathology, but the presence of interface dermatitis narrows the differential to a purpuric drug eruption. Necrotic keratinocytes and full-thickness necrosis were not present on biopsy to support a diagnosis of TEN in our patient. Characteristic features of TEC—including eccrine squamous syringometaplasia, dermal edema, and keratinocyte atypia—were not present on biopsy.⁶ Finally, although TEN should resolve with steroid treatment, TEC is self-limited and thrombotic thrombocytopenic purpura and disseminated intravascular coagulation would not resolve with use of steroids alone. 

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

Health-related social needs and medical financial hardship are associated with increased risk of mortality in adult cancer survivors, based on data from more than 10,000 individuals.

Little is known about the specific association between health-related social needs (HRSNs) and mortality risk even though HRSNs, defined as challenges in affording food, housing, and other necessities of daily living, are potential challenges for cancer survivors, wrote Zhiyuan Zheng, PhD, of the American Cancer Society, Atlanta, and colleagues.

A 2020 study by Dr. Zheng and colleagues published in the Journal of the National Comprehensive Cancer Network (NCCN) showed that food insecurity and financial worries had a negative impact on cancer survivorship. In the new study, published in Cancer, the researchers identified cancer survivors using the 2013-2018 National Health Interview Survey (NHIS) and the NHIS Mortality File through December 31, 2019. The researchers examined mortality using the data from the Centers for Disease Control and Prevention’s National Death Index (NDI) through December 31, 2019, which links to the National Health Interview Survey Data used in the study.

Individuals’ HRSNs were categorized into three groups: severe, moderate, and minor/none. HRSNs included food insecurity and nonmedical financial concerns, such as housing costs (rent, mortgage). Medical financial hardship included material, psychological, and behavioral domains and was divided into three groups: 2-3 domains, 1 domain, or 0 domains.
 

What Are the Potential Financial Implications of this Research?

The high costs of cancer care often cause medical financial hardships for cancer survivors, and expenses also may cause psychological distress and nonmedical financial hardship as survivors try to make ends meet while facing medical bills, wrote Dr. Zheng and colleagues.

Policy makers are increasingly interested in adding HRSNs to insurance coverage; recent guidance from the Centers for Medicare & Medicaid Services (CMS) allows individual states to apply to provide nutrition and housing supports through state Medicaid programs, according to authors of a 2023 article published in JAMA Health Forum.

The new study adds to the understanding of how HRSNs impact people with cancer by examining the association with mortality risk, Yelak Biru, MSc, president and chief executive officer of the International Myeloma Foundation, said in an interview.

“This is a key area of study for addressing the disparities in treatments and outcomes that result in inequities,” said Mr. Biru, a patient advocate and multiple myeloma survivor who was not involved in the study.
 

What Does the New Study Show?

The new study characterized HRSNs in 5,855 adult cancer survivors aged 18-64 years and 5,918 aged 65-79 years. In the 18- to 64-year-old group, 25.5% reported moderate levels of HRSNs, and 18.3% reported severe HRSNs. In patients aged 65-79 years, 15.6% and 6.6% reported moderate HRSNs and severe HRSNs, respectively.

Severe HRSN was significantly associated with higher mortality risk in an adjusted analysis in patients aged 18-64 years (hazard ratio 2.00, P < .001).

Among adults aged 65-79 years, severe HRSN was not associated with higher mortality risk; however, in this older age group, those with 2-3 domains of medical financial hardship had significantly increased mortality risk compared with adults aged 65-79 years with zero domains of medical financial hardship (HR 1.58, P = .007).

Although the findings that HRSNs were associated with increased mortality risk, especially in the younger group, were not surprising, they serve as a call to action to address how HRSNs are contributing to cancer mortality, Mr. Biru said in an interview. “HRSNs, like food or housing insecurity, can lead to patients being unable to undergo the best treatment approach for their cancer,” he said.
 

What Are the Limitations and Research Gaps?

The study findings were limited by several factors including the use of self-reports to measure medical financial hardship, food insecurity, and nonmedical financial concerns in the NHIS, the researchers wrote in their discussion. More research with longer follow-up time beyond 1-5 years is needed, wrote Dr. Zheng and colleagues.

Studies also are needed to illustrate how patient navigation can help prevent patients from falling through the cracks with regard to social needs and financial hardships, Mr. Biru told this news organization.

Other areas for research include how addressing social needs affects health outcomes and whether programs designed to address social needs are effective, he said.

“Finally, qualitative research is needed to capture the lived experiences of cancer survivors facing these challenges. This knowledge can inform the development of more patient-centered interventions and policies that effectively address the social determinants of health and improve overall outcomes for all cancer survivors,” Mr. Biru said.
 

What Is the Takeaway Message for Clinicians?

HRSNs and financial hardship are significantly associated with increased risk of mortality in adult cancer survivors, Dr. Zheng and colleagues concluded. Looking ahead, comprehensive assessment of HRSNs and financial hardship may help clinicians connect patients with relevant services to mitigate the social and financial impacts of cancer, they wrote.

“The takeaway message for oncologists in practice is that addressing [HRSNs] and financial hardship is crucial for providing comprehensive and equitable cancer care,” Mr. Biru said during his interview.

“The impact of social determinants of health on cancer outcomes cannot be ignored, and oncologists play a vital role in identifying and addressing these needs,” he said. Sensitive, discussion-based screenings are needed to identify core needs such as food and transportation, but clinicians also can consider broader social factors and work with a team to connect patients to appropriate resources, he added.

“By recognizing the importance of HRSN screening and taking proactive steps to address these needs, oncologists can contribute to improving health outcomes, reducing healthcare disparities, and providing more equitable cancer care for their patients,” he said.
 

What Other Guidance Is Available?

“High-quality cancer care requires treating the whole person; measuring and addressing anything in their life that could result in poorer health outcomes is a key component of comprehensive care,” Mr. Biru emphasized.

In September 2023, the National Comprehensive Cancer Network (NCCN) convened a working group cochaired by Mr. Biru that developed recommendations for how oncology practices should routinely measure HRSNs (NCCN.org/social-needs).

“The working group proposed that every cancer patient be assessed for food, transportation access, and financial and housing security at least once a year, and be reassessed at every care transition point as well,” Mr. Biru said. Such screenings should include follow-up to connect patients with services to address any HRSNs they are experiencing, he added.

Lead author Dr. Zheng is employed by the American Cancer Society, which as a nonprofit receives funds from the public through fundraising and contributions, as well as some support from corporations and industry to support its mission programs and services. Mr. Biru had no financial conflicts to disclose.

Health-related social needs and medical financial hardship are associated with increased risk of mortality in adult cancer survivors, based on data from more than 10,000 individuals.

Little is known about the specific association between health-related social needs (HRSNs) and mortality risk even though HRSNs, defined as challenges in affording food, housing, and other necessities of daily living, are potential challenges for cancer survivors, wrote Zhiyuan Zheng, PhD, of the American Cancer Society, Atlanta, and colleagues.

A 2020 study by Dr. Zheng and colleagues published in the Journal of the National Comprehensive Cancer Network (NCCN) showed that food insecurity and financial worries had a negative impact on cancer survivorship. In the new study, published in Cancer, the researchers identified cancer survivors using the 2013-2018 National Health Interview Survey (NHIS) and the NHIS Mortality File through December 31, 2019. The researchers examined mortality using the data from the Centers for Disease Control and Prevention’s National Death Index (NDI) through December 31, 2019, which links to the National Health Interview Survey Data used in the study.

Individuals’ HRSNs were categorized into three groups: severe, moderate, and minor/none. HRSNs included food insecurity and nonmedical financial concerns, such as housing costs (rent, mortgage). Medical financial hardship included material, psychological, and behavioral domains and was divided into three groups: 2-3 domains, 1 domain, or 0 domains.
 

What Are the Potential Financial Implications of this Research?

The high costs of cancer care often cause medical financial hardships for cancer survivors, and expenses also may cause psychological distress and nonmedical financial hardship as survivors try to make ends meet while facing medical bills, wrote Dr. Zheng and colleagues.

Policy makers are increasingly interested in adding HRSNs to insurance coverage; recent guidance from the Centers for Medicare & Medicaid Services (CMS) allows individual states to apply to provide nutrition and housing supports through state Medicaid programs, according to authors of a 2023 article published in JAMA Health Forum.

The new study adds to the understanding of how HRSNs impact people with cancer by examining the association with mortality risk, Yelak Biru, MSc, president and chief executive officer of the International Myeloma Foundation, said in an interview.

“This is a key area of study for addressing the disparities in treatments and outcomes that result in inequities,” said Mr. Biru, a patient advocate and multiple myeloma survivor who was not involved in the study.
 

What Does the New Study Show?

The new study characterized HRSNs in 5,855 adult cancer survivors aged 18-64 years and 5,918 aged 65-79 years. In the 18- to 64-year-old group, 25.5% reported moderate levels of HRSNs, and 18.3% reported severe HRSNs. In patients aged 65-79 years, 15.6% and 6.6% reported moderate HRSNs and severe HRSNs, respectively.

Severe HRSN was significantly associated with higher mortality risk in an adjusted analysis in patients aged 18-64 years (hazard ratio 2.00, P < .001).

Among adults aged 65-79 years, severe HRSN was not associated with higher mortality risk; however, in this older age group, those with 2-3 domains of medical financial hardship had significantly increased mortality risk compared with adults aged 65-79 years with zero domains of medical financial hardship (HR 1.58, P = .007).

Although the findings that HRSNs were associated with increased mortality risk, especially in the younger group, were not surprising, they serve as a call to action to address how HRSNs are contributing to cancer mortality, Mr. Biru said in an interview. “HRSNs, like food or housing insecurity, can lead to patients being unable to undergo the best treatment approach for their cancer,” he said.
 

What Are the Limitations and Research Gaps?

The study findings were limited by several factors including the use of self-reports to measure medical financial hardship, food insecurity, and nonmedical financial concerns in the NHIS, the researchers wrote in their discussion. More research with longer follow-up time beyond 1-5 years is needed, wrote Dr. Zheng and colleagues.

Studies also are needed to illustrate how patient navigation can help prevent patients from falling through the cracks with regard to social needs and financial hardships, Mr. Biru told this news organization.

Other areas for research include how addressing social needs affects health outcomes and whether programs designed to address social needs are effective, he said.

“Finally, qualitative research is needed to capture the lived experiences of cancer survivors facing these challenges. This knowledge can inform the development of more patient-centered interventions and policies that effectively address the social determinants of health and improve overall outcomes for all cancer survivors,” Mr. Biru said.
 

What Is the Takeaway Message for Clinicians?

HRSNs and financial hardship are significantly associated with increased risk of mortality in adult cancer survivors, Dr. Zheng and colleagues concluded. Looking ahead, comprehensive assessment of HRSNs and financial hardship may help clinicians connect patients with relevant services to mitigate the social and financial impacts of cancer, they wrote.

“The takeaway message for oncologists in practice is that addressing [HRSNs] and financial hardship is crucial for providing comprehensive and equitable cancer care,” Mr. Biru said during his interview.

“The impact of social determinants of health on cancer outcomes cannot be ignored, and oncologists play a vital role in identifying and addressing these needs,” he said. Sensitive, discussion-based screenings are needed to identify core needs such as food and transportation, but clinicians also can consider broader social factors and work with a team to connect patients to appropriate resources, he added.

“By recognizing the importance of HRSN screening and taking proactive steps to address these needs, oncologists can contribute to improving health outcomes, reducing healthcare disparities, and providing more equitable cancer care for their patients,” he said.
 

What Other Guidance Is Available?

“High-quality cancer care requires treating the whole person; measuring and addressing anything in their life that could result in poorer health outcomes is a key component of comprehensive care,” Mr. Biru emphasized.

In September 2023, the National Comprehensive Cancer Network (NCCN) convened a working group cochaired by Mr. Biru that developed recommendations for how oncology practices should routinely measure HRSNs (NCCN.org/social-needs).

“The working group proposed that every cancer patient be assessed for food, transportation access, and financial and housing security at least once a year, and be reassessed at every care transition point as well,” Mr. Biru said. Such screenings should include follow-up to connect patients with services to address any HRSNs they are experiencing, he added.

Lead author Dr. Zheng is employed by the American Cancer Society, which as a nonprofit receives funds from the public through fundraising and contributions, as well as some support from corporations and industry to support its mission programs and services. Mr. Biru had no financial conflicts to disclose.

Health-related social needs and medical financial hardship are associated with increased risk of mortality in adult cancer survivors, based on data from more than 10,000 individuals.

Little is known about the specific association between health-related social needs (HRSNs) and mortality risk even though HRSNs, defined as challenges in affording food, housing, and other necessities of daily living, are potential challenges for cancer survivors, wrote Zhiyuan Zheng, PhD, of the American Cancer Society, Atlanta, and colleagues.

A 2020 study by Dr. Zheng and colleagues published in the Journal of the National Comprehensive Cancer Network (NCCN) showed that food insecurity and financial worries had a negative impact on cancer survivorship. In the new study, published in Cancer, the researchers identified cancer survivors using the 2013-2018 National Health Interview Survey (NHIS) and the NHIS Mortality File through December 31, 2019. The researchers examined mortality using the data from the Centers for Disease Control and Prevention’s National Death Index (NDI) through December 31, 2019, which links to the National Health Interview Survey Data used in the study.

Individuals’ HRSNs were categorized into three groups: severe, moderate, and minor/none. HRSNs included food insecurity and nonmedical financial concerns, such as housing costs (rent, mortgage). Medical financial hardship included material, psychological, and behavioral domains and was divided into three groups: 2-3 domains, 1 domain, or 0 domains.
 

What Are the Potential Financial Implications of this Research?

The high costs of cancer care often cause medical financial hardships for cancer survivors, and expenses also may cause psychological distress and nonmedical financial hardship as survivors try to make ends meet while facing medical bills, wrote Dr. Zheng and colleagues.

Policy makers are increasingly interested in adding HRSNs to insurance coverage; recent guidance from the Centers for Medicare & Medicaid Services (CMS) allows individual states to apply to provide nutrition and housing supports through state Medicaid programs, according to authors of a 2023 article published in JAMA Health Forum.

The new study adds to the understanding of how HRSNs impact people with cancer by examining the association with mortality risk, Yelak Biru, MSc, president and chief executive officer of the International Myeloma Foundation, said in an interview.

“This is a key area of study for addressing the disparities in treatments and outcomes that result in inequities,” said Mr. Biru, a patient advocate and multiple myeloma survivor who was not involved in the study.
 

What Does the New Study Show?

The new study characterized HRSNs in 5,855 adult cancer survivors aged 18-64 years and 5,918 aged 65-79 years. In the 18- to 64-year-old group, 25.5% reported moderate levels of HRSNs, and 18.3% reported severe HRSNs. In patients aged 65-79 years, 15.6% and 6.6% reported moderate HRSNs and severe HRSNs, respectively.

Severe HRSN was significantly associated with higher mortality risk in an adjusted analysis in patients aged 18-64 years (hazard ratio 2.00, P < .001).

Among adults aged 65-79 years, severe HRSN was not associated with higher mortality risk; however, in this older age group, those with 2-3 domains of medical financial hardship had significantly increased mortality risk compared with adults aged 65-79 years with zero domains of medical financial hardship (HR 1.58, P = .007).

Although the findings that HRSNs were associated with increased mortality risk, especially in the younger group, were not surprising, they serve as a call to action to address how HRSNs are contributing to cancer mortality, Mr. Biru said in an interview. “HRSNs, like food or housing insecurity, can lead to patients being unable to undergo the best treatment approach for their cancer,” he said.
 

What Are the Limitations and Research Gaps?

The study findings were limited by several factors including the use of self-reports to measure medical financial hardship, food insecurity, and nonmedical financial concerns in the NHIS, the researchers wrote in their discussion. More research with longer follow-up time beyond 1-5 years is needed, wrote Dr. Zheng and colleagues.

Studies also are needed to illustrate how patient navigation can help prevent patients from falling through the cracks with regard to social needs and financial hardships, Mr. Biru told this news organization.

Other areas for research include how addressing social needs affects health outcomes and whether programs designed to address social needs are effective, he said.

“Finally, qualitative research is needed to capture the lived experiences of cancer survivors facing these challenges. This knowledge can inform the development of more patient-centered interventions and policies that effectively address the social determinants of health and improve overall outcomes for all cancer survivors,” Mr. Biru said.
 

What Is the Takeaway Message for Clinicians?

HRSNs and financial hardship are significantly associated with increased risk of mortality in adult cancer survivors, Dr. Zheng and colleagues concluded. Looking ahead, comprehensive assessment of HRSNs and financial hardship may help clinicians connect patients with relevant services to mitigate the social and financial impacts of cancer, they wrote.

“The takeaway message for oncologists in practice is that addressing [HRSNs] and financial hardship is crucial for providing comprehensive and equitable cancer care,” Mr. Biru said during his interview.

“The impact of social determinants of health on cancer outcomes cannot be ignored, and oncologists play a vital role in identifying and addressing these needs,” he said. Sensitive, discussion-based screenings are needed to identify core needs such as food and transportation, but clinicians also can consider broader social factors and work with a team to connect patients to appropriate resources, he added.

“By recognizing the importance of HRSN screening and taking proactive steps to address these needs, oncologists can contribute to improving health outcomes, reducing healthcare disparities, and providing more equitable cancer care for their patients,” he said.
 

What Other Guidance Is Available?

“High-quality cancer care requires treating the whole person; measuring and addressing anything in their life that could result in poorer health outcomes is a key component of comprehensive care,” Mr. Biru emphasized.

In September 2023, the National Comprehensive Cancer Network (NCCN) convened a working group cochaired by Mr. Biru that developed recommendations for how oncology practices should routinely measure HRSNs (NCCN.org/social-needs).

“The working group proposed that every cancer patient be assessed for food, transportation access, and financial and housing security at least once a year, and be reassessed at every care transition point as well,” Mr. Biru said. Such screenings should include follow-up to connect patients with services to address any HRSNs they are experiencing, he added.

Lead author Dr. Zheng is employed by the American Cancer Society, which as a nonprofit receives funds from the public through fundraising and contributions, as well as some support from corporations and industry to support its mission programs and services. Mr. Biru had no financial conflicts to disclose.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

The Diagnosis: Spiradenocylindroma

Shave biopsies of our patient’s lesions showed wellcircumscribed dermal nodules resembling a spiradenoma with 3 cell populations: those with lighter nuclei, darker nuclei, and scattered lymphocytes. However, the conspicuous globules of basement membrane material were reminiscent of a cylindroma. These overlapping features and the patient’s history of cylindroma were suggestive of a diagnosis of spiradenocylindroma.

Spiradenocylindroma is an uncommon dermal tumor with features that overlap with spiradenoma and cylindroma.¹ It may manifest as a solitary lesion or multiple lesions and can occur sporadically or in the context of a family history. Histologically, it must be distinguished from other intradermal basaloid neoplasms including conventional cylindroma and spiradenoma, dermal duct tumor, hidradenoma, and trichoblastoma.

When patients present with multiple cylindromas, spiradenomas, or spiradenocylindromas, physicians should consider genetic testing and review of the family history to assess for cylindromatosis gene mutations or Brooke-Spiegler syndrome. Biopsy and histologic examination are important because malignant tumors can evolve from pre-existing spiradenocylindromas, cylindromas, and spiradenomas,² with an increased risk in patients with Brooke-Spiegler syndrome.¹ Our patient declined further genetic workup but continues to follow up with dermatology for monitoring of lesions.

Dermal duct tumors are morphologic variants of poromas that are derived from sweat gland lineage and usually manifest as solitary dome-shaped papules, plaques, or nodules most often seen on acral surfaces as well as the head and neck.³ Clinically, they may be indistinguishable from spiradenocylindromas and require biopsy for histologic evaluation. They can be distinguished from spiradenocylindroma by the presence of small dermal nodules composed of cuboidal cells with ample pink cytoplasm and cuticle-lined ducts (Figure 1).

Trichoblastomas typically are deep-seated basaloid follicular neoplasms on the scalp with papillary mesenchyme resembling the normal fibrous sheath of the hair follicle, often replete with papillary mesenchymal bodies (Figure 2). There generally are no retraction spaces between its basaloid nests and the surrounding stroma, which is unlikely to contain mucin relative to basal cell carcinoma (BCC).^4,5

Adenoid cystic carcinoma is a rare salivary gland tumor that can metastasize to the skin and rarely arises as a primary skin adnexal tumor. It manifests as a slowgrowing mass that can be tender to palpation.⁶ Histologic examination shows dermal islands with cribriform blue and pink spaces. Compared to BCC, adenoid cystic carcinoma cells are enlarged and epithelioid with relatively scarce cytoplasm (Figure 3).^6,7 Adenoid cystic carcinoma can show variable growth patterns including infiltrative nests and trabeculae. Perineural invasion is common, and there is a high risk for local recurrence.⁷ First-line therapy usually is surgical, and postoperative radiotherapy may be required.^6,7

Nodular BCC commonly manifests as an enlarging nonhealing lesion on sun-exposed skin and has many subtypes, typically with arborizing telangiectases on dermoscopy. Histopathologic examination of nodular BCC reveals a nest of basaloid follicular germinative cells in the dermis with peripheral palisading and a fibromyxoid stroma (Figure 4).⁸ Patients with Brooke-Spiegler syndrome are at increased risk for nodular BCC, which may be clinically indistinguishable from spiradenoma, cylindroma, and spiradenocylindroma, necessitating histologic assessment.

The Diagnosis: Spiradenocylindroma

Shave biopsies of our patient’s lesions showed wellcircumscribed dermal nodules resembling a spiradenoma with 3 cell populations: those with lighter nuclei, darker nuclei, and scattered lymphocytes. However, the conspicuous globules of basement membrane material were reminiscent of a cylindroma. These overlapping features and the patient’s history of cylindroma were suggestive of a diagnosis of spiradenocylindroma.

Spiradenocylindroma is an uncommon dermal tumor with features that overlap with spiradenoma and cylindroma.¹ It may manifest as a solitary lesion or multiple lesions and can occur sporadically or in the context of a family history. Histologically, it must be distinguished from other intradermal basaloid neoplasms including conventional cylindroma and spiradenoma, dermal duct tumor, hidradenoma, and trichoblastoma.

When patients present with multiple cylindromas, spiradenomas, or spiradenocylindromas, physicians should consider genetic testing and review of the family history to assess for cylindromatosis gene mutations or Brooke-Spiegler syndrome. Biopsy and histologic examination are important because malignant tumors can evolve from pre-existing spiradenocylindromas, cylindromas, and spiradenomas,² with an increased risk in patients with Brooke-Spiegler syndrome.¹ Our patient declined further genetic workup but continues to follow up with dermatology for monitoring of lesions.

Dermal duct tumors are morphologic variants of poromas that are derived from sweat gland lineage and usually manifest as solitary dome-shaped papules, plaques, or nodules most often seen on acral surfaces as well as the head and neck.³ Clinically, they may be indistinguishable from spiradenocylindromas and require biopsy for histologic evaluation. They can be distinguished from spiradenocylindroma by the presence of small dermal nodules composed of cuboidal cells with ample pink cytoplasm and cuticle-lined ducts (Figure 1).

Trichoblastomas typically are deep-seated basaloid follicular neoplasms on the scalp with papillary mesenchyme resembling the normal fibrous sheath of the hair follicle, often replete with papillary mesenchymal bodies (Figure 2). There generally are no retraction spaces between its basaloid nests and the surrounding stroma, which is unlikely to contain mucin relative to basal cell carcinoma (BCC).^4,5

Adenoid cystic carcinoma is a rare salivary gland tumor that can metastasize to the skin and rarely arises as a primary skin adnexal tumor. It manifests as a slowgrowing mass that can be tender to palpation.⁶ Histologic examination shows dermal islands with cribriform blue and pink spaces. Compared to BCC, adenoid cystic carcinoma cells are enlarged and epithelioid with relatively scarce cytoplasm (Figure 3).^6,7 Adenoid cystic carcinoma can show variable growth patterns including infiltrative nests and trabeculae. Perineural invasion is common, and there is a high risk for local recurrence.⁷ First-line therapy usually is surgical, and postoperative radiotherapy may be required.^6,7

Nodular BCC commonly manifests as an enlarging nonhealing lesion on sun-exposed skin and has many subtypes, typically with arborizing telangiectases on dermoscopy. Histopathologic examination of nodular BCC reveals a nest of basaloid follicular germinative cells in the dermis with peripheral palisading and a fibromyxoid stroma (Figure 4).⁸ Patients with Brooke-Spiegler syndrome are at increased risk for nodular BCC, which may be clinically indistinguishable from spiradenoma, cylindroma, and spiradenocylindroma, necessitating histologic assessment.

The Diagnosis: Spiradenocylindroma

Shave biopsies of our patient’s lesions showed wellcircumscribed dermal nodules resembling a spiradenoma with 3 cell populations: those with lighter nuclei, darker nuclei, and scattered lymphocytes. However, the conspicuous globules of basement membrane material were reminiscent of a cylindroma. These overlapping features and the patient’s history of cylindroma were suggestive of a diagnosis of spiradenocylindroma.

Spiradenocylindroma is an uncommon dermal tumor with features that overlap with spiradenoma and cylindroma.¹ It may manifest as a solitary lesion or multiple lesions and can occur sporadically or in the context of a family history. Histologically, it must be distinguished from other intradermal basaloid neoplasms including conventional cylindroma and spiradenoma, dermal duct tumor, hidradenoma, and trichoblastoma.

When patients present with multiple cylindromas, spiradenomas, or spiradenocylindromas, physicians should consider genetic testing and review of the family history to assess for cylindromatosis gene mutations or Brooke-Spiegler syndrome. Biopsy and histologic examination are important because malignant tumors can evolve from pre-existing spiradenocylindromas, cylindromas, and spiradenomas,² with an increased risk in patients with Brooke-Spiegler syndrome.¹ Our patient declined further genetic workup but continues to follow up with dermatology for monitoring of lesions.

Dermal duct tumors are morphologic variants of poromas that are derived from sweat gland lineage and usually manifest as solitary dome-shaped papules, plaques, or nodules most often seen on acral surfaces as well as the head and neck.³ Clinically, they may be indistinguishable from spiradenocylindromas and require biopsy for histologic evaluation. They can be distinguished from spiradenocylindroma by the presence of small dermal nodules composed of cuboidal cells with ample pink cytoplasm and cuticle-lined ducts (Figure 1).

Trichoblastomas typically are deep-seated basaloid follicular neoplasms on the scalp with papillary mesenchyme resembling the normal fibrous sheath of the hair follicle, often replete with papillary mesenchymal bodies (Figure 2). There generally are no retraction spaces between its basaloid nests and the surrounding stroma, which is unlikely to contain mucin relative to basal cell carcinoma (BCC).^4,5

Adenoid cystic carcinoma is a rare salivary gland tumor that can metastasize to the skin and rarely arises as a primary skin adnexal tumor. It manifests as a slowgrowing mass that can be tender to palpation.⁶ Histologic examination shows dermal islands with cribriform blue and pink spaces. Compared to BCC, adenoid cystic carcinoma cells are enlarged and epithelioid with relatively scarce cytoplasm (Figure 3).^6,7 Adenoid cystic carcinoma can show variable growth patterns including infiltrative nests and trabeculae. Perineural invasion is common, and there is a high risk for local recurrence.⁷ First-line therapy usually is surgical, and postoperative radiotherapy may be required.^6,7

Nodular BCC commonly manifests as an enlarging nonhealing lesion on sun-exposed skin and has many subtypes, typically with arborizing telangiectases on dermoscopy. Histopathologic examination of nodular BCC reveals a nest of basaloid follicular germinative cells in the dermis with peripheral palisading and a fibromyxoid stroma (Figure 4).⁸ Patients with Brooke-Spiegler syndrome are at increased risk for nodular BCC, which may be clinically indistinguishable from spiradenoma, cylindroma, and spiradenocylindroma, necessitating histologic assessment.

To the Editor:

The most common malignancy in the United States is skin cancer, with melanoma accounting for the majority of skin cancer deaths.¹ Despite the lack of established guidelines for routine total-body skin examinations, many patients regularly visit their dermatologist for assessment of pigmented skin lesions.² During the COVID-19 pandemic, many patients were unable to attend in-person dermatology visits, which resulted in many high-risk individuals not receiving care or alternatively seeking virtual care for cutaneous lesions.³ There has been a lack of research in the United States exploring the utilization of teledermatology during the pandemic and its overall impact on the care of patients with a history of skin cancer. We explored the impact of the COVID-19 pandemic on care for patients with skin cancer in a large US population.

Using anonymous survey data from the 2020-2021 National Health Interview Survey,⁴ we conducted a ­population-based, cross-sectional study to evaluate access to care during the COVID-19 pandemic for patients with a self-reported history of skin cancer—melanoma, nonmelanoma skin cancer, or unknown skin cancer. The 3 outcome variables included having a virtual medical appointment in the past 12 months (yes/no), delaying medical care due to the COVID-19 pandemic (yes/no), and not receiving care due to the COVID-19 pandemic (yes/no). Multivariable logistic regression models evaluating the relationship between a history of skin cancer and access to care were constructed using Stata/MP 17.0 (StataCorp LLC). We controlled for patient age; education; race/ethnicity; received public assistance or welfare payments; sex; region; US citizenship status; health insurance status; comorbidities including history of hypertension, diabetes, and hypercholesterolemia; and birthplace in the United States in the logistic regression models.

Our analysis included 46,679 patients aged 18 years or older, of whom 3.4% (weighted)(n=2204) reported a history of skin cancer (eTable 1). The weighted percentage was calculated using National Health Interview Survey design parameters (accounting for the multistage sampling design) to represent the general US population. Compared with those with no history of skin cancer, patients with a history of skin cancer were significantly more likely to delay medical care (adjusted odds ratio [AOR], 1.37; 95% CI, 1.21-1.54; P<.001) or not receive care (AOR, 1.35; 95% CI, 1.16-1.57; P<.001) due to the pandemic and were more likely to have had a virtual medical visit in the past 12 months (AOR, 1.12; 95% CI, 1.00-1.26; P=.05). Additionally, subgroup analysis revealed that females were more likely than males to forego medical care (eTable 2). β Coefficients for independent and dependent variables were further analyzed using logistic regression (eTable 3).

After adjusting for various potential confounders including comorbidities, our results revealed that patients with a history of skin cancer reported that they were less likely to receive in-person medical care due to the COVID-19 pandemic, as high-risk individuals with a history of skin cancer may have stopped receiving total-body skin examinations and dermatology care during the pandemic. Our findings showed that patients with a history of skin cancer were more likely than those without skin cancer to delay or forego care due to the pandemic, which may contribute to a higher incidence of advanced-stage melanomas postpandemic. Trepanowski et al⁵ reported an increased incidence of patients presenting with more advanced melanomas during the pandemic. Telemedicine was more commonly utilized by patients with a history of skin cancer during the pandemic.

In the future, virtual care may help limit advanced stages of skin cancer by serving as a viable alternative to in-person care.⁶ It has been reported that telemedicine can serve as a useful triage service reducing patient wait times.⁷ Teledermatology should not replace in-person care, as there is no evidence of the diagnostic accuracy of this service and many patients still will need to be seen in-person for confirmation of their diagnosis and potential biopsy. Further studies are needed to assess for missed skin cancer diagnoses due to the utilization of telemedicine.

Limitations of this study included a self-reported history of skin cancer, β coefficients that may suggest a high degree of collinearity, and lack of specific survey questions regarding dermatologic care during the COVID-19 pandemic. Further long-term studies exploring the clinical applicability and diagnostic accuracy of virtual medicine visits for cutaneous malignancies are vital, as teledermatology may play an essential role in curbing rising skin cancer rates even beyond the pandemic.

To the Editor:

The most common malignancy in the United States is skin cancer, with melanoma accounting for the majority of skin cancer deaths.¹ Despite the lack of established guidelines for routine total-body skin examinations, many patients regularly visit their dermatologist for assessment of pigmented skin lesions.² During the COVID-19 pandemic, many patients were unable to attend in-person dermatology visits, which resulted in many high-risk individuals not receiving care or alternatively seeking virtual care for cutaneous lesions.³ There has been a lack of research in the United States exploring the utilization of teledermatology during the pandemic and its overall impact on the care of patients with a history of skin cancer. We explored the impact of the COVID-19 pandemic on care for patients with skin cancer in a large US population.

Using anonymous survey data from the 2020-2021 National Health Interview Survey,⁴ we conducted a ­population-based, cross-sectional study to evaluate access to care during the COVID-19 pandemic for patients with a self-reported history of skin cancer—melanoma, nonmelanoma skin cancer, or unknown skin cancer. The 3 outcome variables included having a virtual medical appointment in the past 12 months (yes/no), delaying medical care due to the COVID-19 pandemic (yes/no), and not receiving care due to the COVID-19 pandemic (yes/no). Multivariable logistic regression models evaluating the relationship between a history of skin cancer and access to care were constructed using Stata/MP 17.0 (StataCorp LLC). We controlled for patient age; education; race/ethnicity; received public assistance or welfare payments; sex; region; US citizenship status; health insurance status; comorbidities including history of hypertension, diabetes, and hypercholesterolemia; and birthplace in the United States in the logistic regression models.

Our analysis included 46,679 patients aged 18 years or older, of whom 3.4% (weighted)(n=2204) reported a history of skin cancer (eTable 1). The weighted percentage was calculated using National Health Interview Survey design parameters (accounting for the multistage sampling design) to represent the general US population. Compared with those with no history of skin cancer, patients with a history of skin cancer were significantly more likely to delay medical care (adjusted odds ratio [AOR], 1.37; 95% CI, 1.21-1.54; P<.001) or not receive care (AOR, 1.35; 95% CI, 1.16-1.57; P<.001) due to the pandemic and were more likely to have had a virtual medical visit in the past 12 months (AOR, 1.12; 95% CI, 1.00-1.26; P=.05). Additionally, subgroup analysis revealed that females were more likely than males to forego medical care (eTable 2). β Coefficients for independent and dependent variables were further analyzed using logistic regression (eTable 3).

After adjusting for various potential confounders including comorbidities, our results revealed that patients with a history of skin cancer reported that they were less likely to receive in-person medical care due to the COVID-19 pandemic, as high-risk individuals with a history of skin cancer may have stopped receiving total-body skin examinations and dermatology care during the pandemic. Our findings showed that patients with a history of skin cancer were more likely than those without skin cancer to delay or forego care due to the pandemic, which may contribute to a higher incidence of advanced-stage melanomas postpandemic. Trepanowski et al⁵ reported an increased incidence of patients presenting with more advanced melanomas during the pandemic. Telemedicine was more commonly utilized by patients with a history of skin cancer during the pandemic.

In the future, virtual care may help limit advanced stages of skin cancer by serving as a viable alternative to in-person care.⁶ It has been reported that telemedicine can serve as a useful triage service reducing patient wait times.⁷ Teledermatology should not replace in-person care, as there is no evidence of the diagnostic accuracy of this service and many patients still will need to be seen in-person for confirmation of their diagnosis and potential biopsy. Further studies are needed to assess for missed skin cancer diagnoses due to the utilization of telemedicine.

Limitations of this study included a self-reported history of skin cancer, β coefficients that may suggest a high degree of collinearity, and lack of specific survey questions regarding dermatologic care during the COVID-19 pandemic. Further long-term studies exploring the clinical applicability and diagnostic accuracy of virtual medicine visits for cutaneous malignancies are vital, as teledermatology may play an essential role in curbing rising skin cancer rates even beyond the pandemic.

To the Editor:

The most common malignancy in the United States is skin cancer, with melanoma accounting for the majority of skin cancer deaths.¹ Despite the lack of established guidelines for routine total-body skin examinations, many patients regularly visit their dermatologist for assessment of pigmented skin lesions.² During the COVID-19 pandemic, many patients were unable to attend in-person dermatology visits, which resulted in many high-risk individuals not receiving care or alternatively seeking virtual care for cutaneous lesions.³ There has been a lack of research in the United States exploring the utilization of teledermatology during the pandemic and its overall impact on the care of patients with a history of skin cancer. We explored the impact of the COVID-19 pandemic on care for patients with skin cancer in a large US population.

Using anonymous survey data from the 2020-2021 National Health Interview Survey,⁴ we conducted a ­population-based, cross-sectional study to evaluate access to care during the COVID-19 pandemic for patients with a self-reported history of skin cancer—melanoma, nonmelanoma skin cancer, or unknown skin cancer. The 3 outcome variables included having a virtual medical appointment in the past 12 months (yes/no), delaying medical care due to the COVID-19 pandemic (yes/no), and not receiving care due to the COVID-19 pandemic (yes/no). Multivariable logistic regression models evaluating the relationship between a history of skin cancer and access to care were constructed using Stata/MP 17.0 (StataCorp LLC). We controlled for patient age; education; race/ethnicity; received public assistance or welfare payments; sex; region; US citizenship status; health insurance status; comorbidities including history of hypertension, diabetes, and hypercholesterolemia; and birthplace in the United States in the logistic regression models.

Our analysis included 46,679 patients aged 18 years or older, of whom 3.4% (weighted)(n=2204) reported a history of skin cancer (eTable 1). The weighted percentage was calculated using National Health Interview Survey design parameters (accounting for the multistage sampling design) to represent the general US population. Compared with those with no history of skin cancer, patients with a history of skin cancer were significantly more likely to delay medical care (adjusted odds ratio [AOR], 1.37; 95% CI, 1.21-1.54; P<.001) or not receive care (AOR, 1.35; 95% CI, 1.16-1.57; P<.001) due to the pandemic and were more likely to have had a virtual medical visit in the past 12 months (AOR, 1.12; 95% CI, 1.00-1.26; P=.05). Additionally, subgroup analysis revealed that females were more likely than males to forego medical care (eTable 2). β Coefficients for independent and dependent variables were further analyzed using logistic regression (eTable 3).

After adjusting for various potential confounders including comorbidities, our results revealed that patients with a history of skin cancer reported that they were less likely to receive in-person medical care due to the COVID-19 pandemic, as high-risk individuals with a history of skin cancer may have stopped receiving total-body skin examinations and dermatology care during the pandemic. Our findings showed that patients with a history of skin cancer were more likely than those without skin cancer to delay or forego care due to the pandemic, which may contribute to a higher incidence of advanced-stage melanomas postpandemic. Trepanowski et al⁵ reported an increased incidence of patients presenting with more advanced melanomas during the pandemic. Telemedicine was more commonly utilized by patients with a history of skin cancer during the pandemic.

In the future, virtual care may help limit advanced stages of skin cancer by serving as a viable alternative to in-person care.⁶ It has been reported that telemedicine can serve as a useful triage service reducing patient wait times.⁷ Teledermatology should not replace in-person care, as there is no evidence of the diagnostic accuracy of this service and many patients still will need to be seen in-person for confirmation of their diagnosis and potential biopsy. Further studies are needed to assess for missed skin cancer diagnoses due to the utilization of telemedicine.

Limitations of this study included a self-reported history of skin cancer, β coefficients that may suggest a high degree of collinearity, and lack of specific survey questions regarding dermatologic care during the COVID-19 pandemic. Further long-term studies exploring the clinical applicability and diagnostic accuracy of virtual medicine visits for cutaneous malignancies are vital, as teledermatology may play an essential role in curbing rising skin cancer rates even beyond the pandemic.

To the Editor:

I was unsurprised and gratified by the information presented in the Viewpoint on skin cancer screening by Ngo¹ (Cutis. 2024;113:94-96). In my 30 years as a community dermatologist, I have observed that patients who opt to have periodic full-body skin examinations usually are more health literate, more likely to have a primary care physician (PCP) who has encouraged them to do so (ie, a conscientious practitioner directing their preventive care), more likely to have a strong will to live, and less likely to have multiple stressors that preclude self-care (eg, may be less likely to have a spouse for whom they are a caregiver) compared to those who do not get screened.

Findings on a full-body skin examination may impact patients in many ways, not only by the detection of skin cancers. I have discovered the following:

• evidence of diabetes/insulin resistance in the form of acanthosis nigricans, tinea corporis, erythrasma;
• evidence of rosacea associated with excessive alcohol intake;
• evidence of smoking-related issues such as psoriasis or hidradenitis suppurativa;
• cutaneous evidence of other systemic diseases (eg, autoimmune disease, cancer);
• elucidation of other chronic health problems (eg, psoriasis of the skin as a clue for undiagnosed psoriatic arthritis); and
• detection of parasites on the skin (eg, ticks) or signs of infection that may have notable ramifications (eg, interdigital maceration of a diabetic patient with tinea pedis).

I even saw a patient who had been sent for magnetic resonance imaging for back pain by her internist without any physical examination when she actually had an erosion over the sacrum from a rug burn!

When conducting full-body skin examinations, dermatologists should not underestimate these principles:

• The “magic” of using a relatively noninvasive and sensitive screening tool—comfort and stress reduction for the patient from a thorough visual, tactile, olfactory, and auditory examination.
• Human interaction—especially when the patient is seen annually or even more frequently over a period of years or decades, and especially when an excellent patient-physician rapport has been established.
• The impact of improving a patient’s appearance on their overall sense of well-being (eg, by ­controlling rosacea).
• The opportunity to introduce concepts (ie, educate patients) such as alcohol avoidance, smoking cessation, weight reduction, hygiene, diet, and exercise in a more tangential way than a PCP, as well as to consider with patients the idea that lifestyle modification may be an adjunct, if not a replacement, for prescription treatments.
• The stress reduction that ensues when a variety of self-identified health issues are addressed, for which the only treatment may be reassurance.

I would add to Dr. Ngo’s argument that stratifying patients into skin cancer risk categories may be a useful measure if the only goal of periodic dermatologic evaluation is skin cancer detection. One size rarely fits all when it comes to health recommendations.

In sum, I believe that periodic full-body skin examination is absolutely beneficial to patient care, and I am not at all surprised that all-cause mortality was lower in patients who have those examinations. Furthermore, when I offer my healthy, low-risk patients the option to return in 2 years rather than 1, the vast majority insist on 1 year. My mother used to say, “It’s better to be looked over than to be overlooked,” and I tell my patients that, too—but it seems they already know that instinctively.

To the Editor:

I was unsurprised and gratified by the information presented in the Viewpoint on skin cancer screening by Ngo¹ (Cutis. 2024;113:94-96). In my 30 years as a community dermatologist, I have observed that patients who opt to have periodic full-body skin examinations usually are more health literate, more likely to have a primary care physician (PCP) who has encouraged them to do so (ie, a conscientious practitioner directing their preventive care), more likely to have a strong will to live, and less likely to have multiple stressors that preclude self-care (eg, may be less likely to have a spouse for whom they are a caregiver) compared to those who do not get screened.

Findings on a full-body skin examination may impact patients in many ways, not only by the detection of skin cancers. I have discovered the following:

• evidence of diabetes/insulin resistance in the form of acanthosis nigricans, tinea corporis, erythrasma;
• evidence of rosacea associated with excessive alcohol intake;
• evidence of smoking-related issues such as psoriasis or hidradenitis suppurativa;
• cutaneous evidence of other systemic diseases (eg, autoimmune disease, cancer);
• elucidation of other chronic health problems (eg, psoriasis of the skin as a clue for undiagnosed psoriatic arthritis); and
• detection of parasites on the skin (eg, ticks) or signs of infection that may have notable ramifications (eg, interdigital maceration of a diabetic patient with tinea pedis).

I even saw a patient who had been sent for magnetic resonance imaging for back pain by her internist without any physical examination when she actually had an erosion over the sacrum from a rug burn!

When conducting full-body skin examinations, dermatologists should not underestimate these principles:

• The “magic” of using a relatively noninvasive and sensitive screening tool—comfort and stress reduction for the patient from a thorough visual, tactile, olfactory, and auditory examination.
• Human interaction—especially when the patient is seen annually or even more frequently over a period of years or decades, and especially when an excellent patient-physician rapport has been established.
• The impact of improving a patient’s appearance on their overall sense of well-being (eg, by ­controlling rosacea).
• The opportunity to introduce concepts (ie, educate patients) such as alcohol avoidance, smoking cessation, weight reduction, hygiene, diet, and exercise in a more tangential way than a PCP, as well as to consider with patients the idea that lifestyle modification may be an adjunct, if not a replacement, for prescription treatments.
• The stress reduction that ensues when a variety of self-identified health issues are addressed, for which the only treatment may be reassurance.

I would add to Dr. Ngo’s argument that stratifying patients into skin cancer risk categories may be a useful measure if the only goal of periodic dermatologic evaluation is skin cancer detection. One size rarely fits all when it comes to health recommendations.

In sum, I believe that periodic full-body skin examination is absolutely beneficial to patient care, and I am not at all surprised that all-cause mortality was lower in patients who have those examinations. Furthermore, when I offer my healthy, low-risk patients the option to return in 2 years rather than 1, the vast majority insist on 1 year. My mother used to say, “It’s better to be looked over than to be overlooked,” and I tell my patients that, too—but it seems they already know that instinctively.

To the Editor:

I was unsurprised and gratified by the information presented in the Viewpoint on skin cancer screening by Ngo¹ (Cutis. 2024;113:94-96). In my 30 years as a community dermatologist, I have observed that patients who opt to have periodic full-body skin examinations usually are more health literate, more likely to have a primary care physician (PCP) who has encouraged them to do so (ie, a conscientious practitioner directing their preventive care), more likely to have a strong will to live, and less likely to have multiple stressors that preclude self-care (eg, may be less likely to have a spouse for whom they are a caregiver) compared to those who do not get screened.

Findings on a full-body skin examination may impact patients in many ways, not only by the detection of skin cancers. I have discovered the following:

• evidence of diabetes/insulin resistance in the form of acanthosis nigricans, tinea corporis, erythrasma;
• evidence of rosacea associated with excessive alcohol intake;
• evidence of smoking-related issues such as psoriasis or hidradenitis suppurativa;
• cutaneous evidence of other systemic diseases (eg, autoimmune disease, cancer);
• elucidation of other chronic health problems (eg, psoriasis of the skin as a clue for undiagnosed psoriatic arthritis); and
• detection of parasites on the skin (eg, ticks) or signs of infection that may have notable ramifications (eg, interdigital maceration of a diabetic patient with tinea pedis).

I even saw a patient who had been sent for magnetic resonance imaging for back pain by her internist without any physical examination when she actually had an erosion over the sacrum from a rug burn!

When conducting full-body skin examinations, dermatologists should not underestimate these principles:

• The “magic” of using a relatively noninvasive and sensitive screening tool—comfort and stress reduction for the patient from a thorough visual, tactile, olfactory, and auditory examination.
• Human interaction—especially when the patient is seen annually or even more frequently over a period of years or decades, and especially when an excellent patient-physician rapport has been established.
• The impact of improving a patient’s appearance on their overall sense of well-being (eg, by ­controlling rosacea).
• The opportunity to introduce concepts (ie, educate patients) such as alcohol avoidance, smoking cessation, weight reduction, hygiene, diet, and exercise in a more tangential way than a PCP, as well as to consider with patients the idea that lifestyle modification may be an adjunct, if not a replacement, for prescription treatments.
• The stress reduction that ensues when a variety of self-identified health issues are addressed, for which the only treatment may be reassurance.

I would add to Dr. Ngo’s argument that stratifying patients into skin cancer risk categories may be a useful measure if the only goal of periodic dermatologic evaluation is skin cancer detection. One size rarely fits all when it comes to health recommendations.

In sum, I believe that periodic full-body skin examination is absolutely beneficial to patient care, and I am not at all surprised that all-cause mortality was lower in patients who have those examinations. Furthermore, when I offer my healthy, low-risk patients the option to return in 2 years rather than 1, the vast majority insist on 1 year. My mother used to say, “It’s better to be looked over than to be overlooked,” and I tell my patients that, too—but it seems they already know that instinctively.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

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.

 

 

Clinical Presentation

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.

 

 

Clinical Presentation

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.

 

 

Clinical Presentation

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.