Cutis

The World Health Organization declared COVID-19 a pandemic on March 11, 2020, just 4 months before the start of a new residency cycle. Referred to as “COVID interns,” PGY-1 residents transitioning out of medical school in 2020 faced an unprecedented challenge of doctoring within a confused and ill-prepared health care system, while senior residents scrambled to adjust to their rapidly changing training programs. Each subsequent week brought more sobering news of increasing hospitalizations, intensive care unit admissions, and deaths; hospitals across the country resorted to the redeployment of residents across all specialties to buffer the growing need within their internal medicine and critical care units.¹ And while the news and social media blurred into a collage of ventilator shortages, politicization of science, and “#healthcareheroes,” one study showed53.7% of medical interns (N=108) were struggling with mild to extremely severe depression, while 63.9% reported mild to severe anxiety.²

Many shortcomings of our health care system—ill preparedness, racial disparity, health illiteracy—were highlighted during the COVID-19 pandemic, and providers’ mental health was no exception.³ Classic psychosocial risk factors, such as high demands, lack of control, lack of institutional support, and absence of reward defined the workplace, leading Theorell⁴ to call it “a randomized trial for maximal worsening of the work environment.” Stress and burnout during residency are not novel concepts. A 2002 survey including 415 medical residency programs with a response from more than 4000 residents found depressive symptoms in 35% of respondents, paired with feelings of increased cynicism and decreased humanism despite major curricular reforms and duty hour limitations.⁵ Unfortunately, the statistics in the coming years hardly budged and, in the wake of the pandemic, culminated to more than 50% to 76% of physicians worldwide reporting burnout in 2020.^6-8

As a COVID intern at Brigham and Women’s Hospital (Boston, Massachusetts), I also experienced the demanding workload and witnessed the struggle of my colleagues firsthand. Brigham and Women’s Hospital, similar to many of its peer institutions, implemented frequent mental health check-ins within its curriculum. Known as the Intern Humanistic Curriculum, these check-ins essentially were an echo chamber to unload the psychological burdens of our workdays, and we eagerly shared what made us angry, sad, hopeful, and hopeless. During one such session, I learned about moral injury, a term originating in the military defined as the psychological stress resulting from actions—or the lack of actions—that violates one’s moral or ethical code.⁹ With the onslaught of patient deaths for which most of us felt unprepared, we had all endured varying degrees of moral injury. Greenberg et al⁹ described 2 potential outcomes after moral injury: (1) the development of mental health disorders such as depression and posttraumatic stress disorder, or (2) posttraumatic growth, which is the bolstering of psychological resilience. Notably, the outcome is based on the way someone is supported before, during, and after the challenging incident.⁹

With the aim of psychological growth and developing resilience, residents should prioritize mental health throughout their training. To this end, several resources are readily available, many of which I actively use or frequently revisit, which are reviewed here.

Mindfulness Meditation App

Calm (https://www.calm.com/) is one of several popular mobile applications (apps) that delivers mindfulness mediation—the practice of attending to experiences, thoughts, and emotions without bias or judgment. With more than 100 million downloads, Calm includes meditation tutorials, breathing exercises, nature scenes and sounds, and audio programs taught by mindfulness experts for $69.99 a year or $14.99 a month. Systemic reviews have demonstrated reduced sleep disturbance, decreased ruminative thoughts and emotional reactivity, and increased awareness and acceptance in those practicing mindfulness meditation. Calm users have reported these benefits, with many able to forego the time- and cost-intensive cognitive behavioral therapy that requires highly trained therapists.^10-12

Exercise to Relieve Stress

Both aerobic and anaerobic exercises are antidepressive and anxiolytic and also lower one’s overall sensitivity to stress. Whether it is governed by neurotransmitters such as the activation of the opioid systems or the release of endogenous endorphins or time spent focusing on a different task at hand, the benefits of exercise against mental stressors have been extensively studied and established.¹³ Consider obtaining a new gym membership at the start of residency or joining an intramural team. Both have the added benefit of expanding your social circle.

Socialize With Others

Social isolation and perceived loneliness are key stressors linked to neuroendocrine disturbances that underlie depression, anxiety, and even schizophrenia.^14,15 Throughout residency there will be several social events and opportunities to gather with colleagues—inside or outside of the work environment—and residents should attend as time allows. Even virtual social interactions were found to reduce stress and help in the treatment of social anxiety disorder.¹⁴

 

 

Communicate About Stressors

Open up to your co-residents, friends, and family about any struggles that may be invisible on the outside. Even attendings can empathize with the struggles of residency, and the mentors in place are actively trained to prioritize resident wellness. If verbal communication is not your strength, try journaling. Writing helps to untangle and better define underlying stressors and is itself meditative.^16,17 However, ensure that your journaling is focused on positive emotional responses and aims to determine the positive benefits within any stressful event; those solely expressing negative emotions were found to have higher levels of stress and anxiety afterward than they had before.¹⁷

Seek a Mental Health Specialist

As with all other human ailments, severe mental health disorders require specialists and proper medication. Unfortunately, substantial stigma accompanying mental health continues to permeate medicine, creating considerable barriers for residents in need of care.¹⁸ A 2016 survey of more than 2000 physicians found that those with mental illnesses did not seek treatment due to limited time, fear of being reported to a medical licensing board, concern over obtaining licensure, and shame or embarrassment at the diagnosis.¹⁹ Besides urging residents to seek care, more effort should be invested in addressing the stigma and ensuring confidentiality. In 2021, the internal medicine and medicine-pediatrics residency at the University of Colorado Anschutz Medical Campus (Aurora, Colorado) developed a confidential opt-out, rather than opt-in, mental health program, and appointments were made for all 80 interns in advance. In doing so, they found increased participation and self-reported wellness at a relatively low cost and simple implementation.²⁰ For trainees without such access, online or mobile therapy platforms offering electronic mental health treatment or telepsychiatry also have been employed.^21,22 The onus ultimately is still on the individual to seek the care they need. Although only an anecdotal piece of evidence, I have found the prevalence of physicians taking selective serotonin reuptake inhibitors such as escitalopram, sertraline, or fluoxetine to be strikingly common and quite beneficial.

Final Thoughts

Residency remains rife with financial, emotional, and physical stressors; even as the dust settles on the COVID-19 pandemic, the light shed on the importance of trainee mental health must remain illuminated. For the aforementioned resources to have an impact, residents need to be empowered to openly discuss mental health issues and to seek help if necessary. Finally, in 2018, the Journal of Graduate Medical Education published a 10-year prospective cohort study that found that emotional distress during residency persists in professional practice even 10 years after residency and is associated with future burnout.²³ Trainees should consider prioritizing their mental health to not only improve their quality of life in the present but also as an investment for their future.

The World Health Organization declared COVID-19 a pandemic on March 11, 2020, just 4 months before the start of a new residency cycle. Referred to as “COVID interns,” PGY-1 residents transitioning out of medical school in 2020 faced an unprecedented challenge of doctoring within a confused and ill-prepared health care system, while senior residents scrambled to adjust to their rapidly changing training programs. Each subsequent week brought more sobering news of increasing hospitalizations, intensive care unit admissions, and deaths; hospitals across the country resorted to the redeployment of residents across all specialties to buffer the growing need within their internal medicine and critical care units.¹ And while the news and social media blurred into a collage of ventilator shortages, politicization of science, and “#healthcareheroes,” one study showed53.7% of medical interns (N=108) were struggling with mild to extremely severe depression, while 63.9% reported mild to severe anxiety.²

Many shortcomings of our health care system—ill preparedness, racial disparity, health illiteracy—were highlighted during the COVID-19 pandemic, and providers’ mental health was no exception.³ Classic psychosocial risk factors, such as high demands, lack of control, lack of institutional support, and absence of reward defined the workplace, leading Theorell⁴ to call it “a randomized trial for maximal worsening of the work environment.” Stress and burnout during residency are not novel concepts. A 2002 survey including 415 medical residency programs with a response from more than 4000 residents found depressive symptoms in 35% of respondents, paired with feelings of increased cynicism and decreased humanism despite major curricular reforms and duty hour limitations.⁵ Unfortunately, the statistics in the coming years hardly budged and, in the wake of the pandemic, culminated to more than 50% to 76% of physicians worldwide reporting burnout in 2020.^6-8

As a COVID intern at Brigham and Women’s Hospital (Boston, Massachusetts), I also experienced the demanding workload and witnessed the struggle of my colleagues firsthand. Brigham and Women’s Hospital, similar to many of its peer institutions, implemented frequent mental health check-ins within its curriculum. Known as the Intern Humanistic Curriculum, these check-ins essentially were an echo chamber to unload the psychological burdens of our workdays, and we eagerly shared what made us angry, sad, hopeful, and hopeless. During one such session, I learned about moral injury, a term originating in the military defined as the psychological stress resulting from actions—or the lack of actions—that violates one’s moral or ethical code.⁹ With the onslaught of patient deaths for which most of us felt unprepared, we had all endured varying degrees of moral injury. Greenberg et al⁹ described 2 potential outcomes after moral injury: (1) the development of mental health disorders such as depression and posttraumatic stress disorder, or (2) posttraumatic growth, which is the bolstering of psychological resilience. Notably, the outcome is based on the way someone is supported before, during, and after the challenging incident.⁹

With the aim of psychological growth and developing resilience, residents should prioritize mental health throughout their training. To this end, several resources are readily available, many of which I actively use or frequently revisit, which are reviewed here.

Mindfulness Meditation App

Calm (https://www.calm.com/) is one of several popular mobile applications (apps) that delivers mindfulness mediation—the practice of attending to experiences, thoughts, and emotions without bias or judgment. With more than 100 million downloads, Calm includes meditation tutorials, breathing exercises, nature scenes and sounds, and audio programs taught by mindfulness experts for $69.99 a year or $14.99 a month. Systemic reviews have demonstrated reduced sleep disturbance, decreased ruminative thoughts and emotional reactivity, and increased awareness and acceptance in those practicing mindfulness meditation. Calm users have reported these benefits, with many able to forego the time- and cost-intensive cognitive behavioral therapy that requires highly trained therapists.^10-12

Exercise to Relieve Stress

Both aerobic and anaerobic exercises are antidepressive and anxiolytic and also lower one’s overall sensitivity to stress. Whether it is governed by neurotransmitters such as the activation of the opioid systems or the release of endogenous endorphins or time spent focusing on a different task at hand, the benefits of exercise against mental stressors have been extensively studied and established.¹³ Consider obtaining a new gym membership at the start of residency or joining an intramural team. Both have the added benefit of expanding your social circle.

Socialize With Others

Social isolation and perceived loneliness are key stressors linked to neuroendocrine disturbances that underlie depression, anxiety, and even schizophrenia.^14,15 Throughout residency there will be several social events and opportunities to gather with colleagues—inside or outside of the work environment—and residents should attend as time allows. Even virtual social interactions were found to reduce stress and help in the treatment of social anxiety disorder.¹⁴

 

 

Communicate About Stressors

Open up to your co-residents, friends, and family about any struggles that may be invisible on the outside. Even attendings can empathize with the struggles of residency, and the mentors in place are actively trained to prioritize resident wellness. If verbal communication is not your strength, try journaling. Writing helps to untangle and better define underlying stressors and is itself meditative.^16,17 However, ensure that your journaling is focused on positive emotional responses and aims to determine the positive benefits within any stressful event; those solely expressing negative emotions were found to have higher levels of stress and anxiety afterward than they had before.¹⁷

Seek a Mental Health Specialist

As with all other human ailments, severe mental health disorders require specialists and proper medication. Unfortunately, substantial stigma accompanying mental health continues to permeate medicine, creating considerable barriers for residents in need of care.¹⁸ A 2016 survey of more than 2000 physicians found that those with mental illnesses did not seek treatment due to limited time, fear of being reported to a medical licensing board, concern over obtaining licensure, and shame or embarrassment at the diagnosis.¹⁹ Besides urging residents to seek care, more effort should be invested in addressing the stigma and ensuring confidentiality. In 2021, the internal medicine and medicine-pediatrics residency at the University of Colorado Anschutz Medical Campus (Aurora, Colorado) developed a confidential opt-out, rather than opt-in, mental health program, and appointments were made for all 80 interns in advance. In doing so, they found increased participation and self-reported wellness at a relatively low cost and simple implementation.²⁰ For trainees without such access, online or mobile therapy platforms offering electronic mental health treatment or telepsychiatry also have been employed.^21,22 The onus ultimately is still on the individual to seek the care they need. Although only an anecdotal piece of evidence, I have found the prevalence of physicians taking selective serotonin reuptake inhibitors such as escitalopram, sertraline, or fluoxetine to be strikingly common and quite beneficial.

Final Thoughts

Residency remains rife with financial, emotional, and physical stressors; even as the dust settles on the COVID-19 pandemic, the light shed on the importance of trainee mental health must remain illuminated. For the aforementioned resources to have an impact, residents need to be empowered to openly discuss mental health issues and to seek help if necessary. Finally, in 2018, the Journal of Graduate Medical Education published a 10-year prospective cohort study that found that emotional distress during residency persists in professional practice even 10 years after residency and is associated with future burnout.²³ Trainees should consider prioritizing their mental health to not only improve their quality of life in the present but also as an investment for their future.

The World Health Organization declared COVID-19 a pandemic on March 11, 2020, just 4 months before the start of a new residency cycle. Referred to as “COVID interns,” PGY-1 residents transitioning out of medical school in 2020 faced an unprecedented challenge of doctoring within a confused and ill-prepared health care system, while senior residents scrambled to adjust to their rapidly changing training programs. Each subsequent week brought more sobering news of increasing hospitalizations, intensive care unit admissions, and deaths; hospitals across the country resorted to the redeployment of residents across all specialties to buffer the growing need within their internal medicine and critical care units.¹ And while the news and social media blurred into a collage of ventilator shortages, politicization of science, and “#healthcareheroes,” one study showed53.7% of medical interns (N=108) were struggling with mild to extremely severe depression, while 63.9% reported mild to severe anxiety.²

Many shortcomings of our health care system—ill preparedness, racial disparity, health illiteracy—were highlighted during the COVID-19 pandemic, and providers’ mental health was no exception.³ Classic psychosocial risk factors, such as high demands, lack of control, lack of institutional support, and absence of reward defined the workplace, leading Theorell⁴ to call it “a randomized trial for maximal worsening of the work environment.” Stress and burnout during residency are not novel concepts. A 2002 survey including 415 medical residency programs with a response from more than 4000 residents found depressive symptoms in 35% of respondents, paired with feelings of increased cynicism and decreased humanism despite major curricular reforms and duty hour limitations.⁵ Unfortunately, the statistics in the coming years hardly budged and, in the wake of the pandemic, culminated to more than 50% to 76% of physicians worldwide reporting burnout in 2020.^6-8

As a COVID intern at Brigham and Women’s Hospital (Boston, Massachusetts), I also experienced the demanding workload and witnessed the struggle of my colleagues firsthand. Brigham and Women’s Hospital, similar to many of its peer institutions, implemented frequent mental health check-ins within its curriculum. Known as the Intern Humanistic Curriculum, these check-ins essentially were an echo chamber to unload the psychological burdens of our workdays, and we eagerly shared what made us angry, sad, hopeful, and hopeless. During one such session, I learned about moral injury, a term originating in the military defined as the psychological stress resulting from actions—or the lack of actions—that violates one’s moral or ethical code.⁹ With the onslaught of patient deaths for which most of us felt unprepared, we had all endured varying degrees of moral injury. Greenberg et al⁹ described 2 potential outcomes after moral injury: (1) the development of mental health disorders such as depression and posttraumatic stress disorder, or (2) posttraumatic growth, which is the bolstering of psychological resilience. Notably, the outcome is based on the way someone is supported before, during, and after the challenging incident.⁹

With the aim of psychological growth and developing resilience, residents should prioritize mental health throughout their training. To this end, several resources are readily available, many of which I actively use or frequently revisit, which are reviewed here.

Mindfulness Meditation App

Calm (https://www.calm.com/) is one of several popular mobile applications (apps) that delivers mindfulness mediation—the practice of attending to experiences, thoughts, and emotions without bias or judgment. With more than 100 million downloads, Calm includes meditation tutorials, breathing exercises, nature scenes and sounds, and audio programs taught by mindfulness experts for $69.99 a year or $14.99 a month. Systemic reviews have demonstrated reduced sleep disturbance, decreased ruminative thoughts and emotional reactivity, and increased awareness and acceptance in those practicing mindfulness meditation. Calm users have reported these benefits, with many able to forego the time- and cost-intensive cognitive behavioral therapy that requires highly trained therapists.^10-12

Exercise to Relieve Stress

Both aerobic and anaerobic exercises are antidepressive and anxiolytic and also lower one’s overall sensitivity to stress. Whether it is governed by neurotransmitters such as the activation of the opioid systems or the release of endogenous endorphins or time spent focusing on a different task at hand, the benefits of exercise against mental stressors have been extensively studied and established.¹³ Consider obtaining a new gym membership at the start of residency or joining an intramural team. Both have the added benefit of expanding your social circle.

Socialize With Others

Social isolation and perceived loneliness are key stressors linked to neuroendocrine disturbances that underlie depression, anxiety, and even schizophrenia.^14,15 Throughout residency there will be several social events and opportunities to gather with colleagues—inside or outside of the work environment—and residents should attend as time allows. Even virtual social interactions were found to reduce stress and help in the treatment of social anxiety disorder.¹⁴

 

 

Communicate About Stressors

Open up to your co-residents, friends, and family about any struggles that may be invisible on the outside. Even attendings can empathize with the struggles of residency, and the mentors in place are actively trained to prioritize resident wellness. If verbal communication is not your strength, try journaling. Writing helps to untangle and better define underlying stressors and is itself meditative.^16,17 However, ensure that your journaling is focused on positive emotional responses and aims to determine the positive benefits within any stressful event; those solely expressing negative emotions were found to have higher levels of stress and anxiety afterward than they had before.¹⁷

Seek a Mental Health Specialist

As with all other human ailments, severe mental health disorders require specialists and proper medication. Unfortunately, substantial stigma accompanying mental health continues to permeate medicine, creating considerable barriers for residents in need of care.¹⁸ A 2016 survey of more than 2000 physicians found that those with mental illnesses did not seek treatment due to limited time, fear of being reported to a medical licensing board, concern over obtaining licensure, and shame or embarrassment at the diagnosis.¹⁹ Besides urging residents to seek care, more effort should be invested in addressing the stigma and ensuring confidentiality. In 2021, the internal medicine and medicine-pediatrics residency at the University of Colorado Anschutz Medical Campus (Aurora, Colorado) developed a confidential opt-out, rather than opt-in, mental health program, and appointments were made for all 80 interns in advance. In doing so, they found increased participation and self-reported wellness at a relatively low cost and simple implementation.²⁰ For trainees without such access, online or mobile therapy platforms offering electronic mental health treatment or telepsychiatry also have been employed.^21,22 The onus ultimately is still on the individual to seek the care they need. Although only an anecdotal piece of evidence, I have found the prevalence of physicians taking selective serotonin reuptake inhibitors such as escitalopram, sertraline, or fluoxetine to be strikingly common and quite beneficial.

Final Thoughts

Residency remains rife with financial, emotional, and physical stressors; even as the dust settles on the COVID-19 pandemic, the light shed on the importance of trainee mental health must remain illuminated. For the aforementioned resources to have an impact, residents need to be empowered to openly discuss mental health issues and to seek help if necessary. Finally, in 2018, the Journal of Graduate Medical Education published a 10-year prospective cohort study that found that emotional distress during residency persists in professional practice even 10 years after residency and is associated with future burnout.²³ Trainees should consider prioritizing their mental health to not only improve their quality of life in the present but also as an investment for their future.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

 

 

Adverse Effects of Systemic Treatments

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

 

 

Drug Resistance

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

 

 

Adverse Effects of Systemic Treatments

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

 

 

Drug Resistance

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

 

 

Adverse Effects of Systemic Treatments

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

 

 

Drug Resistance

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

The Diagnosis: Lymphomatoid Papulosis

At the time of the initial visit, a punch biopsy was performed on the posterior shoulder girdle. Histopathology revealed mild epidermal spongiosis and acanthosis with associated parakeratosis and a dermal lymphocytic infiltrate with extravasated erythrocytes consistent with pityriasis rosea (Figure 1). Two weeks after the biopsy, the patient returned for suture removal and to discuss the biopsy results. The patient reported more evolving lesions despite completing the prescribed course of dicloxacillin. At this time, physical examination revealed the persistence of several reddishbrown papules along with new nodular lesions on the arms and thighs, some with central ulceration and crusting (Figure 2). A second biopsy of a nodular lesion on the right distal forearm was performed at this visit along with a superficial tissue culture, which was negative for bacterial or fungal elements. The biopsy revealed an atypical CD30⁺ lymphoid proliferation (Figure 3). These cells were strongly PD-L1 positive and also positive for CD3, CD4, and granzyme-B. Ki67 showed a high proliferation rate, and T-cell gene rearrangement studies were positive. Given these histologic findings and the clinical context of rapidly evolving skin lesions from small papules to nodular skin tumors, a diagnosis of lymphomatoid papulosis (LyP) was established.

Because of the notable pathologic discordance between the 2 biopsy specimens, re-evaluation of the initial specimen was requested. The initial biopsy was subsequently found to be CD30⁺ with an identical peak on gene rearrangement studies as the second biopsy, further validating the diagnosis of LyP (Figure 4). Our patient was offered low-dose methotrexate therapy but declined the treatment plan, as the skin lesions had begun to resolve.

Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder with a characteristic recurrent and self-remitting disease course.^1,2 Although it typically has a benign clinical course, it is histologically malignant and considered a low-grade variant of cutaneous T-cell lymphoma. ^2,3 The classic clinical presentation of LyP involves the presence of reddish-brown papules and nodules typically measuring less than 2.0 cm, which may show evidence of central ulceration, hemorrhage, necrosis, and/or crust formation.^1-5 It is characteristic that a patient may present with these skin lesions in different stages of evolution and that biopsies of these lesions may reflect different histologic features depending on the age of the lesion, making a definitive diagnosis more difficult to obtain if not clinically correlated.^1,2 Any part of the body may be involved; however, there appears to be a predilection for the trunk and extremities in most cases.^1-3,5 The skin eruptions usually are asymptomatic, but pruritus is a commonly associated concern.^1,2,4,5

Lymphomatoid papulosis can have a localized, clustered, or generalized distribution pattern and typically will spontaneously regress without treatment within 3 to 12 weeks of symptom onset.^2,3 Lymphomatoid papulosis has a slight male predominance with a male to female ratio of 1.5:1. It occurs most commonly between 35 and 45 years of age, though it can present at any age. The overall duration of the disease can range from months to decades.^2,3 Lymphomatoid papulosis makes up approximately 15% of all cutaneous T-cell lymphomas.^2,3 Although the overall prognosis is excellent, patients with LyP are at an increased risk of developing cutaneous or systemic lymphoma, most commonly mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin lymphoma.^1-3 This increased lifelong risk is the reason that patients with LyP must be followed long-term every 6 to 12 months for surveillance of emerging malignancy.^1,2,6

The pathogenesis of LyP remains unknown. Some have hypothesized a possible viral trigger; however, there is insufficient data to support this theory.^2,6 A diagnostic hallmark of LyP is its CD30 positivity, which is a known marker for T-cell activation.6 The spontaneous regression of skin lesions that is characteristic of LyP is believed to involve the interactions between CD30 and its ligand (CD30L), which may contribute to apoptosis of neoplastic T cells.^2,3,6 With regards to the possible mechanisms contributing to tumor progression in LyP, a mutation in the transforming growth factor β receptor gene on CD30+ tumor cells within LyP lesions may allow for these cells to evade growth regulation and progress to lymphoma.^2,6 A large percentage of LyP biopsy specimens show evidence of T-cell receptor gene monoclonal rearrangement, which can aid in establishing a diagnosis.^1,2

The histologic features of LyP can vary greatly depending on the age of the lesion sampled.^1,2 Histologic subtypes of LyP have been established, with type A being the most common (approximately 75% of cases), displaying a wedge-shaped infiltrate of scattered or clustered, large, atypical CD30+ T cells.^1,2 Types B through E vary in histologic features, with the exception that all subtypes contain a CD30+ lymphocytic infiltrate.^2,3

Treatment of LyP depends on the symptom/disease burden that the patient is experiencing. For patients with a limited number of nonscarring skin lesions in areas that are not cosmetically sensitive, observation is recommended. ^1-3 For symptomatic patients with an extensive number of lesions, particularly those that may be scarring and/or in cosmetically sensitive areas, low-dose oral methotrexate therapy is considered first-line treatment.^1-4 A methotrexate dose of 5 to 20 mg weekly can be effective in reducing the number and severity of lesions, with duration of treatment depending on clinical response.^1,2 For patients who have contraindications to or who cannot tolerate oral methotrexate, phototherapy using psoralen plus UVA twice weekly for 6 to 8 weeks is another treatment option.^1,2 Topical corticosteroids also can be used in children or for patients experiencing substantial pruritus.^1,2,4 Oral or topical retinoids, topical carmustine or mechlorethamine, and brentuximab (an anti-CD30 monoclonal antibody) are all alternative therapies that have shown some beneficial effects.^1,2 In the event that any of the skin lesions do not spontaneously regress within a 3- to 12-week time frame, surgical excision or radiotherapy can be performed on those lesions.²

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is another CD30+ lymphoproliferative disorder with overlapping clinical and histopathological features of LyP. Recurrent crops of multiple lesions favor a diagnosis of LyP, whereas solitary lesions favor C-ALCL; however, multifocal C-ALCL cases may occur.² Mycosis fungoides is the most common type of cutaneous T-cell lymphoma that characteristically presents in a patch, plaque, tumor progression. Although mycosis fungoides eventually may transform into a CD30⁺ lymphoma, our patient did not display the characteristic clinical progression to suggest this diagnosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica also fall into the spectrum of clonal T-cell cutaneous disorders that more commonly affect the pediatric population. Pityriasis lichenoides et varioliformis acuta has a marked CD8⁺ lymphocyte infiltrate, whereas pityriasis lichenoides chronica has more CD4⁺ lymphocytes. These disorders typically do not stain positive for CD30.²

All patients with a diagnosis of LyP should maintain lifelong, regular, 6- to 12-month follow-up visits to monitor disease status and screen for any evidence of developing malignancy.^1,2,6 A thorough review of clinical history, complete skin examination, and physical examination with a particular focus on detection of lymphadenopathy and hepatosplenomegaly should be included at every followup visit.1 Systemic symptoms such as fever, night sweats, or weight loss are not typical features of LyP; therefore, patients who begin to develop these symptoms should be promptly evaluated for systemic lymphoma.¹

The Diagnosis: Lymphomatoid Papulosis

At the time of the initial visit, a punch biopsy was performed on the posterior shoulder girdle. Histopathology revealed mild epidermal spongiosis and acanthosis with associated parakeratosis and a dermal lymphocytic infiltrate with extravasated erythrocytes consistent with pityriasis rosea (Figure 1). Two weeks after the biopsy, the patient returned for suture removal and to discuss the biopsy results. The patient reported more evolving lesions despite completing the prescribed course of dicloxacillin. At this time, physical examination revealed the persistence of several reddishbrown papules along with new nodular lesions on the arms and thighs, some with central ulceration and crusting (Figure 2). A second biopsy of a nodular lesion on the right distal forearm was performed at this visit along with a superficial tissue culture, which was negative for bacterial or fungal elements. The biopsy revealed an atypical CD30⁺ lymphoid proliferation (Figure 3). These cells were strongly PD-L1 positive and also positive for CD3, CD4, and granzyme-B. Ki67 showed a high proliferation rate, and T-cell gene rearrangement studies were positive. Given these histologic findings and the clinical context of rapidly evolving skin lesions from small papules to nodular skin tumors, a diagnosis of lymphomatoid papulosis (LyP) was established.

Because of the notable pathologic discordance between the 2 biopsy specimens, re-evaluation of the initial specimen was requested. The initial biopsy was subsequently found to be CD30⁺ with an identical peak on gene rearrangement studies as the second biopsy, further validating the diagnosis of LyP (Figure 4). Our patient was offered low-dose methotrexate therapy but declined the treatment plan, as the skin lesions had begun to resolve.

Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder with a characteristic recurrent and self-remitting disease course.^1,2 Although it typically has a benign clinical course, it is histologically malignant and considered a low-grade variant of cutaneous T-cell lymphoma. ^2,3 The classic clinical presentation of LyP involves the presence of reddish-brown papules and nodules typically measuring less than 2.0 cm, which may show evidence of central ulceration, hemorrhage, necrosis, and/or crust formation.^1-5 It is characteristic that a patient may present with these skin lesions in different stages of evolution and that biopsies of these lesions may reflect different histologic features depending on the age of the lesion, making a definitive diagnosis more difficult to obtain if not clinically correlated.^1,2 Any part of the body may be involved; however, there appears to be a predilection for the trunk and extremities in most cases.^1-3,5 The skin eruptions usually are asymptomatic, but pruritus is a commonly associated concern.^1,2,4,5

Lymphomatoid papulosis can have a localized, clustered, or generalized distribution pattern and typically will spontaneously regress without treatment within 3 to 12 weeks of symptom onset.^2,3 Lymphomatoid papulosis has a slight male predominance with a male to female ratio of 1.5:1. It occurs most commonly between 35 and 45 years of age, though it can present at any age. The overall duration of the disease can range from months to decades.^2,3 Lymphomatoid papulosis makes up approximately 15% of all cutaneous T-cell lymphomas.^2,3 Although the overall prognosis is excellent, patients with LyP are at an increased risk of developing cutaneous or systemic lymphoma, most commonly mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin lymphoma.^1-3 This increased lifelong risk is the reason that patients with LyP must be followed long-term every 6 to 12 months for surveillance of emerging malignancy.^1,2,6

The pathogenesis of LyP remains unknown. Some have hypothesized a possible viral trigger; however, there is insufficient data to support this theory.^2,6 A diagnostic hallmark of LyP is its CD30 positivity, which is a known marker for T-cell activation.6 The spontaneous regression of skin lesions that is characteristic of LyP is believed to involve the interactions between CD30 and its ligand (CD30L), which may contribute to apoptosis of neoplastic T cells.^2,3,6 With regards to the possible mechanisms contributing to tumor progression in LyP, a mutation in the transforming growth factor β receptor gene on CD30+ tumor cells within LyP lesions may allow for these cells to evade growth regulation and progress to lymphoma.^2,6 A large percentage of LyP biopsy specimens show evidence of T-cell receptor gene monoclonal rearrangement, which can aid in establishing a diagnosis.^1,2

The histologic features of LyP can vary greatly depending on the age of the lesion sampled.^1,2 Histologic subtypes of LyP have been established, with type A being the most common (approximately 75% of cases), displaying a wedge-shaped infiltrate of scattered or clustered, large, atypical CD30+ T cells.^1,2 Types B through E vary in histologic features, with the exception that all subtypes contain a CD30+ lymphocytic infiltrate.^2,3

Treatment of LyP depends on the symptom/disease burden that the patient is experiencing. For patients with a limited number of nonscarring skin lesions in areas that are not cosmetically sensitive, observation is recommended. ^1-3 For symptomatic patients with an extensive number of lesions, particularly those that may be scarring and/or in cosmetically sensitive areas, low-dose oral methotrexate therapy is considered first-line treatment.^1-4 A methotrexate dose of 5 to 20 mg weekly can be effective in reducing the number and severity of lesions, with duration of treatment depending on clinical response.^1,2 For patients who have contraindications to or who cannot tolerate oral methotrexate, phototherapy using psoralen plus UVA twice weekly for 6 to 8 weeks is another treatment option.^1,2 Topical corticosteroids also can be used in children or for patients experiencing substantial pruritus.^1,2,4 Oral or topical retinoids, topical carmustine or mechlorethamine, and brentuximab (an anti-CD30 monoclonal antibody) are all alternative therapies that have shown some beneficial effects.^1,2 In the event that any of the skin lesions do not spontaneously regress within a 3- to 12-week time frame, surgical excision or radiotherapy can be performed on those lesions.²

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is another CD30+ lymphoproliferative disorder with overlapping clinical and histopathological features of LyP. Recurrent crops of multiple lesions favor a diagnosis of LyP, whereas solitary lesions favor C-ALCL; however, multifocal C-ALCL cases may occur.² Mycosis fungoides is the most common type of cutaneous T-cell lymphoma that characteristically presents in a patch, plaque, tumor progression. Although mycosis fungoides eventually may transform into a CD30⁺ lymphoma, our patient did not display the characteristic clinical progression to suggest this diagnosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica also fall into the spectrum of clonal T-cell cutaneous disorders that more commonly affect the pediatric population. Pityriasis lichenoides et varioliformis acuta has a marked CD8⁺ lymphocyte infiltrate, whereas pityriasis lichenoides chronica has more CD4⁺ lymphocytes. These disorders typically do not stain positive for CD30.²

All patients with a diagnosis of LyP should maintain lifelong, regular, 6- to 12-month follow-up visits to monitor disease status and screen for any evidence of developing malignancy.^1,2,6 A thorough review of clinical history, complete skin examination, and physical examination with a particular focus on detection of lymphadenopathy and hepatosplenomegaly should be included at every followup visit.1 Systemic symptoms such as fever, night sweats, or weight loss are not typical features of LyP; therefore, patients who begin to develop these symptoms should be promptly evaluated for systemic lymphoma.¹

The Diagnosis: Lymphomatoid Papulosis

At the time of the initial visit, a punch biopsy was performed on the posterior shoulder girdle. Histopathology revealed mild epidermal spongiosis and acanthosis with associated parakeratosis and a dermal lymphocytic infiltrate with extravasated erythrocytes consistent with pityriasis rosea (Figure 1). Two weeks after the biopsy, the patient returned for suture removal and to discuss the biopsy results. The patient reported more evolving lesions despite completing the prescribed course of dicloxacillin. At this time, physical examination revealed the persistence of several reddishbrown papules along with new nodular lesions on the arms and thighs, some with central ulceration and crusting (Figure 2). A second biopsy of a nodular lesion on the right distal forearm was performed at this visit along with a superficial tissue culture, which was negative for bacterial or fungal elements. The biopsy revealed an atypical CD30⁺ lymphoid proliferation (Figure 3). These cells were strongly PD-L1 positive and also positive for CD3, CD4, and granzyme-B. Ki67 showed a high proliferation rate, and T-cell gene rearrangement studies were positive. Given these histologic findings and the clinical context of rapidly evolving skin lesions from small papules to nodular skin tumors, a diagnosis of lymphomatoid papulosis (LyP) was established.

Because of the notable pathologic discordance between the 2 biopsy specimens, re-evaluation of the initial specimen was requested. The initial biopsy was subsequently found to be CD30⁺ with an identical peak on gene rearrangement studies as the second biopsy, further validating the diagnosis of LyP (Figure 4). Our patient was offered low-dose methotrexate therapy but declined the treatment plan, as the skin lesions had begun to resolve.

Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder with a characteristic recurrent and self-remitting disease course.^1,2 Although it typically has a benign clinical course, it is histologically malignant and considered a low-grade variant of cutaneous T-cell lymphoma. ^2,3 The classic clinical presentation of LyP involves the presence of reddish-brown papules and nodules typically measuring less than 2.0 cm, which may show evidence of central ulceration, hemorrhage, necrosis, and/or crust formation.^1-5 It is characteristic that a patient may present with these skin lesions in different stages of evolution and that biopsies of these lesions may reflect different histologic features depending on the age of the lesion, making a definitive diagnosis more difficult to obtain if not clinically correlated.^1,2 Any part of the body may be involved; however, there appears to be a predilection for the trunk and extremities in most cases.^1-3,5 The skin eruptions usually are asymptomatic, but pruritus is a commonly associated concern.^1,2,4,5

Lymphomatoid papulosis can have a localized, clustered, or generalized distribution pattern and typically will spontaneously regress without treatment within 3 to 12 weeks of symptom onset.^2,3 Lymphomatoid papulosis has a slight male predominance with a male to female ratio of 1.5:1. It occurs most commonly between 35 and 45 years of age, though it can present at any age. The overall duration of the disease can range from months to decades.^2,3 Lymphomatoid papulosis makes up approximately 15% of all cutaneous T-cell lymphomas.^2,3 Although the overall prognosis is excellent, patients with LyP are at an increased risk of developing cutaneous or systemic lymphoma, most commonly mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin lymphoma.^1-3 This increased lifelong risk is the reason that patients with LyP must be followed long-term every 6 to 12 months for surveillance of emerging malignancy.^1,2,6

The pathogenesis of LyP remains unknown. Some have hypothesized a possible viral trigger; however, there is insufficient data to support this theory.^2,6 A diagnostic hallmark of LyP is its CD30 positivity, which is a known marker for T-cell activation.6 The spontaneous regression of skin lesions that is characteristic of LyP is believed to involve the interactions between CD30 and its ligand (CD30L), which may contribute to apoptosis of neoplastic T cells.^2,3,6 With regards to the possible mechanisms contributing to tumor progression in LyP, a mutation in the transforming growth factor β receptor gene on CD30+ tumor cells within LyP lesions may allow for these cells to evade growth regulation and progress to lymphoma.^2,6 A large percentage of LyP biopsy specimens show evidence of T-cell receptor gene monoclonal rearrangement, which can aid in establishing a diagnosis.^1,2

The histologic features of LyP can vary greatly depending on the age of the lesion sampled.^1,2 Histologic subtypes of LyP have been established, with type A being the most common (approximately 75% of cases), displaying a wedge-shaped infiltrate of scattered or clustered, large, atypical CD30+ T cells.^1,2 Types B through E vary in histologic features, with the exception that all subtypes contain a CD30+ lymphocytic infiltrate.^2,3

Treatment of LyP depends on the symptom/disease burden that the patient is experiencing. For patients with a limited number of nonscarring skin lesions in areas that are not cosmetically sensitive, observation is recommended. ^1-3 For symptomatic patients with an extensive number of lesions, particularly those that may be scarring and/or in cosmetically sensitive areas, low-dose oral methotrexate therapy is considered first-line treatment.^1-4 A methotrexate dose of 5 to 20 mg weekly can be effective in reducing the number and severity of lesions, with duration of treatment depending on clinical response.^1,2 For patients who have contraindications to or who cannot tolerate oral methotrexate, phototherapy using psoralen plus UVA twice weekly for 6 to 8 weeks is another treatment option.^1,2 Topical corticosteroids also can be used in children or for patients experiencing substantial pruritus.^1,2,4 Oral or topical retinoids, topical carmustine or mechlorethamine, and brentuximab (an anti-CD30 monoclonal antibody) are all alternative therapies that have shown some beneficial effects.^1,2 In the event that any of the skin lesions do not spontaneously regress within a 3- to 12-week time frame, surgical excision or radiotherapy can be performed on those lesions.²

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is another CD30+ lymphoproliferative disorder with overlapping clinical and histopathological features of LyP. Recurrent crops of multiple lesions favor a diagnosis of LyP, whereas solitary lesions favor C-ALCL; however, multifocal C-ALCL cases may occur.² Mycosis fungoides is the most common type of cutaneous T-cell lymphoma that characteristically presents in a patch, plaque, tumor progression. Although mycosis fungoides eventually may transform into a CD30⁺ lymphoma, our patient did not display the characteristic clinical progression to suggest this diagnosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica also fall into the spectrum of clonal T-cell cutaneous disorders that more commonly affect the pediatric population. Pityriasis lichenoides et varioliformis acuta has a marked CD8⁺ lymphocyte infiltrate, whereas pityriasis lichenoides chronica has more CD4⁺ lymphocytes. These disorders typically do not stain positive for CD30.²

All patients with a diagnosis of LyP should maintain lifelong, regular, 6- to 12-month follow-up visits to monitor disease status and screen for any evidence of developing malignancy.^1,2,6 A thorough review of clinical history, complete skin examination, and physical examination with a particular focus on detection of lymphadenopathy and hepatosplenomegaly should be included at every followup visit.1 Systemic symptoms such as fever, night sweats, or weight loss are not typical features of LyP; therefore, patients who begin to develop these symptoms should be promptly evaluated for systemic lymphoma.¹

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

Poly-L-lactic acid (PLLA) is a synthetic biologic polymer that is suspended in solution and can be injected for soft-tissue augmentation. The stimulatory molecule functions to increase collagen synthesis as a by-product of its degradation.¹ Poly-L-lactic acid measures 40 to 63 μm and is irregularly shaped, which inhibits product mobility and allows for precise tissue augmentation.² Clinical trials of injectable PLLA have proven its safety with no reported cases of infection, allergies, or serious adverse reactions.^3-5 The most common patient concerns generally are transient in nature, such as swelling, tenderness, pain, bruising, and bleeding. Persistent adverse events of PLLA primarily are papule and nodule formation.⁶ Clinical trials showed a variable incidence of papule/nodule formation between 6% and 44%.² Nodule formation remains a major challenge to achieving optimal results from injectable PLLA. We present a case in which a hyperdiluted formulation of PLLA produced a relatively acute (3-week) onset of multiple nodule formations dispersed on the anterior neck. The nodules were resistant to less-invasive treatment modalities and were further requested to be surgically excised.

Case Report

A 38-year-old woman presented for soft-tissue augmentation of the anterior neck using PLLA to achieve correction of skin laxity and static rhytides. She had a history of successful PLLA injections in the temples, knees, chest, and buttocks over a 5-year period. Forty-eight hours prior to injection, 1 PLLA vial was hydrated with 7 cc bacteriostatic water by using a continuous rotation suspension method over the 48 hours. On the day of injection, the PLLA was further hyperdiluted with 2 cc of 2% lidocaine and an additional 7 cc of bacteriostatic water, for a total of 16 cc diluent. The product was injected using a cannula in the anterior and lateral neck. According to the patient, 3 weeks after the procedure she noticed that some nodules began to form at the cannula insertion sites, while others formed distant from those sites; a total of 10 nodules had formed on the anterior neck (Figure 1).

The bacteriostatic water, lidocaine, and PLLA vial were all confirmed not to be expired. The manufacturer was contacted, and no other adverse reactions have been reported with this particular lot number of PLLA. The nodules initially were treated with injections of large boluses of bacteriostatic saline, which was ineffective. Treatment was then attempted using injections of a solution containing 1.0 mL of 5-fluorouracil (5-FU) 50 mg/mL, 0.4 mL of dexamethasone 4 mg/mL, 0.1 mL of triamcinolone 10 mg/mL, and 0.3 mL hyaluronidase. A series of 4 injections was performed in 2- to 4-week intervals. Two of the nodules resolved completely with this treatment. The remaining 8 nodules subjectively improved in size and softened to palpation but did not resolve completely. At 2 of the injection sites, treatment was complicated with steroid atrophy of the overlying skin. At the patient’s request, the remaining nodules were surgically excised (Figure 2). Histopathology revealed exogenous foreign material consistent with dermal filler (Figure 3).

Comment

Causes of Nodule Formation—Two factors that could contribute to nodule formation are inadequate dispersion of molecules and an insufficient volume of dilution. One study demonstrated that hydration for at least 24 hours is required for adequate PLLA dispersion. Furthermore, sonification for 5 minutes after a 2-hour hydration disperses molecules similarly to the 48-hour hydration.⁷ The PLLA in the current case was hydrated for 48 hours using a continuous rotation suspension method. Therefore, this likely did not play a role in our patient’s nodule formation. The volume of dilution has been shown to impact the incidence of nodule formation.⁸ At present, most injectors (60.4%) reconstitute each vial of PLLA with 9 to 10 mL of diluent.⁹ The PLLA in our patient was reconstituted with 16 mL; therefore, we believe that the anatomic location was the main contributor of nodule formation.

Fillers should be injected in the subcutaneous or deep dermal plane of tissue.¹⁰ The platysma is a superficial muscle that is intimately involved with the overlying skin of the anterior neck, and injections in this area could inadvertently be intramuscular. Intramuscular injections have a higher incidence of nodule formation.¹ Our patient had prior PLLA injections without adverse reactions in numerous other sites, supporting the claim that the anterior neck is prone to nodule formation from PLLA injections.

Management of Noninflammatory Nodules—Initial treatment of nodules with injections of saline was ineffective. This treatment can be used in an attempt to disperse the product. Treatment was then attempted with injections of a solution containing 5-FU, dexamethasone, triamcinolone, and hyaluronidase. Combination steroid therapy may be superior to monotherapy.¹¹ Dexamethasone may exhibit a cytoprotective effect on cells such as fibroblasts when used in combination with triamcinolone; monotherapy steroid use with triamcinolone alone induced fibroblast apoptosis at a much higher level.¹² Hyaluronidase works by breaking cross-links in hyaluronic acid, a glycosaminoglycan polysaccharide prevalent in the skin and connective tissue, which increases tissue permeability and aids in delivery of the other injected fluids.¹³ 5-Fluorouracil is an antimetabolite that may aid in treating nodules by discouraging additional fibroblast activity and fibrosis.¹⁴

The combination of 5-FU, dexamethasone, and triamcinolone has been shown to be successful in treating noninflammatory nodules in as few as 1 treatment.¹⁴ In our patient, hyaluronidase also was used in an attempt to aid delivery of the other injected fluids. If nodules do not resolve with 1 injection, it is recommended to wait at least 8 weeks before repeating the injection to prevent steroid atrophy of the overlying skin. In our patient, the intramuscular placement of the filler contributed to the nodules being resistant to this treatment. During excision, the nodules were tightly embedded in the underlying tissue, which may have prevented the solution from being delivered to the nodule (Figure 2).

Conclusion

Injectable PLLA is approved by the US Food and Drug Administration for soft-tissue augmentation of deep nasolabial folds and facial wrinkles. Off-label use of this product may cause higher incidence of nodule formation. Injectors should be cautious of injecting into the anterior neck. If nodules do form, treatment can be attempted with injections of saline. If that treatment fails, another treatment option is injection(s) of a mixture of 5-FU, dexamethasone, triamcinolone, and hyaluronidase separated by 8-week intervals. Finally, surgical excision is a viable treatment option, as presented in our case.

Poly-L-lactic acid (PLLA) is a synthetic biologic polymer that is suspended in solution and can be injected for soft-tissue augmentation. The stimulatory molecule functions to increase collagen synthesis as a by-product of its degradation.¹ Poly-L-lactic acid measures 40 to 63 μm and is irregularly shaped, which inhibits product mobility and allows for precise tissue augmentation.² Clinical trials of injectable PLLA have proven its safety with no reported cases of infection, allergies, or serious adverse reactions.^3-5 The most common patient concerns generally are transient in nature, such as swelling, tenderness, pain, bruising, and bleeding. Persistent adverse events of PLLA primarily are papule and nodule formation.⁶ Clinical trials showed a variable incidence of papule/nodule formation between 6% and 44%.² Nodule formation remains a major challenge to achieving optimal results from injectable PLLA. We present a case in which a hyperdiluted formulation of PLLA produced a relatively acute (3-week) onset of multiple nodule formations dispersed on the anterior neck. The nodules were resistant to less-invasive treatment modalities and were further requested to be surgically excised.

Case Report

A 38-year-old woman presented for soft-tissue augmentation of the anterior neck using PLLA to achieve correction of skin laxity and static rhytides. She had a history of successful PLLA injections in the temples, knees, chest, and buttocks over a 5-year period. Forty-eight hours prior to injection, 1 PLLA vial was hydrated with 7 cc bacteriostatic water by using a continuous rotation suspension method over the 48 hours. On the day of injection, the PLLA was further hyperdiluted with 2 cc of 2% lidocaine and an additional 7 cc of bacteriostatic water, for a total of 16 cc diluent. The product was injected using a cannula in the anterior and lateral neck. According to the patient, 3 weeks after the procedure she noticed that some nodules began to form at the cannula insertion sites, while others formed distant from those sites; a total of 10 nodules had formed on the anterior neck (Figure 1).

The bacteriostatic water, lidocaine, and PLLA vial were all confirmed not to be expired. The manufacturer was contacted, and no other adverse reactions have been reported with this particular lot number of PLLA. The nodules initially were treated with injections of large boluses of bacteriostatic saline, which was ineffective. Treatment was then attempted using injections of a solution containing 1.0 mL of 5-fluorouracil (5-FU) 50 mg/mL, 0.4 mL of dexamethasone 4 mg/mL, 0.1 mL of triamcinolone 10 mg/mL, and 0.3 mL hyaluronidase. A series of 4 injections was performed in 2- to 4-week intervals. Two of the nodules resolved completely with this treatment. The remaining 8 nodules subjectively improved in size and softened to palpation but did not resolve completely. At 2 of the injection sites, treatment was complicated with steroid atrophy of the overlying skin. At the patient’s request, the remaining nodules were surgically excised (Figure 2). Histopathology revealed exogenous foreign material consistent with dermal filler (Figure 3).

Comment

Causes of Nodule Formation—Two factors that could contribute to nodule formation are inadequate dispersion of molecules and an insufficient volume of dilution. One study demonstrated that hydration for at least 24 hours is required for adequate PLLA dispersion. Furthermore, sonification for 5 minutes after a 2-hour hydration disperses molecules similarly to the 48-hour hydration.⁷ The PLLA in the current case was hydrated for 48 hours using a continuous rotation suspension method. Therefore, this likely did not play a role in our patient’s nodule formation. The volume of dilution has been shown to impact the incidence of nodule formation.⁸ At present, most injectors (60.4%) reconstitute each vial of PLLA with 9 to 10 mL of diluent.⁹ The PLLA in our patient was reconstituted with 16 mL; therefore, we believe that the anatomic location was the main contributor of nodule formation.

Fillers should be injected in the subcutaneous or deep dermal plane of tissue.¹⁰ The platysma is a superficial muscle that is intimately involved with the overlying skin of the anterior neck, and injections in this area could inadvertently be intramuscular. Intramuscular injections have a higher incidence of nodule formation.¹ Our patient had prior PLLA injections without adverse reactions in numerous other sites, supporting the claim that the anterior neck is prone to nodule formation from PLLA injections.

Management of Noninflammatory Nodules—Initial treatment of nodules with injections of saline was ineffective. This treatment can be used in an attempt to disperse the product. Treatment was then attempted with injections of a solution containing 5-FU, dexamethasone, triamcinolone, and hyaluronidase. Combination steroid therapy may be superior to monotherapy.¹¹ Dexamethasone may exhibit a cytoprotective effect on cells such as fibroblasts when used in combination with triamcinolone; monotherapy steroid use with triamcinolone alone induced fibroblast apoptosis at a much higher level.¹² Hyaluronidase works by breaking cross-links in hyaluronic acid, a glycosaminoglycan polysaccharide prevalent in the skin and connective tissue, which increases tissue permeability and aids in delivery of the other injected fluids.¹³ 5-Fluorouracil is an antimetabolite that may aid in treating nodules by discouraging additional fibroblast activity and fibrosis.¹⁴

The combination of 5-FU, dexamethasone, and triamcinolone has been shown to be successful in treating noninflammatory nodules in as few as 1 treatment.¹⁴ In our patient, hyaluronidase also was used in an attempt to aid delivery of the other injected fluids. If nodules do not resolve with 1 injection, it is recommended to wait at least 8 weeks before repeating the injection to prevent steroid atrophy of the overlying skin. In our patient, the intramuscular placement of the filler contributed to the nodules being resistant to this treatment. During excision, the nodules were tightly embedded in the underlying tissue, which may have prevented the solution from being delivered to the nodule (Figure 2).

Conclusion

Injectable PLLA is approved by the US Food and Drug Administration for soft-tissue augmentation of deep nasolabial folds and facial wrinkles. Off-label use of this product may cause higher incidence of nodule formation. Injectors should be cautious of injecting into the anterior neck. If nodules do form, treatment can be attempted with injections of saline. If that treatment fails, another treatment option is injection(s) of a mixture of 5-FU, dexamethasone, triamcinolone, and hyaluronidase separated by 8-week intervals. Finally, surgical excision is a viable treatment option, as presented in our case.

Poly-L-lactic acid (PLLA) is a synthetic biologic polymer that is suspended in solution and can be injected for soft-tissue augmentation. The stimulatory molecule functions to increase collagen synthesis as a by-product of its degradation.¹ Poly-L-lactic acid measures 40 to 63 μm and is irregularly shaped, which inhibits product mobility and allows for precise tissue augmentation.² Clinical trials of injectable PLLA have proven its safety with no reported cases of infection, allergies, or serious adverse reactions.^3-5 The most common patient concerns generally are transient in nature, such as swelling, tenderness, pain, bruising, and bleeding. Persistent adverse events of PLLA primarily are papule and nodule formation.⁶ Clinical trials showed a variable incidence of papule/nodule formation between 6% and 44%.² Nodule formation remains a major challenge to achieving optimal results from injectable PLLA. We present a case in which a hyperdiluted formulation of PLLA produced a relatively acute (3-week) onset of multiple nodule formations dispersed on the anterior neck. The nodules were resistant to less-invasive treatment modalities and were further requested to be surgically excised.

Case Report

A 38-year-old woman presented for soft-tissue augmentation of the anterior neck using PLLA to achieve correction of skin laxity and static rhytides. She had a history of successful PLLA injections in the temples, knees, chest, and buttocks over a 5-year period. Forty-eight hours prior to injection, 1 PLLA vial was hydrated with 7 cc bacteriostatic water by using a continuous rotation suspension method over the 48 hours. On the day of injection, the PLLA was further hyperdiluted with 2 cc of 2% lidocaine and an additional 7 cc of bacteriostatic water, for a total of 16 cc diluent. The product was injected using a cannula in the anterior and lateral neck. According to the patient, 3 weeks after the procedure she noticed that some nodules began to form at the cannula insertion sites, while others formed distant from those sites; a total of 10 nodules had formed on the anterior neck (Figure 1).

The bacteriostatic water, lidocaine, and PLLA vial were all confirmed not to be expired. The manufacturer was contacted, and no other adverse reactions have been reported with this particular lot number of PLLA. The nodules initially were treated with injections of large boluses of bacteriostatic saline, which was ineffective. Treatment was then attempted using injections of a solution containing 1.0 mL of 5-fluorouracil (5-FU) 50 mg/mL, 0.4 mL of dexamethasone 4 mg/mL, 0.1 mL of triamcinolone 10 mg/mL, and 0.3 mL hyaluronidase. A series of 4 injections was performed in 2- to 4-week intervals. Two of the nodules resolved completely with this treatment. The remaining 8 nodules subjectively improved in size and softened to palpation but did not resolve completely. At 2 of the injection sites, treatment was complicated with steroid atrophy of the overlying skin. At the patient’s request, the remaining nodules were surgically excised (Figure 2). Histopathology revealed exogenous foreign material consistent with dermal filler (Figure 3).

Comment

Causes of Nodule Formation—Two factors that could contribute to nodule formation are inadequate dispersion of molecules and an insufficient volume of dilution. One study demonstrated that hydration for at least 24 hours is required for adequate PLLA dispersion. Furthermore, sonification for 5 minutes after a 2-hour hydration disperses molecules similarly to the 48-hour hydration.⁷ The PLLA in the current case was hydrated for 48 hours using a continuous rotation suspension method. Therefore, this likely did not play a role in our patient’s nodule formation. The volume of dilution has been shown to impact the incidence of nodule formation.⁸ At present, most injectors (60.4%) reconstitute each vial of PLLA with 9 to 10 mL of diluent.⁹ The PLLA in our patient was reconstituted with 16 mL; therefore, we believe that the anatomic location was the main contributor of nodule formation.

Fillers should be injected in the subcutaneous or deep dermal plane of tissue.¹⁰ The platysma is a superficial muscle that is intimately involved with the overlying skin of the anterior neck, and injections in this area could inadvertently be intramuscular. Intramuscular injections have a higher incidence of nodule formation.¹ Our patient had prior PLLA injections without adverse reactions in numerous other sites, supporting the claim that the anterior neck is prone to nodule formation from PLLA injections.

Management of Noninflammatory Nodules—Initial treatment of nodules with injections of saline was ineffective. This treatment can be used in an attempt to disperse the product. Treatment was then attempted with injections of a solution containing 5-FU, dexamethasone, triamcinolone, and hyaluronidase. Combination steroid therapy may be superior to monotherapy.¹¹ Dexamethasone may exhibit a cytoprotective effect on cells such as fibroblasts when used in combination with triamcinolone; monotherapy steroid use with triamcinolone alone induced fibroblast apoptosis at a much higher level.¹² Hyaluronidase works by breaking cross-links in hyaluronic acid, a glycosaminoglycan polysaccharide prevalent in the skin and connective tissue, which increases tissue permeability and aids in delivery of the other injected fluids.¹³ 5-Fluorouracil is an antimetabolite that may aid in treating nodules by discouraging additional fibroblast activity and fibrosis.¹⁴

The combination of 5-FU, dexamethasone, and triamcinolone has been shown to be successful in treating noninflammatory nodules in as few as 1 treatment.¹⁴ In our patient, hyaluronidase also was used in an attempt to aid delivery of the other injected fluids. If nodules do not resolve with 1 injection, it is recommended to wait at least 8 weeks before repeating the injection to prevent steroid atrophy of the overlying skin. In our patient, the intramuscular placement of the filler contributed to the nodules being resistant to this treatment. During excision, the nodules were tightly embedded in the underlying tissue, which may have prevented the solution from being delivered to the nodule (Figure 2).

Conclusion

Injectable PLLA is approved by the US Food and Drug Administration for soft-tissue augmentation of deep nasolabial folds and facial wrinkles. Off-label use of this product may cause higher incidence of nodule formation. Injectors should be cautious of injecting into the anterior neck. If nodules do form, treatment can be attempted with injections of saline. If that treatment fails, another treatment option is injection(s) of a mixture of 5-FU, dexamethasone, triamcinolone, and hyaluronidase separated by 8-week intervals. Finally, surgical excision is a viable treatment option, as presented in our case.

The Diagnosis: Granuloma Annulare

A biopsy of a lesion on the right flank demonstrated granulomatous inflammation and interstitial mucin (Figure), characteristic of granuloma annulare (GA).^1,2 Granuloma annulare is a relatively common skin disorder with an unknown etiology. It typically presents as smooth, annular, erythematous plaques.¹ The most common variants of GA are localized, generalized, and subcutaneous. Our case demonstrated Wolf isotopic response, an unrelated skin disease that forms at the same location as a previously healed skin lesion.² It is important to be aware of this phenomenon so that it is not confused with a recurrence of herpes zoster virus (HZV).

Although relatively infrequent, GA is the most common isotopic response following HZV infections.^3-5 Other postherpetic isotopic eruptions include cutaneous malignancies, lichen planus, sarcoidosis, morphea, reactive perforating collagenosis, psoriasis, and infections, among others.^3,5,6 The time between HZV infection and GA can be variable, ranging from a few weeks to many years apart.³

Oftentimes GA will spontaneously resolve within 2 years; however, recurrence is common.^7-9 There currently are no standard treatment guidelines. The most promising treatment options include intralesional or topical glucocorticoids for localized GA as well as phototherapy or hydroxychloroquine for widespread disease.^8,10  

Annular elastolytic giant cell granuloma (also called actinic granuloma) is a rare idiopathic inflammatory skin disease. It is characterized by erythematous annular papules or plaques mainly found on sun-exposed skin, such as the backs of the hands, forearms, or face.^11,12 Therefore, based on the distribution of our patient’s lesions, annular elastolytic giant cell granuloma was an unlikely diagnosis. Furthermore, it is not a known postherpetic isotopic reaction. Annular elastolytic giant cell granuloma can appear histologically similar to GA. Differentiating histologic features include a nonpalisading granuloma as well as the absence of mucin and necrobiosis.¹²

Annular lichen planus is a long-recognized but uncommon clinical variant of lichen planus that typically presents as pruritic, purple, annular plaques on the penis, scrotum, or intertriginous areas.¹³ The violaceous coloring is more characteristic of lichen planus. Histology is helpful in differentiating from GA.

Nummular eczema presents as scattered, welldefined, pruritic, erythematous, coin-shaped, coin-sized plaques in patients with diffusely dry skin.¹⁴ The scaling and serous crusting as well as more prominent pruritus help distinguish it from GA. The appearance of nummular eczema is quite characteristic; therefore, a biopsy typically is unnecessary for diagnosis. However, a potassium hydroxide wet mount examination of a skin scraping should be performed if tinea corporis also is suspected.

Superficial erythema annulare centrifugum classically presents as an annular or arciform pruritic lesion with an advancing outer erythematous edge with an inner rim of scale that most commonly occurs on the lower extremities. ¹⁵ The presence of pruritus and trailing scale helps distinguish this lesion from GA. Histologically, there are epidermal changes of hyperplasia, spongiosis, and parakeratosis, as well as lymphohistiocytic infiltrate surrounding the superficial dermal vessels^.16

We report this case to highlight GA as the most common postherpetic isotopic response. It should be on the differential diagnosis when a patient presents with erythematous, smooth, annular plaques occurring in the distribution of a resolved case of HZV.

The Diagnosis: Granuloma Annulare

A biopsy of a lesion on the right flank demonstrated granulomatous inflammation and interstitial mucin (Figure), characteristic of granuloma annulare (GA).^1,2 Granuloma annulare is a relatively common skin disorder with an unknown etiology. It typically presents as smooth, annular, erythematous plaques.¹ The most common variants of GA are localized, generalized, and subcutaneous. Our case demonstrated Wolf isotopic response, an unrelated skin disease that forms at the same location as a previously healed skin lesion.² It is important to be aware of this phenomenon so that it is not confused with a recurrence of herpes zoster virus (HZV).

Although relatively infrequent, GA is the most common isotopic response following HZV infections.^3-5 Other postherpetic isotopic eruptions include cutaneous malignancies, lichen planus, sarcoidosis, morphea, reactive perforating collagenosis, psoriasis, and infections, among others.^3,5,6 The time between HZV infection and GA can be variable, ranging from a few weeks to many years apart.³

Oftentimes GA will spontaneously resolve within 2 years; however, recurrence is common.^7-9 There currently are no standard treatment guidelines. The most promising treatment options include intralesional or topical glucocorticoids for localized GA as well as phototherapy or hydroxychloroquine for widespread disease.^8,10  

Annular elastolytic giant cell granuloma (also called actinic granuloma) is a rare idiopathic inflammatory skin disease. It is characterized by erythematous annular papules or plaques mainly found on sun-exposed skin, such as the backs of the hands, forearms, or face.^11,12 Therefore, based on the distribution of our patient’s lesions, annular elastolytic giant cell granuloma was an unlikely diagnosis. Furthermore, it is not a known postherpetic isotopic reaction. Annular elastolytic giant cell granuloma can appear histologically similar to GA. Differentiating histologic features include a nonpalisading granuloma as well as the absence of mucin and necrobiosis.¹²

Annular lichen planus is a long-recognized but uncommon clinical variant of lichen planus that typically presents as pruritic, purple, annular plaques on the penis, scrotum, or intertriginous areas.¹³ The violaceous coloring is more characteristic of lichen planus. Histology is helpful in differentiating from GA.

Nummular eczema presents as scattered, welldefined, pruritic, erythematous, coin-shaped, coin-sized plaques in patients with diffusely dry skin.¹⁴ The scaling and serous crusting as well as more prominent pruritus help distinguish it from GA. The appearance of nummular eczema is quite characteristic; therefore, a biopsy typically is unnecessary for diagnosis. However, a potassium hydroxide wet mount examination of a skin scraping should be performed if tinea corporis also is suspected.

Superficial erythema annulare centrifugum classically presents as an annular or arciform pruritic lesion with an advancing outer erythematous edge with an inner rim of scale that most commonly occurs on the lower extremities. ¹⁵ The presence of pruritus and trailing scale helps distinguish this lesion from GA. Histologically, there are epidermal changes of hyperplasia, spongiosis, and parakeratosis, as well as lymphohistiocytic infiltrate surrounding the superficial dermal vessels^.16

We report this case to highlight GA as the most common postherpetic isotopic response. It should be on the differential diagnosis when a patient presents with erythematous, smooth, annular plaques occurring in the distribution of a resolved case of HZV.

The Diagnosis: Granuloma Annulare

A biopsy of a lesion on the right flank demonstrated granulomatous inflammation and interstitial mucin (Figure), characteristic of granuloma annulare (GA).^1,2 Granuloma annulare is a relatively common skin disorder with an unknown etiology. It typically presents as smooth, annular, erythematous plaques.¹ The most common variants of GA are localized, generalized, and subcutaneous. Our case demonstrated Wolf isotopic response, an unrelated skin disease that forms at the same location as a previously healed skin lesion.² It is important to be aware of this phenomenon so that it is not confused with a recurrence of herpes zoster virus (HZV).

Although relatively infrequent, GA is the most common isotopic response following HZV infections.^3-5 Other postherpetic isotopic eruptions include cutaneous malignancies, lichen planus, sarcoidosis, morphea, reactive perforating collagenosis, psoriasis, and infections, among others.^3,5,6 The time between HZV infection and GA can be variable, ranging from a few weeks to many years apart.³

Oftentimes GA will spontaneously resolve within 2 years; however, recurrence is common.^7-9 There currently are no standard treatment guidelines. The most promising treatment options include intralesional or topical glucocorticoids for localized GA as well as phototherapy or hydroxychloroquine for widespread disease.^8,10  

Annular elastolytic giant cell granuloma (also called actinic granuloma) is a rare idiopathic inflammatory skin disease. It is characterized by erythematous annular papules or plaques mainly found on sun-exposed skin, such as the backs of the hands, forearms, or face.^11,12 Therefore, based on the distribution of our patient’s lesions, annular elastolytic giant cell granuloma was an unlikely diagnosis. Furthermore, it is not a known postherpetic isotopic reaction. Annular elastolytic giant cell granuloma can appear histologically similar to GA. Differentiating histologic features include a nonpalisading granuloma as well as the absence of mucin and necrobiosis.¹²

Annular lichen planus is a long-recognized but uncommon clinical variant of lichen planus that typically presents as pruritic, purple, annular plaques on the penis, scrotum, or intertriginous areas.¹³ The violaceous coloring is more characteristic of lichen planus. Histology is helpful in differentiating from GA.

Nummular eczema presents as scattered, welldefined, pruritic, erythematous, coin-shaped, coin-sized plaques in patients with diffusely dry skin.¹⁴ The scaling and serous crusting as well as more prominent pruritus help distinguish it from GA. The appearance of nummular eczema is quite characteristic; therefore, a biopsy typically is unnecessary for diagnosis. However, a potassium hydroxide wet mount examination of a skin scraping should be performed if tinea corporis also is suspected.

Superficial erythema annulare centrifugum classically presents as an annular or arciform pruritic lesion with an advancing outer erythematous edge with an inner rim of scale that most commonly occurs on the lower extremities. ¹⁵ The presence of pruritus and trailing scale helps distinguish this lesion from GA. Histologically, there are epidermal changes of hyperplasia, spongiosis, and parakeratosis, as well as lymphohistiocytic infiltrate surrounding the superficial dermal vessels^.16

We report this case to highlight GA as the most common postherpetic isotopic response. It should be on the differential diagnosis when a patient presents with erythematous, smooth, annular plaques occurring in the distribution of a resolved case of HZV.

The Diagnosis: Chromoblastomycosis

This case highlights the importance of routine skin biopsy and tissue culture when clinical suspicion for mycotic infection is high. Despite nonspecific biopsy results (Figure), a diagnosis of chromoblastomycosis (CBM) was reached based on tissue culture. Surgical excision was not possible in our patient due to the size and location of the lesion. The patient was referred to infectious disease, with the plan to start long-term itraconazole for at least 6 to 12 months.

Cases of CBM were first documented in 1914 and distinguished by the appearance of spherical, brown, muriform cells on skin biopsy—features that now serve as the hallmark of CBM diagnoses.^1,2 The implantation mycosis commonly is caused by agents such as Fonsecaea pedrosoi and Fonsecaea monophora of the bantiana-clade, as classified according to molecular phylogeny²; these agents have been isolated from soil, plants, and wood sources in tropical and subtropical regions and are strongly associated with agricultural activities.³

Chromoblastomycosis lesions tend to be asymptomatic with a variable amount of time between inoculation and lesion presentation, delaying medical care by months to years.³ The fungus causes a granulomatous reaction after skin damage, with noticeable pseudoepitheliomatous hyperplasia of the epidermis and granulomas formed by epithelioid and Langerhans cells in the dermis.⁴ Typically, CBM initially presents as an erythematous macular skin lesion, which then progresses to become more pink, papular, and sometimes pruritic.² Muriform (sclerotic) bodies, which reflect fungal components, extrude transepidermally and appear as black dots on the lesion’s surface.⁴ Chromoblastomycosis is limited to the subcutaneous tissue and has been classified into 5 types of lesions: nodular, tumoral, verrucous, scarring, and plaque.² Diagnosis is established using fungal tests such as potassium hydroxide direct microscopy, which exposes muriform bodies often in combination with dematiaceous hyphae, while fungal culture of F pedrosoi in Sabouraud agar produces velvety dark colonies.³ Although an immune response to CBM infection remains unclear, it has been demonstrated that the response differs based on the severity of the infection. The severe form of CBM produces high levels of IL-10, low levels of IFN-γ, and inefficient T-cell proliferation, while milder forms of CBM display low levels of IL-10, high levels of IFN-γ, and efficient T-cell proliferation.⁵ Complications of CBM include chronic lymphedema, ankylosis, and secondary bacterial infections, which largely are observed in advanced cases; malignant transformation to squamous cell carcinoma, though rare, also has been observed.⁶

Several therapeutic methods have been implemented in the treatment of CBM, but lesions often remain refractory, especially in advanced cases.⁶ Approaches to treatment can be divided into antifungal and physical methods. Commonly employed antifungal agents include itraconazole and terbinafine, which must be taken daily for a period ranging from 6 months to 1 year or longer; flucytosine with or without amphotericin also has been employed.⁴ Among the physical methods, surgical excision is not suggested due to possible dissemination of disease; other options include cryotherapy, thermotherapy, and laser vaporization.⁶ The prognosis has improved since the use of extended-spectrum triazoles, but high rates of refractory disease remain unchanged.²

The differential diagnosis includes other infections. Nocardiosis is a bacterial infection in which cutaneous disease can result in actinomycetoma, which presents with grains that are small, round, and stain blue on hematoxylin and eosin with eosinophilic rays at the periphery.⁷ Although the clinical features and pseudoepitheliomatous hyperplasia seen in CBM can mimic squamous cell carcinoma, the latter would show variable degrees of differentiation, keratinization, nuclear atypia, and architectural atypia with a negative tissue culture.⁸ Eumycetoma is a fungal infection that typically is not caused by F pedrosoi but rather most commonly Madurella mycetomatis.⁹ Leishmaniasis is a parasitic infection in which a biopsy of cutaneous lesions often displays parasite-filled histiocytes.¹⁰

The Diagnosis: Chromoblastomycosis

This case highlights the importance of routine skin biopsy and tissue culture when clinical suspicion for mycotic infection is high. Despite nonspecific biopsy results (Figure), a diagnosis of chromoblastomycosis (CBM) was reached based on tissue culture. Surgical excision was not possible in our patient due to the size and location of the lesion. The patient was referred to infectious disease, with the plan to start long-term itraconazole for at least 6 to 12 months.

Cases of CBM were first documented in 1914 and distinguished by the appearance of spherical, brown, muriform cells on skin biopsy—features that now serve as the hallmark of CBM diagnoses.^1,2 The implantation mycosis commonly is caused by agents such as Fonsecaea pedrosoi and Fonsecaea monophora of the bantiana-clade, as classified according to molecular phylogeny²; these agents have been isolated from soil, plants, and wood sources in tropical and subtropical regions and are strongly associated with agricultural activities.³

Chromoblastomycosis lesions tend to be asymptomatic with a variable amount of time between inoculation and lesion presentation, delaying medical care by months to years.³ The fungus causes a granulomatous reaction after skin damage, with noticeable pseudoepitheliomatous hyperplasia of the epidermis and granulomas formed by epithelioid and Langerhans cells in the dermis.⁴ Typically, CBM initially presents as an erythematous macular skin lesion, which then progresses to become more pink, papular, and sometimes pruritic.² Muriform (sclerotic) bodies, which reflect fungal components, extrude transepidermally and appear as black dots on the lesion’s surface.⁴ Chromoblastomycosis is limited to the subcutaneous tissue and has been classified into 5 types of lesions: nodular, tumoral, verrucous, scarring, and plaque.² Diagnosis is established using fungal tests such as potassium hydroxide direct microscopy, which exposes muriform bodies often in combination with dematiaceous hyphae, while fungal culture of F pedrosoi in Sabouraud agar produces velvety dark colonies.³ Although an immune response to CBM infection remains unclear, it has been demonstrated that the response differs based on the severity of the infection. The severe form of CBM produces high levels of IL-10, low levels of IFN-γ, and inefficient T-cell proliferation, while milder forms of CBM display low levels of IL-10, high levels of IFN-γ, and efficient T-cell proliferation.⁵ Complications of CBM include chronic lymphedema, ankylosis, and secondary bacterial infections, which largely are observed in advanced cases; malignant transformation to squamous cell carcinoma, though rare, also has been observed.⁶

Several therapeutic methods have been implemented in the treatment of CBM, but lesions often remain refractory, especially in advanced cases.⁶ Approaches to treatment can be divided into antifungal and physical methods. Commonly employed antifungal agents include itraconazole and terbinafine, which must be taken daily for a period ranging from 6 months to 1 year or longer; flucytosine with or without amphotericin also has been employed.⁴ Among the physical methods, surgical excision is not suggested due to possible dissemination of disease; other options include cryotherapy, thermotherapy, and laser vaporization.⁶ The prognosis has improved since the use of extended-spectrum triazoles, but high rates of refractory disease remain unchanged.²

The differential diagnosis includes other infections. Nocardiosis is a bacterial infection in which cutaneous disease can result in actinomycetoma, which presents with grains that are small, round, and stain blue on hematoxylin and eosin with eosinophilic rays at the periphery.⁷ Although the clinical features and pseudoepitheliomatous hyperplasia seen in CBM can mimic squamous cell carcinoma, the latter would show variable degrees of differentiation, keratinization, nuclear atypia, and architectural atypia with a negative tissue culture.⁸ Eumycetoma is a fungal infection that typically is not caused by F pedrosoi but rather most commonly Madurella mycetomatis.⁹ Leishmaniasis is a parasitic infection in which a biopsy of cutaneous lesions often displays parasite-filled histiocytes.¹⁰

The Diagnosis: Chromoblastomycosis

This case highlights the importance of routine skin biopsy and tissue culture when clinical suspicion for mycotic infection is high. Despite nonspecific biopsy results (Figure), a diagnosis of chromoblastomycosis (CBM) was reached based on tissue culture. Surgical excision was not possible in our patient due to the size and location of the lesion. The patient was referred to infectious disease, with the plan to start long-term itraconazole for at least 6 to 12 months.

Cases of CBM were first documented in 1914 and distinguished by the appearance of spherical, brown, muriform cells on skin biopsy—features that now serve as the hallmark of CBM diagnoses.^1,2 The implantation mycosis commonly is caused by agents such as Fonsecaea pedrosoi and Fonsecaea monophora of the bantiana-clade, as classified according to molecular phylogeny²; these agents have been isolated from soil, plants, and wood sources in tropical and subtropical regions and are strongly associated with agricultural activities.³

Chromoblastomycosis lesions tend to be asymptomatic with a variable amount of time between inoculation and lesion presentation, delaying medical care by months to years.³ The fungus causes a granulomatous reaction after skin damage, with noticeable pseudoepitheliomatous hyperplasia of the epidermis and granulomas formed by epithelioid and Langerhans cells in the dermis.⁴ Typically, CBM initially presents as an erythematous macular skin lesion, which then progresses to become more pink, papular, and sometimes pruritic.² Muriform (sclerotic) bodies, which reflect fungal components, extrude transepidermally and appear as black dots on the lesion’s surface.⁴ Chromoblastomycosis is limited to the subcutaneous tissue and has been classified into 5 types of lesions: nodular, tumoral, verrucous, scarring, and plaque.² Diagnosis is established using fungal tests such as potassium hydroxide direct microscopy, which exposes muriform bodies often in combination with dematiaceous hyphae, while fungal culture of F pedrosoi in Sabouraud agar produces velvety dark colonies.³ Although an immune response to CBM infection remains unclear, it has been demonstrated that the response differs based on the severity of the infection. The severe form of CBM produces high levels of IL-10, low levels of IFN-γ, and inefficient T-cell proliferation, while milder forms of CBM display low levels of IL-10, high levels of IFN-γ, and efficient T-cell proliferation.⁵ Complications of CBM include chronic lymphedema, ankylosis, and secondary bacterial infections, which largely are observed in advanced cases; malignant transformation to squamous cell carcinoma, though rare, also has been observed.⁶

Several therapeutic methods have been implemented in the treatment of CBM, but lesions often remain refractory, especially in advanced cases.⁶ Approaches to treatment can be divided into antifungal and physical methods. Commonly employed antifungal agents include itraconazole and terbinafine, which must be taken daily for a period ranging from 6 months to 1 year or longer; flucytosine with or without amphotericin also has been employed.⁴ Among the physical methods, surgical excision is not suggested due to possible dissemination of disease; other options include cryotherapy, thermotherapy, and laser vaporization.⁶ The prognosis has improved since the use of extended-spectrum triazoles, but high rates of refractory disease remain unchanged.²

The differential diagnosis includes other infections. Nocardiosis is a bacterial infection in which cutaneous disease can result in actinomycetoma, which presents with grains that are small, round, and stain blue on hematoxylin and eosin with eosinophilic rays at the periphery.⁷ Although the clinical features and pseudoepitheliomatous hyperplasia seen in CBM can mimic squamous cell carcinoma, the latter would show variable degrees of differentiation, keratinization, nuclear atypia, and architectural atypia with a negative tissue culture.⁸ Eumycetoma is a fungal infection that typically is not caused by F pedrosoi but rather most commonly Madurella mycetomatis.⁹ Leishmaniasis is a parasitic infection in which a biopsy of cutaneous lesions often displays parasite-filled histiocytes.¹⁰

Payer Advocacy in Dermatology

Frustrations with payers is a common source of annoyance among dermatologists. Payment rules can seem arbitrary, ever-changing, and not uniform among the various payers. Keeping track of payer requirements can be nearly impossible.

To assist members in handling these concerns, the American Academy of Dermatology Association (AADA) created the Patient Access and Payer Relations (PAPR) committee, which seeks to promote patient access to dermatologic care by addressing issues that may arise with private payers. The committee utilizes a multipronged approach to develop strategies to educate payers on the value of dermatology, addressing systematic payment issues as they arise over time, and building relationships with insurers and employers to promote coverage and payment policies allowing for the highest quality of dermatologic care. The committee is comprised of practicing dermatologists who meet regularly to help guide and implement the AADA’s payer advocacy initiatives.

Identifying payer contacts and forging working relationships is a cornerstone of payer advocacy. In addition to patient access to quality dermatologic services, fair reimbursement is always a primary concern.

Hot Topics in Payer Advocacy

How to Use Modifier −25 Appropriately—The AADA has been advocating for appropriate coverage and reimbursement for services billed by dermatologists; recent examples include assuring appropriate payment for services reported with modifier −25, which is used when a procedure such as a biopsy is performed on the same day as a separate and unrelated evaluation and management (E/M) service, such as psoriasis management. Some payers claim the concurrent nature of the services results in an overlap of office expenses such that these claims should be paid at a lesser amount; however, when procedure codes are frequently billed in association with an office visit, that overlap has already been accounted for as part of the code valuation process, negating the need for additional reduction.

The AADA PAPR committee has created numerous resources for our members to ensure they are using modifier −25 appropriately, particularly now that the US Department of Health and Human Services Office of the Inspector General (OIG) has announced a work plan to audit dermatologists claims reporting modifier −25.¹ The AADA immediately formed a work group, including PAPR committee members, to develop and employ a strategy to educate key decision-makers on the correct use of modifier −25 and highlight appropriate resources to guide members. An introductory call was held with the OIG audit team to discuss the appropriate use of modifier −25 in dermatology as the OIG prepares to develop the parameters of its audit sometime in the future (AADA, unpublished data, 2021).

Working With Dermatology Societies on Payer Issues—The American Academy of Dermatology Association PAPR committee works collaboratively with members of the American Academy of Dermatology, state and local dermatology societies, and private payers to alleviate administrative burdens for dermatologists, maintain appropriate reimbursement for furnished services, and ensure patients can access covered quality care. Collaboration with state dermatology societies is essential to address payer issues that impact their members and provide guidance on effective engagement with their state payers. Recent examples include working with dermatology societies in Massachusetts, Rhode Island, and Florida on strategies to advocate against modifier −25 payment reductions by insurance carriers (AADA, unpublished data, 2021). Additionally, the AADA PAPR committee has been able to provide guidance and technical support as needed to state dermatology societies, such as to the Rhode Island Dermatology Society and the Pennsylvania Academy of Dermatology and Dermatologic Surgery to address payer quality metrics and access to laboratory services, respectively (AADA, unpublished data, 2021).

Patient Access to Affordable Treatments—American Academy of Dermatology Association payer advocacy is anchored to published position statements and clinical guidelines. To strengthen AADA advocacy on payer-mandated drug substitutions for nonmedical reasons and to preserve patient access to medications, the PAPR committee collaborated with the American Academy of Dermatology’s Drug Pricing and Transparency Task Force to update the AADA Position Statement on Patient Access to Affordable Treatments² to address this issue. Essentially, patients who are stable on a medication should be allowed to keep using the same medication without payers changing their coverage for nonmedical reasons or by offering financial incentives to switch.

E/M Coding Issues

Another issue under consideration by several national insurers is E/M-level reassignment. Payers are reviewing claims from providers who are identified as coding at a higher E/M level as compared to their specialty peers. Some insurance carriers are using proprietary algorithms that attempt to link specific diagnoses to certain levels of E/M, triggering claim edits within their claim processing systems (AADA, unpublished data, 2021). The carrier will then either deny the claim or adjust reimbursement to a lower-level E/M service. In discussions with a national carrier on its E/M Leveling Program, the AADA has offered to work with them on appropriate E/M documentation and reporting (AADA, unpublished data, 2021). The AADA also has extensive member resources for guidance on E/M reporting as well as preparing for audits and appealing payer downcoding developed by the coding staff in conjunction with the Coding and Reimbursement Committee.

Recent Efforts From the AADA

Within the AADA, the PAPR committee works closely with the coding, practice management, and regulatory teams to address payer issues and develop resources for members. Recent examples include resources for dermatology practices on the No Surprises Act and what practices need to do to comply (AADA, unpublished data, 2021). The PAPR committee also works collaboratively with other AADA committees and task forces on payer issues as needed; for example, the PAPR committee has been working with the Dermatopathology Rapid Response committee to address member concerns regarding access to the pathology laboratory of their choice. Many payers are seeking to consolidate and save money by requiring the use of preferred laboratories, which impacts patient access to physician office laboratories and physician-recommended reference laboratories. The AADA, along with other medical specialties, has advocated for payers to not create a restrictive network of pathology laboratories within their provider networks and to support dermatologists’ laboratories of choice (AADA, unpublished data, 2021).

Within the payer space, the role of employers in impacting payment and coverage policies continues to rise. In 2021, the AADA leadership approved the employer outreach strategy to engage employers. The overall objectives are to advocate to employers on the value of dermatologic care and access to care provided by board-certified dermatologists. This is a long-term project that is just getting underway (AADA, unpublished data, 2021).

Payer Resource Center for AADA Members

To ensure that AADA members have the resources they need to advocate with payers as well as to keep the PAPR committee aware of emerging payer issues, the AADA created a new private payer resource center for members (https://www.aad.org/member/advocacy/priorities/payer-advocacy), which assists AADA members with common dermatologic concerns with insurers as well as contracting issues. The website also includes an email address for members to report payer issues (privatepayer@aad.org). This information helps the PAPR committee identify and prioritize issues of concern.

Final Thoughts

Given the control that private insurance companies exert over the health care that dermatology patients can access, the AADA in general and the PAPR committee specifically play a valuable role in advocating access to care for dermatology patients.

Payer Advocacy in Dermatology

Frustrations with payers is a common source of annoyance among dermatologists. Payment rules can seem arbitrary, ever-changing, and not uniform among the various payers. Keeping track of payer requirements can be nearly impossible.

To assist members in handling these concerns, the American Academy of Dermatology Association (AADA) created the Patient Access and Payer Relations (PAPR) committee, which seeks to promote patient access to dermatologic care by addressing issues that may arise with private payers. The committee utilizes a multipronged approach to develop strategies to educate payers on the value of dermatology, addressing systematic payment issues as they arise over time, and building relationships with insurers and employers to promote coverage and payment policies allowing for the highest quality of dermatologic care. The committee is comprised of practicing dermatologists who meet regularly to help guide and implement the AADA’s payer advocacy initiatives.

Identifying payer contacts and forging working relationships is a cornerstone of payer advocacy. In addition to patient access to quality dermatologic services, fair reimbursement is always a primary concern.

Hot Topics in Payer Advocacy

How to Use Modifier −25 Appropriately—The AADA has been advocating for appropriate coverage and reimbursement for services billed by dermatologists; recent examples include assuring appropriate payment for services reported with modifier −25, which is used when a procedure such as a biopsy is performed on the same day as a separate and unrelated evaluation and management (E/M) service, such as psoriasis management. Some payers claim the concurrent nature of the services results in an overlap of office expenses such that these claims should be paid at a lesser amount; however, when procedure codes are frequently billed in association with an office visit, that overlap has already been accounted for as part of the code valuation process, negating the need for additional reduction.

The AADA PAPR committee has created numerous resources for our members to ensure they are using modifier −25 appropriately, particularly now that the US Department of Health and Human Services Office of the Inspector General (OIG) has announced a work plan to audit dermatologists claims reporting modifier −25.¹ The AADA immediately formed a work group, including PAPR committee members, to develop and employ a strategy to educate key decision-makers on the correct use of modifier −25 and highlight appropriate resources to guide members. An introductory call was held with the OIG audit team to discuss the appropriate use of modifier −25 in dermatology as the OIG prepares to develop the parameters of its audit sometime in the future (AADA, unpublished data, 2021).

Working With Dermatology Societies on Payer Issues—The American Academy of Dermatology Association PAPR committee works collaboratively with members of the American Academy of Dermatology, state and local dermatology societies, and private payers to alleviate administrative burdens for dermatologists, maintain appropriate reimbursement for furnished services, and ensure patients can access covered quality care. Collaboration with state dermatology societies is essential to address payer issues that impact their members and provide guidance on effective engagement with their state payers. Recent examples include working with dermatology societies in Massachusetts, Rhode Island, and Florida on strategies to advocate against modifier −25 payment reductions by insurance carriers (AADA, unpublished data, 2021). Additionally, the AADA PAPR committee has been able to provide guidance and technical support as needed to state dermatology societies, such as to the Rhode Island Dermatology Society and the Pennsylvania Academy of Dermatology and Dermatologic Surgery to address payer quality metrics and access to laboratory services, respectively (AADA, unpublished data, 2021).

Patient Access to Affordable Treatments—American Academy of Dermatology Association payer advocacy is anchored to published position statements and clinical guidelines. To strengthen AADA advocacy on payer-mandated drug substitutions for nonmedical reasons and to preserve patient access to medications, the PAPR committee collaborated with the American Academy of Dermatology’s Drug Pricing and Transparency Task Force to update the AADA Position Statement on Patient Access to Affordable Treatments² to address this issue. Essentially, patients who are stable on a medication should be allowed to keep using the same medication without payers changing their coverage for nonmedical reasons or by offering financial incentives to switch.

E/M Coding Issues

Another issue under consideration by several national insurers is E/M-level reassignment. Payers are reviewing claims from providers who are identified as coding at a higher E/M level as compared to their specialty peers. Some insurance carriers are using proprietary algorithms that attempt to link specific diagnoses to certain levels of E/M, triggering claim edits within their claim processing systems (AADA, unpublished data, 2021). The carrier will then either deny the claim or adjust reimbursement to a lower-level E/M service. In discussions with a national carrier on its E/M Leveling Program, the AADA has offered to work with them on appropriate E/M documentation and reporting (AADA, unpublished data, 2021). The AADA also has extensive member resources for guidance on E/M reporting as well as preparing for audits and appealing payer downcoding developed by the coding staff in conjunction with the Coding and Reimbursement Committee.

Recent Efforts From the AADA

Within the AADA, the PAPR committee works closely with the coding, practice management, and regulatory teams to address payer issues and develop resources for members. Recent examples include resources for dermatology practices on the No Surprises Act and what practices need to do to comply (AADA, unpublished data, 2021). The PAPR committee also works collaboratively with other AADA committees and task forces on payer issues as needed; for example, the PAPR committee has been working with the Dermatopathology Rapid Response committee to address member concerns regarding access to the pathology laboratory of their choice. Many payers are seeking to consolidate and save money by requiring the use of preferred laboratories, which impacts patient access to physician office laboratories and physician-recommended reference laboratories. The AADA, along with other medical specialties, has advocated for payers to not create a restrictive network of pathology laboratories within their provider networks and to support dermatologists’ laboratories of choice (AADA, unpublished data, 2021).

Within the payer space, the role of employers in impacting payment and coverage policies continues to rise. In 2021, the AADA leadership approved the employer outreach strategy to engage employers. The overall objectives are to advocate to employers on the value of dermatologic care and access to care provided by board-certified dermatologists. This is a long-term project that is just getting underway (AADA, unpublished data, 2021).

Payer Resource Center for AADA Members

To ensure that AADA members have the resources they need to advocate with payers as well as to keep the PAPR committee aware of emerging payer issues, the AADA created a new private payer resource center for members (https://www.aad.org/member/advocacy/priorities/payer-advocacy), which assists AADA members with common dermatologic concerns with insurers as well as contracting issues. The website also includes an email address for members to report payer issues (privatepayer@aad.org). This information helps the PAPR committee identify and prioritize issues of concern.

Final Thoughts

Given the control that private insurance companies exert over the health care that dermatology patients can access, the AADA in general and the PAPR committee specifically play a valuable role in advocating access to care for dermatology patients.

Payer Advocacy in Dermatology

Frustrations with payers is a common source of annoyance among dermatologists. Payment rules can seem arbitrary, ever-changing, and not uniform among the various payers. Keeping track of payer requirements can be nearly impossible.

To assist members in handling these concerns, the American Academy of Dermatology Association (AADA) created the Patient Access and Payer Relations (PAPR) committee, which seeks to promote patient access to dermatologic care by addressing issues that may arise with private payers. The committee utilizes a multipronged approach to develop strategies to educate payers on the value of dermatology, addressing systematic payment issues as they arise over time, and building relationships with insurers and employers to promote coverage and payment policies allowing for the highest quality of dermatologic care. The committee is comprised of practicing dermatologists who meet regularly to help guide and implement the AADA’s payer advocacy initiatives.

Identifying payer contacts and forging working relationships is a cornerstone of payer advocacy. In addition to patient access to quality dermatologic services, fair reimbursement is always a primary concern.

Hot Topics in Payer Advocacy

How to Use Modifier −25 Appropriately—The AADA has been advocating for appropriate coverage and reimbursement for services billed by dermatologists; recent examples include assuring appropriate payment for services reported with modifier −25, which is used when a procedure such as a biopsy is performed on the same day as a separate and unrelated evaluation and management (E/M) service, such as psoriasis management. Some payers claim the concurrent nature of the services results in an overlap of office expenses such that these claims should be paid at a lesser amount; however, when procedure codes are frequently billed in association with an office visit, that overlap has already been accounted for as part of the code valuation process, negating the need for additional reduction.

The AADA PAPR committee has created numerous resources for our members to ensure they are using modifier −25 appropriately, particularly now that the US Department of Health and Human Services Office of the Inspector General (OIG) has announced a work plan to audit dermatologists claims reporting modifier −25.¹ The AADA immediately formed a work group, including PAPR committee members, to develop and employ a strategy to educate key decision-makers on the correct use of modifier −25 and highlight appropriate resources to guide members. An introductory call was held with the OIG audit team to discuss the appropriate use of modifier −25 in dermatology as the OIG prepares to develop the parameters of its audit sometime in the future (AADA, unpublished data, 2021).

Working With Dermatology Societies on Payer Issues—The American Academy of Dermatology Association PAPR committee works collaboratively with members of the American Academy of Dermatology, state and local dermatology societies, and private payers to alleviate administrative burdens for dermatologists, maintain appropriate reimbursement for furnished services, and ensure patients can access covered quality care. Collaboration with state dermatology societies is essential to address payer issues that impact their members and provide guidance on effective engagement with their state payers. Recent examples include working with dermatology societies in Massachusetts, Rhode Island, and Florida on strategies to advocate against modifier −25 payment reductions by insurance carriers (AADA, unpublished data, 2021). Additionally, the AADA PAPR committee has been able to provide guidance and technical support as needed to state dermatology societies, such as to the Rhode Island Dermatology Society and the Pennsylvania Academy of Dermatology and Dermatologic Surgery to address payer quality metrics and access to laboratory services, respectively (AADA, unpublished data, 2021).

Patient Access to Affordable Treatments—American Academy of Dermatology Association payer advocacy is anchored to published position statements and clinical guidelines. To strengthen AADA advocacy on payer-mandated drug substitutions for nonmedical reasons and to preserve patient access to medications, the PAPR committee collaborated with the American Academy of Dermatology’s Drug Pricing and Transparency Task Force to update the AADA Position Statement on Patient Access to Affordable Treatments² to address this issue. Essentially, patients who are stable on a medication should be allowed to keep using the same medication without payers changing their coverage for nonmedical reasons or by offering financial incentives to switch.

E/M Coding Issues

Another issue under consideration by several national insurers is E/M-level reassignment. Payers are reviewing claims from providers who are identified as coding at a higher E/M level as compared to their specialty peers. Some insurance carriers are using proprietary algorithms that attempt to link specific diagnoses to certain levels of E/M, triggering claim edits within their claim processing systems (AADA, unpublished data, 2021). The carrier will then either deny the claim or adjust reimbursement to a lower-level E/M service. In discussions with a national carrier on its E/M Leveling Program, the AADA has offered to work with them on appropriate E/M documentation and reporting (AADA, unpublished data, 2021). The AADA also has extensive member resources for guidance on E/M reporting as well as preparing for audits and appealing payer downcoding developed by the coding staff in conjunction with the Coding and Reimbursement Committee.

Recent Efforts From the AADA

Within the AADA, the PAPR committee works closely with the coding, practice management, and regulatory teams to address payer issues and develop resources for members. Recent examples include resources for dermatology practices on the No Surprises Act and what practices need to do to comply (AADA, unpublished data, 2021). The PAPR committee also works collaboratively with other AADA committees and task forces on payer issues as needed; for example, the PAPR committee has been working with the Dermatopathology Rapid Response committee to address member concerns regarding access to the pathology laboratory of their choice. Many payers are seeking to consolidate and save money by requiring the use of preferred laboratories, which impacts patient access to physician office laboratories and physician-recommended reference laboratories. The AADA, along with other medical specialties, has advocated for payers to not create a restrictive network of pathology laboratories within their provider networks and to support dermatologists’ laboratories of choice (AADA, unpublished data, 2021).

Within the payer space, the role of employers in impacting payment and coverage policies continues to rise. In 2021, the AADA leadership approved the employer outreach strategy to engage employers. The overall objectives are to advocate to employers on the value of dermatologic care and access to care provided by board-certified dermatologists. This is a long-term project that is just getting underway (AADA, unpublished data, 2021).

Payer Resource Center for AADA Members

To ensure that AADA members have the resources they need to advocate with payers as well as to keep the PAPR committee aware of emerging payer issues, the AADA created a new private payer resource center for members (https://www.aad.org/member/advocacy/priorities/payer-advocacy), which assists AADA members with common dermatologic concerns with insurers as well as contracting issues. The website also includes an email address for members to report payer issues (privatepayer@aad.org). This information helps the PAPR committee identify and prioritize issues of concern.

Final Thoughts

Given the control that private insurance companies exert over the health care that dermatology patients can access, the AADA in general and the PAPR committee specifically play a valuable role in advocating access to care for dermatology patients.

Photographs courtesy of Richard P. Usatine, MD (Figure A), and Tizita Yosef Kidane, MD (Figure B).

THE COMPARISON

A Nodular basal cell carcinoma (BCC) with a pearly rolled border, central pigmentation, and telangiectasia on the forehead of an 80-year-old Hispanic woman (light skin tone).

B Nodular BCC on the cheek of a 64-year-old Black man. The dark nonhealing ulcer had a subtle, pearly, rolled border and no visible telangiectasia.

Basal cell carcinoma is most prevalent in individuals with lighter skin tones and rarely affects those with darker skin tones. Unfortunately, the lower incidence and lack of surveillance frequently result in a delayed diagnosis and increased morbidity for the skin of color population.¹

Epidemiology

Basal cell carcinoma is the most common skin cancer in White, Asian, and Hispanic individuals and the second most common in Black individuals. Squamous cell carcinoma is the most common skin cancer in Black individuals.²

Although BCCs are rare in individuals with darker skin tones, they most often develop in sun-exposed areas of the head and neck region.¹ In one study in an academic urban medical center, BCCs were more likely to occur in lightly pigmented vs darkly pigmented Black individuals.³

Key clinical features in people with darker skin tones

The classic BCC manifestation of a pearly papule with rolled borders and telangiectasia may not be seen in the skin of color population, especially among those with darker skin tones.⁴ In patient A, a Hispanic woman, these features are present along with hyperpigmentation. More than 50% of BCCs are pigmented in patients with skin of color vs only 5% in White individuals.^5-7 The incidence of a pigmented BCC is twice as frequent in Hispanic individuals (Figure, A) as in non-Hispanic White individuals.⁷ Any skin cancer can present with ulcerations, so while this is not specific to BCC, it is a reason to consider biopsy.

Worth noting

Pigmented BCC can mimic melanoma clinically and even when viewed with a dermatoscope, but such a suspicious lesion should prompt the clinician to perform a biopsy regardless of the type of suspected cancer. With experience and training, however, physicians can use dermoscopy to help make this distinction.

Note that skin of color is found in a heterogeneous population with a spectrum of skin tones and genetic/ ethnic variability. In my practice in San Antonio (R.P.U.), BCC is uncommon in Black patients and relatively common in Hispanic patients with lighter skin tones (Figure, A). There is speculation that a lower incidence of BCC in the skin of color population leads to a low index of suspicion, which contributes to delayed diagnoses with poorer outcomes. ¹ There are no firm data to support this because the rare occurrence of BCC in darker skin tones makes this a challenge to study.

Health disparity highlight

In general, barriers to health care include poverty, lack of education, lack of health insurance, and systemic racism. One study on keratinocyte skin cancers including BCC and SCC found that these cancers were more costly to treat and required more health care resources, such as ambulatory visits and medication costs, in non-Hispanic Black and Hispanic White patients compared to non- Hispanic White patients.⁸

Final thoughts

Efforts are needed to achieve health equity through education of patients and health care providers about the appearance of BCC in skin of color with the goal of earlier diagnosis. Any nonhealing ulcer on the skin (Figure, B) should prompt consideration of skin cancer regardless of skin color.

Photographs courtesy of Richard P. Usatine, MD (Figure A), and Tizita Yosef Kidane, MD (Figure B).

THE COMPARISON

A Nodular basal cell carcinoma (BCC) with a pearly rolled border, central pigmentation, and telangiectasia on the forehead of an 80-year-old Hispanic woman (light skin tone).

B Nodular BCC on the cheek of a 64-year-old Black man. The dark nonhealing ulcer had a subtle, pearly, rolled border and no visible telangiectasia.

Basal cell carcinoma is most prevalent in individuals with lighter skin tones and rarely affects those with darker skin tones. Unfortunately, the lower incidence and lack of surveillance frequently result in a delayed diagnosis and increased morbidity for the skin of color population.¹

Epidemiology

Basal cell carcinoma is the most common skin cancer in White, Asian, and Hispanic individuals and the second most common in Black individuals. Squamous cell carcinoma is the most common skin cancer in Black individuals.²

Although BCCs are rare in individuals with darker skin tones, they most often develop in sun-exposed areas of the head and neck region.¹ In one study in an academic urban medical center, BCCs were more likely to occur in lightly pigmented vs darkly pigmented Black individuals.³

Key clinical features in people with darker skin tones

The classic BCC manifestation of a pearly papule with rolled borders and telangiectasia may not be seen in the skin of color population, especially among those with darker skin tones.⁴ In patient A, a Hispanic woman, these features are present along with hyperpigmentation. More than 50% of BCCs are pigmented in patients with skin of color vs only 5% in White individuals.^5-7 The incidence of a pigmented BCC is twice as frequent in Hispanic individuals (Figure, A) as in non-Hispanic White individuals.⁷ Any skin cancer can present with ulcerations, so while this is not specific to BCC, it is a reason to consider biopsy.

Worth noting

Pigmented BCC can mimic melanoma clinically and even when viewed with a dermatoscope, but such a suspicious lesion should prompt the clinician to perform a biopsy regardless of the type of suspected cancer. With experience and training, however, physicians can use dermoscopy to help make this distinction.

Note that skin of color is found in a heterogeneous population with a spectrum of skin tones and genetic/ ethnic variability. In my practice in San Antonio (R.P.U.), BCC is uncommon in Black patients and relatively common in Hispanic patients with lighter skin tones (Figure, A). There is speculation that a lower incidence of BCC in the skin of color population leads to a low index of suspicion, which contributes to delayed diagnoses with poorer outcomes. ¹ There are no firm data to support this because the rare occurrence of BCC in darker skin tones makes this a challenge to study.

Health disparity highlight

In general, barriers to health care include poverty, lack of education, lack of health insurance, and systemic racism. One study on keratinocyte skin cancers including BCC and SCC found that these cancers were more costly to treat and required more health care resources, such as ambulatory visits and medication costs, in non-Hispanic Black and Hispanic White patients compared to non- Hispanic White patients.⁸

Final thoughts

Efforts are needed to achieve health equity through education of patients and health care providers about the appearance of BCC in skin of color with the goal of earlier diagnosis. Any nonhealing ulcer on the skin (Figure, B) should prompt consideration of skin cancer regardless of skin color.

Photographs courtesy of Richard P. Usatine, MD (Figure A), and Tizita Yosef Kidane, MD (Figure B).

THE COMPARISON

A Nodular basal cell carcinoma (BCC) with a pearly rolled border, central pigmentation, and telangiectasia on the forehead of an 80-year-old Hispanic woman (light skin tone).

B Nodular BCC on the cheek of a 64-year-old Black man. The dark nonhealing ulcer had a subtle, pearly, rolled border and no visible telangiectasia.

Basal cell carcinoma is most prevalent in individuals with lighter skin tones and rarely affects those with darker skin tones. Unfortunately, the lower incidence and lack of surveillance frequently result in a delayed diagnosis and increased morbidity for the skin of color population.¹

Epidemiology

Basal cell carcinoma is the most common skin cancer in White, Asian, and Hispanic individuals and the second most common in Black individuals. Squamous cell carcinoma is the most common skin cancer in Black individuals.²

Although BCCs are rare in individuals with darker skin tones, they most often develop in sun-exposed areas of the head and neck region.¹ In one study in an academic urban medical center, BCCs were more likely to occur in lightly pigmented vs darkly pigmented Black individuals.³

Key clinical features in people with darker skin tones

The classic BCC manifestation of a pearly papule with rolled borders and telangiectasia may not be seen in the skin of color population, especially among those with darker skin tones.⁴ In patient A, a Hispanic woman, these features are present along with hyperpigmentation. More than 50% of BCCs are pigmented in patients with skin of color vs only 5% in White individuals.^5-7 The incidence of a pigmented BCC is twice as frequent in Hispanic individuals (Figure, A) as in non-Hispanic White individuals.⁷ Any skin cancer can present with ulcerations, so while this is not specific to BCC, it is a reason to consider biopsy.

Worth noting

Pigmented BCC can mimic melanoma clinically and even when viewed with a dermatoscope, but such a suspicious lesion should prompt the clinician to perform a biopsy regardless of the type of suspected cancer. With experience and training, however, physicians can use dermoscopy to help make this distinction.

Note that skin of color is found in a heterogeneous population with a spectrum of skin tones and genetic/ ethnic variability. In my practice in San Antonio (R.P.U.), BCC is uncommon in Black patients and relatively common in Hispanic patients with lighter skin tones (Figure, A). There is speculation that a lower incidence of BCC in the skin of color population leads to a low index of suspicion, which contributes to delayed diagnoses with poorer outcomes. ¹ There are no firm data to support this because the rare occurrence of BCC in darker skin tones makes this a challenge to study.

Health disparity highlight

In general, barriers to health care include poverty, lack of education, lack of health insurance, and systemic racism. One study on keratinocyte skin cancers including BCC and SCC found that these cancers were more costly to treat and required more health care resources, such as ambulatory visits and medication costs, in non-Hispanic Black and Hispanic White patients compared to non- Hispanic White patients.⁸

Final thoughts

Efforts are needed to achieve health equity through education of patients and health care providers about the appearance of BCC in skin of color with the goal of earlier diagnosis. Any nonhealing ulcer on the skin (Figure, B) should prompt consideration of skin cancer regardless of skin color.