The smartphone and smartwatch have spun off multiple apps and platforms for remotely monitoring a host of disease states, including pulmonary diseases and sleep disorders, but, as with any emergent technology, pitfalls come along with the promise and potential.

Meanwhile, technology to remotely monitor respiratory diseases is advancing into other modalities. In recent months, researchers have reported on an artificial intelligence–aided home stethoscope to monitor asthma exacerbations and an ingestible electronic capsule, which has shown some facility for continuous, remote monitoring of sleep apnea and opioid induced respiratory depression.

American College of Chest Physicians

“Smartphones and wearable technology in health care are here to stay,” Mariam Louis, MD, pulmonologist and sleep medicine physician at the University of Florida Health and chair of the nonrespiratory sleep section of the Sleep Medicine Network with the American College of Chest Physicians, said in an interview.

“It is an exciting field, as it encourages patients to be actively involved in their medical care and can potentially offer more real-time feedback regarding the patient’s medical conditions,” she said. “There are currently many apps that are being used to monitor sleep and other diseases. However, the technology is still rudimentary, and much more research is needed to see if these apps are accurate and dependable.”

Studies in the past few months have reported on the accuracy of 18 wearable sleep-tracker devices, finding they overestimated sleep duration by 19 minutes on average (Sleep. 2023 Nov 8. doi: 10.1093/sleep/zsad288). Researchers in the United States also recently reported on the first human trial of an ingestible pill for monitoring sleep apnea that sends data to a receiving device up to six feet away (Device. 2023 Nov 17. doi: 10.1016/j.device.2023.100125), and a group in Poland reported than an AI-aided home stethoscope provided reliable information on asthma exacerbations in 149 patients (Ann Fam Med. 2023;21:517-25).

Targeting Challenges With Polysomnography

All of these technologies aim to overcome challenges with traditional devices, such as polysomnography (PSG) for evaluating sleep. Jaques Reifman, PhD, a senior research scientist at the U.S. Army Medical Research and Development Command in Fort Detrick, Maryland, led the study of 18 wearable sleep trackers. “Both polysomnography and sleep tracking devices in a sense are attempting to reach the same goal: they’re trying to estimate certain sleep parameters,” Dr. Reifman said in an interview.

U.S. Army Medical Research and Development Command

“But they use very different signals,” he added, noting that PSG uses electroencephalography (EEG) to measure electrical signals in the skull whereas most sleep trackers used an accelerometer to measure body movement. “As your wrist moves around, it determines if you are moving or not,” Dr. Reifman said.

“Each of them have their plusses and minuses,” he added. PSG, while it’s considered the gold standard for measuring sleep, isn’t a consumer product. “It generally requires a very sophisticated data acquisition system; they are laden with motion artifacts and you have to have software to remove them before you analyze the data,” Dr. Reifman said. “They generally require an expert to interpret the results, although lately there are a few AI-based algorithms that you can provide the EEG signals to and it does score those stages for you”

Sleep trackers, on the other hand, are consumer products. “They can be used outside the lab, and you can use them to record for long periods of time, which is not really possible with PSG,” Dr. Reifman said. “They are low cost, they are easy to use, small size, and folks have developed algorithms that can directly tell the consumer you slept seven hours last night.

“In that sense, they’re comfortable to use as opposed to using an almost-like shower cap with the EEG and face sensors as part of the PSG montage.”

However, what sleep trackers offer in convenience, they lack in accuracy. “There are things they just cannot do based on the limitations of the signals that they use,” Dr. Reifman said.

The study was actually a meta-analysis of 14 different studies that evaluated 18 different sleep-tracking devices in 364 patients. The meta-analysis found wide variability in accuracy between devices; for example, a 75-minute overestimation of sleep with one device and a one-minute overestimation with another.

And different studies reported variations with the same tracker or different models of a tracker. The Fitbit Charge 2, for example, was found to underestimate sleep by 12 minutes in one study and overestimate sleep by 9 minutes in another, while the Fitbit HR Charge was found to overestimate sleep by 52 minutes in a third study.

The meta-analysis found while sleep trackers have high sensitivity (>90%), they had a relatively low specificity (<50%), Dr. Reifman noted.

“Because they are mainly based on the acceleration of your wrist, if you are laying down in bed and motionless after a few minutes the device is going to think you’re asleep when in reality you’re just motionless, daydreaming or trying to go to sleep but not sleeping, so the specificity to sleep is not that high,” he said.

These types of devices still have obstacles to overcome before they’re more widely used, Dr. Louis said. “All of these technologies are proprietary,” she said. “As such, little is known about the algorithms used to come up with the diagnosis or other conclusions. In addition, the majority of the data cannot be analyzed independently by the providers, limiting some of the usage of these devices for now.”

 

Early Study of Ingestible Capsule

To overcome some of those challenges with collecting data from wearables, researchers from the Massachusetts Institute of Technology and West Virginia University have worked with Celero Systems to develop a pill-sized capsule the patient swallows and which then collects vitals data from inside the gastrointestinal tract. The first in-human study evaluated the device, called the vitals-monitoring (VM) pill, in 10 patients. The study reported the data captured by the pill aligned with that gathered with standard sleep metrics and that it could detect sleep apnea episodes.

The study described the pill as a wireless device that uses a custom configuration of four off-the shelf integrated circuits — a microcontroller, accelerometer, memory component and radio signal — and electronic sensors for ballistic measurements from within the GI tract. The accelerometer measures movement of the abdomen during breathing.

Ingestible devices have actually been around for a couple of decades. The most common, the PillCam, is mostly used by gastroenterologists to capture images of the small intestine.

In the VM pill study, 3 of the 10 human volunteers had a diagnosis of either central or obstructive sleep apnea and wore a continuous positive airway pressure device during the study. The patients also had PSG. The study found that the heart rate accuracy of the VM pill was within 2.5 beats per minute of the PSG measure. The study found no significant difference in the ability of the VM pill to accurately measure respiratory rate with or without CPAP.

Since study completion, the device has been evaluated in another 10 patients, Ben Pless, CEO of Celero Systems, the company developing the VM pill and a coauthor of the study, said in an interview. All patients passed the capsule without any adverse events, he said.

Celero Systems

The capsule carries the advantages of an implantable device without the surgery, Mr. Pless said. “In addition to the product being inside body, it is very good at measuring core temperature and, of course, there are diurnal variations in core temperature,” he said. “Even though this was not in the paper, we found the combination of  monitoring respiration and core temperature is a very powerful way to do sleep staging in a completely unobtrusive and discrete way.”

The first study evaluated the overnight use of the VM pill, but future studies will evaluate longer duration of the device, first up to a week and then extending out to a month, with the goal of collecting data through the entire duration, Mr. Pless said.

“If you want to do ongoing monitoring for events that may have a low incidence, for example COPD exacerbations or some asthma which does not occur every day and you want to do long-term monitoring, an ingestible format where you ultimately take one capsule and you’re monitored for a month in a completely unobtrusive way would be a great way to do patient monitoring,” he said.

This platform could also collect multinight data for sleep studies, he added.

“While this is an exciting technology, there is much more to diagnosing sleep apnea than just heart rate and breathing,” Dr. Louis said. “During a sleep study, we look at oxygen levels, snoring, and many other variables.”

 
 

AI-Aided Stethoscope

The AI-aided stethoscope demonstrated an ability to collect reliable information on asthma exacerbations, the study in Poland found. “The parameters provided are effective for children, especially those younger than 5 years of age,” the study authors wrote.

The study enrolled patients of various ages with asthma, using the AI-aided stethoscope to monitor asthma-related physiologic parameters at home for six months. The stethoscope recorded auscultatory sounds from standard chest point and sent them to a dedicated mobile phone application in which an AI module automatically analyzed the recordings and displayed the results. The researchers trained the AI module using more than 10,000 recordings of respiratory sounds.

The study showed that a host of parameters — wheezes, rhonchi, coarse and fine crackles, heart rate, respiratory rate and inspiration-to-expiration duration ration — measured with the AI-aided stethoscope can detect asthma exacerbations without the need for obtaining peak expiratory flow measurements. It also showed a potential to make asthma diagnosis more straightforward in younger children.

“As we learn more and refine these technologies, we will be able to offer more patient centered and precise medicine to our patients, tailored specifically to their needs,” Dr. Louis said. “AI will certainly play a part in the future.”

Dr. Louis and Dr. Reifman have no relevant relationships to disclose. Mr. Pless is CEO of Celero Systems, a privately held company in Lincoln, Mass.

The smartphone and smartwatch have spun off multiple apps and platforms for remotely monitoring a host of disease states, including pulmonary diseases and sleep disorders, but, as with any emergent technology, pitfalls come along with the promise and potential.

Meanwhile, technology to remotely monitor respiratory diseases is advancing into other modalities. In recent months, researchers have reported on an artificial intelligence–aided home stethoscope to monitor asthma exacerbations and an ingestible electronic capsule, which has shown some facility for continuous, remote monitoring of sleep apnea and opioid induced respiratory depression.

American College of Chest Physicians

“Smartphones and wearable technology in health care are here to stay,” Mariam Louis, MD, pulmonologist and sleep medicine physician at the University of Florida Health and chair of the nonrespiratory sleep section of the Sleep Medicine Network with the American College of Chest Physicians, said in an interview.

“It is an exciting field, as it encourages patients to be actively involved in their medical care and can potentially offer more real-time feedback regarding the patient’s medical conditions,” she said. “There are currently many apps that are being used to monitor sleep and other diseases. However, the technology is still rudimentary, and much more research is needed to see if these apps are accurate and dependable.”

Studies in the past few months have reported on the accuracy of 18 wearable sleep-tracker devices, finding they overestimated sleep duration by 19 minutes on average (Sleep. 2023 Nov 8. doi: 10.1093/sleep/zsad288). Researchers in the United States also recently reported on the first human trial of an ingestible pill for monitoring sleep apnea that sends data to a receiving device up to six feet away (Device. 2023 Nov 17. doi: 10.1016/j.device.2023.100125), and a group in Poland reported than an AI-aided home stethoscope provided reliable information on asthma exacerbations in 149 patients (Ann Fam Med. 2023;21:517-25).

Targeting Challenges With Polysomnography

All of these technologies aim to overcome challenges with traditional devices, such as polysomnography (PSG) for evaluating sleep. Jaques Reifman, PhD, a senior research scientist at the U.S. Army Medical Research and Development Command in Fort Detrick, Maryland, led the study of 18 wearable sleep trackers. “Both polysomnography and sleep tracking devices in a sense are attempting to reach the same goal: they’re trying to estimate certain sleep parameters,” Dr. Reifman said in an interview.

U.S. Army Medical Research and Development Command

“But they use very different signals,” he added, noting that PSG uses electroencephalography (EEG) to measure electrical signals in the skull whereas most sleep trackers used an accelerometer to measure body movement. “As your wrist moves around, it determines if you are moving or not,” Dr. Reifman said.

“Each of them have their plusses and minuses,” he added. PSG, while it’s considered the gold standard for measuring sleep, isn’t a consumer product. “It generally requires a very sophisticated data acquisition system; they are laden with motion artifacts and you have to have software to remove them before you analyze the data,” Dr. Reifman said. “They generally require an expert to interpret the results, although lately there are a few AI-based algorithms that you can provide the EEG signals to and it does score those stages for you”

Sleep trackers, on the other hand, are consumer products. “They can be used outside the lab, and you can use them to record for long periods of time, which is not really possible with PSG,” Dr. Reifman said. “They are low cost, they are easy to use, small size, and folks have developed algorithms that can directly tell the consumer you slept seven hours last night.

“In that sense, they’re comfortable to use as opposed to using an almost-like shower cap with the EEG and face sensors as part of the PSG montage.”

However, what sleep trackers offer in convenience, they lack in accuracy. “There are things they just cannot do based on the limitations of the signals that they use,” Dr. Reifman said.

The study was actually a meta-analysis of 14 different studies that evaluated 18 different sleep-tracking devices in 364 patients. The meta-analysis found wide variability in accuracy between devices; for example, a 75-minute overestimation of sleep with one device and a one-minute overestimation with another.

And different studies reported variations with the same tracker or different models of a tracker. The Fitbit Charge 2, for example, was found to underestimate sleep by 12 minutes in one study and overestimate sleep by 9 minutes in another, while the Fitbit HR Charge was found to overestimate sleep by 52 minutes in a third study.

The meta-analysis found while sleep trackers have high sensitivity (>90%), they had a relatively low specificity (<50%), Dr. Reifman noted.

“Because they are mainly based on the acceleration of your wrist, if you are laying down in bed and motionless after a few minutes the device is going to think you’re asleep when in reality you’re just motionless, daydreaming or trying to go to sleep but not sleeping, so the specificity to sleep is not that high,” he said.

These types of devices still have obstacles to overcome before they’re more widely used, Dr. Louis said. “All of these technologies are proprietary,” she said. “As such, little is known about the algorithms used to come up with the diagnosis or other conclusions. In addition, the majority of the data cannot be analyzed independently by the providers, limiting some of the usage of these devices for now.”

 

Early Study of Ingestible Capsule

To overcome some of those challenges with collecting data from wearables, researchers from the Massachusetts Institute of Technology and West Virginia University have worked with Celero Systems to develop a pill-sized capsule the patient swallows and which then collects vitals data from inside the gastrointestinal tract. The first in-human study evaluated the device, called the vitals-monitoring (VM) pill, in 10 patients. The study reported the data captured by the pill aligned with that gathered with standard sleep metrics and that it could detect sleep apnea episodes.

The study described the pill as a wireless device that uses a custom configuration of four off-the shelf integrated circuits — a microcontroller, accelerometer, memory component and radio signal — and electronic sensors for ballistic measurements from within the GI tract. The accelerometer measures movement of the abdomen during breathing.

Ingestible devices have actually been around for a couple of decades. The most common, the PillCam, is mostly used by gastroenterologists to capture images of the small intestine.

In the VM pill study, 3 of the 10 human volunteers had a diagnosis of either central or obstructive sleep apnea and wore a continuous positive airway pressure device during the study. The patients also had PSG. The study found that the heart rate accuracy of the VM pill was within 2.5 beats per minute of the PSG measure. The study found no significant difference in the ability of the VM pill to accurately measure respiratory rate with or without CPAP.

Since study completion, the device has been evaluated in another 10 patients, Ben Pless, CEO of Celero Systems, the company developing the VM pill and a coauthor of the study, said in an interview. All patients passed the capsule without any adverse events, he said.

Celero Systems

The capsule carries the advantages of an implantable device without the surgery, Mr. Pless said. “In addition to the product being inside body, it is very good at measuring core temperature and, of course, there are diurnal variations in core temperature,” he said. “Even though this was not in the paper, we found the combination of  monitoring respiration and core temperature is a very powerful way to do sleep staging in a completely unobtrusive and discrete way.”

The first study evaluated the overnight use of the VM pill, but future studies will evaluate longer duration of the device, first up to a week and then extending out to a month, with the goal of collecting data through the entire duration, Mr. Pless said.

“If you want to do ongoing monitoring for events that may have a low incidence, for example COPD exacerbations or some asthma which does not occur every day and you want to do long-term monitoring, an ingestible format where you ultimately take one capsule and you’re monitored for a month in a completely unobtrusive way would be a great way to do patient monitoring,” he said.

This platform could also collect multinight data for sleep studies, he added.

“While this is an exciting technology, there is much more to diagnosing sleep apnea than just heart rate and breathing,” Dr. Louis said. “During a sleep study, we look at oxygen levels, snoring, and many other variables.”

 
 

AI-Aided Stethoscope

The AI-aided stethoscope demonstrated an ability to collect reliable information on asthma exacerbations, the study in Poland found. “The parameters provided are effective for children, especially those younger than 5 years of age,” the study authors wrote.

The study enrolled patients of various ages with asthma, using the AI-aided stethoscope to monitor asthma-related physiologic parameters at home for six months. The stethoscope recorded auscultatory sounds from standard chest point and sent them to a dedicated mobile phone application in which an AI module automatically analyzed the recordings and displayed the results. The researchers trained the AI module using more than 10,000 recordings of respiratory sounds.

The study showed that a host of parameters — wheezes, rhonchi, coarse and fine crackles, heart rate, respiratory rate and inspiration-to-expiration duration ration — measured with the AI-aided stethoscope can detect asthma exacerbations without the need for obtaining peak expiratory flow measurements. It also showed a potential to make asthma diagnosis more straightforward in younger children.

“As we learn more and refine these technologies, we will be able to offer more patient centered and precise medicine to our patients, tailored specifically to their needs,” Dr. Louis said. “AI will certainly play a part in the future.”

Dr. Louis and Dr. Reifman have no relevant relationships to disclose. Mr. Pless is CEO of Celero Systems, a privately held company in Lincoln, Mass.

The smartphone and smartwatch have spun off multiple apps and platforms for remotely monitoring a host of disease states, including pulmonary diseases and sleep disorders, but, as with any emergent technology, pitfalls come along with the promise and potential.

Meanwhile, technology to remotely monitor respiratory diseases is advancing into other modalities. In recent months, researchers have reported on an artificial intelligence–aided home stethoscope to monitor asthma exacerbations and an ingestible electronic capsule, which has shown some facility for continuous, remote monitoring of sleep apnea and opioid induced respiratory depression.

American College of Chest Physicians

“Smartphones and wearable technology in health care are here to stay,” Mariam Louis, MD, pulmonologist and sleep medicine physician at the University of Florida Health and chair of the nonrespiratory sleep section of the Sleep Medicine Network with the American College of Chest Physicians, said in an interview.

“It is an exciting field, as it encourages patients to be actively involved in their medical care and can potentially offer more real-time feedback regarding the patient’s medical conditions,” she said. “There are currently many apps that are being used to monitor sleep and other diseases. However, the technology is still rudimentary, and much more research is needed to see if these apps are accurate and dependable.”

Studies in the past few months have reported on the accuracy of 18 wearable sleep-tracker devices, finding they overestimated sleep duration by 19 minutes on average (Sleep. 2023 Nov 8. doi: 10.1093/sleep/zsad288). Researchers in the United States also recently reported on the first human trial of an ingestible pill for monitoring sleep apnea that sends data to a receiving device up to six feet away (Device. 2023 Nov 17. doi: 10.1016/j.device.2023.100125), and a group in Poland reported than an AI-aided home stethoscope provided reliable information on asthma exacerbations in 149 patients (Ann Fam Med. 2023;21:517-25).

Targeting Challenges With Polysomnography

All of these technologies aim to overcome challenges with traditional devices, such as polysomnography (PSG) for evaluating sleep. Jaques Reifman, PhD, a senior research scientist at the U.S. Army Medical Research and Development Command in Fort Detrick, Maryland, led the study of 18 wearable sleep trackers. “Both polysomnography and sleep tracking devices in a sense are attempting to reach the same goal: they’re trying to estimate certain sleep parameters,” Dr. Reifman said in an interview.

U.S. Army Medical Research and Development Command

“But they use very different signals,” he added, noting that PSG uses electroencephalography (EEG) to measure electrical signals in the skull whereas most sleep trackers used an accelerometer to measure body movement. “As your wrist moves around, it determines if you are moving or not,” Dr. Reifman said.

“Each of them have their plusses and minuses,” he added. PSG, while it’s considered the gold standard for measuring sleep, isn’t a consumer product. “It generally requires a very sophisticated data acquisition system; they are laden with motion artifacts and you have to have software to remove them before you analyze the data,” Dr. Reifman said. “They generally require an expert to interpret the results, although lately there are a few AI-based algorithms that you can provide the EEG signals to and it does score those stages for you”

Sleep trackers, on the other hand, are consumer products. “They can be used outside the lab, and you can use them to record for long periods of time, which is not really possible with PSG,” Dr. Reifman said. “They are low cost, they are easy to use, small size, and folks have developed algorithms that can directly tell the consumer you slept seven hours last night.

“In that sense, they’re comfortable to use as opposed to using an almost-like shower cap with the EEG and face sensors as part of the PSG montage.”

However, what sleep trackers offer in convenience, they lack in accuracy. “There are things they just cannot do based on the limitations of the signals that they use,” Dr. Reifman said.

The study was actually a meta-analysis of 14 different studies that evaluated 18 different sleep-tracking devices in 364 patients. The meta-analysis found wide variability in accuracy between devices; for example, a 75-minute overestimation of sleep with one device and a one-minute overestimation with another.

And different studies reported variations with the same tracker or different models of a tracker. The Fitbit Charge 2, for example, was found to underestimate sleep by 12 minutes in one study and overestimate sleep by 9 minutes in another, while the Fitbit HR Charge was found to overestimate sleep by 52 minutes in a third study.

The meta-analysis found while sleep trackers have high sensitivity (>90%), they had a relatively low specificity (<50%), Dr. Reifman noted.

“Because they are mainly based on the acceleration of your wrist, if you are laying down in bed and motionless after a few minutes the device is going to think you’re asleep when in reality you’re just motionless, daydreaming or trying to go to sleep but not sleeping, so the specificity to sleep is not that high,” he said.

These types of devices still have obstacles to overcome before they’re more widely used, Dr. Louis said. “All of these technologies are proprietary,” she said. “As such, little is known about the algorithms used to come up with the diagnosis or other conclusions. In addition, the majority of the data cannot be analyzed independently by the providers, limiting some of the usage of these devices for now.”

 

Early Study of Ingestible Capsule

To overcome some of those challenges with collecting data from wearables, researchers from the Massachusetts Institute of Technology and West Virginia University have worked with Celero Systems to develop a pill-sized capsule the patient swallows and which then collects vitals data from inside the gastrointestinal tract. The first in-human study evaluated the device, called the vitals-monitoring (VM) pill, in 10 patients. The study reported the data captured by the pill aligned with that gathered with standard sleep metrics and that it could detect sleep apnea episodes.

The study described the pill as a wireless device that uses a custom configuration of four off-the shelf integrated circuits — a microcontroller, accelerometer, memory component and radio signal — and electronic sensors for ballistic measurements from within the GI tract. The accelerometer measures movement of the abdomen during breathing.

Ingestible devices have actually been around for a couple of decades. The most common, the PillCam, is mostly used by gastroenterologists to capture images of the small intestine.

In the VM pill study, 3 of the 10 human volunteers had a diagnosis of either central or obstructive sleep apnea and wore a continuous positive airway pressure device during the study. The patients also had PSG. The study found that the heart rate accuracy of the VM pill was within 2.5 beats per minute of the PSG measure. The study found no significant difference in the ability of the VM pill to accurately measure respiratory rate with or without CPAP.

Since study completion, the device has been evaluated in another 10 patients, Ben Pless, CEO of Celero Systems, the company developing the VM pill and a coauthor of the study, said in an interview. All patients passed the capsule without any adverse events, he said.

Celero Systems

The capsule carries the advantages of an implantable device without the surgery, Mr. Pless said. “In addition to the product being inside body, it is very good at measuring core temperature and, of course, there are diurnal variations in core temperature,” he said. “Even though this was not in the paper, we found the combination of  monitoring respiration and core temperature is a very powerful way to do sleep staging in a completely unobtrusive and discrete way.”

The first study evaluated the overnight use of the VM pill, but future studies will evaluate longer duration of the device, first up to a week and then extending out to a month, with the goal of collecting data through the entire duration, Mr. Pless said.

“If you want to do ongoing monitoring for events that may have a low incidence, for example COPD exacerbations or some asthma which does not occur every day and you want to do long-term monitoring, an ingestible format where you ultimately take one capsule and you’re monitored for a month in a completely unobtrusive way would be a great way to do patient monitoring,” he said.

This platform could also collect multinight data for sleep studies, he added.

“While this is an exciting technology, there is much more to diagnosing sleep apnea than just heart rate and breathing,” Dr. Louis said. “During a sleep study, we look at oxygen levels, snoring, and many other variables.”

 
 

AI-Aided Stethoscope

The AI-aided stethoscope demonstrated an ability to collect reliable information on asthma exacerbations, the study in Poland found. “The parameters provided are effective for children, especially those younger than 5 years of age,” the study authors wrote.

The study enrolled patients of various ages with asthma, using the AI-aided stethoscope to monitor asthma-related physiologic parameters at home for six months. The stethoscope recorded auscultatory sounds from standard chest point and sent them to a dedicated mobile phone application in which an AI module automatically analyzed the recordings and displayed the results. The researchers trained the AI module using more than 10,000 recordings of respiratory sounds.

The study showed that a host of parameters — wheezes, rhonchi, coarse and fine crackles, heart rate, respiratory rate and inspiration-to-expiration duration ration — measured with the AI-aided stethoscope can detect asthma exacerbations without the need for obtaining peak expiratory flow measurements. It also showed a potential to make asthma diagnosis more straightforward in younger children.

“As we learn more and refine these technologies, we will be able to offer more patient centered and precise medicine to our patients, tailored specifically to their needs,” Dr. Louis said. “AI will certainly play a part in the future.”

Dr. Louis and Dr. Reifman have no relevant relationships to disclose. Mr. Pless is CEO of Celero Systems, a privately held company in Lincoln, Mass.

As medical students, we often assume we are exempt from the diagnoses we learn about. During the first 2 years of medical school, we learn about alopecia as a condition that may be associated with stress, hormonal imbalances, nutrient deficiencies, and aging. However, our curricula do not explore the subtypes, psychosocial impact, or even the overwhelming number of Black women who are disproportionately affected by alopecia. For Black women, hair is a colossal part of their cultural identity, learning from a young age how to nurture and style natural coils. It becomes devastating when women begin to lose them. 

The diagnosis of alopecia subtypes in Black women has been explored in the literature; however, understanding the unique experiences of young Black women is an important part of patient care, as alopecia often is destructive to the patient’s self-image. Therefore, it is important to shed light on these experiences so others feel empowered and supported in their journeys. Herein, we share the experiences of 2 authors (J.D. and C.A.V.O.)—both young Black women—who navigated unexpected hair loss in medical school.

Jewell’s Story

During my first year of medical school, I noticed my hair was shedding more than usual, and my ponytail was not as thick as it once was. I also had an area in my crown that was abnormally thin. My parents suggested that it was a consequence of stress, but I knew something was not right. With only 1 Black dermatologist within 2 hours of Nashville, Tennessee, I remember worrying about seeing a dermatologist who did not understand Black hair. I still scheduled an appointment, but I remember debating if I should straighten my hair or wear my naturally curly Afro. The first dermatologist I saw diagnosed me with seborrheic dermatitis—without even examining my scalp. She told me that I had a “full head of hair” and that I had nothing to worry about. I was unconvinced. Weeks later, I met with another dermatologist who took the time to listen to my concerns. After a scalp biopsy and laboratory work, she diagnosed me with telogen effluvium and androgenetic alopecia. Months later, I had the opportunity to visit the Black dermatologist, and she diagnosed me with central centrifugal cicatricial alopecia. I am grateful for the earlier dermatologists I saw, but I finally feel at ease with my diagnosis and treatment plan after being seen by the latter.

Chidubem’s Story 

From a young age, I was conditioned to think my hair was thick, unmanageable, and a nuisance. I grew accustomed to people yanking on my hair, and my gentle whispers of “this hurts” and “the braid is too tight” being ignored. That continued into adulthood. While studying for the US Medical Licensing Examination, I noticed a burning sensation on my scalp. I decided to ignore it. However, as the days progressed, the slight burning sensation turned into intense burning and itching. I still ignored it. Not only did I lack the funds for a dermatology appointment, but my licensing examination was approaching, and it was more important than anything related to my hair. After the examination, I eventually made an appointment with my primary care physician, who attributed my symptoms to the stressors of medical school. “I think you are having migraines,” she told me. So, I continued to ignore my symptoms. A year passed, and a hair braider pointed out that I had 2 well-defined bald patches on my scalp. I remember feeling angry and confused as to how I missed those findings. I could no longer ignore it—it bothered me less when no one else knew about it. I quickly made a dermatology appointment. Although I opted out of a biopsy, we decided to treat my hair loss empirically, and I have experienced drastic improvement.

Final Thoughts

We are 2 Black women living more than 500 miles away from each other at different medical institutions, yet we share the same experience, which many other women unfortunately face alone. It is not uncommon for us to feel unheard, dismissed, or misdiagnosed. We write this for the Black woman sorting through the feelings of confusion and shock as she traces the hairless spot on her scalp. We write this for the medical student ignoring their symptoms until after their examination. We even write this for any nondermatologists uncomfortable with diagnosing and treating textured hair. To improve patient satisfaction and overall health outcomes, physicians must approach patients with both knowledge and cultural competency. Most importantly, dermatologists (and other physicians) should be appropriately trained in not only the structural differences of textured hair but also the unique practices and beliefs among Black women in relation to their hair.

Acknowledgments—Jewell Dinkins is the inaugural recipient of the Janssen–Skin of Color Research Fellowship at Howard University (Washington, DC), and Chidubem A.V. Okeke is the inaugural recipient of the Women’s Dermatologic Society–La Roche-Posay dermatology fellowship at Howard University.

As medical students, we often assume we are exempt from the diagnoses we learn about. During the first 2 years of medical school, we learn about alopecia as a condition that may be associated with stress, hormonal imbalances, nutrient deficiencies, and aging. However, our curricula do not explore the subtypes, psychosocial impact, or even the overwhelming number of Black women who are disproportionately affected by alopecia. For Black women, hair is a colossal part of their cultural identity, learning from a young age how to nurture and style natural coils. It becomes devastating when women begin to lose them. 

The diagnosis of alopecia subtypes in Black women has been explored in the literature; however, understanding the unique experiences of young Black women is an important part of patient care, as alopecia often is destructive to the patient’s self-image. Therefore, it is important to shed light on these experiences so others feel empowered and supported in their journeys. Herein, we share the experiences of 2 authors (J.D. and C.A.V.O.)—both young Black women—who navigated unexpected hair loss in medical school.

Jewell’s Story

During my first year of medical school, I noticed my hair was shedding more than usual, and my ponytail was not as thick as it once was. I also had an area in my crown that was abnormally thin. My parents suggested that it was a consequence of stress, but I knew something was not right. With only 1 Black dermatologist within 2 hours of Nashville, Tennessee, I remember worrying about seeing a dermatologist who did not understand Black hair. I still scheduled an appointment, but I remember debating if I should straighten my hair or wear my naturally curly Afro. The first dermatologist I saw diagnosed me with seborrheic dermatitis—without even examining my scalp. She told me that I had a “full head of hair” and that I had nothing to worry about. I was unconvinced. Weeks later, I met with another dermatologist who took the time to listen to my concerns. After a scalp biopsy and laboratory work, she diagnosed me with telogen effluvium and androgenetic alopecia. Months later, I had the opportunity to visit the Black dermatologist, and she diagnosed me with central centrifugal cicatricial alopecia. I am grateful for the earlier dermatologists I saw, but I finally feel at ease with my diagnosis and treatment plan after being seen by the latter.

Chidubem’s Story 

From a young age, I was conditioned to think my hair was thick, unmanageable, and a nuisance. I grew accustomed to people yanking on my hair, and my gentle whispers of “this hurts” and “the braid is too tight” being ignored. That continued into adulthood. While studying for the US Medical Licensing Examination, I noticed a burning sensation on my scalp. I decided to ignore it. However, as the days progressed, the slight burning sensation turned into intense burning and itching. I still ignored it. Not only did I lack the funds for a dermatology appointment, but my licensing examination was approaching, and it was more important than anything related to my hair. After the examination, I eventually made an appointment with my primary care physician, who attributed my symptoms to the stressors of medical school. “I think you are having migraines,” she told me. So, I continued to ignore my symptoms. A year passed, and a hair braider pointed out that I had 2 well-defined bald patches on my scalp. I remember feeling angry and confused as to how I missed those findings. I could no longer ignore it—it bothered me less when no one else knew about it. I quickly made a dermatology appointment. Although I opted out of a biopsy, we decided to treat my hair loss empirically, and I have experienced drastic improvement.

Final Thoughts

We are 2 Black women living more than 500 miles away from each other at different medical institutions, yet we share the same experience, which many other women unfortunately face alone. It is not uncommon for us to feel unheard, dismissed, or misdiagnosed. We write this for the Black woman sorting through the feelings of confusion and shock as she traces the hairless spot on her scalp. We write this for the medical student ignoring their symptoms until after their examination. We even write this for any nondermatologists uncomfortable with diagnosing and treating textured hair. To improve patient satisfaction and overall health outcomes, physicians must approach patients with both knowledge and cultural competency. Most importantly, dermatologists (and other physicians) should be appropriately trained in not only the structural differences of textured hair but also the unique practices and beliefs among Black women in relation to their hair.

Acknowledgments—Jewell Dinkins is the inaugural recipient of the Janssen–Skin of Color Research Fellowship at Howard University (Washington, DC), and Chidubem A.V. Okeke is the inaugural recipient of the Women’s Dermatologic Society–La Roche-Posay dermatology fellowship at Howard University.

As medical students, we often assume we are exempt from the diagnoses we learn about. During the first 2 years of medical school, we learn about alopecia as a condition that may be associated with stress, hormonal imbalances, nutrient deficiencies, and aging. However, our curricula do not explore the subtypes, psychosocial impact, or even the overwhelming number of Black women who are disproportionately affected by alopecia. For Black women, hair is a colossal part of their cultural identity, learning from a young age how to nurture and style natural coils. It becomes devastating when women begin to lose them. 

The diagnosis of alopecia subtypes in Black women has been explored in the literature; however, understanding the unique experiences of young Black women is an important part of patient care, as alopecia often is destructive to the patient’s self-image. Therefore, it is important to shed light on these experiences so others feel empowered and supported in their journeys. Herein, we share the experiences of 2 authors (J.D. and C.A.V.O.)—both young Black women—who navigated unexpected hair loss in medical school.

Jewell’s Story

During my first year of medical school, I noticed my hair was shedding more than usual, and my ponytail was not as thick as it once was. I also had an area in my crown that was abnormally thin. My parents suggested that it was a consequence of stress, but I knew something was not right. With only 1 Black dermatologist within 2 hours of Nashville, Tennessee, I remember worrying about seeing a dermatologist who did not understand Black hair. I still scheduled an appointment, but I remember debating if I should straighten my hair or wear my naturally curly Afro. The first dermatologist I saw diagnosed me with seborrheic dermatitis—without even examining my scalp. She told me that I had a “full head of hair” and that I had nothing to worry about. I was unconvinced. Weeks later, I met with another dermatologist who took the time to listen to my concerns. After a scalp biopsy and laboratory work, she diagnosed me with telogen effluvium and androgenetic alopecia. Months later, I had the opportunity to visit the Black dermatologist, and she diagnosed me with central centrifugal cicatricial alopecia. I am grateful for the earlier dermatologists I saw, but I finally feel at ease with my diagnosis and treatment plan after being seen by the latter.

Chidubem’s Story 

From a young age, I was conditioned to think my hair was thick, unmanageable, and a nuisance. I grew accustomed to people yanking on my hair, and my gentle whispers of “this hurts” and “the braid is too tight” being ignored. That continued into adulthood. While studying for the US Medical Licensing Examination, I noticed a burning sensation on my scalp. I decided to ignore it. However, as the days progressed, the slight burning sensation turned into intense burning and itching. I still ignored it. Not only did I lack the funds for a dermatology appointment, but my licensing examination was approaching, and it was more important than anything related to my hair. After the examination, I eventually made an appointment with my primary care physician, who attributed my symptoms to the stressors of medical school. “I think you are having migraines,” she told me. So, I continued to ignore my symptoms. A year passed, and a hair braider pointed out that I had 2 well-defined bald patches on my scalp. I remember feeling angry and confused as to how I missed those findings. I could no longer ignore it—it bothered me less when no one else knew about it. I quickly made a dermatology appointment. Although I opted out of a biopsy, we decided to treat my hair loss empirically, and I have experienced drastic improvement.

Final Thoughts

We are 2 Black women living more than 500 miles away from each other at different medical institutions, yet we share the same experience, which many other women unfortunately face alone. It is not uncommon for us to feel unheard, dismissed, or misdiagnosed. We write this for the Black woman sorting through the feelings of confusion and shock as she traces the hairless spot on her scalp. We write this for the medical student ignoring their symptoms until after their examination. We even write this for any nondermatologists uncomfortable with diagnosing and treating textured hair. To improve patient satisfaction and overall health outcomes, physicians must approach patients with both knowledge and cultural competency. Most importantly, dermatologists (and other physicians) should be appropriately trained in not only the structural differences of textured hair but also the unique practices and beliefs among Black women in relation to their hair.

Acknowledgments—Jewell Dinkins is the inaugural recipient of the Janssen–Skin of Color Research Fellowship at Howard University (Washington, DC), and Chidubem A.V. Okeke is the inaugural recipient of the Women’s Dermatologic Society–La Roche-Posay dermatology fellowship at Howard University.

To the Editor:

Lenalidomide is a thalidomide analogue used to treat various hematologic malignancies, including non-Hodgkin lymphoma, myelodysplastic syndrome, and multiple myeloma (MM).¹ Lenalidomide is referred to as a degrader therapeutic because it induces targeted protein degradation of disease-relevant proteins (eg, Ikaros family zinc finger protein 1 [IKZF1], Ikaros family zinc finger protein 3 [IKZF3], and casein kinase I isoform-α [CK1α]) as its primary mechanism of action.^1,2 Although cutaneous adverse events are relatively common among thalidomide analogues, the morphologic and histopathologic descriptions of these drug eruptions have not been fully elucidated.^3,4 We report a novel pityriasiform drug eruption followed by a clinical eruption suggestive of blaschkitis in a patient with MM who was being treated with lenalidomide.

A 76-year-old man presented to the dermatology clinic with a progressive, mildly pruritic eruption on the chest and axillae of 1 year’s duration. He had a medical history of chronic hepatitis B, malignant carcinoid tumor of the colon, prostate cancer, and MM. The eruption emerged 1 to 2 weeks after the patient started oral lenalidomide 10 mg/d and oral dexamethasone40 mg/wk following autologous stem cell transplantation for MM. The patient had not received any other therapy for MM.

Physical examination revealed multiple erythematous, hyperpigmented, scaly papules and plaques on the lateral chest and within the axillae (Figure 1). A skin biopsy from the left axilla demonstrated a mild lichenoid and perivascular lymphocytic infiltrate with scattered eosinophils, neutrophils, and extravasated erythrocytes. The overlying epidermis showed spongiosis with parakeratosis in addition to lymphocytic exocytosis (Figure 2). No fungal organisms were highlighted on periodic acid–Schiff staining. After this evaluation, we recommended that the patient discontinue lenalidomide and start taking a topical over-the-counter corticosteroid for 2 weeks. Over time, he noted marked improvement in the eruption and associated pruritus.

After a drug holiday of 2 months, the patient resumed a maintenance dosage of oral lenalidomide 10 mg/d. Four or 5 days after restarting lenalidomide, a pruritic eruption appeared that involved the axillae and the left lower abdomen, circling around to the left lower back. The axillary eruption resolved with a topical over-the-counter corticosteroid; the abdominal eruption persisted.

At the 3-month follow-up visit, physical examination revealed erythematous macules and papules that coalesced over a salmon-colored base along the lines of Blaschko extending from the left lower abdominal quadrant, crossing the left flank, and continuing to the left lower back without crossing the midline (Figure 3).

We recommended that the patient continue treatment through this eruption; he was instructed to apply a corticosteroid cream and resume lenalidomide at the maintenance dosage. A month later, he reported that the eruption and associated pruritus resolved with the corticosteroid cream and resumption of the maintenance dose of lenalidomide. The patient noted no further spread of the eruption.

Cutaneous adverse events are common following lenalidomide. In prior trials, the overall incidence of any-grade rash following lenalidomide exposure was 22% to 33%.⁵ A meta-analysis of 10 trials determined the overall incidence of all-grade and high-grade cutaneous adverse events after exposure to lenalidomide was 27.2% and 3.6%, respectively.⁶ Our case represents a pityriasiform eruption due to lenalidomide followed by a secondary eruption suggestive of blaschkitis.

The rash due to lenalidomide has been described as morbilliform, urticarial, dermatitic, acneform, and undefined.⁷ Lenalidomide-induced rash typically develops during the first month of therapy, similar to our patient’s presentation. It has even been observed in the first week of therapy.⁸ Severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.^5,6 Risk factors associated with rash secondary to lenalidomide include advanced age (≥70 years), presence of Bence-Jones protein-type MM in urine, and no prior chemotherapy.⁸ Our patient had 2 of these risk factors: advanced age and no prior chemotherapy for MM. The exact pathogenesis by which lenalidomide leads to a pityriasiform eruption, as in our patient, or to a rash in general is unclear. Studies have hypothesized that a lenalidomide-induced rash could be attributable to a delayed hypersensitivity type IV reaction or to a reaction related to the molecular mechanism of action of the drug.⁹

At the molecular level, the antimyeloma effects of lenalidomide include promoting degradation of transcription factors IKZF1 and IKZF3, which subsequently increases production of IL-2.^1,2,9 Recombinant IL-2 has been associated with an increased incidence of rash in other cancers.⁹ Overexpression of programmed death 1(PD-1) and its ligand (PD-L1) has been demonstrated in MM; lenalidomide has been shown to downregulate both PD-1 and PD-L1. Patients receiving PD-1 and PD-L1 inhibitors commonly have developed rash.⁹ However, the association between lenalidomide and its downregulation of PD-1 and PD-L1 leading to rash has not been fully elucidated. Given the multiple malignancies in our patient—MM, prostate cancer, malignant carcinoid tumor—an underlying paraneoplastic phenomenon may be possible. Additionally, because our patient initially received dexamethasone along with lenalidomide, the manifestation of the initial pityriasiform rash may have been less severe due to the steroid use. Although our patient underwent a 2-month drug holiday following the initial pityriasiform eruption, most lenalidomide-induced rashes do not necessitate discontinuation of the drug.^5,7

Our patient’s secondary drug eruption was clinically suggestive of lenalidomide-induced blaschkitis. A report of a German patient with plasmacytoma described a unilateral papular exanthem that developed 4 months after lenalidomide was initiated.¹⁰ The papular exanthem following the lines of Blaschko lines extended from that patient’s posterior left foot to the calf and on to the thigh and flank,¹⁰ which was more extensive than our patient’s eruption. Blaschkitis in this patient resolved with a corticosteroid cream and UV light therapy¹⁰; lenalidomide was not discontinued, similar to our patient.

The pathogenesis of our patient’s secondary eruption that preferentially involved the lines of Blaschko is unclear. After the initial pityriasiform eruption, the secondary eruption was blaschkitis. Distinguishing dermatomes from the lines of Blaschko, which are thought to represent pathways of epidermal cell migration and proliferation during embryologic development, is important. Genodermatoses such as incontinentia pigmenti and hypomelanosis of Ito involve the lines of Blaschko¹¹; other disorders in the differential diagnosis of linear configurations include linear lichen planus, linear cutaneous lupus erythematosus, linear morphea, and lichen striatus.¹¹ Notably, drug-induced blaschkitis is rare.

Cutaneous adverse reactions from thalidomide analogues are relatively common. Our case of lenalidomide-associated blaschkitis that developed following an initial pityriasiform drug eruption in a patient with MM highlights that dermatologists need to collaborate with the oncologist regarding the severity of drug eruptions to determine if the patient should continue treatment through the cutaneous eruptions or discontinue a vital medication.

To the Editor:

Lenalidomide is a thalidomide analogue used to treat various hematologic malignancies, including non-Hodgkin lymphoma, myelodysplastic syndrome, and multiple myeloma (MM).¹ Lenalidomide is referred to as a degrader therapeutic because it induces targeted protein degradation of disease-relevant proteins (eg, Ikaros family zinc finger protein 1 [IKZF1], Ikaros family zinc finger protein 3 [IKZF3], and casein kinase I isoform-α [CK1α]) as its primary mechanism of action.^1,2 Although cutaneous adverse events are relatively common among thalidomide analogues, the morphologic and histopathologic descriptions of these drug eruptions have not been fully elucidated.^3,4 We report a novel pityriasiform drug eruption followed by a clinical eruption suggestive of blaschkitis in a patient with MM who was being treated with lenalidomide.

A 76-year-old man presented to the dermatology clinic with a progressive, mildly pruritic eruption on the chest and axillae of 1 year’s duration. He had a medical history of chronic hepatitis B, malignant carcinoid tumor of the colon, prostate cancer, and MM. The eruption emerged 1 to 2 weeks after the patient started oral lenalidomide 10 mg/d and oral dexamethasone40 mg/wk following autologous stem cell transplantation for MM. The patient had not received any other therapy for MM.

Physical examination revealed multiple erythematous, hyperpigmented, scaly papules and plaques on the lateral chest and within the axillae (Figure 1). A skin biopsy from the left axilla demonstrated a mild lichenoid and perivascular lymphocytic infiltrate with scattered eosinophils, neutrophils, and extravasated erythrocytes. The overlying epidermis showed spongiosis with parakeratosis in addition to lymphocytic exocytosis (Figure 2). No fungal organisms were highlighted on periodic acid–Schiff staining. After this evaluation, we recommended that the patient discontinue lenalidomide and start taking a topical over-the-counter corticosteroid for 2 weeks. Over time, he noted marked improvement in the eruption and associated pruritus.

After a drug holiday of 2 months, the patient resumed a maintenance dosage of oral lenalidomide 10 mg/d. Four or 5 days after restarting lenalidomide, a pruritic eruption appeared that involved the axillae and the left lower abdomen, circling around to the left lower back. The axillary eruption resolved with a topical over-the-counter corticosteroid; the abdominal eruption persisted.

At the 3-month follow-up visit, physical examination revealed erythematous macules and papules that coalesced over a salmon-colored base along the lines of Blaschko extending from the left lower abdominal quadrant, crossing the left flank, and continuing to the left lower back without crossing the midline (Figure 3).

We recommended that the patient continue treatment through this eruption; he was instructed to apply a corticosteroid cream and resume lenalidomide at the maintenance dosage. A month later, he reported that the eruption and associated pruritus resolved with the corticosteroid cream and resumption of the maintenance dose of lenalidomide. The patient noted no further spread of the eruption.

Cutaneous adverse events are common following lenalidomide. In prior trials, the overall incidence of any-grade rash following lenalidomide exposure was 22% to 33%.⁵ A meta-analysis of 10 trials determined the overall incidence of all-grade and high-grade cutaneous adverse events after exposure to lenalidomide was 27.2% and 3.6%, respectively.⁶ Our case represents a pityriasiform eruption due to lenalidomide followed by a secondary eruption suggestive of blaschkitis.

The rash due to lenalidomide has been described as morbilliform, urticarial, dermatitic, acneform, and undefined.⁷ Lenalidomide-induced rash typically develops during the first month of therapy, similar to our patient’s presentation. It has even been observed in the first week of therapy.⁸ Severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.^5,6 Risk factors associated with rash secondary to lenalidomide include advanced age (≥70 years), presence of Bence-Jones protein-type MM in urine, and no prior chemotherapy.⁸ Our patient had 2 of these risk factors: advanced age and no prior chemotherapy for MM. The exact pathogenesis by which lenalidomide leads to a pityriasiform eruption, as in our patient, or to a rash in general is unclear. Studies have hypothesized that a lenalidomide-induced rash could be attributable to a delayed hypersensitivity type IV reaction or to a reaction related to the molecular mechanism of action of the drug.⁹

At the molecular level, the antimyeloma effects of lenalidomide include promoting degradation of transcription factors IKZF1 and IKZF3, which subsequently increases production of IL-2.^1,2,9 Recombinant IL-2 has been associated with an increased incidence of rash in other cancers.⁹ Overexpression of programmed death 1(PD-1) and its ligand (PD-L1) has been demonstrated in MM; lenalidomide has been shown to downregulate both PD-1 and PD-L1. Patients receiving PD-1 and PD-L1 inhibitors commonly have developed rash.⁹ However, the association between lenalidomide and its downregulation of PD-1 and PD-L1 leading to rash has not been fully elucidated. Given the multiple malignancies in our patient—MM, prostate cancer, malignant carcinoid tumor—an underlying paraneoplastic phenomenon may be possible. Additionally, because our patient initially received dexamethasone along with lenalidomide, the manifestation of the initial pityriasiform rash may have been less severe due to the steroid use. Although our patient underwent a 2-month drug holiday following the initial pityriasiform eruption, most lenalidomide-induced rashes do not necessitate discontinuation of the drug.^5,7

Our patient’s secondary drug eruption was clinically suggestive of lenalidomide-induced blaschkitis. A report of a German patient with plasmacytoma described a unilateral papular exanthem that developed 4 months after lenalidomide was initiated.¹⁰ The papular exanthem following the lines of Blaschko lines extended from that patient’s posterior left foot to the calf and on to the thigh and flank,¹⁰ which was more extensive than our patient’s eruption. Blaschkitis in this patient resolved with a corticosteroid cream and UV light therapy¹⁰; lenalidomide was not discontinued, similar to our patient.

The pathogenesis of our patient’s secondary eruption that preferentially involved the lines of Blaschko is unclear. After the initial pityriasiform eruption, the secondary eruption was blaschkitis. Distinguishing dermatomes from the lines of Blaschko, which are thought to represent pathways of epidermal cell migration and proliferation during embryologic development, is important. Genodermatoses such as incontinentia pigmenti and hypomelanosis of Ito involve the lines of Blaschko¹¹; other disorders in the differential diagnosis of linear configurations include linear lichen planus, linear cutaneous lupus erythematosus, linear morphea, and lichen striatus.¹¹ Notably, drug-induced blaschkitis is rare.

Cutaneous adverse reactions from thalidomide analogues are relatively common. Our case of lenalidomide-associated blaschkitis that developed following an initial pityriasiform drug eruption in a patient with MM highlights that dermatologists need to collaborate with the oncologist regarding the severity of drug eruptions to determine if the patient should continue treatment through the cutaneous eruptions or discontinue a vital medication.

To the Editor:

Lenalidomide is a thalidomide analogue used to treat various hematologic malignancies, including non-Hodgkin lymphoma, myelodysplastic syndrome, and multiple myeloma (MM).¹ Lenalidomide is referred to as a degrader therapeutic because it induces targeted protein degradation of disease-relevant proteins (eg, Ikaros family zinc finger protein 1 [IKZF1], Ikaros family zinc finger protein 3 [IKZF3], and casein kinase I isoform-α [CK1α]) as its primary mechanism of action.^1,2 Although cutaneous adverse events are relatively common among thalidomide analogues, the morphologic and histopathologic descriptions of these drug eruptions have not been fully elucidated.^3,4 We report a novel pityriasiform drug eruption followed by a clinical eruption suggestive of blaschkitis in a patient with MM who was being treated with lenalidomide.

A 76-year-old man presented to the dermatology clinic with a progressive, mildly pruritic eruption on the chest and axillae of 1 year’s duration. He had a medical history of chronic hepatitis B, malignant carcinoid tumor of the colon, prostate cancer, and MM. The eruption emerged 1 to 2 weeks after the patient started oral lenalidomide 10 mg/d and oral dexamethasone40 mg/wk following autologous stem cell transplantation for MM. The patient had not received any other therapy for MM.

Physical examination revealed multiple erythematous, hyperpigmented, scaly papules and plaques on the lateral chest and within the axillae (Figure 1). A skin biopsy from the left axilla demonstrated a mild lichenoid and perivascular lymphocytic infiltrate with scattered eosinophils, neutrophils, and extravasated erythrocytes. The overlying epidermis showed spongiosis with parakeratosis in addition to lymphocytic exocytosis (Figure 2). No fungal organisms were highlighted on periodic acid–Schiff staining. After this evaluation, we recommended that the patient discontinue lenalidomide and start taking a topical over-the-counter corticosteroid for 2 weeks. Over time, he noted marked improvement in the eruption and associated pruritus.

After a drug holiday of 2 months, the patient resumed a maintenance dosage of oral lenalidomide 10 mg/d. Four or 5 days after restarting lenalidomide, a pruritic eruption appeared that involved the axillae and the left lower abdomen, circling around to the left lower back. The axillary eruption resolved with a topical over-the-counter corticosteroid; the abdominal eruption persisted.

At the 3-month follow-up visit, physical examination revealed erythematous macules and papules that coalesced over a salmon-colored base along the lines of Blaschko extending from the left lower abdominal quadrant, crossing the left flank, and continuing to the left lower back without crossing the midline (Figure 3).

We recommended that the patient continue treatment through this eruption; he was instructed to apply a corticosteroid cream and resume lenalidomide at the maintenance dosage. A month later, he reported that the eruption and associated pruritus resolved with the corticosteroid cream and resumption of the maintenance dose of lenalidomide. The patient noted no further spread of the eruption.

Cutaneous adverse events are common following lenalidomide. In prior trials, the overall incidence of any-grade rash following lenalidomide exposure was 22% to 33%.⁵ A meta-analysis of 10 trials determined the overall incidence of all-grade and high-grade cutaneous adverse events after exposure to lenalidomide was 27.2% and 3.6%, respectively.⁶ Our case represents a pityriasiform eruption due to lenalidomide followed by a secondary eruption suggestive of blaschkitis.

The rash due to lenalidomide has been described as morbilliform, urticarial, dermatitic, acneform, and undefined.⁷ Lenalidomide-induced rash typically develops during the first month of therapy, similar to our patient’s presentation. It has even been observed in the first week of therapy.⁸ Severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.^5,6 Risk factors associated with rash secondary to lenalidomide include advanced age (≥70 years), presence of Bence-Jones protein-type MM in urine, and no prior chemotherapy.⁸ Our patient had 2 of these risk factors: advanced age and no prior chemotherapy for MM. The exact pathogenesis by which lenalidomide leads to a pityriasiform eruption, as in our patient, or to a rash in general is unclear. Studies have hypothesized that a lenalidomide-induced rash could be attributable to a delayed hypersensitivity type IV reaction or to a reaction related to the molecular mechanism of action of the drug.⁹

At the molecular level, the antimyeloma effects of lenalidomide include promoting degradation of transcription factors IKZF1 and IKZF3, which subsequently increases production of IL-2.^1,2,9 Recombinant IL-2 has been associated with an increased incidence of rash in other cancers.⁹ Overexpression of programmed death 1(PD-1) and its ligand (PD-L1) has been demonstrated in MM; lenalidomide has been shown to downregulate both PD-1 and PD-L1. Patients receiving PD-1 and PD-L1 inhibitors commonly have developed rash.⁹ However, the association between lenalidomide and its downregulation of PD-1 and PD-L1 leading to rash has not been fully elucidated. Given the multiple malignancies in our patient—MM, prostate cancer, malignant carcinoid tumor—an underlying paraneoplastic phenomenon may be possible. Additionally, because our patient initially received dexamethasone along with lenalidomide, the manifestation of the initial pityriasiform rash may have been less severe due to the steroid use. Although our patient underwent a 2-month drug holiday following the initial pityriasiform eruption, most lenalidomide-induced rashes do not necessitate discontinuation of the drug.^5,7

Our patient’s secondary drug eruption was clinically suggestive of lenalidomide-induced blaschkitis. A report of a German patient with plasmacytoma described a unilateral papular exanthem that developed 4 months after lenalidomide was initiated.¹⁰ The papular exanthem following the lines of Blaschko lines extended from that patient’s posterior left foot to the calf and on to the thigh and flank,¹⁰ which was more extensive than our patient’s eruption. Blaschkitis in this patient resolved with a corticosteroid cream and UV light therapy¹⁰; lenalidomide was not discontinued, similar to our patient.

The pathogenesis of our patient’s secondary eruption that preferentially involved the lines of Blaschko is unclear. After the initial pityriasiform eruption, the secondary eruption was blaschkitis. Distinguishing dermatomes from the lines of Blaschko, which are thought to represent pathways of epidermal cell migration and proliferation during embryologic development, is important. Genodermatoses such as incontinentia pigmenti and hypomelanosis of Ito involve the lines of Blaschko¹¹; other disorders in the differential diagnosis of linear configurations include linear lichen planus, linear cutaneous lupus erythematosus, linear morphea, and lichen striatus.¹¹ Notably, drug-induced blaschkitis is rare.

Cutaneous adverse reactions from thalidomide analogues are relatively common. Our case of lenalidomide-associated blaschkitis that developed following an initial pityriasiform drug eruption in a patient with MM highlights that dermatologists need to collaborate with the oncologist regarding the severity of drug eruptions to determine if the patient should continue treatment through the cutaneous eruptions or discontinue a vital medication.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

To the Editor:

Reactive angioendotheliomatosis (RAE) is a rare self-limited cutaneous vascular proliferation of endothelial cells within blood vessels that manifests clinically as infiltrated red-blue patches and plaques with purpura that can progress to occlude vascular lumina. The etiology of RAE is mostly idiopathic; however, the disorder typically occurs in association with a range of systemic diseases, including infection, cryoglobulinemia, leukemia, antiphospholipid syndrome, peripheral vascular disease, and arteriovenous fistula. Histopathologic examination of these lesions shows marked proliferation of endothelial cells, including occlusion of the lumen of blood vessels over wide areas.

After ruling out malignancy, treatment of RAE focuses on targeting the underlying cause or disease, if any is present; 75% of reported cases occur in association with systemic disease.¹ Onset can occur at any age without predilection for sex. Reactive angioendotheliomatosis commonly manifests on the extremities but may occur on the head and neck in rare instances.²

The rarity of the condition and its poorly defined clinical characteristics make it difficult to develop a treatment plan. There are no standardized treatment guidelines for the reactive form of angiomatosis. We report a case of RAE that developed 2 weeks after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson Innovative Medicine [formerly Janssen Pharmaceutical Companies of Johnson & Johnson]) that improved following 2 weeks of treatment with a topical corticosteroid and an oral antihistamine.

A 58-year-old man presented to an outpatient dermatology clinic with pruritus and occasional paresthesia associated with a rash over the left arm of 1 month’s duration. The patient suspected that the rash may have formed secondary to the bite of oak mites on the arms and chest while he was carrying milled wood. Further inquiry into the patient’s history revealed that he received the Ad26.COV2.S vaccine 2 weeks prior to the appearance of the rash. He denied mechanical trauma. His medical history included hypercholesterolemia and a mild COVID-19 infection 8 months prior to the appearance of the rash that did not require hospitalization. He denied fever or chills during the 2 weeks following vaccination. The pruritus was minimally relieved for short periods with over-the-counter calamine lotion. The patient’s medication regimen included daily pravastatin and loratadine at the time of the initial visit. He used acetaminophen as needed for knee pain.

Physical examination revealed palpable purpura in a dermatomal distribution with nonpitting edema over the left scapula (Figure 1A), left anterolateral shoulder, left lateral volar forearm, and thenar eminence of the left hand (Figure 1B). Notably, the entire right arm, conjunctivae, tongue, lips, and bilateral fingernails were clear. Three 4-mm punch biopsies were performed at the initial presentation: 1 perilesional biopsy for direct immunofluorescence testing and 2 lesional biopsies for routine histologic evaluation. An extensive serologic workup failed to reveal abnormalities. An activated partial thromboplastin time, dilute Russell viper venom time, serum protein electrophoresis, and levels of rheumatoid factor and angiotensin-converting enzyme were within reference range. Anticardiolipin antibodies IgA, IgM, and IgG were negative. A cryoglobulin test was negative.

Histopathology revealed a proliferation of irregularly shaped vascular spaces with plump endothelium in the papillary dermis (Figure 2). Scattered leukocyte common antigen-positive lymphocytes were noted within lesions. The epidermis appeared normal, without evidence of spongiosis or alteration of the stratum corneum. Immunohistochemical studies of the perilesional skin biopsy revealed positivity for CD31 and D2-40 (Figure 3). Specimens were negative for CD20 and human herpesvirus 8. Direct immunofluorescence of the perilesional biopsy was negative.

A diagnosis of RAE was made based on clinical and histologic findings. Treatment with triamcinolone ointment 0.1% twice daily and oral cetirizine 10 mg twice daily was initiated. Re-evaluation 2 weeks later revealed notable improvement in the affected areas, including decreased edema, improvement of the purpura, and absence of pruritus. The patient noted no further spread or blister formation while the active areas were being treated with the topical steroid. The treatment regimen was modified to triamcinolone ointment 0.1% once daily, and cetirizine was discontinued. At 3-month follow-up, active areas had completely resolved (Figure 4) and triamcinolone was discontinued. To date, the patient has not had recurrence of symptoms and remains healthy.

Gottron and Nikolowski³ reported the first case of RAE in an adult patient who presented with purpuric patches secondary to skin infarction. Current definitions use the umbrella term cutaneous reactive angiomatosis to cover 3 major subtypes: reactive angioendotheliomatosis, diffuse dermal angioendotheliomatosis, and acroangiodermatitis (pseudo-Kaposi sarcoma [KS]). The manifestation of these subgroups is clinically similar, and they must be differentiated through histologic evaluation.⁴

Reactive angioendotheliomatosis has an unknown pathogenesis and is poorly defined clinically. The exact pathophysiology is unknown but likely is linked to vaso-occlusion and hypoxia.¹ A PubMed search of articles indexed for MEDLINE, as well as a review of Science Direct, Google Scholar, and Cochrane Library, using the terms reactive angioendotheliomatosis, COVID, vaccine, Ad26.COV2.S, and RAE in any combination revealed no prior cases of RAE in association with Ad26.COV2.S vaccination.

By the late 1980s, systemic angioendotheliomatosis was segregated into 2 distinct entities: malignant and reactive.⁴ The differential diagnosis of malignant systemic angioendotheliomatosis includes KS and angiosarcoma; nonmalignant causes are the variants of cutaneous reactive angiomatosis. It is important to rule out KS because of its malignant and deceptive nature. It is unknown if KS originates in blood vessels or lymphatic endothelial cells; however, evidence is strongly in favor of blood vessel origin using CD31 and CD34 endothelial markers.⁵ CD34 positivity is more reliable than CD31 in diagnosing KS, but the absence of both markers does not offer enough evidence to rule out KS on its own.⁶

In our patient, histopathology revealed cells positive for CD31 and D2-40; the latter is a lymphatic endothelial cell marker that stains the endothelium of lymphatic channels but not blood vessels.⁷ Positive D2-40 can be indicative of KS and non-KS lesions, each with a distinct staining pattern. D2-40 staining on non-KS lesions is confined to lymphatic vessels, as it was in our patient; in contrast, spindle-shaped cells also will be stained in KS lesions.⁸

Another cell marker, CD20, is a B cell–specific protein that can be measured to help diagnose malignant diseases such as B-cell lymphoma and leukemia. Human herpesvirus 8 (also known as KS-associated herpesvirus) is the infectious cause of KS and traditionally has been detected using methods such as the polymerase chain reaction.^9,10

Most cases of RAE are idiopathic and occur in association with systemic disease, which was not the case in our patient. We speculated that his reaction was most likely triggered by vascular transfection of endothelial cells secondary to Ad26.COV2.S vaccination. Alternatively, vaccination may have caused vascular occlusion, though the lack of cyanosis, nail changes, and route of inoculant make this less likely.

All approved COVID-19 vaccines are designed solely for intramuscular injection. In comparison to other types of tissue, muscles have superior vascularity, allowing for enhanced mobilization of compounds, which results in faster systemic circulation.¹¹ Alternative methods of injection, including intravascular, subcutaneous, and intradermal, may lead to decreased efficacy or adverse events, or both.

Prior cases of RAE have been treated with laser therapy, topical or systemic corticosteroids, excisional removal, or topical β-blockers, such as timolol.¹²β-Blocking agents act on β-adrenergic receptors on endothelial cells to inhibit angiogenesis by reducing release of blood vessel growth-signaling molecules and triggering apoptosis. In this patient, topical steroids and oral antihistamines were sufficient treatment.

Vaccine-related adverse events have been reported but remain rare. The benefits of Ad26.COV2.S vaccination for protection against COVID-19 outweigh the extremely low risk for adverse events.¹³ For that reason, the Centers for Disease Control and Prevention recommends a booster for individuals who are eligible to maximize protection. Intramuscular injection of Ad26.COV2.S resulted in a lower incidence of moderate to severe COVID-19 cases in all age groups vs the placebo group. Hypersensitivity adverse events were reported in 0.4% of Ad26.COV2.S-vaccinated patients vs 0.4% of patients who received a placebo; the more common reactions were nonanaphylactic.¹³

There have been 12 reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, which sparked nationwide controversy over the safety of the Ad26.COV2.S vaccine.¹⁴ After further investigation into those reports, the US Food and Drug Administration and the Centers for Disease Control and Prevention concluded that the benefits of the Ad26.COV2.S vaccine outweigh the low risk for associated thrombosis.¹⁵

Although adverse reactions are rare, it is important that health care providers take proper safety measures before and while administering any COVID-19 vaccine. Patients should be screened for contraindications to the COVID-19 vaccine to mitigate adverse effects seen in the small percentage of patients who may need to take alternative precautions.

The broad tissue tropism and high transmissibility of SARS-CoV-2 are the main contributors to its infection having reached pandemic scale. The spike (S) protein on SARS-CoV-2 binds to ACE2, the most thoroughly studied SARS-CoV-2 receptor, which is found in a range of tissues, including arterial endothelial cells, leading to its transfection. Several studies have proposed that expression of the S protein causes endothelial dysfunction through cytokine release, activation of complement, and ultimately microvascular occlusion.¹⁶

Recent developments in the use of viral-like particles, such as vesicular stomatitis virus, may mitigate future cases of RAE that are associated with endothelial cell transfection. Vesicular stomatitis virus is a popular model virus for research applications due to its glycoprotein and matrix protein contributing to its broad tropism. Recent efforts to alter these proteins have successfully limited the broad tropism of vesicular stomatitis virus.¹⁷

The SARS-CoV-2 virus must be handled in a Biosafety Level 3 laboratory. Conversely, pseudoviruses can be handled in lower containment facilities due to their safe and efficacious nature, offering an avenue to expedite vaccine development against many viral outbreaks, including SARS-CoV-2.¹⁸

An increasing number of cutaneous manifestations have been associated with COVID-19 infection and vaccination. Eruptive pseudoangiomatosis, a rare self-limiting exanthem, has been reported in association with ­COVID-19 vaccination.¹⁹ Eruptive pseudoangiomatosis manifests as erythematous blanchable papules that resemble angiomas, typically in a widespread distribution. Eruptive pseudoangiomatosis has striking similarities to RAE histologically; both manifest as dilated dermal blood vessels with plump endothelial cells.

Our case is unique because of the vasculitic palpable nature of the lesions, which were localized to the left arm. Eruptive pseudoangiomatosis formation after COVID-19 infection or SARS-CoV-2 vaccination may suggest alteration of ACE2 by binding of S protein.²⁰ Such alteration of the ACE2 pathway would lead to inflammation of angiotensin II, causing proliferation of endothelial cells in the formation of angiomalike lesions. This hypothesis suggests a paraviral eruption secondary to an immunologic reaction, not a classical virtual eruption from direct contact of the virus on blood vessels. Although EPA and RAE are harmless and self-limiting, these reports will spread awareness of the increasing number of skin manifestations related to COVID-19 and SARS-CoV-2 virus vaccination.

Acknowledgment—Thoughtful insights and comments on this manuscript were provided by Christine J. Ko, MD (New Haven, Connecticut); Christine L. Egan, MD (Glen Mills, Pennsylvania); Howard A. Bueller, MD (Delray Beach, Florida); and Juan Pablo Robles, PhD (Juriquilla, Mexico).

To the Editor:

Reactive angioendotheliomatosis (RAE) is a rare self-limited cutaneous vascular proliferation of endothelial cells within blood vessels that manifests clinically as infiltrated red-blue patches and plaques with purpura that can progress to occlude vascular lumina. The etiology of RAE is mostly idiopathic; however, the disorder typically occurs in association with a range of systemic diseases, including infection, cryoglobulinemia, leukemia, antiphospholipid syndrome, peripheral vascular disease, and arteriovenous fistula. Histopathologic examination of these lesions shows marked proliferation of endothelial cells, including occlusion of the lumen of blood vessels over wide areas.

After ruling out malignancy, treatment of RAE focuses on targeting the underlying cause or disease, if any is present; 75% of reported cases occur in association with systemic disease.¹ Onset can occur at any age without predilection for sex. Reactive angioendotheliomatosis commonly manifests on the extremities but may occur on the head and neck in rare instances.²

The rarity of the condition and its poorly defined clinical characteristics make it difficult to develop a treatment plan. There are no standardized treatment guidelines for the reactive form of angiomatosis. We report a case of RAE that developed 2 weeks after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson Innovative Medicine [formerly Janssen Pharmaceutical Companies of Johnson & Johnson]) that improved following 2 weeks of treatment with a topical corticosteroid and an oral antihistamine.

A 58-year-old man presented to an outpatient dermatology clinic with pruritus and occasional paresthesia associated with a rash over the left arm of 1 month’s duration. The patient suspected that the rash may have formed secondary to the bite of oak mites on the arms and chest while he was carrying milled wood. Further inquiry into the patient’s history revealed that he received the Ad26.COV2.S vaccine 2 weeks prior to the appearance of the rash. He denied mechanical trauma. His medical history included hypercholesterolemia and a mild COVID-19 infection 8 months prior to the appearance of the rash that did not require hospitalization. He denied fever or chills during the 2 weeks following vaccination. The pruritus was minimally relieved for short periods with over-the-counter calamine lotion. The patient’s medication regimen included daily pravastatin and loratadine at the time of the initial visit. He used acetaminophen as needed for knee pain.

Physical examination revealed palpable purpura in a dermatomal distribution with nonpitting edema over the left scapula (Figure 1A), left anterolateral shoulder, left lateral volar forearm, and thenar eminence of the left hand (Figure 1B). Notably, the entire right arm, conjunctivae, tongue, lips, and bilateral fingernails were clear. Three 4-mm punch biopsies were performed at the initial presentation: 1 perilesional biopsy for direct immunofluorescence testing and 2 lesional biopsies for routine histologic evaluation. An extensive serologic workup failed to reveal abnormalities. An activated partial thromboplastin time, dilute Russell viper venom time, serum protein electrophoresis, and levels of rheumatoid factor and angiotensin-converting enzyme were within reference range. Anticardiolipin antibodies IgA, IgM, and IgG were negative. A cryoglobulin test was negative.

Histopathology revealed a proliferation of irregularly shaped vascular spaces with plump endothelium in the papillary dermis (Figure 2). Scattered leukocyte common antigen-positive lymphocytes were noted within lesions. The epidermis appeared normal, without evidence of spongiosis or alteration of the stratum corneum. Immunohistochemical studies of the perilesional skin biopsy revealed positivity for CD31 and D2-40 (Figure 3). Specimens were negative for CD20 and human herpesvirus 8. Direct immunofluorescence of the perilesional biopsy was negative.

A diagnosis of RAE was made based on clinical and histologic findings. Treatment with triamcinolone ointment 0.1% twice daily and oral cetirizine 10 mg twice daily was initiated. Re-evaluation 2 weeks later revealed notable improvement in the affected areas, including decreased edema, improvement of the purpura, and absence of pruritus. The patient noted no further spread or blister formation while the active areas were being treated with the topical steroid. The treatment regimen was modified to triamcinolone ointment 0.1% once daily, and cetirizine was discontinued. At 3-month follow-up, active areas had completely resolved (Figure 4) and triamcinolone was discontinued. To date, the patient has not had recurrence of symptoms and remains healthy.

Gottron and Nikolowski³ reported the first case of RAE in an adult patient who presented with purpuric patches secondary to skin infarction. Current definitions use the umbrella term cutaneous reactive angiomatosis to cover 3 major subtypes: reactive angioendotheliomatosis, diffuse dermal angioendotheliomatosis, and acroangiodermatitis (pseudo-Kaposi sarcoma [KS]). The manifestation of these subgroups is clinically similar, and they must be differentiated through histologic evaluation.⁴

Reactive angioendotheliomatosis has an unknown pathogenesis and is poorly defined clinically. The exact pathophysiology is unknown but likely is linked to vaso-occlusion and hypoxia.¹ A PubMed search of articles indexed for MEDLINE, as well as a review of Science Direct, Google Scholar, and Cochrane Library, using the terms reactive angioendotheliomatosis, COVID, vaccine, Ad26.COV2.S, and RAE in any combination revealed no prior cases of RAE in association with Ad26.COV2.S vaccination.

By the late 1980s, systemic angioendotheliomatosis was segregated into 2 distinct entities: malignant and reactive.⁴ The differential diagnosis of malignant systemic angioendotheliomatosis includes KS and angiosarcoma; nonmalignant causes are the variants of cutaneous reactive angiomatosis. It is important to rule out KS because of its malignant and deceptive nature. It is unknown if KS originates in blood vessels or lymphatic endothelial cells; however, evidence is strongly in favor of blood vessel origin using CD31 and CD34 endothelial markers.⁵ CD34 positivity is more reliable than CD31 in diagnosing KS, but the absence of both markers does not offer enough evidence to rule out KS on its own.⁶

In our patient, histopathology revealed cells positive for CD31 and D2-40; the latter is a lymphatic endothelial cell marker that stains the endothelium of lymphatic channels but not blood vessels.⁷ Positive D2-40 can be indicative of KS and non-KS lesions, each with a distinct staining pattern. D2-40 staining on non-KS lesions is confined to lymphatic vessels, as it was in our patient; in contrast, spindle-shaped cells also will be stained in KS lesions.⁸

Another cell marker, CD20, is a B cell–specific protein that can be measured to help diagnose malignant diseases such as B-cell lymphoma and leukemia. Human herpesvirus 8 (also known as KS-associated herpesvirus) is the infectious cause of KS and traditionally has been detected using methods such as the polymerase chain reaction.^9,10

Most cases of RAE are idiopathic and occur in association with systemic disease, which was not the case in our patient. We speculated that his reaction was most likely triggered by vascular transfection of endothelial cells secondary to Ad26.COV2.S vaccination. Alternatively, vaccination may have caused vascular occlusion, though the lack of cyanosis, nail changes, and route of inoculant make this less likely.

All approved COVID-19 vaccines are designed solely for intramuscular injection. In comparison to other types of tissue, muscles have superior vascularity, allowing for enhanced mobilization of compounds, which results in faster systemic circulation.¹¹ Alternative methods of injection, including intravascular, subcutaneous, and intradermal, may lead to decreased efficacy or adverse events, or both.

Prior cases of RAE have been treated with laser therapy, topical or systemic corticosteroids, excisional removal, or topical β-blockers, such as timolol.¹²β-Blocking agents act on β-adrenergic receptors on endothelial cells to inhibit angiogenesis by reducing release of blood vessel growth-signaling molecules and triggering apoptosis. In this patient, topical steroids and oral antihistamines were sufficient treatment.

Vaccine-related adverse events have been reported but remain rare. The benefits of Ad26.COV2.S vaccination for protection against COVID-19 outweigh the extremely low risk for adverse events.¹³ For that reason, the Centers for Disease Control and Prevention recommends a booster for individuals who are eligible to maximize protection. Intramuscular injection of Ad26.COV2.S resulted in a lower incidence of moderate to severe COVID-19 cases in all age groups vs the placebo group. Hypersensitivity adverse events were reported in 0.4% of Ad26.COV2.S-vaccinated patients vs 0.4% of patients who received a placebo; the more common reactions were nonanaphylactic.¹³

There have been 12 reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, which sparked nationwide controversy over the safety of the Ad26.COV2.S vaccine.¹⁴ After further investigation into those reports, the US Food and Drug Administration and the Centers for Disease Control and Prevention concluded that the benefits of the Ad26.COV2.S vaccine outweigh the low risk for associated thrombosis.¹⁵

Although adverse reactions are rare, it is important that health care providers take proper safety measures before and while administering any COVID-19 vaccine. Patients should be screened for contraindications to the COVID-19 vaccine to mitigate adverse effects seen in the small percentage of patients who may need to take alternative precautions.

The broad tissue tropism and high transmissibility of SARS-CoV-2 are the main contributors to its infection having reached pandemic scale. The spike (S) protein on SARS-CoV-2 binds to ACE2, the most thoroughly studied SARS-CoV-2 receptor, which is found in a range of tissues, including arterial endothelial cells, leading to its transfection. Several studies have proposed that expression of the S protein causes endothelial dysfunction through cytokine release, activation of complement, and ultimately microvascular occlusion.¹⁶

Recent developments in the use of viral-like particles, such as vesicular stomatitis virus, may mitigate future cases of RAE that are associated with endothelial cell transfection. Vesicular stomatitis virus is a popular model virus for research applications due to its glycoprotein and matrix protein contributing to its broad tropism. Recent efforts to alter these proteins have successfully limited the broad tropism of vesicular stomatitis virus.¹⁷

The SARS-CoV-2 virus must be handled in a Biosafety Level 3 laboratory. Conversely, pseudoviruses can be handled in lower containment facilities due to their safe and efficacious nature, offering an avenue to expedite vaccine development against many viral outbreaks, including SARS-CoV-2.¹⁸

An increasing number of cutaneous manifestations have been associated with COVID-19 infection and vaccination. Eruptive pseudoangiomatosis, a rare self-limiting exanthem, has been reported in association with ­COVID-19 vaccination.¹⁹ Eruptive pseudoangiomatosis manifests as erythematous blanchable papules that resemble angiomas, typically in a widespread distribution. Eruptive pseudoangiomatosis has striking similarities to RAE histologically; both manifest as dilated dermal blood vessels with plump endothelial cells.

Our case is unique because of the vasculitic palpable nature of the lesions, which were localized to the left arm. Eruptive pseudoangiomatosis formation after COVID-19 infection or SARS-CoV-2 vaccination may suggest alteration of ACE2 by binding of S protein.²⁰ Such alteration of the ACE2 pathway would lead to inflammation of angiotensin II, causing proliferation of endothelial cells in the formation of angiomalike lesions. This hypothesis suggests a paraviral eruption secondary to an immunologic reaction, not a classical virtual eruption from direct contact of the virus on blood vessels. Although EPA and RAE are harmless and self-limiting, these reports will spread awareness of the increasing number of skin manifestations related to COVID-19 and SARS-CoV-2 virus vaccination.

Acknowledgment—Thoughtful insights and comments on this manuscript were provided by Christine J. Ko, MD (New Haven, Connecticut); Christine L. Egan, MD (Glen Mills, Pennsylvania); Howard A. Bueller, MD (Delray Beach, Florida); and Juan Pablo Robles, PhD (Juriquilla, Mexico).

To the Editor:

Reactive angioendotheliomatosis (RAE) is a rare self-limited cutaneous vascular proliferation of endothelial cells within blood vessels that manifests clinically as infiltrated red-blue patches and plaques with purpura that can progress to occlude vascular lumina. The etiology of RAE is mostly idiopathic; however, the disorder typically occurs in association with a range of systemic diseases, including infection, cryoglobulinemia, leukemia, antiphospholipid syndrome, peripheral vascular disease, and arteriovenous fistula. Histopathologic examination of these lesions shows marked proliferation of endothelial cells, including occlusion of the lumen of blood vessels over wide areas.

After ruling out malignancy, treatment of RAE focuses on targeting the underlying cause or disease, if any is present; 75% of reported cases occur in association with systemic disease.¹ Onset can occur at any age without predilection for sex. Reactive angioendotheliomatosis commonly manifests on the extremities but may occur on the head and neck in rare instances.²

The rarity of the condition and its poorly defined clinical characteristics make it difficult to develop a treatment plan. There are no standardized treatment guidelines for the reactive form of angiomatosis. We report a case of RAE that developed 2 weeks after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson Innovative Medicine [formerly Janssen Pharmaceutical Companies of Johnson & Johnson]) that improved following 2 weeks of treatment with a topical corticosteroid and an oral antihistamine.

A 58-year-old man presented to an outpatient dermatology clinic with pruritus and occasional paresthesia associated with a rash over the left arm of 1 month’s duration. The patient suspected that the rash may have formed secondary to the bite of oak mites on the arms and chest while he was carrying milled wood. Further inquiry into the patient’s history revealed that he received the Ad26.COV2.S vaccine 2 weeks prior to the appearance of the rash. He denied mechanical trauma. His medical history included hypercholesterolemia and a mild COVID-19 infection 8 months prior to the appearance of the rash that did not require hospitalization. He denied fever or chills during the 2 weeks following vaccination. The pruritus was minimally relieved for short periods with over-the-counter calamine lotion. The patient’s medication regimen included daily pravastatin and loratadine at the time of the initial visit. He used acetaminophen as needed for knee pain.

Physical examination revealed palpable purpura in a dermatomal distribution with nonpitting edema over the left scapula (Figure 1A), left anterolateral shoulder, left lateral volar forearm, and thenar eminence of the left hand (Figure 1B). Notably, the entire right arm, conjunctivae, tongue, lips, and bilateral fingernails were clear. Three 4-mm punch biopsies were performed at the initial presentation: 1 perilesional biopsy for direct immunofluorescence testing and 2 lesional biopsies for routine histologic evaluation. An extensive serologic workup failed to reveal abnormalities. An activated partial thromboplastin time, dilute Russell viper venom time, serum protein electrophoresis, and levels of rheumatoid factor and angiotensin-converting enzyme were within reference range. Anticardiolipin antibodies IgA, IgM, and IgG were negative. A cryoglobulin test was negative.

Histopathology revealed a proliferation of irregularly shaped vascular spaces with plump endothelium in the papillary dermis (Figure 2). Scattered leukocyte common antigen-positive lymphocytes were noted within lesions. The epidermis appeared normal, without evidence of spongiosis or alteration of the stratum corneum. Immunohistochemical studies of the perilesional skin biopsy revealed positivity for CD31 and D2-40 (Figure 3). Specimens were negative for CD20 and human herpesvirus 8. Direct immunofluorescence of the perilesional biopsy was negative.

A diagnosis of RAE was made based on clinical and histologic findings. Treatment with triamcinolone ointment 0.1% twice daily and oral cetirizine 10 mg twice daily was initiated. Re-evaluation 2 weeks later revealed notable improvement in the affected areas, including decreased edema, improvement of the purpura, and absence of pruritus. The patient noted no further spread or blister formation while the active areas were being treated with the topical steroid. The treatment regimen was modified to triamcinolone ointment 0.1% once daily, and cetirizine was discontinued. At 3-month follow-up, active areas had completely resolved (Figure 4) and triamcinolone was discontinued. To date, the patient has not had recurrence of symptoms and remains healthy.

Gottron and Nikolowski³ reported the first case of RAE in an adult patient who presented with purpuric patches secondary to skin infarction. Current definitions use the umbrella term cutaneous reactive angiomatosis to cover 3 major subtypes: reactive angioendotheliomatosis, diffuse dermal angioendotheliomatosis, and acroangiodermatitis (pseudo-Kaposi sarcoma [KS]). The manifestation of these subgroups is clinically similar, and they must be differentiated through histologic evaluation.⁴

Reactive angioendotheliomatosis has an unknown pathogenesis and is poorly defined clinically. The exact pathophysiology is unknown but likely is linked to vaso-occlusion and hypoxia.¹ A PubMed search of articles indexed for MEDLINE, as well as a review of Science Direct, Google Scholar, and Cochrane Library, using the terms reactive angioendotheliomatosis, COVID, vaccine, Ad26.COV2.S, and RAE in any combination revealed no prior cases of RAE in association with Ad26.COV2.S vaccination.

By the late 1980s, systemic angioendotheliomatosis was segregated into 2 distinct entities: malignant and reactive.⁴ The differential diagnosis of malignant systemic angioendotheliomatosis includes KS and angiosarcoma; nonmalignant causes are the variants of cutaneous reactive angiomatosis. It is important to rule out KS because of its malignant and deceptive nature. It is unknown if KS originates in blood vessels or lymphatic endothelial cells; however, evidence is strongly in favor of blood vessel origin using CD31 and CD34 endothelial markers.⁵ CD34 positivity is more reliable than CD31 in diagnosing KS, but the absence of both markers does not offer enough evidence to rule out KS on its own.⁶

In our patient, histopathology revealed cells positive for CD31 and D2-40; the latter is a lymphatic endothelial cell marker that stains the endothelium of lymphatic channels but not blood vessels.⁷ Positive D2-40 can be indicative of KS and non-KS lesions, each with a distinct staining pattern. D2-40 staining on non-KS lesions is confined to lymphatic vessels, as it was in our patient; in contrast, spindle-shaped cells also will be stained in KS lesions.⁸

Another cell marker, CD20, is a B cell–specific protein that can be measured to help diagnose malignant diseases such as B-cell lymphoma and leukemia. Human herpesvirus 8 (also known as KS-associated herpesvirus) is the infectious cause of KS and traditionally has been detected using methods such as the polymerase chain reaction.^9,10

Most cases of RAE are idiopathic and occur in association with systemic disease, which was not the case in our patient. We speculated that his reaction was most likely triggered by vascular transfection of endothelial cells secondary to Ad26.COV2.S vaccination. Alternatively, vaccination may have caused vascular occlusion, though the lack of cyanosis, nail changes, and route of inoculant make this less likely.

All approved COVID-19 vaccines are designed solely for intramuscular injection. In comparison to other types of tissue, muscles have superior vascularity, allowing for enhanced mobilization of compounds, which results in faster systemic circulation.¹¹ Alternative methods of injection, including intravascular, subcutaneous, and intradermal, may lead to decreased efficacy or adverse events, or both.

Prior cases of RAE have been treated with laser therapy, topical or systemic corticosteroids, excisional removal, or topical β-blockers, such as timolol.¹²β-Blocking agents act on β-adrenergic receptors on endothelial cells to inhibit angiogenesis by reducing release of blood vessel growth-signaling molecules and triggering apoptosis. In this patient, topical steroids and oral antihistamines were sufficient treatment.

Vaccine-related adverse events have been reported but remain rare. The benefits of Ad26.COV2.S vaccination for protection against COVID-19 outweigh the extremely low risk for adverse events.¹³ For that reason, the Centers for Disease Control and Prevention recommends a booster for individuals who are eligible to maximize protection. Intramuscular injection of Ad26.COV2.S resulted in a lower incidence of moderate to severe COVID-19 cases in all age groups vs the placebo group. Hypersensitivity adverse events were reported in 0.4% of Ad26.COV2.S-vaccinated patients vs 0.4% of patients who received a placebo; the more common reactions were nonanaphylactic.¹³

There have been 12 reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, which sparked nationwide controversy over the safety of the Ad26.COV2.S vaccine.¹⁴ After further investigation into those reports, the US Food and Drug Administration and the Centers for Disease Control and Prevention concluded that the benefits of the Ad26.COV2.S vaccine outweigh the low risk for associated thrombosis.¹⁵

Although adverse reactions are rare, it is important that health care providers take proper safety measures before and while administering any COVID-19 vaccine. Patients should be screened for contraindications to the COVID-19 vaccine to mitigate adverse effects seen in the small percentage of patients who may need to take alternative precautions.

The broad tissue tropism and high transmissibility of SARS-CoV-2 are the main contributors to its infection having reached pandemic scale. The spike (S) protein on SARS-CoV-2 binds to ACE2, the most thoroughly studied SARS-CoV-2 receptor, which is found in a range of tissues, including arterial endothelial cells, leading to its transfection. Several studies have proposed that expression of the S protein causes endothelial dysfunction through cytokine release, activation of complement, and ultimately microvascular occlusion.¹⁶

Recent developments in the use of viral-like particles, such as vesicular stomatitis virus, may mitigate future cases of RAE that are associated with endothelial cell transfection. Vesicular stomatitis virus is a popular model virus for research applications due to its glycoprotein and matrix protein contributing to its broad tropism. Recent efforts to alter these proteins have successfully limited the broad tropism of vesicular stomatitis virus.¹⁷

The SARS-CoV-2 virus must be handled in a Biosafety Level 3 laboratory. Conversely, pseudoviruses can be handled in lower containment facilities due to their safe and efficacious nature, offering an avenue to expedite vaccine development against many viral outbreaks, including SARS-CoV-2.¹⁸

An increasing number of cutaneous manifestations have been associated with COVID-19 infection and vaccination. Eruptive pseudoangiomatosis, a rare self-limiting exanthem, has been reported in association with ­COVID-19 vaccination.¹⁹ Eruptive pseudoangiomatosis manifests as erythematous blanchable papules that resemble angiomas, typically in a widespread distribution. Eruptive pseudoangiomatosis has striking similarities to RAE histologically; both manifest as dilated dermal blood vessels with plump endothelial cells.

Our case is unique because of the vasculitic palpable nature of the lesions, which were localized to the left arm. Eruptive pseudoangiomatosis formation after COVID-19 infection or SARS-CoV-2 vaccination may suggest alteration of ACE2 by binding of S protein.²⁰ Such alteration of the ACE2 pathway would lead to inflammation of angiotensin II, causing proliferation of endothelial cells in the formation of angiomalike lesions. This hypothesis suggests a paraviral eruption secondary to an immunologic reaction, not a classical virtual eruption from direct contact of the virus on blood vessels. Although EPA and RAE are harmless and self-limiting, these reports will spread awareness of the increasing number of skin manifestations related to COVID-19 and SARS-CoV-2 virus vaccination.

Acknowledgment—Thoughtful insights and comments on this manuscript were provided by Christine J. Ko, MD (New Haven, Connecticut); Christine L. Egan, MD (Glen Mills, Pennsylvania); Howard A. Bueller, MD (Delray Beach, Florida); and Juan Pablo Robles, PhD (Juriquilla, Mexico).

Measuring serum hormone concentrations in postmenopausal women at high risk for developing breast cancer may help identify those most likely to benefit from preventive treatment with an aromatase inhibitor, according to findings from a case-control study using data from a large breast cancer prevention trial.

In the randomized, placebo-controlled IBIS-II prevention trial of 3864 women aged 40-70 years at increased risk for developing breast cancer, treatment with the aromatase inhibitor anastrozole was associated with a 49% reduction in breast cancer incidence. At median follow-up of 131 months, breast cancer occurred in 85 (4.4%) versus 165 (8.5%) of patients in the anastrozole and placebo arms, respectively.

A preplanned case-control study involving 212 participants from the anastrozole group (72 cases and 140 controls) and 416 from the placebo group (142 cases and 274 controls), showed a significant trend toward increasing breast cancer risk with increasing estradiol-to-sex hormone binding globulin (SHBG) ratio in the placebo group, but not in the anastrozole group (trend per quartile, 1.25 vs 1.06), reported Jack Cuzick, PhD, of the Wolfson Institute of Population Health, Queen Mary University of London, UK, and colleagues.

A weaker but still significant effect was observed for the testosterone-SHBG ratio in the placebo group (trend, 1.21), but again, no such effect was seen in the anastrozole group (trend, 1.18).

A relative benefit was seen for anastrozole in estradiol concentration quartiles 2, 3, and 4 (relative risk [RR], 0.55, 0.54, and 0.56, respectively), but not in quartile 1.

The findings were published online December 6 in The Lancet Oncology.

Study participants were recruited from 153 breast cancer treatment centers across 18 countries and randomized in a 1:1 ratio to receive 1 mg of oral anastrozole daily or placebo. For the case-control analysis, the investigators looked at the effects of baseline estradiol to SHBG ratio on the development of all breast cancers, including ductal carcinoma in situ. They also assessed the relative benefit of anastrozole versus placebo.

Case patients were those diagnosed with breast cancer after trial entry through data cutoff on October 22, 2019, and who had not used hormone replacement therapy within 3 months of trial entry or during the trial. Controls were participants without breast cancer who were randomly selected and matched according to treatment group, age, and follow-up time.

“Although the association between estradiol and breast cancer risk is well established, less is known about whether the concentrations of these hormones have an effect on the efficacy of preventive therapy with selective estrogen receptor modulators or aromatase inhibitors in women at increased risk of developing breast cancer,” the investigators noted, explaining that in the current analysis, they “tested the hypothesis that, for women with a low estradiol–SHBG ratio, anastrozole would provide little or no reduction in the risk of breast cancer.”

The results from the placebo group “confirm the increasing risk of breast cancer associated with higher estradiol and testosterone concentrations, and a decreasing risk associated with increasing SHBG concentrations in women who were not randomly allocated to receive anastrozole,” they said.

“However, to our knowledge, this is the first report of the effect of low concentrations of estradiol or testosterone on a lack of response to aromatase inhibitor treatment, either as a preventive measure or in the adjuvant setting,” they added. “These data provide support for the hypothesis that preventive therapy with an aromatase inhibitor is likely to be most effective for women with higher estradiol-to-SHBG ratios and, conversely, of little or no benefit for those with low estradiol-to-SHBG ratios.”

Thus, measurement of estradiol and SHBG concentrations might be helpful in making decisions about using inhibitors both for treatment and prevention, they continued, underscoring the importance of using assays sensitive enough to measure low estradiol concentrations in the plasma in postmenopausal women.

“We used a very sensitive liquid chromatography–tandem mass spectroscopy assay (lower limit of sensitivity of 3 pmol/L), which allowed us to accurately measure the low concentrations of estradiol and SHBG in the serum samples from our population of postmenopausal women. Wider use of this type of assay or a similar assay will be necessary to implement any of the actions suggested by this study,” they explained.

The findings “suggest a potential role for measuring estradiol, testosterone, and SHBG more widely, both in determining which individuals are at high risk and the likely response to endocrine treatment,” they concluded, noting that measuring serum hormones is inexpensive and, if used more routinely in high-risk clinics and for treatment of early breast cancer, could “substantially improve disease management.”

This study was funded by Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund. Dr. Cuzick reported receiving royalties from Cancer Research UK for commercial use of the IBIS (Tyrer-Cuzick) breast cancer risk evaluation software.

Measuring serum hormone concentrations in postmenopausal women at high risk for developing breast cancer may help identify those most likely to benefit from preventive treatment with an aromatase inhibitor, according to findings from a case-control study using data from a large breast cancer prevention trial.

In the randomized, placebo-controlled IBIS-II prevention trial of 3864 women aged 40-70 years at increased risk for developing breast cancer, treatment with the aromatase inhibitor anastrozole was associated with a 49% reduction in breast cancer incidence. At median follow-up of 131 months, breast cancer occurred in 85 (4.4%) versus 165 (8.5%) of patients in the anastrozole and placebo arms, respectively.

A preplanned case-control study involving 212 participants from the anastrozole group (72 cases and 140 controls) and 416 from the placebo group (142 cases and 274 controls), showed a significant trend toward increasing breast cancer risk with increasing estradiol-to-sex hormone binding globulin (SHBG) ratio in the placebo group, but not in the anastrozole group (trend per quartile, 1.25 vs 1.06), reported Jack Cuzick, PhD, of the Wolfson Institute of Population Health, Queen Mary University of London, UK, and colleagues.

A weaker but still significant effect was observed for the testosterone-SHBG ratio in the placebo group (trend, 1.21), but again, no such effect was seen in the anastrozole group (trend, 1.18).

A relative benefit was seen for anastrozole in estradiol concentration quartiles 2, 3, and 4 (relative risk [RR], 0.55, 0.54, and 0.56, respectively), but not in quartile 1.

The findings were published online December 6 in The Lancet Oncology.

Study participants were recruited from 153 breast cancer treatment centers across 18 countries and randomized in a 1:1 ratio to receive 1 mg of oral anastrozole daily or placebo. For the case-control analysis, the investigators looked at the effects of baseline estradiol to SHBG ratio on the development of all breast cancers, including ductal carcinoma in situ. They also assessed the relative benefit of anastrozole versus placebo.

Case patients were those diagnosed with breast cancer after trial entry through data cutoff on October 22, 2019, and who had not used hormone replacement therapy within 3 months of trial entry or during the trial. Controls were participants without breast cancer who were randomly selected and matched according to treatment group, age, and follow-up time.

“Although the association between estradiol and breast cancer risk is well established, less is known about whether the concentrations of these hormones have an effect on the efficacy of preventive therapy with selective estrogen receptor modulators or aromatase inhibitors in women at increased risk of developing breast cancer,” the investigators noted, explaining that in the current analysis, they “tested the hypothesis that, for women with a low estradiol–SHBG ratio, anastrozole would provide little or no reduction in the risk of breast cancer.”

The results from the placebo group “confirm the increasing risk of breast cancer associated with higher estradiol and testosterone concentrations, and a decreasing risk associated with increasing SHBG concentrations in women who were not randomly allocated to receive anastrozole,” they said.

“However, to our knowledge, this is the first report of the effect of low concentrations of estradiol or testosterone on a lack of response to aromatase inhibitor treatment, either as a preventive measure or in the adjuvant setting,” they added. “These data provide support for the hypothesis that preventive therapy with an aromatase inhibitor is likely to be most effective for women with higher estradiol-to-SHBG ratios and, conversely, of little or no benefit for those with low estradiol-to-SHBG ratios.”

Thus, measurement of estradiol and SHBG concentrations might be helpful in making decisions about using inhibitors both for treatment and prevention, they continued, underscoring the importance of using assays sensitive enough to measure low estradiol concentrations in the plasma in postmenopausal women.

“We used a very sensitive liquid chromatography–tandem mass spectroscopy assay (lower limit of sensitivity of 3 pmol/L), which allowed us to accurately measure the low concentrations of estradiol and SHBG in the serum samples from our population of postmenopausal women. Wider use of this type of assay or a similar assay will be necessary to implement any of the actions suggested by this study,” they explained.

The findings “suggest a potential role for measuring estradiol, testosterone, and SHBG more widely, both in determining which individuals are at high risk and the likely response to endocrine treatment,” they concluded, noting that measuring serum hormones is inexpensive and, if used more routinely in high-risk clinics and for treatment of early breast cancer, could “substantially improve disease management.”

This study was funded by Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund. Dr. Cuzick reported receiving royalties from Cancer Research UK for commercial use of the IBIS (Tyrer-Cuzick) breast cancer risk evaluation software.

Measuring serum hormone concentrations in postmenopausal women at high risk for developing breast cancer may help identify those most likely to benefit from preventive treatment with an aromatase inhibitor, according to findings from a case-control study using data from a large breast cancer prevention trial.

In the randomized, placebo-controlled IBIS-II prevention trial of 3864 women aged 40-70 years at increased risk for developing breast cancer, treatment with the aromatase inhibitor anastrozole was associated with a 49% reduction in breast cancer incidence. At median follow-up of 131 months, breast cancer occurred in 85 (4.4%) versus 165 (8.5%) of patients in the anastrozole and placebo arms, respectively.

A preplanned case-control study involving 212 participants from the anastrozole group (72 cases and 140 controls) and 416 from the placebo group (142 cases and 274 controls), showed a significant trend toward increasing breast cancer risk with increasing estradiol-to-sex hormone binding globulin (SHBG) ratio in the placebo group, but not in the anastrozole group (trend per quartile, 1.25 vs 1.06), reported Jack Cuzick, PhD, of the Wolfson Institute of Population Health, Queen Mary University of London, UK, and colleagues.

A weaker but still significant effect was observed for the testosterone-SHBG ratio in the placebo group (trend, 1.21), but again, no such effect was seen in the anastrozole group (trend, 1.18).

A relative benefit was seen for anastrozole in estradiol concentration quartiles 2, 3, and 4 (relative risk [RR], 0.55, 0.54, and 0.56, respectively), but not in quartile 1.

The findings were published online December 6 in The Lancet Oncology.

Study participants were recruited from 153 breast cancer treatment centers across 18 countries and randomized in a 1:1 ratio to receive 1 mg of oral anastrozole daily or placebo. For the case-control analysis, the investigators looked at the effects of baseline estradiol to SHBG ratio on the development of all breast cancers, including ductal carcinoma in situ. They also assessed the relative benefit of anastrozole versus placebo.

Case patients were those diagnosed with breast cancer after trial entry through data cutoff on October 22, 2019, and who had not used hormone replacement therapy within 3 months of trial entry or during the trial. Controls were participants without breast cancer who were randomly selected and matched according to treatment group, age, and follow-up time.

“Although the association between estradiol and breast cancer risk is well established, less is known about whether the concentrations of these hormones have an effect on the efficacy of preventive therapy with selective estrogen receptor modulators or aromatase inhibitors in women at increased risk of developing breast cancer,” the investigators noted, explaining that in the current analysis, they “tested the hypothesis that, for women with a low estradiol–SHBG ratio, anastrozole would provide little or no reduction in the risk of breast cancer.”

The results from the placebo group “confirm the increasing risk of breast cancer associated with higher estradiol and testosterone concentrations, and a decreasing risk associated with increasing SHBG concentrations in women who were not randomly allocated to receive anastrozole,” they said.

“However, to our knowledge, this is the first report of the effect of low concentrations of estradiol or testosterone on a lack of response to aromatase inhibitor treatment, either as a preventive measure or in the adjuvant setting,” they added. “These data provide support for the hypothesis that preventive therapy with an aromatase inhibitor is likely to be most effective for women with higher estradiol-to-SHBG ratios and, conversely, of little or no benefit for those with low estradiol-to-SHBG ratios.”

Thus, measurement of estradiol and SHBG concentrations might be helpful in making decisions about using inhibitors both for treatment and prevention, they continued, underscoring the importance of using assays sensitive enough to measure low estradiol concentrations in the plasma in postmenopausal women.

“We used a very sensitive liquid chromatography–tandem mass spectroscopy assay (lower limit of sensitivity of 3 pmol/L), which allowed us to accurately measure the low concentrations of estradiol and SHBG in the serum samples from our population of postmenopausal women. Wider use of this type of assay or a similar assay will be necessary to implement any of the actions suggested by this study,” they explained.

The findings “suggest a potential role for measuring estradiol, testosterone, and SHBG more widely, both in determining which individuals are at high risk and the likely response to endocrine treatment,” they concluded, noting that measuring serum hormones is inexpensive and, if used more routinely in high-risk clinics and for treatment of early breast cancer, could “substantially improve disease management.”

This study was funded by Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund. Dr. Cuzick reported receiving royalties from Cancer Research UK for commercial use of the IBIS (Tyrer-Cuzick) breast cancer risk evaluation software.

TOPLINE:

Removing race and incorporating social determinants of health (SDOH) into the pooled cohort risk equations (PCEs) for predicting atherosclerotic cardiovascular disease (ASCVD) outcomes made no difference to patients’ risk scores.

METHODOLOGY:

• Primary prevention guidelines recommend using risk prediction algorithms to assess the 10-year ASCVD risk, with the currently recommended PCEs including race.
• Researchers evaluated the incremental value of revised risk prediction equations excluding race and introducing SDOH in 11,638 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort.
• Participants were aged between 45 and 79 years, had no history of ASCVD, and were not taking statins.
• Participants were followed up to 10 years for incident ASCVD, including myocardial infarction, coronary heart disease death, and fatal and nonfatal stroke.

TAKEAWAY:

• Risk prediction equations performed similarly in race- and sex-stratified PCEs (C-statistic [95% CI])
• Black female: 0.71 (0.68-0.75); Black male: 0.68 (0.64-0.73); White female: 0.77 (0.74-0.80); White male: 0.68 (0.65-0.71)
• Race-free sex-specific PCEs yielded similar discrimination as race- and sex-stratified PCEs (C-statistic [95% CI]):
• Black female: 0.71 (0.67-0.75); Black male: 0.68 (0.63-0.72); White female: 0.76 (0.73-0.80); White male: 0.68 (0.65-0.71)
• The addition of SDOH to race-free sex-specific PCEs did not improve model performance (C-statistic [95% CI]):
• Black female: 0.72 (0.68-0.76); Black male: 0.68 (0.64-0.72); White female: 0.77 (0.74-0.80); White male: 0.68 (0.65-0.71)

IN PRACTICE:

“The major takeaway is we need to rethink the idea of race in cardiovascular risk prediction,” lead author Arnab Ghosh, MD, assistant professor of medicine at Weill Cornell Medical College and a hospitalist at New York-Presbyterian/Weill Cornell Medical Center, said in a press release.

“It’s essential for clinicians and scientists to consider how to appropriately address the health effects of race as a social construct, which has contributed to health disparities in cardiovascular outcomes,” Dr. Ghosh added.

SOURCE:

The study led by Dr. Ghosh was published online on December 6, 2023, in JAMA Cardiology with an Editor’s Note.

LIMITATIONS:

The study required informed consent for inclusion, which may have led to selection bias.

The REGARDS cohort’s SDOH may not have captured all social and socioeconomic influences on ASCVD outcomes.

DISCLOSURES:

The research was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging of the National Institutes of Health, Department of Health and Human Services, and others. Some authors declared receiving funding, grants, or personal fees from various sources.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Removing race and incorporating social determinants of health (SDOH) into the pooled cohort risk equations (PCEs) for predicting atherosclerotic cardiovascular disease (ASCVD) outcomes made no difference to patients’ risk scores.

METHODOLOGY:

• Primary prevention guidelines recommend using risk prediction algorithms to assess the 10-year ASCVD risk, with the currently recommended PCEs including race.
• Researchers evaluated the incremental value of revised risk prediction equations excluding race and introducing SDOH in 11,638 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort.
• Participants were aged between 45 and 79 years, had no history of ASCVD, and were not taking statins.
• Participants were followed up to 10 years for incident ASCVD, including myocardial infarction, coronary heart disease death, and fatal and nonfatal stroke.

TAKEAWAY:

• Risk prediction equations performed similarly in race- and sex-stratified PCEs (C-statistic [95% CI])
• Black female: 0.71 (0.68-0.75); Black male: 0.68 (0.64-0.73); White female: 0.77 (0.74-0.80); White male: 0.68 (0.65-0.71)
• Race-free sex-specific PCEs yielded similar discrimination as race- and sex-stratified PCEs (C-statistic [95% CI]):
• Black female: 0.71 (0.67-0.75); Black male: 0.68 (0.63-0.72); White female: 0.76 (0.73-0.80); White male: 0.68 (0.65-0.71)
• The addition of SDOH to race-free sex-specific PCEs did not improve model performance (C-statistic [95% CI]):
• Black female: 0.72 (0.68-0.76); Black male: 0.68 (0.64-0.72); White female: 0.77 (0.74-0.80); White male: 0.68 (0.65-0.71)

IN PRACTICE:

“The major takeaway is we need to rethink the idea of race in cardiovascular risk prediction,” lead author Arnab Ghosh, MD, assistant professor of medicine at Weill Cornell Medical College and a hospitalist at New York-Presbyterian/Weill Cornell Medical Center, said in a press release.

“It’s essential for clinicians and scientists to consider how to appropriately address the health effects of race as a social construct, which has contributed to health disparities in cardiovascular outcomes,” Dr. Ghosh added.

SOURCE:

The study led by Dr. Ghosh was published online on December 6, 2023, in JAMA Cardiology with an Editor’s Note.

LIMITATIONS:

The study required informed consent for inclusion, which may have led to selection bias.

The REGARDS cohort’s SDOH may not have captured all social and socioeconomic influences on ASCVD outcomes.

DISCLOSURES:

The research was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging of the National Institutes of Health, Department of Health and Human Services, and others. Some authors declared receiving funding, grants, or personal fees from various sources.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Removing race and incorporating social determinants of health (SDOH) into the pooled cohort risk equations (PCEs) for predicting atherosclerotic cardiovascular disease (ASCVD) outcomes made no difference to patients’ risk scores.

METHODOLOGY:

• Primary prevention guidelines recommend using risk prediction algorithms to assess the 10-year ASCVD risk, with the currently recommended PCEs including race.
• Researchers evaluated the incremental value of revised risk prediction equations excluding race and introducing SDOH in 11,638 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort.
• Participants were aged between 45 and 79 years, had no history of ASCVD, and were not taking statins.
• Participants were followed up to 10 years for incident ASCVD, including myocardial infarction, coronary heart disease death, and fatal and nonfatal stroke.

TAKEAWAY:

• Risk prediction equations performed similarly in race- and sex-stratified PCEs (C-statistic [95% CI])
• Black female: 0.71 (0.68-0.75); Black male: 0.68 (0.64-0.73); White female: 0.77 (0.74-0.80); White male: 0.68 (0.65-0.71)
• Race-free sex-specific PCEs yielded similar discrimination as race- and sex-stratified PCEs (C-statistic [95% CI]):
• Black female: 0.71 (0.67-0.75); Black male: 0.68 (0.63-0.72); White female: 0.76 (0.73-0.80); White male: 0.68 (0.65-0.71)
• The addition of SDOH to race-free sex-specific PCEs did not improve model performance (C-statistic [95% CI]):
• Black female: 0.72 (0.68-0.76); Black male: 0.68 (0.64-0.72); White female: 0.77 (0.74-0.80); White male: 0.68 (0.65-0.71)

IN PRACTICE:

“The major takeaway is we need to rethink the idea of race in cardiovascular risk prediction,” lead author Arnab Ghosh, MD, assistant professor of medicine at Weill Cornell Medical College and a hospitalist at New York-Presbyterian/Weill Cornell Medical Center, said in a press release.

“It’s essential for clinicians and scientists to consider how to appropriately address the health effects of race as a social construct, which has contributed to health disparities in cardiovascular outcomes,” Dr. Ghosh added.

SOURCE:

The study led by Dr. Ghosh was published online on December 6, 2023, in JAMA Cardiology with an Editor’s Note.

LIMITATIONS:

The study required informed consent for inclusion, which may have led to selection bias.

The REGARDS cohort’s SDOH may not have captured all social and socioeconomic influences on ASCVD outcomes.

DISCLOSURES:

The research was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging of the National Institutes of Health, Department of Health and Human Services, and others. Some authors declared receiving funding, grants, or personal fees from various sources.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Two proposed new multiple myeloma staging systems offer similar prognostic accuracy compared with the standard staging system, but the new systems provide more refined risk classifications across different disease stages. 

The findings should encourage greater use of these newer staging systems in routine clinical practice, first author Manni Mohyuddin, MD, said during a presentation at the American Society of Hematology annual meeting.

Dr. Mohyuddin and his colleagues retrospectively compared the standard Revised International Staging System (R-ISS) with two newer systems, the Second Revision of the R-ISS (R2-ISS) and the Mayo Additive Staging System (MASS), using real-world data from nearly 500 patients with newly diagnosed multiple myeloma.

The R-ISS, the most common multiple myeloma staging system, incorporates a range of prognostic features, including high-risk genetic markers assessed using fluorescence in situ hybridization as well as levels of lactate dehydrogenase, albumin, and beta-2 microglobulin, explained Dr. Mohyuddin, assistant professor at the Huntsman Cancer Institute, University of Utah, Salt Lake City.

R2-ISS and MASS include additional factors that reflect experts’ growing understanding of multiple myeloma. Specifically, the systems also evaluate a gain of chromosome 1q, in which patients have an extra copy of chromosome 1q, as well as the additive effects of multiple high-risk cytogenetic abnormalities, both of which indicate worse prognosis in multiple myeloma, Dr. Mohyuddin said in an interview.

To compare the three staging systems, the investigators used information on newly diagnosed patients in the Flatiron Health EHR–derived deidentified database, which includes data from cancer clinics across the United States. Patients were followed from first-line treatment initiation until death, the end of the study period, or last recorded activity.

The patients from the database had a median age of 70 years, and most had not received a transplant. The most common cytogenetic abnormality was gain 1q, present in about one third of patients. 

Given that the R2-ISS originated from patients in clinical trials, Dr. Mohyuddin noted the importance of assessing how the system would perform in a real-world setting. 

Of the 497 patients in the analysis, the R-ISS staging system classified 24% as stage I, 63% as stage II, and 13% as stage III. Overall survival differed across these R-ISS stages, indicating the system was prognostic for survival. Median overall survival was not reached for those with stage I disease, was 62.9 months for those with stage II disease, and 37.6 months for those with stage III disease.

Because the R-ISS doesn’t consider the additive effect of multiple cytogenetic abnormalities, many patients end up in the R-ISS stage II category but ultimately may have vastly different outcomes, Dr. Mohyuddin said.

The R2-ISS includes four risk categories, which provide more granularity to the stage II classification: Stage I is low risk, stage II is low-intermediate, stage III is intermediate, and stage IV is high risk. Using this staging system, 20% of patients were stage I, 25% were stage II, 46% were stage III, and 9% were stage IV.

The R2-ISS was also prognostic for survival, which generally worsened from stage I to stage IV: Median overall survival was not reached in stage I patients, was 69.3 months for stage II, 50.0 months for stage III, and 50.6 months for stage IV patients. However, Dr. Mohyuddin noted that there was some overlap in the survival curves for stages I and II and for stages III and IV.

When applying MASS, 34% of patients were categorized as stage I, 35% as stage II, and 31% as stage III disease. This system was prognostic for survival as well, with median overall survival of 76.9 months for stage I, 61.2 months for stage II, and 45.0 months for stage III.

With R2-ISS, many of those in R-ISS stage II are moved into stage I and III. With MASS, the R-ISS stage II patients are more evenly distributed across stages I, II, and III.

In other words, “we show that both these newer staging systems basically recategorize patients into different stages,” essentially “decreasing the number of people in the large, ambiguous (R-ISS) stage II category,” said Dr. Mohyuddin. 

Dr. Mohyuddin and colleagues also evaluated the staging systems in fully adjusted analyses that controlled for age, race/ethnicity, sex, practice type, and diagnosis year. 

Using R2-ISS, stage I patients had a similar risk for death compared with stage II patients (hazard ratio [HR], 1.2). Compared with stage I patients, stage III and IV patients had comparable risks for death, both about 2.5-fold higher than in those with stage I disease (HR, 2.4 and 2.6, respectively). 

Compared with stage I MASS patients, those with stage II had a twofold higher risk for death (HR, 2.0), and those with stage III had an almost threefold higher risk (HR, 2.7). 

Although no system considers all factors associated with myeloma outcomes, R2-ISS and MASS do offer a benefit over R-ISS, Dr. Mohyuddin said.

He added that the R2-ISS and MASS are similar from a statistical standpoint, but he gave MASS a slight edge for use in clinical practice.

MASS “more cleanly demarcated [patients] into prognostic subsets,” plus it is “a little easier to remember by heart,” he explained. MASS also puts more emphasis on the presence of multiple high-risk cytogenetic abnormalities, which is a worse prognostic in this era of quadruplet therapy for multiple myeloma, he added.

Because the study largely took place in an era when triplet therapy dominated, “we would be curious to see, with longer follow-up and more use of quadruplets, how these staging systems would perform,” he said. 

Despite the benefits of these newer staging systems, many factors play a role in multiple myeloma outcomes, Dr. Mohyuddin explained. Staging systems are “only a piece of the puzzle.”

Dr. Mohyuddin reported having no financial interests to disclose.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Two proposed new multiple myeloma staging systems offer similar prognostic accuracy compared with the standard staging system, but the new systems provide more refined risk classifications across different disease stages. 

The findings should encourage greater use of these newer staging systems in routine clinical practice, first author Manni Mohyuddin, MD, said during a presentation at the American Society of Hematology annual meeting.

Dr. Mohyuddin and his colleagues retrospectively compared the standard Revised International Staging System (R-ISS) with two newer systems, the Second Revision of the R-ISS (R2-ISS) and the Mayo Additive Staging System (MASS), using real-world data from nearly 500 patients with newly diagnosed multiple myeloma.

The R-ISS, the most common multiple myeloma staging system, incorporates a range of prognostic features, including high-risk genetic markers assessed using fluorescence in situ hybridization as well as levels of lactate dehydrogenase, albumin, and beta-2 microglobulin, explained Dr. Mohyuddin, assistant professor at the Huntsman Cancer Institute, University of Utah, Salt Lake City.

R2-ISS and MASS include additional factors that reflect experts’ growing understanding of multiple myeloma. Specifically, the systems also evaluate a gain of chromosome 1q, in which patients have an extra copy of chromosome 1q, as well as the additive effects of multiple high-risk cytogenetic abnormalities, both of which indicate worse prognosis in multiple myeloma, Dr. Mohyuddin said in an interview.

To compare the three staging systems, the investigators used information on newly diagnosed patients in the Flatiron Health EHR–derived deidentified database, which includes data from cancer clinics across the United States. Patients were followed from first-line treatment initiation until death, the end of the study period, or last recorded activity.

The patients from the database had a median age of 70 years, and most had not received a transplant. The most common cytogenetic abnormality was gain 1q, present in about one third of patients. 

Given that the R2-ISS originated from patients in clinical trials, Dr. Mohyuddin noted the importance of assessing how the system would perform in a real-world setting. 

Of the 497 patients in the analysis, the R-ISS staging system classified 24% as stage I, 63% as stage II, and 13% as stage III. Overall survival differed across these R-ISS stages, indicating the system was prognostic for survival. Median overall survival was not reached for those with stage I disease, was 62.9 months for those with stage II disease, and 37.6 months for those with stage III disease.

Because the R-ISS doesn’t consider the additive effect of multiple cytogenetic abnormalities, many patients end up in the R-ISS stage II category but ultimately may have vastly different outcomes, Dr. Mohyuddin said.

The R2-ISS includes four risk categories, which provide more granularity to the stage II classification: Stage I is low risk, stage II is low-intermediate, stage III is intermediate, and stage IV is high risk. Using this staging system, 20% of patients were stage I, 25% were stage II, 46% were stage III, and 9% were stage IV.

The R2-ISS was also prognostic for survival, which generally worsened from stage I to stage IV: Median overall survival was not reached in stage I patients, was 69.3 months for stage II, 50.0 months for stage III, and 50.6 months for stage IV patients. However, Dr. Mohyuddin noted that there was some overlap in the survival curves for stages I and II and for stages III and IV.

When applying MASS, 34% of patients were categorized as stage I, 35% as stage II, and 31% as stage III disease. This system was prognostic for survival as well, with median overall survival of 76.9 months for stage I, 61.2 months for stage II, and 45.0 months for stage III.

With R2-ISS, many of those in R-ISS stage II are moved into stage I and III. With MASS, the R-ISS stage II patients are more evenly distributed across stages I, II, and III.

In other words, “we show that both these newer staging systems basically recategorize patients into different stages,” essentially “decreasing the number of people in the large, ambiguous (R-ISS) stage II category,” said Dr. Mohyuddin. 

Dr. Mohyuddin and colleagues also evaluated the staging systems in fully adjusted analyses that controlled for age, race/ethnicity, sex, practice type, and diagnosis year. 

Using R2-ISS, stage I patients had a similar risk for death compared with stage II patients (hazard ratio [HR], 1.2). Compared with stage I patients, stage III and IV patients had comparable risks for death, both about 2.5-fold higher than in those with stage I disease (HR, 2.4 and 2.6, respectively). 

Compared with stage I MASS patients, those with stage II had a twofold higher risk for death (HR, 2.0), and those with stage III had an almost threefold higher risk (HR, 2.7). 

Although no system considers all factors associated with myeloma outcomes, R2-ISS and MASS do offer a benefit over R-ISS, Dr. Mohyuddin said.

He added that the R2-ISS and MASS are similar from a statistical standpoint, but he gave MASS a slight edge for use in clinical practice.

MASS “more cleanly demarcated [patients] into prognostic subsets,” plus it is “a little easier to remember by heart,” he explained. MASS also puts more emphasis on the presence of multiple high-risk cytogenetic abnormalities, which is a worse prognostic in this era of quadruplet therapy for multiple myeloma, he added.

Because the study largely took place in an era when triplet therapy dominated, “we would be curious to see, with longer follow-up and more use of quadruplets, how these staging systems would perform,” he said. 

Despite the benefits of these newer staging systems, many factors play a role in multiple myeloma outcomes, Dr. Mohyuddin explained. Staging systems are “only a piece of the puzzle.”

Dr. Mohyuddin reported having no financial interests to disclose.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Two proposed new multiple myeloma staging systems offer similar prognostic accuracy compared with the standard staging system, but the new systems provide more refined risk classifications across different disease stages. 

The findings should encourage greater use of these newer staging systems in routine clinical practice, first author Manni Mohyuddin, MD, said during a presentation at the American Society of Hematology annual meeting.

Dr. Mohyuddin and his colleagues retrospectively compared the standard Revised International Staging System (R-ISS) with two newer systems, the Second Revision of the R-ISS (R2-ISS) and the Mayo Additive Staging System (MASS), using real-world data from nearly 500 patients with newly diagnosed multiple myeloma.

The R-ISS, the most common multiple myeloma staging system, incorporates a range of prognostic features, including high-risk genetic markers assessed using fluorescence in situ hybridization as well as levels of lactate dehydrogenase, albumin, and beta-2 microglobulin, explained Dr. Mohyuddin, assistant professor at the Huntsman Cancer Institute, University of Utah, Salt Lake City.

R2-ISS and MASS include additional factors that reflect experts’ growing understanding of multiple myeloma. Specifically, the systems also evaluate a gain of chromosome 1q, in which patients have an extra copy of chromosome 1q, as well as the additive effects of multiple high-risk cytogenetic abnormalities, both of which indicate worse prognosis in multiple myeloma, Dr. Mohyuddin said in an interview.

To compare the three staging systems, the investigators used information on newly diagnosed patients in the Flatiron Health EHR–derived deidentified database, which includes data from cancer clinics across the United States. Patients were followed from first-line treatment initiation until death, the end of the study period, or last recorded activity.

The patients from the database had a median age of 70 years, and most had not received a transplant. The most common cytogenetic abnormality was gain 1q, present in about one third of patients. 

Given that the R2-ISS originated from patients in clinical trials, Dr. Mohyuddin noted the importance of assessing how the system would perform in a real-world setting. 

Of the 497 patients in the analysis, the R-ISS staging system classified 24% as stage I, 63% as stage II, and 13% as stage III. Overall survival differed across these R-ISS stages, indicating the system was prognostic for survival. Median overall survival was not reached for those with stage I disease, was 62.9 months for those with stage II disease, and 37.6 months for those with stage III disease.

Because the R-ISS doesn’t consider the additive effect of multiple cytogenetic abnormalities, many patients end up in the R-ISS stage II category but ultimately may have vastly different outcomes, Dr. Mohyuddin said.

The R2-ISS includes four risk categories, which provide more granularity to the stage II classification: Stage I is low risk, stage II is low-intermediate, stage III is intermediate, and stage IV is high risk. Using this staging system, 20% of patients were stage I, 25% were stage II, 46% were stage III, and 9% were stage IV.

The R2-ISS was also prognostic for survival, which generally worsened from stage I to stage IV: Median overall survival was not reached in stage I patients, was 69.3 months for stage II, 50.0 months for stage III, and 50.6 months for stage IV patients. However, Dr. Mohyuddin noted that there was some overlap in the survival curves for stages I and II and for stages III and IV.

When applying MASS, 34% of patients were categorized as stage I, 35% as stage II, and 31% as stage III disease. This system was prognostic for survival as well, with median overall survival of 76.9 months for stage I, 61.2 months for stage II, and 45.0 months for stage III.

With R2-ISS, many of those in R-ISS stage II are moved into stage I and III. With MASS, the R-ISS stage II patients are more evenly distributed across stages I, II, and III.

In other words, “we show that both these newer staging systems basically recategorize patients into different stages,” essentially “decreasing the number of people in the large, ambiguous (R-ISS) stage II category,” said Dr. Mohyuddin. 

Dr. Mohyuddin and colleagues also evaluated the staging systems in fully adjusted analyses that controlled for age, race/ethnicity, sex, practice type, and diagnosis year. 

Using R2-ISS, stage I patients had a similar risk for death compared with stage II patients (hazard ratio [HR], 1.2). Compared with stage I patients, stage III and IV patients had comparable risks for death, both about 2.5-fold higher than in those with stage I disease (HR, 2.4 and 2.6, respectively). 

Compared with stage I MASS patients, those with stage II had a twofold higher risk for death (HR, 2.0), and those with stage III had an almost threefold higher risk (HR, 2.7). 

Although no system considers all factors associated with myeloma outcomes, R2-ISS and MASS do offer a benefit over R-ISS, Dr. Mohyuddin said.

He added that the R2-ISS and MASS are similar from a statistical standpoint, but he gave MASS a slight edge for use in clinical practice.

MASS “more cleanly demarcated [patients] into prognostic subsets,” plus it is “a little easier to remember by heart,” he explained. MASS also puts more emphasis on the presence of multiple high-risk cytogenetic abnormalities, which is a worse prognostic in this era of quadruplet therapy for multiple myeloma, he added.

Because the study largely took place in an era when triplet therapy dominated, “we would be curious to see, with longer follow-up and more use of quadruplets, how these staging systems would perform,” he said. 

Despite the benefits of these newer staging systems, many factors play a role in multiple myeloma outcomes, Dr. Mohyuddin explained. Staging systems are “only a piece of the puzzle.”

Dr. Mohyuddin reported having no financial interests to disclose.
 

A version of this article appeared on Medscape.com.