Angiosarcomas are uncommon, high-grade malignant tumors of endothelial cell origin that can arise via the lymphatics or vasculature. They typically occur spontaneously; however, there have been cases reported of benign vascular transformation. These tumors are more commonly found in elderly men on the head and neck in sun-damaged skin. Radiation-induced angiosarcoma occurs in an estimated 0.05%-0.3% of patients with breast cancer who underwent surgery and radiation therapy. This is a late complication, typically occurring about 5-10 years after radiation. Stewart-Treves syndrome, chronic lymphedema occurring after breast cancer treatment with axillary node dissection, increases the risk of angiosarcoma. As a vascular tumor, angiosarcoma spreads hematogenously and carries a poor prognosis if not caught early. Differential diagnoses include other vascular tumors such as retiform hemangioendothelioma. In this specific patient, the differential diagnosis includes Paget’s disease, chronic radiation skin changes, and eczema.

Histopathologically, angiosarcomas exhibit abnormal, pleomorphic, malignant endothelial cells. As the tumor progresses, the cell architecture becomes more distorted and cells form layers with papillary projections into the vascular lumen. Malignant cells may stain positive for CD31, CD34, the oncogene ERG and the proto-oncogene FLI-1. Histology in this patient revealed radiation changes in the dermis, as well as few vascular channels lined by large endothelial cells with marked nuclear atypia, in the form of large nucleoli and variably coarse chromatin. The cells were positive for MYC.

Treatment of angiosarcoma involves a multidisciplinary approach. Resection with wide margins is generally the treatment of choice. However, recurrence is relatively common, which may be a result of microsatellite deposits of the tumor. Perioperative radiation is recommended, and adjuvant chemotherapy often is recommended for metastatic disease. Specifically, paclitaxel has been found to promote survival in some cases of cutaneous angiosarcoma. Metastatic disease may be treated with cytotoxic drugs such as anthracyclines and taxanes. Additionally, targeted therapy including anti-VEGF drugs and tyrosine kinase inhibitors have been tested.

The case and photo were submitted by Mr. Shapiro of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Dr. Bilu Martin. The column was edited by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

Cohen-Hallaleh RB et al. Clin Sarcoma Res. 2017 Aug 7:7:15.

Cozzi S et al. Rep Pract Oncol Radiother. 2021 Sep 30;26(5):827-32.

Spiker AM, Mangla A, Ramsey ML. Angiosarcoma. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island, Fla.: StatPearls Publishing; 2023 Jan-. Available from: www.ncbi.nlm.nih.gov/books/NBK441983/

Angiosarcomas are uncommon, high-grade malignant tumors of endothelial cell origin that can arise via the lymphatics or vasculature. They typically occur spontaneously; however, there have been cases reported of benign vascular transformation. These tumors are more commonly found in elderly men on the head and neck in sun-damaged skin. Radiation-induced angiosarcoma occurs in an estimated 0.05%-0.3% of patients with breast cancer who underwent surgery and radiation therapy. This is a late complication, typically occurring about 5-10 years after radiation. Stewart-Treves syndrome, chronic lymphedema occurring after breast cancer treatment with axillary node dissection, increases the risk of angiosarcoma. As a vascular tumor, angiosarcoma spreads hematogenously and carries a poor prognosis if not caught early. Differential diagnoses include other vascular tumors such as retiform hemangioendothelioma. In this specific patient, the differential diagnosis includes Paget’s disease, chronic radiation skin changes, and eczema.

Histopathologically, angiosarcomas exhibit abnormal, pleomorphic, malignant endothelial cells. As the tumor progresses, the cell architecture becomes more distorted and cells form layers with papillary projections into the vascular lumen. Malignant cells may stain positive for CD31, CD34, the oncogene ERG and the proto-oncogene FLI-1. Histology in this patient revealed radiation changes in the dermis, as well as few vascular channels lined by large endothelial cells with marked nuclear atypia, in the form of large nucleoli and variably coarse chromatin. The cells were positive for MYC.

Treatment of angiosarcoma involves a multidisciplinary approach. Resection with wide margins is generally the treatment of choice. However, recurrence is relatively common, which may be a result of microsatellite deposits of the tumor. Perioperative radiation is recommended, and adjuvant chemotherapy often is recommended for metastatic disease. Specifically, paclitaxel has been found to promote survival in some cases of cutaneous angiosarcoma. Metastatic disease may be treated with cytotoxic drugs such as anthracyclines and taxanes. Additionally, targeted therapy including anti-VEGF drugs and tyrosine kinase inhibitors have been tested.

The case and photo were submitted by Mr. Shapiro of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Dr. Bilu Martin. The column was edited by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

Cohen-Hallaleh RB et al. Clin Sarcoma Res. 2017 Aug 7:7:15.

Cozzi S et al. Rep Pract Oncol Radiother. 2021 Sep 30;26(5):827-32.

Spiker AM, Mangla A, Ramsey ML. Angiosarcoma. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island, Fla.: StatPearls Publishing; 2023 Jan-. Available from: www.ncbi.nlm.nih.gov/books/NBK441983/

Angiosarcomas are uncommon, high-grade malignant tumors of endothelial cell origin that can arise via the lymphatics or vasculature. They typically occur spontaneously; however, there have been cases reported of benign vascular transformation. These tumors are more commonly found in elderly men on the head and neck in sun-damaged skin. Radiation-induced angiosarcoma occurs in an estimated 0.05%-0.3% of patients with breast cancer who underwent surgery and radiation therapy. This is a late complication, typically occurring about 5-10 years after radiation. Stewart-Treves syndrome, chronic lymphedema occurring after breast cancer treatment with axillary node dissection, increases the risk of angiosarcoma. As a vascular tumor, angiosarcoma spreads hematogenously and carries a poor prognosis if not caught early. Differential diagnoses include other vascular tumors such as retiform hemangioendothelioma. In this specific patient, the differential diagnosis includes Paget’s disease, chronic radiation skin changes, and eczema.

Histopathologically, angiosarcomas exhibit abnormal, pleomorphic, malignant endothelial cells. As the tumor progresses, the cell architecture becomes more distorted and cells form layers with papillary projections into the vascular lumen. Malignant cells may stain positive for CD31, CD34, the oncogene ERG and the proto-oncogene FLI-1. Histology in this patient revealed radiation changes in the dermis, as well as few vascular channels lined by large endothelial cells with marked nuclear atypia, in the form of large nucleoli and variably coarse chromatin. The cells were positive for MYC.

Treatment of angiosarcoma involves a multidisciplinary approach. Resection with wide margins is generally the treatment of choice. However, recurrence is relatively common, which may be a result of microsatellite deposits of the tumor. Perioperative radiation is recommended, and adjuvant chemotherapy often is recommended for metastatic disease. Specifically, paclitaxel has been found to promote survival in some cases of cutaneous angiosarcoma. Metastatic disease may be treated with cytotoxic drugs such as anthracyclines and taxanes. Additionally, targeted therapy including anti-VEGF drugs and tyrosine kinase inhibitors have been tested.

The case and photo were submitted by Mr. Shapiro of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Dr. Bilu Martin. The column was edited by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

Cohen-Hallaleh RB et al. Clin Sarcoma Res. 2017 Aug 7:7:15.

Cozzi S et al. Rep Pract Oncol Radiother. 2021 Sep 30;26(5):827-32.

Spiker AM, Mangla A, Ramsey ML. Angiosarcoma. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island, Fla.: StatPearls Publishing; 2023 Jan-. Available from: www.ncbi.nlm.nih.gov/books/NBK441983/

The Food and Drug Administration has approved the Paradise Ultrasound Renal Denervation system for the treatment of hypertension, Recor Medical and parent company Otsuka Medical Devices have announced.
 

Approval follows a positive review by the FDA’s Circulatory Systems Device panel in August that deemed the system both safe and effective in lowering blood pressure for adults with uncontrolled hypertension who may be inadequately responsive to, or who are intolerant of, antihypertensive medications. 

Olivier Le Moal/Getty Images

Data supporting approval were provided by the RADIANCE program, the pivotal RADIANCE II trial, as well as RADIANCE-HTN SOLO and RADIANCE-HTN TRIO. RADIANCE II and RADIANCE-HTN SOLO studied patients with mild to moderate hypertension in an “off-meds” setting, and RADIANCE-HTN TRIO enrolled patients with resistant hypertension on standardized triple antihypertensive therapy.  

Renal denervation is intended as an adjunctive treatment option when lifestyle changes and medication have not resulted in adequate blood pressure control, the statement notes. It works by denervating the sympathetic nerves surrounding the renal arteries, reducing the overactivity that can lead to hypertension.

The system delivers two to three doses of 360-degree ultrasound energy, lasting 7 seconds each, through each of the main renal arteries to the surrounding nerves. This particular system is water-cooled to protect the renal artery wall, the statement adds.

“Given the significant blood pressure reductions seen in the ultrasound renal denervation trials, the Paradise Ultrasound Renal Denervation system offers a much-needed advancement in our currently available options to control hypertension,” site principal investigator Naomi Fisher, MD, associate professor of medicine, Harvard Medical School, and director of hypertension service and hypertension innovation, division of endocrinology, diabetes, and hypertension at Brigham and Women’s Hospital, Boston, said in the statement.

Ultrasound renal denervation “has proven efficacy in patients with truly resistant hypertension, a population for whom medication therapy often fails. It is also effective in patients with mild to moderate hypertension who cannot tolerate enough medication to control their blood pressure,” Dr. Fisher added.

The Paradise ultrasound renal denervation system previously received CE mark and has been successfully introduced in Europe and is an investigational device in Japan, the companies note.

A second renal denervation system, the Symplicity Spyral Renal Denervation System (Medtronic) underwent FDA panel review the day after the Paradise system review in August, and although the panel voted unanimously that the Symplicity system is safe, they were split on whether or not it was efficacious. A final decision on approval by the FDA of that system is still pending.

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

The Food and Drug Administration has approved the Paradise Ultrasound Renal Denervation system for the treatment of hypertension, Recor Medical and parent company Otsuka Medical Devices have announced.
 

Approval follows a positive review by the FDA’s Circulatory Systems Device panel in August that deemed the system both safe and effective in lowering blood pressure for adults with uncontrolled hypertension who may be inadequately responsive to, or who are intolerant of, antihypertensive medications. 

Olivier Le Moal/Getty Images

Data supporting approval were provided by the RADIANCE program, the pivotal RADIANCE II trial, as well as RADIANCE-HTN SOLO and RADIANCE-HTN TRIO. RADIANCE II and RADIANCE-HTN SOLO studied patients with mild to moderate hypertension in an “off-meds” setting, and RADIANCE-HTN TRIO enrolled patients with resistant hypertension on standardized triple antihypertensive therapy.  

Renal denervation is intended as an adjunctive treatment option when lifestyle changes and medication have not resulted in adequate blood pressure control, the statement notes. It works by denervating the sympathetic nerves surrounding the renal arteries, reducing the overactivity that can lead to hypertension.

The system delivers two to three doses of 360-degree ultrasound energy, lasting 7 seconds each, through each of the main renal arteries to the surrounding nerves. This particular system is water-cooled to protect the renal artery wall, the statement adds.

“Given the significant blood pressure reductions seen in the ultrasound renal denervation trials, the Paradise Ultrasound Renal Denervation system offers a much-needed advancement in our currently available options to control hypertension,” site principal investigator Naomi Fisher, MD, associate professor of medicine, Harvard Medical School, and director of hypertension service and hypertension innovation, division of endocrinology, diabetes, and hypertension at Brigham and Women’s Hospital, Boston, said in the statement.

Ultrasound renal denervation “has proven efficacy in patients with truly resistant hypertension, a population for whom medication therapy often fails. It is also effective in patients with mild to moderate hypertension who cannot tolerate enough medication to control their blood pressure,” Dr. Fisher added.

The Paradise ultrasound renal denervation system previously received CE mark and has been successfully introduced in Europe and is an investigational device in Japan, the companies note.

A second renal denervation system, the Symplicity Spyral Renal Denervation System (Medtronic) underwent FDA panel review the day after the Paradise system review in August, and although the panel voted unanimously that the Symplicity system is safe, they were split on whether or not it was efficacious. A final decision on approval by the FDA of that system is still pending.

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

The Food and Drug Administration has approved the Paradise Ultrasound Renal Denervation system for the treatment of hypertension, Recor Medical and parent company Otsuka Medical Devices have announced.
 

Approval follows a positive review by the FDA’s Circulatory Systems Device panel in August that deemed the system both safe and effective in lowering blood pressure for adults with uncontrolled hypertension who may be inadequately responsive to, or who are intolerant of, antihypertensive medications. 

Olivier Le Moal/Getty Images

Data supporting approval were provided by the RADIANCE program, the pivotal RADIANCE II trial, as well as RADIANCE-HTN SOLO and RADIANCE-HTN TRIO. RADIANCE II and RADIANCE-HTN SOLO studied patients with mild to moderate hypertension in an “off-meds” setting, and RADIANCE-HTN TRIO enrolled patients with resistant hypertension on standardized triple antihypertensive therapy.  

Renal denervation is intended as an adjunctive treatment option when lifestyle changes and medication have not resulted in adequate blood pressure control, the statement notes. It works by denervating the sympathetic nerves surrounding the renal arteries, reducing the overactivity that can lead to hypertension.

The system delivers two to three doses of 360-degree ultrasound energy, lasting 7 seconds each, through each of the main renal arteries to the surrounding nerves. This particular system is water-cooled to protect the renal artery wall, the statement adds.

“Given the significant blood pressure reductions seen in the ultrasound renal denervation trials, the Paradise Ultrasound Renal Denervation system offers a much-needed advancement in our currently available options to control hypertension,” site principal investigator Naomi Fisher, MD, associate professor of medicine, Harvard Medical School, and director of hypertension service and hypertension innovation, division of endocrinology, diabetes, and hypertension at Brigham and Women’s Hospital, Boston, said in the statement.

Ultrasound renal denervation “has proven efficacy in patients with truly resistant hypertension, a population for whom medication therapy often fails. It is also effective in patients with mild to moderate hypertension who cannot tolerate enough medication to control their blood pressure,” Dr. Fisher added.

The Paradise ultrasound renal denervation system previously received CE mark and has been successfully introduced in Europe and is an investigational device in Japan, the companies note.

A second renal denervation system, the Symplicity Spyral Renal Denervation System (Medtronic) underwent FDA panel review the day after the Paradise system review in August, and although the panel voted unanimously that the Symplicity system is safe, they were split on whether or not it was efficacious. A final decision on approval by the FDA of that system is still pending.

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

Short- or long-term use of opioids may increase risk of poor outcomes in patients with inflammatory bowel disease (IBD), according to investigators.

These findings amplify the safety signal from previous inpatient studies by showing that even a short course of opioids in an outpatient setting may increase risks of corticosteroid use and emergency department utilization, prompting caution among prescribers, reported Laura Telfer, MS, of Penn State College of Medicine, Hershey, Pa., and colleagues.

“Opioids are frequently prescribed to treat pain associated with IBD,” the investigators wrote in Gastro Hep Advances. “Unfortunately, they are associated with many problems in IBD, including increased risk of emergency room visits, hospitalization, surgery, and mortality. Chronic opioid use may also exacerbate symptoms and induce IBD flares, prompting discontinuation, thus increasing the risk of opioid withdrawal syndrome. Ironically, there is no published evidence that opioids even help to improve abdominal pain in IBD, particularly in the long term. Notably, most studies investigating opioid use in IBD have been limited to hospitalized patients, and few have directly evaluated the impact of opioid prescription length.”

Penn State College of Medicine

To address this knowledge gap, Ms. Telfer and colleagues conducted a retrospective, population-based cohort study involving patients with IBD who were classified as either long-term opioid users, short-term opioid users, or nonusers. Drawing data from more than 80,000 patients in the TriNetX Diamond Network, the investigators evaluated relative, intergroup risks for corticosteroid use, emergency department utilization, mortality, and IBD-related surgery.

Comparing short-term opioid users and nonusers revealed that short-term use more than doubled the risk of corticosteroid prescription (relative risk [RR], 2.517; P less than .001), and increased the risk of an emergency department visit by approximately 32% (RR, 1.315; P less than .001). Long-term use was associated with a similar doubling in risk of corticosteroid prescription (RR, 2.383; P less than .001), and an even greater risk of emergency department utilization (RR, 2.083; P less than .001). Risks of death or IBD-related surgery did not differ for either of these comparisons.

Next, the investigators compared long-term opioid use versus short-term opioid use. This suggested a duration-related effect, as long-term users were 57% more likely than were short-term users to utilize emergency department services (RR, 1.572; P less than .001). No significant differences for the other outcomes were detected in this comparison.

“Unlike previous studies, we did not find an association between opioid use and IBD-related surgery or death,” the investigators wrote. “Notably, these [previously reported] associations utilized opioid dosage (e.g., morphine equivalent or number of prescriptions), rather than length of opioid prescription (as we did). We also focused on IBD outpatients, while prior studies evaluated (in part or completely) inpatient populations, who typically present with more severe illness.”

Still, they added, the present findings should serve as a warning to prescribers considering even a short course of opioids for patients with IBD.

“This study demonstrates that prescribing opioids to IBD outpatients carries significant, specific risks, regardless of prescription length,” Ms. Telfer and colleagues wrote. “Healthcare professionals should exercise caution before prescribing these agents.”

The study was supported by the Peter and Marshia Carlino Early Career Professorship in Inflammatory Bowel Disease, the Margot E. Walrath Career Development Professorship in Gastroenterology, and the National Institutes of Health. The investigators disclosed no conflicts of interest.

Short- or long-term use of opioids may increase risk of poor outcomes in patients with inflammatory bowel disease (IBD), according to investigators.

These findings amplify the safety signal from previous inpatient studies by showing that even a short course of opioids in an outpatient setting may increase risks of corticosteroid use and emergency department utilization, prompting caution among prescribers, reported Laura Telfer, MS, of Penn State College of Medicine, Hershey, Pa., and colleagues.

“Opioids are frequently prescribed to treat pain associated with IBD,” the investigators wrote in Gastro Hep Advances. “Unfortunately, they are associated with many problems in IBD, including increased risk of emergency room visits, hospitalization, surgery, and mortality. Chronic opioid use may also exacerbate symptoms and induce IBD flares, prompting discontinuation, thus increasing the risk of opioid withdrawal syndrome. Ironically, there is no published evidence that opioids even help to improve abdominal pain in IBD, particularly in the long term. Notably, most studies investigating opioid use in IBD have been limited to hospitalized patients, and few have directly evaluated the impact of opioid prescription length.”

Penn State College of Medicine

To address this knowledge gap, Ms. Telfer and colleagues conducted a retrospective, population-based cohort study involving patients with IBD who were classified as either long-term opioid users, short-term opioid users, or nonusers. Drawing data from more than 80,000 patients in the TriNetX Diamond Network, the investigators evaluated relative, intergroup risks for corticosteroid use, emergency department utilization, mortality, and IBD-related surgery.

Comparing short-term opioid users and nonusers revealed that short-term use more than doubled the risk of corticosteroid prescription (relative risk [RR], 2.517; P less than .001), and increased the risk of an emergency department visit by approximately 32% (RR, 1.315; P less than .001). Long-term use was associated with a similar doubling in risk of corticosteroid prescription (RR, 2.383; P less than .001), and an even greater risk of emergency department utilization (RR, 2.083; P less than .001). Risks of death or IBD-related surgery did not differ for either of these comparisons.

Next, the investigators compared long-term opioid use versus short-term opioid use. This suggested a duration-related effect, as long-term users were 57% more likely than were short-term users to utilize emergency department services (RR, 1.572; P less than .001). No significant differences for the other outcomes were detected in this comparison.

“Unlike previous studies, we did not find an association between opioid use and IBD-related surgery or death,” the investigators wrote. “Notably, these [previously reported] associations utilized opioid dosage (e.g., morphine equivalent or number of prescriptions), rather than length of opioid prescription (as we did). We also focused on IBD outpatients, while prior studies evaluated (in part or completely) inpatient populations, who typically present with more severe illness.”

Still, they added, the present findings should serve as a warning to prescribers considering even a short course of opioids for patients with IBD.

“This study demonstrates that prescribing opioids to IBD outpatients carries significant, specific risks, regardless of prescription length,” Ms. Telfer and colleagues wrote. “Healthcare professionals should exercise caution before prescribing these agents.”

The study was supported by the Peter and Marshia Carlino Early Career Professorship in Inflammatory Bowel Disease, the Margot E. Walrath Career Development Professorship in Gastroenterology, and the National Institutes of Health. The investigators disclosed no conflicts of interest.

Short- or long-term use of opioids may increase risk of poor outcomes in patients with inflammatory bowel disease (IBD), according to investigators.

These findings amplify the safety signal from previous inpatient studies by showing that even a short course of opioids in an outpatient setting may increase risks of corticosteroid use and emergency department utilization, prompting caution among prescribers, reported Laura Telfer, MS, of Penn State College of Medicine, Hershey, Pa., and colleagues.

“Opioids are frequently prescribed to treat pain associated with IBD,” the investigators wrote in Gastro Hep Advances. “Unfortunately, they are associated with many problems in IBD, including increased risk of emergency room visits, hospitalization, surgery, and mortality. Chronic opioid use may also exacerbate symptoms and induce IBD flares, prompting discontinuation, thus increasing the risk of opioid withdrawal syndrome. Ironically, there is no published evidence that opioids even help to improve abdominal pain in IBD, particularly in the long term. Notably, most studies investigating opioid use in IBD have been limited to hospitalized patients, and few have directly evaluated the impact of opioid prescription length.”

Penn State College of Medicine

To address this knowledge gap, Ms. Telfer and colleagues conducted a retrospective, population-based cohort study involving patients with IBD who were classified as either long-term opioid users, short-term opioid users, or nonusers. Drawing data from more than 80,000 patients in the TriNetX Diamond Network, the investigators evaluated relative, intergroup risks for corticosteroid use, emergency department utilization, mortality, and IBD-related surgery.

Comparing short-term opioid users and nonusers revealed that short-term use more than doubled the risk of corticosteroid prescription (relative risk [RR], 2.517; P less than .001), and increased the risk of an emergency department visit by approximately 32% (RR, 1.315; P less than .001). Long-term use was associated with a similar doubling in risk of corticosteroid prescription (RR, 2.383; P less than .001), and an even greater risk of emergency department utilization (RR, 2.083; P less than .001). Risks of death or IBD-related surgery did not differ for either of these comparisons.

Next, the investigators compared long-term opioid use versus short-term opioid use. This suggested a duration-related effect, as long-term users were 57% more likely than were short-term users to utilize emergency department services (RR, 1.572; P less than .001). No significant differences for the other outcomes were detected in this comparison.

“Unlike previous studies, we did not find an association between opioid use and IBD-related surgery or death,” the investigators wrote. “Notably, these [previously reported] associations utilized opioid dosage (e.g., morphine equivalent or number of prescriptions), rather than length of opioid prescription (as we did). We also focused on IBD outpatients, while prior studies evaluated (in part or completely) inpatient populations, who typically present with more severe illness.”

Still, they added, the present findings should serve as a warning to prescribers considering even a short course of opioids for patients with IBD.

“This study demonstrates that prescribing opioids to IBD outpatients carries significant, specific risks, regardless of prescription length,” Ms. Telfer and colleagues wrote. “Healthcare professionals should exercise caution before prescribing these agents.”

The study was supported by the Peter and Marshia Carlino Early Career Professorship in Inflammatory Bowel Disease, the Margot E. Walrath Career Development Professorship in Gastroenterology, and the National Institutes of Health. The investigators disclosed no conflicts of interest.

MADRID – Fine particulate matter pollution in the atmosphere around homes and workplaces increases the risk for breast cancer, according to a new analysis of the XENAIR study presented at the European Society of Medical Oncology (ESMO) Congress 2023. Béatrice Fervers, MD, PhD, head of the environmental cancer prevention department at the Léon Bérard Center, Lyon, France, presented her findings.

“To our knowledge, this study is the first to examine the risk of breast cancer associated with long-term exposure of subjects to atmospheric pollution both at home and in the workplace, estimated using a very small spatial resolution [statistical] model,” said the researchers.

“Our data showed a statistically significant association between long-term exposure to fine particulate matter air pollution, at home and at work, and risk of breast cancer. This [finding] contrasts with previous research that looked only at fine particulate exposure where women were living and showed small or no effects on breast cancer risk,” said Dr. Fervers in a press release issued before the Congress.

The XENAIR study carried out on the prospective, longitudinal E3N cohort a year ago showed an increased risk for breast cancer after exposure to five atmospheric pollutants. Notably, it showed an increased risk in women exposed to BaP and PCB153, two pollutants classed as endocrine-disrupting chemicals, during perimenopause.
 

Increased linear risk

In this new analysis, exposure to PM2.5, PM10, and NO2 pollution at home and in the workplace of 2,419 women with breast cancer was compared with that of 2,984 women without breast cancer during the period from 1990 to 2011.

This was a case-control study in which participants were matched by department of residence in France, age (± 1 year), date (± 3 months), and menopausal status at the time of the blood draw.

Breast cancer risk increased by 28% when exposure to fine particulate (PM2.5) air pollution increased by 10 mcg/m3. The increment is approximately equivalent to the difference in PM2.5 particulate concentration typically seen in rural versus urban areas of Europe.

Smaller increases in breast cancer risk were also recorded in women exposed to high levels of larger particulate air pollution (PM10 and NO2).

No change in effect was seen according to menopausal status. Analyses that examined hormone receptor status showed a positive but not significant association for PM2.5 in cases of estrogen receptor positive breast cancer.

Dr. Fervers and colleagues plan to investigate the effects of pollution exposure during the commute to get a complete picture of effects on breast cancer risk.
 

Regulators respond

Charles Swanton, PhD, a clinician scientist at the Francis Crick Institute, London, emphasized the importance of these new results for breast cancer. At last year’s ESMO Congress, he explained how particulate matter air pollution caused tumor proliferation in patients with a certain type of genetic mutation.

“Fine particle pollutants can penetrate deep into the lungs, enter the bloodstream, and be absorbed into breast and other tissue. There is already evidence that air pollutants can change the architecture of the breast. It will be important to test if pollutants allow cells in breast tissue with pre-existing mutations to expand and drive tumor promotion, possibly through inflammatory processes, similar to our observations in nonsmokers with lung cancer,” said Dr. Swanton in the ESMO press release.

“It is very concerning that small pollutant particles in the air and indeed microplastic particles of similar size are getting into the environment when we don’t yet understand their potential to promote cancer. There is an urgent need to set up laboratory studies to investigate the effects of these small air pollutant particles on the latency, grade, aggression, and progression of breast tumors,” he added.

“There is now strong epidemiological and biological evidence for the link between PM2.5 particulate exposure and cancer, and there are good clinical and economic reasons for reducing pollution to prevent cancers,” said Jean-Yves Blay, MD, PhD, director of public policy for ESMO.

Following a proposal from the European Commission in October 2022 to reduce the limit for PM2.5 particulates in the air from the current 25 mcg/m3 to 10 mcg/m3 by 2030, ESMO urged a further reduction in the PM2.5 limit to 5 mcg/m3, in line with the World Health Organization’s air quality guidance, according to the press release.

“Reducing PM2.5 particles in the air to the WHO recommended level is critical because of their association with a variety of tumor types, including breast cancer,” Dr. Blay added.

In September 2023, the European Parliament adopted in a plenary session its report on the ongoing revision of the EU Ambient Air Quality Directives, which reflects ESMO’s recommendations to set the annual limit value for PM2.5 at 5 mcg/m³. This adoption opens interinstitutional negotiations between the legislators (the European Parliament, European Commission, and EU Council) to agree on the final text of the directive.

“By supporting our requests with solid scientific evidence, we are offering a new dimension to health public policy. The work is not over, and change will not happen overnight, but we are moving in the right direction,” concluded Dr. Blay.

The new analysis of the XENAIR study was funded by ARC Foundation for cancer research; the French Agency for Food, Environmental, and Occupational Health and Safety; French National League against Cancer; and Fondation de France, an independent private organization, recognized as being in the public interest. The authors report no relevant financial relationships.

This article was translated from the Medscape French edition and a version appeared on Medscape.com.

MADRID – Fine particulate matter pollution in the atmosphere around homes and workplaces increases the risk for breast cancer, according to a new analysis of the XENAIR study presented at the European Society of Medical Oncology (ESMO) Congress 2023. Béatrice Fervers, MD, PhD, head of the environmental cancer prevention department at the Léon Bérard Center, Lyon, France, presented her findings.

“To our knowledge, this study is the first to examine the risk of breast cancer associated with long-term exposure of subjects to atmospheric pollution both at home and in the workplace, estimated using a very small spatial resolution [statistical] model,” said the researchers.

“Our data showed a statistically significant association between long-term exposure to fine particulate matter air pollution, at home and at work, and risk of breast cancer. This [finding] contrasts with previous research that looked only at fine particulate exposure where women were living and showed small or no effects on breast cancer risk,” said Dr. Fervers in a press release issued before the Congress.

The XENAIR study carried out on the prospective, longitudinal E3N cohort a year ago showed an increased risk for breast cancer after exposure to five atmospheric pollutants. Notably, it showed an increased risk in women exposed to BaP and PCB153, two pollutants classed as endocrine-disrupting chemicals, during perimenopause.
 

Increased linear risk

In this new analysis, exposure to PM2.5, PM10, and NO2 pollution at home and in the workplace of 2,419 women with breast cancer was compared with that of 2,984 women without breast cancer during the period from 1990 to 2011.

This was a case-control study in which participants were matched by department of residence in France, age (± 1 year), date (± 3 months), and menopausal status at the time of the blood draw.

Breast cancer risk increased by 28% when exposure to fine particulate (PM2.5) air pollution increased by 10 mcg/m3. The increment is approximately equivalent to the difference in PM2.5 particulate concentration typically seen in rural versus urban areas of Europe.

Smaller increases in breast cancer risk were also recorded in women exposed to high levels of larger particulate air pollution (PM10 and NO2).

No change in effect was seen according to menopausal status. Analyses that examined hormone receptor status showed a positive but not significant association for PM2.5 in cases of estrogen receptor positive breast cancer.

Dr. Fervers and colleagues plan to investigate the effects of pollution exposure during the commute to get a complete picture of effects on breast cancer risk.
 

Regulators respond

Charles Swanton, PhD, a clinician scientist at the Francis Crick Institute, London, emphasized the importance of these new results for breast cancer. At last year’s ESMO Congress, he explained how particulate matter air pollution caused tumor proliferation in patients with a certain type of genetic mutation.

“Fine particle pollutants can penetrate deep into the lungs, enter the bloodstream, and be absorbed into breast and other tissue. There is already evidence that air pollutants can change the architecture of the breast. It will be important to test if pollutants allow cells in breast tissue with pre-existing mutations to expand and drive tumor promotion, possibly through inflammatory processes, similar to our observations in nonsmokers with lung cancer,” said Dr. Swanton in the ESMO press release.

“It is very concerning that small pollutant particles in the air and indeed microplastic particles of similar size are getting into the environment when we don’t yet understand their potential to promote cancer. There is an urgent need to set up laboratory studies to investigate the effects of these small air pollutant particles on the latency, grade, aggression, and progression of breast tumors,” he added.

“There is now strong epidemiological and biological evidence for the link between PM2.5 particulate exposure and cancer, and there are good clinical and economic reasons for reducing pollution to prevent cancers,” said Jean-Yves Blay, MD, PhD, director of public policy for ESMO.

Following a proposal from the European Commission in October 2022 to reduce the limit for PM2.5 particulates in the air from the current 25 mcg/m3 to 10 mcg/m3 by 2030, ESMO urged a further reduction in the PM2.5 limit to 5 mcg/m3, in line with the World Health Organization’s air quality guidance, according to the press release.

“Reducing PM2.5 particles in the air to the WHO recommended level is critical because of their association with a variety of tumor types, including breast cancer,” Dr. Blay added.

In September 2023, the European Parliament adopted in a plenary session its report on the ongoing revision of the EU Ambient Air Quality Directives, which reflects ESMO’s recommendations to set the annual limit value for PM2.5 at 5 mcg/m³. This adoption opens interinstitutional negotiations between the legislators (the European Parliament, European Commission, and EU Council) to agree on the final text of the directive.

“By supporting our requests with solid scientific evidence, we are offering a new dimension to health public policy. The work is not over, and change will not happen overnight, but we are moving in the right direction,” concluded Dr. Blay.

The new analysis of the XENAIR study was funded by ARC Foundation for cancer research; the French Agency for Food, Environmental, and Occupational Health and Safety; French National League against Cancer; and Fondation de France, an independent private organization, recognized as being in the public interest. The authors report no relevant financial relationships.

This article was translated from the Medscape French edition and a version appeared on Medscape.com.

MADRID – Fine particulate matter pollution in the atmosphere around homes and workplaces increases the risk for breast cancer, according to a new analysis of the XENAIR study presented at the European Society of Medical Oncology (ESMO) Congress 2023. Béatrice Fervers, MD, PhD, head of the environmental cancer prevention department at the Léon Bérard Center, Lyon, France, presented her findings.

“To our knowledge, this study is the first to examine the risk of breast cancer associated with long-term exposure of subjects to atmospheric pollution both at home and in the workplace, estimated using a very small spatial resolution [statistical] model,” said the researchers.

“Our data showed a statistically significant association between long-term exposure to fine particulate matter air pollution, at home and at work, and risk of breast cancer. This [finding] contrasts with previous research that looked only at fine particulate exposure where women were living and showed small or no effects on breast cancer risk,” said Dr. Fervers in a press release issued before the Congress.

The XENAIR study carried out on the prospective, longitudinal E3N cohort a year ago showed an increased risk for breast cancer after exposure to five atmospheric pollutants. Notably, it showed an increased risk in women exposed to BaP and PCB153, two pollutants classed as endocrine-disrupting chemicals, during perimenopause.
 

Increased linear risk

In this new analysis, exposure to PM2.5, PM10, and NO2 pollution at home and in the workplace of 2,419 women with breast cancer was compared with that of 2,984 women without breast cancer during the period from 1990 to 2011.

This was a case-control study in which participants were matched by department of residence in France, age (± 1 year), date (± 3 months), and menopausal status at the time of the blood draw.

Breast cancer risk increased by 28% when exposure to fine particulate (PM2.5) air pollution increased by 10 mcg/m3. The increment is approximately equivalent to the difference in PM2.5 particulate concentration typically seen in rural versus urban areas of Europe.

Smaller increases in breast cancer risk were also recorded in women exposed to high levels of larger particulate air pollution (PM10 and NO2).

No change in effect was seen according to menopausal status. Analyses that examined hormone receptor status showed a positive but not significant association for PM2.5 in cases of estrogen receptor positive breast cancer.

Dr. Fervers and colleagues plan to investigate the effects of pollution exposure during the commute to get a complete picture of effects on breast cancer risk.
 

Regulators respond

Charles Swanton, PhD, a clinician scientist at the Francis Crick Institute, London, emphasized the importance of these new results for breast cancer. At last year’s ESMO Congress, he explained how particulate matter air pollution caused tumor proliferation in patients with a certain type of genetic mutation.

“Fine particle pollutants can penetrate deep into the lungs, enter the bloodstream, and be absorbed into breast and other tissue. There is already evidence that air pollutants can change the architecture of the breast. It will be important to test if pollutants allow cells in breast tissue with pre-existing mutations to expand and drive tumor promotion, possibly through inflammatory processes, similar to our observations in nonsmokers with lung cancer,” said Dr. Swanton in the ESMO press release.

“It is very concerning that small pollutant particles in the air and indeed microplastic particles of similar size are getting into the environment when we don’t yet understand their potential to promote cancer. There is an urgent need to set up laboratory studies to investigate the effects of these small air pollutant particles on the latency, grade, aggression, and progression of breast tumors,” he added.

“There is now strong epidemiological and biological evidence for the link between PM2.5 particulate exposure and cancer, and there are good clinical and economic reasons for reducing pollution to prevent cancers,” said Jean-Yves Blay, MD, PhD, director of public policy for ESMO.

Following a proposal from the European Commission in October 2022 to reduce the limit for PM2.5 particulates in the air from the current 25 mcg/m3 to 10 mcg/m3 by 2030, ESMO urged a further reduction in the PM2.5 limit to 5 mcg/m3, in line with the World Health Organization’s air quality guidance, according to the press release.

“Reducing PM2.5 particles in the air to the WHO recommended level is critical because of their association with a variety of tumor types, including breast cancer,” Dr. Blay added.

In September 2023, the European Parliament adopted in a plenary session its report on the ongoing revision of the EU Ambient Air Quality Directives, which reflects ESMO’s recommendations to set the annual limit value for PM2.5 at 5 mcg/m³. This adoption opens interinstitutional negotiations between the legislators (the European Parliament, European Commission, and EU Council) to agree on the final text of the directive.

“By supporting our requests with solid scientific evidence, we are offering a new dimension to health public policy. The work is not over, and change will not happen overnight, but we are moving in the right direction,” concluded Dr. Blay.

The new analysis of the XENAIR study was funded by ARC Foundation for cancer research; the French Agency for Food, Environmental, and Occupational Health and Safety; French National League against Cancer; and Fondation de France, an independent private organization, recognized as being in the public interest. The authors report no relevant financial relationships.

This article was translated from the Medscape French edition and a version appeared on Medscape.com.

TOPLINE:

Obtaining standing office blood pressure measurements improves detection of hypertension, either alone or when added to a seated BP reading, results of a new study suggest.

METHODOLOGY:

• The study included 125 adults, mean age 49 years and 62% female, who were free of cardiovascular disease and had no previous history of hypertension.
• Researchers collected data on 24-hour ambulatory blood pressure monitoring (ABPM), and three BP measurements in the seated position, then three in the standing position.
• They assessed overall diagnostic accuracy of seated and standing BP using the area under the receiver operating characteristic (AUROC) curve and considered a Bayes factor (BF) of 3 or greater as significant.
• They defined the presence of hypertension (HTN) by the 2017 American College of Cardiology/American Heart Association and 2023 European Society of Hypertension HTN guidelines based on ABPM.
• Sensitivity and specificity of standing BP was determined using cutoffs derived from Youden index, while sensitivity and specificity of seated BP was determined using the cutoff of 130/80 mm Hg and by 140/90 mm Hg.

TAKEAWAY:

• The AUROC for standing office systolic blood pressure (SBP; 0.81; 0.71-0.92) was significantly higher than for seated office SBP (0.70; 0.49-0.91) in diagnosing HTN when defined as an average 24-hour SBP ≥ 125 mm Hg (BF = 11.8), and significantly higher for seated versus standing office diastolic blood pressure (DBP; 0.65; 0.49-0.82) in diagnosing HTN when defined as an average 24-hour DBP ≥ 75 mm Hg (BF = 4.9).
• The AUROCs for adding standing office BP to seated office BP improved the accuracy of detecting HTN, compared with seated office BP alone when HTN was defined as an average 24-hour SBP/DBP ≥ 125/75 mm Hg or daytime SBP/DBP ≥ 130/80 mm Hg, or when defined as an average 24-hour SBP/DBP ≥ 130/80 mm Hg or daytime SBP/DBP ≥ 135/85 mm Hg (all BFs > 3).
• Sensitivity of standing SBP was 71%, compared with 43% for seated SBP.

IN PRACTICE:

The “excellent diagnostic performance” for standing BP measures revealed by the study “highlights that standing office BP has acceptable discriminative capabilities in identifying the presence of hypertension in adults,” the authors write.

SOURCE:

The study was conducted by John M. Giacona, Hypertension Section, department of internal medicine, University of Texas Southwestern Medical Center, Dallas, and colleagues. It was published online in Scientific Reports.

LIMITATIONS:

As the study enrolled only adults free of comorbidities who were not taking antihypertensive medications, the results may not be applicable to other patients. The study design was retrospective, and the order of BP measurements was not randomized (standing BP measurements were obtained only after seated BP).

DISCLOSURES:

The study was supported by the National Institutes of Health. The authors have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Obtaining standing office blood pressure measurements improves detection of hypertension, either alone or when added to a seated BP reading, results of a new study suggest.

METHODOLOGY:

• The study included 125 adults, mean age 49 years and 62% female, who were free of cardiovascular disease and had no previous history of hypertension.
• Researchers collected data on 24-hour ambulatory blood pressure monitoring (ABPM), and three BP measurements in the seated position, then three in the standing position.
• They assessed overall diagnostic accuracy of seated and standing BP using the area under the receiver operating characteristic (AUROC) curve and considered a Bayes factor (BF) of 3 or greater as significant.
• They defined the presence of hypertension (HTN) by the 2017 American College of Cardiology/American Heart Association and 2023 European Society of Hypertension HTN guidelines based on ABPM.
• Sensitivity and specificity of standing BP was determined using cutoffs derived from Youden index, while sensitivity and specificity of seated BP was determined using the cutoff of 130/80 mm Hg and by 140/90 mm Hg.

TAKEAWAY:

• The AUROC for standing office systolic blood pressure (SBP; 0.81; 0.71-0.92) was significantly higher than for seated office SBP (0.70; 0.49-0.91) in diagnosing HTN when defined as an average 24-hour SBP ≥ 125 mm Hg (BF = 11.8), and significantly higher for seated versus standing office diastolic blood pressure (DBP; 0.65; 0.49-0.82) in diagnosing HTN when defined as an average 24-hour DBP ≥ 75 mm Hg (BF = 4.9).
• The AUROCs for adding standing office BP to seated office BP improved the accuracy of detecting HTN, compared with seated office BP alone when HTN was defined as an average 24-hour SBP/DBP ≥ 125/75 mm Hg or daytime SBP/DBP ≥ 130/80 mm Hg, or when defined as an average 24-hour SBP/DBP ≥ 130/80 mm Hg or daytime SBP/DBP ≥ 135/85 mm Hg (all BFs > 3).
• Sensitivity of standing SBP was 71%, compared with 43% for seated SBP.

IN PRACTICE:

The “excellent diagnostic performance” for standing BP measures revealed by the study “highlights that standing office BP has acceptable discriminative capabilities in identifying the presence of hypertension in adults,” the authors write.

SOURCE:

The study was conducted by John M. Giacona, Hypertension Section, department of internal medicine, University of Texas Southwestern Medical Center, Dallas, and colleagues. It was published online in Scientific Reports.

LIMITATIONS:

As the study enrolled only adults free of comorbidities who were not taking antihypertensive medications, the results may not be applicable to other patients. The study design was retrospective, and the order of BP measurements was not randomized (standing BP measurements were obtained only after seated BP).

DISCLOSURES:

The study was supported by the National Institutes of Health. The authors have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Obtaining standing office blood pressure measurements improves detection of hypertension, either alone or when added to a seated BP reading, results of a new study suggest.

METHODOLOGY:

• The study included 125 adults, mean age 49 years and 62% female, who were free of cardiovascular disease and had no previous history of hypertension.
• Researchers collected data on 24-hour ambulatory blood pressure monitoring (ABPM), and three BP measurements in the seated position, then three in the standing position.
• They assessed overall diagnostic accuracy of seated and standing BP using the area under the receiver operating characteristic (AUROC) curve and considered a Bayes factor (BF) of 3 or greater as significant.
• They defined the presence of hypertension (HTN) by the 2017 American College of Cardiology/American Heart Association and 2023 European Society of Hypertension HTN guidelines based on ABPM.
• Sensitivity and specificity of standing BP was determined using cutoffs derived from Youden index, while sensitivity and specificity of seated BP was determined using the cutoff of 130/80 mm Hg and by 140/90 mm Hg.

TAKEAWAY:

• The AUROC for standing office systolic blood pressure (SBP; 0.81; 0.71-0.92) was significantly higher than for seated office SBP (0.70; 0.49-0.91) in diagnosing HTN when defined as an average 24-hour SBP ≥ 125 mm Hg (BF = 11.8), and significantly higher for seated versus standing office diastolic blood pressure (DBP; 0.65; 0.49-0.82) in diagnosing HTN when defined as an average 24-hour DBP ≥ 75 mm Hg (BF = 4.9).
• The AUROCs for adding standing office BP to seated office BP improved the accuracy of detecting HTN, compared with seated office BP alone when HTN was defined as an average 24-hour SBP/DBP ≥ 125/75 mm Hg or daytime SBP/DBP ≥ 130/80 mm Hg, or when defined as an average 24-hour SBP/DBP ≥ 130/80 mm Hg or daytime SBP/DBP ≥ 135/85 mm Hg (all BFs > 3).
• Sensitivity of standing SBP was 71%, compared with 43% for seated SBP.

IN PRACTICE:

The “excellent diagnostic performance” for standing BP measures revealed by the study “highlights that standing office BP has acceptable discriminative capabilities in identifying the presence of hypertension in adults,” the authors write.

SOURCE:

The study was conducted by John M. Giacona, Hypertension Section, department of internal medicine, University of Texas Southwestern Medical Center, Dallas, and colleagues. It was published online in Scientific Reports.

LIMITATIONS:

As the study enrolled only adults free of comorbidities who were not taking antihypertensive medications, the results may not be applicable to other patients. The study design was retrospective, and the order of BP measurements was not randomized (standing BP measurements were obtained only after seated BP).

DISCLOSURES:

The study was supported by the National Institutes of Health. The authors have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

The Food and Drug Administration has approved tirzepatide for chronic weight management in adults with obesity or overweight.

Eli Lilly will market tirzepatide injections for weight management under the trade name Zepbound. It was approved in May 2022 for treating type 2 diabetes. The new indication is for adults with either obesity, defined as a body mass index of 30 kg/m² or greater, or overweight, with a BMI of 27 or greater with at least one weight-related comorbidity, including hypertension, type 2 diabetes, or dyslipidemia.

“Obesity and overweight are serious conditions that can be associated with some of the leading causes of death, such as heart disease, stroke, and diabetes,” said John Sharretts, MD, director of the division of diabetes, lipid disorders, and obesity in the FDA’s Center for Drug Evaluation and Research. “In light of increasing rates of both obesity and overweight in the United States, today’s approval addresses an unmet medical need.”

A once-weekly injection, tirzepatide reduces appetite by activating two gut hormones, glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The dosage is increased over 4-20 weeks to achieve a weekly dose target of 5 mg, 10 mg, or 15 mg maximum.

Efficacy was established in two pivotal randomized, double-blind, placebo-controlled trials of adults with obesity or overweight plus another condition. One trial measured weight reduction after 72 weeks in a total of 2,519 patients without diabetes who received either 5 mg, 10 mg or 15 mg of tirzepatide once weekly. Those who received the 15-mg dose achieved on average 18% of their initial body weight, compared with placebo.

The other pivotal trial enrolled a total of 938 patients with type 2 diabetes. These patients achieved an average weight loss of 12% with once-weekly tirzepatide compared to placebo.

Another trial, which was presented at the 2023 Obesity Week meeting and was published in Nature Medicine, showed clinically meaningful added weight loss for adults with obesity who did not have diabetes and who had already experienced weight loss of at least 5% after a 12-week intensive lifestyle intervention.

Another trial, which was reported at the 2023 annual meeting of the European Association for the Study of Diabetes, found that tirzepatide continued to produce “highly significant weight loss” when the drug was continued in a 1-year follow-up trial. Those who discontinued taking the drug regained some weight but not all.

Tirzepatide can cause gastrointestinal side effects, such as nausea, diarrhea, vomiting, constipation, and abdominal pain or discomfort. Site reactions, hypersensitivity, hair loss, burping, and gastrointestinal reflux disease have also been reported.

The medication should not be used by patients with a personal or family history of medullary thyroid cancer or by patients with multiple endocrine neoplasia syndrome type 2. It should also not be used in combination with Mounjaro or another GLP-1 receptor agonist. The safety and effectiveness of the coadministration of tirzepatide with other medications for weight management have not been established.

Zepbound should go to market in the United States by the end of 2023, with an anticipated monthly list price of $1,060, according to a news release from Eli Lilly.

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

The Food and Drug Administration has approved tirzepatide for chronic weight management in adults with obesity or overweight.

Eli Lilly will market tirzepatide injections for weight management under the trade name Zepbound. It was approved in May 2022 for treating type 2 diabetes. The new indication is for adults with either obesity, defined as a body mass index of 30 kg/m² or greater, or overweight, with a BMI of 27 or greater with at least one weight-related comorbidity, including hypertension, type 2 diabetes, or dyslipidemia.

“Obesity and overweight are serious conditions that can be associated with some of the leading causes of death, such as heart disease, stroke, and diabetes,” said John Sharretts, MD, director of the division of diabetes, lipid disorders, and obesity in the FDA’s Center for Drug Evaluation and Research. “In light of increasing rates of both obesity and overweight in the United States, today’s approval addresses an unmet medical need.”

A once-weekly injection, tirzepatide reduces appetite by activating two gut hormones, glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The dosage is increased over 4-20 weeks to achieve a weekly dose target of 5 mg, 10 mg, or 15 mg maximum.

Efficacy was established in two pivotal randomized, double-blind, placebo-controlled trials of adults with obesity or overweight plus another condition. One trial measured weight reduction after 72 weeks in a total of 2,519 patients without diabetes who received either 5 mg, 10 mg or 15 mg of tirzepatide once weekly. Those who received the 15-mg dose achieved on average 18% of their initial body weight, compared with placebo.

The other pivotal trial enrolled a total of 938 patients with type 2 diabetes. These patients achieved an average weight loss of 12% with once-weekly tirzepatide compared to placebo.

Another trial, which was presented at the 2023 Obesity Week meeting and was published in Nature Medicine, showed clinically meaningful added weight loss for adults with obesity who did not have diabetes and who had already experienced weight loss of at least 5% after a 12-week intensive lifestyle intervention.

Another trial, which was reported at the 2023 annual meeting of the European Association for the Study of Diabetes, found that tirzepatide continued to produce “highly significant weight loss” when the drug was continued in a 1-year follow-up trial. Those who discontinued taking the drug regained some weight but not all.

Tirzepatide can cause gastrointestinal side effects, such as nausea, diarrhea, vomiting, constipation, and abdominal pain or discomfort. Site reactions, hypersensitivity, hair loss, burping, and gastrointestinal reflux disease have also been reported.

The medication should not be used by patients with a personal or family history of medullary thyroid cancer or by patients with multiple endocrine neoplasia syndrome type 2. It should also not be used in combination with Mounjaro or another GLP-1 receptor agonist. The safety and effectiveness of the coadministration of tirzepatide with other medications for weight management have not been established.

Zepbound should go to market in the United States by the end of 2023, with an anticipated monthly list price of $1,060, according to a news release from Eli Lilly.

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

The Food and Drug Administration has approved tirzepatide for chronic weight management in adults with obesity or overweight.

Eli Lilly will market tirzepatide injections for weight management under the trade name Zepbound. It was approved in May 2022 for treating type 2 diabetes. The new indication is for adults with either obesity, defined as a body mass index of 30 kg/m² or greater, or overweight, with a BMI of 27 or greater with at least one weight-related comorbidity, including hypertension, type 2 diabetes, or dyslipidemia.

“Obesity and overweight are serious conditions that can be associated with some of the leading causes of death, such as heart disease, stroke, and diabetes,” said John Sharretts, MD, director of the division of diabetes, lipid disorders, and obesity in the FDA’s Center for Drug Evaluation and Research. “In light of increasing rates of both obesity and overweight in the United States, today’s approval addresses an unmet medical need.”

A once-weekly injection, tirzepatide reduces appetite by activating two gut hormones, glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The dosage is increased over 4-20 weeks to achieve a weekly dose target of 5 mg, 10 mg, or 15 mg maximum.

Efficacy was established in two pivotal randomized, double-blind, placebo-controlled trials of adults with obesity or overweight plus another condition. One trial measured weight reduction after 72 weeks in a total of 2,519 patients without diabetes who received either 5 mg, 10 mg or 15 mg of tirzepatide once weekly. Those who received the 15-mg dose achieved on average 18% of their initial body weight, compared with placebo.

The other pivotal trial enrolled a total of 938 patients with type 2 diabetes. These patients achieved an average weight loss of 12% with once-weekly tirzepatide compared to placebo.

Another trial, which was presented at the 2023 Obesity Week meeting and was published in Nature Medicine, showed clinically meaningful added weight loss for adults with obesity who did not have diabetes and who had already experienced weight loss of at least 5% after a 12-week intensive lifestyle intervention.

Another trial, which was reported at the 2023 annual meeting of the European Association for the Study of Diabetes, found that tirzepatide continued to produce “highly significant weight loss” when the drug was continued in a 1-year follow-up trial. Those who discontinued taking the drug regained some weight but not all.

Tirzepatide can cause gastrointestinal side effects, such as nausea, diarrhea, vomiting, constipation, and abdominal pain or discomfort. Site reactions, hypersensitivity, hair loss, burping, and gastrointestinal reflux disease have also been reported.

The medication should not be used by patients with a personal or family history of medullary thyroid cancer or by patients with multiple endocrine neoplasia syndrome type 2. It should also not be used in combination with Mounjaro or another GLP-1 receptor agonist. The safety and effectiveness of the coadministration of tirzepatide with other medications for weight management have not been established.

Zepbound should go to market in the United States by the end of 2023, with an anticipated monthly list price of $1,060, according to a news release from Eli Lilly.

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

It takes an average of 4 years for a pancreatic lesion to progress from high-grade dysplasia (HGD) to cancer, suggesting a window of opportunity for screening, based on a microsimulation model.

To seize this opportunity, however, a greater understanding of natural disease course is needed, along with more sensitive screening tools, reported Brechtje D. M. Koopmann, MD, of Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues.

Previous studies have suggested that the window of opportunity for pancreatic cancer screening may span decades, with estimates ranging from 12 to 50 years, the investigators wrote. Their report was published in Gastroenterology.

“Unfortunately, the poor results of pancreatic cancer screening do not align with this assumption, leaving unanswered whether this large window of opportunity truly exists,” they noted. “Microsimulation modeling, combined with available, if limited data, can provide new information on the natural disease course.”

For the present study, the investigators used the Microsimulation Screening Analysis (MISCAN) model, which has guided development of screening programs around the world for cervical, breast, and colorectal cancer. The model incorporates natural disease course, screening, and demographic data, then uses observable inputs such as precursor lesion prevalence and cancer incidence to estimate unobservable outcomes like stage durations and precursor lesion onset.

Dr. Koopmann and colleagues programmed this model with Dutch pancreatic cancer incidence data and findings from Japanese autopsy cases without pancreatic cancer.

First, the model offered insights into precursor lesion prevalence.

The estimated prevalence of any cystic lesion in the pancreas was 6.1% for individuals 50 years of age and 29.6% for those 80 years of age. Solid precursor lesions (PanINs) were estimated to be mainly multifocal (three or more lesions) in individuals older than 80 years. By this age, almost 12% had at least two PanINs. For those lesions that eventually became cancerous, the mean time since cyst onset was estimated to be 8.8 years, and mean time since PanIN onset was 9.0 years.

However, less than 10% of cystic and PanIN lesions progress to become cancers. PanIN lesions are not visible on imaging, and therefore current screening focuses on finding cystic precursor lesions, although these represent only about 10% of pancreatic cancers.

“Given the low pancreatic cancer progression risk of cysts, evaluation of the efficiency of current surveillance guidelines is necessary,” the investigators noted.

Screening should instead focus on identifying high-grade dysplastic lesions, they suggested. While these lesions may have a very low estimated prevalence, at just 0.3% among individuals 90 years of age, they present the greatest risk of pancreatic cancer.

For precursor cysts exhibiting HGD that progressed to pancreatic cancer, the mean interval between dysplasia and cancer was just 4 years. Among 13.7% of individuals, the interval was less than 1 year, suggesting an even shorter window of opportunity for screening.

Beyond this brief timeframe, low test sensitivity explains why screening efforts to date have fallen short, the investigators wrote.

Better tests are “urgently needed,” they added, while acknowledging the challenges inherent to this endeavor. Previous research has shown that precursor lesions in the pancreas are often less than 5 mm in diameter, making them extremely challenging to detect. An effective tool would need to identify solid precursor lesions (PanINs), and also need to simultaneously determine grade of dysplasia.

“Biomarkers could be the future in this matter,” the investigators suggested.

Dr. Koopmann and colleagues concluded by noting that more research is needed to characterize the pathophysiology of pancreatic cancer. On their part, “the current model will be validated, adjusted, and improved whenever new data from autopsy or prospective surveillance studies become available.”

The study was funded in part by Maag Lever Darm Stichting. The investigators disclosed no conflicts of interest.

It takes an average of 4 years for a pancreatic lesion to progress from high-grade dysplasia (HGD) to cancer, suggesting a window of opportunity for screening, based on a microsimulation model.

To seize this opportunity, however, a greater understanding of natural disease course is needed, along with more sensitive screening tools, reported Brechtje D. M. Koopmann, MD, of Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues.

Previous studies have suggested that the window of opportunity for pancreatic cancer screening may span decades, with estimates ranging from 12 to 50 years, the investigators wrote. Their report was published in Gastroenterology.

“Unfortunately, the poor results of pancreatic cancer screening do not align with this assumption, leaving unanswered whether this large window of opportunity truly exists,” they noted. “Microsimulation modeling, combined with available, if limited data, can provide new information on the natural disease course.”

For the present study, the investigators used the Microsimulation Screening Analysis (MISCAN) model, which has guided development of screening programs around the world for cervical, breast, and colorectal cancer. The model incorporates natural disease course, screening, and demographic data, then uses observable inputs such as precursor lesion prevalence and cancer incidence to estimate unobservable outcomes like stage durations and precursor lesion onset.

Dr. Koopmann and colleagues programmed this model with Dutch pancreatic cancer incidence data and findings from Japanese autopsy cases without pancreatic cancer.

First, the model offered insights into precursor lesion prevalence.

The estimated prevalence of any cystic lesion in the pancreas was 6.1% for individuals 50 years of age and 29.6% for those 80 years of age. Solid precursor lesions (PanINs) were estimated to be mainly multifocal (three or more lesions) in individuals older than 80 years. By this age, almost 12% had at least two PanINs. For those lesions that eventually became cancerous, the mean time since cyst onset was estimated to be 8.8 years, and mean time since PanIN onset was 9.0 years.

However, less than 10% of cystic and PanIN lesions progress to become cancers. PanIN lesions are not visible on imaging, and therefore current screening focuses on finding cystic precursor lesions, although these represent only about 10% of pancreatic cancers.

“Given the low pancreatic cancer progression risk of cysts, evaluation of the efficiency of current surveillance guidelines is necessary,” the investigators noted.

Screening should instead focus on identifying high-grade dysplastic lesions, they suggested. While these lesions may have a very low estimated prevalence, at just 0.3% among individuals 90 years of age, they present the greatest risk of pancreatic cancer.

For precursor cysts exhibiting HGD that progressed to pancreatic cancer, the mean interval between dysplasia and cancer was just 4 years. Among 13.7% of individuals, the interval was less than 1 year, suggesting an even shorter window of opportunity for screening.

Beyond this brief timeframe, low test sensitivity explains why screening efforts to date have fallen short, the investigators wrote.

Better tests are “urgently needed,” they added, while acknowledging the challenges inherent to this endeavor. Previous research has shown that precursor lesions in the pancreas are often less than 5 mm in diameter, making them extremely challenging to detect. An effective tool would need to identify solid precursor lesions (PanINs), and also need to simultaneously determine grade of dysplasia.

“Biomarkers could be the future in this matter,” the investigators suggested.

Dr. Koopmann and colleagues concluded by noting that more research is needed to characterize the pathophysiology of pancreatic cancer. On their part, “the current model will be validated, adjusted, and improved whenever new data from autopsy or prospective surveillance studies become available.”

The study was funded in part by Maag Lever Darm Stichting. The investigators disclosed no conflicts of interest.

It takes an average of 4 years for a pancreatic lesion to progress from high-grade dysplasia (HGD) to cancer, suggesting a window of opportunity for screening, based on a microsimulation model.

To seize this opportunity, however, a greater understanding of natural disease course is needed, along with more sensitive screening tools, reported Brechtje D. M. Koopmann, MD, of Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues.

Previous studies have suggested that the window of opportunity for pancreatic cancer screening may span decades, with estimates ranging from 12 to 50 years, the investigators wrote. Their report was published in Gastroenterology.

“Unfortunately, the poor results of pancreatic cancer screening do not align with this assumption, leaving unanswered whether this large window of opportunity truly exists,” they noted. “Microsimulation modeling, combined with available, if limited data, can provide new information on the natural disease course.”

For the present study, the investigators used the Microsimulation Screening Analysis (MISCAN) model, which has guided development of screening programs around the world for cervical, breast, and colorectal cancer. The model incorporates natural disease course, screening, and demographic data, then uses observable inputs such as precursor lesion prevalence and cancer incidence to estimate unobservable outcomes like stage durations and precursor lesion onset.

Dr. Koopmann and colleagues programmed this model with Dutch pancreatic cancer incidence data and findings from Japanese autopsy cases without pancreatic cancer.

First, the model offered insights into precursor lesion prevalence.

The estimated prevalence of any cystic lesion in the pancreas was 6.1% for individuals 50 years of age and 29.6% for those 80 years of age. Solid precursor lesions (PanINs) were estimated to be mainly multifocal (three or more lesions) in individuals older than 80 years. By this age, almost 12% had at least two PanINs. For those lesions that eventually became cancerous, the mean time since cyst onset was estimated to be 8.8 years, and mean time since PanIN onset was 9.0 years.

However, less than 10% of cystic and PanIN lesions progress to become cancers. PanIN lesions are not visible on imaging, and therefore current screening focuses on finding cystic precursor lesions, although these represent only about 10% of pancreatic cancers.

“Given the low pancreatic cancer progression risk of cysts, evaluation of the efficiency of current surveillance guidelines is necessary,” the investigators noted.

Screening should instead focus on identifying high-grade dysplastic lesions, they suggested. While these lesions may have a very low estimated prevalence, at just 0.3% among individuals 90 years of age, they present the greatest risk of pancreatic cancer.

For precursor cysts exhibiting HGD that progressed to pancreatic cancer, the mean interval between dysplasia and cancer was just 4 years. Among 13.7% of individuals, the interval was less than 1 year, suggesting an even shorter window of opportunity for screening.

Beyond this brief timeframe, low test sensitivity explains why screening efforts to date have fallen short, the investigators wrote.

Better tests are “urgently needed,” they added, while acknowledging the challenges inherent to this endeavor. Previous research has shown that precursor lesions in the pancreas are often less than 5 mm in diameter, making them extremely challenging to detect. An effective tool would need to identify solid precursor lesions (PanINs), and also need to simultaneously determine grade of dysplasia.

“Biomarkers could be the future in this matter,” the investigators suggested.

Dr. Koopmann and colleagues concluded by noting that more research is needed to characterize the pathophysiology of pancreatic cancer. On their part, “the current model will be validated, adjusted, and improved whenever new data from autopsy or prospective surveillance studies become available.”

The study was funded in part by Maag Lever Darm Stichting. The investigators disclosed no conflicts of interest.

Alopecia areata (AA) is an autoimmune disease that immunopathogenetically is thought to be due to breakdown of the immune privilege of the proximal hair follicle during the anagen growth phase. Alopecia areata has been reported to have a lifetime prevalence of 1.7%.¹ Recent studies have specifically identified cytotoxic CD8⁺ NKG2D⁺ T cells as being responsible for the activation of AA.^2-4 Two interleukins—IL-2 and IL-15—have been implicated to be cytotoxic sensitizers allowing CD8⁺ T cells to secrete IFN-γ and recognize autoantigens via major histocompatibility complex class I.^5,6 Janus kinases (JAKs) are enzymes that play major roles in many different molecular processes. Specifically, JAK1/3 has been determined to arbitrate IL-15 activation of receptors on CD8⁺ T cells.⁷ These cells then interact with CD4 T cells, mast cells, and other inflammatory cells to cause destruction of the hair follicle without damage to the keratinocyte and melanocyte stem cells, allowing for reversible yet relapsing hair loss.⁸

Treatment of AA is difficult, requiring patience and strict compliance while taking into account duration of disease, age at presentation, site involvement, patient expectations, cost and insurance coverage, prior therapies, and any comorbidities. At the time of this case, no US Food and Drug Administration–approved drug regimen existed for the treatment of AA, and, to date, no treatment is preventative.⁴ We present a case of a patient with alopecia universalis of 11 years’ duration that was refractory to intralesional triamcinolone, clobetasol, minoxidil, and UVB brush therapy yet was successfully treated with tofacitinib.

Case Report

A 29-year-old otherwise-healthy woman presented to our clinic for treatment of alopecia universalis of 11 years’ duration that flared intermittently despite various treatments. Her medical history was unremarkable; however, she had a brother with alopecia universalis. She had no family history of any other autoimmune disorders. At the current presentation, the patient was known to have alopecia universalis with scant evidence of exclamation-point hairs on dermoscopy. Her treatment plan at this point consisted of intralesional triamcinolone to the active areas at 10 mg/mL every 4 weeks, plus clobetasol foam 0.05% at bedtime, minoxidil foam 5% at bedtime, and a UVB brush 3 times a week for 6 months before progressing to universalis type because of hair loss in the eyebrows and eyelashes. This treatment plan continued for 1 year with minimal improvement of the alopecia (Figure 1).

The patient was dissatisfied and wanted to discontinue therapy. Because these treatment options were exhausted with minimal benefit, the patient was then considered for treatment with tofacitinib. Baseline studies were performed, including purified protein derivative, complete blood cell count with differential, comprehensive metabolic panel, lipid profile, and liver function tests, all of which were within reference range. Insurance initially denied coverage of this therapy; a prior authorization was subsequently submitted and denied. A letter of medical necessity was then proposed, and approval for tofacitinib was finally granted. The patient was started on tofacitinib 5 mg twice daily and was monitored every 2 months with a complete blood cell count, comprehensive metabolic panel, lipid panels, and liver function tests. She had a platelet count of 112,000/μL (reference range, 150,000–450,000/μL) at baseline, and continued monitoring revealed a platelet count of 83,000 after 7 months of treatment. This platelet abnormality was evaluated by a hematologist and found to be within reference range; subsequent monitoring did not reveal any abnormalities.

Initial hair growth on the scalp was diffuse with thin, white to light brown hairs in areas of hair loss at months 1 and 2, with progressive hair growth over months 3 to 7. Eyebrow hair growth was noted beginning at month 6. One year later, only hair regrowth occurred without any adverse events (Figure 2). After 5 years of treatment, the patient had a full head of thick hair (Figure 3). The tofacitinib dosage was 5 mg twice daily at initiation, and after 1 year increased to 10 mg twice daily. Her medical insurance subsequently changed and the regimen was adjusted to an 11-mg tablet and 5-mg tablet daily. She remained on this regimen with success.

Comment

Use of JAK Inhibitors—Reports and studies have shed light on the use and efficacy of JAK inhibitors in AA (Table).^5-11 Tofacitinib is a selective JAK1/3 inhibitor that predominantly inhibits JAK3 but also inhibits JAK1, albeit to a lesser degree, which interferes with the JAK/STAT (signal transducer and activator of transcription) cascade responsible for the production, differentiation, and function of various B cells, T cells, and natural killer cells.² Although it was developed for the management of allograft rejection, tofacitinib has made headway in rheumatology for treatment of patients with moderate to severe rheumatoid arthritis who are unable to take or are not responding to methotrexate.² Since 2014, tofacitinib has been introduced to the therapeutic realm for AA but is not yet approved by the US Food and Drug Administration.^3,4

In 2014, Craiglow and King⁵ reported use of tofacitinib with dosages beginning at 10 mg/d and increasing to 15 mg/d in a patient with alopecia universalis and psoriasis. Total hair regrowth was noted after 8 months of therapy.⁵ Xing et al⁶ described 3 patients treated with ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis, at an oral dose of 20 mg twice daily with near-complete hair regrowth after 5 months of treatment.⁶ Biopsies from lesions at baseline and after 3 months of therapy revealed a reduction in perifollicular T cells and in HLA class I and II expression in follicles.⁶ A patient in Italy with essential thrombocythemia and concurrent alopecia universalis was enrolled in a clinical trial with ruxolitinib and was treated with 15 mg twice daily. After 10 months of treatment, the patient had progressive hair regrowth that was sustained for more than 50 months of therapy.⁷ Baricitinib, a JAK1/2 inhibitor, was used in a 17-year-old adolescent boy to assess efficacy of the drug in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome.⁸ The patient also had longstanding patch-type AA that was resistance to treatment and progressed to an ophiasis pattern even though he was on immunosuppressive therapies. He was on 12 mg of prednisone daily at the start of therapy with baricitinib 7 mg daily initially. The baricitinib regimen was titrated up to 7 mg in the morning and 4 mg in the evening, with tapering of prednisone to 3 mg daily after 6 months of initiation. Within 3 months of therapy, hair regrowth occurred, with only a resultant patch on the occipital scalp that further resolved after 6 more months of therapy, resulting in total persistent hair growth.⁸ A 40-year-old woman with moderate to severe alopecia universalis was treated with tofacitinib 5 mg twice daily, revealing near-complete hair regrowth after 4 months of treatment; regrowth of eyebrows and eyelashes also was seen.⁹ However, discontinuation of treatment resulted in hair loss. Microarray analyses of biopsy specimens of lesioned sites at baseline revealed elevated IFN-γ and cytotoxic T cell-level signatures that subsequently decreased—albeit not to normal control levels—after 4 weeks of treatment.⁹ Being that IFN-γ receptors mediate their effects through JAK1/2, JAK1/3, tofacitinib, ruxolitinib, and baricitinib seem to be in sync with the immunopathogenesis of AA and thus may be the therapy of choice in the near future.

A recent retrospective study assessing response to tofacitinib in adults with AA (>40% hair loss), alopecia totalis, alopecia universalis, and stable or progressive diseases for at least 6 months determined a clinical response in 50 of 65 (77%) patients, with 13 patients exhibiting a complete response.¹⁰ Patients in this study were started on tofacitinib 5 mg twice daily with the addition of adjuvant pulsed prednisone (300 mg once monthly for 3 doses) with or without doubled dosing of tofacitinib if they had a halt in hair regrowth. This study demonstrated some benefit when pulsed prednisone was combined with the daily tofacitinib therapy. However, the study emphasized the importance of maintenance therapy, as 8 patients experienced hair loss with discontinuation after previously having hair regrowth; 5 (63%) of these patients experienced regrowth with augmentation of dosing or addition of adjuvant therapy.¹⁰

Another group of investigators assessed the efficacy of tofacitinib 5 mg in 13 adolescents aged 12 to 17 years, most with alopecia universalis (46% [6/13]); 10 of 13 (77%) patients responded to treatment with a mean duration of 6.5 months. The patients who had alopecia totalis and alopecia universalis for more than 10 years were poor responders to tofacitinib, and in fact, 1 of 13 (33%) patients in the study who did not respond to therapy had disease for 12 years.¹¹ Therefore, starting tofacitinib either long-term or intermittently should be considered in children diagnosed early with severe AA, alopecia totalis, or alopecia universalis to prevent irreversible hair loss or progressive disease^12,13; however, further data are required to assess efficacy and long-term benefits of this type of regimen.

Safety Profile—Widespread use of a medication is determined not only by its efficacy profile but also its safety profile. With any medication that exhibits immunosuppressive effects, adverse events must be considered and thoroughly discussed with patients and their primary care physicians. A prospective, open-label, single-arm trial examined the efficacy and safety of tofacitinib 5 mg twice daily in the treatment of AA and its more severe forms over 3 months.¹² Of the 66 patients who completed the trial, 64% (42/66) exhibited a positive response to tofacitinib. Relapse was noted in 8.5 weeks after discontinuation of tofacitinib, reiterating the potential need for a maintenance regimen. In this study, 25.8% (17/66) of patients experienced infections as adverse events including (in decreasing order) upper respiratory tract infections, urinary tract infections, herpes zoster, conjunctivitis, bronchitis, mononucleosis, and paronychia. No reports of new or recurrent malignancy were noted. Other more constitutional adverse events were noted including headaches, abdominal pain, acne, diarrhea, fatigue, nausea, pruritus, hot flashes, cough, folliculitis, weight gain, dry eyes, and amenorrhea. One patient with a pre-existing liver condition experienced transaminitis that resolved with weight loss. There also were noted increases in low- and high-density lipoprotein levels.¹² Our patient with baseline thrombocytopenia had mild drops in platelet count that subsequently stabilized and did not result in any bleeding abnormalities.

Duration of Therapy—Tofacitinib has demonstrated some preliminary success in the management of AA, but the appropriate duration of treatment requires further investigation. Our patient has been on tofacitinib for more than 5 years. She started at a total dosage of 10 mg/d, which increased to 16 mg/d. Initial dosing with maintenance regimens needs to be established for further widespread use to maximize benefit and minimize harm.

At what point do we decide to continue or stop treatment in patients who do not respond as expected or plateau? This is another critical question; our patient had periods of slowed growth and plateauing, but knowing the risks and benefits, she continued the medication and eventually experienced improved regrowth again.

Conclusion

Throughout the literature and in our patient, tofacitinib has demonstrated efficacy in treating AA. When other conventional therapies have failed, use of tofacitinib should be considered.

Alopecia areata (AA) is an autoimmune disease that immunopathogenetically is thought to be due to breakdown of the immune privilege of the proximal hair follicle during the anagen growth phase. Alopecia areata has been reported to have a lifetime prevalence of 1.7%.¹ Recent studies have specifically identified cytotoxic CD8⁺ NKG2D⁺ T cells as being responsible for the activation of AA.^2-4 Two interleukins—IL-2 and IL-15—have been implicated to be cytotoxic sensitizers allowing CD8⁺ T cells to secrete IFN-γ and recognize autoantigens via major histocompatibility complex class I.^5,6 Janus kinases (JAKs) are enzymes that play major roles in many different molecular processes. Specifically, JAK1/3 has been determined to arbitrate IL-15 activation of receptors on CD8⁺ T cells.⁷ These cells then interact with CD4 T cells, mast cells, and other inflammatory cells to cause destruction of the hair follicle without damage to the keratinocyte and melanocyte stem cells, allowing for reversible yet relapsing hair loss.⁸

Treatment of AA is difficult, requiring patience and strict compliance while taking into account duration of disease, age at presentation, site involvement, patient expectations, cost and insurance coverage, prior therapies, and any comorbidities. At the time of this case, no US Food and Drug Administration–approved drug regimen existed for the treatment of AA, and, to date, no treatment is preventative.⁴ We present a case of a patient with alopecia universalis of 11 years’ duration that was refractory to intralesional triamcinolone, clobetasol, minoxidil, and UVB brush therapy yet was successfully treated with tofacitinib.

Case Report

A 29-year-old otherwise-healthy woman presented to our clinic for treatment of alopecia universalis of 11 years’ duration that flared intermittently despite various treatments. Her medical history was unremarkable; however, she had a brother with alopecia universalis. She had no family history of any other autoimmune disorders. At the current presentation, the patient was known to have alopecia universalis with scant evidence of exclamation-point hairs on dermoscopy. Her treatment plan at this point consisted of intralesional triamcinolone to the active areas at 10 mg/mL every 4 weeks, plus clobetasol foam 0.05% at bedtime, minoxidil foam 5% at bedtime, and a UVB brush 3 times a week for 6 months before progressing to universalis type because of hair loss in the eyebrows and eyelashes. This treatment plan continued for 1 year with minimal improvement of the alopecia (Figure 1).

The patient was dissatisfied and wanted to discontinue therapy. Because these treatment options were exhausted with minimal benefit, the patient was then considered for treatment with tofacitinib. Baseline studies were performed, including purified protein derivative, complete blood cell count with differential, comprehensive metabolic panel, lipid profile, and liver function tests, all of which were within reference range. Insurance initially denied coverage of this therapy; a prior authorization was subsequently submitted and denied. A letter of medical necessity was then proposed, and approval for tofacitinib was finally granted. The patient was started on tofacitinib 5 mg twice daily and was monitored every 2 months with a complete blood cell count, comprehensive metabolic panel, lipid panels, and liver function tests. She had a platelet count of 112,000/μL (reference range, 150,000–450,000/μL) at baseline, and continued monitoring revealed a platelet count of 83,000 after 7 months of treatment. This platelet abnormality was evaluated by a hematologist and found to be within reference range; subsequent monitoring did not reveal any abnormalities.

Initial hair growth on the scalp was diffuse with thin, white to light brown hairs in areas of hair loss at months 1 and 2, with progressive hair growth over months 3 to 7. Eyebrow hair growth was noted beginning at month 6. One year later, only hair regrowth occurred without any adverse events (Figure 2). After 5 years of treatment, the patient had a full head of thick hair (Figure 3). The tofacitinib dosage was 5 mg twice daily at initiation, and after 1 year increased to 10 mg twice daily. Her medical insurance subsequently changed and the regimen was adjusted to an 11-mg tablet and 5-mg tablet daily. She remained on this regimen with success.

Comment

Use of JAK Inhibitors—Reports and studies have shed light on the use and efficacy of JAK inhibitors in AA (Table).^5-11 Tofacitinib is a selective JAK1/3 inhibitor that predominantly inhibits JAK3 but also inhibits JAK1, albeit to a lesser degree, which interferes with the JAK/STAT (signal transducer and activator of transcription) cascade responsible for the production, differentiation, and function of various B cells, T cells, and natural killer cells.² Although it was developed for the management of allograft rejection, tofacitinib has made headway in rheumatology for treatment of patients with moderate to severe rheumatoid arthritis who are unable to take or are not responding to methotrexate.² Since 2014, tofacitinib has been introduced to the therapeutic realm for AA but is not yet approved by the US Food and Drug Administration.^3,4

In 2014, Craiglow and King⁵ reported use of tofacitinib with dosages beginning at 10 mg/d and increasing to 15 mg/d in a patient with alopecia universalis and psoriasis. Total hair regrowth was noted after 8 months of therapy.⁵ Xing et al⁶ described 3 patients treated with ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis, at an oral dose of 20 mg twice daily with near-complete hair regrowth after 5 months of treatment.⁶ Biopsies from lesions at baseline and after 3 months of therapy revealed a reduction in perifollicular T cells and in HLA class I and II expression in follicles.⁶ A patient in Italy with essential thrombocythemia and concurrent alopecia universalis was enrolled in a clinical trial with ruxolitinib and was treated with 15 mg twice daily. After 10 months of treatment, the patient had progressive hair regrowth that was sustained for more than 50 months of therapy.⁷ Baricitinib, a JAK1/2 inhibitor, was used in a 17-year-old adolescent boy to assess efficacy of the drug in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome.⁸ The patient also had longstanding patch-type AA that was resistance to treatment and progressed to an ophiasis pattern even though he was on immunosuppressive therapies. He was on 12 mg of prednisone daily at the start of therapy with baricitinib 7 mg daily initially. The baricitinib regimen was titrated up to 7 mg in the morning and 4 mg in the evening, with tapering of prednisone to 3 mg daily after 6 months of initiation. Within 3 months of therapy, hair regrowth occurred, with only a resultant patch on the occipital scalp that further resolved after 6 more months of therapy, resulting in total persistent hair growth.⁸ A 40-year-old woman with moderate to severe alopecia universalis was treated with tofacitinib 5 mg twice daily, revealing near-complete hair regrowth after 4 months of treatment; regrowth of eyebrows and eyelashes also was seen.⁹ However, discontinuation of treatment resulted in hair loss. Microarray analyses of biopsy specimens of lesioned sites at baseline revealed elevated IFN-γ and cytotoxic T cell-level signatures that subsequently decreased—albeit not to normal control levels—after 4 weeks of treatment.⁹ Being that IFN-γ receptors mediate their effects through JAK1/2, JAK1/3, tofacitinib, ruxolitinib, and baricitinib seem to be in sync with the immunopathogenesis of AA and thus may be the therapy of choice in the near future.

A recent retrospective study assessing response to tofacitinib in adults with AA (>40% hair loss), alopecia totalis, alopecia universalis, and stable or progressive diseases for at least 6 months determined a clinical response in 50 of 65 (77%) patients, with 13 patients exhibiting a complete response.¹⁰ Patients in this study were started on tofacitinib 5 mg twice daily with the addition of adjuvant pulsed prednisone (300 mg once monthly for 3 doses) with or without doubled dosing of tofacitinib if they had a halt in hair regrowth. This study demonstrated some benefit when pulsed prednisone was combined with the daily tofacitinib therapy. However, the study emphasized the importance of maintenance therapy, as 8 patients experienced hair loss with discontinuation after previously having hair regrowth; 5 (63%) of these patients experienced regrowth with augmentation of dosing or addition of adjuvant therapy.¹⁰

Another group of investigators assessed the efficacy of tofacitinib 5 mg in 13 adolescents aged 12 to 17 years, most with alopecia universalis (46% [6/13]); 10 of 13 (77%) patients responded to treatment with a mean duration of 6.5 months. The patients who had alopecia totalis and alopecia universalis for more than 10 years were poor responders to tofacitinib, and in fact, 1 of 13 (33%) patients in the study who did not respond to therapy had disease for 12 years.¹¹ Therefore, starting tofacitinib either long-term or intermittently should be considered in children diagnosed early with severe AA, alopecia totalis, or alopecia universalis to prevent irreversible hair loss or progressive disease^12,13; however, further data are required to assess efficacy and long-term benefits of this type of regimen.

Safety Profile—Widespread use of a medication is determined not only by its efficacy profile but also its safety profile. With any medication that exhibits immunosuppressive effects, adverse events must be considered and thoroughly discussed with patients and their primary care physicians. A prospective, open-label, single-arm trial examined the efficacy and safety of tofacitinib 5 mg twice daily in the treatment of AA and its more severe forms over 3 months.¹² Of the 66 patients who completed the trial, 64% (42/66) exhibited a positive response to tofacitinib. Relapse was noted in 8.5 weeks after discontinuation of tofacitinib, reiterating the potential need for a maintenance regimen. In this study, 25.8% (17/66) of patients experienced infections as adverse events including (in decreasing order) upper respiratory tract infections, urinary tract infections, herpes zoster, conjunctivitis, bronchitis, mononucleosis, and paronychia. No reports of new or recurrent malignancy were noted. Other more constitutional adverse events were noted including headaches, abdominal pain, acne, diarrhea, fatigue, nausea, pruritus, hot flashes, cough, folliculitis, weight gain, dry eyes, and amenorrhea. One patient with a pre-existing liver condition experienced transaminitis that resolved with weight loss. There also were noted increases in low- and high-density lipoprotein levels.¹² Our patient with baseline thrombocytopenia had mild drops in platelet count that subsequently stabilized and did not result in any bleeding abnormalities.

Duration of Therapy—Tofacitinib has demonstrated some preliminary success in the management of AA, but the appropriate duration of treatment requires further investigation. Our patient has been on tofacitinib for more than 5 years. She started at a total dosage of 10 mg/d, which increased to 16 mg/d. Initial dosing with maintenance regimens needs to be established for further widespread use to maximize benefit and minimize harm.

At what point do we decide to continue or stop treatment in patients who do not respond as expected or plateau? This is another critical question; our patient had periods of slowed growth and plateauing, but knowing the risks and benefits, she continued the medication and eventually experienced improved regrowth again.

Conclusion

Throughout the literature and in our patient, tofacitinib has demonstrated efficacy in treating AA. When other conventional therapies have failed, use of tofacitinib should be considered.

Alopecia areata (AA) is an autoimmune disease that immunopathogenetically is thought to be due to breakdown of the immune privilege of the proximal hair follicle during the anagen growth phase. Alopecia areata has been reported to have a lifetime prevalence of 1.7%.¹ Recent studies have specifically identified cytotoxic CD8⁺ NKG2D⁺ T cells as being responsible for the activation of AA.^2-4 Two interleukins—IL-2 and IL-15—have been implicated to be cytotoxic sensitizers allowing CD8⁺ T cells to secrete IFN-γ and recognize autoantigens via major histocompatibility complex class I.^5,6 Janus kinases (JAKs) are enzymes that play major roles in many different molecular processes. Specifically, JAK1/3 has been determined to arbitrate IL-15 activation of receptors on CD8⁺ T cells.⁷ These cells then interact with CD4 T cells, mast cells, and other inflammatory cells to cause destruction of the hair follicle without damage to the keratinocyte and melanocyte stem cells, allowing for reversible yet relapsing hair loss.⁸

Treatment of AA is difficult, requiring patience and strict compliance while taking into account duration of disease, age at presentation, site involvement, patient expectations, cost and insurance coverage, prior therapies, and any comorbidities. At the time of this case, no US Food and Drug Administration–approved drug regimen existed for the treatment of AA, and, to date, no treatment is preventative.⁴ We present a case of a patient with alopecia universalis of 11 years’ duration that was refractory to intralesional triamcinolone, clobetasol, minoxidil, and UVB brush therapy yet was successfully treated with tofacitinib.

Case Report

A 29-year-old otherwise-healthy woman presented to our clinic for treatment of alopecia universalis of 11 years’ duration that flared intermittently despite various treatments. Her medical history was unremarkable; however, she had a brother with alopecia universalis. She had no family history of any other autoimmune disorders. At the current presentation, the patient was known to have alopecia universalis with scant evidence of exclamation-point hairs on dermoscopy. Her treatment plan at this point consisted of intralesional triamcinolone to the active areas at 10 mg/mL every 4 weeks, plus clobetasol foam 0.05% at bedtime, minoxidil foam 5% at bedtime, and a UVB brush 3 times a week for 6 months before progressing to universalis type because of hair loss in the eyebrows and eyelashes. This treatment plan continued for 1 year with minimal improvement of the alopecia (Figure 1).

The patient was dissatisfied and wanted to discontinue therapy. Because these treatment options were exhausted with minimal benefit, the patient was then considered for treatment with tofacitinib. Baseline studies were performed, including purified protein derivative, complete blood cell count with differential, comprehensive metabolic panel, lipid profile, and liver function tests, all of which were within reference range. Insurance initially denied coverage of this therapy; a prior authorization was subsequently submitted and denied. A letter of medical necessity was then proposed, and approval for tofacitinib was finally granted. The patient was started on tofacitinib 5 mg twice daily and was monitored every 2 months with a complete blood cell count, comprehensive metabolic panel, lipid panels, and liver function tests. She had a platelet count of 112,000/μL (reference range, 150,000–450,000/μL) at baseline, and continued monitoring revealed a platelet count of 83,000 after 7 months of treatment. This platelet abnormality was evaluated by a hematologist and found to be within reference range; subsequent monitoring did not reveal any abnormalities.

Initial hair growth on the scalp was diffuse with thin, white to light brown hairs in areas of hair loss at months 1 and 2, with progressive hair growth over months 3 to 7. Eyebrow hair growth was noted beginning at month 6. One year later, only hair regrowth occurred without any adverse events (Figure 2). After 5 years of treatment, the patient had a full head of thick hair (Figure 3). The tofacitinib dosage was 5 mg twice daily at initiation, and after 1 year increased to 10 mg twice daily. Her medical insurance subsequently changed and the regimen was adjusted to an 11-mg tablet and 5-mg tablet daily. She remained on this regimen with success.

Comment

Use of JAK Inhibitors—Reports and studies have shed light on the use and efficacy of JAK inhibitors in AA (Table).^5-11 Tofacitinib is a selective JAK1/3 inhibitor that predominantly inhibits JAK3 but also inhibits JAK1, albeit to a lesser degree, which interferes with the JAK/STAT (signal transducer and activator of transcription) cascade responsible for the production, differentiation, and function of various B cells, T cells, and natural killer cells.² Although it was developed for the management of allograft rejection, tofacitinib has made headway in rheumatology for treatment of patients with moderate to severe rheumatoid arthritis who are unable to take or are not responding to methotrexate.² Since 2014, tofacitinib has been introduced to the therapeutic realm for AA but is not yet approved by the US Food and Drug Administration.^3,4

In 2014, Craiglow and King⁵ reported use of tofacitinib with dosages beginning at 10 mg/d and increasing to 15 mg/d in a patient with alopecia universalis and psoriasis. Total hair regrowth was noted after 8 months of therapy.⁵ Xing et al⁶ described 3 patients treated with ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis, at an oral dose of 20 mg twice daily with near-complete hair regrowth after 5 months of treatment.⁶ Biopsies from lesions at baseline and after 3 months of therapy revealed a reduction in perifollicular T cells and in HLA class I and II expression in follicles.⁶ A patient in Italy with essential thrombocythemia and concurrent alopecia universalis was enrolled in a clinical trial with ruxolitinib and was treated with 15 mg twice daily. After 10 months of treatment, the patient had progressive hair regrowth that was sustained for more than 50 months of therapy.⁷ Baricitinib, a JAK1/2 inhibitor, was used in a 17-year-old adolescent boy to assess efficacy of the drug in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome.⁸ The patient also had longstanding patch-type AA that was resistance to treatment and progressed to an ophiasis pattern even though he was on immunosuppressive therapies. He was on 12 mg of prednisone daily at the start of therapy with baricitinib 7 mg daily initially. The baricitinib regimen was titrated up to 7 mg in the morning and 4 mg in the evening, with tapering of prednisone to 3 mg daily after 6 months of initiation. Within 3 months of therapy, hair regrowth occurred, with only a resultant patch on the occipital scalp that further resolved after 6 more months of therapy, resulting in total persistent hair growth.⁸ A 40-year-old woman with moderate to severe alopecia universalis was treated with tofacitinib 5 mg twice daily, revealing near-complete hair regrowth after 4 months of treatment; regrowth of eyebrows and eyelashes also was seen.⁹ However, discontinuation of treatment resulted in hair loss. Microarray analyses of biopsy specimens of lesioned sites at baseline revealed elevated IFN-γ and cytotoxic T cell-level signatures that subsequently decreased—albeit not to normal control levels—after 4 weeks of treatment.⁹ Being that IFN-γ receptors mediate their effects through JAK1/2, JAK1/3, tofacitinib, ruxolitinib, and baricitinib seem to be in sync with the immunopathogenesis of AA and thus may be the therapy of choice in the near future.

A recent retrospective study assessing response to tofacitinib in adults with AA (>40% hair loss), alopecia totalis, alopecia universalis, and stable or progressive diseases for at least 6 months determined a clinical response in 50 of 65 (77%) patients, with 13 patients exhibiting a complete response.¹⁰ Patients in this study were started on tofacitinib 5 mg twice daily with the addition of adjuvant pulsed prednisone (300 mg once monthly for 3 doses) with or without doubled dosing of tofacitinib if they had a halt in hair regrowth. This study demonstrated some benefit when pulsed prednisone was combined with the daily tofacitinib therapy. However, the study emphasized the importance of maintenance therapy, as 8 patients experienced hair loss with discontinuation after previously having hair regrowth; 5 (63%) of these patients experienced regrowth with augmentation of dosing or addition of adjuvant therapy.¹⁰

Another group of investigators assessed the efficacy of tofacitinib 5 mg in 13 adolescents aged 12 to 17 years, most with alopecia universalis (46% [6/13]); 10 of 13 (77%) patients responded to treatment with a mean duration of 6.5 months. The patients who had alopecia totalis and alopecia universalis for more than 10 years were poor responders to tofacitinib, and in fact, 1 of 13 (33%) patients in the study who did not respond to therapy had disease for 12 years.¹¹ Therefore, starting tofacitinib either long-term or intermittently should be considered in children diagnosed early with severe AA, alopecia totalis, or alopecia universalis to prevent irreversible hair loss or progressive disease^12,13; however, further data are required to assess efficacy and long-term benefits of this type of regimen.

Safety Profile—Widespread use of a medication is determined not only by its efficacy profile but also its safety profile. With any medication that exhibits immunosuppressive effects, adverse events must be considered and thoroughly discussed with patients and their primary care physicians. A prospective, open-label, single-arm trial examined the efficacy and safety of tofacitinib 5 mg twice daily in the treatment of AA and its more severe forms over 3 months.¹² Of the 66 patients who completed the trial, 64% (42/66) exhibited a positive response to tofacitinib. Relapse was noted in 8.5 weeks after discontinuation of tofacitinib, reiterating the potential need for a maintenance regimen. In this study, 25.8% (17/66) of patients experienced infections as adverse events including (in decreasing order) upper respiratory tract infections, urinary tract infections, herpes zoster, conjunctivitis, bronchitis, mononucleosis, and paronychia. No reports of new or recurrent malignancy were noted. Other more constitutional adverse events were noted including headaches, abdominal pain, acne, diarrhea, fatigue, nausea, pruritus, hot flashes, cough, folliculitis, weight gain, dry eyes, and amenorrhea. One patient with a pre-existing liver condition experienced transaminitis that resolved with weight loss. There also were noted increases in low- and high-density lipoprotein levels.¹² Our patient with baseline thrombocytopenia had mild drops in platelet count that subsequently stabilized and did not result in any bleeding abnormalities.

Duration of Therapy—Tofacitinib has demonstrated some preliminary success in the management of AA, but the appropriate duration of treatment requires further investigation. Our patient has been on tofacitinib for more than 5 years. She started at a total dosage of 10 mg/d, which increased to 16 mg/d. Initial dosing with maintenance regimens needs to be established for further widespread use to maximize benefit and minimize harm.

At what point do we decide to continue or stop treatment in patients who do not respond as expected or plateau? This is another critical question; our patient had periods of slowed growth and plateauing, but knowing the risks and benefits, she continued the medication and eventually experienced improved regrowth again.

Conclusion

Throughout the literature and in our patient, tofacitinib has demonstrated efficacy in treating AA. When other conventional therapies have failed, use of tofacitinib should be considered.

Case Report

An otherwise healthy 13-year-old boy was referred to pediatric dermatology with multiple asymptomatic erythematous papules throughout the trunk and arms of 6 months’ duration. He denied fevers, night sweats, or weight loss. A punch biopsy revealed a dense atypical lymphoid infiltrate with follicular prominence extending periadnexally and perivascularly, which was most consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (Figures 1A and 1B). Cells were positive for Bcl-2, CD23, and CD20 (Figure 1C). Polymerase chain reaction analysis of the immunoglobulin heavy and κ chain gene rearrangements were positive, indicating the presence of a clonal B-cell expansion. The patient’s complete blood cell count, complete metabolic profile, serum lactate dehydrogenase, and erythrocyte sedimentation rate were within reference range. Lyme disease antibodies, Helicobacter pylori testing, thyroid function testing, thyroid antibodies, anti–Sjogren syndrome–related antigen A antibody, and anti–Sjogren syndrome–related antigen B were negative. Additionally, positron emission tomography (PET) with computed tomography (CT) revealed no abnormalities. He was diagnosed with stage T3b primary cutaneous marginal zone lymphoma (PCMZL) due to cutaneous involvement of 3 or more body regions.

The patient was started on clobetasol ointment 0.05% twice daily to the affected areas. After 2 months, he had progression of cutaneous disease, including increased number of lesions; erythema; and induration of lesions on the chest, back, and arms (Figure 2A) and was started on oral doxycycline 100 mg twice daily with subsequent notable improvement of the skin lesions at 2-week follow-up, including decreased erythema and induration of all lesions. He then received intralesional triamcinolone 20 mg/mL injections to 4 residual lesions; clobetasol ointment 0.05% twice daily was continued for the remaining lesions as needed for pruritus. He continued doxycycline for 4 months with further improvement of lesions (Figure 2B). Six months after discontinuing doxycycline, 2 small residual lesions remained on the left arm and back, but the patient did not develop any new or recurrent lesions.

Comment

Clinical Presentation—Primary cutaneous B-cell lymphomas include PCMZL, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma. Primary cutaneous marginal zone lymphoma is an indolent extranodal B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells, and mature plasma cells.¹

Primary cutaneous marginal zone lymphoma typically presents in the fourth to sixth decades of life and is rare in children, with fewer than 40 cases in patients younger than 20 years.² Amitay-Laish and colleagues² reported 29 patients with pediatric PCMZL ranging in age from 1 to 19.5 years at diagnosis, with the majority of patients diagnosed after 10 years of age. Clinically, patients present with multifocal, erythematous to brown, dermal papules, plaques, and nodules most commonly distributed on the trunk and arms. A retrospective review of 11 pediatric patients with PCMZL over a median of 5.5 years demonstrated that the clinical presentation, histopathology, molecular findings, and prognosis of pediatric PCMZL appears similar to adult PCMZL.² Cutaneous relapse is common, but extracutaneous spread is rare. The prognosis is excellent, with a disease-free survival rate of 93%.³

Diagnosis—The diagnosis of PCMZL requires histopathologic analysis of involved skin as well as exclusion of extracutaneous disease at the time of diagnosis during initial staging evaluation. Histologically there are nodular infiltrates of small lymphocytes in interfollicular compartments, reactive germinal centers, and clonality with monotypic immunoglobulin heavy chain genes.⁴ Laboratory workup should include complete blood cell count with differential, complete metabolic panel, and serum lactate dehydrogenase level. If lymphocytosis is present, flow cytometry of peripheral blood cells should be performed. Radiographic imaging with contrast-enhanced CT or PET/CT of the chest, abdomen, and pelvis should be performed for routine staging in most patients, with imaging of the neck recommended when cervical lymphadenopathy is detected.⁵ Patients with multifocal skin lesions should receive PET/CT to exclude systemic disease and assess lymph nodes. Bone marrow studies are not required for diagnosis.^5,6

Associated Conditions—Systemic marginal zone lymphoma has been associated with autoimmune conditions, including Hashimoto thyroiditis and Sjögren syndrome; however, this association has not been shown in PCMZL and was not found in our patient.^7,8Borrelia-positive serology has been described in cases of PCMZL in Europe. The pathogenesis has been speculated to be due to chronic antigen stimulation related to the geographic distribution of Borrelia species.⁹ In endemic areas, Borrelia testing with serology or DNA testing of skin is recommended; however, there has been no strong correlation between Borrelia burgdorferi and PCMZL found in North America or Asia.^9,10Helicobacter pylori has been associated with gastric mucosal-associated lymphatic tissue lymphoma, which responds well to antibiotic therapy. However, an association between PCMZL and H pylori has not been well described.¹¹

Management—Several treatment modalities have been attempted in patients with PCMZL with varying efficacy. Given the rarity of this disease, there is no standard therapy. Treatment options include radiation therapy, excision, topical steroids, intralesional steroids, intralesional rituximab, and antibiotics.^2,12-14 Case reports of pediatric patients have demonstrated improvement with excision,^15-19 intralesional steroids,^20,21 intralesional rituximab,²² and clobetasol cream.^23,24 In asymptomatic patients, watchful waiting often is employed given the overall indolent nature of PCMZL. Antibiotic therapy may be favored in Borrelia-positive cases. However, even in B burgdorferi–negative patients, there have been cases where there is response to antibiotics, particularly doxycycline.^2,15,25 We elected for a trial of doxycycline in our patient based on these prior reports, along with the overall favorable side-effect profile of doxycycline for adolescents and our patient’s widespread cutaneous involvement.

Doxycycline is utilized in pediatric patients 8 years and older for numerous indications, including treatment of acne, Rocky Mountain spotted fever, and Lyme disease. Use of doxycycline in younger patients typically is avoided given the risk for dental enamel hypoplasia, tooth discoloration, and possible delays in skeletal development. Originally utilized for its antibacterial effects as an intracellular inhibitor of protein synthesis, doxycycline has been repurposed for oncologic therapies. It has been shown to have cytotoxic and antiproliferative properties in various cancer cells and also may inhibit leukemic cell migration.²⁶ In PCMZL, doxycycline initially was utilized in Borrelia-positive patients in Europe and found to improve disease clearance.²⁷ In patients without Borrelia infection, doxycycline is thought to enhance apoptosis through caspase-3 activation along with p53 and Bax upregulation.²⁸

Intralesional triamcinolone alone may not be feasible in pediatric PCMZL patients because of widespread involvement, and doxycycline may be considered as a treatment option. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients, as demonstrated in our case.

Acknowledgment—We thank Ali Nael Amzajerdi, MD (Orange, California), for his contributions to the pathologic imaging in this report.

Case Report

An otherwise healthy 13-year-old boy was referred to pediatric dermatology with multiple asymptomatic erythematous papules throughout the trunk and arms of 6 months’ duration. He denied fevers, night sweats, or weight loss. A punch biopsy revealed a dense atypical lymphoid infiltrate with follicular prominence extending periadnexally and perivascularly, which was most consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (Figures 1A and 1B). Cells were positive for Bcl-2, CD23, and CD20 (Figure 1C). Polymerase chain reaction analysis of the immunoglobulin heavy and κ chain gene rearrangements were positive, indicating the presence of a clonal B-cell expansion. The patient’s complete blood cell count, complete metabolic profile, serum lactate dehydrogenase, and erythrocyte sedimentation rate were within reference range. Lyme disease antibodies, Helicobacter pylori testing, thyroid function testing, thyroid antibodies, anti–Sjogren syndrome–related antigen A antibody, and anti–Sjogren syndrome–related antigen B were negative. Additionally, positron emission tomography (PET) with computed tomography (CT) revealed no abnormalities. He was diagnosed with stage T3b primary cutaneous marginal zone lymphoma (PCMZL) due to cutaneous involvement of 3 or more body regions.

The patient was started on clobetasol ointment 0.05% twice daily to the affected areas. After 2 months, he had progression of cutaneous disease, including increased number of lesions; erythema; and induration of lesions on the chest, back, and arms (Figure 2A) and was started on oral doxycycline 100 mg twice daily with subsequent notable improvement of the skin lesions at 2-week follow-up, including decreased erythema and induration of all lesions. He then received intralesional triamcinolone 20 mg/mL injections to 4 residual lesions; clobetasol ointment 0.05% twice daily was continued for the remaining lesions as needed for pruritus. He continued doxycycline for 4 months with further improvement of lesions (Figure 2B). Six months after discontinuing doxycycline, 2 small residual lesions remained on the left arm and back, but the patient did not develop any new or recurrent lesions.

Comment

Clinical Presentation—Primary cutaneous B-cell lymphomas include PCMZL, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma. Primary cutaneous marginal zone lymphoma is an indolent extranodal B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells, and mature plasma cells.¹

Primary cutaneous marginal zone lymphoma typically presents in the fourth to sixth decades of life and is rare in children, with fewer than 40 cases in patients younger than 20 years.² Amitay-Laish and colleagues² reported 29 patients with pediatric PCMZL ranging in age from 1 to 19.5 years at diagnosis, with the majority of patients diagnosed after 10 years of age. Clinically, patients present with multifocal, erythematous to brown, dermal papules, plaques, and nodules most commonly distributed on the trunk and arms. A retrospective review of 11 pediatric patients with PCMZL over a median of 5.5 years demonstrated that the clinical presentation, histopathology, molecular findings, and prognosis of pediatric PCMZL appears similar to adult PCMZL.² Cutaneous relapse is common, but extracutaneous spread is rare. The prognosis is excellent, with a disease-free survival rate of 93%.³

Diagnosis—The diagnosis of PCMZL requires histopathologic analysis of involved skin as well as exclusion of extracutaneous disease at the time of diagnosis during initial staging evaluation. Histologically there are nodular infiltrates of small lymphocytes in interfollicular compartments, reactive germinal centers, and clonality with monotypic immunoglobulin heavy chain genes.⁴ Laboratory workup should include complete blood cell count with differential, complete metabolic panel, and serum lactate dehydrogenase level. If lymphocytosis is present, flow cytometry of peripheral blood cells should be performed. Radiographic imaging with contrast-enhanced CT or PET/CT of the chest, abdomen, and pelvis should be performed for routine staging in most patients, with imaging of the neck recommended when cervical lymphadenopathy is detected.⁵ Patients with multifocal skin lesions should receive PET/CT to exclude systemic disease and assess lymph nodes. Bone marrow studies are not required for diagnosis.^5,6

Associated Conditions—Systemic marginal zone lymphoma has been associated with autoimmune conditions, including Hashimoto thyroiditis and Sjögren syndrome; however, this association has not been shown in PCMZL and was not found in our patient.^7,8Borrelia-positive serology has been described in cases of PCMZL in Europe. The pathogenesis has been speculated to be due to chronic antigen stimulation related to the geographic distribution of Borrelia species.⁹ In endemic areas, Borrelia testing with serology or DNA testing of skin is recommended; however, there has been no strong correlation between Borrelia burgdorferi and PCMZL found in North America or Asia.^9,10Helicobacter pylori has been associated with gastric mucosal-associated lymphatic tissue lymphoma, which responds well to antibiotic therapy. However, an association between PCMZL and H pylori has not been well described.¹¹

Management—Several treatment modalities have been attempted in patients with PCMZL with varying efficacy. Given the rarity of this disease, there is no standard therapy. Treatment options include radiation therapy, excision, topical steroids, intralesional steroids, intralesional rituximab, and antibiotics.^2,12-14 Case reports of pediatric patients have demonstrated improvement with excision,^15-19 intralesional steroids,^20,21 intralesional rituximab,²² and clobetasol cream.^23,24 In asymptomatic patients, watchful waiting often is employed given the overall indolent nature of PCMZL. Antibiotic therapy may be favored in Borrelia-positive cases. However, even in B burgdorferi–negative patients, there have been cases where there is response to antibiotics, particularly doxycycline.^2,15,25 We elected for a trial of doxycycline in our patient based on these prior reports, along with the overall favorable side-effect profile of doxycycline for adolescents and our patient’s widespread cutaneous involvement.

Doxycycline is utilized in pediatric patients 8 years and older for numerous indications, including treatment of acne, Rocky Mountain spotted fever, and Lyme disease. Use of doxycycline in younger patients typically is avoided given the risk for dental enamel hypoplasia, tooth discoloration, and possible delays in skeletal development. Originally utilized for its antibacterial effects as an intracellular inhibitor of protein synthesis, doxycycline has been repurposed for oncologic therapies. It has been shown to have cytotoxic and antiproliferative properties in various cancer cells and also may inhibit leukemic cell migration.²⁶ In PCMZL, doxycycline initially was utilized in Borrelia-positive patients in Europe and found to improve disease clearance.²⁷ In patients without Borrelia infection, doxycycline is thought to enhance apoptosis through caspase-3 activation along with p53 and Bax upregulation.²⁸

Intralesional triamcinolone alone may not be feasible in pediatric PCMZL patients because of widespread involvement, and doxycycline may be considered as a treatment option. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients, as demonstrated in our case.

Acknowledgment—We thank Ali Nael Amzajerdi, MD (Orange, California), for his contributions to the pathologic imaging in this report.

Case Report

An otherwise healthy 13-year-old boy was referred to pediatric dermatology with multiple asymptomatic erythematous papules throughout the trunk and arms of 6 months’ duration. He denied fevers, night sweats, or weight loss. A punch biopsy revealed a dense atypical lymphoid infiltrate with follicular prominence extending periadnexally and perivascularly, which was most consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (Figures 1A and 1B). Cells were positive for Bcl-2, CD23, and CD20 (Figure 1C). Polymerase chain reaction analysis of the immunoglobulin heavy and κ chain gene rearrangements were positive, indicating the presence of a clonal B-cell expansion. The patient’s complete blood cell count, complete metabolic profile, serum lactate dehydrogenase, and erythrocyte sedimentation rate were within reference range. Lyme disease antibodies, Helicobacter pylori testing, thyroid function testing, thyroid antibodies, anti–Sjogren syndrome–related antigen A antibody, and anti–Sjogren syndrome–related antigen B were negative. Additionally, positron emission tomography (PET) with computed tomography (CT) revealed no abnormalities. He was diagnosed with stage T3b primary cutaneous marginal zone lymphoma (PCMZL) due to cutaneous involvement of 3 or more body regions.

The patient was started on clobetasol ointment 0.05% twice daily to the affected areas. After 2 months, he had progression of cutaneous disease, including increased number of lesions; erythema; and induration of lesions on the chest, back, and arms (Figure 2A) and was started on oral doxycycline 100 mg twice daily with subsequent notable improvement of the skin lesions at 2-week follow-up, including decreased erythema and induration of all lesions. He then received intralesional triamcinolone 20 mg/mL injections to 4 residual lesions; clobetasol ointment 0.05% twice daily was continued for the remaining lesions as needed for pruritus. He continued doxycycline for 4 months with further improvement of lesions (Figure 2B). Six months after discontinuing doxycycline, 2 small residual lesions remained on the left arm and back, but the patient did not develop any new or recurrent lesions.

Comment

Clinical Presentation—Primary cutaneous B-cell lymphomas include PCMZL, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma. Primary cutaneous marginal zone lymphoma is an indolent extranodal B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells, and mature plasma cells.¹

Primary cutaneous marginal zone lymphoma typically presents in the fourth to sixth decades of life and is rare in children, with fewer than 40 cases in patients younger than 20 years.² Amitay-Laish and colleagues² reported 29 patients with pediatric PCMZL ranging in age from 1 to 19.5 years at diagnosis, with the majority of patients diagnosed after 10 years of age. Clinically, patients present with multifocal, erythematous to brown, dermal papules, plaques, and nodules most commonly distributed on the trunk and arms. A retrospective review of 11 pediatric patients with PCMZL over a median of 5.5 years demonstrated that the clinical presentation, histopathology, molecular findings, and prognosis of pediatric PCMZL appears similar to adult PCMZL.² Cutaneous relapse is common, but extracutaneous spread is rare. The prognosis is excellent, with a disease-free survival rate of 93%.³

Diagnosis—The diagnosis of PCMZL requires histopathologic analysis of involved skin as well as exclusion of extracutaneous disease at the time of diagnosis during initial staging evaluation. Histologically there are nodular infiltrates of small lymphocytes in interfollicular compartments, reactive germinal centers, and clonality with monotypic immunoglobulin heavy chain genes.⁴ Laboratory workup should include complete blood cell count with differential, complete metabolic panel, and serum lactate dehydrogenase level. If lymphocytosis is present, flow cytometry of peripheral blood cells should be performed. Radiographic imaging with contrast-enhanced CT or PET/CT of the chest, abdomen, and pelvis should be performed for routine staging in most patients, with imaging of the neck recommended when cervical lymphadenopathy is detected.⁵ Patients with multifocal skin lesions should receive PET/CT to exclude systemic disease and assess lymph nodes. Bone marrow studies are not required for diagnosis.^5,6

Associated Conditions—Systemic marginal zone lymphoma has been associated with autoimmune conditions, including Hashimoto thyroiditis and Sjögren syndrome; however, this association has not been shown in PCMZL and was not found in our patient.^7,8Borrelia-positive serology has been described in cases of PCMZL in Europe. The pathogenesis has been speculated to be due to chronic antigen stimulation related to the geographic distribution of Borrelia species.⁹ In endemic areas, Borrelia testing with serology or DNA testing of skin is recommended; however, there has been no strong correlation between Borrelia burgdorferi and PCMZL found in North America or Asia.^9,10Helicobacter pylori has been associated with gastric mucosal-associated lymphatic tissue lymphoma, which responds well to antibiotic therapy. However, an association between PCMZL and H pylori has not been well described.¹¹

Management—Several treatment modalities have been attempted in patients with PCMZL with varying efficacy. Given the rarity of this disease, there is no standard therapy. Treatment options include radiation therapy, excision, topical steroids, intralesional steroids, intralesional rituximab, and antibiotics.^2,12-14 Case reports of pediatric patients have demonstrated improvement with excision,^15-19 intralesional steroids,^20,21 intralesional rituximab,²² and clobetasol cream.^23,24 In asymptomatic patients, watchful waiting often is employed given the overall indolent nature of PCMZL. Antibiotic therapy may be favored in Borrelia-positive cases. However, even in B burgdorferi–negative patients, there have been cases where there is response to antibiotics, particularly doxycycline.^2,15,25 We elected for a trial of doxycycline in our patient based on these prior reports, along with the overall favorable side-effect profile of doxycycline for adolescents and our patient’s widespread cutaneous involvement.

Doxycycline is utilized in pediatric patients 8 years and older for numerous indications, including treatment of acne, Rocky Mountain spotted fever, and Lyme disease. Use of doxycycline in younger patients typically is avoided given the risk for dental enamel hypoplasia, tooth discoloration, and possible delays in skeletal development. Originally utilized for its antibacterial effects as an intracellular inhibitor of protein synthesis, doxycycline has been repurposed for oncologic therapies. It has been shown to have cytotoxic and antiproliferative properties in various cancer cells and also may inhibit leukemic cell migration.²⁶ In PCMZL, doxycycline initially was utilized in Borrelia-positive patients in Europe and found to improve disease clearance.²⁷ In patients without Borrelia infection, doxycycline is thought to enhance apoptosis through caspase-3 activation along with p53 and Bax upregulation.²⁸

Intralesional triamcinolone alone may not be feasible in pediatric PCMZL patients because of widespread involvement, and doxycycline may be considered as a treatment option. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients, as demonstrated in our case.

Acknowledgment—We thank Ali Nael Amzajerdi, MD (Orange, California), for his contributions to the pathologic imaging in this report.

Preoperative biopsy results in patients with esophageal adenocarcinoma (EAC) often misrepresent true tumor grade, according to a recent retrospective study.

Inaccurate preoperative biopsy findings could mean that patients who are candidates for endoscopic resection (ER) are unnecessarily undergoing esophagectomy, a procedure with greater risks of morbidity and mortality, reported Ravi S. Shah, MD, of Cleveland Clinic, and colleagues.

Cleveland Clinic

“It is unclear how accurate tumor differentiation on endoscopic biopsies is and if it can be used for clinical decision-making,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “Given that tumors may be considerably heterogeneous in gland formation, the limited amount of tissue obtained from endoscopic forceps biopsies may not be representative of the entire tumor for pathologic grading, which may result in discrepant tumor grading between biopsy and resection specimens.”

While previous studies have compared esophagogastroduodenoscopy-guided biopsy results with histological findings after surgical resection, scant evidence is available to compare biopsy findings with both surgically and endoscopically resected tissue.

Despite this potential knowledge gap, “many patients with poorly differentiated EAC on preresection biopsy do not undergo ER, with the belief that the final resection pathology would be noncurative,” the investigators noted.

To help clarify how congruent pre- and postoperative biopsies are for both resection methods, Dr. Shah and colleagues conducted a retrospective study involving 346 EAC lesions. Samples were drawn from 121 ERs and 225 esophagectomies performed at two tertiary referral centers. Preoperative and postoperative findings were compared for accuracy and for level of agreement via Gwet’s AC2 interrater analysis.

For all evaluable lesions, preoperative biopsy had an accuracy of 68%, with a “substantial” agreement coefficient (Gwet’s AC2, 0.70; P less than .001). Accuracy in the esophagectomy group was similar, at 72%, again with “substantial” agreement (Gwet’s AC2, 0.74; P less than .001). For the ER group, however, accuracy was just 56%, with a “moderate” level of agreement (Gwet’s AC2, 0.60; P less than .001).

“We speculate that the discrepancy of tumor differentiation on endoscopic forceps biopsies and resection specimens is due to nonrepresentative sampling of tumors to accurately determine the percentage of gland formation and thus tumor grade,” the investigators noted.

Further analysis showed that 22.7% of moderately differentiated tumors were upgraded to poorly differentiated upon final histology. Conversely, 19.6% of poorly differentiated tumors were downgraded to moderately differentiated. Downgrading was even more common among T1a tumors, 40% of which were changed from poorly to moderately differentiated between pre- and postprocedural histology.

These latter findings concerning downgrading are particularly relevant for clinical decision-making, the investigators noted, as patients with poorly differentiated EAC on preoperative biopsy are typically sent for esophagectomy – a more invasive and riskier procedure – out of concern that ER will be noncurative.

“If poor differentiation was the only high-risk feature, these patients may have unnecessarily undergone esophagectomy,” Dr. Shah and colleagues wrote. “Especially in marginal surgical candidates, staging ER should be considered in patients with early esophageal cancer with preoperative biopsies showing poorly differentiated cancer.”

The investigators disclosed relationships with Medtronic, Lucid Diagnostics, Lumendi, and others.

Preoperative biopsy results in patients with esophageal adenocarcinoma (EAC) often misrepresent true tumor grade, according to a recent retrospective study.

Inaccurate preoperative biopsy findings could mean that patients who are candidates for endoscopic resection (ER) are unnecessarily undergoing esophagectomy, a procedure with greater risks of morbidity and mortality, reported Ravi S. Shah, MD, of Cleveland Clinic, and colleagues.

Cleveland Clinic

“It is unclear how accurate tumor differentiation on endoscopic biopsies is and if it can be used for clinical decision-making,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “Given that tumors may be considerably heterogeneous in gland formation, the limited amount of tissue obtained from endoscopic forceps biopsies may not be representative of the entire tumor for pathologic grading, which may result in discrepant tumor grading between biopsy and resection specimens.”

While previous studies have compared esophagogastroduodenoscopy-guided biopsy results with histological findings after surgical resection, scant evidence is available to compare biopsy findings with both surgically and endoscopically resected tissue.

Despite this potential knowledge gap, “many patients with poorly differentiated EAC on preresection biopsy do not undergo ER, with the belief that the final resection pathology would be noncurative,” the investigators noted.

To help clarify how congruent pre- and postoperative biopsies are for both resection methods, Dr. Shah and colleagues conducted a retrospective study involving 346 EAC lesions. Samples were drawn from 121 ERs and 225 esophagectomies performed at two tertiary referral centers. Preoperative and postoperative findings were compared for accuracy and for level of agreement via Gwet’s AC2 interrater analysis.

For all evaluable lesions, preoperative biopsy had an accuracy of 68%, with a “substantial” agreement coefficient (Gwet’s AC2, 0.70; P less than .001). Accuracy in the esophagectomy group was similar, at 72%, again with “substantial” agreement (Gwet’s AC2, 0.74; P less than .001). For the ER group, however, accuracy was just 56%, with a “moderate” level of agreement (Gwet’s AC2, 0.60; P less than .001).

“We speculate that the discrepancy of tumor differentiation on endoscopic forceps biopsies and resection specimens is due to nonrepresentative sampling of tumors to accurately determine the percentage of gland formation and thus tumor grade,” the investigators noted.

Further analysis showed that 22.7% of moderately differentiated tumors were upgraded to poorly differentiated upon final histology. Conversely, 19.6% of poorly differentiated tumors were downgraded to moderately differentiated. Downgrading was even more common among T1a tumors, 40% of which were changed from poorly to moderately differentiated between pre- and postprocedural histology.

These latter findings concerning downgrading are particularly relevant for clinical decision-making, the investigators noted, as patients with poorly differentiated EAC on preoperative biopsy are typically sent for esophagectomy – a more invasive and riskier procedure – out of concern that ER will be noncurative.

“If poor differentiation was the only high-risk feature, these patients may have unnecessarily undergone esophagectomy,” Dr. Shah and colleagues wrote. “Especially in marginal surgical candidates, staging ER should be considered in patients with early esophageal cancer with preoperative biopsies showing poorly differentiated cancer.”

The investigators disclosed relationships with Medtronic, Lucid Diagnostics, Lumendi, and others.

Preoperative biopsy results in patients with esophageal adenocarcinoma (EAC) often misrepresent true tumor grade, according to a recent retrospective study.

Inaccurate preoperative biopsy findings could mean that patients who are candidates for endoscopic resection (ER) are unnecessarily undergoing esophagectomy, a procedure with greater risks of morbidity and mortality, reported Ravi S. Shah, MD, of Cleveland Clinic, and colleagues.

Cleveland Clinic

“It is unclear how accurate tumor differentiation on endoscopic biopsies is and if it can be used for clinical decision-making,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “Given that tumors may be considerably heterogeneous in gland formation, the limited amount of tissue obtained from endoscopic forceps biopsies may not be representative of the entire tumor for pathologic grading, which may result in discrepant tumor grading between biopsy and resection specimens.”

While previous studies have compared esophagogastroduodenoscopy-guided biopsy results with histological findings after surgical resection, scant evidence is available to compare biopsy findings with both surgically and endoscopically resected tissue.

Despite this potential knowledge gap, “many patients with poorly differentiated EAC on preresection biopsy do not undergo ER, with the belief that the final resection pathology would be noncurative,” the investigators noted.

To help clarify how congruent pre- and postoperative biopsies are for both resection methods, Dr. Shah and colleagues conducted a retrospective study involving 346 EAC lesions. Samples were drawn from 121 ERs and 225 esophagectomies performed at two tertiary referral centers. Preoperative and postoperative findings were compared for accuracy and for level of agreement via Gwet’s AC2 interrater analysis.

For all evaluable lesions, preoperative biopsy had an accuracy of 68%, with a “substantial” agreement coefficient (Gwet’s AC2, 0.70; P less than .001). Accuracy in the esophagectomy group was similar, at 72%, again with “substantial” agreement (Gwet’s AC2, 0.74; P less than .001). For the ER group, however, accuracy was just 56%, with a “moderate” level of agreement (Gwet’s AC2, 0.60; P less than .001).

“We speculate that the discrepancy of tumor differentiation on endoscopic forceps biopsies and resection specimens is due to nonrepresentative sampling of tumors to accurately determine the percentage of gland formation and thus tumor grade,” the investigators noted.

Further analysis showed that 22.7% of moderately differentiated tumors were upgraded to poorly differentiated upon final histology. Conversely, 19.6% of poorly differentiated tumors were downgraded to moderately differentiated. Downgrading was even more common among T1a tumors, 40% of which were changed from poorly to moderately differentiated between pre- and postprocedural histology.

These latter findings concerning downgrading are particularly relevant for clinical decision-making, the investigators noted, as patients with poorly differentiated EAC on preoperative biopsy are typically sent for esophagectomy – a more invasive and riskier procedure – out of concern that ER will be noncurative.

“If poor differentiation was the only high-risk feature, these patients may have unnecessarily undergone esophagectomy,” Dr. Shah and colleagues wrote. “Especially in marginal surgical candidates, staging ER should be considered in patients with early esophageal cancer with preoperative biopsies showing poorly differentiated cancer.”

The investigators disclosed relationships with Medtronic, Lucid Diagnostics, Lumendi, and others.