Practice Gap

In light of inflation, rising costs of procedures, and decreased reimbursements,¹ there is an increased need to identify and utilize inexpensive multitasking tools that can serve the dermatologic surgeon from preoperative to postoperative care. The 70% isopropyl alcohol swab may be the dermatologist’s most cost-effective and versatile surgical tool.

The Technique

When assessing a lesion, alcohol swabs can remove scale, crust, or residue from personal care products to help reveal primary morphology. They aid in the diagnosis of porokeratosis by highlighting the cornoid lamella when used following application of gentian violet.² The alcohol swab also can lay down a liquid interface to facilitate contact dermoscopy and improve visualization while also reducing the transmission of pathogens by the dermatoscope.³ Rubbing an area with an alcohol swab can induce vasodilation of scar tissue, which also may help localize a prior biopsy or surgical site (Figure).

Before a surgical site is marked, an initial cleanse with an alcohol swab serves to both remove debris and provide antisepsis ahead of the procedure. Additionally, the swab may improve adherence of skin markers by clearing excess lipid from the skin surface. Assessing the amount of debris and oil removed in the process can help determine a patient’s baseline level of hygiene, which can aid postoperative wound care planning. In extreme cases, use of an alcohol swab may help diagnose dermatitis neglecta or terra firma-forme dermatosis by completely removing any pigmentation.⁴ 

After surgery, the alcohol swab can remove skin marker(s) and blood and prepare the site for the surgical dressing. There also is some evidence to suggest that cleansing the surgical site with an alcohol swab as part of routine postoperative wound care may decrease incidence of surgical-site infection.⁵ At follow-up, the swab can remove crust and clean the skin before suture removal. If infection is suspected, the swab can cleanse skin before a wound culture is obtained to remove skin commensals and flora on the outer surface of the wound.

Practice Implications

The 70% isopropyl alcohol swab can assist the dermatologist in numerous tasks related to everyday procedures. It is readily available in every clinic and costs only a few cents.

Practice Gap

In light of inflation, rising costs of procedures, and decreased reimbursements,¹ there is an increased need to identify and utilize inexpensive multitasking tools that can serve the dermatologic surgeon from preoperative to postoperative care. The 70% isopropyl alcohol swab may be the dermatologist’s most cost-effective and versatile surgical tool.

The Technique

When assessing a lesion, alcohol swabs can remove scale, crust, or residue from personal care products to help reveal primary morphology. They aid in the diagnosis of porokeratosis by highlighting the cornoid lamella when used following application of gentian violet.² The alcohol swab also can lay down a liquid interface to facilitate contact dermoscopy and improve visualization while also reducing the transmission of pathogens by the dermatoscope.³ Rubbing an area with an alcohol swab can induce vasodilation of scar tissue, which also may help localize a prior biopsy or surgical site (Figure).

Before a surgical site is marked, an initial cleanse with an alcohol swab serves to both remove debris and provide antisepsis ahead of the procedure. Additionally, the swab may improve adherence of skin markers by clearing excess lipid from the skin surface. Assessing the amount of debris and oil removed in the process can help determine a patient’s baseline level of hygiene, which can aid postoperative wound care planning. In extreme cases, use of an alcohol swab may help diagnose dermatitis neglecta or terra firma-forme dermatosis by completely removing any pigmentation.⁴ 

After surgery, the alcohol swab can remove skin marker(s) and blood and prepare the site for the surgical dressing. There also is some evidence to suggest that cleansing the surgical site with an alcohol swab as part of routine postoperative wound care may decrease incidence of surgical-site infection.⁵ At follow-up, the swab can remove crust and clean the skin before suture removal. If infection is suspected, the swab can cleanse skin before a wound culture is obtained to remove skin commensals and flora on the outer surface of the wound.

Practice Implications

The 70% isopropyl alcohol swab can assist the dermatologist in numerous tasks related to everyday procedures. It is readily available in every clinic and costs only a few cents.

Practice Gap

In light of inflation, rising costs of procedures, and decreased reimbursements,¹ there is an increased need to identify and utilize inexpensive multitasking tools that can serve the dermatologic surgeon from preoperative to postoperative care. The 70% isopropyl alcohol swab may be the dermatologist’s most cost-effective and versatile surgical tool.

The Technique

When assessing a lesion, alcohol swabs can remove scale, crust, or residue from personal care products to help reveal primary morphology. They aid in the diagnosis of porokeratosis by highlighting the cornoid lamella when used following application of gentian violet.² The alcohol swab also can lay down a liquid interface to facilitate contact dermoscopy and improve visualization while also reducing the transmission of pathogens by the dermatoscope.³ Rubbing an area with an alcohol swab can induce vasodilation of scar tissue, which also may help localize a prior biopsy or surgical site (Figure).

Before a surgical site is marked, an initial cleanse with an alcohol swab serves to both remove debris and provide antisepsis ahead of the procedure. Additionally, the swab may improve adherence of skin markers by clearing excess lipid from the skin surface. Assessing the amount of debris and oil removed in the process can help determine a patient’s baseline level of hygiene, which can aid postoperative wound care planning. In extreme cases, use of an alcohol swab may help diagnose dermatitis neglecta or terra firma-forme dermatosis by completely removing any pigmentation.⁴ 

After surgery, the alcohol swab can remove skin marker(s) and blood and prepare the site for the surgical dressing. There also is some evidence to suggest that cleansing the surgical site with an alcohol swab as part of routine postoperative wound care may decrease incidence of surgical-site infection.⁵ At follow-up, the swab can remove crust and clean the skin before suture removal. If infection is suspected, the swab can cleanse skin before a wound culture is obtained to remove skin commensals and flora on the outer surface of the wound.

Practice Implications

The 70% isopropyl alcohol swab can assist the dermatologist in numerous tasks related to everyday procedures. It is readily available in every clinic and costs only a few cents.

Evidence-based guidelines for managing atopic dermatitis (AD) issued by The American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters (JTFPP) incorporate a decade of new treatments and new methodological standards for making recommendations. The new guidelines update 2012 recommendations.

The JTFPP AD guidelines represent “an evolution” in trustworthy allergy guidelines and provide systematic reviews of the evidence with multidisciplinary panelist engagement, adherence to a rigorous guideline development process, the involvement of the patient and caregiver voice from start to finish, clear translation of evidence to clinically actionable and contextual recommendations, and novel approaches to facilitate knowledge translation, task force cochair Derek K. Chu, MD, PhD, said in an interview. Dr. Chu, director of the Evidence in Allergy research group at McMaster University, Hamilton, Ontario, Canada, cochaired the task force with Lynda Schneider, MD, section chief of the allergy and asthma program at Boston Children’s Hospital.

The new guidelines were published online on December 17, 2023, in Annals of Allergy, Asthma, & Immunology. They include 25 recommendations and address optimal use of topical treatments, such as topical corticosteroids, topical calcineurin inhibitors, topical JAK inhibitors, topical crisaborole, and topical antimicrobials; dilute bleach baths; dietary elimination; allergen immunotherapy by subcutaneous (SCIT) and sublingual (SLIT) routes; and systemic treatments with dupilumab and tralokinumab, cyclosporine, azathioprine, methotrexate, mycophenolate, oral JAK inhibitors, systemic corticosteroids; and phototherapy.

“There’s something in here for all clinicians — from primary care to AD experts— and patients may benefit as well, so the key individual recommendations will vary,” Dr. Chu told this news organization.

“Throughout the guideline, we emphasize shared decision-making, key factors to consider for each recommendation, and the specific evidence behind each recommendation,” he said. “There is a major focus on addressing equity, diversity, inclusiveness; and addressing health disparities, and key gaps to address in future research.”

Among the changes to the 2012 JTFPP guidelines, the 2023 update suggests using dilute bleach baths for patients with AD with moderate to severe disease as an additive therapy and suggests using allergen immunotherapy (AIT) for moderate to severe AD.

In other changes, the 2023 update suggests against using elimination diets for AD; recommends against very low dose baricitinib (1 mg); suggests against azathioprine, methotrexate, and mycophenolate mofetil; and suggests against adding topical JAK inhibitors, such as ruxolitinib, for patients with mild to moderate AD refractory to moisturization alone.

The 38-page guidelines include an infographic that summarizes comparative effects of systemic treatments on patient-important outcomes for AD that are important to patients, and includes other key summary tables that can be used at the point of care.

In addition to addressing evidence underlying each recommendation, the guideline’s eAppendix contains 1- to 2-page handouts that address practical issues for each treatment and can be used to facilitate shared decision making.

Dr. Chu said that the updated guidelines “provide important changes to almost all aspects of AD care — my own and my colleagues’ — and I strongly recommend all clinicians treating AD to read the full guidelines and use them in clinical practice. We’re grateful to all our contributors, especially our patient and caregiver partners, for helping make these guidelines. We will continue to periodically update the guidelines as part of maintaining them as living guidelines.”

The guidelines incorporate the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach for assessing the certainty of the evidence.

The work was funded by the AAAAI/ACAAI JTFPP. Dr. Chu disclosed that he has received a faculty development award from the AAAAI Foundation and research grants to McMaster from the Canadian Institutes of Health Research, the Ontario Ministry of Health, and the Ontario Medical Association.

Evidence-based guidelines for managing atopic dermatitis (AD) issued by The American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters (JTFPP) incorporate a decade of new treatments and new methodological standards for making recommendations. The new guidelines update 2012 recommendations.

The JTFPP AD guidelines represent “an evolution” in trustworthy allergy guidelines and provide systematic reviews of the evidence with multidisciplinary panelist engagement, adherence to a rigorous guideline development process, the involvement of the patient and caregiver voice from start to finish, clear translation of evidence to clinically actionable and contextual recommendations, and novel approaches to facilitate knowledge translation, task force cochair Derek K. Chu, MD, PhD, said in an interview. Dr. Chu, director of the Evidence in Allergy research group at McMaster University, Hamilton, Ontario, Canada, cochaired the task force with Lynda Schneider, MD, section chief of the allergy and asthma program at Boston Children’s Hospital.

The new guidelines were published online on December 17, 2023, in Annals of Allergy, Asthma, & Immunology. They include 25 recommendations and address optimal use of topical treatments, such as topical corticosteroids, topical calcineurin inhibitors, topical JAK inhibitors, topical crisaborole, and topical antimicrobials; dilute bleach baths; dietary elimination; allergen immunotherapy by subcutaneous (SCIT) and sublingual (SLIT) routes; and systemic treatments with dupilumab and tralokinumab, cyclosporine, azathioprine, methotrexate, mycophenolate, oral JAK inhibitors, systemic corticosteroids; and phototherapy.

“There’s something in here for all clinicians — from primary care to AD experts— and patients may benefit as well, so the key individual recommendations will vary,” Dr. Chu told this news organization.

“Throughout the guideline, we emphasize shared decision-making, key factors to consider for each recommendation, and the specific evidence behind each recommendation,” he said. “There is a major focus on addressing equity, diversity, inclusiveness; and addressing health disparities, and key gaps to address in future research.”

Among the changes to the 2012 JTFPP guidelines, the 2023 update suggests using dilute bleach baths for patients with AD with moderate to severe disease as an additive therapy and suggests using allergen immunotherapy (AIT) for moderate to severe AD.

In other changes, the 2023 update suggests against using elimination diets for AD; recommends against very low dose baricitinib (1 mg); suggests against azathioprine, methotrexate, and mycophenolate mofetil; and suggests against adding topical JAK inhibitors, such as ruxolitinib, for patients with mild to moderate AD refractory to moisturization alone.

The 38-page guidelines include an infographic that summarizes comparative effects of systemic treatments on patient-important outcomes for AD that are important to patients, and includes other key summary tables that can be used at the point of care.

In addition to addressing evidence underlying each recommendation, the guideline’s eAppendix contains 1- to 2-page handouts that address practical issues for each treatment and can be used to facilitate shared decision making.

Dr. Chu said that the updated guidelines “provide important changes to almost all aspects of AD care — my own and my colleagues’ — and I strongly recommend all clinicians treating AD to read the full guidelines and use them in clinical practice. We’re grateful to all our contributors, especially our patient and caregiver partners, for helping make these guidelines. We will continue to periodically update the guidelines as part of maintaining them as living guidelines.”

The guidelines incorporate the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach for assessing the certainty of the evidence.

The work was funded by the AAAAI/ACAAI JTFPP. Dr. Chu disclosed that he has received a faculty development award from the AAAAI Foundation and research grants to McMaster from the Canadian Institutes of Health Research, the Ontario Ministry of Health, and the Ontario Medical Association.

Evidence-based guidelines for managing atopic dermatitis (AD) issued by The American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters (JTFPP) incorporate a decade of new treatments and new methodological standards for making recommendations. The new guidelines update 2012 recommendations.

The JTFPP AD guidelines represent “an evolution” in trustworthy allergy guidelines and provide systematic reviews of the evidence with multidisciplinary panelist engagement, adherence to a rigorous guideline development process, the involvement of the patient and caregiver voice from start to finish, clear translation of evidence to clinically actionable and contextual recommendations, and novel approaches to facilitate knowledge translation, task force cochair Derek K. Chu, MD, PhD, said in an interview. Dr. Chu, director of the Evidence in Allergy research group at McMaster University, Hamilton, Ontario, Canada, cochaired the task force with Lynda Schneider, MD, section chief of the allergy and asthma program at Boston Children’s Hospital.

The new guidelines were published online on December 17, 2023, in Annals of Allergy, Asthma, & Immunology. They include 25 recommendations and address optimal use of topical treatments, such as topical corticosteroids, topical calcineurin inhibitors, topical JAK inhibitors, topical crisaborole, and topical antimicrobials; dilute bleach baths; dietary elimination; allergen immunotherapy by subcutaneous (SCIT) and sublingual (SLIT) routes; and systemic treatments with dupilumab and tralokinumab, cyclosporine, azathioprine, methotrexate, mycophenolate, oral JAK inhibitors, systemic corticosteroids; and phototherapy.

“There’s something in here for all clinicians — from primary care to AD experts— and patients may benefit as well, so the key individual recommendations will vary,” Dr. Chu told this news organization.

“Throughout the guideline, we emphasize shared decision-making, key factors to consider for each recommendation, and the specific evidence behind each recommendation,” he said. “There is a major focus on addressing equity, diversity, inclusiveness; and addressing health disparities, and key gaps to address in future research.”

Among the changes to the 2012 JTFPP guidelines, the 2023 update suggests using dilute bleach baths for patients with AD with moderate to severe disease as an additive therapy and suggests using allergen immunotherapy (AIT) for moderate to severe AD.

In other changes, the 2023 update suggests against using elimination diets for AD; recommends against very low dose baricitinib (1 mg); suggests against azathioprine, methotrexate, and mycophenolate mofetil; and suggests against adding topical JAK inhibitors, such as ruxolitinib, for patients with mild to moderate AD refractory to moisturization alone.

The 38-page guidelines include an infographic that summarizes comparative effects of systemic treatments on patient-important outcomes for AD that are important to patients, and includes other key summary tables that can be used at the point of care.

In addition to addressing evidence underlying each recommendation, the guideline’s eAppendix contains 1- to 2-page handouts that address practical issues for each treatment and can be used to facilitate shared decision making.

Dr. Chu said that the updated guidelines “provide important changes to almost all aspects of AD care — my own and my colleagues’ — and I strongly recommend all clinicians treating AD to read the full guidelines and use them in clinical practice. We’re grateful to all our contributors, especially our patient and caregiver partners, for helping make these guidelines. We will continue to periodically update the guidelines as part of maintaining them as living guidelines.”

The guidelines incorporate the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach for assessing the certainty of the evidence.

The work was funded by the AAAAI/ACAAI JTFPP. Dr. Chu disclosed that he has received a faculty development award from the AAAAI Foundation and research grants to McMaster from the Canadian Institutes of Health Research, the Ontario Ministry of Health, and the Ontario Medical Association.

The assessment and diagnosis of melanocytic lesions can present a formidable challenge to even a seasoned pathologist, which is especially true when dealing with the subset of nevi occurring at special sites—where baseline variations inherent to particular locations on the body can preclude the use of features routinely used to diagnose malignancy elsewhere. These so-called special-site nevi previously have been described in the literature along with suggested criteria for differentiating malignant lesions from their benign counterparts.¹ Locations generally considered to be special sites include the acral skin, anogenital region, breast, ear, and flexural regions.^1,2

When evaluating non–special-site melanocytic lesions, general characteristics associated with a malignant diagnosis include confluence or pagetoid spread of melanocytes, nuclear pleomorphism, cytologic atypia, and irregular architecture³; however, these features can be compatible with a benign diagnosis in special-site nevi depending on their extent and the site in question. Although they can be atypical, special-site nevi tend to have the bulk of their architectural distortion and cytologic atypia in the center of the lesion as opposed to the edges.¹ If a given lesion is from a special site but lacks this reassuring feature, special care should be taken to rule out malignancy.

Preferentially expressed antigen in melanoma (PRAME) is an antigen first identified in tumor-reactive T-cell populations in patients with malignant melanoma. It is the product of an oncogene that frequently is overexpressed in melanomas, lung squamous cell carcinomas, sarcomas, and acute leukemias.⁴ It functions as an antagonist of the retinoic acid signaling pathway, which normally serves to induce further cell differentiation, senescence, or apoptosis.⁵ PRAME inhibits retinoid signaling by forming a complex with both the ligand-bound retinoic acid holoreceptor and the polycomb protein EZH2, which blocks retinoid-dependent gene expression by encouraging chromatin condensation at the RARβ promoter site⁵; therefore, expressing PRAME allows lesional cells a substantial growth advantage.

PRAME expression has been extensively characterized in non–special-site nevi and has filled the need for a rather specific marker of melanoma.^6-10 Although PRAME has been studied in acral nevi,¹¹ the expression pattern in nevi of special sites has yet to be elucidated. Herein, we present a dataset characterizing PRAME expression in these challenging lesions.

Methods

We performed a retrospective case review at the University of Virginia (Charlottesville, Virginia) and collected a panel of 36 special-site nevi that previously were diagnosed as benign by a trained dermatopathologist from January 2020 through December 2022. Special-site nevi were identified using a natural language filter for the following terms: acral, palm, sole, ear, auricular, lip, axilla, armpit, breast, groin, labia, vulva, umbilicus, and penis. This study was approved by the University of Virginia institutional review board.

The original hematoxylin and eosin slides used for primary diagnosis were re-examined to verify the prior diagnosis of benign nevus at a special site. We performed a detailed microscopic examination of all benign nevi in our cohort to determine the frequency of various characteristics at each special site. Sections were prepared from the formalin-fixed and paraffin-embedded tissue blocks and stained with a commercial PRAME antibody (#219650 [Abcam] at a 1:50 dilution) and counterstain. A trained dermatopathologist (S.S.R.) examined the stained sections and recorded the percentage of tumor cells with nuclear PRAME staining. We reported our results using previously established criteria for scoring PRAME immunohistochemistry⁷: 0 for no expression, 1+ for 1% to 25% expression, 2+ for 26% to 50% expression, 3+ for 51% to 75% expression, and 4+ for diffuse or 76% to 100% expression. Only strong clonal expression within a population of cells was graded.

Data handling and statistical testing were performed using the R Project for Statistical Computing (https://www.r-project.org/). Significance testing was performed using the Fisher exact test. Plot construction was performed using ggplot2 (https://ggplot2.tidyverse.org/).

Our study cohort included 36 special-site nevi, and the control cohort comprised 25 melanoma in situ (MIS) or invasive melanoma (IM) lesions occurring at special sites. Table 1 provides a breakdown of the study and control cohorts by lesion site. Table 2 details the results of our microscopic examination, describing frequency of various characteristics of special-site nevi stratified by site.

Of the 36 special-site nevi in our cohort, 20 (56%) had no staining (0) for PRAME, 11 (31%) demonstrated 1+ PRAME expression, 3 (8%) demonstrated 2+ PRAME expression, and 2 (6%) demonstrated 3+ PRAME expression. No nevi showed 4+ expression. In the control cohort, 24 of 25 (96%) MIS and IM showed 3+ or 4+ expression, with 21 (84%) demonstrating ­diffuse/4+ expression. One control case (4%) demonstrated 0 PRAME expression. These data are summarized in Table 3 and Figure 1. There is a significant difference in diffuse (4+) PRAME expression between special-site nevi and MIS/IM occurring at special sites (P=1.039×10^-12).

Based on our cohort, a positivity threshold of 3+ for PRAME expression for the diagnosis of melanoma in a special-site lesion would have a sensitivity of 96% and a specificity of 94%, while a positivity threshold of 4+ for PRAME expression would have a sensitivity of 84% and a specificity of 100%. Figures 2 through 4 show photomicrographs of a special-site nevus of the breast, which appropriately does not stain for PRAME; Figures 5 and 6 show an MIS at a special site that appropriately stains for PRAME.

Comment

The distinction between benign and malignant pigmented lesions at special sites presents a fair challenge for pathologists due to the larger degree of leniency for architectural distortion and cytologic atypia in benign lesions at these sites. The presence of architectural distortion or cytologic atypia at the lesion’s edge makes rendering a benign diagnosis especially difficult, and the need for a validated immunohistochemical stain is apparent. In our cohort, strong clonal PRAME expression provided a reliable immunohistochemical marker, allowing for the distinction of malignant lesions from benign nevi at special sites. Diffuse faint PRAME expression was present in several benign nevi within our cohort, and these lesions were considered negative (0) in our analysis.

Given the described test characteristics, we support the implementation of PRAME immunohistochemistry with a positivity threshold of 4+ expression as an ancillary test supporting the diagnosis of IM or MIS in special sites, which would allow clinicians to leverage the high specificity of 4+ PRAME expression to distinguish an IM or MIS from a benign nevus occurring at a special site. We do not recommend the use of 4+ PRAME expression as a screening test for melanoma or MIS among special-site nevi due to its comparatively low sensitivity; however, no one marker is always reliable, and we recommend continued clinicopathologic correlation for all cases. Although PRAME can assist in the delineation of malignant lesions from benign ones, microscopic examination of hematoxylin and eosin–stained section remains the gold standard for diagnosing malignant melanoma and MIS.

Although our case series included nevi and MIS/IM from all special sites, we were limited in the number of acrogenital and ear nevi included due to a relative paucity of biopsied benign nevi from these locations at the University of Virginia. Additionally, although the magnitude of the difference in PRAME expression between the study and control groups is sufficient to demonstrate statistical significance, the overall strength of our argument would be increased with a larger study group. We were limited by the number of cases available at our institution, which did not utilize PRAME during the initial diagnosis of the case; including these cases in the study group would have undermined the integrity of our argument because the differentiation of benign vs malignant initially was made using PRAME immunohistochemistry.

Conclusion

Due to their atypical features, special-site nevi can be challenging to assess. In this study, we showed that PRAME expression can be a reliable marker to distinguish benign from malignant lesions. Our results showed that 100% of benign special-site nevi demonstrated 3+ expression or less, with 56% (20/36) demonstrating no expression at all. The presence of diffuse PRAME expression (4+ PRAME staining) appears to be a specific indicator of a malignant lesion, but results should always be interpreted with respect to the patient’s clinical history and the lesion’s histomorphologic features. Further study of a larger sample size would allow refinement of the sensitivity and specificity of diffuse PRAME expression in the determination of malignancy for special-site lesions.

Acknowledgment—The authors thank the pathologistsat the University of Virginia Biorepository and Tissue Research Facility (Charlottesville, Virginia) for their skill and expertise in performing immunohistochemical staining for this study.

The assessment and diagnosis of melanocytic lesions can present a formidable challenge to even a seasoned pathologist, which is especially true when dealing with the subset of nevi occurring at special sites—where baseline variations inherent to particular locations on the body can preclude the use of features routinely used to diagnose malignancy elsewhere. These so-called special-site nevi previously have been described in the literature along with suggested criteria for differentiating malignant lesions from their benign counterparts.¹ Locations generally considered to be special sites include the acral skin, anogenital region, breast, ear, and flexural regions.^1,2

When evaluating non–special-site melanocytic lesions, general characteristics associated with a malignant diagnosis include confluence or pagetoid spread of melanocytes, nuclear pleomorphism, cytologic atypia, and irregular architecture³; however, these features can be compatible with a benign diagnosis in special-site nevi depending on their extent and the site in question. Although they can be atypical, special-site nevi tend to have the bulk of their architectural distortion and cytologic atypia in the center of the lesion as opposed to the edges.¹ If a given lesion is from a special site but lacks this reassuring feature, special care should be taken to rule out malignancy.

Preferentially expressed antigen in melanoma (PRAME) is an antigen first identified in tumor-reactive T-cell populations in patients with malignant melanoma. It is the product of an oncogene that frequently is overexpressed in melanomas, lung squamous cell carcinomas, sarcomas, and acute leukemias.⁴ It functions as an antagonist of the retinoic acid signaling pathway, which normally serves to induce further cell differentiation, senescence, or apoptosis.⁵ PRAME inhibits retinoid signaling by forming a complex with both the ligand-bound retinoic acid holoreceptor and the polycomb protein EZH2, which blocks retinoid-dependent gene expression by encouraging chromatin condensation at the RARβ promoter site⁵; therefore, expressing PRAME allows lesional cells a substantial growth advantage.

PRAME expression has been extensively characterized in non–special-site nevi and has filled the need for a rather specific marker of melanoma.^6-10 Although PRAME has been studied in acral nevi,¹¹ the expression pattern in nevi of special sites has yet to be elucidated. Herein, we present a dataset characterizing PRAME expression in these challenging lesions.

Methods

We performed a retrospective case review at the University of Virginia (Charlottesville, Virginia) and collected a panel of 36 special-site nevi that previously were diagnosed as benign by a trained dermatopathologist from January 2020 through December 2022. Special-site nevi were identified using a natural language filter for the following terms: acral, palm, sole, ear, auricular, lip, axilla, armpit, breast, groin, labia, vulva, umbilicus, and penis. This study was approved by the University of Virginia institutional review board.

The original hematoxylin and eosin slides used for primary diagnosis were re-examined to verify the prior diagnosis of benign nevus at a special site. We performed a detailed microscopic examination of all benign nevi in our cohort to determine the frequency of various characteristics at each special site. Sections were prepared from the formalin-fixed and paraffin-embedded tissue blocks and stained with a commercial PRAME antibody (#219650 [Abcam] at a 1:50 dilution) and counterstain. A trained dermatopathologist (S.S.R.) examined the stained sections and recorded the percentage of tumor cells with nuclear PRAME staining. We reported our results using previously established criteria for scoring PRAME immunohistochemistry⁷: 0 for no expression, 1+ for 1% to 25% expression, 2+ for 26% to 50% expression, 3+ for 51% to 75% expression, and 4+ for diffuse or 76% to 100% expression. Only strong clonal expression within a population of cells was graded.

Data handling and statistical testing were performed using the R Project for Statistical Computing (https://www.r-project.org/). Significance testing was performed using the Fisher exact test. Plot construction was performed using ggplot2 (https://ggplot2.tidyverse.org/).

Our study cohort included 36 special-site nevi, and the control cohort comprised 25 melanoma in situ (MIS) or invasive melanoma (IM) lesions occurring at special sites. Table 1 provides a breakdown of the study and control cohorts by lesion site. Table 2 details the results of our microscopic examination, describing frequency of various characteristics of special-site nevi stratified by site.

Of the 36 special-site nevi in our cohort, 20 (56%) had no staining (0) for PRAME, 11 (31%) demonstrated 1+ PRAME expression, 3 (8%) demonstrated 2+ PRAME expression, and 2 (6%) demonstrated 3+ PRAME expression. No nevi showed 4+ expression. In the control cohort, 24 of 25 (96%) MIS and IM showed 3+ or 4+ expression, with 21 (84%) demonstrating ­diffuse/4+ expression. One control case (4%) demonstrated 0 PRAME expression. These data are summarized in Table 3 and Figure 1. There is a significant difference in diffuse (4+) PRAME expression between special-site nevi and MIS/IM occurring at special sites (P=1.039×10^-12).

Based on our cohort, a positivity threshold of 3+ for PRAME expression for the diagnosis of melanoma in a special-site lesion would have a sensitivity of 96% and a specificity of 94%, while a positivity threshold of 4+ for PRAME expression would have a sensitivity of 84% and a specificity of 100%. Figures 2 through 4 show photomicrographs of a special-site nevus of the breast, which appropriately does not stain for PRAME; Figures 5 and 6 show an MIS at a special site that appropriately stains for PRAME.

Comment

The distinction between benign and malignant pigmented lesions at special sites presents a fair challenge for pathologists due to the larger degree of leniency for architectural distortion and cytologic atypia in benign lesions at these sites. The presence of architectural distortion or cytologic atypia at the lesion’s edge makes rendering a benign diagnosis especially difficult, and the need for a validated immunohistochemical stain is apparent. In our cohort, strong clonal PRAME expression provided a reliable immunohistochemical marker, allowing for the distinction of malignant lesions from benign nevi at special sites. Diffuse faint PRAME expression was present in several benign nevi within our cohort, and these lesions were considered negative (0) in our analysis.

Given the described test characteristics, we support the implementation of PRAME immunohistochemistry with a positivity threshold of 4+ expression as an ancillary test supporting the diagnosis of IM or MIS in special sites, which would allow clinicians to leverage the high specificity of 4+ PRAME expression to distinguish an IM or MIS from a benign nevus occurring at a special site. We do not recommend the use of 4+ PRAME expression as a screening test for melanoma or MIS among special-site nevi due to its comparatively low sensitivity; however, no one marker is always reliable, and we recommend continued clinicopathologic correlation for all cases. Although PRAME can assist in the delineation of malignant lesions from benign ones, microscopic examination of hematoxylin and eosin–stained section remains the gold standard for diagnosing malignant melanoma and MIS.

Although our case series included nevi and MIS/IM from all special sites, we were limited in the number of acrogenital and ear nevi included due to a relative paucity of biopsied benign nevi from these locations at the University of Virginia. Additionally, although the magnitude of the difference in PRAME expression between the study and control groups is sufficient to demonstrate statistical significance, the overall strength of our argument would be increased with a larger study group. We were limited by the number of cases available at our institution, which did not utilize PRAME during the initial diagnosis of the case; including these cases in the study group would have undermined the integrity of our argument because the differentiation of benign vs malignant initially was made using PRAME immunohistochemistry.

Conclusion

Due to their atypical features, special-site nevi can be challenging to assess. In this study, we showed that PRAME expression can be a reliable marker to distinguish benign from malignant lesions. Our results showed that 100% of benign special-site nevi demonstrated 3+ expression or less, with 56% (20/36) demonstrating no expression at all. The presence of diffuse PRAME expression (4+ PRAME staining) appears to be a specific indicator of a malignant lesion, but results should always be interpreted with respect to the patient’s clinical history and the lesion’s histomorphologic features. Further study of a larger sample size would allow refinement of the sensitivity and specificity of diffuse PRAME expression in the determination of malignancy for special-site lesions.

Acknowledgment—The authors thank the pathologistsat the University of Virginia Biorepository and Tissue Research Facility (Charlottesville, Virginia) for their skill and expertise in performing immunohistochemical staining for this study.

The assessment and diagnosis of melanocytic lesions can present a formidable challenge to even a seasoned pathologist, which is especially true when dealing with the subset of nevi occurring at special sites—where baseline variations inherent to particular locations on the body can preclude the use of features routinely used to diagnose malignancy elsewhere. These so-called special-site nevi previously have been described in the literature along with suggested criteria for differentiating malignant lesions from their benign counterparts.¹ Locations generally considered to be special sites include the acral skin, anogenital region, breast, ear, and flexural regions.^1,2

When evaluating non–special-site melanocytic lesions, general characteristics associated with a malignant diagnosis include confluence or pagetoid spread of melanocytes, nuclear pleomorphism, cytologic atypia, and irregular architecture³; however, these features can be compatible with a benign diagnosis in special-site nevi depending on their extent and the site in question. Although they can be atypical, special-site nevi tend to have the bulk of their architectural distortion and cytologic atypia in the center of the lesion as opposed to the edges.¹ If a given lesion is from a special site but lacks this reassuring feature, special care should be taken to rule out malignancy.

Preferentially expressed antigen in melanoma (PRAME) is an antigen first identified in tumor-reactive T-cell populations in patients with malignant melanoma. It is the product of an oncogene that frequently is overexpressed in melanomas, lung squamous cell carcinomas, sarcomas, and acute leukemias.⁴ It functions as an antagonist of the retinoic acid signaling pathway, which normally serves to induce further cell differentiation, senescence, or apoptosis.⁵ PRAME inhibits retinoid signaling by forming a complex with both the ligand-bound retinoic acid holoreceptor and the polycomb protein EZH2, which blocks retinoid-dependent gene expression by encouraging chromatin condensation at the RARβ promoter site⁵; therefore, expressing PRAME allows lesional cells a substantial growth advantage.

PRAME expression has been extensively characterized in non–special-site nevi and has filled the need for a rather specific marker of melanoma.^6-10 Although PRAME has been studied in acral nevi,¹¹ the expression pattern in nevi of special sites has yet to be elucidated. Herein, we present a dataset characterizing PRAME expression in these challenging lesions.

Methods

We performed a retrospective case review at the University of Virginia (Charlottesville, Virginia) and collected a panel of 36 special-site nevi that previously were diagnosed as benign by a trained dermatopathologist from January 2020 through December 2022. Special-site nevi were identified using a natural language filter for the following terms: acral, palm, sole, ear, auricular, lip, axilla, armpit, breast, groin, labia, vulva, umbilicus, and penis. This study was approved by the University of Virginia institutional review board.

The original hematoxylin and eosin slides used for primary diagnosis were re-examined to verify the prior diagnosis of benign nevus at a special site. We performed a detailed microscopic examination of all benign nevi in our cohort to determine the frequency of various characteristics at each special site. Sections were prepared from the formalin-fixed and paraffin-embedded tissue blocks and stained with a commercial PRAME antibody (#219650 [Abcam] at a 1:50 dilution) and counterstain. A trained dermatopathologist (S.S.R.) examined the stained sections and recorded the percentage of tumor cells with nuclear PRAME staining. We reported our results using previously established criteria for scoring PRAME immunohistochemistry⁷: 0 for no expression, 1+ for 1% to 25% expression, 2+ for 26% to 50% expression, 3+ for 51% to 75% expression, and 4+ for diffuse or 76% to 100% expression. Only strong clonal expression within a population of cells was graded.

Data handling and statistical testing were performed using the R Project for Statistical Computing (https://www.r-project.org/). Significance testing was performed using the Fisher exact test. Plot construction was performed using ggplot2 (https://ggplot2.tidyverse.org/).

Our study cohort included 36 special-site nevi, and the control cohort comprised 25 melanoma in situ (MIS) or invasive melanoma (IM) lesions occurring at special sites. Table 1 provides a breakdown of the study and control cohorts by lesion site. Table 2 details the results of our microscopic examination, describing frequency of various characteristics of special-site nevi stratified by site.

Of the 36 special-site nevi in our cohort, 20 (56%) had no staining (0) for PRAME, 11 (31%) demonstrated 1+ PRAME expression, 3 (8%) demonstrated 2+ PRAME expression, and 2 (6%) demonstrated 3+ PRAME expression. No nevi showed 4+ expression. In the control cohort, 24 of 25 (96%) MIS and IM showed 3+ or 4+ expression, with 21 (84%) demonstrating ­diffuse/4+ expression. One control case (4%) demonstrated 0 PRAME expression. These data are summarized in Table 3 and Figure 1. There is a significant difference in diffuse (4+) PRAME expression between special-site nevi and MIS/IM occurring at special sites (P=1.039×10^-12).

Based on our cohort, a positivity threshold of 3+ for PRAME expression for the diagnosis of melanoma in a special-site lesion would have a sensitivity of 96% and a specificity of 94%, while a positivity threshold of 4+ for PRAME expression would have a sensitivity of 84% and a specificity of 100%. Figures 2 through 4 show photomicrographs of a special-site nevus of the breast, which appropriately does not stain for PRAME; Figures 5 and 6 show an MIS at a special site that appropriately stains for PRAME.

Comment

The distinction between benign and malignant pigmented lesions at special sites presents a fair challenge for pathologists due to the larger degree of leniency for architectural distortion and cytologic atypia in benign lesions at these sites. The presence of architectural distortion or cytologic atypia at the lesion’s edge makes rendering a benign diagnosis especially difficult, and the need for a validated immunohistochemical stain is apparent. In our cohort, strong clonal PRAME expression provided a reliable immunohistochemical marker, allowing for the distinction of malignant lesions from benign nevi at special sites. Diffuse faint PRAME expression was present in several benign nevi within our cohort, and these lesions were considered negative (0) in our analysis.

Given the described test characteristics, we support the implementation of PRAME immunohistochemistry with a positivity threshold of 4+ expression as an ancillary test supporting the diagnosis of IM or MIS in special sites, which would allow clinicians to leverage the high specificity of 4+ PRAME expression to distinguish an IM or MIS from a benign nevus occurring at a special site. We do not recommend the use of 4+ PRAME expression as a screening test for melanoma or MIS among special-site nevi due to its comparatively low sensitivity; however, no one marker is always reliable, and we recommend continued clinicopathologic correlation for all cases. Although PRAME can assist in the delineation of malignant lesions from benign ones, microscopic examination of hematoxylin and eosin–stained section remains the gold standard for diagnosing malignant melanoma and MIS.

Although our case series included nevi and MIS/IM from all special sites, we were limited in the number of acrogenital and ear nevi included due to a relative paucity of biopsied benign nevi from these locations at the University of Virginia. Additionally, although the magnitude of the difference in PRAME expression between the study and control groups is sufficient to demonstrate statistical significance, the overall strength of our argument would be increased with a larger study group. We were limited by the number of cases available at our institution, which did not utilize PRAME during the initial diagnosis of the case; including these cases in the study group would have undermined the integrity of our argument because the differentiation of benign vs malignant initially was made using PRAME immunohistochemistry.

Conclusion

Due to their atypical features, special-site nevi can be challenging to assess. In this study, we showed that PRAME expression can be a reliable marker to distinguish benign from malignant lesions. Our results showed that 100% of benign special-site nevi demonstrated 3+ expression or less, with 56% (20/36) demonstrating no expression at all. The presence of diffuse PRAME expression (4+ PRAME staining) appears to be a specific indicator of a malignant lesion, but results should always be interpreted with respect to the patient’s clinical history and the lesion’s histomorphologic features. Further study of a larger sample size would allow refinement of the sensitivity and specificity of diffuse PRAME expression in the determination of malignancy for special-site lesions.

Acknowledgment—The authors thank the pathologistsat the University of Virginia Biorepository and Tissue Research Facility (Charlottesville, Virginia) for their skill and expertise in performing immunohistochemical staining for this study.

Approximately 20% of the general population has a contact allergy.¹ Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction mediated by T lymphocytes.² Axillary ACD presentation is variable but typically includes an eczematous eruption with erythematous scaly patches or plaques. Common products in contact with the axillae include deodorants, antiperspirants, razors, bodywash, and clothing.

Axillary skin is distinct from skin elsewhere on the body due to both anatomical characteristics and unique human self-care practices. Axillary skin has reduced barrier function, faster stratum corneum turnover, and altered lipid levels.^3-5 Moreover, the axillae often are subject to shaving or other hair removal practices that alter the local environment, as layers of stratum corneum and hair are mechanically removed, which causes irritation and predisposes the skin to enhanced sensitivity to topical exposures.^6,7 With the abundance of apocrine and eccrine glands, the axillae are prone to sweat, which also can accentuate contact allergy.^2,3 Other factors, such as occlusion and friction, contribute to axillary contact allergy.^8,9

Patch testing is the gold standard for the diagnosis of ACD and aids in identification of culprit allergens. A thorough patient history and examination of the rash distribution may provide further clues; for example, dermatitis due to a deodorant typically affects the vault, whereas textile dye dermatitis tends to spare the vault.^10,11 Baseline-limited patch testing detects up to two-thirds of clinically relevant allergens.¹² Therefore, patients may require subsequent testing with supplemental allergens.

The differential diagnosis for axillary lesions is broad—including inflammatory diseases such as irritant contact dermatitis and hidradenitis suppurativa, genetic disorders such as Hailey-Hailey disease, and infectious causes such as erythrasma—but may be narrowed with a thorough physical examination and patient history, histopathology, bedside diagnostic techniques (eg, scrapings and Wood lamp examination), and patch testing. Systemic contact dermatitis (SCD) or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) also may be suspected in cases of intertriginous dermatoses.

We review the potential allergens in products used on the axillae as well as the management of axillary ACD. We also discuss axillary dermatitis as a manifestation of SCD and SDRIFE.

Top Allergens in Products Used on the Axillae

Fragrance—A 1982 North American Contact Dermatitis Group study on cosmetic products identified fragrances as the most common cause of ACD,¹³ and this trend continues to hold true with more recent data.¹⁴ The incidence of fragrance allergy may be increasing, with positive patch tests to a fragrance chemical in 10% of patch test clinic populations.¹⁵ Fragrances are a ubiquitous ingredient in deodorants and antiperspirants, which are important sources implicated in the development and elicitation of fragrance ACD.¹⁶ One study found that fragrance was present in 97 of 107 (90%) deodorants available at Walgreens pharmacies.¹¹

In a study of patients with a history of an axillary rash caused by a deodorant spray, Johansen et al¹⁷ reported that the likelihood of fragrance allergy is increased by a factor of 2.4. This risk of developing a fragrance allergy may be exacerbated in those who shave; Edman¹⁸ reported that the odds ratio of developing a fragrance allergy among men who shave their beards was 2.9. Although there are no specific data on the effects of shaving on ACD, shaving in general can induce localized irritation and increase percutaneous absorption.¹⁹

The individual fragrance components in deodorants most likely to cause ACD include hydroxycitronellal, eugenol, and geraniol—all constituent ingredients in patch test formulations of fragrance mixture I.^11,20 Other common fragrance allergens associated with ACD include hydroxymethylpentylcyclohexenecarboxaldehyde, farnesol, and balsam of Peru.^21-27 Hydroperoxides of limonene and linalool, common fragrances in detergents and personal care products, are increasingly recognized as contact allergens and have been reported to cause axillary ACD from deodorants.^28-30

Dermatitis involving the bilateral axillary vaults wherever deodorant or antiperspirant was directly applied is the most common presentation of ACD due to fragrance (Figure 1).¹⁷ An eczematous eruption is common, though scale may be less apparent than in nonflexural regions. Axillary ACD secondary to fragrances also may result from use of fragranced laundry detergents, fabric softeners, soaps, and perfumes, and may spare the vaults.^10,29,31,32 Less common presentations of axillary ACD due to fragrance include pigmented dermatoses; for example, ACD from an antiperspirant containing hydroperoxide of limonene presented as hyperpigmented patches with minimal erythema and scaling in the edges of the axillary folds.^33,34

Diagnosis of a fragrance ACD typically is made with a standard patch test series including fragrance mixture I and balsam of Peru, which may detect 75% and 50% of fragrance sensitivities, respectively.³⁵ Patch testing may be followed with a repeated open application test of the product in question.³⁶ Additionally, it may be appropriate to test for other fragrance allergens including balsam of Tolu, fragrance mixture II, lichen acid mix, and hydroxyperoxides of linalool and limonene (among other botanicals) if standard patch testing is negative and suspicion of fragrance ACD remains elevated.¹¹

Propylene Glycol—Propylene glycol (PG)—a versatile substance that functions as a solvent, humectant, emulsifier, stabilizer, and antimicrobial—is the second most common contact allergen present in deodorants.¹¹ It is prevalent in both personal care and household products, including deodorants, cosmetics, foods, toothpaste, cleaning agents, and detergents.^11,37 Propylene glycol is both an allergen and an irritant. Among deodorants/antiperspirants, PG is both a common irritant and allergen, as its concentration may be particularly high (as much as 73%).³⁸ One commonly reported example of PG contact dermatitis is from the topical medicament minoxidil.^39,40

Patch testing data have demonstrated a positivity rate for PG ranging between 0.1% to 3.8%. The variability in these findings likely is due to differences in the tested concentrations of PG, as higher concentrations sometimes required to elicit an allergic reaction also may create a stronger irritation effect.⁴¹ Propylene glycol irritancy and the occlusive nature of the axillae may enhance sensitization to other allergens, as demonstrated by Agren-Jonsson and Magnusson,⁴² who reported sensitization to propantheline bromide and trichlorocarbanilide in patients who used a lotion with 90% PG. Many PG-containing products beyond deodorants/antiperspirants may be applied to the axillae, including steroid creams, lotions, shaving creams, and bodywashes.^38,43

The diagnosis of PG allergy via patch testing is challenging and at times controversial given its irritant nature. False-positive irritant reactions have been documented, characterized by a weak reaction at 48 hours that is absent by 96 hours (decrescendo reaction). A reaction may not appear until 96 hours (crescendo reaction), which typically indicates a true contact allergy but in the case of PG also may be the substance acting as a “late irritant.”⁴⁴ Fast (<24 hours) and well-demarcated reactions suggest irritation.⁴⁵ Regardless, reactions to PG on patch testing, even those regarded as weak, may be considered relevant in consideration of the clinical context.³⁷

Aluminum—Aluminum is the active ingredient in most antiperspirants, typically in the form of aluminum chloride, aluminum chlorohydrate, aluminum zirconium trichlorohydrex gly, or aluminum zirconium tetrachlorohydrex gly.⁴⁶ Aluminum mechanically obstructs the eccrine glands to reduce sweat.⁴⁷ Although aluminum is an uncommon allergen, a possible presentation of aluminum allergy is axillary vault dermatitis secondary to antiperspirant use.⁴⁶ Another potential manifestation is a ringlike reaction to the Finn Chambers (SmartPractice) used in patch testing.⁴⁶ In one case of aluminum-induced axillary dermatitis, a 28-year-old woman presented with eczema of the axillae, and subsequent patch testing revealed an allergy to aluminum chloride. The rash resolved upon cessation of use of an aluminum-containing deodorant.⁴⁸

Aluminum has been reported to cause granulomatous dermatitis in the axillae. This reaction typically presents as red-brown, pruritic papules limited to the area in which deodorant was applied, with histopathology revealing epithelioid granulomas.^49-51

Alum deodorants—considered a natural alternative—contain aluminum bound to potassium or ammonium in the form of a crystal or powder. Alum crystal deodorants have been reported to cause both a typical erythematous pruritic dermatitis as well as a granulomatous dermatitis with red-brown papules.^52,53 The granulomatous dermatitis caused by either form of aluminum resolves with avoidance and use of topical steroids or topical tacrolimus.^49,50,52,53

The diagnosis of aluminum ACD via patch testing may be identified with empty Finn Chambers, which are metallic aluminum, or with patch placement of aluminum chloride hexahydrate, though the former is only positive in patients with a strong allergy.^54,55 In 2022, aluminum was named Allergen of the Year by the American Contact Dermatitis Society, with recommendations to conduct patch testing with aluminum chloride hexahydrate 10% rather than the traditional 2% to increase diagnostic yield.⁵⁵ Additionally, it is recommended that aluminum be included in baseline patch testing for children due to the high prevalence of aluminum allergy in children and early exposure via childhood vaccines.^54-56 In patients with aluminum allergy, providers may suggest purchasing aluminum-free deodorants or provide recipes for homemade deodorant that includes ingredients such as arrowroot powder, cornstarch, and diatomaceous earth.⁴⁶

Nickel—Nickel is the most commonly identified contact allergen on patch testing yet an infrequent cause of axillary dermatitis. A case report from 2014 described axillary dermatitis in a woman that worsened during a positive patch test to nickel. Improvement was noted when the patient switched to titanium shaving razors.⁵⁷ Nickel allergy also may present in the form of SCD. In one report, a woman developed dermatitis of the flexural areas, including the axillae, 3 months after undergoing a sterilization procedure in which nickel-containing tubal implants were placed.⁵⁸ Patch testing revealed a positive reaction to nickel. The patient experienced complete resolution of the steroid-resistant dermatitis following removal of the implants via salpingectomy.⁵⁸

Textile Dye—In contrast to dermatitis caused by deodorants/antiperspirants, contact allergy to textile dyes presents as dermatitis involving the axillary borders but sparing the axillary vaults (Figures 2 and 3).¹⁰ Other potential presentations of textile dye dermatitis include erythema multiforme–like eruptions and erythematous wheal–type reactions.⁵⁹ Textile dyes are classified as disperse vs nondisperse, with the majority of contact dermatoses caused by disperse dyes, specifically Disperse Orange 1, blue 106, and blue 124.^60-62 Ryberg et al⁶¹ found that the axilla is one of the more common locations to be affected by textile dye allergy, particularly in women, which was further supported by Seidenari et al,⁶³ who found that skin folds were affected in 27% of study participants allergic to textile dyes (N=437), a finding that is likely due to friction, sweat, and occlusion.⁶² In one case report of a patient with dermatitis caused by reactive dyes, the garment required 3 washes before the patient experienced resolution of dermatitis.⁶⁴ For patients with textile dye dermatitis, mitigation strategies include washing clothing before wearing, especially for darkly dyed items; avoiding tight clothing; wearing garments made of cotton, wool, silk, or linen; and choosing light-colored garments.^9,64,65

Axillary Dermatitis as a Manifestation of SCD and SDRIFE

Systemic contact dermatitis occurs when an individual who was previously sensitized to a particular allergen develops ACD of the skin with systemic exposure to that allergen or immunochemically related allergens. Exposure may occur via ingestion, inhalation, intravenous, intramuscular, and transepidermal routes.⁶⁶ Systemic contact dermatitis manifests in a variety of ways, including focal flares at sites of prior contact dermatitis (recall reaction), vesicular hand dermatitis, intertriginous eruptions including axillary dermatitis, and generalized eruptions.⁶⁷

Systemic contact dermatitis rarely involves systemic symptoms, and onset typically is within days of exposure. The 3 most common groups of allergens causing SCD are metals, medications, and plants and herbals.⁶⁸ These allergens have all been reported to cause axillary dermatitis via SCD.^58,69,70 Foods containing balsam of Peru that may lead to SCD include citrus, chocolate, tomato, and certain alcohols.^70,71 Patients with a positive patch test to balsam of Peru may experience improvement of their dermatitis after reduction of balsam of Peru–rich foods from their diet.⁷⁰ Metals implicated in SCD include mercury, nickel, and gold.^72-74 Finally, PG ingestion also has been implicated in cases of SCD.³⁷

Symmetrical drug-related intertriginous and flexural exanthema is another condition that presents as intertriginous dermatitis and differs from SCD in that the eruption does not require presensitization; there may be no known prior exposure to the agent causing dermatitis. Historically, SDRIFE was described as baboon syndrome because of its frequent involvement of the buttocks with diffuse, well-demarcated, erythematous dermatitis resembling that of a baboon. This term is no longer used due to its insensitive nature and incomplete depiction of SDRIFE, which can affect body sites other than the buttocks.^68,75,76 Specific criteria to make this diagnosis include sharply demarcated and/or V-shaped erythema of the gluteal/perianal area, involvement of at least 1 other intertriginous or flexural region, symmetry of affected areas, and an absence of systemic symptoms.⁷⁶ There also may be papules, pustules, and vesicles present in affected areas. Symmetrical drug-related intertriginous and flexural exanthema most often is caused by β-lactam antibiotics, but other associated drugs include chemotherapeutic agents, such as mitomycin C.⁷⁶

Histopathology of both SCD and SDRIFE is variable and typically nonspecific, often revealing epidermal spongiosis and a perivascular mononuclear cell infiltrate with occasional neutrophils and eosinophils.⁷⁶ A case of SCD to mercury presenting as intertriginous dermatitis demonstrated a leukocytoclastic vasculitis pattern on biopsy.⁷⁷

Systemic contact dermatitis is diagnosed via a patch test, while SDRIFE typically has a negative patch test result and requires oral rechallenge testing, which reproduces the rash within hours.^78,79

Additional Allergens Causing Axillary ACD

Although fragrance is the most common allergen in deodorants, other ingredients have been shown to cause axillary ACD (Table).^80-90 In addition to these ingredients, allergens not previously mentioned that may be present in deodorants include lanolin, essential oils, and parabens.¹¹ Methylisothiazolinone in laundry detergent also has been found to instigate ACD.⁹¹ Fragrances and preservatives in laundry detergents also may contribute to dermatitis.⁹²

Other products that have caused axillary contact dermatitis include topical exposure to medicaments including clindamycin,⁹³ ethylenediamine in nystatin cream,⁹⁴ methylprednisolone acetate⁹⁵ and dipropylene glycol in a hydrocortisone lotion,⁹⁶ wood dusts from tropical hardwoods,⁹⁷ and tobacco.⁹⁸

Management of ACD

The most effective strategy in the management of patients with contact dermatitis is avoidance of the offending agent. Additionally, clinicians may recommend the use of topical steroids and/or calcineurin inhibitors to hasten resolution.²

For patients with contact dermatitis, a clinician may recommend product substitutions with few potential allergens to use prior to patch testing. Patients with a fragrance allergy should look for products specifically labeled as “fragrance free” rather than “hypoallergenic” or “unscented,” as the latter two may still contain minimal amounts of fragrance.³⁵ Patients should be educated on the functions of the allergens to which they are allergic so they may adequately avoid potential sources of contact.⁹⁹ For suspected textile dye dermatitis, instructing patients to wash clothing before wearing and to avoid synthetic fabrics, dark dyes, and tightly fitted clothing may help.^9,64,65

The differential diagnosis for axillary lesions is broad, including infectious, inflammatory, and autoimmune etiologies. Irritant contact dermatitis (ICD) presents similar to ACD, though it is more immediate in onsetand typically demonstrates symptoms of burning and stinging rather than pruritus. Although histopathology is not reliable in differentiating ICD and ACD, it has been shown that focal parakeratosis is associated with ACD, whereas necrotic epidermal keratinocytes are found in ICD.¹⁰⁰

Intertrigo presents as large, erythematous, opposing patches or plaques confined to inguinal, submammary, axillary, and/or abdominal folds. Findings of beefy red erythema and peripheral satellite pustules may implicate presence of Candida, which can be identified with potassium hydroxide preparations.

Inverse psoriasis presents as sharply demarcated, erythematous, moist, smooth plaques or patches with minimal scale. The most common area of involvement is the inguinal folds, followed by the axillae, inframammary folds, perianal area, umbilicus, and retroauricular areas. Involvement of the elbows and knees or a positive family history of psoriasis may be useful knowledge in establishing the diagnosis. A biopsy may show dermal eosinophils, epidermal spongiosis, and focal serum in the scale, in addition to features of typical psoriasis plaques.¹⁰¹

Seborrheic dermatitis typically is an erythematous eruption, often with yellowish greasy scale. Simultaneous involvement of the face and scalp may be noted. Although typically a clinical diagnosis, biopsy demonstrates shoulder parakeratosis with follicular plugging and lymphocytic exocytosis.

Hailey-Hailey disease (also called benign familial pemphigus) is an autosomal-dominant genetic condition presenting as moist, malodorous, painful, vegetative plaques, patches, or scaly pustules in flexural areas, frequently with flaccid blisters. Lesions are provoked by traumatic stimuli. Onset occurs in the second to fourth decades and may improve with age. The diagnosis is confirmed by biopsy, which demonstrates acantholysis of the epidermis. The moist superficial patches of Hailey-Hailey disease help distinguish it from comparably drier Darier disease, the other acantholytic disease of the axillae.

Granular parakeratosis (also called hyperkeratotic flexural erythema) is an uncommon dermatosis most often observed in middle-aged women. It presents as red-brown keratotic papules coalescing into plaques, often with overlying scale in intertriginous areas. This disorder may be related to exposure to aluminum, a key component of antiperspirants.¹⁰² Diagnosis with a skin biopsy demonstrates granular parakeratosis.

Infections most commonly include erythrasma, tinea, and candidiasis. Erythrasma caused by Corynebacterium minutissimum may present in the axillae and/or groin with sharply demarcated, red-brown patches. Wood lamp examination reveals coral red fluorescence. Tinea corporis, a dermatophyte infection, may present as scaly erythematous plaques with advancing borders and central clearing. Fungal cultures and potassium hydroxide preparations are useful to confirm the diagnosis.

Pseudofolliculitis barbae most often is thought of as a condition affecting the beard in Black men, but it also may present in individuals of all races who shave the axillary and inguinal regions. Typical features include pruritic inflammatory papules and pustules with surrounding erythema and hyperpigmentation.

Fox-Fordyce disease is a disorder of the apocrine sweat glands that presents as several flesh-colored, perifollicular, monomorphic papules in the axillae. It typically is a disease of young females and also can involve the areola and vulva. Histopathology may show hyperkeratosis, irregular acanthosis, and dilated sweat glands.

Hidradenitis suppurativa is a chronic inflammatory condition that presents with multiple cysts; nodules; abscesses; sinus tract formation; and suppuration of the axillary, anogenital, and sometimes inframammary areas, typically at the onset of puberty. The diagnosis is best supported by history and physical examination, which may be notable for recurrent abscesses, draining tracts, double comedones, and ropelike scarring.

Extramammary Paget disease is a rare malignancy affecting apocrine gland–bearing areas, including axillary and genital regions. It most commonly presents as a unilateral or asymmetric, scaly, erythematous plaque. Histopathology demonstrates Paget cells with abundant clear cytoplasm and pleomorphic nuclei, typically grouped in the lower portion of the epidermis.

Final Thoughts

Axillary dermatoses often can be challenging to diagnose given the range of pathologies that can present in intertriginous areas. Allergic contact dermatitis is a common culprit due to unique anatomical considerations and self-care practices, including shaving/hair removal; use of deodorants, antiperspirants, bodywashes, and clothing; and frictional and moisture influences. The most likely offender among contact allergens is fragrance, but other possibilities to consider include PG, preservatives, aluminum, nickel, and textile dyes. Albeit less common, systemic exposure to allergens may result in SCD and SDRIFE with a rash in intertriginous zones, including the axillae. Additionally, other infectious, inflammatory, and autoimmune etiologies should be considered and ruled out.

Patch testing is the most reliable method to diagnose suspected ACD. Once confirmed, management includes the use of topical steroids and avoidance of the causative agent. Additionally, patients should be informed of the American Contact Dermatitis Society Contact Allergen Management Program (https://www.contactderm.org/patient-support/camp-access), which provides patients with useful information on products that are safe to use based on their patch testing results.

Approximately 20% of the general population has a contact allergy.¹ Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction mediated by T lymphocytes.² Axillary ACD presentation is variable but typically includes an eczematous eruption with erythematous scaly patches or plaques. Common products in contact with the axillae include deodorants, antiperspirants, razors, bodywash, and clothing.

Axillary skin is distinct from skin elsewhere on the body due to both anatomical characteristics and unique human self-care practices. Axillary skin has reduced barrier function, faster stratum corneum turnover, and altered lipid levels.^3-5 Moreover, the axillae often are subject to shaving or other hair removal practices that alter the local environment, as layers of stratum corneum and hair are mechanically removed, which causes irritation and predisposes the skin to enhanced sensitivity to topical exposures.^6,7 With the abundance of apocrine and eccrine glands, the axillae are prone to sweat, which also can accentuate contact allergy.^2,3 Other factors, such as occlusion and friction, contribute to axillary contact allergy.^8,9

Patch testing is the gold standard for the diagnosis of ACD and aids in identification of culprit allergens. A thorough patient history and examination of the rash distribution may provide further clues; for example, dermatitis due to a deodorant typically affects the vault, whereas textile dye dermatitis tends to spare the vault.^10,11 Baseline-limited patch testing detects up to two-thirds of clinically relevant allergens.¹² Therefore, patients may require subsequent testing with supplemental allergens.

The differential diagnosis for axillary lesions is broad—including inflammatory diseases such as irritant contact dermatitis and hidradenitis suppurativa, genetic disorders such as Hailey-Hailey disease, and infectious causes such as erythrasma—but may be narrowed with a thorough physical examination and patient history, histopathology, bedside diagnostic techniques (eg, scrapings and Wood lamp examination), and patch testing. Systemic contact dermatitis (SCD) or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) also may be suspected in cases of intertriginous dermatoses.

We review the potential allergens in products used on the axillae as well as the management of axillary ACD. We also discuss axillary dermatitis as a manifestation of SCD and SDRIFE.

Top Allergens in Products Used on the Axillae

Fragrance—A 1982 North American Contact Dermatitis Group study on cosmetic products identified fragrances as the most common cause of ACD,¹³ and this trend continues to hold true with more recent data.¹⁴ The incidence of fragrance allergy may be increasing, with positive patch tests to a fragrance chemical in 10% of patch test clinic populations.¹⁵ Fragrances are a ubiquitous ingredient in deodorants and antiperspirants, which are important sources implicated in the development and elicitation of fragrance ACD.¹⁶ One study found that fragrance was present in 97 of 107 (90%) deodorants available at Walgreens pharmacies.¹¹

In a study of patients with a history of an axillary rash caused by a deodorant spray, Johansen et al¹⁷ reported that the likelihood of fragrance allergy is increased by a factor of 2.4. This risk of developing a fragrance allergy may be exacerbated in those who shave; Edman¹⁸ reported that the odds ratio of developing a fragrance allergy among men who shave their beards was 2.9. Although there are no specific data on the effects of shaving on ACD, shaving in general can induce localized irritation and increase percutaneous absorption.¹⁹

The individual fragrance components in deodorants most likely to cause ACD include hydroxycitronellal, eugenol, and geraniol—all constituent ingredients in patch test formulations of fragrance mixture I.^11,20 Other common fragrance allergens associated with ACD include hydroxymethylpentylcyclohexenecarboxaldehyde, farnesol, and balsam of Peru.^21-27 Hydroperoxides of limonene and linalool, common fragrances in detergents and personal care products, are increasingly recognized as contact allergens and have been reported to cause axillary ACD from deodorants.^28-30

Dermatitis involving the bilateral axillary vaults wherever deodorant or antiperspirant was directly applied is the most common presentation of ACD due to fragrance (Figure 1).¹⁷ An eczematous eruption is common, though scale may be less apparent than in nonflexural regions. Axillary ACD secondary to fragrances also may result from use of fragranced laundry detergents, fabric softeners, soaps, and perfumes, and may spare the vaults.^10,29,31,32 Less common presentations of axillary ACD due to fragrance include pigmented dermatoses; for example, ACD from an antiperspirant containing hydroperoxide of limonene presented as hyperpigmented patches with minimal erythema and scaling in the edges of the axillary folds.^33,34

Diagnosis of a fragrance ACD typically is made with a standard patch test series including fragrance mixture I and balsam of Peru, which may detect 75% and 50% of fragrance sensitivities, respectively.³⁵ Patch testing may be followed with a repeated open application test of the product in question.³⁶ Additionally, it may be appropriate to test for other fragrance allergens including balsam of Tolu, fragrance mixture II, lichen acid mix, and hydroxyperoxides of linalool and limonene (among other botanicals) if standard patch testing is negative and suspicion of fragrance ACD remains elevated.¹¹

Propylene Glycol—Propylene glycol (PG)—a versatile substance that functions as a solvent, humectant, emulsifier, stabilizer, and antimicrobial—is the second most common contact allergen present in deodorants.¹¹ It is prevalent in both personal care and household products, including deodorants, cosmetics, foods, toothpaste, cleaning agents, and detergents.^11,37 Propylene glycol is both an allergen and an irritant. Among deodorants/antiperspirants, PG is both a common irritant and allergen, as its concentration may be particularly high (as much as 73%).³⁸ One commonly reported example of PG contact dermatitis is from the topical medicament minoxidil.^39,40

Patch testing data have demonstrated a positivity rate for PG ranging between 0.1% to 3.8%. The variability in these findings likely is due to differences in the tested concentrations of PG, as higher concentrations sometimes required to elicit an allergic reaction also may create a stronger irritation effect.⁴¹ Propylene glycol irritancy and the occlusive nature of the axillae may enhance sensitization to other allergens, as demonstrated by Agren-Jonsson and Magnusson,⁴² who reported sensitization to propantheline bromide and trichlorocarbanilide in patients who used a lotion with 90% PG. Many PG-containing products beyond deodorants/antiperspirants may be applied to the axillae, including steroid creams, lotions, shaving creams, and bodywashes.^38,43

The diagnosis of PG allergy via patch testing is challenging and at times controversial given its irritant nature. False-positive irritant reactions have been documented, characterized by a weak reaction at 48 hours that is absent by 96 hours (decrescendo reaction). A reaction may not appear until 96 hours (crescendo reaction), which typically indicates a true contact allergy but in the case of PG also may be the substance acting as a “late irritant.”⁴⁴ Fast (<24 hours) and well-demarcated reactions suggest irritation.⁴⁵ Regardless, reactions to PG on patch testing, even those regarded as weak, may be considered relevant in consideration of the clinical context.³⁷

Aluminum—Aluminum is the active ingredient in most antiperspirants, typically in the form of aluminum chloride, aluminum chlorohydrate, aluminum zirconium trichlorohydrex gly, or aluminum zirconium tetrachlorohydrex gly.⁴⁶ Aluminum mechanically obstructs the eccrine glands to reduce sweat.⁴⁷ Although aluminum is an uncommon allergen, a possible presentation of aluminum allergy is axillary vault dermatitis secondary to antiperspirant use.⁴⁶ Another potential manifestation is a ringlike reaction to the Finn Chambers (SmartPractice) used in patch testing.⁴⁶ In one case of aluminum-induced axillary dermatitis, a 28-year-old woman presented with eczema of the axillae, and subsequent patch testing revealed an allergy to aluminum chloride. The rash resolved upon cessation of use of an aluminum-containing deodorant.⁴⁸

Aluminum has been reported to cause granulomatous dermatitis in the axillae. This reaction typically presents as red-brown, pruritic papules limited to the area in which deodorant was applied, with histopathology revealing epithelioid granulomas.^49-51

Alum deodorants—considered a natural alternative—contain aluminum bound to potassium or ammonium in the form of a crystal or powder. Alum crystal deodorants have been reported to cause both a typical erythematous pruritic dermatitis as well as a granulomatous dermatitis with red-brown papules.^52,53 The granulomatous dermatitis caused by either form of aluminum resolves with avoidance and use of topical steroids or topical tacrolimus.^49,50,52,53

The diagnosis of aluminum ACD via patch testing may be identified with empty Finn Chambers, which are metallic aluminum, or with patch placement of aluminum chloride hexahydrate, though the former is only positive in patients with a strong allergy.^54,55 In 2022, aluminum was named Allergen of the Year by the American Contact Dermatitis Society, with recommendations to conduct patch testing with aluminum chloride hexahydrate 10% rather than the traditional 2% to increase diagnostic yield.⁵⁵ Additionally, it is recommended that aluminum be included in baseline patch testing for children due to the high prevalence of aluminum allergy in children and early exposure via childhood vaccines.^54-56 In patients with aluminum allergy, providers may suggest purchasing aluminum-free deodorants or provide recipes for homemade deodorant that includes ingredients such as arrowroot powder, cornstarch, and diatomaceous earth.⁴⁶

Nickel—Nickel is the most commonly identified contact allergen on patch testing yet an infrequent cause of axillary dermatitis. A case report from 2014 described axillary dermatitis in a woman that worsened during a positive patch test to nickel. Improvement was noted when the patient switched to titanium shaving razors.⁵⁷ Nickel allergy also may present in the form of SCD. In one report, a woman developed dermatitis of the flexural areas, including the axillae, 3 months after undergoing a sterilization procedure in which nickel-containing tubal implants were placed.⁵⁸ Patch testing revealed a positive reaction to nickel. The patient experienced complete resolution of the steroid-resistant dermatitis following removal of the implants via salpingectomy.⁵⁸

Textile Dye—In contrast to dermatitis caused by deodorants/antiperspirants, contact allergy to textile dyes presents as dermatitis involving the axillary borders but sparing the axillary vaults (Figures 2 and 3).¹⁰ Other potential presentations of textile dye dermatitis include erythema multiforme–like eruptions and erythematous wheal–type reactions.⁵⁹ Textile dyes are classified as disperse vs nondisperse, with the majority of contact dermatoses caused by disperse dyes, specifically Disperse Orange 1, blue 106, and blue 124.^60-62 Ryberg et al⁶¹ found that the axilla is one of the more common locations to be affected by textile dye allergy, particularly in women, which was further supported by Seidenari et al,⁶³ who found that skin folds were affected in 27% of study participants allergic to textile dyes (N=437), a finding that is likely due to friction, sweat, and occlusion.⁶² In one case report of a patient with dermatitis caused by reactive dyes, the garment required 3 washes before the patient experienced resolution of dermatitis.⁶⁴ For patients with textile dye dermatitis, mitigation strategies include washing clothing before wearing, especially for darkly dyed items; avoiding tight clothing; wearing garments made of cotton, wool, silk, or linen; and choosing light-colored garments.^9,64,65

Axillary Dermatitis as a Manifestation of SCD and SDRIFE

Systemic contact dermatitis occurs when an individual who was previously sensitized to a particular allergen develops ACD of the skin with systemic exposure to that allergen or immunochemically related allergens. Exposure may occur via ingestion, inhalation, intravenous, intramuscular, and transepidermal routes.⁶⁶ Systemic contact dermatitis manifests in a variety of ways, including focal flares at sites of prior contact dermatitis (recall reaction), vesicular hand dermatitis, intertriginous eruptions including axillary dermatitis, and generalized eruptions.⁶⁷

Systemic contact dermatitis rarely involves systemic symptoms, and onset typically is within days of exposure. The 3 most common groups of allergens causing SCD are metals, medications, and plants and herbals.⁶⁸ These allergens have all been reported to cause axillary dermatitis via SCD.^58,69,70 Foods containing balsam of Peru that may lead to SCD include citrus, chocolate, tomato, and certain alcohols.^70,71 Patients with a positive patch test to balsam of Peru may experience improvement of their dermatitis after reduction of balsam of Peru–rich foods from their diet.⁷⁰ Metals implicated in SCD include mercury, nickel, and gold.^72-74 Finally, PG ingestion also has been implicated in cases of SCD.³⁷

Symmetrical drug-related intertriginous and flexural exanthema is another condition that presents as intertriginous dermatitis and differs from SCD in that the eruption does not require presensitization; there may be no known prior exposure to the agent causing dermatitis. Historically, SDRIFE was described as baboon syndrome because of its frequent involvement of the buttocks with diffuse, well-demarcated, erythematous dermatitis resembling that of a baboon. This term is no longer used due to its insensitive nature and incomplete depiction of SDRIFE, which can affect body sites other than the buttocks.^68,75,76 Specific criteria to make this diagnosis include sharply demarcated and/or V-shaped erythema of the gluteal/perianal area, involvement of at least 1 other intertriginous or flexural region, symmetry of affected areas, and an absence of systemic symptoms.⁷⁶ There also may be papules, pustules, and vesicles present in affected areas. Symmetrical drug-related intertriginous and flexural exanthema most often is caused by β-lactam antibiotics, but other associated drugs include chemotherapeutic agents, such as mitomycin C.⁷⁶

Histopathology of both SCD and SDRIFE is variable and typically nonspecific, often revealing epidermal spongiosis and a perivascular mononuclear cell infiltrate with occasional neutrophils and eosinophils.⁷⁶ A case of SCD to mercury presenting as intertriginous dermatitis demonstrated a leukocytoclastic vasculitis pattern on biopsy.⁷⁷

Systemic contact dermatitis is diagnosed via a patch test, while SDRIFE typically has a negative patch test result and requires oral rechallenge testing, which reproduces the rash within hours.^78,79

Additional Allergens Causing Axillary ACD

Although fragrance is the most common allergen in deodorants, other ingredients have been shown to cause axillary ACD (Table).^80-90 In addition to these ingredients, allergens not previously mentioned that may be present in deodorants include lanolin, essential oils, and parabens.¹¹ Methylisothiazolinone in laundry detergent also has been found to instigate ACD.⁹¹ Fragrances and preservatives in laundry detergents also may contribute to dermatitis.⁹²

Other products that have caused axillary contact dermatitis include topical exposure to medicaments including clindamycin,⁹³ ethylenediamine in nystatin cream,⁹⁴ methylprednisolone acetate⁹⁵ and dipropylene glycol in a hydrocortisone lotion,⁹⁶ wood dusts from tropical hardwoods,⁹⁷ and tobacco.⁹⁸

Management of ACD

The most effective strategy in the management of patients with contact dermatitis is avoidance of the offending agent. Additionally, clinicians may recommend the use of topical steroids and/or calcineurin inhibitors to hasten resolution.²

For patients with contact dermatitis, a clinician may recommend product substitutions with few potential allergens to use prior to patch testing. Patients with a fragrance allergy should look for products specifically labeled as “fragrance free” rather than “hypoallergenic” or “unscented,” as the latter two may still contain minimal amounts of fragrance.³⁵ Patients should be educated on the functions of the allergens to which they are allergic so they may adequately avoid potential sources of contact.⁹⁹ For suspected textile dye dermatitis, instructing patients to wash clothing before wearing and to avoid synthetic fabrics, dark dyes, and tightly fitted clothing may help.^9,64,65

The differential diagnosis for axillary lesions is broad, including infectious, inflammatory, and autoimmune etiologies. Irritant contact dermatitis (ICD) presents similar to ACD, though it is more immediate in onsetand typically demonstrates symptoms of burning and stinging rather than pruritus. Although histopathology is not reliable in differentiating ICD and ACD, it has been shown that focal parakeratosis is associated with ACD, whereas necrotic epidermal keratinocytes are found in ICD.¹⁰⁰

Intertrigo presents as large, erythematous, opposing patches or plaques confined to inguinal, submammary, axillary, and/or abdominal folds. Findings of beefy red erythema and peripheral satellite pustules may implicate presence of Candida, which can be identified with potassium hydroxide preparations.

Inverse psoriasis presents as sharply demarcated, erythematous, moist, smooth plaques or patches with minimal scale. The most common area of involvement is the inguinal folds, followed by the axillae, inframammary folds, perianal area, umbilicus, and retroauricular areas. Involvement of the elbows and knees or a positive family history of psoriasis may be useful knowledge in establishing the diagnosis. A biopsy may show dermal eosinophils, epidermal spongiosis, and focal serum in the scale, in addition to features of typical psoriasis plaques.¹⁰¹

Seborrheic dermatitis typically is an erythematous eruption, often with yellowish greasy scale. Simultaneous involvement of the face and scalp may be noted. Although typically a clinical diagnosis, biopsy demonstrates shoulder parakeratosis with follicular plugging and lymphocytic exocytosis.

Hailey-Hailey disease (also called benign familial pemphigus) is an autosomal-dominant genetic condition presenting as moist, malodorous, painful, vegetative plaques, patches, or scaly pustules in flexural areas, frequently with flaccid blisters. Lesions are provoked by traumatic stimuli. Onset occurs in the second to fourth decades and may improve with age. The diagnosis is confirmed by biopsy, which demonstrates acantholysis of the epidermis. The moist superficial patches of Hailey-Hailey disease help distinguish it from comparably drier Darier disease, the other acantholytic disease of the axillae.

Granular parakeratosis (also called hyperkeratotic flexural erythema) is an uncommon dermatosis most often observed in middle-aged women. It presents as red-brown keratotic papules coalescing into plaques, often with overlying scale in intertriginous areas. This disorder may be related to exposure to aluminum, a key component of antiperspirants.¹⁰² Diagnosis with a skin biopsy demonstrates granular parakeratosis.

Infections most commonly include erythrasma, tinea, and candidiasis. Erythrasma caused by Corynebacterium minutissimum may present in the axillae and/or groin with sharply demarcated, red-brown patches. Wood lamp examination reveals coral red fluorescence. Tinea corporis, a dermatophyte infection, may present as scaly erythematous plaques with advancing borders and central clearing. Fungal cultures and potassium hydroxide preparations are useful to confirm the diagnosis.

Pseudofolliculitis barbae most often is thought of as a condition affecting the beard in Black men, but it also may present in individuals of all races who shave the axillary and inguinal regions. Typical features include pruritic inflammatory papules and pustules with surrounding erythema and hyperpigmentation.

Fox-Fordyce disease is a disorder of the apocrine sweat glands that presents as several flesh-colored, perifollicular, monomorphic papules in the axillae. It typically is a disease of young females and also can involve the areola and vulva. Histopathology may show hyperkeratosis, irregular acanthosis, and dilated sweat glands.

Hidradenitis suppurativa is a chronic inflammatory condition that presents with multiple cysts; nodules; abscesses; sinus tract formation; and suppuration of the axillary, anogenital, and sometimes inframammary areas, typically at the onset of puberty. The diagnosis is best supported by history and physical examination, which may be notable for recurrent abscesses, draining tracts, double comedones, and ropelike scarring.

Extramammary Paget disease is a rare malignancy affecting apocrine gland–bearing areas, including axillary and genital regions. It most commonly presents as a unilateral or asymmetric, scaly, erythematous plaque. Histopathology demonstrates Paget cells with abundant clear cytoplasm and pleomorphic nuclei, typically grouped in the lower portion of the epidermis.

Final Thoughts

Axillary dermatoses often can be challenging to diagnose given the range of pathologies that can present in intertriginous areas. Allergic contact dermatitis is a common culprit due to unique anatomical considerations and self-care practices, including shaving/hair removal; use of deodorants, antiperspirants, bodywashes, and clothing; and frictional and moisture influences. The most likely offender among contact allergens is fragrance, but other possibilities to consider include PG, preservatives, aluminum, nickel, and textile dyes. Albeit less common, systemic exposure to allergens may result in SCD and SDRIFE with a rash in intertriginous zones, including the axillae. Additionally, other infectious, inflammatory, and autoimmune etiologies should be considered and ruled out.

Patch testing is the most reliable method to diagnose suspected ACD. Once confirmed, management includes the use of topical steroids and avoidance of the causative agent. Additionally, patients should be informed of the American Contact Dermatitis Society Contact Allergen Management Program (https://www.contactderm.org/patient-support/camp-access), which provides patients with useful information on products that are safe to use based on their patch testing results.

Approximately 20% of the general population has a contact allergy.¹ Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction mediated by T lymphocytes.² Axillary ACD presentation is variable but typically includes an eczematous eruption with erythematous scaly patches or plaques. Common products in contact with the axillae include deodorants, antiperspirants, razors, bodywash, and clothing.

Axillary skin is distinct from skin elsewhere on the body due to both anatomical characteristics and unique human self-care practices. Axillary skin has reduced barrier function, faster stratum corneum turnover, and altered lipid levels.^3-5 Moreover, the axillae often are subject to shaving or other hair removal practices that alter the local environment, as layers of stratum corneum and hair are mechanically removed, which causes irritation and predisposes the skin to enhanced sensitivity to topical exposures.^6,7 With the abundance of apocrine and eccrine glands, the axillae are prone to sweat, which also can accentuate contact allergy.^2,3 Other factors, such as occlusion and friction, contribute to axillary contact allergy.^8,9

Patch testing is the gold standard for the diagnosis of ACD and aids in identification of culprit allergens. A thorough patient history and examination of the rash distribution may provide further clues; for example, dermatitis due to a deodorant typically affects the vault, whereas textile dye dermatitis tends to spare the vault.^10,11 Baseline-limited patch testing detects up to two-thirds of clinically relevant allergens.¹² Therefore, patients may require subsequent testing with supplemental allergens.

The differential diagnosis for axillary lesions is broad—including inflammatory diseases such as irritant contact dermatitis and hidradenitis suppurativa, genetic disorders such as Hailey-Hailey disease, and infectious causes such as erythrasma—but may be narrowed with a thorough physical examination and patient history, histopathology, bedside diagnostic techniques (eg, scrapings and Wood lamp examination), and patch testing. Systemic contact dermatitis (SCD) or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) also may be suspected in cases of intertriginous dermatoses.

We review the potential allergens in products used on the axillae as well as the management of axillary ACD. We also discuss axillary dermatitis as a manifestation of SCD and SDRIFE.

Top Allergens in Products Used on the Axillae

Fragrance—A 1982 North American Contact Dermatitis Group study on cosmetic products identified fragrances as the most common cause of ACD,¹³ and this trend continues to hold true with more recent data.¹⁴ The incidence of fragrance allergy may be increasing, with positive patch tests to a fragrance chemical in 10% of patch test clinic populations.¹⁵ Fragrances are a ubiquitous ingredient in deodorants and antiperspirants, which are important sources implicated in the development and elicitation of fragrance ACD.¹⁶ One study found that fragrance was present in 97 of 107 (90%) deodorants available at Walgreens pharmacies.¹¹

In a study of patients with a history of an axillary rash caused by a deodorant spray, Johansen et al¹⁷ reported that the likelihood of fragrance allergy is increased by a factor of 2.4. This risk of developing a fragrance allergy may be exacerbated in those who shave; Edman¹⁸ reported that the odds ratio of developing a fragrance allergy among men who shave their beards was 2.9. Although there are no specific data on the effects of shaving on ACD, shaving in general can induce localized irritation and increase percutaneous absorption.¹⁹

The individual fragrance components in deodorants most likely to cause ACD include hydroxycitronellal, eugenol, and geraniol—all constituent ingredients in patch test formulations of fragrance mixture I.^11,20 Other common fragrance allergens associated with ACD include hydroxymethylpentylcyclohexenecarboxaldehyde, farnesol, and balsam of Peru.^21-27 Hydroperoxides of limonene and linalool, common fragrances in detergents and personal care products, are increasingly recognized as contact allergens and have been reported to cause axillary ACD from deodorants.^28-30

Dermatitis involving the bilateral axillary vaults wherever deodorant or antiperspirant was directly applied is the most common presentation of ACD due to fragrance (Figure 1).¹⁷ An eczematous eruption is common, though scale may be less apparent than in nonflexural regions. Axillary ACD secondary to fragrances also may result from use of fragranced laundry detergents, fabric softeners, soaps, and perfumes, and may spare the vaults.^10,29,31,32 Less common presentations of axillary ACD due to fragrance include pigmented dermatoses; for example, ACD from an antiperspirant containing hydroperoxide of limonene presented as hyperpigmented patches with minimal erythema and scaling in the edges of the axillary folds.^33,34

Diagnosis of a fragrance ACD typically is made with a standard patch test series including fragrance mixture I and balsam of Peru, which may detect 75% and 50% of fragrance sensitivities, respectively.³⁵ Patch testing may be followed with a repeated open application test of the product in question.³⁶ Additionally, it may be appropriate to test for other fragrance allergens including balsam of Tolu, fragrance mixture II, lichen acid mix, and hydroxyperoxides of linalool and limonene (among other botanicals) if standard patch testing is negative and suspicion of fragrance ACD remains elevated.¹¹

Propylene Glycol—Propylene glycol (PG)—a versatile substance that functions as a solvent, humectant, emulsifier, stabilizer, and antimicrobial—is the second most common contact allergen present in deodorants.¹¹ It is prevalent in both personal care and household products, including deodorants, cosmetics, foods, toothpaste, cleaning agents, and detergents.^11,37 Propylene glycol is both an allergen and an irritant. Among deodorants/antiperspirants, PG is both a common irritant and allergen, as its concentration may be particularly high (as much as 73%).³⁸ One commonly reported example of PG contact dermatitis is from the topical medicament minoxidil.^39,40

Patch testing data have demonstrated a positivity rate for PG ranging between 0.1% to 3.8%. The variability in these findings likely is due to differences in the tested concentrations of PG, as higher concentrations sometimes required to elicit an allergic reaction also may create a stronger irritation effect.⁴¹ Propylene glycol irritancy and the occlusive nature of the axillae may enhance sensitization to other allergens, as demonstrated by Agren-Jonsson and Magnusson,⁴² who reported sensitization to propantheline bromide and trichlorocarbanilide in patients who used a lotion with 90% PG. Many PG-containing products beyond deodorants/antiperspirants may be applied to the axillae, including steroid creams, lotions, shaving creams, and bodywashes.^38,43

The diagnosis of PG allergy via patch testing is challenging and at times controversial given its irritant nature. False-positive irritant reactions have been documented, characterized by a weak reaction at 48 hours that is absent by 96 hours (decrescendo reaction). A reaction may not appear until 96 hours (crescendo reaction), which typically indicates a true contact allergy but in the case of PG also may be the substance acting as a “late irritant.”⁴⁴ Fast (<24 hours) and well-demarcated reactions suggest irritation.⁴⁵ Regardless, reactions to PG on patch testing, even those regarded as weak, may be considered relevant in consideration of the clinical context.³⁷

Aluminum—Aluminum is the active ingredient in most antiperspirants, typically in the form of aluminum chloride, aluminum chlorohydrate, aluminum zirconium trichlorohydrex gly, or aluminum zirconium tetrachlorohydrex gly.⁴⁶ Aluminum mechanically obstructs the eccrine glands to reduce sweat.⁴⁷ Although aluminum is an uncommon allergen, a possible presentation of aluminum allergy is axillary vault dermatitis secondary to antiperspirant use.⁴⁶ Another potential manifestation is a ringlike reaction to the Finn Chambers (SmartPractice) used in patch testing.⁴⁶ In one case of aluminum-induced axillary dermatitis, a 28-year-old woman presented with eczema of the axillae, and subsequent patch testing revealed an allergy to aluminum chloride. The rash resolved upon cessation of use of an aluminum-containing deodorant.⁴⁸

Aluminum has been reported to cause granulomatous dermatitis in the axillae. This reaction typically presents as red-brown, pruritic papules limited to the area in which deodorant was applied, with histopathology revealing epithelioid granulomas.^49-51

Alum deodorants—considered a natural alternative—contain aluminum bound to potassium or ammonium in the form of a crystal or powder. Alum crystal deodorants have been reported to cause both a typical erythematous pruritic dermatitis as well as a granulomatous dermatitis with red-brown papules.^52,53 The granulomatous dermatitis caused by either form of aluminum resolves with avoidance and use of topical steroids or topical tacrolimus.^49,50,52,53

The diagnosis of aluminum ACD via patch testing may be identified with empty Finn Chambers, which are metallic aluminum, or with patch placement of aluminum chloride hexahydrate, though the former is only positive in patients with a strong allergy.^54,55 In 2022, aluminum was named Allergen of the Year by the American Contact Dermatitis Society, with recommendations to conduct patch testing with aluminum chloride hexahydrate 10% rather than the traditional 2% to increase diagnostic yield.⁵⁵ Additionally, it is recommended that aluminum be included in baseline patch testing for children due to the high prevalence of aluminum allergy in children and early exposure via childhood vaccines.^54-56 In patients with aluminum allergy, providers may suggest purchasing aluminum-free deodorants or provide recipes for homemade deodorant that includes ingredients such as arrowroot powder, cornstarch, and diatomaceous earth.⁴⁶

Nickel—Nickel is the most commonly identified contact allergen on patch testing yet an infrequent cause of axillary dermatitis. A case report from 2014 described axillary dermatitis in a woman that worsened during a positive patch test to nickel. Improvement was noted when the patient switched to titanium shaving razors.⁵⁷ Nickel allergy also may present in the form of SCD. In one report, a woman developed dermatitis of the flexural areas, including the axillae, 3 months after undergoing a sterilization procedure in which nickel-containing tubal implants were placed.⁵⁸ Patch testing revealed a positive reaction to nickel. The patient experienced complete resolution of the steroid-resistant dermatitis following removal of the implants via salpingectomy.⁵⁸

Textile Dye—In contrast to dermatitis caused by deodorants/antiperspirants, contact allergy to textile dyes presents as dermatitis involving the axillary borders but sparing the axillary vaults (Figures 2 and 3).¹⁰ Other potential presentations of textile dye dermatitis include erythema multiforme–like eruptions and erythematous wheal–type reactions.⁵⁹ Textile dyes are classified as disperse vs nondisperse, with the majority of contact dermatoses caused by disperse dyes, specifically Disperse Orange 1, blue 106, and blue 124.^60-62 Ryberg et al⁶¹ found that the axilla is one of the more common locations to be affected by textile dye allergy, particularly in women, which was further supported by Seidenari et al,⁶³ who found that skin folds were affected in 27% of study participants allergic to textile dyes (N=437), a finding that is likely due to friction, sweat, and occlusion.⁶² In one case report of a patient with dermatitis caused by reactive dyes, the garment required 3 washes before the patient experienced resolution of dermatitis.⁶⁴ For patients with textile dye dermatitis, mitigation strategies include washing clothing before wearing, especially for darkly dyed items; avoiding tight clothing; wearing garments made of cotton, wool, silk, or linen; and choosing light-colored garments.^9,64,65

Axillary Dermatitis as a Manifestation of SCD and SDRIFE

Systemic contact dermatitis occurs when an individual who was previously sensitized to a particular allergen develops ACD of the skin with systemic exposure to that allergen or immunochemically related allergens. Exposure may occur via ingestion, inhalation, intravenous, intramuscular, and transepidermal routes.⁶⁶ Systemic contact dermatitis manifests in a variety of ways, including focal flares at sites of prior contact dermatitis (recall reaction), vesicular hand dermatitis, intertriginous eruptions including axillary dermatitis, and generalized eruptions.⁶⁷

Systemic contact dermatitis rarely involves systemic symptoms, and onset typically is within days of exposure. The 3 most common groups of allergens causing SCD are metals, medications, and plants and herbals.⁶⁸ These allergens have all been reported to cause axillary dermatitis via SCD.^58,69,70 Foods containing balsam of Peru that may lead to SCD include citrus, chocolate, tomato, and certain alcohols.^70,71 Patients with a positive patch test to balsam of Peru may experience improvement of their dermatitis after reduction of balsam of Peru–rich foods from their diet.⁷⁰ Metals implicated in SCD include mercury, nickel, and gold.^72-74 Finally, PG ingestion also has been implicated in cases of SCD.³⁷

Symmetrical drug-related intertriginous and flexural exanthema is another condition that presents as intertriginous dermatitis and differs from SCD in that the eruption does not require presensitization; there may be no known prior exposure to the agent causing dermatitis. Historically, SDRIFE was described as baboon syndrome because of its frequent involvement of the buttocks with diffuse, well-demarcated, erythematous dermatitis resembling that of a baboon. This term is no longer used due to its insensitive nature and incomplete depiction of SDRIFE, which can affect body sites other than the buttocks.^68,75,76 Specific criteria to make this diagnosis include sharply demarcated and/or V-shaped erythema of the gluteal/perianal area, involvement of at least 1 other intertriginous or flexural region, symmetry of affected areas, and an absence of systemic symptoms.⁷⁶ There also may be papules, pustules, and vesicles present in affected areas. Symmetrical drug-related intertriginous and flexural exanthema most often is caused by β-lactam antibiotics, but other associated drugs include chemotherapeutic agents, such as mitomycin C.⁷⁶

Histopathology of both SCD and SDRIFE is variable and typically nonspecific, often revealing epidermal spongiosis and a perivascular mononuclear cell infiltrate with occasional neutrophils and eosinophils.⁷⁶ A case of SCD to mercury presenting as intertriginous dermatitis demonstrated a leukocytoclastic vasculitis pattern on biopsy.⁷⁷

Systemic contact dermatitis is diagnosed via a patch test, while SDRIFE typically has a negative patch test result and requires oral rechallenge testing, which reproduces the rash within hours.^78,79

Additional Allergens Causing Axillary ACD

Although fragrance is the most common allergen in deodorants, other ingredients have been shown to cause axillary ACD (Table).^80-90 In addition to these ingredients, allergens not previously mentioned that may be present in deodorants include lanolin, essential oils, and parabens.¹¹ Methylisothiazolinone in laundry detergent also has been found to instigate ACD.⁹¹ Fragrances and preservatives in laundry detergents also may contribute to dermatitis.⁹²

Other products that have caused axillary contact dermatitis include topical exposure to medicaments including clindamycin,⁹³ ethylenediamine in nystatin cream,⁹⁴ methylprednisolone acetate⁹⁵ and dipropylene glycol in a hydrocortisone lotion,⁹⁶ wood dusts from tropical hardwoods,⁹⁷ and tobacco.⁹⁸

Management of ACD

The most effective strategy in the management of patients with contact dermatitis is avoidance of the offending agent. Additionally, clinicians may recommend the use of topical steroids and/or calcineurin inhibitors to hasten resolution.²

For patients with contact dermatitis, a clinician may recommend product substitutions with few potential allergens to use prior to patch testing. Patients with a fragrance allergy should look for products specifically labeled as “fragrance free” rather than “hypoallergenic” or “unscented,” as the latter two may still contain minimal amounts of fragrance.³⁵ Patients should be educated on the functions of the allergens to which they are allergic so they may adequately avoid potential sources of contact.⁹⁹ For suspected textile dye dermatitis, instructing patients to wash clothing before wearing and to avoid synthetic fabrics, dark dyes, and tightly fitted clothing may help.^9,64,65

The differential diagnosis for axillary lesions is broad, including infectious, inflammatory, and autoimmune etiologies. Irritant contact dermatitis (ICD) presents similar to ACD, though it is more immediate in onsetand typically demonstrates symptoms of burning and stinging rather than pruritus. Although histopathology is not reliable in differentiating ICD and ACD, it has been shown that focal parakeratosis is associated with ACD, whereas necrotic epidermal keratinocytes are found in ICD.¹⁰⁰

Intertrigo presents as large, erythematous, opposing patches or plaques confined to inguinal, submammary, axillary, and/or abdominal folds. Findings of beefy red erythema and peripheral satellite pustules may implicate presence of Candida, which can be identified with potassium hydroxide preparations.

Inverse psoriasis presents as sharply demarcated, erythematous, moist, smooth plaques or patches with minimal scale. The most common area of involvement is the inguinal folds, followed by the axillae, inframammary folds, perianal area, umbilicus, and retroauricular areas. Involvement of the elbows and knees or a positive family history of psoriasis may be useful knowledge in establishing the diagnosis. A biopsy may show dermal eosinophils, epidermal spongiosis, and focal serum in the scale, in addition to features of typical psoriasis plaques.¹⁰¹

Seborrheic dermatitis typically is an erythematous eruption, often with yellowish greasy scale. Simultaneous involvement of the face and scalp may be noted. Although typically a clinical diagnosis, biopsy demonstrates shoulder parakeratosis with follicular plugging and lymphocytic exocytosis.

Hailey-Hailey disease (also called benign familial pemphigus) is an autosomal-dominant genetic condition presenting as moist, malodorous, painful, vegetative plaques, patches, or scaly pustules in flexural areas, frequently with flaccid blisters. Lesions are provoked by traumatic stimuli. Onset occurs in the second to fourth decades and may improve with age. The diagnosis is confirmed by biopsy, which demonstrates acantholysis of the epidermis. The moist superficial patches of Hailey-Hailey disease help distinguish it from comparably drier Darier disease, the other acantholytic disease of the axillae.

Granular parakeratosis (also called hyperkeratotic flexural erythema) is an uncommon dermatosis most often observed in middle-aged women. It presents as red-brown keratotic papules coalescing into plaques, often with overlying scale in intertriginous areas. This disorder may be related to exposure to aluminum, a key component of antiperspirants.¹⁰² Diagnosis with a skin biopsy demonstrates granular parakeratosis.

Infections most commonly include erythrasma, tinea, and candidiasis. Erythrasma caused by Corynebacterium minutissimum may present in the axillae and/or groin with sharply demarcated, red-brown patches. Wood lamp examination reveals coral red fluorescence. Tinea corporis, a dermatophyte infection, may present as scaly erythematous plaques with advancing borders and central clearing. Fungal cultures and potassium hydroxide preparations are useful to confirm the diagnosis.

Pseudofolliculitis barbae most often is thought of as a condition affecting the beard in Black men, but it also may present in individuals of all races who shave the axillary and inguinal regions. Typical features include pruritic inflammatory papules and pustules with surrounding erythema and hyperpigmentation.

Fox-Fordyce disease is a disorder of the apocrine sweat glands that presents as several flesh-colored, perifollicular, monomorphic papules in the axillae. It typically is a disease of young females and also can involve the areola and vulva. Histopathology may show hyperkeratosis, irregular acanthosis, and dilated sweat glands.

Hidradenitis suppurativa is a chronic inflammatory condition that presents with multiple cysts; nodules; abscesses; sinus tract formation; and suppuration of the axillary, anogenital, and sometimes inframammary areas, typically at the onset of puberty. The diagnosis is best supported by history and physical examination, which may be notable for recurrent abscesses, draining tracts, double comedones, and ropelike scarring.

Extramammary Paget disease is a rare malignancy affecting apocrine gland–bearing areas, including axillary and genital regions. It most commonly presents as a unilateral or asymmetric, scaly, erythematous plaque. Histopathology demonstrates Paget cells with abundant clear cytoplasm and pleomorphic nuclei, typically grouped in the lower portion of the epidermis.

Final Thoughts

Axillary dermatoses often can be challenging to diagnose given the range of pathologies that can present in intertriginous areas. Allergic contact dermatitis is a common culprit due to unique anatomical considerations and self-care practices, including shaving/hair removal; use of deodorants, antiperspirants, bodywashes, and clothing; and frictional and moisture influences. The most likely offender among contact allergens is fragrance, but other possibilities to consider include PG, preservatives, aluminum, nickel, and textile dyes. Albeit less common, systemic exposure to allergens may result in SCD and SDRIFE with a rash in intertriginous zones, including the axillae. Additionally, other infectious, inflammatory, and autoimmune etiologies should be considered and ruled out.

Patch testing is the most reliable method to diagnose suspected ACD. Once confirmed, management includes the use of topical steroids and avoidance of the causative agent. Additionally, patients should be informed of the American Contact Dermatitis Society Contact Allergen Management Program (https://www.contactderm.org/patient-support/camp-access), which provides patients with useful information on products that are safe to use based on their patch testing results.

As many as one-quarter of human cancers are related to chronic inflammation, chronic infection, or both.¹ Extrinsic inflammation leads to generation of proinflammatory cytokines that in turn recruit other inflammatory cells, which is thought to generate a positive amplification loop.² Intrinsic stimuli from proto-oncogenes and mutations in tumor suppressor genes lead to transformed cancer cells that also secrete proinflammatory cytokines, thus propagating the cycle.

Numerous factors have been observed in association with tumor growth, progression, invasion, and metastasis.³ One factor for the development of squamous cell carcinoma (SCC) may be chronic inflammatory dermatoses. To date, reviews of chronic inflammation–associated malignancy have focused on solid organ cancers. We sought to provide an up-to-date review of SCC arising within chronic dermatoses, with an emphasis on the anatomic location of dermatoses involved in the transformation of cancer cells, the lag time from onset of dermatosis to diagnosis of SCC, and the distinctive mechanisms thought to be involved in the tumorigenesis in particular dermatoses.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic cutaneous lupus erythematosus variant with a female to male predominance of 3:1,⁴ and DLE lesions are prone to malignant transformation. Retrospective cohort studies have attempted to characterize who is at risk for SCC and how SCCs behave depending on their location. Cohorts from China,⁵ India,⁶ and Japan⁷ have noted a higher rate of SCC within DLE lesions in men (female to male ratios of 1:2.2, 1:1.6, and 1:2, respectively) and shorter lag times for SCC onset within DLE lesions of the lips (13, 5, and 10 years, respectively) compared to SCC arising in DLE elsewhere (19.2, 11.2, and 26 years, respectively). Studies have noted that DLE lesions of the lips may be prone to more rapid SCC tumorigenesis compared to DLE on cutaneous sites. One study reported SCC in DLE recurrence, metastasis, and death rates of 29%, 16.1%, and 19.4%, respectively,⁵ which exceeds reported rates in non-DLE SCCs (20%, 0.5% to 6%, and 1%, respectively).^5,8

Because SCC arising within DLE is most common on the lips (Figure 1), it has been hypothesized that the high rate of transformation of DLE lesions on the lips may be due to constant exposure to irritation and tobacco, which may accelerate carcinogenesis.⁵ It also has been hypothesized that atrophic discoid lesions have lost sun protection and are more prone to mutagenic UV radiation,⁹ as SCCs arising in DLE lesions virtually always display prominent solar elastosis⁶; however, SCC has been observed to arise in non–sun-exposed DLE lesions in both White and Black patients.¹⁰

Photograph courtesy of Andrea Murina, MD.

Additionally, use of immunosuppressant medications may accelerate the emergence of malignancy or more aggressive forms of malignancy; however, patients with autoimmune disease have a greater risk for malignancy at baseline,¹¹ thus making it difficult to determine the excess risk from medications. There also may be a role for human papillomavirus (HPV) accelerating SCC development in DLE lesions, as demonstrated in a case of SCC arising in DLE lesions of the ears, with viral staining evident within the tumors.¹² However, testing for HPV is not routinely performed in these cases.

Dermatologists need to be aware of the relatively rapid tumorigenesis and aggressive behavior of transformation and aggression seen with SCC arising within orolabial DLE lesions compared to cutaneous lesions, especially those on the lips.

Lichen Planus

Although patients with typical cutaneous lichen planus lesions do not have an increased risk for SCC,¹³ variants of lichen planus may predispose patients to SCC.

Oral Lichen Planus—Oral lichen planus (OLP) lesions are prone to malignant transformation. A systematic review of 16 studies evaluating the risk for OLP-associated SCC revealed an overall transformation rate of 1.09%, with a mean lag time of 4.3 years,¹⁴ compared to a reference rate of 0.2% for oral SCC.¹⁵ A meta-analysis of 19,676 patients with OLP and other oral lichenoid lesions revealed an oral SCC rate of 1.1%, with higher rates of transformation seen in cigarette smokers, alcoholics, and patients with hepatitis C virus infection.¹⁶ The ulcerative subtype of OLP appears to present a greater risk for malignant transformation.¹⁵ Dermatologists also should be cognizant that treatments for OLP such as topical calcineurin inhibitors may support the development of malignancy within inflammatory lesions.¹⁷

Hypertrophic Lichen Planus—The hypertrophic variant of lichen planus (HLP) also is prone to malignant transformation. A 1991 epidemiologic study from Sweden of malignancy arising in lichen planus revealed a disproportionate number of cases arising in verrucous or hypertrophic lesions, with a mean of 12.2 years from onset of the dermatosis to malignancy diagnosis.¹³ A subsequent 2015 retrospective study of 38 patients revealed that SCC had a propensity for the lower limb, favoring the pretibial region and the calf over the foot and the ankle with a reported lag time of 11 years.¹⁸

Although metastatic SCC arising in HLP is rare, 2 cases have been reported. A 24-year-old woman presented with an HLP plaque on the lower leg that developed during childhood and rapidly enlarged 2 months prior to presentation; she eventually died from metastatic disease.¹⁹ In another case, a 34-year-old man presented with an HLP lesion of approximately 10 years’ duration. A well-differentiated SCC was excised, and he developed lymph node metastases 5 months later.²⁰

It is important to note that HLP on the legs often is misdiagnosed as SCC, as pseudoepitheliomatous hyperplasia and squamous metaplasia can be difficult to differentiate clinically and histologically.^21,22 In the case of multiple eruptive SCCs of the lower leg, clinical correlation is essential to avoid unnecessary and ineffective surgical treatment.

Patients with HLP may exhibit Wickham striae, follicular accentuation, and mucocutaneous lichen planus at other sites, or a correlative initiation of possible culprit medications.²³ Because true SCC arising within HLP is relatively rare, its malignant potential is not as clear as those arising within DLE; however, the lower limb appears to be the most common location for SCC within HLP.Nail Lichen Planus—Squamous cell carcinoma arising in nail lichen planus is rare. A report of 2 patients were diagnosed with lichen planus approximately 15 years prior to diagnosis of ungual SCC.²⁴ Given the rarity of this presentation, it is difficult to ascertain the approximate lag time and other risk factors. Furthermore, the role of HPV in these cases was not ruled out. Oncogenic HPV strains have been reported in patients with periungual SCC.^25,26

Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that favors the anogenital area in a female to male ratio of 10:1.²⁷ It is considered a premalignant condition for SCC tumorigenesis and may be a strong predictor of vulvar SCC (Figure 2), as 62% of vulvar SCC cases (N=78) may have adjacent LS.²⁸

Photograph courtesy of Laura C. Williams, MD (New Orleans, Louisiana).

In a Dutch cohort of 3038 women with LS, 2.6% of patients developed vulvar SCC at a median of 3.3 years after LS diagnosis.²⁹ Other studies have estimated a lag time of 4 years until SCC presentation.³⁰ An Italian cohort of 976 women similarly observed that 2.7% of patients developed premalignancy or SCC.³¹ It was previously estimated that 3% to 5% of patients with LS developed SCC; however, prior studies may have included cases of vulvar intraepithelial neoplasia with low risk for invasive SCC, which might have overestimated true risk of SCC.³² Another confounding factor for elucidating SCC on a background of LS may be the presence of HPV.³³ Extragenital LS does not appear to have similar potential for malignant transformation.³⁴

In a prospective Australian cohort of 507 women with LS (mean age, 55.4 years), remission was induced with potent topical corticosteroids.³⁵ Patients who were adherent to a topical regimen did not develop SCC during follow-up. Those who were nonadherent or partially adherent had a 4.7% risk for SCC.³⁵ In a similar prospective study of 83 women in France, the SCC rate was 9.6% in lesions that were untreated or irregularly treated.³⁶ These studies provide essential evidence that appropriately treating LS can prevent SCC at a later date, though longer-term data are lacking.

The rate of SCC arising in male genital LS may approach 8.4%,³⁷ with a lag time of 17 years from onset of LS to SCC diagnosis.³⁸ Although circumcision often is considered curative for male genital LS, patients have been observed to develop penile SCC at least 5 years after circumcision.³⁹ Male penile SCC in a background of LS may not necessarily be HPV associated.⁴⁰

Marjolin Ulcer

Chronic ulcers or scars, typically postburn scars, may undergo malignant transformation, with SCC being the most common carcinoma.⁴¹ Squamous cell carcinoma in the context of a chronic ulcer or wound is known as a Marjolin ulcer (MU). Up to 2% of burn scars have been observed to undergo malignant transformation.⁴² Marjolin ulcers tend to behave aggressively once they form, and it has been proposed that removal of scar tissue may be a preventive therapeutic strategy.⁴³ Cohort studies of MU on the lower extremities have observed lag times of 26.4⁴⁴ and 37.9⁴⁵ years, with both studies also noting relatively high rates of local recurrence.

The pathogenesis of MU appears to be multifactorial. Chronic inflammation and scar formation have been implicated. Chronic inflammation and irritation of lesions at natural creases are thought to increase mitotic activity,⁴¹ and local accumulation of toxin may promote mutagenesis.⁴⁶ Scar formation may create a locally immunoprivileged site, allowing for developing tumors to evade the immune system⁴⁷ and become even more aggressive as the tumor accumulates.⁴⁸ Scar formation also may prevent the ability of immune cells to penetrate the tumor microenvironment and access lymphatic channels.⁴⁹

Hidradenitis Suppurativa

As many as 3.2% of patients with chronic hidradenitis suppurativa (HS) experience malignant transformation to SCC.⁵⁰ Early HS displays subclinical lymphedema in affected sites, which can progress to chronic fibrosis, stasis, and accumulation of protein-rich fluid.⁵¹ Stasis changes have been associated with altered local inflammatory proteins, such as toll-like receptors, β-defensins, and interleukins.⁵²

A retrospective cohort study of 12 patients revealed a lag time of 28.5 years from HS diagnosis to the manifestation of malignancy.⁵³ After local excision, 7 patients developed recurrence, with 100% mortality. Squamous cell carcinomas were well differentiated and moderately differentiated.⁵³ A 2017 literature review of 62 case reports calculated a mean lag time of 27 years. Despite 85% of SCCs being well differentiated and moderately differentiated, nearly half of patients died within 2 years.⁵⁴ As seen in other inflammatory conditions, HPV can complicate perineal HS and promote SCC tumorigenesis.⁵⁵

Squamous cell carcinomas arising within HS lesions are more prevalent in males (6.75:1 ratio),^54,56 despite HS being more prevalent in females (2:1 ratio).⁵⁷ Similar to DLE, SCCs arising in HS are aggressive and are seen more in males, despite both conditions being female predominant. Incidence and mortality rates for primary cutaneous SCC are higher for men vs women⁵⁸; however, the discordance in aggressive behavior seen more commonly in SCC arising from HS or DLE in male patients has yet to be explained.

Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.⁵⁹ The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.

Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.⁶⁰ Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.⁶¹ Although SCCs tend to be well differentiated in RDEB (73.9%),⁶¹ they also exhibit highly aggressive behavior.⁶² In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.⁶³

As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.⁶⁴ There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.⁶⁵ Mutations in p53,⁶⁶ local alterations in transforming growth factor β activity,⁶⁷ and downstream matrix metalloproteinase activity⁶⁸ have been implicated.

Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.⁶⁹ Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.⁷⁰ A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.⁷¹

There does not appear to be evidence for HPV involvement in RDEB-associated SCC.⁷² Squamous cell carcinoma development in RDEB appears to be multifactorial,⁷³ but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.⁷³

Conclusion

Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.


As many as one-quarter of human cancers are related to chronic inflammation, chronic infection, or both.¹ Extrinsic inflammation leads to generation of proinflammatory cytokines that in turn recruit other inflammatory cells, which is thought to generate a positive amplification loop.² Intrinsic stimuli from proto-oncogenes and mutations in tumor suppressor genes lead to transformed cancer cells that also secrete proinflammatory cytokines, thus propagating the cycle.

Numerous factors have been observed in association with tumor growth, progression, invasion, and metastasis.³ One factor for the development of squamous cell carcinoma (SCC) may be chronic inflammatory dermatoses. To date, reviews of chronic inflammation–associated malignancy have focused on solid organ cancers. We sought to provide an up-to-date review of SCC arising within chronic dermatoses, with an emphasis on the anatomic location of dermatoses involved in the transformation of cancer cells, the lag time from onset of dermatosis to diagnosis of SCC, and the distinctive mechanisms thought to be involved in the tumorigenesis in particular dermatoses.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic cutaneous lupus erythematosus variant with a female to male predominance of 3:1,⁴ and DLE lesions are prone to malignant transformation. Retrospective cohort studies have attempted to characterize who is at risk for SCC and how SCCs behave depending on their location. Cohorts from China,⁵ India,⁶ and Japan⁷ have noted a higher rate of SCC within DLE lesions in men (female to male ratios of 1:2.2, 1:1.6, and 1:2, respectively) and shorter lag times for SCC onset within DLE lesions of the lips (13, 5, and 10 years, respectively) compared to SCC arising in DLE elsewhere (19.2, 11.2, and 26 years, respectively). Studies have noted that DLE lesions of the lips may be prone to more rapid SCC tumorigenesis compared to DLE on cutaneous sites. One study reported SCC in DLE recurrence, metastasis, and death rates of 29%, 16.1%, and 19.4%, respectively,⁵ which exceeds reported rates in non-DLE SCCs (20%, 0.5% to 6%, and 1%, respectively).^5,8

Because SCC arising within DLE is most common on the lips (Figure 1), it has been hypothesized that the high rate of transformation of DLE lesions on the lips may be due to constant exposure to irritation and tobacco, which may accelerate carcinogenesis.⁵ It also has been hypothesized that atrophic discoid lesions have lost sun protection and are more prone to mutagenic UV radiation,⁹ as SCCs arising in DLE lesions virtually always display prominent solar elastosis⁶; however, SCC has been observed to arise in non–sun-exposed DLE lesions in both White and Black patients.¹⁰

Photograph courtesy of Andrea Murina, MD.

Additionally, use of immunosuppressant medications may accelerate the emergence of malignancy or more aggressive forms of malignancy; however, patients with autoimmune disease have a greater risk for malignancy at baseline,¹¹ thus making it difficult to determine the excess risk from medications. There also may be a role for human papillomavirus (HPV) accelerating SCC development in DLE lesions, as demonstrated in a case of SCC arising in DLE lesions of the ears, with viral staining evident within the tumors.¹² However, testing for HPV is not routinely performed in these cases.

Dermatologists need to be aware of the relatively rapid tumorigenesis and aggressive behavior of transformation and aggression seen with SCC arising within orolabial DLE lesions compared to cutaneous lesions, especially those on the lips.

Lichen Planus

Although patients with typical cutaneous lichen planus lesions do not have an increased risk for SCC,¹³ variants of lichen planus may predispose patients to SCC.

Oral Lichen Planus—Oral lichen planus (OLP) lesions are prone to malignant transformation. A systematic review of 16 studies evaluating the risk for OLP-associated SCC revealed an overall transformation rate of 1.09%, with a mean lag time of 4.3 years,¹⁴ compared to a reference rate of 0.2% for oral SCC.¹⁵ A meta-analysis of 19,676 patients with OLP and other oral lichenoid lesions revealed an oral SCC rate of 1.1%, with higher rates of transformation seen in cigarette smokers, alcoholics, and patients with hepatitis C virus infection.¹⁶ The ulcerative subtype of OLP appears to present a greater risk for malignant transformation.¹⁵ Dermatologists also should be cognizant that treatments for OLP such as topical calcineurin inhibitors may support the development of malignancy within inflammatory lesions.¹⁷

Hypertrophic Lichen Planus—The hypertrophic variant of lichen planus (HLP) also is prone to malignant transformation. A 1991 epidemiologic study from Sweden of malignancy arising in lichen planus revealed a disproportionate number of cases arising in verrucous or hypertrophic lesions, with a mean of 12.2 years from onset of the dermatosis to malignancy diagnosis.¹³ A subsequent 2015 retrospective study of 38 patients revealed that SCC had a propensity for the lower limb, favoring the pretibial region and the calf over the foot and the ankle with a reported lag time of 11 years.¹⁸

Although metastatic SCC arising in HLP is rare, 2 cases have been reported. A 24-year-old woman presented with an HLP plaque on the lower leg that developed during childhood and rapidly enlarged 2 months prior to presentation; she eventually died from metastatic disease.¹⁹ In another case, a 34-year-old man presented with an HLP lesion of approximately 10 years’ duration. A well-differentiated SCC was excised, and he developed lymph node metastases 5 months later.²⁰

It is important to note that HLP on the legs often is misdiagnosed as SCC, as pseudoepitheliomatous hyperplasia and squamous metaplasia can be difficult to differentiate clinically and histologically.^21,22 In the case of multiple eruptive SCCs of the lower leg, clinical correlation is essential to avoid unnecessary and ineffective surgical treatment.

Patients with HLP may exhibit Wickham striae, follicular accentuation, and mucocutaneous lichen planus at other sites, or a correlative initiation of possible culprit medications.²³ Because true SCC arising within HLP is relatively rare, its malignant potential is not as clear as those arising within DLE; however, the lower limb appears to be the most common location for SCC within HLP.Nail Lichen Planus—Squamous cell carcinoma arising in nail lichen planus is rare. A report of 2 patients were diagnosed with lichen planus approximately 15 years prior to diagnosis of ungual SCC.²⁴ Given the rarity of this presentation, it is difficult to ascertain the approximate lag time and other risk factors. Furthermore, the role of HPV in these cases was not ruled out. Oncogenic HPV strains have been reported in patients with periungual SCC.^25,26

Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that favors the anogenital area in a female to male ratio of 10:1.²⁷ It is considered a premalignant condition for SCC tumorigenesis and may be a strong predictor of vulvar SCC (Figure 2), as 62% of vulvar SCC cases (N=78) may have adjacent LS.²⁸

Photograph courtesy of Laura C. Williams, MD (New Orleans, Louisiana).

In a Dutch cohort of 3038 women with LS, 2.6% of patients developed vulvar SCC at a median of 3.3 years after LS diagnosis.²⁹ Other studies have estimated a lag time of 4 years until SCC presentation.³⁰ An Italian cohort of 976 women similarly observed that 2.7% of patients developed premalignancy or SCC.³¹ It was previously estimated that 3% to 5% of patients with LS developed SCC; however, prior studies may have included cases of vulvar intraepithelial neoplasia with low risk for invasive SCC, which might have overestimated true risk of SCC.³² Another confounding factor for elucidating SCC on a background of LS may be the presence of HPV.³³ Extragenital LS does not appear to have similar potential for malignant transformation.³⁴

In a prospective Australian cohort of 507 women with LS (mean age, 55.4 years), remission was induced with potent topical corticosteroids.³⁵ Patients who were adherent to a topical regimen did not develop SCC during follow-up. Those who were nonadherent or partially adherent had a 4.7% risk for SCC.³⁵ In a similar prospective study of 83 women in France, the SCC rate was 9.6% in lesions that were untreated or irregularly treated.³⁶ These studies provide essential evidence that appropriately treating LS can prevent SCC at a later date, though longer-term data are lacking.

The rate of SCC arising in male genital LS may approach 8.4%,³⁷ with a lag time of 17 years from onset of LS to SCC diagnosis.³⁸ Although circumcision often is considered curative for male genital LS, patients have been observed to develop penile SCC at least 5 years after circumcision.³⁹ Male penile SCC in a background of LS may not necessarily be HPV associated.⁴⁰

Marjolin Ulcer

Chronic ulcers or scars, typically postburn scars, may undergo malignant transformation, with SCC being the most common carcinoma.⁴¹ Squamous cell carcinoma in the context of a chronic ulcer or wound is known as a Marjolin ulcer (MU). Up to 2% of burn scars have been observed to undergo malignant transformation.⁴² Marjolin ulcers tend to behave aggressively once they form, and it has been proposed that removal of scar tissue may be a preventive therapeutic strategy.⁴³ Cohort studies of MU on the lower extremities have observed lag times of 26.4⁴⁴ and 37.9⁴⁵ years, with both studies also noting relatively high rates of local recurrence.

The pathogenesis of MU appears to be multifactorial. Chronic inflammation and scar formation have been implicated. Chronic inflammation and irritation of lesions at natural creases are thought to increase mitotic activity,⁴¹ and local accumulation of toxin may promote mutagenesis.⁴⁶ Scar formation may create a locally immunoprivileged site, allowing for developing tumors to evade the immune system⁴⁷ and become even more aggressive as the tumor accumulates.⁴⁸ Scar formation also may prevent the ability of immune cells to penetrate the tumor microenvironment and access lymphatic channels.⁴⁹

Hidradenitis Suppurativa

As many as 3.2% of patients with chronic hidradenitis suppurativa (HS) experience malignant transformation to SCC.⁵⁰ Early HS displays subclinical lymphedema in affected sites, which can progress to chronic fibrosis, stasis, and accumulation of protein-rich fluid.⁵¹ Stasis changes have been associated with altered local inflammatory proteins, such as toll-like receptors, β-defensins, and interleukins.⁵²

A retrospective cohort study of 12 patients revealed a lag time of 28.5 years from HS diagnosis to the manifestation of malignancy.⁵³ After local excision, 7 patients developed recurrence, with 100% mortality. Squamous cell carcinomas were well differentiated and moderately differentiated.⁵³ A 2017 literature review of 62 case reports calculated a mean lag time of 27 years. Despite 85% of SCCs being well differentiated and moderately differentiated, nearly half of patients died within 2 years.⁵⁴ As seen in other inflammatory conditions, HPV can complicate perineal HS and promote SCC tumorigenesis.⁵⁵

Squamous cell carcinomas arising within HS lesions are more prevalent in males (6.75:1 ratio),^54,56 despite HS being more prevalent in females (2:1 ratio).⁵⁷ Similar to DLE, SCCs arising in HS are aggressive and are seen more in males, despite both conditions being female predominant. Incidence and mortality rates for primary cutaneous SCC are higher for men vs women⁵⁸; however, the discordance in aggressive behavior seen more commonly in SCC arising from HS or DLE in male patients has yet to be explained.

Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.⁵⁹ The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.

Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.⁶⁰ Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.⁶¹ Although SCCs tend to be well differentiated in RDEB (73.9%),⁶¹ they also exhibit highly aggressive behavior.⁶² In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.⁶³

As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.⁶⁴ There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.⁶⁵ Mutations in p53,⁶⁶ local alterations in transforming growth factor β activity,⁶⁷ and downstream matrix metalloproteinase activity⁶⁸ have been implicated.

Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.⁶⁹ Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.⁷⁰ A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.⁷¹

There does not appear to be evidence for HPV involvement in RDEB-associated SCC.⁷² Squamous cell carcinoma development in RDEB appears to be multifactorial,⁷³ but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.⁷³

Conclusion

Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.


As many as one-quarter of human cancers are related to chronic inflammation, chronic infection, or both.¹ Extrinsic inflammation leads to generation of proinflammatory cytokines that in turn recruit other inflammatory cells, which is thought to generate a positive amplification loop.² Intrinsic stimuli from proto-oncogenes and mutations in tumor suppressor genes lead to transformed cancer cells that also secrete proinflammatory cytokines, thus propagating the cycle.

Numerous factors have been observed in association with tumor growth, progression, invasion, and metastasis.³ One factor for the development of squamous cell carcinoma (SCC) may be chronic inflammatory dermatoses. To date, reviews of chronic inflammation–associated malignancy have focused on solid organ cancers. We sought to provide an up-to-date review of SCC arising within chronic dermatoses, with an emphasis on the anatomic location of dermatoses involved in the transformation of cancer cells, the lag time from onset of dermatosis to diagnosis of SCC, and the distinctive mechanisms thought to be involved in the tumorigenesis in particular dermatoses.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic cutaneous lupus erythematosus variant with a female to male predominance of 3:1,⁴ and DLE lesions are prone to malignant transformation. Retrospective cohort studies have attempted to characterize who is at risk for SCC and how SCCs behave depending on their location. Cohorts from China,⁵ India,⁶ and Japan⁷ have noted a higher rate of SCC within DLE lesions in men (female to male ratios of 1:2.2, 1:1.6, and 1:2, respectively) and shorter lag times for SCC onset within DLE lesions of the lips (13, 5, and 10 years, respectively) compared to SCC arising in DLE elsewhere (19.2, 11.2, and 26 years, respectively). Studies have noted that DLE lesions of the lips may be prone to more rapid SCC tumorigenesis compared to DLE on cutaneous sites. One study reported SCC in DLE recurrence, metastasis, and death rates of 29%, 16.1%, and 19.4%, respectively,⁵ which exceeds reported rates in non-DLE SCCs (20%, 0.5% to 6%, and 1%, respectively).^5,8

Because SCC arising within DLE is most common on the lips (Figure 1), it has been hypothesized that the high rate of transformation of DLE lesions on the lips may be due to constant exposure to irritation and tobacco, which may accelerate carcinogenesis.⁵ It also has been hypothesized that atrophic discoid lesions have lost sun protection and are more prone to mutagenic UV radiation,⁹ as SCCs arising in DLE lesions virtually always display prominent solar elastosis⁶; however, SCC has been observed to arise in non–sun-exposed DLE lesions in both White and Black patients.¹⁰

Photograph courtesy of Andrea Murina, MD.

Additionally, use of immunosuppressant medications may accelerate the emergence of malignancy or more aggressive forms of malignancy; however, patients with autoimmune disease have a greater risk for malignancy at baseline,¹¹ thus making it difficult to determine the excess risk from medications. There also may be a role for human papillomavirus (HPV) accelerating SCC development in DLE lesions, as demonstrated in a case of SCC arising in DLE lesions of the ears, with viral staining evident within the tumors.¹² However, testing for HPV is not routinely performed in these cases.

Dermatologists need to be aware of the relatively rapid tumorigenesis and aggressive behavior of transformation and aggression seen with SCC arising within orolabial DLE lesions compared to cutaneous lesions, especially those on the lips.

Lichen Planus

Although patients with typical cutaneous lichen planus lesions do not have an increased risk for SCC,¹³ variants of lichen planus may predispose patients to SCC.

Oral Lichen Planus—Oral lichen planus (OLP) lesions are prone to malignant transformation. A systematic review of 16 studies evaluating the risk for OLP-associated SCC revealed an overall transformation rate of 1.09%, with a mean lag time of 4.3 years,¹⁴ compared to a reference rate of 0.2% for oral SCC.¹⁵ A meta-analysis of 19,676 patients with OLP and other oral lichenoid lesions revealed an oral SCC rate of 1.1%, with higher rates of transformation seen in cigarette smokers, alcoholics, and patients with hepatitis C virus infection.¹⁶ The ulcerative subtype of OLP appears to present a greater risk for malignant transformation.¹⁵ Dermatologists also should be cognizant that treatments for OLP such as topical calcineurin inhibitors may support the development of malignancy within inflammatory lesions.¹⁷

Hypertrophic Lichen Planus—The hypertrophic variant of lichen planus (HLP) also is prone to malignant transformation. A 1991 epidemiologic study from Sweden of malignancy arising in lichen planus revealed a disproportionate number of cases arising in verrucous or hypertrophic lesions, with a mean of 12.2 years from onset of the dermatosis to malignancy diagnosis.¹³ A subsequent 2015 retrospective study of 38 patients revealed that SCC had a propensity for the lower limb, favoring the pretibial region and the calf over the foot and the ankle with a reported lag time of 11 years.¹⁸

Although metastatic SCC arising in HLP is rare, 2 cases have been reported. A 24-year-old woman presented with an HLP plaque on the lower leg that developed during childhood and rapidly enlarged 2 months prior to presentation; she eventually died from metastatic disease.¹⁹ In another case, a 34-year-old man presented with an HLP lesion of approximately 10 years’ duration. A well-differentiated SCC was excised, and he developed lymph node metastases 5 months later.²⁰

It is important to note that HLP on the legs often is misdiagnosed as SCC, as pseudoepitheliomatous hyperplasia and squamous metaplasia can be difficult to differentiate clinically and histologically.^21,22 In the case of multiple eruptive SCCs of the lower leg, clinical correlation is essential to avoid unnecessary and ineffective surgical treatment.

Patients with HLP may exhibit Wickham striae, follicular accentuation, and mucocutaneous lichen planus at other sites, or a correlative initiation of possible culprit medications.²³ Because true SCC arising within HLP is relatively rare, its malignant potential is not as clear as those arising within DLE; however, the lower limb appears to be the most common location for SCC within HLP.Nail Lichen Planus—Squamous cell carcinoma arising in nail lichen planus is rare. A report of 2 patients were diagnosed with lichen planus approximately 15 years prior to diagnosis of ungual SCC.²⁴ Given the rarity of this presentation, it is difficult to ascertain the approximate lag time and other risk factors. Furthermore, the role of HPV in these cases was not ruled out. Oncogenic HPV strains have been reported in patients with periungual SCC.^25,26

Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that favors the anogenital area in a female to male ratio of 10:1.²⁷ It is considered a premalignant condition for SCC tumorigenesis and may be a strong predictor of vulvar SCC (Figure 2), as 62% of vulvar SCC cases (N=78) may have adjacent LS.²⁸

Photograph courtesy of Laura C. Williams, MD (New Orleans, Louisiana).

In a Dutch cohort of 3038 women with LS, 2.6% of patients developed vulvar SCC at a median of 3.3 years after LS diagnosis.²⁹ Other studies have estimated a lag time of 4 years until SCC presentation.³⁰ An Italian cohort of 976 women similarly observed that 2.7% of patients developed premalignancy or SCC.³¹ It was previously estimated that 3% to 5% of patients with LS developed SCC; however, prior studies may have included cases of vulvar intraepithelial neoplasia with low risk for invasive SCC, which might have overestimated true risk of SCC.³² Another confounding factor for elucidating SCC on a background of LS may be the presence of HPV.³³ Extragenital LS does not appear to have similar potential for malignant transformation.³⁴

In a prospective Australian cohort of 507 women with LS (mean age, 55.4 years), remission was induced with potent topical corticosteroids.³⁵ Patients who were adherent to a topical regimen did not develop SCC during follow-up. Those who were nonadherent or partially adherent had a 4.7% risk for SCC.³⁵ In a similar prospective study of 83 women in France, the SCC rate was 9.6% in lesions that were untreated or irregularly treated.³⁶ These studies provide essential evidence that appropriately treating LS can prevent SCC at a later date, though longer-term data are lacking.

The rate of SCC arising in male genital LS may approach 8.4%,³⁷ with a lag time of 17 years from onset of LS to SCC diagnosis.³⁸ Although circumcision often is considered curative for male genital LS, patients have been observed to develop penile SCC at least 5 years after circumcision.³⁹ Male penile SCC in a background of LS may not necessarily be HPV associated.⁴⁰

Marjolin Ulcer

Chronic ulcers or scars, typically postburn scars, may undergo malignant transformation, with SCC being the most common carcinoma.⁴¹ Squamous cell carcinoma in the context of a chronic ulcer or wound is known as a Marjolin ulcer (MU). Up to 2% of burn scars have been observed to undergo malignant transformation.⁴² Marjolin ulcers tend to behave aggressively once they form, and it has been proposed that removal of scar tissue may be a preventive therapeutic strategy.⁴³ Cohort studies of MU on the lower extremities have observed lag times of 26.4⁴⁴ and 37.9⁴⁵ years, with both studies also noting relatively high rates of local recurrence.

The pathogenesis of MU appears to be multifactorial. Chronic inflammation and scar formation have been implicated. Chronic inflammation and irritation of lesions at natural creases are thought to increase mitotic activity,⁴¹ and local accumulation of toxin may promote mutagenesis.⁴⁶ Scar formation may create a locally immunoprivileged site, allowing for developing tumors to evade the immune system⁴⁷ and become even more aggressive as the tumor accumulates.⁴⁸ Scar formation also may prevent the ability of immune cells to penetrate the tumor microenvironment and access lymphatic channels.⁴⁹

Hidradenitis Suppurativa

As many as 3.2% of patients with chronic hidradenitis suppurativa (HS) experience malignant transformation to SCC.⁵⁰ Early HS displays subclinical lymphedema in affected sites, which can progress to chronic fibrosis, stasis, and accumulation of protein-rich fluid.⁵¹ Stasis changes have been associated with altered local inflammatory proteins, such as toll-like receptors, β-defensins, and interleukins.⁵²

A retrospective cohort study of 12 patients revealed a lag time of 28.5 years from HS diagnosis to the manifestation of malignancy.⁵³ After local excision, 7 patients developed recurrence, with 100% mortality. Squamous cell carcinomas were well differentiated and moderately differentiated.⁵³ A 2017 literature review of 62 case reports calculated a mean lag time of 27 years. Despite 85% of SCCs being well differentiated and moderately differentiated, nearly half of patients died within 2 years.⁵⁴ As seen in other inflammatory conditions, HPV can complicate perineal HS and promote SCC tumorigenesis.⁵⁵

Squamous cell carcinomas arising within HS lesions are more prevalent in males (6.75:1 ratio),^54,56 despite HS being more prevalent in females (2:1 ratio).⁵⁷ Similar to DLE, SCCs arising in HS are aggressive and are seen more in males, despite both conditions being female predominant. Incidence and mortality rates for primary cutaneous SCC are higher for men vs women⁵⁸; however, the discordance in aggressive behavior seen more commonly in SCC arising from HS or DLE in male patients has yet to be explained.

Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.⁵⁹ The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.

Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.⁶⁰ Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.⁶¹ Although SCCs tend to be well differentiated in RDEB (73.9%),⁶¹ they also exhibit highly aggressive behavior.⁶² In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.⁶³

As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.⁶⁴ There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.⁶⁵ Mutations in p53,⁶⁶ local alterations in transforming growth factor β activity,⁶⁷ and downstream matrix metalloproteinase activity⁶⁸ have been implicated.

Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.⁶⁹ Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.⁷⁰ A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.⁷¹

There does not appear to be evidence for HPV involvement in RDEB-associated SCC.⁷² Squamous cell carcinoma development in RDEB appears to be multifactorial,⁷³ but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.⁷³

Conclusion

Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.


America was already facing a critical health care workforce shortage before the COVID-19 pandemic exacerbated the problem. The American Medical Association (AMA) projects that there will be a national shortage of up to 48,000 primary care physicians and 77,100 non-primary care physicians by 2034.

The dearth is particularly striking among physicians who practice in rural areas and those who are Native American. As of 2021, fewer than 3000 physicians—of 841,322—identified as American Indian or Alaska Native, according to the latest statistics from the Physician Specialty Data Report, published by the Association of American Medical Colleges (AAMC).

The lack of Native American physicians is “nothing new, it’s been going on for decades,” says Mary Owen (Tlingit), MD, director of the Center of American Indian and Minority Health and associate dean of Native American Health at the University of Minnesota Medical School, speaking in a Native America Calling podcast in October.

“These numbers are… actually lessening—and we had paltry numbers to begin with,” said Owen. “It doesn’t take a genius to look back and figure out where it’s from. We don’t have enough students coming through the pathways in the first place. For instance, our high school graduation rate in this country is easily 10 points below that of non-Natives. In Duluth, Minnesota, the high school graduation rate is only 43%… We have to recognize that this is an area we have to work on.”

Senators Tim Kaine (D-VA) and Alex Padilla (D-CA) have introduced the Expanding Medical Education Act, legislation to get more students from underrepresented groups into the physician pipeline. The bill would provide grants through the Health Resources and Services Administration (HRSA) for colleges and universities to establish or expand allopathic (MD-granting) or osteopathic (DO-granting) medical schools in underserved areas or at institutions for underrepresented populations, including Historically Black Colleges and Universities (HBCUs).

Addressing Rural Needs

However, projections on the growth of health care professions show that supply will not meet demand over the next 10 years. The shortage is more dire in rural areas. According to the US Department of Health and Human Services (HHS), since 2010, more than 150 rural hospitals have either closed their doors entirely or stopped providing inpatient hospital services. Often, rural communities have fewer local HCPs available.

More than half (54%) of American Indian or Alaska Native people live in rural and small-town areas, and 68% live on or near their tribal homelands, according to the nonprofit First Nations Development Institute. Many live far—even hours—away from the nearest health care facility. But according to Population Health in Rural America in 2020: Proceedings of a Workshop, only 10% of primary care practitioners and < 7% of specialty care practitioners live in rural areas. About 5% of rural counties do not have any family physicians. What’s more, language and culture differ among the nearly 600 tribes across the country. The Indian Health Council, for instance, counts 9 individual reservations and tribes within a 5-mile radius in San Diego County, “all of which have their own unique customs,” which contribute to the “level of care they deem appropriate.”

“If you’re a rural impoverished community, it’s hard to recruit doctors. We’re more likely to return to our communities,” said Donald K. Warne (Oglala Lakota), MD, MPH, Associate Dean for Diversity, Equity, and Inclusion at the University of North Dakota School of Medicine and Health Sciences, during the 2019 American Indian or Alaska Native Physicians Summit, which was cosponsored by the AMA, Association of American Indian Physicians (AAIP), and the AAMC.

“Communities of color and those living in rural and underserved areas have long faced significant barriers to health care, including a lack of providers that look like them or practice close by,” said Senator Kaine in a statement. “Since research shows that physicians are more likely to practice in the areas they’re from, supporting medical schools at minority-serving institutions and HBCUs in underserved areas can help improve care in those communities.”

Where Are the Native Medical Students?

Only 9% of medical schools have more than 4 American Indian or Alaska Native students; 43% have none, says Siobhan M. Wescott, MD, MPH, chair of the AMA Minority Affairs Section (MAS), and an assistant professor at the University of North Dakota. Dr. Wescott, who hosted the AMA co-sponsored summit on behalf of the AMA-MAS, is an Alaska Native and 1 of only 3 physicians from her tribe. The AAMC has also found that less than half of MD-granting medical schools in the US have enrolled more than 5 Native students.

Among other things, the Expanding Medical Education Act would prioritize grants to institutions of higher education that propose to use the funds to establish a medical school or branch campus in an area in which no other such school is based and is a medically underserved community or “health professional shortage” area. Eligible uses for the grants include hiring diverse faculty and other staff, and recruiting students from underrepresented racial and ethnic minorities, students from rural and underserved areas, low-income students, and first-generation college students.

The legislation has been endorsed by the AAMC, American Association of Colleges of Osteopathic Medicine, Association of American Indian Physicians, Association of Clinicians for the Underserved, National Hispanic Medical Association, Society for Advancement of Chicanos/Hispanics and Native Americans in Science, and Ochsner Health.

Funding Is Key

Federal agencies are investing in funding and training. Medicare is allocating 1000 new training slots for medical residents, prioritizing rural and underserved areas. Centers for Medicare and Medicaid Services (CMS) is offering another 200 slots, at least 100 of which are specifically for psychiatry residencies in 2026. HHS awarded more than $11 million through the Rural Residency Planning and Development Program (RRPD) to help establish new rural residency programs. Accredited RRPD-funded programs are already training more than 300 resident physicians in family medicine, internal medicine, psychiatry, and general surgery. HRSA published an opportunity for $5 million in FY 2024 to develop and implement clinical rotations for physician assistant students in rural areas that will integrate behavioral health with primary care services.

The Biden-Harris Administration has already taken several steps to improve access to health care for the more than 60 million people who live in rural areas, including: building on the Affordable Care Act and Inflation Reduction Act to increase access to affordable health coverage and care for those living in rural communities; keeping more rural hospitals open to provide critical services in their communities; and bolstering the rural health workforce, including for primary care and behavioral HCPs.

The administration also has funded small rural hospitals and Medicare-certified Rural Health Clinics. Critical access hospitals and small hospitals in rural areas have a new option: to convert to a Rural Emergency Hospital (REH), a new Medicare provider type. CMS has changed the payment method for Tribal and Indian Health Services–operated REHs, to address certain barriers that may have discouraged Tribal and Indian Health Service (IHS)–operated hospitals from converting to REHs. Beginning in FY 2022, HHS, through HRSA, dedicated $5 million to provide technical assistance to rural hospitals that are considering converting to the REH designation.

HHS also has several grant opportunities to support rural communities, including $28 million to provide direct health services and expand infrastructure and $16 million to provide technical assistance to rural hospitals facing financial distress. This year, 60 rural hospitals will receive technical assistance to maintain financial viability and ensure continued access to care.

The HRSA National Health Service Corps Rural Community Loan Repayment Program has invested $80 million to support substance use disorder treatment, assist in recovery, and prevent overdose deaths. Medicare will also cover opioid use disorder treatment services delivered by mobile units of registered opioid treatment programs, which can now be accessed via telehealth or audio-only communications.

Curricula Also Lack Native Diversity

As of 2017, only 11% of MD-granting schools in the US say they have included Native American health content in their curricula. Dr. Owen notes some of the challenges indigenous students face: They are in a crowd that is primarily non-Native, far from their own family and community; unlike White students, they usually do not have mentors; they may not have the wherewithal to continue school and graduate.

A 2022 study of the association of sociodemographic characteristics with US medical student attrition, published in JAMA Internal Medicine, found that American Indian, Alaska Native, Native Hawaiian, and Pacific Islander students were more than 4 times as likely to drop out compared with White students. More than 10% of Indigenous medical students don’t graduate—the highest of any group the researchers examined.

In 1973 the University of North Dakota, for instance, launched Indians Into Medicine (INMED), a program that has since recruited, supported, and trained 250 American Indian doctors, and, in 2019, the country’s first PhD program in indigenous health. Dr. Warne, the director of INMED, calls it “by far, the most successful indigenous medical training program in the world,” having helped 228 American Indians and Alaska Natives graduate since its inception. A new cohort of 6 students has just enrolled.

Oregon Health & Science University (OHSU) received $800,000 in federal funding for its Future Leaders in Indigenous Health (FLIGHT) project, managed through OHSU’s Northwest Native American Center of Excellence (NNACoE). In 2012, just 8 Native students were enrolled in the OHSU School of Medicine; a decade later, there were 29. In 2022, the newest medical class included 12 American Indian or Alaska Native students. According to the school, it is believed to be the largest group of Natives in any single US medical school MD class in history. The number of Native faculty in the OHSU School of Medicine grew from 7 in 2014 to 13 in 2022.

America was already facing a critical health care workforce shortage before the COVID-19 pandemic exacerbated the problem. The American Medical Association (AMA) projects that there will be a national shortage of up to 48,000 primary care physicians and 77,100 non-primary care physicians by 2034.

The dearth is particularly striking among physicians who practice in rural areas and those who are Native American. As of 2021, fewer than 3000 physicians—of 841,322—identified as American Indian or Alaska Native, according to the latest statistics from the Physician Specialty Data Report, published by the Association of American Medical Colleges (AAMC).

The lack of Native American physicians is “nothing new, it’s been going on for decades,” says Mary Owen (Tlingit), MD, director of the Center of American Indian and Minority Health and associate dean of Native American Health at the University of Minnesota Medical School, speaking in a Native America Calling podcast in October.

“These numbers are… actually lessening—and we had paltry numbers to begin with,” said Owen. “It doesn’t take a genius to look back and figure out where it’s from. We don’t have enough students coming through the pathways in the first place. For instance, our high school graduation rate in this country is easily 10 points below that of non-Natives. In Duluth, Minnesota, the high school graduation rate is only 43%… We have to recognize that this is an area we have to work on.”

Senators Tim Kaine (D-VA) and Alex Padilla (D-CA) have introduced the Expanding Medical Education Act, legislation to get more students from underrepresented groups into the physician pipeline. The bill would provide grants through the Health Resources and Services Administration (HRSA) for colleges and universities to establish or expand allopathic (MD-granting) or osteopathic (DO-granting) medical schools in underserved areas or at institutions for underrepresented populations, including Historically Black Colleges and Universities (HBCUs).

Addressing Rural Needs

However, projections on the growth of health care professions show that supply will not meet demand over the next 10 years. The shortage is more dire in rural areas. According to the US Department of Health and Human Services (HHS), since 2010, more than 150 rural hospitals have either closed their doors entirely or stopped providing inpatient hospital services. Often, rural communities have fewer local HCPs available.

More than half (54%) of American Indian or Alaska Native people live in rural and small-town areas, and 68% live on or near their tribal homelands, according to the nonprofit First Nations Development Institute. Many live far—even hours—away from the nearest health care facility. But according to Population Health in Rural America in 2020: Proceedings of a Workshop, only 10% of primary care practitioners and < 7% of specialty care practitioners live in rural areas. About 5% of rural counties do not have any family physicians. What’s more, language and culture differ among the nearly 600 tribes across the country. The Indian Health Council, for instance, counts 9 individual reservations and tribes within a 5-mile radius in San Diego County, “all of which have their own unique customs,” which contribute to the “level of care they deem appropriate.”

“If you’re a rural impoverished community, it’s hard to recruit doctors. We’re more likely to return to our communities,” said Donald K. Warne (Oglala Lakota), MD, MPH, Associate Dean for Diversity, Equity, and Inclusion at the University of North Dakota School of Medicine and Health Sciences, during the 2019 American Indian or Alaska Native Physicians Summit, which was cosponsored by the AMA, Association of American Indian Physicians (AAIP), and the AAMC.

“Communities of color and those living in rural and underserved areas have long faced significant barriers to health care, including a lack of providers that look like them or practice close by,” said Senator Kaine in a statement. “Since research shows that physicians are more likely to practice in the areas they’re from, supporting medical schools at minority-serving institutions and HBCUs in underserved areas can help improve care in those communities.”

Where Are the Native Medical Students?

Only 9% of medical schools have more than 4 American Indian or Alaska Native students; 43% have none, says Siobhan M. Wescott, MD, MPH, chair of the AMA Minority Affairs Section (MAS), and an assistant professor at the University of North Dakota. Dr. Wescott, who hosted the AMA co-sponsored summit on behalf of the AMA-MAS, is an Alaska Native and 1 of only 3 physicians from her tribe. The AAMC has also found that less than half of MD-granting medical schools in the US have enrolled more than 5 Native students.

Among other things, the Expanding Medical Education Act would prioritize grants to institutions of higher education that propose to use the funds to establish a medical school or branch campus in an area in which no other such school is based and is a medically underserved community or “health professional shortage” area. Eligible uses for the grants include hiring diverse faculty and other staff, and recruiting students from underrepresented racial and ethnic minorities, students from rural and underserved areas, low-income students, and first-generation college students.

The legislation has been endorsed by the AAMC, American Association of Colleges of Osteopathic Medicine, Association of American Indian Physicians, Association of Clinicians for the Underserved, National Hispanic Medical Association, Society for Advancement of Chicanos/Hispanics and Native Americans in Science, and Ochsner Health.

Funding Is Key

Federal agencies are investing in funding and training. Medicare is allocating 1000 new training slots for medical residents, prioritizing rural and underserved areas. Centers for Medicare and Medicaid Services (CMS) is offering another 200 slots, at least 100 of which are specifically for psychiatry residencies in 2026. HHS awarded more than $11 million through the Rural Residency Planning and Development Program (RRPD) to help establish new rural residency programs. Accredited RRPD-funded programs are already training more than 300 resident physicians in family medicine, internal medicine, psychiatry, and general surgery. HRSA published an opportunity for $5 million in FY 2024 to develop and implement clinical rotations for physician assistant students in rural areas that will integrate behavioral health with primary care services.

The Biden-Harris Administration has already taken several steps to improve access to health care for the more than 60 million people who live in rural areas, including: building on the Affordable Care Act and Inflation Reduction Act to increase access to affordable health coverage and care for those living in rural communities; keeping more rural hospitals open to provide critical services in their communities; and bolstering the rural health workforce, including for primary care and behavioral HCPs.

The administration also has funded small rural hospitals and Medicare-certified Rural Health Clinics. Critical access hospitals and small hospitals in rural areas have a new option: to convert to a Rural Emergency Hospital (REH), a new Medicare provider type. CMS has changed the payment method for Tribal and Indian Health Services–operated REHs, to address certain barriers that may have discouraged Tribal and Indian Health Service (IHS)–operated hospitals from converting to REHs. Beginning in FY 2022, HHS, through HRSA, dedicated $5 million to provide technical assistance to rural hospitals that are considering converting to the REH designation.

HHS also has several grant opportunities to support rural communities, including $28 million to provide direct health services and expand infrastructure and $16 million to provide technical assistance to rural hospitals facing financial distress. This year, 60 rural hospitals will receive technical assistance to maintain financial viability and ensure continued access to care.

The HRSA National Health Service Corps Rural Community Loan Repayment Program has invested $80 million to support substance use disorder treatment, assist in recovery, and prevent overdose deaths. Medicare will also cover opioid use disorder treatment services delivered by mobile units of registered opioid treatment programs, which can now be accessed via telehealth or audio-only communications.

Curricula Also Lack Native Diversity

As of 2017, only 11% of MD-granting schools in the US say they have included Native American health content in their curricula. Dr. Owen notes some of the challenges indigenous students face: They are in a crowd that is primarily non-Native, far from their own family and community; unlike White students, they usually do not have mentors; they may not have the wherewithal to continue school and graduate.

A 2022 study of the association of sociodemographic characteristics with US medical student attrition, published in JAMA Internal Medicine, found that American Indian, Alaska Native, Native Hawaiian, and Pacific Islander students were more than 4 times as likely to drop out compared with White students. More than 10% of Indigenous medical students don’t graduate—the highest of any group the researchers examined.

In 1973 the University of North Dakota, for instance, launched Indians Into Medicine (INMED), a program that has since recruited, supported, and trained 250 American Indian doctors, and, in 2019, the country’s first PhD program in indigenous health. Dr. Warne, the director of INMED, calls it “by far, the most successful indigenous medical training program in the world,” having helped 228 American Indians and Alaska Natives graduate since its inception. A new cohort of 6 students has just enrolled.

Oregon Health & Science University (OHSU) received $800,000 in federal funding for its Future Leaders in Indigenous Health (FLIGHT) project, managed through OHSU’s Northwest Native American Center of Excellence (NNACoE). In 2012, just 8 Native students were enrolled in the OHSU School of Medicine; a decade later, there were 29. In 2022, the newest medical class included 12 American Indian or Alaska Native students. According to the school, it is believed to be the largest group of Natives in any single US medical school MD class in history. The number of Native faculty in the OHSU School of Medicine grew from 7 in 2014 to 13 in 2022.

America was already facing a critical health care workforce shortage before the COVID-19 pandemic exacerbated the problem. The American Medical Association (AMA) projects that there will be a national shortage of up to 48,000 primary care physicians and 77,100 non-primary care physicians by 2034.

The dearth is particularly striking among physicians who practice in rural areas and those who are Native American. As of 2021, fewer than 3000 physicians—of 841,322—identified as American Indian or Alaska Native, according to the latest statistics from the Physician Specialty Data Report, published by the Association of American Medical Colleges (AAMC).

The lack of Native American physicians is “nothing new, it’s been going on for decades,” says Mary Owen (Tlingit), MD, director of the Center of American Indian and Minority Health and associate dean of Native American Health at the University of Minnesota Medical School, speaking in a Native America Calling podcast in October.

“These numbers are… actually lessening—and we had paltry numbers to begin with,” said Owen. “It doesn’t take a genius to look back and figure out where it’s from. We don’t have enough students coming through the pathways in the first place. For instance, our high school graduation rate in this country is easily 10 points below that of non-Natives. In Duluth, Minnesota, the high school graduation rate is only 43%… We have to recognize that this is an area we have to work on.”

Senators Tim Kaine (D-VA) and Alex Padilla (D-CA) have introduced the Expanding Medical Education Act, legislation to get more students from underrepresented groups into the physician pipeline. The bill would provide grants through the Health Resources and Services Administration (HRSA) for colleges and universities to establish or expand allopathic (MD-granting) or osteopathic (DO-granting) medical schools in underserved areas or at institutions for underrepresented populations, including Historically Black Colleges and Universities (HBCUs).

Addressing Rural Needs

However, projections on the growth of health care professions show that supply will not meet demand over the next 10 years. The shortage is more dire in rural areas. According to the US Department of Health and Human Services (HHS), since 2010, more than 150 rural hospitals have either closed their doors entirely or stopped providing inpatient hospital services. Often, rural communities have fewer local HCPs available.

More than half (54%) of American Indian or Alaska Native people live in rural and small-town areas, and 68% live on or near their tribal homelands, according to the nonprofit First Nations Development Institute. Many live far—even hours—away from the nearest health care facility. But according to Population Health in Rural America in 2020: Proceedings of a Workshop, only 10% of primary care practitioners and < 7% of specialty care practitioners live in rural areas. About 5% of rural counties do not have any family physicians. What’s more, language and culture differ among the nearly 600 tribes across the country. The Indian Health Council, for instance, counts 9 individual reservations and tribes within a 5-mile radius in San Diego County, “all of which have their own unique customs,” which contribute to the “level of care they deem appropriate.”

“If you’re a rural impoverished community, it’s hard to recruit doctors. We’re more likely to return to our communities,” said Donald K. Warne (Oglala Lakota), MD, MPH, Associate Dean for Diversity, Equity, and Inclusion at the University of North Dakota School of Medicine and Health Sciences, during the 2019 American Indian or Alaska Native Physicians Summit, which was cosponsored by the AMA, Association of American Indian Physicians (AAIP), and the AAMC.

“Communities of color and those living in rural and underserved areas have long faced significant barriers to health care, including a lack of providers that look like them or practice close by,” said Senator Kaine in a statement. “Since research shows that physicians are more likely to practice in the areas they’re from, supporting medical schools at minority-serving institutions and HBCUs in underserved areas can help improve care in those communities.”

Where Are the Native Medical Students?

Only 9% of medical schools have more than 4 American Indian or Alaska Native students; 43% have none, says Siobhan M. Wescott, MD, MPH, chair of the AMA Minority Affairs Section (MAS), and an assistant professor at the University of North Dakota. Dr. Wescott, who hosted the AMA co-sponsored summit on behalf of the AMA-MAS, is an Alaska Native and 1 of only 3 physicians from her tribe. The AAMC has also found that less than half of MD-granting medical schools in the US have enrolled more than 5 Native students.

Among other things, the Expanding Medical Education Act would prioritize grants to institutions of higher education that propose to use the funds to establish a medical school or branch campus in an area in which no other such school is based and is a medically underserved community or “health professional shortage” area. Eligible uses for the grants include hiring diverse faculty and other staff, and recruiting students from underrepresented racial and ethnic minorities, students from rural and underserved areas, low-income students, and first-generation college students.

The legislation has been endorsed by the AAMC, American Association of Colleges of Osteopathic Medicine, Association of American Indian Physicians, Association of Clinicians for the Underserved, National Hispanic Medical Association, Society for Advancement of Chicanos/Hispanics and Native Americans in Science, and Ochsner Health.

Funding Is Key

Federal agencies are investing in funding and training. Medicare is allocating 1000 new training slots for medical residents, prioritizing rural and underserved areas. Centers for Medicare and Medicaid Services (CMS) is offering another 200 slots, at least 100 of which are specifically for psychiatry residencies in 2026. HHS awarded more than $11 million through the Rural Residency Planning and Development Program (RRPD) to help establish new rural residency programs. Accredited RRPD-funded programs are already training more than 300 resident physicians in family medicine, internal medicine, psychiatry, and general surgery. HRSA published an opportunity for $5 million in FY 2024 to develop and implement clinical rotations for physician assistant students in rural areas that will integrate behavioral health with primary care services.

The Biden-Harris Administration has already taken several steps to improve access to health care for the more than 60 million people who live in rural areas, including: building on the Affordable Care Act and Inflation Reduction Act to increase access to affordable health coverage and care for those living in rural communities; keeping more rural hospitals open to provide critical services in their communities; and bolstering the rural health workforce, including for primary care and behavioral HCPs.

The administration also has funded small rural hospitals and Medicare-certified Rural Health Clinics. Critical access hospitals and small hospitals in rural areas have a new option: to convert to a Rural Emergency Hospital (REH), a new Medicare provider type. CMS has changed the payment method for Tribal and Indian Health Services–operated REHs, to address certain barriers that may have discouraged Tribal and Indian Health Service (IHS)–operated hospitals from converting to REHs. Beginning in FY 2022, HHS, through HRSA, dedicated $5 million to provide technical assistance to rural hospitals that are considering converting to the REH designation.

HHS also has several grant opportunities to support rural communities, including $28 million to provide direct health services and expand infrastructure and $16 million to provide technical assistance to rural hospitals facing financial distress. This year, 60 rural hospitals will receive technical assistance to maintain financial viability and ensure continued access to care.

The HRSA National Health Service Corps Rural Community Loan Repayment Program has invested $80 million to support substance use disorder treatment, assist in recovery, and prevent overdose deaths. Medicare will also cover opioid use disorder treatment services delivered by mobile units of registered opioid treatment programs, which can now be accessed via telehealth or audio-only communications.

Curricula Also Lack Native Diversity

As of 2017, only 11% of MD-granting schools in the US say they have included Native American health content in their curricula. Dr. Owen notes some of the challenges indigenous students face: They are in a crowd that is primarily non-Native, far from their own family and community; unlike White students, they usually do not have mentors; they may not have the wherewithal to continue school and graduate.

A 2022 study of the association of sociodemographic characteristics with US medical student attrition, published in JAMA Internal Medicine, found that American Indian, Alaska Native, Native Hawaiian, and Pacific Islander students were more than 4 times as likely to drop out compared with White students. More than 10% of Indigenous medical students don’t graduate—the highest of any group the researchers examined.

In 1973 the University of North Dakota, for instance, launched Indians Into Medicine (INMED), a program that has since recruited, supported, and trained 250 American Indian doctors, and, in 2019, the country’s first PhD program in indigenous health. Dr. Warne, the director of INMED, calls it “by far, the most successful indigenous medical training program in the world,” having helped 228 American Indians and Alaska Natives graduate since its inception. A new cohort of 6 students has just enrolled.

Oregon Health & Science University (OHSU) received $800,000 in federal funding for its Future Leaders in Indigenous Health (FLIGHT) project, managed through OHSU’s Northwest Native American Center of Excellence (NNACoE). In 2012, just 8 Native students were enrolled in the OHSU School of Medicine; a decade later, there were 29. In 2022, the newest medical class included 12 American Indian or Alaska Native students. According to the school, it is believed to be the largest group of Natives in any single US medical school MD class in history. The number of Native faculty in the OHSU School of Medicine grew from 7 in 2014 to 13 in 2022.

SAN DIEGO — Clinicians are encountering unique challenges as the American Society of Hematology (ASH) develops the first-ever clinical practice guidelines for treating acute lymphocytic leukemia (ALL) in adolescents and young adults, a wide-ranging age span that runs from older teenagers to thirtysomethings on the cusp of middle age.

At the crux of the matter is the unusual nature of ALL, said University of Chicago leukemia specialist Wendy Stock, MD, in a presentation at the annual meeting of the American Society of Hematology in December 2023. The disease is both rare and unique since it spans the entire lifetime from infancy to old age, she said.

The guidelines will focus on adolescents and young adults, which the National Cancer Institute defines as those aged 15-39. For these patients, “treatment is administered by the whole gamut of practitioners in the world of hematology, from pediatricians to adult hematologist/oncologists, which provides unique challenges in terms of understanding and access to care,” Dr. Stock said.

As she explained, ALL “is the bread and butter of pediatric oncology, but in the world of adult hematology-oncology, many patients are treated in small-practice settings where there have been very few uniform approaches available to the treating practitioners,” she said. “There’s not going to ever be the ability to get every — or even the majority — of adults into those big academic centers.”

Meanwhile, research from around the world has highlighted major mortality gaps between pediatric and adult care in ALL. “This has been our huge challenge: Is it the treatment approach? Is it the disease biology, the patient biology, the doctors who treat these diseases? Is it the geographic location where they’re treated? Well, we now know that, of course, it’s probably all of the above, and a lot more than that.”

In light of the need for guidance in ALL treatment, it will be crucial to disseminate data and recommendations via the guidelines, she said.

In 2021, ASH members approved the development of new clinical practice guidelines for this population. The process so far has been difficult, said pediatric oncologist Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Toronto, Ontario, at the ASH presentation.

“At one point,” Dr. Gupta recalled, “someone on our methodology team said this was the most challenging systematic review and guideline creation that they’d ever worked on, which is not what you want to hear as a co-chair.”

One major challenge for the guideline drafters is to balance ALL research findings that cover only certain ages, Dr. Gupta said. A study, for example, may only include patients up to age 21 or over age 35, making it difficult to decide how it fits into a larger evidence base for adolescents and young adults.

“We don’t always have perfect evidence. But we’re trying to take all of that and translate it into a formalized systematic review,” he said. “This is tricky for any guideline. But ALL poses a particular challenge because of how the evidence base is spread out.”

Another challenge is figuring out how to review psychosocial interventions in ALL. They are obviously crucial, he said. But should guidelines only take into account strategies that were tested in ALL? Or should they look at a wider perspective and encompass research into non–ALL-specific approaches?

In terms of guidance about frontline treatment, the guideline developers are focusing on several topics, said University of Rochester hematologist/oncologist Kristen O’Dwyer, MD, at the ASH presentation. These include: Should adolescents and young adults receive pediatric or adult regimens? Where do targeted therapy, immunotherapy, steroids, allogeneic stem cell transplants, and central nervous system (CNS) prophylaxis fit in?

“Finally, there are a series of questions that are addressing the toxicity prevention and management that go along with these intensive chemotherapy regimens,” she said.

On one front, there’s a “knowledge gap” about the value of stem cell transplant vs pediatric-inspired chemotherapy as postremission therapies, Dr. O’Dwyer said, because there are no direct comparisons. What to do? “There are retrospective comparisons that are emerging along with population-level analysis, single-arm observational studies that suggest that a pediatric-based chemotherapy approach is superior with similar relapse rates and less treatment-related mortality,” she said.

ASH expects to release a draft of its ALL guidelines for adolescents and young adults later this year and publish final recommendations in late 2024 or early 2025.

Dr. Stock, Dr. Gupta, and Dr. O’Dwyer have no disclosures.

SAN DIEGO — Clinicians are encountering unique challenges as the American Society of Hematology (ASH) develops the first-ever clinical practice guidelines for treating acute lymphocytic leukemia (ALL) in adolescents and young adults, a wide-ranging age span that runs from older teenagers to thirtysomethings on the cusp of middle age.

At the crux of the matter is the unusual nature of ALL, said University of Chicago leukemia specialist Wendy Stock, MD, in a presentation at the annual meeting of the American Society of Hematology in December 2023. The disease is both rare and unique since it spans the entire lifetime from infancy to old age, she said.

The guidelines will focus on adolescents and young adults, which the National Cancer Institute defines as those aged 15-39. For these patients, “treatment is administered by the whole gamut of practitioners in the world of hematology, from pediatricians to adult hematologist/oncologists, which provides unique challenges in terms of understanding and access to care,” Dr. Stock said.

As she explained, ALL “is the bread and butter of pediatric oncology, but in the world of adult hematology-oncology, many patients are treated in small-practice settings where there have been very few uniform approaches available to the treating practitioners,” she said. “There’s not going to ever be the ability to get every — or even the majority — of adults into those big academic centers.”

Meanwhile, research from around the world has highlighted major mortality gaps between pediatric and adult care in ALL. “This has been our huge challenge: Is it the treatment approach? Is it the disease biology, the patient biology, the doctors who treat these diseases? Is it the geographic location where they’re treated? Well, we now know that, of course, it’s probably all of the above, and a lot more than that.”

In light of the need for guidance in ALL treatment, it will be crucial to disseminate data and recommendations via the guidelines, she said.

In 2021, ASH members approved the development of new clinical practice guidelines for this population. The process so far has been difficult, said pediatric oncologist Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Toronto, Ontario, at the ASH presentation.

“At one point,” Dr. Gupta recalled, “someone on our methodology team said this was the most challenging systematic review and guideline creation that they’d ever worked on, which is not what you want to hear as a co-chair.”

One major challenge for the guideline drafters is to balance ALL research findings that cover only certain ages, Dr. Gupta said. A study, for example, may only include patients up to age 21 or over age 35, making it difficult to decide how it fits into a larger evidence base for adolescents and young adults.

“We don’t always have perfect evidence. But we’re trying to take all of that and translate it into a formalized systematic review,” he said. “This is tricky for any guideline. But ALL poses a particular challenge because of how the evidence base is spread out.”

Another challenge is figuring out how to review psychosocial interventions in ALL. They are obviously crucial, he said. But should guidelines only take into account strategies that were tested in ALL? Or should they look at a wider perspective and encompass research into non–ALL-specific approaches?

In terms of guidance about frontline treatment, the guideline developers are focusing on several topics, said University of Rochester hematologist/oncologist Kristen O’Dwyer, MD, at the ASH presentation. These include: Should adolescents and young adults receive pediatric or adult regimens? Where do targeted therapy, immunotherapy, steroids, allogeneic stem cell transplants, and central nervous system (CNS) prophylaxis fit in?

“Finally, there are a series of questions that are addressing the toxicity prevention and management that go along with these intensive chemotherapy regimens,” she said.

On one front, there’s a “knowledge gap” about the value of stem cell transplant vs pediatric-inspired chemotherapy as postremission therapies, Dr. O’Dwyer said, because there are no direct comparisons. What to do? “There are retrospective comparisons that are emerging along with population-level analysis, single-arm observational studies that suggest that a pediatric-based chemotherapy approach is superior with similar relapse rates and less treatment-related mortality,” she said.

ASH expects to release a draft of its ALL guidelines for adolescents and young adults later this year and publish final recommendations in late 2024 or early 2025.

Dr. Stock, Dr. Gupta, and Dr. O’Dwyer have no disclosures.

SAN DIEGO — Clinicians are encountering unique challenges as the American Society of Hematology (ASH) develops the first-ever clinical practice guidelines for treating acute lymphocytic leukemia (ALL) in adolescents and young adults, a wide-ranging age span that runs from older teenagers to thirtysomethings on the cusp of middle age.

At the crux of the matter is the unusual nature of ALL, said University of Chicago leukemia specialist Wendy Stock, MD, in a presentation at the annual meeting of the American Society of Hematology in December 2023. The disease is both rare and unique since it spans the entire lifetime from infancy to old age, she said.

The guidelines will focus on adolescents and young adults, which the National Cancer Institute defines as those aged 15-39. For these patients, “treatment is administered by the whole gamut of practitioners in the world of hematology, from pediatricians to adult hematologist/oncologists, which provides unique challenges in terms of understanding and access to care,” Dr. Stock said.

As she explained, ALL “is the bread and butter of pediatric oncology, but in the world of adult hematology-oncology, many patients are treated in small-practice settings where there have been very few uniform approaches available to the treating practitioners,” she said. “There’s not going to ever be the ability to get every — or even the majority — of adults into those big academic centers.”

Meanwhile, research from around the world has highlighted major mortality gaps between pediatric and adult care in ALL. “This has been our huge challenge: Is it the treatment approach? Is it the disease biology, the patient biology, the doctors who treat these diseases? Is it the geographic location where they’re treated? Well, we now know that, of course, it’s probably all of the above, and a lot more than that.”

In light of the need for guidance in ALL treatment, it will be crucial to disseminate data and recommendations via the guidelines, she said.

In 2021, ASH members approved the development of new clinical practice guidelines for this population. The process so far has been difficult, said pediatric oncologist Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Toronto, Ontario, at the ASH presentation.

“At one point,” Dr. Gupta recalled, “someone on our methodology team said this was the most challenging systematic review and guideline creation that they’d ever worked on, which is not what you want to hear as a co-chair.”

One major challenge for the guideline drafters is to balance ALL research findings that cover only certain ages, Dr. Gupta said. A study, for example, may only include patients up to age 21 or over age 35, making it difficult to decide how it fits into a larger evidence base for adolescents and young adults.

“We don’t always have perfect evidence. But we’re trying to take all of that and translate it into a formalized systematic review,” he said. “This is tricky for any guideline. But ALL poses a particular challenge because of how the evidence base is spread out.”

Another challenge is figuring out how to review psychosocial interventions in ALL. They are obviously crucial, he said. But should guidelines only take into account strategies that were tested in ALL? Or should they look at a wider perspective and encompass research into non–ALL-specific approaches?

In terms of guidance about frontline treatment, the guideline developers are focusing on several topics, said University of Rochester hematologist/oncologist Kristen O’Dwyer, MD, at the ASH presentation. These include: Should adolescents and young adults receive pediatric or adult regimens? Where do targeted therapy, immunotherapy, steroids, allogeneic stem cell transplants, and central nervous system (CNS) prophylaxis fit in?

“Finally, there are a series of questions that are addressing the toxicity prevention and management that go along with these intensive chemotherapy regimens,” she said.

On one front, there’s a “knowledge gap” about the value of stem cell transplant vs pediatric-inspired chemotherapy as postremission therapies, Dr. O’Dwyer said, because there are no direct comparisons. What to do? “There are retrospective comparisons that are emerging along with population-level analysis, single-arm observational studies that suggest that a pediatric-based chemotherapy approach is superior with similar relapse rates and less treatment-related mortality,” she said.

ASH expects to release a draft of its ALL guidelines for adolescents and young adults later this year and publish final recommendations in late 2024 or early 2025.

Dr. Stock, Dr. Gupta, and Dr. O’Dwyer have no disclosures.

TOPLINE:

A new study shows sudden cardiac deaths among collegiate athletes decreased over a recent 20-year period, but risks are still elevated among males, Black players, and basketball players, suggesting more intensive screening among these groups is needed.

METHODOLOGY:

• The study examined incidence and surrounding circumstances of sudden cardiac death (SCD) among student athletes who competed in at least one varsity sport at National Collegiate Athletic Association (NCAA) Division I, II, or III institutions in the 20 years from July 1, 2002, to June 30, 2022.
• Researchers determined causes of death and gathered demographic characteristics using multiple methods, including review of autopsy and other official documents, Internet searches, and contacts to next of kin, coaches, athletic trainers, coroners, medical examiners, scholarship foundations, and physicians involved in the case.
• SCD was defined as sudden unexpected death attributable to a cardiac cause, or a sudden death in a structurally normal heart with no other explanation for death and a history consistent with cardiac-related death that occurred within an hour of symptom onset, or an unwitnessed death occurring within 24 hours of the person being alive.
• Researchers calculated incidence rates over a typical 4-year collegiate career and reported these as athlete-years.

TAKEAWAY:

• The incidence of SCD, which accounted for 13% of the 1102 total deaths during the study period, decreased over time, with a 5-year incidence rate ratio (IRR) of 0.71 (95% CI, 0.61-0.82), while noncardiovascular deaths remained stable.
• IRR for males versus females was 3.79 (95% CI, 2.45-5.88) and for Black versus White athletes was 2.79 (95% CI, 1.98-3.94).
• Basketball and football players were at increased risk of SCD; for example, the incidence rate among Division I Black male basketball athletes was 1:1924 per 4-year athlete-years.
• The most common postmortem finding was autopsy-negative sudden unexplained death, at 19%, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (17%) and hypertrophic cardiomyopathy (13%), with no cases of death attributable to COVID-19 myocarditis.

IN PRACTICE:

Although the reason for the decrease in SCD is unknown, “our data suggest that strategies to reduce SCD among competing athletes may be having a positive effect,” wrote the authors. More intensive screening strategies among groups with high SCD incidence may be warranted, they added.

SOURCE:

The study was conducted by Bradley J. Petek, MD, Sports Cardiology Program, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. It was published online November 13 in Circulation and presented at the American Heart Association scientific sessions (abstract 479).

LIMITATIONS:

Some cases of SCD may have been missed as there is no mandatory reporting system in the United States. Approaches to cardiac autopsy and reporting varied significantly. The cause of death was unknown in 16 cases, and postmortem genetic testing was available for only 3% of athletes. As the study didn’t have data on resuscitated sudden cardiac arrest or preparticipation cardiovascular screening practices and findings, definitive conclusions couldn’t be drawn regarding causal factors underlying the decreased incidence of SCD.

DISCLOSURES:

There was no outside funding source. Dr. Petek has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

A version of this article appeared on Medscape.com.

TOPLINE:

A new study shows sudden cardiac deaths among collegiate athletes decreased over a recent 20-year period, but risks are still elevated among males, Black players, and basketball players, suggesting more intensive screening among these groups is needed.

METHODOLOGY:

• The study examined incidence and surrounding circumstances of sudden cardiac death (SCD) among student athletes who competed in at least one varsity sport at National Collegiate Athletic Association (NCAA) Division I, II, or III institutions in the 20 years from July 1, 2002, to June 30, 2022.
• Researchers determined causes of death and gathered demographic characteristics using multiple methods, including review of autopsy and other official documents, Internet searches, and contacts to next of kin, coaches, athletic trainers, coroners, medical examiners, scholarship foundations, and physicians involved in the case.
• SCD was defined as sudden unexpected death attributable to a cardiac cause, or a sudden death in a structurally normal heart with no other explanation for death and a history consistent with cardiac-related death that occurred within an hour of symptom onset, or an unwitnessed death occurring within 24 hours of the person being alive.
• Researchers calculated incidence rates over a typical 4-year collegiate career and reported these as athlete-years.

TAKEAWAY:

• The incidence of SCD, which accounted for 13% of the 1102 total deaths during the study period, decreased over time, with a 5-year incidence rate ratio (IRR) of 0.71 (95% CI, 0.61-0.82), while noncardiovascular deaths remained stable.
• IRR for males versus females was 3.79 (95% CI, 2.45-5.88) and for Black versus White athletes was 2.79 (95% CI, 1.98-3.94).
• Basketball and football players were at increased risk of SCD; for example, the incidence rate among Division I Black male basketball athletes was 1:1924 per 4-year athlete-years.
• The most common postmortem finding was autopsy-negative sudden unexplained death, at 19%, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (17%) and hypertrophic cardiomyopathy (13%), with no cases of death attributable to COVID-19 myocarditis.

IN PRACTICE:

Although the reason for the decrease in SCD is unknown, “our data suggest that strategies to reduce SCD among competing athletes may be having a positive effect,” wrote the authors. More intensive screening strategies among groups with high SCD incidence may be warranted, they added.

SOURCE:

The study was conducted by Bradley J. Petek, MD, Sports Cardiology Program, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. It was published online November 13 in Circulation and presented at the American Heart Association scientific sessions (abstract 479).

LIMITATIONS:

Some cases of SCD may have been missed as there is no mandatory reporting system in the United States. Approaches to cardiac autopsy and reporting varied significantly. The cause of death was unknown in 16 cases, and postmortem genetic testing was available for only 3% of athletes. As the study didn’t have data on resuscitated sudden cardiac arrest or preparticipation cardiovascular screening practices and findings, definitive conclusions couldn’t be drawn regarding causal factors underlying the decreased incidence of SCD.

DISCLOSURES:

There was no outside funding source. Dr. Petek has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

A version of this article appeared on Medscape.com.

TOPLINE:

A new study shows sudden cardiac deaths among collegiate athletes decreased over a recent 20-year period, but risks are still elevated among males, Black players, and basketball players, suggesting more intensive screening among these groups is needed.

METHODOLOGY:

• The study examined incidence and surrounding circumstances of sudden cardiac death (SCD) among student athletes who competed in at least one varsity sport at National Collegiate Athletic Association (NCAA) Division I, II, or III institutions in the 20 years from July 1, 2002, to June 30, 2022.
• Researchers determined causes of death and gathered demographic characteristics using multiple methods, including review of autopsy and other official documents, Internet searches, and contacts to next of kin, coaches, athletic trainers, coroners, medical examiners, scholarship foundations, and physicians involved in the case.
• SCD was defined as sudden unexpected death attributable to a cardiac cause, or a sudden death in a structurally normal heart with no other explanation for death and a history consistent with cardiac-related death that occurred within an hour of symptom onset, or an unwitnessed death occurring within 24 hours of the person being alive.
• Researchers calculated incidence rates over a typical 4-year collegiate career and reported these as athlete-years.

TAKEAWAY:

• The incidence of SCD, which accounted for 13% of the 1102 total deaths during the study period, decreased over time, with a 5-year incidence rate ratio (IRR) of 0.71 (95% CI, 0.61-0.82), while noncardiovascular deaths remained stable.
• IRR for males versus females was 3.79 (95% CI, 2.45-5.88) and for Black versus White athletes was 2.79 (95% CI, 1.98-3.94).
• Basketball and football players were at increased risk of SCD; for example, the incidence rate among Division I Black male basketball athletes was 1:1924 per 4-year athlete-years.
• The most common postmortem finding was autopsy-negative sudden unexplained death, at 19%, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (17%) and hypertrophic cardiomyopathy (13%), with no cases of death attributable to COVID-19 myocarditis.

IN PRACTICE:

Although the reason for the decrease in SCD is unknown, “our data suggest that strategies to reduce SCD among competing athletes may be having a positive effect,” wrote the authors. More intensive screening strategies among groups with high SCD incidence may be warranted, they added.

SOURCE:

The study was conducted by Bradley J. Petek, MD, Sports Cardiology Program, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. It was published online November 13 in Circulation and presented at the American Heart Association scientific sessions (abstract 479).

LIMITATIONS:

Some cases of SCD may have been missed as there is no mandatory reporting system in the United States. Approaches to cardiac autopsy and reporting varied significantly. The cause of death was unknown in 16 cases, and postmortem genetic testing was available for only 3% of athletes. As the study didn’t have data on resuscitated sudden cardiac arrest or preparticipation cardiovascular screening practices and findings, definitive conclusions couldn’t be drawn regarding causal factors underlying the decreased incidence of SCD.

DISCLOSURES:

There was no outside funding source. Dr. Petek has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

A version of this article appeared on Medscape.com.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

In 2023, CHEST awarded $300,000 in clinical research and community impact grants to 15 individuals. Grant recipients are recognized for their scientifically meritorious achievements, with rigorous metrics to track their project’s progress, and have innovative, novel approaches to addressing their research topic.

CHEST grants have made a difference in patients’ lives by leading to breakthroughs in the treatment and/or management of chest diseases and patient care. This year’s grant-funded projects run the gamut of topics within chest medicine, ranging from lung cancer and COPD to tuberculosis and idiopathic pulmonary fibrosis.

Here’s a glimpse into two of this year’s grant winners and their projects.

For a full list of the 2023 grant winners, visit chestnet.org/grant-recipients.
 

Air pollution in sarcoidosis

This year, the John R. Addrizzo, MD, FCCP Research Grant in Sarcoidosis was awarded to Ali Mustafa, MD, of the Johns Hopkins Hospital in Baltimore, MD, for his project “Air Pollution in Sarcoidosis.”

Courtesy CHEST

The project’s aim is to investigate the feasibility of studying indoor and outdoor air pollution in patients with pulmonary sarcoidosis.

According to Dr. Mustafa’s application, pulmonary sarcoidosis is one of the most common interstitial lung diseases in the United States, and mortality due to sarcoidosis has risen by more than 3% in recent decades.

While the etiology of sarcoidosis remains elusive, evidence points toward a combination of genetic predisposition with external environmental triggers affecting disease onset. One small study of 16 individuals with fibrotic pulmonary sarcoidosis assessed the association between local levels of outdoor air pollutants to clinical outcomes. This study found that increased short-term exposure was associated with increased respiratory symptom severity and worse health-related quality of life.

Additionally, significant health disparities exist in sarcoidosis. Black individuals with sarcoidosis have worse pulmonary function, higher rates of multiorgan disease, and as much as a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Socioeconomic status and Black race have also been associated with increased exposure to air pollution and closer proximity to high toxic emission facilities, suggesting higher exposure to outdoor air pollution.

Racial disparities are present and particularly important in sarcoidosis. Black individuals are more likely to have more advanced disease at diagnosis, have a six-fold increase in hospitalization, and a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Little is known about the drivers of these disparities; however, environmental exposure has been implicated in sarcoidosis pathogenesis and incidence and may be an important contributor.

Dr. Mustafa’s preliminary work suggests disparities in exposure to air pollution among individuals with sarcoidosis may be contributing to inequities in clinical outcomes.
 

Determinants of medication non-adherence among adults with chronic obstructive pulmonary disease

The CHEST/ALA/ATS Respiratory Health Equity Research Award was given to Stephanie LaBedz, MD, of the University of Illinois Chicago. The Respiratory Health Equity Research Award is jointly supported by the American Lung Association, the American Thoracic Society, and CHEST.

Courtesy CHEST

Dr. LaBedz’s project, “Determinants of Medication Non-Adherence Among Adults With Chronic Obstructive Pulmonary Disease,” aims to use behavioral science theory to identify barriers and facilitators to COPD medication adherence.

Studies suggest racial minorities and individuals of low socioeconomic status (SES) are less likely to be adherent to COPD medications compared with White and high SES patients with COPD. Interventions designed to improve COPD medication adherence must address barriers to adherence experienced by these groups to avoid perpetuating disparities in adherence and downstream outcomes disparities.

For her project, Dr. LaBedz will focus on examining barriers and facilitators of COPD medication adherence, including social determinants of health and other structural barriers faced by these vulnerable populations. She will use the information gained from the qualitative study to design interventions that address the barriers to adherence faced by these groups.

Her long-term goal is to improve COPD medication adherence in vulnerable patients with COPD in order to improve the health status and reduce health disparities experienced by racial/ethnic minority and low SES patients with COPD.

In 2023, CHEST awarded $300,000 in clinical research and community impact grants to 15 individuals. Grant recipients are recognized for their scientifically meritorious achievements, with rigorous metrics to track their project’s progress, and have innovative, novel approaches to addressing their research topic.

CHEST grants have made a difference in patients’ lives by leading to breakthroughs in the treatment and/or management of chest diseases and patient care. This year’s grant-funded projects run the gamut of topics within chest medicine, ranging from lung cancer and COPD to tuberculosis and idiopathic pulmonary fibrosis.

Here’s a glimpse into two of this year’s grant winners and their projects.

For a full list of the 2023 grant winners, visit chestnet.org/grant-recipients.
 

Air pollution in sarcoidosis

This year, the John R. Addrizzo, MD, FCCP Research Grant in Sarcoidosis was awarded to Ali Mustafa, MD, of the Johns Hopkins Hospital in Baltimore, MD, for his project “Air Pollution in Sarcoidosis.”

Courtesy CHEST

The project’s aim is to investigate the feasibility of studying indoor and outdoor air pollution in patients with pulmonary sarcoidosis.

According to Dr. Mustafa’s application, pulmonary sarcoidosis is one of the most common interstitial lung diseases in the United States, and mortality due to sarcoidosis has risen by more than 3% in recent decades.

While the etiology of sarcoidosis remains elusive, evidence points toward a combination of genetic predisposition with external environmental triggers affecting disease onset. One small study of 16 individuals with fibrotic pulmonary sarcoidosis assessed the association between local levels of outdoor air pollutants to clinical outcomes. This study found that increased short-term exposure was associated with increased respiratory symptom severity and worse health-related quality of life.

Additionally, significant health disparities exist in sarcoidosis. Black individuals with sarcoidosis have worse pulmonary function, higher rates of multiorgan disease, and as much as a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Socioeconomic status and Black race have also been associated with increased exposure to air pollution and closer proximity to high toxic emission facilities, suggesting higher exposure to outdoor air pollution.

Racial disparities are present and particularly important in sarcoidosis. Black individuals are more likely to have more advanced disease at diagnosis, have a six-fold increase in hospitalization, and a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Little is known about the drivers of these disparities; however, environmental exposure has been implicated in sarcoidosis pathogenesis and incidence and may be an important contributor.

Dr. Mustafa’s preliminary work suggests disparities in exposure to air pollution among individuals with sarcoidosis may be contributing to inequities in clinical outcomes.
 

Determinants of medication non-adherence among adults with chronic obstructive pulmonary disease

The CHEST/ALA/ATS Respiratory Health Equity Research Award was given to Stephanie LaBedz, MD, of the University of Illinois Chicago. The Respiratory Health Equity Research Award is jointly supported by the American Lung Association, the American Thoracic Society, and CHEST.

Courtesy CHEST

Dr. LaBedz’s project, “Determinants of Medication Non-Adherence Among Adults With Chronic Obstructive Pulmonary Disease,” aims to use behavioral science theory to identify barriers and facilitators to COPD medication adherence.

Studies suggest racial minorities and individuals of low socioeconomic status (SES) are less likely to be adherent to COPD medications compared with White and high SES patients with COPD. Interventions designed to improve COPD medication adherence must address barriers to adherence experienced by these groups to avoid perpetuating disparities in adherence and downstream outcomes disparities.

For her project, Dr. LaBedz will focus on examining barriers and facilitators of COPD medication adherence, including social determinants of health and other structural barriers faced by these vulnerable populations. She will use the information gained from the qualitative study to design interventions that address the barriers to adherence faced by these groups.

Her long-term goal is to improve COPD medication adherence in vulnerable patients with COPD in order to improve the health status and reduce health disparities experienced by racial/ethnic minority and low SES patients with COPD.

In 2023, CHEST awarded $300,000 in clinical research and community impact grants to 15 individuals. Grant recipients are recognized for their scientifically meritorious achievements, with rigorous metrics to track their project’s progress, and have innovative, novel approaches to addressing their research topic.

CHEST grants have made a difference in patients’ lives by leading to breakthroughs in the treatment and/or management of chest diseases and patient care. This year’s grant-funded projects run the gamut of topics within chest medicine, ranging from lung cancer and COPD to tuberculosis and idiopathic pulmonary fibrosis.

Here’s a glimpse into two of this year’s grant winners and their projects.

For a full list of the 2023 grant winners, visit chestnet.org/grant-recipients.
 

Air pollution in sarcoidosis

This year, the John R. Addrizzo, MD, FCCP Research Grant in Sarcoidosis was awarded to Ali Mustafa, MD, of the Johns Hopkins Hospital in Baltimore, MD, for his project “Air Pollution in Sarcoidosis.”

Courtesy CHEST

The project’s aim is to investigate the feasibility of studying indoor and outdoor air pollution in patients with pulmonary sarcoidosis.

According to Dr. Mustafa’s application, pulmonary sarcoidosis is one of the most common interstitial lung diseases in the United States, and mortality due to sarcoidosis has risen by more than 3% in recent decades.

While the etiology of sarcoidosis remains elusive, evidence points toward a combination of genetic predisposition with external environmental triggers affecting disease onset. One small study of 16 individuals with fibrotic pulmonary sarcoidosis assessed the association between local levels of outdoor air pollutants to clinical outcomes. This study found that increased short-term exposure was associated with increased respiratory symptom severity and worse health-related quality of life.

Additionally, significant health disparities exist in sarcoidosis. Black individuals with sarcoidosis have worse pulmonary function, higher rates of multiorgan disease, and as much as a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Socioeconomic status and Black race have also been associated with increased exposure to air pollution and closer proximity to high toxic emission facilities, suggesting higher exposure to outdoor air pollution.

Racial disparities are present and particularly important in sarcoidosis. Black individuals are more likely to have more advanced disease at diagnosis, have a six-fold increase in hospitalization, and a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Little is known about the drivers of these disparities; however, environmental exposure has been implicated in sarcoidosis pathogenesis and incidence and may be an important contributor.

Dr. Mustafa’s preliminary work suggests disparities in exposure to air pollution among individuals with sarcoidosis may be contributing to inequities in clinical outcomes.
 

Determinants of medication non-adherence among adults with chronic obstructive pulmonary disease

The CHEST/ALA/ATS Respiratory Health Equity Research Award was given to Stephanie LaBedz, MD, of the University of Illinois Chicago. The Respiratory Health Equity Research Award is jointly supported by the American Lung Association, the American Thoracic Society, and CHEST.

Courtesy CHEST

Dr. LaBedz’s project, “Determinants of Medication Non-Adherence Among Adults With Chronic Obstructive Pulmonary Disease,” aims to use behavioral science theory to identify barriers and facilitators to COPD medication adherence.

Studies suggest racial minorities and individuals of low socioeconomic status (SES) are less likely to be adherent to COPD medications compared with White and high SES patients with COPD. Interventions designed to improve COPD medication adherence must address barriers to adherence experienced by these groups to avoid perpetuating disparities in adherence and downstream outcomes disparities.

For her project, Dr. LaBedz will focus on examining barriers and facilitators of COPD medication adherence, including social determinants of health and other structural barriers faced by these vulnerable populations. She will use the information gained from the qualitative study to design interventions that address the barriers to adherence faced by these groups.

Her long-term goal is to improve COPD medication adherence in vulnerable patients with COPD in order to improve the health status and reduce health disparities experienced by racial/ethnic minority and low SES patients with COPD.