Cutis

Purpose of Medical Standards in the US Military

Young adults in the United States traditionally have viewed military service as a viable career given its stable salary, career training, opportunities for progression, comprehensive health care coverage, tuition assistance, and other benefits; however, not all who desire to serve in the US Military are eligible to join. The Department of Defense (DoD) maintains fitness and health requirements (ie, accession standards), which are codified in DoD Instruction 6130.03, Volume 1,¹ that help ensure potential recruits can safely and fully perform their military duties. These accession standards change over time with the evolving understanding of diseases, medical advances, and accrued experience conducting operations in various environments. Accession standards serve to both preserve the health of the applicant and to ensure military mission success.

Dermatologic diseases have been prevalent in conflicts throughout US military history, representing a considerable source of morbidity to service members, inability of service members to remain on active duty, and costly use of resources. Hospitalizations of US Army soldiers for skin conditions led to the loss of more than 2 million days of service in World War I.² In World War II, skin diseases made up 25% and 75% of all temperate and tropical climate visits, respectively. Cutaneous diseases were the most frequently addressed category for US service members in Vietnam, representing more than 1.5 million visits and nearly 10% of disease-related evacuations.² Skin disease remains vital in 21st-century conflict. At a military hospital in Afghanistan, a review of 2421 outpatient medical records from June through July 2007 identified that dermatologic conditions resulted in 20% of military patient evaluations, 7% of nontraumatic hospital admissions, and 2% of total patient evacuations, at an estimated cost of $80,000 per evacuee.³ Between 2003 and 2006, 918 service members were evacuated for dermatologic reasons from combat zones in Afghanistan and Iraq.⁴

Unpredictable military environments may result in flares of a previously controlled condition, new skin diseases, or infection with endemic diseases. Mild cases of common conditions such as psoriasis or atopic dermatitis can present an unacceptable risk for severe flare in the setting of deployed military operations.⁵ Personnel may face extremes in temperature and humidity and work long hours under stress with limited or nonexistent opportunities for hygiene or self-care. Shared equipment and close living quarters permit the spread of infectious diseases and complicate the treatment of infestations. Military equipment and supplies such as gas masks and insect repellents can contain compounds that act as irritants or sensitizing agents, leading to contact dermatitis or urticaria. When dermatologic conditions develop or flare, further challenges are associated with evaluation and management. Health care resources vary considerably by location, with potential limitations in the availability of medications; supplies; refrigeration capabilities; and laboratory, microbiology, and histology services. Furthermore, dermatology referrals and services typically are not feasible in most deployed settings,³ though teledermatology has been available in the armed forces since 2002.

Deployed environments compound the consequences of dermatologic conditions and can impact the military mission. Military units deploy with the number of personnel needed to complete a mission and cannot replace members who become ill or injured or are medically evacuated. Something seemingly trivial, such as poor sleep due to pruritic dermatitis, may impair daytime alertness with potentially grave consequences in critical tasks such as guard or flying duties. The evacuation of a service member can compromise those left behind, and losing a service member with a unique required skill set may jeopardize a unit’s chance of success. Additionally, the impact of an evacuation itself extends beyond its direct cost and effects on the service member’s unit. The military does not maintain dedicated medical evacuation aircraft, instead repurposing aircraft in the deployed setting as needed.⁶ Evacuations can delay flights initially scheduled to move troops, ammunition, food, or other supplies and equipment elsewhere.

Disqualifying Skin and Soft Tissue Conditions

Current accession standards, which are listed in a publicly released document (DoD Instruction 6130.03, Volume 1), are updated based on medical, societal, and technical advances.¹ These standards differ from retention standards, which apply to members actively serving in the military. Although the DoD creates a minimum standard for the entire military, the US Army, Navy, and Air Force adopt these standards and adjust as required for each branch’s needs. An updated copy can be found on the DoD Directives Division website (https://www.esd.whs.mil/dd/) or Med Standards, a third-party mobile application (app) available as a free download for Apple iOS and Android devices (https://www.doc-apps.com/). The app also includes each military branch’s interpretation of the requirements.

The accession standards outline medical conditions that, if present or verified in an applicant’s medical history, preclude joining the military (eTable). These standards are organized into general systems, with a section dedicated to dermatologic (skin and soft tissue) conditions.¹ When a candidate has a potentially disqualifying medical condition identified by a screening questionnaire, medical record review, or military entrance physical examination, a referral for a determination of fitness for duty may be required. Medical accession standards are not solely driven by the diagnosis but also by the extent, nature, and timing of medical management. Procedures or prescriptions requiring frequent clinical monitoring, special handling, or severe dietary restrictions may deem the applicant’s condition potentially unsuitable. The need for immunosuppressive, anticoagulant, or refrigerated medications can impact a patient’s eligibility due to future deployment requirements and suitability for prolonged service, especially if treated for any substantial length of time. Chronic dermatologic conditions that are unresponsive to treatment, are susceptible to exacerbation despite treatment, require regular follow-up care, or interfere with the wear of military gear may be inconsistent with future deployment standards. Although the dermatologist should primarily focus on the skin and soft tissue conditions section of the accession standards, some dermatologic conditions can overlap with other medical systems and be located in a different section; for example, the section on lower extremity conditions includes a disqualifying condition of “[c]urrent ingrown toenails, if infected or symptomatic.”¹

Waiver Process

Medical conditions listed in the accession standards are deemed ineligible for military service; however, applicants can apply for a waiver.¹ The goal is for service members to be well controlled without treatment or with treatment widely available at military clinics and hospitals. Waivers ensure that service members are “[m]edically capable of performing duties without aggravating physical defects or medical conditions,” are “[m]edically adaptable to the military environment without geographical area limitations,” and are “free of medical conditions or physical defects that may reasonably be expected to require excessive time lost from duty for necessary treatment or hospitalization, or may result in separation from the Military Service for unfitness.”¹ The waiver process requires an evaluation from specialists with verification and documentation but does not guarantee approval. Although each military branch follows the same guidelines for disqualifying medical conditions, the evaluation and waiver process varies.

Considerations for Civilian Dermatologists

For several reasons, accurate and detailed medical documentation is essential for patients who pursue military service. Applicants must complete detailed health questionnaires and may need to provide copies of health records. The military electronic health record connects to large civilian health information exchanges and pulls primary documentation from records at many hospitals and clinics. Although applicants may request supportive clarification from their dermatologists, the military relies on primary medical documentation throughout the recruitment process. Accurate diagnostic codes reduce ambiguity, as accession standards are organized by diagnosis; for example, an unspecified history of psoriasis disqualifies applicants unless documentation supports nonrecurrent childhood guttate psoriasis.¹ Clear documentation of symptom severity, response to treatment, or resolution of a condition may elucidate suitability for service when matching a potentially disqualifying condition to a standard is not straightforward. Correct documentation will ensure that potential service members achieve a waiver when it is appropriate. If they are found to be unfit, it may save a patient from a bad outcome or a military unit from mission failure.

Dermatologists in the United States can reference current military medical accession standards to guide patients when needed. For example, a prospective recruit may be hesitant to start isotretinoin for severe nodulocystic acne, concerned that this medication may preclude them from joining the military. The current standards state that “[a]pplicants under treatment with systemic retinoids . . . do not meet the standard until 4 weeks after completing therapy,” while active severe nodulocystic acne is a disqualifying condition.¹ Therefore, the patient could proceed with isotretinoin therapy and, pending clinical response, meet accession standards as soon as 4 weeks after treatment. A clear understanding of the purpose of these standards, including protecting the applicant’s health and maximizing the chance of combat mission accomplishment, helps to reinforce responsibilities when caring for patients who wish to serve.

Purpose of Medical Standards in the US Military

Young adults in the United States traditionally have viewed military service as a viable career given its stable salary, career training, opportunities for progression, comprehensive health care coverage, tuition assistance, and other benefits; however, not all who desire to serve in the US Military are eligible to join. The Department of Defense (DoD) maintains fitness and health requirements (ie, accession standards), which are codified in DoD Instruction 6130.03, Volume 1,¹ that help ensure potential recruits can safely and fully perform their military duties. These accession standards change over time with the evolving understanding of diseases, medical advances, and accrued experience conducting operations in various environments. Accession standards serve to both preserve the health of the applicant and to ensure military mission success.

Dermatologic diseases have been prevalent in conflicts throughout US military history, representing a considerable source of morbidity to service members, inability of service members to remain on active duty, and costly use of resources. Hospitalizations of US Army soldiers for skin conditions led to the loss of more than 2 million days of service in World War I.² In World War II, skin diseases made up 25% and 75% of all temperate and tropical climate visits, respectively. Cutaneous diseases were the most frequently addressed category for US service members in Vietnam, representing more than 1.5 million visits and nearly 10% of disease-related evacuations.² Skin disease remains vital in 21st-century conflict. At a military hospital in Afghanistan, a review of 2421 outpatient medical records from June through July 2007 identified that dermatologic conditions resulted in 20% of military patient evaluations, 7% of nontraumatic hospital admissions, and 2% of total patient evacuations, at an estimated cost of $80,000 per evacuee.³ Between 2003 and 2006, 918 service members were evacuated for dermatologic reasons from combat zones in Afghanistan and Iraq.⁴

Unpredictable military environments may result in flares of a previously controlled condition, new skin diseases, or infection with endemic diseases. Mild cases of common conditions such as psoriasis or atopic dermatitis can present an unacceptable risk for severe flare in the setting of deployed military operations.⁵ Personnel may face extremes in temperature and humidity and work long hours under stress with limited or nonexistent opportunities for hygiene or self-care. Shared equipment and close living quarters permit the spread of infectious diseases and complicate the treatment of infestations. Military equipment and supplies such as gas masks and insect repellents can contain compounds that act as irritants or sensitizing agents, leading to contact dermatitis or urticaria. When dermatologic conditions develop or flare, further challenges are associated with evaluation and management. Health care resources vary considerably by location, with potential limitations in the availability of medications; supplies; refrigeration capabilities; and laboratory, microbiology, and histology services. Furthermore, dermatology referrals and services typically are not feasible in most deployed settings,³ though teledermatology has been available in the armed forces since 2002.

Deployed environments compound the consequences of dermatologic conditions and can impact the military mission. Military units deploy with the number of personnel needed to complete a mission and cannot replace members who become ill or injured or are medically evacuated. Something seemingly trivial, such as poor sleep due to pruritic dermatitis, may impair daytime alertness with potentially grave consequences in critical tasks such as guard or flying duties. The evacuation of a service member can compromise those left behind, and losing a service member with a unique required skill set may jeopardize a unit’s chance of success. Additionally, the impact of an evacuation itself extends beyond its direct cost and effects on the service member’s unit. The military does not maintain dedicated medical evacuation aircraft, instead repurposing aircraft in the deployed setting as needed.⁶ Evacuations can delay flights initially scheduled to move troops, ammunition, food, or other supplies and equipment elsewhere.

Disqualifying Skin and Soft Tissue Conditions

Current accession standards, which are listed in a publicly released document (DoD Instruction 6130.03, Volume 1), are updated based on medical, societal, and technical advances.¹ These standards differ from retention standards, which apply to members actively serving in the military. Although the DoD creates a minimum standard for the entire military, the US Army, Navy, and Air Force adopt these standards and adjust as required for each branch’s needs. An updated copy can be found on the DoD Directives Division website (https://www.esd.whs.mil/dd/) or Med Standards, a third-party mobile application (app) available as a free download for Apple iOS and Android devices (https://www.doc-apps.com/). The app also includes each military branch’s interpretation of the requirements.

The accession standards outline medical conditions that, if present or verified in an applicant’s medical history, preclude joining the military (eTable). These standards are organized into general systems, with a section dedicated to dermatologic (skin and soft tissue) conditions.¹ When a candidate has a potentially disqualifying medical condition identified by a screening questionnaire, medical record review, or military entrance physical examination, a referral for a determination of fitness for duty may be required. Medical accession standards are not solely driven by the diagnosis but also by the extent, nature, and timing of medical management. Procedures or prescriptions requiring frequent clinical monitoring, special handling, or severe dietary restrictions may deem the applicant’s condition potentially unsuitable. The need for immunosuppressive, anticoagulant, or refrigerated medications can impact a patient’s eligibility due to future deployment requirements and suitability for prolonged service, especially if treated for any substantial length of time. Chronic dermatologic conditions that are unresponsive to treatment, are susceptible to exacerbation despite treatment, require regular follow-up care, or interfere with the wear of military gear may be inconsistent with future deployment standards. Although the dermatologist should primarily focus on the skin and soft tissue conditions section of the accession standards, some dermatologic conditions can overlap with other medical systems and be located in a different section; for example, the section on lower extremity conditions includes a disqualifying condition of “[c]urrent ingrown toenails, if infected or symptomatic.”¹

Waiver Process

Medical conditions listed in the accession standards are deemed ineligible for military service; however, applicants can apply for a waiver.¹ The goal is for service members to be well controlled without treatment or with treatment widely available at military clinics and hospitals. Waivers ensure that service members are “[m]edically capable of performing duties without aggravating physical defects or medical conditions,” are “[m]edically adaptable to the military environment without geographical area limitations,” and are “free of medical conditions or physical defects that may reasonably be expected to require excessive time lost from duty for necessary treatment or hospitalization, or may result in separation from the Military Service for unfitness.”¹ The waiver process requires an evaluation from specialists with verification and documentation but does not guarantee approval. Although each military branch follows the same guidelines for disqualifying medical conditions, the evaluation and waiver process varies.

Considerations for Civilian Dermatologists

For several reasons, accurate and detailed medical documentation is essential for patients who pursue military service. Applicants must complete detailed health questionnaires and may need to provide copies of health records. The military electronic health record connects to large civilian health information exchanges and pulls primary documentation from records at many hospitals and clinics. Although applicants may request supportive clarification from their dermatologists, the military relies on primary medical documentation throughout the recruitment process. Accurate diagnostic codes reduce ambiguity, as accession standards are organized by diagnosis; for example, an unspecified history of psoriasis disqualifies applicants unless documentation supports nonrecurrent childhood guttate psoriasis.¹ Clear documentation of symptom severity, response to treatment, or resolution of a condition may elucidate suitability for service when matching a potentially disqualifying condition to a standard is not straightforward. Correct documentation will ensure that potential service members achieve a waiver when it is appropriate. If they are found to be unfit, it may save a patient from a bad outcome or a military unit from mission failure.

Dermatologists in the United States can reference current military medical accession standards to guide patients when needed. For example, a prospective recruit may be hesitant to start isotretinoin for severe nodulocystic acne, concerned that this medication may preclude them from joining the military. The current standards state that “[a]pplicants under treatment with systemic retinoids . . . do not meet the standard until 4 weeks after completing therapy,” while active severe nodulocystic acne is a disqualifying condition.¹ Therefore, the patient could proceed with isotretinoin therapy and, pending clinical response, meet accession standards as soon as 4 weeks after treatment. A clear understanding of the purpose of these standards, including protecting the applicant’s health and maximizing the chance of combat mission accomplishment, helps to reinforce responsibilities when caring for patients who wish to serve.

Purpose of Medical Standards in the US Military

Young adults in the United States traditionally have viewed military service as a viable career given its stable salary, career training, opportunities for progression, comprehensive health care coverage, tuition assistance, and other benefits; however, not all who desire to serve in the US Military are eligible to join. The Department of Defense (DoD) maintains fitness and health requirements (ie, accession standards), which are codified in DoD Instruction 6130.03, Volume 1,¹ that help ensure potential recruits can safely and fully perform their military duties. These accession standards change over time with the evolving understanding of diseases, medical advances, and accrued experience conducting operations in various environments. Accession standards serve to both preserve the health of the applicant and to ensure military mission success.

Dermatologic diseases have been prevalent in conflicts throughout US military history, representing a considerable source of morbidity to service members, inability of service members to remain on active duty, and costly use of resources. Hospitalizations of US Army soldiers for skin conditions led to the loss of more than 2 million days of service in World War I.² In World War II, skin diseases made up 25% and 75% of all temperate and tropical climate visits, respectively. Cutaneous diseases were the most frequently addressed category for US service members in Vietnam, representing more than 1.5 million visits and nearly 10% of disease-related evacuations.² Skin disease remains vital in 21st-century conflict. At a military hospital in Afghanistan, a review of 2421 outpatient medical records from June through July 2007 identified that dermatologic conditions resulted in 20% of military patient evaluations, 7% of nontraumatic hospital admissions, and 2% of total patient evacuations, at an estimated cost of $80,000 per evacuee.³ Between 2003 and 2006, 918 service members were evacuated for dermatologic reasons from combat zones in Afghanistan and Iraq.⁴

Unpredictable military environments may result in flares of a previously controlled condition, new skin diseases, or infection with endemic diseases. Mild cases of common conditions such as psoriasis or atopic dermatitis can present an unacceptable risk for severe flare in the setting of deployed military operations.⁵ Personnel may face extremes in temperature and humidity and work long hours under stress with limited or nonexistent opportunities for hygiene or self-care. Shared equipment and close living quarters permit the spread of infectious diseases and complicate the treatment of infestations. Military equipment and supplies such as gas masks and insect repellents can contain compounds that act as irritants or sensitizing agents, leading to contact dermatitis or urticaria. When dermatologic conditions develop or flare, further challenges are associated with evaluation and management. Health care resources vary considerably by location, with potential limitations in the availability of medications; supplies; refrigeration capabilities; and laboratory, microbiology, and histology services. Furthermore, dermatology referrals and services typically are not feasible in most deployed settings,³ though teledermatology has been available in the armed forces since 2002.

Deployed environments compound the consequences of dermatologic conditions and can impact the military mission. Military units deploy with the number of personnel needed to complete a mission and cannot replace members who become ill or injured or are medically evacuated. Something seemingly trivial, such as poor sleep due to pruritic dermatitis, may impair daytime alertness with potentially grave consequences in critical tasks such as guard or flying duties. The evacuation of a service member can compromise those left behind, and losing a service member with a unique required skill set may jeopardize a unit’s chance of success. Additionally, the impact of an evacuation itself extends beyond its direct cost and effects on the service member’s unit. The military does not maintain dedicated medical evacuation aircraft, instead repurposing aircraft in the deployed setting as needed.⁶ Evacuations can delay flights initially scheduled to move troops, ammunition, food, or other supplies and equipment elsewhere.

Disqualifying Skin and Soft Tissue Conditions

Current accession standards, which are listed in a publicly released document (DoD Instruction 6130.03, Volume 1), are updated based on medical, societal, and technical advances.¹ These standards differ from retention standards, which apply to members actively serving in the military. Although the DoD creates a minimum standard for the entire military, the US Army, Navy, and Air Force adopt these standards and adjust as required for each branch’s needs. An updated copy can be found on the DoD Directives Division website (https://www.esd.whs.mil/dd/) or Med Standards, a third-party mobile application (app) available as a free download for Apple iOS and Android devices (https://www.doc-apps.com/). The app also includes each military branch’s interpretation of the requirements.

The accession standards outline medical conditions that, if present or verified in an applicant’s medical history, preclude joining the military (eTable). These standards are organized into general systems, with a section dedicated to dermatologic (skin and soft tissue) conditions.¹ When a candidate has a potentially disqualifying medical condition identified by a screening questionnaire, medical record review, or military entrance physical examination, a referral for a determination of fitness for duty may be required. Medical accession standards are not solely driven by the diagnosis but also by the extent, nature, and timing of medical management. Procedures or prescriptions requiring frequent clinical monitoring, special handling, or severe dietary restrictions may deem the applicant’s condition potentially unsuitable. The need for immunosuppressive, anticoagulant, or refrigerated medications can impact a patient’s eligibility due to future deployment requirements and suitability for prolonged service, especially if treated for any substantial length of time. Chronic dermatologic conditions that are unresponsive to treatment, are susceptible to exacerbation despite treatment, require regular follow-up care, or interfere with the wear of military gear may be inconsistent with future deployment standards. Although the dermatologist should primarily focus on the skin and soft tissue conditions section of the accession standards, some dermatologic conditions can overlap with other medical systems and be located in a different section; for example, the section on lower extremity conditions includes a disqualifying condition of “[c]urrent ingrown toenails, if infected or symptomatic.”¹

Waiver Process

Medical conditions listed in the accession standards are deemed ineligible for military service; however, applicants can apply for a waiver.¹ The goal is for service members to be well controlled without treatment or with treatment widely available at military clinics and hospitals. Waivers ensure that service members are “[m]edically capable of performing duties without aggravating physical defects or medical conditions,” are “[m]edically adaptable to the military environment without geographical area limitations,” and are “free of medical conditions or physical defects that may reasonably be expected to require excessive time lost from duty for necessary treatment or hospitalization, or may result in separation from the Military Service for unfitness.”¹ The waiver process requires an evaluation from specialists with verification and documentation but does not guarantee approval. Although each military branch follows the same guidelines for disqualifying medical conditions, the evaluation and waiver process varies.

Considerations for Civilian Dermatologists

For several reasons, accurate and detailed medical documentation is essential for patients who pursue military service. Applicants must complete detailed health questionnaires and may need to provide copies of health records. The military electronic health record connects to large civilian health information exchanges and pulls primary documentation from records at many hospitals and clinics. Although applicants may request supportive clarification from their dermatologists, the military relies on primary medical documentation throughout the recruitment process. Accurate diagnostic codes reduce ambiguity, as accession standards are organized by diagnosis; for example, an unspecified history of psoriasis disqualifies applicants unless documentation supports nonrecurrent childhood guttate psoriasis.¹ Clear documentation of symptom severity, response to treatment, or resolution of a condition may elucidate suitability for service when matching a potentially disqualifying condition to a standard is not straightforward. Correct documentation will ensure that potential service members achieve a waiver when it is appropriate. If they are found to be unfit, it may save a patient from a bad outcome or a military unit from mission failure.

Dermatologists in the United States can reference current military medical accession standards to guide patients when needed. For example, a prospective recruit may be hesitant to start isotretinoin for severe nodulocystic acne, concerned that this medication may preclude them from joining the military. The current standards state that “[a]pplicants under treatment with systemic retinoids . . . do not meet the standard until 4 weeks after completing therapy,” while active severe nodulocystic acne is a disqualifying condition.¹ Therefore, the patient could proceed with isotretinoin therapy and, pending clinical response, meet accession standards as soon as 4 weeks after treatment. A clear understanding of the purpose of these standards, including protecting the applicant’s health and maximizing the chance of combat mission accomplishment, helps to reinforce responsibilities when caring for patients who wish to serve.

Practice Gap

Repair of a conchal defect requires careful consideration to achieve an optimal outcome. Reconstruction should resurface exposed cartilage, restore the natural projection of the auricle, and direct sound into the external auditory meatus. Patients also should be able to wear glasses and a hearing aid.

The reconstructive ladder for most conchal bowl defects includes secondary intention healing, full-thickness skin grafting (FTSG), and either a revolving-door flap or a flip-flop flap. Secondary intention and FTSG are appropriate for superficial defects, in which the loss of cartilage is not substantial.^1,2 Revolving-door and flip-flop flaps are single-stage retroauricular approaches used to repair relatively small defects of the conchal bowl.³ However, reconstructive options are limited for a large defect in which there is extensive loss of cartilage; 3-stage retroauricular approaches have been utilized. The anterior pedicled retroauricular flap is a 3-stage repair that can be utilized to reconstruct a through-and-through defect of the central ear:

• Stage 1: an anteriorly based retroauricular pedicle is incised, hinged over, and sutured to the medial aspect of the defect, resurfacing the posterior ear.
• Stage 2: the pedicle is severed and the flap is folded on itself to resurface the anterior ear.
• Stage 3: the folded edge is de-epithelialized and set into the lateral defect.⁴

The revolving-door flap also uses a 3-stage approach and is utilized for a full-thickness central auricular defect:

• Stage 1: a revolving-door flap is used to resurface the anterior ear.
• Stage 2: a cartilage graft provides structural support.
• Stage 3: division and inset with an FTSG is used to resurface the posterior ear.

The anterior pedicled retroauricular flap and revolving-door flap techniques are useful for defects when there is intact posterior auricular skin but not when there is extensive loss of cartilage. Other downsides to these 3-stage approaches are the time and multiple procedures required.⁵

We describe the technique of a retroauricular pull-through sandwich flap for repair of a large conchal bowl defect with extensive cartilage loss and intact posterior auricular skin.

Technique

A 62-year-old man presented for treatment of a 2.6×2.4-cm nodular and infiltrative basal cell carcinoma of the right conchal bowl. The tumor was cleared with 3 stages of Mohs micrographic surgery, resulting in a 5.5×4.2-cm defect with complete loss of cartilage throughout the concha, helical crus, and inner rim of the antihelix (Figure 1). A 2-stage repair was performed utilizing a cartilage graft and a pull-through retroauricular interpolation flap.

Stage 1—A cartilage graft was harvested from the left concha and sutured into the central defect for structural support (Figure 2). An incision was then made through the posterior auricular skin, just medial to the residual antihelical cartilage, and a retroauricular interpolation flap was pulled through this incision to resurface the lateral two-thirds of the conchal bowl defect. This created a “sandwich” of tissue, with the following layers (ordered from anterior to posterior): retroauricular interpolation flap, cartilage graft, and intact posterior auricular skin.

A preauricular banner transposition flap was used to repair the medial one-third of the conchal defect. A small area was left to heal by secondary intention (Figure 3).

Stage 2—The patient returned 3 weeks later for division and inset of the retroauricular interpolation flap. The pedicle of the flap was severed and its free edge was sutured into the lateral aspect of the defect. The posterior auricular incision that the flap had been pulled through in stage 1 of the repair was closed in a layered fashion, and the secondary defect of the postauricular scalp was left to heal by secondary intention (Figure 4).

Final Results—At follow-up 1 month later, the patient was noted to have good aesthetic and functional outcomes (Figure 5).

Practice Implications

The retroauricular pull-through sandwich flap combines a cartilage graft and a retroauricular interpolation flap pulled through an incision in the posterior auricular skin to resurface the anterior ear. This repair is most useful for a large conchal bowl defect in which there is extensive missing cartilage but intact posterior auricular skin.

The retroauricular scalp is a substantial tissue reservoir with robust vasculature; an interpolation flap from this area frequently is used to repair an extensive ear defect. The most common use of an interpolation flap is for a large helical defect; however, the flap also can be pulled through an incision in the posterior auricular skin to the front of the ear in a manner similar to revolving-door and flip-flop flaps, thus allowing for increased flap reach.

A cartilage graft provides structural support, helping to maintain auricular projection. The helical arcades provide a robust vascular supply and maintain viability of the helical rim tissue, despite the large aperture created for the pull-through flap.

We recommend this 2-stage repair for large conchal bowl defects with extensive cartilage loss and intact posterior auricular skin.

Practice Gap

Repair of a conchal defect requires careful consideration to achieve an optimal outcome. Reconstruction should resurface exposed cartilage, restore the natural projection of the auricle, and direct sound into the external auditory meatus. Patients also should be able to wear glasses and a hearing aid.

The reconstructive ladder for most conchal bowl defects includes secondary intention healing, full-thickness skin grafting (FTSG), and either a revolving-door flap or a flip-flop flap. Secondary intention and FTSG are appropriate for superficial defects, in which the loss of cartilage is not substantial.^1,2 Revolving-door and flip-flop flaps are single-stage retroauricular approaches used to repair relatively small defects of the conchal bowl.³ However, reconstructive options are limited for a large defect in which there is extensive loss of cartilage; 3-stage retroauricular approaches have been utilized. The anterior pedicled retroauricular flap is a 3-stage repair that can be utilized to reconstruct a through-and-through defect of the central ear:

• Stage 1: an anteriorly based retroauricular pedicle is incised, hinged over, and sutured to the medial aspect of the defect, resurfacing the posterior ear.
• Stage 2: the pedicle is severed and the flap is folded on itself to resurface the anterior ear.
• Stage 3: the folded edge is de-epithelialized and set into the lateral defect.⁴

The revolving-door flap also uses a 3-stage approach and is utilized for a full-thickness central auricular defect:

• Stage 1: a revolving-door flap is used to resurface the anterior ear.
• Stage 2: a cartilage graft provides structural support.
• Stage 3: division and inset with an FTSG is used to resurface the posterior ear.

The anterior pedicled retroauricular flap and revolving-door flap techniques are useful for defects when there is intact posterior auricular skin but not when there is extensive loss of cartilage. Other downsides to these 3-stage approaches are the time and multiple procedures required.⁵

We describe the technique of a retroauricular pull-through sandwich flap for repair of a large conchal bowl defect with extensive cartilage loss and intact posterior auricular skin.

Technique

A 62-year-old man presented for treatment of a 2.6×2.4-cm nodular and infiltrative basal cell carcinoma of the right conchal bowl. The tumor was cleared with 3 stages of Mohs micrographic surgery, resulting in a 5.5×4.2-cm defect with complete loss of cartilage throughout the concha, helical crus, and inner rim of the antihelix (Figure 1). A 2-stage repair was performed utilizing a cartilage graft and a pull-through retroauricular interpolation flap.

Stage 1—A cartilage graft was harvested from the left concha and sutured into the central defect for structural support (Figure 2). An incision was then made through the posterior auricular skin, just medial to the residual antihelical cartilage, and a retroauricular interpolation flap was pulled through this incision to resurface the lateral two-thirds of the conchal bowl defect. This created a “sandwich” of tissue, with the following layers (ordered from anterior to posterior): retroauricular interpolation flap, cartilage graft, and intact posterior auricular skin.

A preauricular banner transposition flap was used to repair the medial one-third of the conchal defect. A small area was left to heal by secondary intention (Figure 3).

Stage 2—The patient returned 3 weeks later for division and inset of the retroauricular interpolation flap. The pedicle of the flap was severed and its free edge was sutured into the lateral aspect of the defect. The posterior auricular incision that the flap had been pulled through in stage 1 of the repair was closed in a layered fashion, and the secondary defect of the postauricular scalp was left to heal by secondary intention (Figure 4).

Final Results—At follow-up 1 month later, the patient was noted to have good aesthetic and functional outcomes (Figure 5).

Practice Implications

The retroauricular pull-through sandwich flap combines a cartilage graft and a retroauricular interpolation flap pulled through an incision in the posterior auricular skin to resurface the anterior ear. This repair is most useful for a large conchal bowl defect in which there is extensive missing cartilage but intact posterior auricular skin.

The retroauricular scalp is a substantial tissue reservoir with robust vasculature; an interpolation flap from this area frequently is used to repair an extensive ear defect. The most common use of an interpolation flap is for a large helical defect; however, the flap also can be pulled through an incision in the posterior auricular skin to the front of the ear in a manner similar to revolving-door and flip-flop flaps, thus allowing for increased flap reach.

A cartilage graft provides structural support, helping to maintain auricular projection. The helical arcades provide a robust vascular supply and maintain viability of the helical rim tissue, despite the large aperture created for the pull-through flap.

We recommend this 2-stage repair for large conchal bowl defects with extensive cartilage loss and intact posterior auricular skin.

Practice Gap

Repair of a conchal defect requires careful consideration to achieve an optimal outcome. Reconstruction should resurface exposed cartilage, restore the natural projection of the auricle, and direct sound into the external auditory meatus. Patients also should be able to wear glasses and a hearing aid.

The reconstructive ladder for most conchal bowl defects includes secondary intention healing, full-thickness skin grafting (FTSG), and either a revolving-door flap or a flip-flop flap. Secondary intention and FTSG are appropriate for superficial defects, in which the loss of cartilage is not substantial.^1,2 Revolving-door and flip-flop flaps are single-stage retroauricular approaches used to repair relatively small defects of the conchal bowl.³ However, reconstructive options are limited for a large defect in which there is extensive loss of cartilage; 3-stage retroauricular approaches have been utilized. The anterior pedicled retroauricular flap is a 3-stage repair that can be utilized to reconstruct a through-and-through defect of the central ear:

• Stage 1: an anteriorly based retroauricular pedicle is incised, hinged over, and sutured to the medial aspect of the defect, resurfacing the posterior ear.
• Stage 2: the pedicle is severed and the flap is folded on itself to resurface the anterior ear.
• Stage 3: the folded edge is de-epithelialized and set into the lateral defect.⁴

The revolving-door flap also uses a 3-stage approach and is utilized for a full-thickness central auricular defect:

• Stage 1: a revolving-door flap is used to resurface the anterior ear.
• Stage 2: a cartilage graft provides structural support.
• Stage 3: division and inset with an FTSG is used to resurface the posterior ear.

The anterior pedicled retroauricular flap and revolving-door flap techniques are useful for defects when there is intact posterior auricular skin but not when there is extensive loss of cartilage. Other downsides to these 3-stage approaches are the time and multiple procedures required.⁵

We describe the technique of a retroauricular pull-through sandwich flap for repair of a large conchal bowl defect with extensive cartilage loss and intact posterior auricular skin.

Technique

A 62-year-old man presented for treatment of a 2.6×2.4-cm nodular and infiltrative basal cell carcinoma of the right conchal bowl. The tumor was cleared with 3 stages of Mohs micrographic surgery, resulting in a 5.5×4.2-cm defect with complete loss of cartilage throughout the concha, helical crus, and inner rim of the antihelix (Figure 1). A 2-stage repair was performed utilizing a cartilage graft and a pull-through retroauricular interpolation flap.

Stage 1—A cartilage graft was harvested from the left concha and sutured into the central defect for structural support (Figure 2). An incision was then made through the posterior auricular skin, just medial to the residual antihelical cartilage, and a retroauricular interpolation flap was pulled through this incision to resurface the lateral two-thirds of the conchal bowl defect. This created a “sandwich” of tissue, with the following layers (ordered from anterior to posterior): retroauricular interpolation flap, cartilage graft, and intact posterior auricular skin.

A preauricular banner transposition flap was used to repair the medial one-third of the conchal defect. A small area was left to heal by secondary intention (Figure 3).

Stage 2—The patient returned 3 weeks later for division and inset of the retroauricular interpolation flap. The pedicle of the flap was severed and its free edge was sutured into the lateral aspect of the defect. The posterior auricular incision that the flap had been pulled through in stage 1 of the repair was closed in a layered fashion, and the secondary defect of the postauricular scalp was left to heal by secondary intention (Figure 4).

Final Results—At follow-up 1 month later, the patient was noted to have good aesthetic and functional outcomes (Figure 5).

Practice Implications

The retroauricular pull-through sandwich flap combines a cartilage graft and a retroauricular interpolation flap pulled through an incision in the posterior auricular skin to resurface the anterior ear. This repair is most useful for a large conchal bowl defect in which there is extensive missing cartilage but intact posterior auricular skin.

The retroauricular scalp is a substantial tissue reservoir with robust vasculature; an interpolation flap from this area frequently is used to repair an extensive ear defect. The most common use of an interpolation flap is for a large helical defect; however, the flap also can be pulled through an incision in the posterior auricular skin to the front of the ear in a manner similar to revolving-door and flip-flop flaps, thus allowing for increased flap reach.

A cartilage graft provides structural support, helping to maintain auricular projection. The helical arcades provide a robust vascular supply and maintain viability of the helical rim tissue, despite the large aperture created for the pull-through flap.

We recommend this 2-stage repair for large conchal bowl defects with extensive cartilage loss and intact posterior auricular skin.

Isotretinoin is used in the treatment of nodulocystic and severe papulopustular acne. During the treatment period, laboratory monitoring is recommended to identify the risk for complications such as hepatotoxicity, teratogenicity, rhabdomyolysis, hyperlipidemia, and pancreatitis.¹ There is a lack of consensus of the frequency of follow-up of laboratory parameters during isotretinoin treatment. This study evaluated the changes in laboratory parameters used in daily practice for patients with acne who were treated with isotretinoin to determine the optimum test repetition frequency.

Materials and Methods

We conducted a retrospective study of data from patients who received oral isotretinoin therapy for acne between January 2021 and July 2022 via the electronic medical records at Konya Numune Hospital and Konya Private Medova Hospital (both in Konya, Turkey). Patients who received an oral isotretinoin total cumulative dose greater than 120 mg/kg were included in the study. Patient demographic data; cumulative isotretinoin doses; and alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), creatinine kinase (CK), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels during treatment were recorded. Baseline laboratory levels of those parameters were compared with levels of the same parameters from the second and fourth months of treatment. Comparisons for all parameters were made between the second- and fourth-month levels. Reference ranges are shown in Table 1. Abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grading system.² This study was approved by the Karatay University (Konya, Turkey) ethical committee.

Statistical Analysis—The descriptive statistics of the measurements were presented as means, standard deviations, or medians (first and third quartiles). With respect to the normal distribution, the consistency of the measurements was evaluated with the Kolmogorov-Smirnov test, and small deviations from the normal distribution were observed. Changes in laboratory measurements were evaluated with simple repeated-measures analysis of variance, and changes that differed significantly were determined by a Holm-Sidak post hoc test. Relationships between total cumulative doses and laboratory measurements at second visits were evaluated by the Pearson correlation analysis. The statistical significance level was P<.05. SPSS Statistics 23 (IBM) was used in the calculations.

Results

Consecutive Data at Baseline and Follow-up—A total of 415 patients with a mean age (SD) of 21.49 (7.25) years (range, 12–53 years) were included in our study. The mean total cumulative dose (SD) of the patients was 7267.27 (1878.4) mg. The consecutive data of the means of the laboratory parameters are shown in Table 1 and Figure 1. There was no significant change in the ALT levels between baseline and the fourth month as well as between the second- and fourth-month assessments (both P=.311). When comparing the differences among AST, GGT, and LDL-C measurements, the levels increased significantly between baseline and the second month and between baseline and the fourth month (all P<.001). There was no significant difference in CK levels at all assessments (all P=.304). When the differences between TG measurements were compared, the changes between baseline and the second month (P<.001), baseline and the fourth month (P<.001), and the second and fourth months (P=.013) were significant (Figure 1).

Abnormal Laboratory Measurements—The distribution of abnormal laboratory measurements during treatment is shown in Table 2 and Figure 2. Grade 3 or higher elevations of liver transaminases (ALT, AST) and GGT were observed in fewer than 2% of patients during treatment compared with baseline (grade 3 elevations of ALT and AST together in 2 patients; grade 4 AST elevation in 1 patient; grade 3 elevations of ALT, AST, and GGT combined in 1 patient; isolated grade 3 GGT elevation in 1 patient). All of the patients who developed grade 3 liver transaminases and isolated grade 3 GGT elevation had improved values when these were rechecked within 2 weeks.

In the patient who developed hepatotoxicity in the second month, the ALT level rose from a baseline of 19 U/L to 169 U/L, the AST level from a baseline of 19 U/L to 61 U/L, and the GGT level from a baseline of 24 U/L to 124 U/L. The patient was asymptomatic. Liver function test levels returned to reference range 4 weeks after discontinuation of therapy. Hepatotoxicity did not recur after treatment was re-administered.

The patient who developed grade 4 AST elevation (364 U/L) experienced fatigue and myalgia. He had done vigorous exercise up to 2 days before the test and also had a grade 4 CK elevation (12,310 U/L). He was thought to have isotretinoin-related rhabdomyolysis. His treatment was discontinued, and he was advised to hydrate and rest. Treatment was re-started after 2 weeks. With frequent laboratory monitoring and avoidance of vigorous physical activity, the patient completed the remaining course of isotretinoin without any laboratory abnormalities or symptoms.

Creatinine kinase abnormalities in the second and fourth months compared with baseline were not statistically significant. The patients with grade 3 or higher CK elevations, except for the case with rhabdomyolysis, had no clinical signs or other characteristic laboratory findings of rhabdomyolysis.

Hypercholesterolemia (LDL-C ≥130 mg/dL) occurred most frequently, with a maximum of 280 mg/dL in 1 patient (in the fourth month) and less than 250 mg/dL in all other patients. Hypercholesterolemia occurred in 183 (44.1%) patients in the second month and in 166 (40.0%) patients in the fourth month. However, baseline abnormalities also were frequent (86 [20.7%]), and hypercholesterolemia persisted in the second and fourth months in all of these patients.

It was observed that the patients with TG abnormalities increased continuously in the second (99 [23.9%]) and fourth (113 [27.2%]) months compared with baseline (49 [11.8%]). Grade 3 TG elevations were observed in 2.2% of patients (n=9; 5 patients in the second month, 4 patients in the fourth month) during treatment compared with baseline, and all patients had grade 1 or 2 hypertriglyceridemia at baseline. Of the patients with grade 3 TG elevation, 3 patients in the second month and 2 patients in the fourth month were obese at baseline. No grade 4 TG elevations were observed. Complications related to hyperlipidemia, such as pancreatitis, were observed in 1 patient. No patient terminated treatment because of lipid abnormalities. The treatment of our patients with major hypercholesterolemia and/or grade 3 hypertriglyceridemia was interrupted. The hyperlipidemia of these patients was controlled by a low-fat diet and a short-term dose reduction.

Relationship Between Total Cumulative Dose and Laboratory Parameters—The relationships between the total cumulative dose and changes up to the fourth month are presented in Table 3. As the total dose increased, the changes in TG and LDL-C levels significantly increased in the fourth month (both P=.001). However, the degree of these relationships was weak. No significant correlation was found between the periodic changes of other laboratory parameters and the total dose.

Comment

The parameters followed in our study show that TG levels tend to increase continuously from baseline during isotretinoin treatment, while ALT, AST, GGT, and LDL-C levels increase in the second month and decrease at 4 months. Although this same trend occurs with CK levels, the change was not statistically significant. The most common laboratory abnormality in our study was hyperlipidemia. Levels of LDL-C and TG were both found to be statistically elevated in the second and fourth months of treatment compared with baseline. Parthasarathy et al³ reported that obesity had an important role in the increase of lipid levels in patients using isotretinoin at baseline. In our study, 5 of 9 patients (55.6%) with grade 3 TG elevation were obese, which supports the theory that obesity plays an important role in the increase in lipid levels. Up-to-date laboratory follow-up of lipids suggests that there is no need to follow up serum lipids after the second month of treatment. Patients with risk factors for hyperlipidemia, such as abdominal obesity and familial hyperlipidemia, do not require further follow-up if there is no increase in serum lipids in the first month of treatment.¹ The presence of grade 1 or 2 hypertriglyceridemia at baseline in all our patients with grade 3 TG elevation may suggest that periodic laboratory follow-up during isotretinoin treatment is necessary to detect patients with grade 3 and higher TG levels.

The lack of knowledge of other risk factors (eg, familial hyperlipidemia, insulin resistance) for hyperlipidemia in all patients at baseline may be a limitation of our study. Although hypercholesterolemia persisted in the follow-up of our patients with initial LDL-C abnormalities, hypercholesterolemia over 250 mg/dL was very rare (1 patient). Possible complications associated with serum lipid abnormalities are pancreatitis and metabolic syndrome.⁴ In our study, none of the patients with lipid abnormalities had any relevant clinical sequelae. The dose-dependent elevation of the changes in LDL-C and TG (Table 3) may be important to predict the significant elevation of lipids and the associated complications in patients with a high total cumulative dose target that may require a long treatment duration. However, considering the short follow-up periods in our patients, the absence of clinical sequelae may be misleading. There are differences in recommendations between the US and European guidelines for isotretinoin dosage. Although the US guidelines recommend a total cumulative dose target, the European guidelines recommend low-dose isotretinoin daily for at least 6 months instead of a cumulative dose.^5,6 The relationship between change in lipids and total cumulative dose in our study may not be similar in patients treated with the dosing regimen recommended by the European guidelines, as our patients received a total cumulative dose instead of a daily low-dose isotretinoin regimen, unlike the European guidelines.⁵

Most liver transaminase abnormalities were detected in the second month. Abnormalities in GGT were seen in the second month and remained elevated at the next follow-up. However, clinically important grade 3 transaminase and GGT elevations were rare. It has been reported that GGT levels are more specific than transaminases in measuring hepatotoxicity.⁷ The fact that our patient with hepatotoxicity had a grade 3 GGT elevation in addition to grade 3 transaminase elevations supports that GGT elevation is more specific than transaminase levels in measuring hepatotoxicity. When these parameters were rechecked in our patients with grade 3 transaminase elevations, except in the case of hepatotoxicity, transaminase elevations did not recur, and GGT elevations did not accompany elevated transaminases, which suggested that transaminases may be elevated due to an extrahepatic origin (eg, hemolysis, exercise).

Rhabdomyolysis secondary to isotretinoin is rare in the literature of acne studies. In addition to clinical findings such as myalgia and fatigue, increased CK and abnormal liver enzymes, specifically AST, suggest the development of rhabdomyolysis.⁸ Our patient who developed rhabdomyolysis also had a recent history of vigorous exercise, grade 4 CK, and AST elevations. Other patients with isolated grade 3 CK elevations were informed about possible clinical signs of rhabdomyolysis, and they were able to complete their courses without any incident. According to a study by Landau et al,⁹ isotretinoin-associated hyperCKemia has been reported as benign. Similarly, our study found that isolated CK elevation during isotretinoin treatment may be misleading as a sign of rhabdomyolysis. Instead, CK monitoring may be more appropriate and cost-effective in patients with suspected clinical signs of rhabdomyolysis or in those with major elevations in transaminases, especially AST.

Conclusion

According to our study, hyperlipidemia was the most common complication in acne patients using isotretinoin. It may be appropriate to monitor the TG level at 2-month intervals in patients with grade 1 or 2 TG elevation at baseline to detect the possible risk for developing grade 3 hyperlipidemia. Periodic monitoring of LDL-C and TG levels may be appropriate, especially in patients who require a high total cumulative dose of isotretinoin. Clinically important liver enzyme abnormalities were rare in our study. Our findings support the idea that routine monthly monitoring of normal laboratory parameters is unnecessary and wasteful. Additionally, periodic monitoring of abnormal laboratory parameters should be considered on an individual basis.

Isotretinoin is used in the treatment of nodulocystic and severe papulopustular acne. During the treatment period, laboratory monitoring is recommended to identify the risk for complications such as hepatotoxicity, teratogenicity, rhabdomyolysis, hyperlipidemia, and pancreatitis.¹ There is a lack of consensus of the frequency of follow-up of laboratory parameters during isotretinoin treatment. This study evaluated the changes in laboratory parameters used in daily practice for patients with acne who were treated with isotretinoin to determine the optimum test repetition frequency.

Materials and Methods

We conducted a retrospective study of data from patients who received oral isotretinoin therapy for acne between January 2021 and July 2022 via the electronic medical records at Konya Numune Hospital and Konya Private Medova Hospital (both in Konya, Turkey). Patients who received an oral isotretinoin total cumulative dose greater than 120 mg/kg were included in the study. Patient demographic data; cumulative isotretinoin doses; and alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), creatinine kinase (CK), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels during treatment were recorded. Baseline laboratory levels of those parameters were compared with levels of the same parameters from the second and fourth months of treatment. Comparisons for all parameters were made between the second- and fourth-month levels. Reference ranges are shown in Table 1. Abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grading system.² This study was approved by the Karatay University (Konya, Turkey) ethical committee.

Statistical Analysis—The descriptive statistics of the measurements were presented as means, standard deviations, or medians (first and third quartiles). With respect to the normal distribution, the consistency of the measurements was evaluated with the Kolmogorov-Smirnov test, and small deviations from the normal distribution were observed. Changes in laboratory measurements were evaluated with simple repeated-measures analysis of variance, and changes that differed significantly were determined by a Holm-Sidak post hoc test. Relationships between total cumulative doses and laboratory measurements at second visits were evaluated by the Pearson correlation analysis. The statistical significance level was P<.05. SPSS Statistics 23 (IBM) was used in the calculations.

Results

Consecutive Data at Baseline and Follow-up—A total of 415 patients with a mean age (SD) of 21.49 (7.25) years (range, 12–53 years) were included in our study. The mean total cumulative dose (SD) of the patients was 7267.27 (1878.4) mg. The consecutive data of the means of the laboratory parameters are shown in Table 1 and Figure 1. There was no significant change in the ALT levels between baseline and the fourth month as well as between the second- and fourth-month assessments (both P=.311). When comparing the differences among AST, GGT, and LDL-C measurements, the levels increased significantly between baseline and the second month and between baseline and the fourth month (all P<.001). There was no significant difference in CK levels at all assessments (all P=.304). When the differences between TG measurements were compared, the changes between baseline and the second month (P<.001), baseline and the fourth month (P<.001), and the second and fourth months (P=.013) were significant (Figure 1).

Abnormal Laboratory Measurements—The distribution of abnormal laboratory measurements during treatment is shown in Table 2 and Figure 2. Grade 3 or higher elevations of liver transaminases (ALT, AST) and GGT were observed in fewer than 2% of patients during treatment compared with baseline (grade 3 elevations of ALT and AST together in 2 patients; grade 4 AST elevation in 1 patient; grade 3 elevations of ALT, AST, and GGT combined in 1 patient; isolated grade 3 GGT elevation in 1 patient). All of the patients who developed grade 3 liver transaminases and isolated grade 3 GGT elevation had improved values when these were rechecked within 2 weeks.

In the patient who developed hepatotoxicity in the second month, the ALT level rose from a baseline of 19 U/L to 169 U/L, the AST level from a baseline of 19 U/L to 61 U/L, and the GGT level from a baseline of 24 U/L to 124 U/L. The patient was asymptomatic. Liver function test levels returned to reference range 4 weeks after discontinuation of therapy. Hepatotoxicity did not recur after treatment was re-administered.

The patient who developed grade 4 AST elevation (364 U/L) experienced fatigue and myalgia. He had done vigorous exercise up to 2 days before the test and also had a grade 4 CK elevation (12,310 U/L). He was thought to have isotretinoin-related rhabdomyolysis. His treatment was discontinued, and he was advised to hydrate and rest. Treatment was re-started after 2 weeks. With frequent laboratory monitoring and avoidance of vigorous physical activity, the patient completed the remaining course of isotretinoin without any laboratory abnormalities or symptoms.

Creatinine kinase abnormalities in the second and fourth months compared with baseline were not statistically significant. The patients with grade 3 or higher CK elevations, except for the case with rhabdomyolysis, had no clinical signs or other characteristic laboratory findings of rhabdomyolysis.

Hypercholesterolemia (LDL-C ≥130 mg/dL) occurred most frequently, with a maximum of 280 mg/dL in 1 patient (in the fourth month) and less than 250 mg/dL in all other patients. Hypercholesterolemia occurred in 183 (44.1%) patients in the second month and in 166 (40.0%) patients in the fourth month. However, baseline abnormalities also were frequent (86 [20.7%]), and hypercholesterolemia persisted in the second and fourth months in all of these patients.

It was observed that the patients with TG abnormalities increased continuously in the second (99 [23.9%]) and fourth (113 [27.2%]) months compared with baseline (49 [11.8%]). Grade 3 TG elevations were observed in 2.2% of patients (n=9; 5 patients in the second month, 4 patients in the fourth month) during treatment compared with baseline, and all patients had grade 1 or 2 hypertriglyceridemia at baseline. Of the patients with grade 3 TG elevation, 3 patients in the second month and 2 patients in the fourth month were obese at baseline. No grade 4 TG elevations were observed. Complications related to hyperlipidemia, such as pancreatitis, were observed in 1 patient. No patient terminated treatment because of lipid abnormalities. The treatment of our patients with major hypercholesterolemia and/or grade 3 hypertriglyceridemia was interrupted. The hyperlipidemia of these patients was controlled by a low-fat diet and a short-term dose reduction.

Relationship Between Total Cumulative Dose and Laboratory Parameters—The relationships between the total cumulative dose and changes up to the fourth month are presented in Table 3. As the total dose increased, the changes in TG and LDL-C levels significantly increased in the fourth month (both P=.001). However, the degree of these relationships was weak. No significant correlation was found between the periodic changes of other laboratory parameters and the total dose.

Comment

The parameters followed in our study show that TG levels tend to increase continuously from baseline during isotretinoin treatment, while ALT, AST, GGT, and LDL-C levels increase in the second month and decrease at 4 months. Although this same trend occurs with CK levels, the change was not statistically significant. The most common laboratory abnormality in our study was hyperlipidemia. Levels of LDL-C and TG were both found to be statistically elevated in the second and fourth months of treatment compared with baseline. Parthasarathy et al³ reported that obesity had an important role in the increase of lipid levels in patients using isotretinoin at baseline. In our study, 5 of 9 patients (55.6%) with grade 3 TG elevation were obese, which supports the theory that obesity plays an important role in the increase in lipid levels. Up-to-date laboratory follow-up of lipids suggests that there is no need to follow up serum lipids after the second month of treatment. Patients with risk factors for hyperlipidemia, such as abdominal obesity and familial hyperlipidemia, do not require further follow-up if there is no increase in serum lipids in the first month of treatment.¹ The presence of grade 1 or 2 hypertriglyceridemia at baseline in all our patients with grade 3 TG elevation may suggest that periodic laboratory follow-up during isotretinoin treatment is necessary to detect patients with grade 3 and higher TG levels.

The lack of knowledge of other risk factors (eg, familial hyperlipidemia, insulin resistance) for hyperlipidemia in all patients at baseline may be a limitation of our study. Although hypercholesterolemia persisted in the follow-up of our patients with initial LDL-C abnormalities, hypercholesterolemia over 250 mg/dL was very rare (1 patient). Possible complications associated with serum lipid abnormalities are pancreatitis and metabolic syndrome.⁴ In our study, none of the patients with lipid abnormalities had any relevant clinical sequelae. The dose-dependent elevation of the changes in LDL-C and TG (Table 3) may be important to predict the significant elevation of lipids and the associated complications in patients with a high total cumulative dose target that may require a long treatment duration. However, considering the short follow-up periods in our patients, the absence of clinical sequelae may be misleading. There are differences in recommendations between the US and European guidelines for isotretinoin dosage. Although the US guidelines recommend a total cumulative dose target, the European guidelines recommend low-dose isotretinoin daily for at least 6 months instead of a cumulative dose.^5,6 The relationship between change in lipids and total cumulative dose in our study may not be similar in patients treated with the dosing regimen recommended by the European guidelines, as our patients received a total cumulative dose instead of a daily low-dose isotretinoin regimen, unlike the European guidelines.⁵

Most liver transaminase abnormalities were detected in the second month. Abnormalities in GGT were seen in the second month and remained elevated at the next follow-up. However, clinically important grade 3 transaminase and GGT elevations were rare. It has been reported that GGT levels are more specific than transaminases in measuring hepatotoxicity.⁷ The fact that our patient with hepatotoxicity had a grade 3 GGT elevation in addition to grade 3 transaminase elevations supports that GGT elevation is more specific than transaminase levels in measuring hepatotoxicity. When these parameters were rechecked in our patients with grade 3 transaminase elevations, except in the case of hepatotoxicity, transaminase elevations did not recur, and GGT elevations did not accompany elevated transaminases, which suggested that transaminases may be elevated due to an extrahepatic origin (eg, hemolysis, exercise).

Rhabdomyolysis secondary to isotretinoin is rare in the literature of acne studies. In addition to clinical findings such as myalgia and fatigue, increased CK and abnormal liver enzymes, specifically AST, suggest the development of rhabdomyolysis.⁸ Our patient who developed rhabdomyolysis also had a recent history of vigorous exercise, grade 4 CK, and AST elevations. Other patients with isolated grade 3 CK elevations were informed about possible clinical signs of rhabdomyolysis, and they were able to complete their courses without any incident. According to a study by Landau et al,⁹ isotretinoin-associated hyperCKemia has been reported as benign. Similarly, our study found that isolated CK elevation during isotretinoin treatment may be misleading as a sign of rhabdomyolysis. Instead, CK monitoring may be more appropriate and cost-effective in patients with suspected clinical signs of rhabdomyolysis or in those with major elevations in transaminases, especially AST.

Conclusion

According to our study, hyperlipidemia was the most common complication in acne patients using isotretinoin. It may be appropriate to monitor the TG level at 2-month intervals in patients with grade 1 or 2 TG elevation at baseline to detect the possible risk for developing grade 3 hyperlipidemia. Periodic monitoring of LDL-C and TG levels may be appropriate, especially in patients who require a high total cumulative dose of isotretinoin. Clinically important liver enzyme abnormalities were rare in our study. Our findings support the idea that routine monthly monitoring of normal laboratory parameters is unnecessary and wasteful. Additionally, periodic monitoring of abnormal laboratory parameters should be considered on an individual basis.

Isotretinoin is used in the treatment of nodulocystic and severe papulopustular acne. During the treatment period, laboratory monitoring is recommended to identify the risk for complications such as hepatotoxicity, teratogenicity, rhabdomyolysis, hyperlipidemia, and pancreatitis.¹ There is a lack of consensus of the frequency of follow-up of laboratory parameters during isotretinoin treatment. This study evaluated the changes in laboratory parameters used in daily practice for patients with acne who were treated with isotretinoin to determine the optimum test repetition frequency.

Materials and Methods

We conducted a retrospective study of data from patients who received oral isotretinoin therapy for acne between January 2021 and July 2022 via the electronic medical records at Konya Numune Hospital and Konya Private Medova Hospital (both in Konya, Turkey). Patients who received an oral isotretinoin total cumulative dose greater than 120 mg/kg were included in the study. Patient demographic data; cumulative isotretinoin doses; and alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), creatinine kinase (CK), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels during treatment were recorded. Baseline laboratory levels of those parameters were compared with levels of the same parameters from the second and fourth months of treatment. Comparisons for all parameters were made between the second- and fourth-month levels. Reference ranges are shown in Table 1. Abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grading system.² This study was approved by the Karatay University (Konya, Turkey) ethical committee.

Statistical Analysis—The descriptive statistics of the measurements were presented as means, standard deviations, or medians (first and third quartiles). With respect to the normal distribution, the consistency of the measurements was evaluated with the Kolmogorov-Smirnov test, and small deviations from the normal distribution were observed. Changes in laboratory measurements were evaluated with simple repeated-measures analysis of variance, and changes that differed significantly were determined by a Holm-Sidak post hoc test. Relationships between total cumulative doses and laboratory measurements at second visits were evaluated by the Pearson correlation analysis. The statistical significance level was P<.05. SPSS Statistics 23 (IBM) was used in the calculations.

Results

Consecutive Data at Baseline and Follow-up—A total of 415 patients with a mean age (SD) of 21.49 (7.25) years (range, 12–53 years) were included in our study. The mean total cumulative dose (SD) of the patients was 7267.27 (1878.4) mg. The consecutive data of the means of the laboratory parameters are shown in Table 1 and Figure 1. There was no significant change in the ALT levels between baseline and the fourth month as well as between the second- and fourth-month assessments (both P=.311). When comparing the differences among AST, GGT, and LDL-C measurements, the levels increased significantly between baseline and the second month and between baseline and the fourth month (all P<.001). There was no significant difference in CK levels at all assessments (all P=.304). When the differences between TG measurements were compared, the changes between baseline and the second month (P<.001), baseline and the fourth month (P<.001), and the second and fourth months (P=.013) were significant (Figure 1).

Abnormal Laboratory Measurements—The distribution of abnormal laboratory measurements during treatment is shown in Table 2 and Figure 2. Grade 3 or higher elevations of liver transaminases (ALT, AST) and GGT were observed in fewer than 2% of patients during treatment compared with baseline (grade 3 elevations of ALT and AST together in 2 patients; grade 4 AST elevation in 1 patient; grade 3 elevations of ALT, AST, and GGT combined in 1 patient; isolated grade 3 GGT elevation in 1 patient). All of the patients who developed grade 3 liver transaminases and isolated grade 3 GGT elevation had improved values when these were rechecked within 2 weeks.

In the patient who developed hepatotoxicity in the second month, the ALT level rose from a baseline of 19 U/L to 169 U/L, the AST level from a baseline of 19 U/L to 61 U/L, and the GGT level from a baseline of 24 U/L to 124 U/L. The patient was asymptomatic. Liver function test levels returned to reference range 4 weeks after discontinuation of therapy. Hepatotoxicity did not recur after treatment was re-administered.

The patient who developed grade 4 AST elevation (364 U/L) experienced fatigue and myalgia. He had done vigorous exercise up to 2 days before the test and also had a grade 4 CK elevation (12,310 U/L). He was thought to have isotretinoin-related rhabdomyolysis. His treatment was discontinued, and he was advised to hydrate and rest. Treatment was re-started after 2 weeks. With frequent laboratory monitoring and avoidance of vigorous physical activity, the patient completed the remaining course of isotretinoin without any laboratory abnormalities or symptoms.

Creatinine kinase abnormalities in the second and fourth months compared with baseline were not statistically significant. The patients with grade 3 or higher CK elevations, except for the case with rhabdomyolysis, had no clinical signs or other characteristic laboratory findings of rhabdomyolysis.

Hypercholesterolemia (LDL-C ≥130 mg/dL) occurred most frequently, with a maximum of 280 mg/dL in 1 patient (in the fourth month) and less than 250 mg/dL in all other patients. Hypercholesterolemia occurred in 183 (44.1%) patients in the second month and in 166 (40.0%) patients in the fourth month. However, baseline abnormalities also were frequent (86 [20.7%]), and hypercholesterolemia persisted in the second and fourth months in all of these patients.

It was observed that the patients with TG abnormalities increased continuously in the second (99 [23.9%]) and fourth (113 [27.2%]) months compared with baseline (49 [11.8%]). Grade 3 TG elevations were observed in 2.2% of patients (n=9; 5 patients in the second month, 4 patients in the fourth month) during treatment compared with baseline, and all patients had grade 1 or 2 hypertriglyceridemia at baseline. Of the patients with grade 3 TG elevation, 3 patients in the second month and 2 patients in the fourth month were obese at baseline. No grade 4 TG elevations were observed. Complications related to hyperlipidemia, such as pancreatitis, were observed in 1 patient. No patient terminated treatment because of lipid abnormalities. The treatment of our patients with major hypercholesterolemia and/or grade 3 hypertriglyceridemia was interrupted. The hyperlipidemia of these patients was controlled by a low-fat diet and a short-term dose reduction.

Relationship Between Total Cumulative Dose and Laboratory Parameters—The relationships between the total cumulative dose and changes up to the fourth month are presented in Table 3. As the total dose increased, the changes in TG and LDL-C levels significantly increased in the fourth month (both P=.001). However, the degree of these relationships was weak. No significant correlation was found between the periodic changes of other laboratory parameters and the total dose.

Comment

The parameters followed in our study show that TG levels tend to increase continuously from baseline during isotretinoin treatment, while ALT, AST, GGT, and LDL-C levels increase in the second month and decrease at 4 months. Although this same trend occurs with CK levels, the change was not statistically significant. The most common laboratory abnormality in our study was hyperlipidemia. Levels of LDL-C and TG were both found to be statistically elevated in the second and fourth months of treatment compared with baseline. Parthasarathy et al³ reported that obesity had an important role in the increase of lipid levels in patients using isotretinoin at baseline. In our study, 5 of 9 patients (55.6%) with grade 3 TG elevation were obese, which supports the theory that obesity plays an important role in the increase in lipid levels. Up-to-date laboratory follow-up of lipids suggests that there is no need to follow up serum lipids after the second month of treatment. Patients with risk factors for hyperlipidemia, such as abdominal obesity and familial hyperlipidemia, do not require further follow-up if there is no increase in serum lipids in the first month of treatment.¹ The presence of grade 1 or 2 hypertriglyceridemia at baseline in all our patients with grade 3 TG elevation may suggest that periodic laboratory follow-up during isotretinoin treatment is necessary to detect patients with grade 3 and higher TG levels.

The lack of knowledge of other risk factors (eg, familial hyperlipidemia, insulin resistance) for hyperlipidemia in all patients at baseline may be a limitation of our study. Although hypercholesterolemia persisted in the follow-up of our patients with initial LDL-C abnormalities, hypercholesterolemia over 250 mg/dL was very rare (1 patient). Possible complications associated with serum lipid abnormalities are pancreatitis and metabolic syndrome.⁴ In our study, none of the patients with lipid abnormalities had any relevant clinical sequelae. The dose-dependent elevation of the changes in LDL-C and TG (Table 3) may be important to predict the significant elevation of lipids and the associated complications in patients with a high total cumulative dose target that may require a long treatment duration. However, considering the short follow-up periods in our patients, the absence of clinical sequelae may be misleading. There are differences in recommendations between the US and European guidelines for isotretinoin dosage. Although the US guidelines recommend a total cumulative dose target, the European guidelines recommend low-dose isotretinoin daily for at least 6 months instead of a cumulative dose.^5,6 The relationship between change in lipids and total cumulative dose in our study may not be similar in patients treated with the dosing regimen recommended by the European guidelines, as our patients received a total cumulative dose instead of a daily low-dose isotretinoin regimen, unlike the European guidelines.⁵

Most liver transaminase abnormalities were detected in the second month. Abnormalities in GGT were seen in the second month and remained elevated at the next follow-up. However, clinically important grade 3 transaminase and GGT elevations were rare. It has been reported that GGT levels are more specific than transaminases in measuring hepatotoxicity.⁷ The fact that our patient with hepatotoxicity had a grade 3 GGT elevation in addition to grade 3 transaminase elevations supports that GGT elevation is more specific than transaminase levels in measuring hepatotoxicity. When these parameters were rechecked in our patients with grade 3 transaminase elevations, except in the case of hepatotoxicity, transaminase elevations did not recur, and GGT elevations did not accompany elevated transaminases, which suggested that transaminases may be elevated due to an extrahepatic origin (eg, hemolysis, exercise).

Rhabdomyolysis secondary to isotretinoin is rare in the literature of acne studies. In addition to clinical findings such as myalgia and fatigue, increased CK and abnormal liver enzymes, specifically AST, suggest the development of rhabdomyolysis.⁸ Our patient who developed rhabdomyolysis also had a recent history of vigorous exercise, grade 4 CK, and AST elevations. Other patients with isolated grade 3 CK elevations were informed about possible clinical signs of rhabdomyolysis, and they were able to complete their courses without any incident. According to a study by Landau et al,⁹ isotretinoin-associated hyperCKemia has been reported as benign. Similarly, our study found that isolated CK elevation during isotretinoin treatment may be misleading as a sign of rhabdomyolysis. Instead, CK monitoring may be more appropriate and cost-effective in patients with suspected clinical signs of rhabdomyolysis or in those with major elevations in transaminases, especially AST.

Conclusion

According to our study, hyperlipidemia was the most common complication in acne patients using isotretinoin. It may be appropriate to monitor the TG level at 2-month intervals in patients with grade 1 or 2 TG elevation at baseline to detect the possible risk for developing grade 3 hyperlipidemia. Periodic monitoring of LDL-C and TG levels may be appropriate, especially in patients who require a high total cumulative dose of isotretinoin. Clinically important liver enzyme abnormalities were rare in our study. Our findings support the idea that routine monthly monitoring of normal laboratory parameters is unnecessary and wasteful. Additionally, periodic monitoring of abnormal laboratory parameters should be considered on an individual basis.

It is interesting to observe the changes in dermatology that have occurred over the last 1 to 2 decades, especially as major advances in basic science research techniques have rapidly expanded our current understanding of the pathophysiology of many disease states—psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, vitiligo, hidradenitis suppurativa, and lichen planus.¹ Although acne vulgaris (AV) and rosacea do not make front-page news quite as often as some of these other aforementioned disease states in the pathophysiology arena, advances still have been made in understanding the pathophysiology, albeit slower and often less popularized in dermatology publications and other forms of media.^2-4

If one looks at our fundamental understanding of AV, most of the discussion over multiple decades has been driven by new treatments and in some cases new formulations and packaging differences with topical agents. Although we understood that adrenarche, a subsequent increase in androgen synthesis, and the ensuing sebocyte development with formation of sebum were prerequisites for the development of AV, the absence of therapeutic options to address these vital components of AV—especially US Food and Drug Administration (FDA)–approved therapies—resulted in limited discussion about this specific area.⁵ Rather, the discussion was dominated by the notable role of Propionibacterium acnes (now called Cutibacterium acnes) in AV pathophysiology, as we had therapies such as benzoyl peroxide and antibiotics that improved AV in direct correlation with reductions in P acnes.⁶ This was soon coupled with an advanced understanding of how to reduce follicular hyperkeratinization with the development of topical tretinoin, followed by 3 other topical retinoids over time—adapalene, tazarotene, and trifarotene. Over subsequent years, slowly emerging basic science developments and collective data reviews added to our understanding of AV and how different therapies appear to work, including the role of toll-like receptors, anti-inflammatory properties of tetracyclines, and inflammasomes.^7-9 Without a doubt, the availability of oral isotretinoin revolutionized AV therapy, especially in patients with severe refractory disease, with advanced formulations allowing for optimization of sustained remission without the need for high dietary fat intake.^10-12

Progress in the pathophysiology of rosacea has been slower to develop, with the first true discussion of specific clinical presentations published after the new millennium.¹³ This was followed by more advanced basic science and clinical research, which led to an improved ability to understand modes of action of various therapies and to correlate treatment selection with specific visible manifestations of rosacea, including incorporation of physical devices.^14-16 A newer perspective on evaluation and management of rosacea moved away from the “buckets” of rosacea subtypes to phenotypes observed at the time of clinical presentation.^17,18

I could elaborate on research advancements with both diseases, but the bottom line is that information, developments, and current perspectives change over time. Keeping up is a challenge for all who study and practice dermatology. It is human nature to revert to what we already believe and do, which sometimes remains valid and other times is quite outdated and truly replaced by more optimal approaches. With AV and rosacea, progress is much slower in availability of newer agents. With AV, new agents have included topical dapsone, oral sarecycline, and topical clascoterone, with the latter being the first FDA-approved topical agent to mitigate the effects of androgens and sebum in both males and females. For rosacea, the 2 most recent FDA-approved therapies are minocycline foam and microencapsulated benzoyl peroxide. All of these therapies are proven to be effective for the modes of action and skin manifestations they specifically manage. Over the upcoming year, we are hoping to see the first triple-combination topical product come to market for AV, which will prompt our minds to consider if and how 3 established agents can work together to further augment treatment efficacy with favorable tolerability and safety.

Where will all of this end up? It is hard to say. We still have several other areas to tackle with both disease states, including establishing a well-substantiated understanding of the pathophysiologic role of the microbiome, sorting out the role of antibiotic use due to concerns about bacterial resistance, integration of FDA-approved physical devices in AV, and data on both diet and optimized skin care, to name a few.^19-21

There is a lot on the plate to accomplish and digest. I have remained very involved in this subject matter for almost 3 decades and am still feeling the growing pains. Fortunately, the satisfaction of being part of a process so important to the lives of millions of patients makes this worth every moment. Stay tuned—more valuable information is to come.

It is interesting to observe the changes in dermatology that have occurred over the last 1 to 2 decades, especially as major advances in basic science research techniques have rapidly expanded our current understanding of the pathophysiology of many disease states—psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, vitiligo, hidradenitis suppurativa, and lichen planus.¹ Although acne vulgaris (AV) and rosacea do not make front-page news quite as often as some of these other aforementioned disease states in the pathophysiology arena, advances still have been made in understanding the pathophysiology, albeit slower and often less popularized in dermatology publications and other forms of media.^2-4

If one looks at our fundamental understanding of AV, most of the discussion over multiple decades has been driven by new treatments and in some cases new formulations and packaging differences with topical agents. Although we understood that adrenarche, a subsequent increase in androgen synthesis, and the ensuing sebocyte development with formation of sebum were prerequisites for the development of AV, the absence of therapeutic options to address these vital components of AV—especially US Food and Drug Administration (FDA)–approved therapies—resulted in limited discussion about this specific area.⁵ Rather, the discussion was dominated by the notable role of Propionibacterium acnes (now called Cutibacterium acnes) in AV pathophysiology, as we had therapies such as benzoyl peroxide and antibiotics that improved AV in direct correlation with reductions in P acnes.⁶ This was soon coupled with an advanced understanding of how to reduce follicular hyperkeratinization with the development of topical tretinoin, followed by 3 other topical retinoids over time—adapalene, tazarotene, and trifarotene. Over subsequent years, slowly emerging basic science developments and collective data reviews added to our understanding of AV and how different therapies appear to work, including the role of toll-like receptors, anti-inflammatory properties of tetracyclines, and inflammasomes.^7-9 Without a doubt, the availability of oral isotretinoin revolutionized AV therapy, especially in patients with severe refractory disease, with advanced formulations allowing for optimization of sustained remission without the need for high dietary fat intake.^10-12

Progress in the pathophysiology of rosacea has been slower to develop, with the first true discussion of specific clinical presentations published after the new millennium.¹³ This was followed by more advanced basic science and clinical research, which led to an improved ability to understand modes of action of various therapies and to correlate treatment selection with specific visible manifestations of rosacea, including incorporation of physical devices.^14-16 A newer perspective on evaluation and management of rosacea moved away from the “buckets” of rosacea subtypes to phenotypes observed at the time of clinical presentation.^17,18

I could elaborate on research advancements with both diseases, but the bottom line is that information, developments, and current perspectives change over time. Keeping up is a challenge for all who study and practice dermatology. It is human nature to revert to what we already believe and do, which sometimes remains valid and other times is quite outdated and truly replaced by more optimal approaches. With AV and rosacea, progress is much slower in availability of newer agents. With AV, new agents have included topical dapsone, oral sarecycline, and topical clascoterone, with the latter being the first FDA-approved topical agent to mitigate the effects of androgens and sebum in both males and females. For rosacea, the 2 most recent FDA-approved therapies are minocycline foam and microencapsulated benzoyl peroxide. All of these therapies are proven to be effective for the modes of action and skin manifestations they specifically manage. Over the upcoming year, we are hoping to see the first triple-combination topical product come to market for AV, which will prompt our minds to consider if and how 3 established agents can work together to further augment treatment efficacy with favorable tolerability and safety.

Where will all of this end up? It is hard to say. We still have several other areas to tackle with both disease states, including establishing a well-substantiated understanding of the pathophysiologic role of the microbiome, sorting out the role of antibiotic use due to concerns about bacterial resistance, integration of FDA-approved physical devices in AV, and data on both diet and optimized skin care, to name a few.^19-21

There is a lot on the plate to accomplish and digest. I have remained very involved in this subject matter for almost 3 decades and am still feeling the growing pains. Fortunately, the satisfaction of being part of a process so important to the lives of millions of patients makes this worth every moment. Stay tuned—more valuable information is to come.

It is interesting to observe the changes in dermatology that have occurred over the last 1 to 2 decades, especially as major advances in basic science research techniques have rapidly expanded our current understanding of the pathophysiology of many disease states—psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, vitiligo, hidradenitis suppurativa, and lichen planus.¹ Although acne vulgaris (AV) and rosacea do not make front-page news quite as often as some of these other aforementioned disease states in the pathophysiology arena, advances still have been made in understanding the pathophysiology, albeit slower and often less popularized in dermatology publications and other forms of media.^2-4

If one looks at our fundamental understanding of AV, most of the discussion over multiple decades has been driven by new treatments and in some cases new formulations and packaging differences with topical agents. Although we understood that adrenarche, a subsequent increase in androgen synthesis, and the ensuing sebocyte development with formation of sebum were prerequisites for the development of AV, the absence of therapeutic options to address these vital components of AV—especially US Food and Drug Administration (FDA)–approved therapies—resulted in limited discussion about this specific area.⁵ Rather, the discussion was dominated by the notable role of Propionibacterium acnes (now called Cutibacterium acnes) in AV pathophysiology, as we had therapies such as benzoyl peroxide and antibiotics that improved AV in direct correlation with reductions in P acnes.⁶ This was soon coupled with an advanced understanding of how to reduce follicular hyperkeratinization with the development of topical tretinoin, followed by 3 other topical retinoids over time—adapalene, tazarotene, and trifarotene. Over subsequent years, slowly emerging basic science developments and collective data reviews added to our understanding of AV and how different therapies appear to work, including the role of toll-like receptors, anti-inflammatory properties of tetracyclines, and inflammasomes.^7-9 Without a doubt, the availability of oral isotretinoin revolutionized AV therapy, especially in patients with severe refractory disease, with advanced formulations allowing for optimization of sustained remission without the need for high dietary fat intake.^10-12

Progress in the pathophysiology of rosacea has been slower to develop, with the first true discussion of specific clinical presentations published after the new millennium.¹³ This was followed by more advanced basic science and clinical research, which led to an improved ability to understand modes of action of various therapies and to correlate treatment selection with specific visible manifestations of rosacea, including incorporation of physical devices.^14-16 A newer perspective on evaluation and management of rosacea moved away from the “buckets” of rosacea subtypes to phenotypes observed at the time of clinical presentation.^17,18

I could elaborate on research advancements with both diseases, but the bottom line is that information, developments, and current perspectives change over time. Keeping up is a challenge for all who study and practice dermatology. It is human nature to revert to what we already believe and do, which sometimes remains valid and other times is quite outdated and truly replaced by more optimal approaches. With AV and rosacea, progress is much slower in availability of newer agents. With AV, new agents have included topical dapsone, oral sarecycline, and topical clascoterone, with the latter being the first FDA-approved topical agent to mitigate the effects of androgens and sebum in both males and females. For rosacea, the 2 most recent FDA-approved therapies are minocycline foam and microencapsulated benzoyl peroxide. All of these therapies are proven to be effective for the modes of action and skin manifestations they specifically manage. Over the upcoming year, we are hoping to see the first triple-combination topical product come to market for AV, which will prompt our minds to consider if and how 3 established agents can work together to further augment treatment efficacy with favorable tolerability and safety.

Where will all of this end up? It is hard to say. We still have several other areas to tackle with both disease states, including establishing a well-substantiated understanding of the pathophysiologic role of the microbiome, sorting out the role of antibiotic use due to concerns about bacterial resistance, integration of FDA-approved physical devices in AV, and data on both diet and optimized skin care, to name a few.^19-21

There is a lot on the plate to accomplish and digest. I have remained very involved in this subject matter for almost 3 decades and am still feeling the growing pains. Fortunately, the satisfaction of being part of a process so important to the lives of millions of patients makes this worth every moment. Stay tuned—more valuable information is to come.

The Diagnosis: Cutaneous Metastasis

A shave biopsy of the lip revealed a diffuse cellular infiltrate filling the superficial and deep dermis (Figure 1A). Morphologically, the cells had abundant clear cytoplasm with eccentrically located, pleomorphic, hyperchromatic nuclei with occasional prominent nucleoli (Figure 1B). The cells stained positive for AE1/ AE3 on immunohistochemistry (Figure 2). A punch biopsy of the nodule in the right axillary vault revealed a morphologically similar proliferation of cells. A colonoscopy revealed a completely obstructing circumferential mass in the distal ascending colon. A biopsy of the mass confirmed invasive adenocarcinoma, supporting a diagnosis of cutaneous metastases from adenocarcinoma of the colon. The patient underwent resection of the lip tumor and started multiagent chemotherapy for his newly diagnosed stage IV adenocarcinoma of the colon. The patient died, despite therapy.

Cutaneous metastasis from solid malignancies is uncommon, as only 1.3% of them exhibit cutaneous manifestations at presentation.¹ Cutaneous metastasis from signet ring cell adenocarcinoma (SRCA) of the colon is uncommon, and cutaneous metastasis of colorectal SRCA rarely precedes the diagnosis of the primary lesion.² Among the colorectal cancers that metastasize to the skin, metastasis to the face occurs in only 0.5% of patients.³

Signet ring cell adenocarcinomas are poorly differentiated adenocarcinomas histologically characterized by the neoplastic cells’ circular to ovoid appearance with a flattened top.^4,5 This distinctive shape is from the displacement of the nucleus to the periphery of the cell due to the accumulation of intracytoplasmic mucin.⁴ Classically, malignancies are characterized as an SRCA if more than 50% of the cells have a signet ring cell morphology; if the signet ring cells comprise less than 50% of the neoplasm, the tumor is designated as an adenocarcinoma with signet ring morphology.⁴ The most common cause of cutaneous metastasis with signet ring morphology is gastric cancer, while colorectal carcinoma is less common.1 Colorectal SRCAs usually are found in the right colon or the rectum in comparison to other colonic sites.⁶

Clinically, cutaneous metastasis can present in a variety of ways. The most common presentation is nodular lesions that may coalesce to become zosteriform in configuration or lesions that mimic inflammatory dermatoses.⁷ Cutaneous metastasis is more common in breast and lung cancer, and when it occurs secondary to colorectal cancer, cutaneous metastasis rarely predates the detection of the primary neoplasm.²

The clinical appearance of metastasis is not specific and can mimic many entities⁸; therefore, a high index of suspicion must be employed when managing patients, even those without a history of internal malignancy. In our patient, the smooth nodular lesion appeared similar to a basal cell carcinoma; however, basal cell carcinomas appear more pearly, and arborizing telangiectasia often is seen.⁹ Merkel cell carcinoma is common on sundamaged skin of the head and neck but clinically appears more violaceous than the lesion seen in our patient.¹⁰ Paracoccidioidomycosis may form ulcerated papulonodules or plaques, especially around the nose and mouth. In many of these cases, lesions develop from contiguous lesions of the oral mucosa; therefore, the presence of oral lesions will help distinguish this infectious entity from cutaneous metastasis. Multiple lesions usually are identified when there is hematogenous dissemination.¹¹ Mycosis fungoides is a subtype of cutaneous T-cell lymphoma and is characterized by multiple patches, plaques, and nodules on sun-protected areas. Involvement of the head and neck is not common, except in the folliculotropic subtype, which has a separate and distinct clinical morphology.¹²

The development of signet ring morphology from an adenocarcinoma can be attributed to the activation of phosphatidylinositol 3-kinase (PI3K), which leads to downstream activation of mitogen-activated protein kinase (MAPK) and the subsequent loss of intercellular tight junctions. The mucin 4 gene, MUC4, also is upregulated by PI3K activation and possesses antiapoptotic and mitogenic effects in addition to its mucin secretory function.¹³

The neoplastic cells in SRCAs stain positive for mucicarmine, Alcian blue, and periodic acid–Schiff, which highlights the mucinous component of the cells.⁷ Immunohistochemical stains with CK7, CK20, AE1/AE3, and epithelial membrane antigen can be implemented to confirm an epithelial origin of the primary cancer.^7,13 CK20 is a low-molecular-weight cytokeratin normally expressed by Merkel cells and by the epithelium of the gastrointestinal tract and urothelium, whereas CK7 expression typically is expressed in the lungs, ovaries, endometrium, and breasts, but not in the lower gastrointestinal tract.¹⁴ Differentiating primary cutaneous adenocarcinoma from cutaneous metastasis can be accomplished with a thorough clinical history; however, p63 positivity supports a primary cutaneous lesion and may be useful in certain situations.⁷ CDX2 stains can be utilized to aid in localizing the primary neoplasm when it is unknown, and when positive, it suggests a lower gastrointestinal tract origin. However, special AT-rich sequence-binding protein 2 (SATB2) recently has been proposed as a replacement immunohistochemical marker for CDX2, as it has greater specificity for SRCA of the lower gastrointestinal tract.¹⁵ Benign entities with signet ring cell morphology are difficult to distinguish from SRCA; however, malignant lesions are more likely to demonstrate an infiltrative growth pattern, frequent mitotic figures, and apoptosis. Immunohistochemistry also can be utilized to support the diagnosis of benign proliferation with signet ring morphology, as benign lesions often will demonstrate E-cadherin positivity and negativity for p53 and Ki-67.¹³

Cutaneous metastasis usually correlates to advanced disease and generally indicates a worse prognosis.¹³ Signet ring cell morphology in both gastric and colorectal cancer portends a poor prognosis, and there is a lower overall survival in patients with these malignancies compared to cancers of the same organ with non–signet ring cell morphology.^4,8

The Diagnosis: Cutaneous Metastasis

A shave biopsy of the lip revealed a diffuse cellular infiltrate filling the superficial and deep dermis (Figure 1A). Morphologically, the cells had abundant clear cytoplasm with eccentrically located, pleomorphic, hyperchromatic nuclei with occasional prominent nucleoli (Figure 1B). The cells stained positive for AE1/ AE3 on immunohistochemistry (Figure 2). A punch biopsy of the nodule in the right axillary vault revealed a morphologically similar proliferation of cells. A colonoscopy revealed a completely obstructing circumferential mass in the distal ascending colon. A biopsy of the mass confirmed invasive adenocarcinoma, supporting a diagnosis of cutaneous metastases from adenocarcinoma of the colon. The patient underwent resection of the lip tumor and started multiagent chemotherapy for his newly diagnosed stage IV adenocarcinoma of the colon. The patient died, despite therapy.

Cutaneous metastasis from solid malignancies is uncommon, as only 1.3% of them exhibit cutaneous manifestations at presentation.¹ Cutaneous metastasis from signet ring cell adenocarcinoma (SRCA) of the colon is uncommon, and cutaneous metastasis of colorectal SRCA rarely precedes the diagnosis of the primary lesion.² Among the colorectal cancers that metastasize to the skin, metastasis to the face occurs in only 0.5% of patients.³

Signet ring cell adenocarcinomas are poorly differentiated adenocarcinomas histologically characterized by the neoplastic cells’ circular to ovoid appearance with a flattened top.^4,5 This distinctive shape is from the displacement of the nucleus to the periphery of the cell due to the accumulation of intracytoplasmic mucin.⁴ Classically, malignancies are characterized as an SRCA if more than 50% of the cells have a signet ring cell morphology; if the signet ring cells comprise less than 50% of the neoplasm, the tumor is designated as an adenocarcinoma with signet ring morphology.⁴ The most common cause of cutaneous metastasis with signet ring morphology is gastric cancer, while colorectal carcinoma is less common.1 Colorectal SRCAs usually are found in the right colon or the rectum in comparison to other colonic sites.⁶

Clinically, cutaneous metastasis can present in a variety of ways. The most common presentation is nodular lesions that may coalesce to become zosteriform in configuration or lesions that mimic inflammatory dermatoses.⁷ Cutaneous metastasis is more common in breast and lung cancer, and when it occurs secondary to colorectal cancer, cutaneous metastasis rarely predates the detection of the primary neoplasm.²

The clinical appearance of metastasis is not specific and can mimic many entities⁸; therefore, a high index of suspicion must be employed when managing patients, even those without a history of internal malignancy. In our patient, the smooth nodular lesion appeared similar to a basal cell carcinoma; however, basal cell carcinomas appear more pearly, and arborizing telangiectasia often is seen.⁹ Merkel cell carcinoma is common on sundamaged skin of the head and neck but clinically appears more violaceous than the lesion seen in our patient.¹⁰ Paracoccidioidomycosis may form ulcerated papulonodules or plaques, especially around the nose and mouth. In many of these cases, lesions develop from contiguous lesions of the oral mucosa; therefore, the presence of oral lesions will help distinguish this infectious entity from cutaneous metastasis. Multiple lesions usually are identified when there is hematogenous dissemination.¹¹ Mycosis fungoides is a subtype of cutaneous T-cell lymphoma and is characterized by multiple patches, plaques, and nodules on sun-protected areas. Involvement of the head and neck is not common, except in the folliculotropic subtype, which has a separate and distinct clinical morphology.¹²

The development of signet ring morphology from an adenocarcinoma can be attributed to the activation of phosphatidylinositol 3-kinase (PI3K), which leads to downstream activation of mitogen-activated protein kinase (MAPK) and the subsequent loss of intercellular tight junctions. The mucin 4 gene, MUC4, also is upregulated by PI3K activation and possesses antiapoptotic and mitogenic effects in addition to its mucin secretory function.¹³

The neoplastic cells in SRCAs stain positive for mucicarmine, Alcian blue, and periodic acid–Schiff, which highlights the mucinous component of the cells.⁷ Immunohistochemical stains with CK7, CK20, AE1/AE3, and epithelial membrane antigen can be implemented to confirm an epithelial origin of the primary cancer.^7,13 CK20 is a low-molecular-weight cytokeratin normally expressed by Merkel cells and by the epithelium of the gastrointestinal tract and urothelium, whereas CK7 expression typically is expressed in the lungs, ovaries, endometrium, and breasts, but not in the lower gastrointestinal tract.¹⁴ Differentiating primary cutaneous adenocarcinoma from cutaneous metastasis can be accomplished with a thorough clinical history; however, p63 positivity supports a primary cutaneous lesion and may be useful in certain situations.⁷ CDX2 stains can be utilized to aid in localizing the primary neoplasm when it is unknown, and when positive, it suggests a lower gastrointestinal tract origin. However, special AT-rich sequence-binding protein 2 (SATB2) recently has been proposed as a replacement immunohistochemical marker for CDX2, as it has greater specificity for SRCA of the lower gastrointestinal tract.¹⁵ Benign entities with signet ring cell morphology are difficult to distinguish from SRCA; however, malignant lesions are more likely to demonstrate an infiltrative growth pattern, frequent mitotic figures, and apoptosis. Immunohistochemistry also can be utilized to support the diagnosis of benign proliferation with signet ring morphology, as benign lesions often will demonstrate E-cadherin positivity and negativity for p53 and Ki-67.¹³

Cutaneous metastasis usually correlates to advanced disease and generally indicates a worse prognosis.¹³ Signet ring cell morphology in both gastric and colorectal cancer portends a poor prognosis, and there is a lower overall survival in patients with these malignancies compared to cancers of the same organ with non–signet ring cell morphology.^4,8

The Diagnosis: Cutaneous Metastasis

A shave biopsy of the lip revealed a diffuse cellular infiltrate filling the superficial and deep dermis (Figure 1A). Morphologically, the cells had abundant clear cytoplasm with eccentrically located, pleomorphic, hyperchromatic nuclei with occasional prominent nucleoli (Figure 1B). The cells stained positive for AE1/ AE3 on immunohistochemistry (Figure 2). A punch biopsy of the nodule in the right axillary vault revealed a morphologically similar proliferation of cells. A colonoscopy revealed a completely obstructing circumferential mass in the distal ascending colon. A biopsy of the mass confirmed invasive adenocarcinoma, supporting a diagnosis of cutaneous metastases from adenocarcinoma of the colon. The patient underwent resection of the lip tumor and started multiagent chemotherapy for his newly diagnosed stage IV adenocarcinoma of the colon. The patient died, despite therapy.

Cutaneous metastasis from solid malignancies is uncommon, as only 1.3% of them exhibit cutaneous manifestations at presentation.¹ Cutaneous metastasis from signet ring cell adenocarcinoma (SRCA) of the colon is uncommon, and cutaneous metastasis of colorectal SRCA rarely precedes the diagnosis of the primary lesion.² Among the colorectal cancers that metastasize to the skin, metastasis to the face occurs in only 0.5% of patients.³

Signet ring cell adenocarcinomas are poorly differentiated adenocarcinomas histologically characterized by the neoplastic cells’ circular to ovoid appearance with a flattened top.^4,5 This distinctive shape is from the displacement of the nucleus to the periphery of the cell due to the accumulation of intracytoplasmic mucin.⁴ Classically, malignancies are characterized as an SRCA if more than 50% of the cells have a signet ring cell morphology; if the signet ring cells comprise less than 50% of the neoplasm, the tumor is designated as an adenocarcinoma with signet ring morphology.⁴ The most common cause of cutaneous metastasis with signet ring morphology is gastric cancer, while colorectal carcinoma is less common.1 Colorectal SRCAs usually are found in the right colon or the rectum in comparison to other colonic sites.⁶

Clinically, cutaneous metastasis can present in a variety of ways. The most common presentation is nodular lesions that may coalesce to become zosteriform in configuration or lesions that mimic inflammatory dermatoses.⁷ Cutaneous metastasis is more common in breast and lung cancer, and when it occurs secondary to colorectal cancer, cutaneous metastasis rarely predates the detection of the primary neoplasm.²

The clinical appearance of metastasis is not specific and can mimic many entities⁸; therefore, a high index of suspicion must be employed when managing patients, even those without a history of internal malignancy. In our patient, the smooth nodular lesion appeared similar to a basal cell carcinoma; however, basal cell carcinomas appear more pearly, and arborizing telangiectasia often is seen.⁹ Merkel cell carcinoma is common on sundamaged skin of the head and neck but clinically appears more violaceous than the lesion seen in our patient.¹⁰ Paracoccidioidomycosis may form ulcerated papulonodules or plaques, especially around the nose and mouth. In many of these cases, lesions develop from contiguous lesions of the oral mucosa; therefore, the presence of oral lesions will help distinguish this infectious entity from cutaneous metastasis. Multiple lesions usually are identified when there is hematogenous dissemination.¹¹ Mycosis fungoides is a subtype of cutaneous T-cell lymphoma and is characterized by multiple patches, plaques, and nodules on sun-protected areas. Involvement of the head and neck is not common, except in the folliculotropic subtype, which has a separate and distinct clinical morphology.¹²

The development of signet ring morphology from an adenocarcinoma can be attributed to the activation of phosphatidylinositol 3-kinase (PI3K), which leads to downstream activation of mitogen-activated protein kinase (MAPK) and the subsequent loss of intercellular tight junctions. The mucin 4 gene, MUC4, also is upregulated by PI3K activation and possesses antiapoptotic and mitogenic effects in addition to its mucin secretory function.¹³

The neoplastic cells in SRCAs stain positive for mucicarmine, Alcian blue, and periodic acid–Schiff, which highlights the mucinous component of the cells.⁷ Immunohistochemical stains with CK7, CK20, AE1/AE3, and epithelial membrane antigen can be implemented to confirm an epithelial origin of the primary cancer.^7,13 CK20 is a low-molecular-weight cytokeratin normally expressed by Merkel cells and by the epithelium of the gastrointestinal tract and urothelium, whereas CK7 expression typically is expressed in the lungs, ovaries, endometrium, and breasts, but not in the lower gastrointestinal tract.¹⁴ Differentiating primary cutaneous adenocarcinoma from cutaneous metastasis can be accomplished with a thorough clinical history; however, p63 positivity supports a primary cutaneous lesion and may be useful in certain situations.⁷ CDX2 stains can be utilized to aid in localizing the primary neoplasm when it is unknown, and when positive, it suggests a lower gastrointestinal tract origin. However, special AT-rich sequence-binding protein 2 (SATB2) recently has been proposed as a replacement immunohistochemical marker for CDX2, as it has greater specificity for SRCA of the lower gastrointestinal tract.¹⁵ Benign entities with signet ring cell morphology are difficult to distinguish from SRCA; however, malignant lesions are more likely to demonstrate an infiltrative growth pattern, frequent mitotic figures, and apoptosis. Immunohistochemistry also can be utilized to support the diagnosis of benign proliferation with signet ring morphology, as benign lesions often will demonstrate E-cadherin positivity and negativity for p53 and Ki-67.¹³

Cutaneous metastasis usually correlates to advanced disease and generally indicates a worse prognosis.¹³ Signet ring cell morphology in both gastric and colorectal cancer portends a poor prognosis, and there is a lower overall survival in patients with these malignancies compared to cancers of the same organ with non–signet ring cell morphology.^4,8

To the Editor:

Porocarcinoma is a rare malignancy of the eccrine sweat glands and is commonly misdiagnosed clinically. We present 2 cases of porocarcinoma and highlight key features of this uncommon disease.

A 65-year-old man presented to the emergency department with a chief concern of a bump on the head of 8 months' duration that gradually enlarged. The lesion recently became painful and contributed to frequent headaches. He reported a history of smoking 1 pack per day and denied trauma to the area or history of immunosuppression. He had no personal or family history of skin cancer. Physical examination revealed a 1.4-cm, heterochromic, pedunculated, keratotic tumor with crusting on the right temporal scalp (Figure 1). No lymphadenopathy was appreciated. The clinical differential diagnosis included irritated seborrheic keratosis, pyogenic granuloma, polypoid malignant melanoma, and nonmelanoma skin cancer. A biopsy of the lesion demonstrated a proliferation of cuboidal cells with focal ductular differentiation arranged in interanastamosing strands arising from the epidermis (Figure 2). Scattered mitotic figures, including atypical forms, cytologic atypia, and foci of necrosis, also were present. The findings were consistent with features of porocarcinoma. Contrast computed tomography of the neck showed no evidence of metastatic disease within the neck. A wide local excision was performed and yielded a tumor measuring 1.8×1.6×0.7 cm with a depth of 0.3 cm and uninvolved margins. No lymphovascular or perineural invasion was identified. At 4-month follow-up, the patient had a well-healed scar on the right scalp without evidence of recurrence or lymphadenopathy.

A 32-year-old woman presented to dermatology with a chief concern of a mass on the back of 2 years’ duration that rapidly enlarged and became painful following irritation from her bra strap 2 months earlier. She had no relevant medical history. Physical examination revealed a firm, tender, heterochromic nodule measuring 3.0×2.8 cm on the left mid back inferior to the left scapula (Figure 3). The lesion expressed serosanguineous discharge. No lymphadenopathy was appreciated on examination. The clinical differential diagnosis included an inflamed cyst, nodular melanoma, cutaneous metastasis, and nonmelanoma skin cancer. The patient underwent an excisional biopsy, which demonstrated porocarcinoma with positive margins, microsatellitosis, and evidence of lymphovascular invasion. Carcinoembryonic antigen immunohistochemistry highlighted ducts within the tumor (Figure 4). The patient underwent re-excision with 2-cm margins, and no residual tumor was appreciated on pathology.

Positron emission tomography and computed tomography revealed a hypermetabolic left axillary lymph node. Ultrasound-guided fine-needle aspiration was positive for malignant cells consistent with metastatic carcinoma. Dissection of left axillary lymph nodes yielded metastatic porocarcinoma in 2 of 13 nodes. The largest tumor deposit measured 0.9 cm, and no extracapsular extension was identified. The patient continues to be monitored with semiannual full-body skin examinations as well as positron emission tomography and computed tomography scans, with no evidence of recurrence 2 years later.

Porocarcinoma is a rare malignancy of the skin arising from the eccrine sweat glands¹ with an incidence rate of 0.4 cases per 1 million person-years in the United States. These tumors represent 0.005% to 0.01% of all skin cancers.² The mean age of onset is approximately 65 years with no predilection for sex. The mean time from initial presentation to treatment is 5.6 to 8.5 years.^3-5

Eccrine sweat glands consist of a straight intradermal duct (syrinx); coiled intradermal duct; and spiral intraepidermal duct (acrosyringium), which opens onto the skin. Both eccrine poromas (solitary benign eccrine gland tumors) and eccrine porocarcinomas develop from the acrosyringium. Eccrine poromas most commonly are found in sites containing the highest density of eccrine glands such as the palms, soles, axillae, and forehead, whereas porocarcinomas most commonly are found on the head, neck, arms, and legs.^1,3,4,6,7 A solitary painless nodule that may ulcerate or bleed is the most common presentation.^1,3-5,7

The etiology of eccrine porocarcinoma is poorly understood, but it has been found to arise de novo or to develop from pre-existing poromas or even from nevus sebaceus of Jadassohn. Chronic sunlight exposure, irradiation, lymphedema, trauma, and immunosuppression (eg, Hodgkin disease, chronic lymphocytic leukemia, HIV) have been reported as potential predisposing factors.^3,4,6,8,9

Eccrine porocarcinoma often is clinically misdiagnosed as nonmelanoma skin cancer, pyogenic granuloma, amelanotic melanoma, fibroma, verruca vulgaris, or metastatic carcinoma. Appropriate classification is essential, as metastasis is present in 25% to 31% of cases, and local recurrence occurs in 20% to 25% of cases.^1,3-5,7

Microscopically, porocarcinomas are comprised of atypical basaloid epithelial cells with focal ductular differentiation. Typically, there is an extensive intraepidermal component that invades into the dermis in anastomosing ribbons and cords. The degree of nuclear atypia, mitotic activity, and invasive growth pattern, as well as the presence of necrosis, are useful histologic features to differentiate porocarcinoma from poroma, which may be present in the background. Given the sometimes-extensive squamous differentiation, porocarcinoma can be confused with squamous cell carcinoma. In these cases, immunohistochemical stains such as epithelial membrane antigen or carcinoembryonic antigen can be used to highlight the ductal differentiation.^1,5,8,10

Poor histologic prognostic indicators include a high mitotic index (>14 mitoses per field), a tumor depth greater than 7 mm, and evidence of lymphovascular invasion. Positive lymph node involvement is associated with a 65% to 67% mortality rate.^1,8

Because of its propensity to metastasize via the lymphatic system and the high mortality rate associated with such metastases, early identification and treatment are essential. Treatment is accomplished via Mohs micrographic surgery or wide local excision with negative margins. Lymphadenectomy is indicated if regional lymph nodes are involved. Radiation and chemotherapy have been used in patients with metastatic and recurrent disease with mixed results.^1,3-5,7 There is no adequate standardized chemotherapy or drug regimen established for porocarcinoma.⁵ Tsunoda et al¹¹ proposed that sentinel lymph node biopsy should be considered first-line management of eccrine porocarcinoma; however, this remains unproven on the basis of a limited case series. Others conclude that sentinel lymph node biopsy should be recommended for cases with poor histologic prognostic features.^1,5

To the Editor:

Porocarcinoma is a rare malignancy of the eccrine sweat glands and is commonly misdiagnosed clinically. We present 2 cases of porocarcinoma and highlight key features of this uncommon disease.

A 65-year-old man presented to the emergency department with a chief concern of a bump on the head of 8 months' duration that gradually enlarged. The lesion recently became painful and contributed to frequent headaches. He reported a history of smoking 1 pack per day and denied trauma to the area or history of immunosuppression. He had no personal or family history of skin cancer. Physical examination revealed a 1.4-cm, heterochromic, pedunculated, keratotic tumor with crusting on the right temporal scalp (Figure 1). No lymphadenopathy was appreciated. The clinical differential diagnosis included irritated seborrheic keratosis, pyogenic granuloma, polypoid malignant melanoma, and nonmelanoma skin cancer. A biopsy of the lesion demonstrated a proliferation of cuboidal cells with focal ductular differentiation arranged in interanastamosing strands arising from the epidermis (Figure 2). Scattered mitotic figures, including atypical forms, cytologic atypia, and foci of necrosis, also were present. The findings were consistent with features of porocarcinoma. Contrast computed tomography of the neck showed no evidence of metastatic disease within the neck. A wide local excision was performed and yielded a tumor measuring 1.8×1.6×0.7 cm with a depth of 0.3 cm and uninvolved margins. No lymphovascular or perineural invasion was identified. At 4-month follow-up, the patient had a well-healed scar on the right scalp without evidence of recurrence or lymphadenopathy.

A 32-year-old woman presented to dermatology with a chief concern of a mass on the back of 2 years’ duration that rapidly enlarged and became painful following irritation from her bra strap 2 months earlier. She had no relevant medical history. Physical examination revealed a firm, tender, heterochromic nodule measuring 3.0×2.8 cm on the left mid back inferior to the left scapula (Figure 3). The lesion expressed serosanguineous discharge. No lymphadenopathy was appreciated on examination. The clinical differential diagnosis included an inflamed cyst, nodular melanoma, cutaneous metastasis, and nonmelanoma skin cancer. The patient underwent an excisional biopsy, which demonstrated porocarcinoma with positive margins, microsatellitosis, and evidence of lymphovascular invasion. Carcinoembryonic antigen immunohistochemistry highlighted ducts within the tumor (Figure 4). The patient underwent re-excision with 2-cm margins, and no residual tumor was appreciated on pathology.

Positron emission tomography and computed tomography revealed a hypermetabolic left axillary lymph node. Ultrasound-guided fine-needle aspiration was positive for malignant cells consistent with metastatic carcinoma. Dissection of left axillary lymph nodes yielded metastatic porocarcinoma in 2 of 13 nodes. The largest tumor deposit measured 0.9 cm, and no extracapsular extension was identified. The patient continues to be monitored with semiannual full-body skin examinations as well as positron emission tomography and computed tomography scans, with no evidence of recurrence 2 years later.

Porocarcinoma is a rare malignancy of the skin arising from the eccrine sweat glands¹ with an incidence rate of 0.4 cases per 1 million person-years in the United States. These tumors represent 0.005% to 0.01% of all skin cancers.² The mean age of onset is approximately 65 years with no predilection for sex. The mean time from initial presentation to treatment is 5.6 to 8.5 years.^3-5

Eccrine sweat glands consist of a straight intradermal duct (syrinx); coiled intradermal duct; and spiral intraepidermal duct (acrosyringium), which opens onto the skin. Both eccrine poromas (solitary benign eccrine gland tumors) and eccrine porocarcinomas develop from the acrosyringium. Eccrine poromas most commonly are found in sites containing the highest density of eccrine glands such as the palms, soles, axillae, and forehead, whereas porocarcinomas most commonly are found on the head, neck, arms, and legs.^1,3,4,6,7 A solitary painless nodule that may ulcerate or bleed is the most common presentation.^1,3-5,7

The etiology of eccrine porocarcinoma is poorly understood, but it has been found to arise de novo or to develop from pre-existing poromas or even from nevus sebaceus of Jadassohn. Chronic sunlight exposure, irradiation, lymphedema, trauma, and immunosuppression (eg, Hodgkin disease, chronic lymphocytic leukemia, HIV) have been reported as potential predisposing factors.^3,4,6,8,9

Eccrine porocarcinoma often is clinically misdiagnosed as nonmelanoma skin cancer, pyogenic granuloma, amelanotic melanoma, fibroma, verruca vulgaris, or metastatic carcinoma. Appropriate classification is essential, as metastasis is present in 25% to 31% of cases, and local recurrence occurs in 20% to 25% of cases.^1,3-5,7

Microscopically, porocarcinomas are comprised of atypical basaloid epithelial cells with focal ductular differentiation. Typically, there is an extensive intraepidermal component that invades into the dermis in anastomosing ribbons and cords. The degree of nuclear atypia, mitotic activity, and invasive growth pattern, as well as the presence of necrosis, are useful histologic features to differentiate porocarcinoma from poroma, which may be present in the background. Given the sometimes-extensive squamous differentiation, porocarcinoma can be confused with squamous cell carcinoma. In these cases, immunohistochemical stains such as epithelial membrane antigen or carcinoembryonic antigen can be used to highlight the ductal differentiation.^1,5,8,10

Poor histologic prognostic indicators include a high mitotic index (>14 mitoses per field), a tumor depth greater than 7 mm, and evidence of lymphovascular invasion. Positive lymph node involvement is associated with a 65% to 67% mortality rate.^1,8

Because of its propensity to metastasize via the lymphatic system and the high mortality rate associated with such metastases, early identification and treatment are essential. Treatment is accomplished via Mohs micrographic surgery or wide local excision with negative margins. Lymphadenectomy is indicated if regional lymph nodes are involved. Radiation and chemotherapy have been used in patients with metastatic and recurrent disease with mixed results.^1,3-5,7 There is no adequate standardized chemotherapy or drug regimen established for porocarcinoma.⁵ Tsunoda et al¹¹ proposed that sentinel lymph node biopsy should be considered first-line management of eccrine porocarcinoma; however, this remains unproven on the basis of a limited case series. Others conclude that sentinel lymph node biopsy should be recommended for cases with poor histologic prognostic features.^1,5

To the Editor:

Porocarcinoma is a rare malignancy of the eccrine sweat glands and is commonly misdiagnosed clinically. We present 2 cases of porocarcinoma and highlight key features of this uncommon disease.

A 65-year-old man presented to the emergency department with a chief concern of a bump on the head of 8 months' duration that gradually enlarged. The lesion recently became painful and contributed to frequent headaches. He reported a history of smoking 1 pack per day and denied trauma to the area or history of immunosuppression. He had no personal or family history of skin cancer. Physical examination revealed a 1.4-cm, heterochromic, pedunculated, keratotic tumor with crusting on the right temporal scalp (Figure 1). No lymphadenopathy was appreciated. The clinical differential diagnosis included irritated seborrheic keratosis, pyogenic granuloma, polypoid malignant melanoma, and nonmelanoma skin cancer. A biopsy of the lesion demonstrated a proliferation of cuboidal cells with focal ductular differentiation arranged in interanastamosing strands arising from the epidermis (Figure 2). Scattered mitotic figures, including atypical forms, cytologic atypia, and foci of necrosis, also were present. The findings were consistent with features of porocarcinoma. Contrast computed tomography of the neck showed no evidence of metastatic disease within the neck. A wide local excision was performed and yielded a tumor measuring 1.8×1.6×0.7 cm with a depth of 0.3 cm and uninvolved margins. No lymphovascular or perineural invasion was identified. At 4-month follow-up, the patient had a well-healed scar on the right scalp without evidence of recurrence or lymphadenopathy.

A 32-year-old woman presented to dermatology with a chief concern of a mass on the back of 2 years’ duration that rapidly enlarged and became painful following irritation from her bra strap 2 months earlier. She had no relevant medical history. Physical examination revealed a firm, tender, heterochromic nodule measuring 3.0×2.8 cm on the left mid back inferior to the left scapula (Figure 3). The lesion expressed serosanguineous discharge. No lymphadenopathy was appreciated on examination. The clinical differential diagnosis included an inflamed cyst, nodular melanoma, cutaneous metastasis, and nonmelanoma skin cancer. The patient underwent an excisional biopsy, which demonstrated porocarcinoma with positive margins, microsatellitosis, and evidence of lymphovascular invasion. Carcinoembryonic antigen immunohistochemistry highlighted ducts within the tumor (Figure 4). The patient underwent re-excision with 2-cm margins, and no residual tumor was appreciated on pathology.

Positron emission tomography and computed tomography revealed a hypermetabolic left axillary lymph node. Ultrasound-guided fine-needle aspiration was positive for malignant cells consistent with metastatic carcinoma. Dissection of left axillary lymph nodes yielded metastatic porocarcinoma in 2 of 13 nodes. The largest tumor deposit measured 0.9 cm, and no extracapsular extension was identified. The patient continues to be monitored with semiannual full-body skin examinations as well as positron emission tomography and computed tomography scans, with no evidence of recurrence 2 years later.

Porocarcinoma is a rare malignancy of the skin arising from the eccrine sweat glands¹ with an incidence rate of 0.4 cases per 1 million person-years in the United States. These tumors represent 0.005% to 0.01% of all skin cancers.² The mean age of onset is approximately 65 years with no predilection for sex. The mean time from initial presentation to treatment is 5.6 to 8.5 years.^3-5

Eccrine sweat glands consist of a straight intradermal duct (syrinx); coiled intradermal duct; and spiral intraepidermal duct (acrosyringium), which opens onto the skin. Both eccrine poromas (solitary benign eccrine gland tumors) and eccrine porocarcinomas develop from the acrosyringium. Eccrine poromas most commonly are found in sites containing the highest density of eccrine glands such as the palms, soles, axillae, and forehead, whereas porocarcinomas most commonly are found on the head, neck, arms, and legs.^1,3,4,6,7 A solitary painless nodule that may ulcerate or bleed is the most common presentation.^1,3-5,7

The etiology of eccrine porocarcinoma is poorly understood, but it has been found to arise de novo or to develop from pre-existing poromas or even from nevus sebaceus of Jadassohn. Chronic sunlight exposure, irradiation, lymphedema, trauma, and immunosuppression (eg, Hodgkin disease, chronic lymphocytic leukemia, HIV) have been reported as potential predisposing factors.^3,4,6,8,9

Eccrine porocarcinoma often is clinically misdiagnosed as nonmelanoma skin cancer, pyogenic granuloma, amelanotic melanoma, fibroma, verruca vulgaris, or metastatic carcinoma. Appropriate classification is essential, as metastasis is present in 25% to 31% of cases, and local recurrence occurs in 20% to 25% of cases.^1,3-5,7

Microscopically, porocarcinomas are comprised of atypical basaloid epithelial cells with focal ductular differentiation. Typically, there is an extensive intraepidermal component that invades into the dermis in anastomosing ribbons and cords. The degree of nuclear atypia, mitotic activity, and invasive growth pattern, as well as the presence of necrosis, are useful histologic features to differentiate porocarcinoma from poroma, which may be present in the background. Given the sometimes-extensive squamous differentiation, porocarcinoma can be confused with squamous cell carcinoma. In these cases, immunohistochemical stains such as epithelial membrane antigen or carcinoembryonic antigen can be used to highlight the ductal differentiation.^1,5,8,10

Poor histologic prognostic indicators include a high mitotic index (>14 mitoses per field), a tumor depth greater than 7 mm, and evidence of lymphovascular invasion. Positive lymph node involvement is associated with a 65% to 67% mortality rate.^1,8

Because of its propensity to metastasize via the lymphatic system and the high mortality rate associated with such metastases, early identification and treatment are essential. Treatment is accomplished via Mohs micrographic surgery or wide local excision with negative margins. Lymphadenectomy is indicated if regional lymph nodes are involved. Radiation and chemotherapy have been used in patients with metastatic and recurrent disease with mixed results.^1,3-5,7 There is no adequate standardized chemotherapy or drug regimen established for porocarcinoma.⁵ Tsunoda et al¹¹ proposed that sentinel lymph node biopsy should be considered first-line management of eccrine porocarcinoma; however, this remains unproven on the basis of a limited case series. Others conclude that sentinel lymph node biopsy should be recommended for cases with poor histologic prognostic features.^1,5

To the Editor:

Peer-reviewed publications are important determinants for promotions, academic leadership, and grants in dermatology.¹ The impact of the COVID-19 pandemic on dermatology research productivity remains an area of investigation. We sought to determine authorship trends for males and females during the pandemic.

A cross-sectional retrospective study of the top 20 dermatology journals—determined by impact factor and Google Scholar H5-index—was conducted to identify manuscripts with submission date specified prepandemic (May 1, 2019–October 31, 2019) and during the pandemic (May 1, 2020–October 31, 2020). Submission date, first/last author name, sex, and affiliated country were extracted. Single authors were designated as first authors. Gender API (https://gender-api.com/en/) classified gender. A χ² test (P<.05) compared differences in proportions of female first/last authors from 2019 to 2020.

Overall, 811 and 1061 articles submitted in 2019 and 2020, respectively, were included. There were 1517 articles submitted to clinical journals and 355 articles submitted to basic science journals (Table). For the 7 clinical journals included, there was a 7.7% decrease in the proportion of female last authors in 2020 vs 2019 (P=.002), with the largest decrease between August and September 2020. Although other comparisons did not yield statistically significant differences (P>.05 all)(Table), several trends were observed. For clinical journals, there was a 1.8% decrease in the proportion of female first authors. For the 4 basic science journals included, there was a 4.9% increase and a 0.3% decrease in percentages of female first and last authors, respectively, for 2020 vs 2019.

Our findings indicate that the COVID-19 pandemic may have impacted female authors’ productivity in clinical dermatology publications. In a survey-based study for 2010 to 2011, female physician-researchers (n=437) spent 8.5 more hours per week on domestic activities and childcare and were more likely to take time off for childcare if their partner worked full time compared with males (n=612)(42.6% vs 12.4%, respectively).² Our observation that female last authors had a significant decrease in publications may suggest that this population had a disproportionate burden of domestic labor and childcare during the pandemic. It is possible that last authors, who generally are more senior researchers, may be more likely to have childcare, eldercare, and other types of domestic responsibilities. Similarly, in a study of surgery submissions (n=1068), there were 6%, 7%, and 4% decreases in percentages of female last, corresponding, and first authors, respectively, from 2019 to 2020.³Our study had limitations. Only 11 journals were analyzed because others did not have specified submission dates. Some journals only provided submission information for a subset of articles (eg, those published in the In Press section), which may have accounted for the large discrepancy in submission numbers for 2019 to 2020. Gender could not be determined for 1% of authors and was limited to female and male. Although our study submission time frame (May–October 2020) aimed at identifying research conducted during the height of the COVID-19 pandemic, some of these studies may have been conducted months or years before the pandemic. Future studies should focus on longer and more comprehensive time frames. Finally, estimated dates of stay-at-home orders fail to consider differences within countries.

The proportion of female US-affiliated first and last authors publishing in dermatology journals increased from 12% to 48% in 1976 and from 6% to 31% in 2006,⁴ which is encouraging. However, a gender gap persists, with one-third of National Institutes of Health grants in dermatology and one-fourth of research project grants in dermatology awarded to women.⁵ Consequences of the pandemic on academic productivity may include fewer women represented in higher academic ranks, lower compensation, and lower career satisfaction compared with men.¹ We urge academic institutions and funding agencies to recognize and take action to mitigate long-term sequelae. Extended grant end dates and submission periods, funding opportunities dedicated to women, and prioritization of female-authored submissions are some strategies that can safeguard equitable career progression in dermatology research.

To the Editor:

Peer-reviewed publications are important determinants for promotions, academic leadership, and grants in dermatology.¹ The impact of the COVID-19 pandemic on dermatology research productivity remains an area of investigation. We sought to determine authorship trends for males and females during the pandemic.

A cross-sectional retrospective study of the top 20 dermatology journals—determined by impact factor and Google Scholar H5-index—was conducted to identify manuscripts with submission date specified prepandemic (May 1, 2019–October 31, 2019) and during the pandemic (May 1, 2020–October 31, 2020). Submission date, first/last author name, sex, and affiliated country were extracted. Single authors were designated as first authors. Gender API (https://gender-api.com/en/) classified gender. A χ² test (P<.05) compared differences in proportions of female first/last authors from 2019 to 2020.

Overall, 811 and 1061 articles submitted in 2019 and 2020, respectively, were included. There were 1517 articles submitted to clinical journals and 355 articles submitted to basic science journals (Table). For the 7 clinical journals included, there was a 7.7% decrease in the proportion of female last authors in 2020 vs 2019 (P=.002), with the largest decrease between August and September 2020. Although other comparisons did not yield statistically significant differences (P>.05 all)(Table), several trends were observed. For clinical journals, there was a 1.8% decrease in the proportion of female first authors. For the 4 basic science journals included, there was a 4.9% increase and a 0.3% decrease in percentages of female first and last authors, respectively, for 2020 vs 2019.

Our findings indicate that the COVID-19 pandemic may have impacted female authors’ productivity in clinical dermatology publications. In a survey-based study for 2010 to 2011, female physician-researchers (n=437) spent 8.5 more hours per week on domestic activities and childcare and were more likely to take time off for childcare if their partner worked full time compared with males (n=612)(42.6% vs 12.4%, respectively).² Our observation that female last authors had a significant decrease in publications may suggest that this population had a disproportionate burden of domestic labor and childcare during the pandemic. It is possible that last authors, who generally are more senior researchers, may be more likely to have childcare, eldercare, and other types of domestic responsibilities. Similarly, in a study of surgery submissions (n=1068), there were 6%, 7%, and 4% decreases in percentages of female last, corresponding, and first authors, respectively, from 2019 to 2020.³Our study had limitations. Only 11 journals were analyzed because others did not have specified submission dates. Some journals only provided submission information for a subset of articles (eg, those published in the In Press section), which may have accounted for the large discrepancy in submission numbers for 2019 to 2020. Gender could not be determined for 1% of authors and was limited to female and male. Although our study submission time frame (May–October 2020) aimed at identifying research conducted during the height of the COVID-19 pandemic, some of these studies may have been conducted months or years before the pandemic. Future studies should focus on longer and more comprehensive time frames. Finally, estimated dates of stay-at-home orders fail to consider differences within countries.

The proportion of female US-affiliated first and last authors publishing in dermatology journals increased from 12% to 48% in 1976 and from 6% to 31% in 2006,⁴ which is encouraging. However, a gender gap persists, with one-third of National Institutes of Health grants in dermatology and one-fourth of research project grants in dermatology awarded to women.⁵ Consequences of the pandemic on academic productivity may include fewer women represented in higher academic ranks, lower compensation, and lower career satisfaction compared with men.¹ We urge academic institutions and funding agencies to recognize and take action to mitigate long-term sequelae. Extended grant end dates and submission periods, funding opportunities dedicated to women, and prioritization of female-authored submissions are some strategies that can safeguard equitable career progression in dermatology research.

To the Editor:

Peer-reviewed publications are important determinants for promotions, academic leadership, and grants in dermatology.¹ The impact of the COVID-19 pandemic on dermatology research productivity remains an area of investigation. We sought to determine authorship trends for males and females during the pandemic.

A cross-sectional retrospective study of the top 20 dermatology journals—determined by impact factor and Google Scholar H5-index—was conducted to identify manuscripts with submission date specified prepandemic (May 1, 2019–October 31, 2019) and during the pandemic (May 1, 2020–October 31, 2020). Submission date, first/last author name, sex, and affiliated country were extracted. Single authors were designated as first authors. Gender API (https://gender-api.com/en/) classified gender. A χ² test (P<.05) compared differences in proportions of female first/last authors from 2019 to 2020.

Overall, 811 and 1061 articles submitted in 2019 and 2020, respectively, were included. There were 1517 articles submitted to clinical journals and 355 articles submitted to basic science journals (Table). For the 7 clinical journals included, there was a 7.7% decrease in the proportion of female last authors in 2020 vs 2019 (P=.002), with the largest decrease between August and September 2020. Although other comparisons did not yield statistically significant differences (P>.05 all)(Table), several trends were observed. For clinical journals, there was a 1.8% decrease in the proportion of female first authors. For the 4 basic science journals included, there was a 4.9% increase and a 0.3% decrease in percentages of female first and last authors, respectively, for 2020 vs 2019.

Our findings indicate that the COVID-19 pandemic may have impacted female authors’ productivity in clinical dermatology publications. In a survey-based study for 2010 to 2011, female physician-researchers (n=437) spent 8.5 more hours per week on domestic activities and childcare and were more likely to take time off for childcare if their partner worked full time compared with males (n=612)(42.6% vs 12.4%, respectively).² Our observation that female last authors had a significant decrease in publications may suggest that this population had a disproportionate burden of domestic labor and childcare during the pandemic. It is possible that last authors, who generally are more senior researchers, may be more likely to have childcare, eldercare, and other types of domestic responsibilities. Similarly, in a study of surgery submissions (n=1068), there were 6%, 7%, and 4% decreases in percentages of female last, corresponding, and first authors, respectively, from 2019 to 2020.³Our study had limitations. Only 11 journals were analyzed because others did not have specified submission dates. Some journals only provided submission information for a subset of articles (eg, those published in the In Press section), which may have accounted for the large discrepancy in submission numbers for 2019 to 2020. Gender could not be determined for 1% of authors and was limited to female and male. Although our study submission time frame (May–October 2020) aimed at identifying research conducted during the height of the COVID-19 pandemic, some of these studies may have been conducted months or years before the pandemic. Future studies should focus on longer and more comprehensive time frames. Finally, estimated dates of stay-at-home orders fail to consider differences within countries.

The proportion of female US-affiliated first and last authors publishing in dermatology journals increased from 12% to 48% in 1976 and from 6% to 31% in 2006,⁴ which is encouraging. However, a gender gap persists, with one-third of National Institutes of Health grants in dermatology and one-fourth of research project grants in dermatology awarded to women.⁵ Consequences of the pandemic on academic productivity may include fewer women represented in higher academic ranks, lower compensation, and lower career satisfaction compared with men.¹ We urge academic institutions and funding agencies to recognize and take action to mitigate long-term sequelae. Extended grant end dates and submission periods, funding opportunities dedicated to women, and prioritization of female-authored submissions are some strategies that can safeguard equitable career progression in dermatology research.

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, was first described in 1964. ¹ Since then, several subtypes of SS have been recognized, including classic or idiopathic, which typically follows an acute viral illness; cancer related, typically in the form of a paraneoplastic syndrome; and drug induced. ² Drug-induced SS is defined by the following: (1) an abrupt onset of painful erythematous plaques or nodules; (2) histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis; (3) pyrexia above 38 ° C; (4) temporal relationship between drug and clinical presentation or temporally related recurrence after rechallenge; and (5) temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids. ³ All 5 criteria must be met to make a diagnosis of drug-induced SS. Since these criteria were established by Walker and Cohen, ³ various drugs have been identified as causative agents, including antibiotics, antiepileptics, antiretrovirals, antineoplastic agents, antipsychotics, oral contraceptives, nonsteroidal anti-inflammatory agents, and retinoids. ⁴ W e present a rare case of SS caused by dupilumab, a monoclonal antibody therapy, used in the treatment of severe eosinophilic asthma and atopic dermatitis.

Case Report

A 53-year-old woman presented with painful skin lesions, arthralgia, fever, and leukocytosis following initiation of dupilumab. She had a history of adult-onset, severe, persistent eosinophilic asthma, as well as chronic rhinosinusitis with nasal polyps, plaque psoriasis, and hypertrophic cardiomyopathy. She started mepolizumab 3 years prior to the current presentation for persistently uncontrolled asthma with a baseline peripheral eosinophil count of 860 cells/µL. After 3 years of minimal response to mepolizumab, she was started on dupilumab. Within 2 weeks of the first dose of dupilumab, she started experiencing bilateral knee pain. She subsequently developed daily fevers (temperature, 38.3 °C to 39.4 °C), fatigue, and pain in the back of the neck and head. After the second dose of dupilumab, she started experiencing painful skin lesions on the bilateral knuckles, elbows, and abdomen (Figure 1). She had difficulty using her hands and walking secondary to intense arthralgia involving the bilateral finger joints, elbows, and knees. Her primary care physician obtained a laboratory evaluation, which revealed an elevated total white blood cell count of 20×10³/mm³ (reference range, 4–11×10³/mm³) with 27.5% neutrophils and severely elevated eosinophils above her baseline to 57.3% with an absolute eosinophil count of 11,700 cells/µL (reference range, <400 cells/µL). Further assessment revealed an elevated erythrocyte sedimentation rate of 64 mm/h (reference range, 0–30 mm/h) and C-reactive protein level of 34 mg/dL (reference range, ≤0.80 mg/dL), with negative antinuclear antibody, rheumatoid factor, antineutrophilic cytoplasmic antibody, and Lyme antibody. IgG, IgA, and IgM levels were within reference range, and the IgE level was not elevated above her baseline. She had normal serum tryptase, and a peripheral D816V c-KIT mutation was not detected. She was subsequently hospitalized for further evaluation, at which time there was no fever or localizing infectious signs or symptoms. An infectious evaluation including urinalysis; respiratory swab for adenovirus, coronaviruses, human metapneumovirus, rhinovirus/enterovirus, influenza A and B, parainfluenza viruses, respiratory syncytial virus, Chlamydophila pneumoniae, and Mycoplasma pneumoniae; Lyme serology; and a computed tomography (CT) scan of the chest, abdomen, and pelvis revealed no evidence of infection. A parasite evaluation was ordered but was not performed. There was no evidence of malignancy on CT of the chest, abdomen, and pelvis or CT of the head without contrast. A lumbar puncture was considered but was ultimately deferred.

At the current presentation, the patient was following up in the dermatology clinic shortly after discharge. The lesions on the fingers and arms were described by the dermatologist as deep, erythematous, 0.5-cm bullous papules. The differential diagnosis at this time included a cutaneous or systemic infection, vasculitis, drug eruption, or cutaneous manifestation of an autoimmune condition. A shave biopsy of a skin lesion on the right hand demonstrated epidermal necrosis with a dense dermal neutrophilic infiltrate consistent with a neutrophilic dermatosis (Figure 2). There was no evidence of leukocytoclastic vasculitis. The histologic differential diagnosis included cutaneous infection, neutrophilic dermatosis of the hand, and SS. Special stains for infectious organisms including Gram, Grocott methenamine-silver, and auramine-rhodamine stains were negative for bacterial, fungal, and mycobacterial organisms, ruling out cutaneous infection. A diagnosis of drug-induced SS was made based on the histologic findings, diffuse distribution of the lesions, negative infectious evaluation, lack of underlying malignancy or autoimmune conditions, and onset following initiation of dupilumab.

Dupilumab was discontinued, and the patient was started on prednisone with rapid improvement in the symptoms. She underwent a slow taper of the prednisone over approximately 2 months with a slow downtrend of eosinophils. She was transitioned to a different biologic agent, benralizumab, with no further recurrence of the rash or arthralgia.

Comment

Dupilumab is a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13 signaling by binding to the IL-4Rα subunit. By blocking IL-4Rα, dupilumab inhibits IL-4 and IL-13 cytokine-induced inflammatory responses, including the release of proinflammatory cytokines, chemokines, nitric oxide, and IgE. Currently, dupilumab is approved to treat refractory forms of moderate to severe asthma characterized by an eosinophilic phenotype or with corticosteroid-dependent asthma, moderate to severe atopic dermatitis, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis. The most common adverse events (incidence ≥1%) are injection-site reactions, oropharyngeal pain, and eosinophilia.⁵ Interestingly, our patient did exhibit a high degree of eosinophilia; however, she met all criteria for drug-induced SS, and the skin biopsy was not consistent with an eosinophilic process. Notably, the peripheral neutrophils were not elevated. Neutrophilia often is seen in classic SS but is not required for a diagnosis of drug-induced SS. Rare cases of dupilumab-associated arthritis and serum sickness–like reaction have been described,^6-8 but our patient’s presentation was distinct, given other described signs, symptoms, and skin biopsy results. Histopathology results were not consistent with leukocytoclastic vasculitis, a potential mimicker of SS. Although the infectious and paraneoplastic evaluation was not exhaustive, the negative imaging from head to pelvis, the lack of recurrence of skin lesions, and the laboratory abnormalities after dupilumab discontinuation supported the conclusion that the culprit was not an infection or underlying malignancy. She had not started any other medications during this time frame, leaving dupilumab as the most likely offending agent. The mechanism for this reaction is not clear. It is possible that inhibition of IL-4 and IL-13 in the T helper 2 (T_H2) cell pathway may have led to upregulated IL-17–mediated inflammation⁹ as well as a neutrophilic process in the skin, but this would not explain the concurrent peripheral eosinophilia that was noted. Further studies are needed to investigate the pathophysiology of SS.

Conclusion

We report a rare case of dupilumab-induced SS. Corticosteroids accompanied by cessation of the medication proved to be an effective treatment. Prescribers must be aware of SS as a potential adverse reaction, as prompt recognition and treatment are needed.

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, was first described in 1964. ¹ Since then, several subtypes of SS have been recognized, including classic or idiopathic, which typically follows an acute viral illness; cancer related, typically in the form of a paraneoplastic syndrome; and drug induced. ² Drug-induced SS is defined by the following: (1) an abrupt onset of painful erythematous plaques or nodules; (2) histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis; (3) pyrexia above 38 ° C; (4) temporal relationship between drug and clinical presentation or temporally related recurrence after rechallenge; and (5) temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids. ³ All 5 criteria must be met to make a diagnosis of drug-induced SS. Since these criteria were established by Walker and Cohen, ³ various drugs have been identified as causative agents, including antibiotics, antiepileptics, antiretrovirals, antineoplastic agents, antipsychotics, oral contraceptives, nonsteroidal anti-inflammatory agents, and retinoids. ⁴ W e present a rare case of SS caused by dupilumab, a monoclonal antibody therapy, used in the treatment of severe eosinophilic asthma and atopic dermatitis.

Case Report

A 53-year-old woman presented with painful skin lesions, arthralgia, fever, and leukocytosis following initiation of dupilumab. She had a history of adult-onset, severe, persistent eosinophilic asthma, as well as chronic rhinosinusitis with nasal polyps, plaque psoriasis, and hypertrophic cardiomyopathy. She started mepolizumab 3 years prior to the current presentation for persistently uncontrolled asthma with a baseline peripheral eosinophil count of 860 cells/µL. After 3 years of minimal response to mepolizumab, she was started on dupilumab. Within 2 weeks of the first dose of dupilumab, she started experiencing bilateral knee pain. She subsequently developed daily fevers (temperature, 38.3 °C to 39.4 °C), fatigue, and pain in the back of the neck and head. After the second dose of dupilumab, she started experiencing painful skin lesions on the bilateral knuckles, elbows, and abdomen (Figure 1). She had difficulty using her hands and walking secondary to intense arthralgia involving the bilateral finger joints, elbows, and knees. Her primary care physician obtained a laboratory evaluation, which revealed an elevated total white blood cell count of 20×10³/mm³ (reference range, 4–11×10³/mm³) with 27.5% neutrophils and severely elevated eosinophils above her baseline to 57.3% with an absolute eosinophil count of 11,700 cells/µL (reference range, <400 cells/µL). Further assessment revealed an elevated erythrocyte sedimentation rate of 64 mm/h (reference range, 0–30 mm/h) and C-reactive protein level of 34 mg/dL (reference range, ≤0.80 mg/dL), with negative antinuclear antibody, rheumatoid factor, antineutrophilic cytoplasmic antibody, and Lyme antibody. IgG, IgA, and IgM levels were within reference range, and the IgE level was not elevated above her baseline. She had normal serum tryptase, and a peripheral D816V c-KIT mutation was not detected. She was subsequently hospitalized for further evaluation, at which time there was no fever or localizing infectious signs or symptoms. An infectious evaluation including urinalysis; respiratory swab for adenovirus, coronaviruses, human metapneumovirus, rhinovirus/enterovirus, influenza A and B, parainfluenza viruses, respiratory syncytial virus, Chlamydophila pneumoniae, and Mycoplasma pneumoniae; Lyme serology; and a computed tomography (CT) scan of the chest, abdomen, and pelvis revealed no evidence of infection. A parasite evaluation was ordered but was not performed. There was no evidence of malignancy on CT of the chest, abdomen, and pelvis or CT of the head without contrast. A lumbar puncture was considered but was ultimately deferred.

At the current presentation, the patient was following up in the dermatology clinic shortly after discharge. The lesions on the fingers and arms were described by the dermatologist as deep, erythematous, 0.5-cm bullous papules. The differential diagnosis at this time included a cutaneous or systemic infection, vasculitis, drug eruption, or cutaneous manifestation of an autoimmune condition. A shave biopsy of a skin lesion on the right hand demonstrated epidermal necrosis with a dense dermal neutrophilic infiltrate consistent with a neutrophilic dermatosis (Figure 2). There was no evidence of leukocytoclastic vasculitis. The histologic differential diagnosis included cutaneous infection, neutrophilic dermatosis of the hand, and SS. Special stains for infectious organisms including Gram, Grocott methenamine-silver, and auramine-rhodamine stains were negative for bacterial, fungal, and mycobacterial organisms, ruling out cutaneous infection. A diagnosis of drug-induced SS was made based on the histologic findings, diffuse distribution of the lesions, negative infectious evaluation, lack of underlying malignancy or autoimmune conditions, and onset following initiation of dupilumab.

Dupilumab was discontinued, and the patient was started on prednisone with rapid improvement in the symptoms. She underwent a slow taper of the prednisone over approximately 2 months with a slow downtrend of eosinophils. She was transitioned to a different biologic agent, benralizumab, with no further recurrence of the rash or arthralgia.

Comment

Dupilumab is a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13 signaling by binding to the IL-4Rα subunit. By blocking IL-4Rα, dupilumab inhibits IL-4 and IL-13 cytokine-induced inflammatory responses, including the release of proinflammatory cytokines, chemokines, nitric oxide, and IgE. Currently, dupilumab is approved to treat refractory forms of moderate to severe asthma characterized by an eosinophilic phenotype or with corticosteroid-dependent asthma, moderate to severe atopic dermatitis, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis. The most common adverse events (incidence ≥1%) are injection-site reactions, oropharyngeal pain, and eosinophilia.⁵ Interestingly, our patient did exhibit a high degree of eosinophilia; however, she met all criteria for drug-induced SS, and the skin biopsy was not consistent with an eosinophilic process. Notably, the peripheral neutrophils were not elevated. Neutrophilia often is seen in classic SS but is not required for a diagnosis of drug-induced SS. Rare cases of dupilumab-associated arthritis and serum sickness–like reaction have been described,^6-8 but our patient’s presentation was distinct, given other described signs, symptoms, and skin biopsy results. Histopathology results were not consistent with leukocytoclastic vasculitis, a potential mimicker of SS. Although the infectious and paraneoplastic evaluation was not exhaustive, the negative imaging from head to pelvis, the lack of recurrence of skin lesions, and the laboratory abnormalities after dupilumab discontinuation supported the conclusion that the culprit was not an infection or underlying malignancy. She had not started any other medications during this time frame, leaving dupilumab as the most likely offending agent. The mechanism for this reaction is not clear. It is possible that inhibition of IL-4 and IL-13 in the T helper 2 (T_H2) cell pathway may have led to upregulated IL-17–mediated inflammation⁹ as well as a neutrophilic process in the skin, but this would not explain the concurrent peripheral eosinophilia that was noted. Further studies are needed to investigate the pathophysiology of SS.

Conclusion

We report a rare case of dupilumab-induced SS. Corticosteroids accompanied by cessation of the medication proved to be an effective treatment. Prescribers must be aware of SS as a potential adverse reaction, as prompt recognition and treatment are needed.

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, was first described in 1964. ¹ Since then, several subtypes of SS have been recognized, including classic or idiopathic, which typically follows an acute viral illness; cancer related, typically in the form of a paraneoplastic syndrome; and drug induced. ² Drug-induced SS is defined by the following: (1) an abrupt onset of painful erythematous plaques or nodules; (2) histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis; (3) pyrexia above 38 ° C; (4) temporal relationship between drug and clinical presentation or temporally related recurrence after rechallenge; and (5) temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids. ³ All 5 criteria must be met to make a diagnosis of drug-induced SS. Since these criteria were established by Walker and Cohen, ³ various drugs have been identified as causative agents, including antibiotics, antiepileptics, antiretrovirals, antineoplastic agents, antipsychotics, oral contraceptives, nonsteroidal anti-inflammatory agents, and retinoids. ⁴ W e present a rare case of SS caused by dupilumab, a monoclonal antibody therapy, used in the treatment of severe eosinophilic asthma and atopic dermatitis.

Case Report

A 53-year-old woman presented with painful skin lesions, arthralgia, fever, and leukocytosis following initiation of dupilumab. She had a history of adult-onset, severe, persistent eosinophilic asthma, as well as chronic rhinosinusitis with nasal polyps, plaque psoriasis, and hypertrophic cardiomyopathy. She started mepolizumab 3 years prior to the current presentation for persistently uncontrolled asthma with a baseline peripheral eosinophil count of 860 cells/µL. After 3 years of minimal response to mepolizumab, she was started on dupilumab. Within 2 weeks of the first dose of dupilumab, she started experiencing bilateral knee pain. She subsequently developed daily fevers (temperature, 38.3 °C to 39.4 °C), fatigue, and pain in the back of the neck and head. After the second dose of dupilumab, she started experiencing painful skin lesions on the bilateral knuckles, elbows, and abdomen (Figure 1). She had difficulty using her hands and walking secondary to intense arthralgia involving the bilateral finger joints, elbows, and knees. Her primary care physician obtained a laboratory evaluation, which revealed an elevated total white blood cell count of 20×10³/mm³ (reference range, 4–11×10³/mm³) with 27.5% neutrophils and severely elevated eosinophils above her baseline to 57.3% with an absolute eosinophil count of 11,700 cells/µL (reference range, <400 cells/µL). Further assessment revealed an elevated erythrocyte sedimentation rate of 64 mm/h (reference range, 0–30 mm/h) and C-reactive protein level of 34 mg/dL (reference range, ≤0.80 mg/dL), with negative antinuclear antibody, rheumatoid factor, antineutrophilic cytoplasmic antibody, and Lyme antibody. IgG, IgA, and IgM levels were within reference range, and the IgE level was not elevated above her baseline. She had normal serum tryptase, and a peripheral D816V c-KIT mutation was not detected. She was subsequently hospitalized for further evaluation, at which time there was no fever or localizing infectious signs or symptoms. An infectious evaluation including urinalysis; respiratory swab for adenovirus, coronaviruses, human metapneumovirus, rhinovirus/enterovirus, influenza A and B, parainfluenza viruses, respiratory syncytial virus, Chlamydophila pneumoniae, and Mycoplasma pneumoniae; Lyme serology; and a computed tomography (CT) scan of the chest, abdomen, and pelvis revealed no evidence of infection. A parasite evaluation was ordered but was not performed. There was no evidence of malignancy on CT of the chest, abdomen, and pelvis or CT of the head without contrast. A lumbar puncture was considered but was ultimately deferred.

At the current presentation, the patient was following up in the dermatology clinic shortly after discharge. The lesions on the fingers and arms were described by the dermatologist as deep, erythematous, 0.5-cm bullous papules. The differential diagnosis at this time included a cutaneous or systemic infection, vasculitis, drug eruption, or cutaneous manifestation of an autoimmune condition. A shave biopsy of a skin lesion on the right hand demonstrated epidermal necrosis with a dense dermal neutrophilic infiltrate consistent with a neutrophilic dermatosis (Figure 2). There was no evidence of leukocytoclastic vasculitis. The histologic differential diagnosis included cutaneous infection, neutrophilic dermatosis of the hand, and SS. Special stains for infectious organisms including Gram, Grocott methenamine-silver, and auramine-rhodamine stains were negative for bacterial, fungal, and mycobacterial organisms, ruling out cutaneous infection. A diagnosis of drug-induced SS was made based on the histologic findings, diffuse distribution of the lesions, negative infectious evaluation, lack of underlying malignancy or autoimmune conditions, and onset following initiation of dupilumab.

Dupilumab was discontinued, and the patient was started on prednisone with rapid improvement in the symptoms. She underwent a slow taper of the prednisone over approximately 2 months with a slow downtrend of eosinophils. She was transitioned to a different biologic agent, benralizumab, with no further recurrence of the rash or arthralgia.

Comment

Dupilumab is a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13 signaling by binding to the IL-4Rα subunit. By blocking IL-4Rα, dupilumab inhibits IL-4 and IL-13 cytokine-induced inflammatory responses, including the release of proinflammatory cytokines, chemokines, nitric oxide, and IgE. Currently, dupilumab is approved to treat refractory forms of moderate to severe asthma characterized by an eosinophilic phenotype or with corticosteroid-dependent asthma, moderate to severe atopic dermatitis, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis. The most common adverse events (incidence ≥1%) are injection-site reactions, oropharyngeal pain, and eosinophilia.⁵ Interestingly, our patient did exhibit a high degree of eosinophilia; however, she met all criteria for drug-induced SS, and the skin biopsy was not consistent with an eosinophilic process. Notably, the peripheral neutrophils were not elevated. Neutrophilia often is seen in classic SS but is not required for a diagnosis of drug-induced SS. Rare cases of dupilumab-associated arthritis and serum sickness–like reaction have been described,^6-8 but our patient’s presentation was distinct, given other described signs, symptoms, and skin biopsy results. Histopathology results were not consistent with leukocytoclastic vasculitis, a potential mimicker of SS. Although the infectious and paraneoplastic evaluation was not exhaustive, the negative imaging from head to pelvis, the lack of recurrence of skin lesions, and the laboratory abnormalities after dupilumab discontinuation supported the conclusion that the culprit was not an infection or underlying malignancy. She had not started any other medications during this time frame, leaving dupilumab as the most likely offending agent. The mechanism for this reaction is not clear. It is possible that inhibition of IL-4 and IL-13 in the T helper 2 (T_H2) cell pathway may have led to upregulated IL-17–mediated inflammation⁹ as well as a neutrophilic process in the skin, but this would not explain the concurrent peripheral eosinophilia that was noted. Further studies are needed to investigate the pathophysiology of SS.

Conclusion

We report a rare case of dupilumab-induced SS. Corticosteroids accompanied by cessation of the medication proved to be an effective treatment. Prescribers must be aware of SS as a potential adverse reaction, as prompt recognition and treatment are needed.

To the Editor:

A 58-year-old woman presented to our dermatology clinic with a pruritic weeping eruption circumferentially on the distal digits of both hands of 5 weeks’ duration. The patient disclosed that she had been receiving dip powder manicures at a local nail salon approximately every 2 weeks over the last 3 to 6 months. She had received frequent acrylic nail extensions over the last 8 years prior to starting the dip powder manicures. Physical examination revealed well-demarcated eczematous plaques involving the lateral and proximal nail folds of the right thumb with an overlying serous crust and loss of the cuticle (Figure 1A). Erythematous plaques with firm deep-seated microvesicles also were present on the other digits, distributed distal to the distal interphalangeal joints (Figure 1B). She was diagnosed with dyshidroticlike contact dermatitis and paronychia. Treatment included phenol 1.5% colorless solution and clobetasol ointment 0.05% for twice-daily application to the affected areas. The patient also was advised to stop receiving manicures. At 1-month follow-up, the paronychia had resolved and the dermatitis had nearly resolved.

Dip powder manicures use a wet adhesive base coat with acrylic powder and an activator topcoat to initiate a chemical reaction that hardens and sets the nail polish. The colored powder typically is applied by dipping the digit up to the distal interphalangeal joint into a small container of loose powder and then brushing away the excess (Figure 2). Acrylate, a chemical present in dip powders, is a known allergen and has been associated with the development of allergic contact dermatitis and onychodystrophy in patients after receiving acrylic and UV-cured gel polish manicures.^1,2 Inadequate sanitation practices at nail salons also have been associated with infection transmission.^3,4 Additionally, the news media has covered the potential risk of infection due to contamination from reused dip manicure powder and the use of communal powder containers.⁵

To increase clinical awareness of the dip manicure technique, we describe the presentation and successful treatment of dyshidroticlike contact dermatitis and paronychia that occurred in a patient after she received a dip powder manicure. Dermatoses and infection limited to the distal phalanges will present in patients more frequently as dip powder manicures continue to increase in popularity and frequency.

To the Editor:

A 58-year-old woman presented to our dermatology clinic with a pruritic weeping eruption circumferentially on the distal digits of both hands of 5 weeks’ duration. The patient disclosed that she had been receiving dip powder manicures at a local nail salon approximately every 2 weeks over the last 3 to 6 months. She had received frequent acrylic nail extensions over the last 8 years prior to starting the dip powder manicures. Physical examination revealed well-demarcated eczematous plaques involving the lateral and proximal nail folds of the right thumb with an overlying serous crust and loss of the cuticle (Figure 1A). Erythematous plaques with firm deep-seated microvesicles also were present on the other digits, distributed distal to the distal interphalangeal joints (Figure 1B). She was diagnosed with dyshidroticlike contact dermatitis and paronychia. Treatment included phenol 1.5% colorless solution and clobetasol ointment 0.05% for twice-daily application to the affected areas. The patient also was advised to stop receiving manicures. At 1-month follow-up, the paronychia had resolved and the dermatitis had nearly resolved.

Dip powder manicures use a wet adhesive base coat with acrylic powder and an activator topcoat to initiate a chemical reaction that hardens and sets the nail polish. The colored powder typically is applied by dipping the digit up to the distal interphalangeal joint into a small container of loose powder and then brushing away the excess (Figure 2). Acrylate, a chemical present in dip powders, is a known allergen and has been associated with the development of allergic contact dermatitis and onychodystrophy in patients after receiving acrylic and UV-cured gel polish manicures.^1,2 Inadequate sanitation practices at nail salons also have been associated with infection transmission.^3,4 Additionally, the news media has covered the potential risk of infection due to contamination from reused dip manicure powder and the use of communal powder containers.⁵

To increase clinical awareness of the dip manicure technique, we describe the presentation and successful treatment of dyshidroticlike contact dermatitis and paronychia that occurred in a patient after she received a dip powder manicure. Dermatoses and infection limited to the distal phalanges will present in patients more frequently as dip powder manicures continue to increase in popularity and frequency.

To the Editor:

A 58-year-old woman presented to our dermatology clinic with a pruritic weeping eruption circumferentially on the distal digits of both hands of 5 weeks’ duration. The patient disclosed that she had been receiving dip powder manicures at a local nail salon approximately every 2 weeks over the last 3 to 6 months. She had received frequent acrylic nail extensions over the last 8 years prior to starting the dip powder manicures. Physical examination revealed well-demarcated eczematous plaques involving the lateral and proximal nail folds of the right thumb with an overlying serous crust and loss of the cuticle (Figure 1A). Erythematous plaques with firm deep-seated microvesicles also were present on the other digits, distributed distal to the distal interphalangeal joints (Figure 1B). She was diagnosed with dyshidroticlike contact dermatitis and paronychia. Treatment included phenol 1.5% colorless solution and clobetasol ointment 0.05% for twice-daily application to the affected areas. The patient also was advised to stop receiving manicures. At 1-month follow-up, the paronychia had resolved and the dermatitis had nearly resolved.

Dip powder manicures use a wet adhesive base coat with acrylic powder and an activator topcoat to initiate a chemical reaction that hardens and sets the nail polish. The colored powder typically is applied by dipping the digit up to the distal interphalangeal joint into a small container of loose powder and then brushing away the excess (Figure 2). Acrylate, a chemical present in dip powders, is a known allergen and has been associated with the development of allergic contact dermatitis and onychodystrophy in patients after receiving acrylic and UV-cured gel polish manicures.^1,2 Inadequate sanitation practices at nail salons also have been associated with infection transmission.^3,4 Additionally, the news media has covered the potential risk of infection due to contamination from reused dip manicure powder and the use of communal powder containers.⁵

To increase clinical awareness of the dip manicure technique, we describe the presentation and successful treatment of dyshidroticlike contact dermatitis and paronychia that occurred in a patient after she received a dip powder manicure. Dermatoses and infection limited to the distal phalanges will present in patients more frequently as dip powder manicures continue to increase in popularity and frequency.

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵