Dermatopathology

Health care spending in the United States remained relatively flat from 2019 to 2021 and only increased 2.7% in 2021, reaching $4.3 billion or $12,914 per person. Physician services account for 15% of health care spending (Figure). Relative value units (RVUs) signify the time it took a physician to complete a task multiplied by a conversion factor (CF). When RVUs initially were created in 1992 by what is now the Centers for Medicare &Medicaid Services (CMS), the CF was $32.00. Thirty-one years later, the CF is $33.89 in 2023; however, it would be $66.00 if the CF had increased with inflation.¹ If the proposed 2024 Medicare physician fee schedule (MPFS) is adopted, the payment formula would decrease by 3.4% ($32.75) relative to the 2023 fee schedule ($33.89), which would be a 9% decrease relative to 2019 ($36.04).^2,3 This reduction is due to the budget neutrality adjustment required by changes in RVUs, implementation of the evaluation and management (E/M) add-on code G2211, and proposed increases in primary are services.^2,3 Since 2001, Medicare physician payment has declined by 26%.⁴ Adjustments to the CF typically are made based on 3 factors: (1) the Medicare Economic Index (MEI); (2) an expenditure target performance adjustment; and (3) miscellaneous adjustments, including those for budget neutrality required by law. Despite continued substantial increases in practice expenses, physicians’ reimbursement has remained flat while other service providers, such as those in skilled nursing facilities and hospitals, have received favorable payment increases compared to practice cost inflation and the Consumer Price Index.⁴

The CMS will not incorporate 2017 MEI cost weights for the RVUs in the MPFS rate setting for 2024 because all key measures of practice expenses in the MEI accelerated in 2022. Instead, the CMS is updating data on practice expense per hour to calculate payment for physician services with a survey for physician practices that launched on July 31, 2023.⁵ The American Medical Association contracted with Mathematica, an independent research company, to conduct a physician practice information survey that will be used to determine indirect practice expenses. Physicians should be on the lookout for emails regarding completion of these surveys and the appropriate financial expert in their practice should be contacted so the responses are accurate, as these data are key to future updates in the Medicare pay formula used to reimburse physicians.

Impact of Medicare Cuts

The recent congressional debt limit deal set spending caps for the next 2 fiscal years. Dermatology is facing an overall payment reduction of 1.87% (range, 1%–4%).^2,3 The impact will depend on the services offered in an individual practice; for example, payment for a punch biopsy (Current Procedural Terminology [CPT] code 11104) would decrease by 3.9%. Payment for benign destruction (CPT code 17110) would decrease by 2.8%, and payment for even simple E/M of an established patient (CPT code 99213) would decrease by 1.6%. Overall, there would be a reduction of 2.75% for dermatopathology services, with a decrease of 2% for CPT code 88305 global and decreases for the technical component of 1% and professional component of 3%.^2,3

Medicare cuts have reached a critical level, and physicians cannot continue to absorb the costs to own and operate their practices.⁴ This has led to health market consolidation, which in turn limits competition and patient access while driving up health care costs and driving down the quality of care. Small independent rural practices as well as those caring for historically marginalized patients will be disproportionately affected.

Proposed Addition of E/M Code G2211

In the calendar year (CY) 2021 final rule, the CMS tried to adopt a new add-on code—G2211—patients with a serious or complex condition that typically require referral and coordination of multispecialty care. Per the CMS, the primary policy goal of G2211 is to increase payments to primary care physicians and to reimburse them more appropriately for the care provided to patients with a serious or complex condition.^2,3 It can be reported in conjunction with all office and outpatient E/M visits to better account for additional resources associated with primary care, or similarly ongoing medical care related to a patient’s single, serious condition, or complex condition.³ Typically, G2211 would not be used by dermatologists, as this add-on code requires visit complexity inherent to E/M associated with medical care services that serve as the continuing focal point for all needed health care services and/or with medical care services that are part of ongoing care related to a patient’s single serious condition or a complex condition.^2,3

Initially, the CMS assumed that G2211 would be reported with 90% of all office and outpatient E/M visit claims, which would account for a considerable portion of total MPFS schedule spending; however, the House of Medicine disagreed and believed it would be 75%.^2,3 Given the extremely high utilization estimate, G2211 would have had a substantial effect on budget neutrality, accounting for an estimated increase of $3.3 billion and a corresponding 3.0% cut to the CY 2021 MPFS. Because of the potential payment reductions to physicians and a successful advocacy effort by organized medicine, including the American Academy of Dermatology Association (AADA), Congress delayed implementation of G2211 until CY 2024. Modifier -25 cannot be reported with G2211. The CMS revised its utilization assumptions from 90% of all E/M services to an initial utilization of 38% and then 54% when fully adopted. The proposed 2024 payment for G2211 is an additional $16.05.^2,3

Advancing Health Equity With Healthcare Common Procedure Coding System G Codes

The CMS is proposing coding and payment for several new services to help underserved populations, including addressing unmet health-related social needs that can potentially interfere with the diagnosis and treatment of medical conditions, which includes paying for certain caregiver training services as well as payment for community health integration services.^2,3 These are the first MPFS services designed to include care involving community health workers, who link underserved communities with critical health care and social services in the community. Additionally, the rule also proposes coding and payment for evaluating the risks related to social factors that affect a patient’s health, such as access to affordable quality health care, that can take place during an annual wellness visit or in combination with an E/M visit.^2,3 As dermatologists, we should be familiar with this set of G codes, as we will likely use them in practice for patients with transportation needs.

 

 

Advocacy Efforts on Medicare Payment Reform

Medicare physician payment reform needs to happen at a national level. Advocacy efforts by the AADA and other groups have been underway to mitigate the proposed 2024 cuts. The Strengthening Medicare for Patients and Providers Act (HR 2474) is a bill that was introduced by a bipartisan coalition of physicians to provide an inflation-based increase in Medicare payments in 2024 and beyond.⁶

Other Legislative Updates Affecting Dermatology

Modifier -25—Cigna’s policy requiring dermatologists to submit documentation to use modifier -25 when billing with E/M CPT codes 99212 through 99215 has been delayed indefinitely.⁷ If a payer denies a dermatologist payment, contact the AADA Patient Access and Payer Relations committee (privatepayer@aad.org) for assistance.

Telehealth and Digital Pathology—Recent legislation authorized extension of many of the Medicare telehealth and digital pathology flexibilities that were put in place during the COVID-19 public health emergency through December 31, 2024.^8,9 Seventeen newly approved CPT telemedicine codes for new and established patient audio-visual and audio-only visits recently were surveyed.^2,3 The data from the survey will be used as a key element in assigning a specific RVU to the CMS and will be included in the MPFS.

Thirty additional new digital pathology add-on CPT category III codes for 2024 were added to the ones from 2023.^2,3 These codes can be used to report additional clinical staff work and service requirements associated with digitizing glass microscope slides for primary diagnosis. They cannot be used for archival or educational purposes, clinical conferences, training, or validating artificial intelligence algorithms. Category III codes used for emerging technologies have no assigned RVUs or reimbursement.^2,3

The Cures Act—The Cures Act aims to ensure that patients have timely access to their health information.¹⁰ It requires all physicians to make their office notes, laboratory results, and other diagnostic reports available to patients as soon as the office receives them. The rules went into effect on April 5, 2021, with a limited definition of electronic health information; on October 6, 2022, the Cures Act rule expanded to include all electronic health information. The AADA has urged the Office of the National Coordinator for Health Information Technology to collaborate with stakeholder organizations to re-evaluate federal policies concerning the immediate release of electronic health information and information blocking, particularly in cases with life-altering diagnoses.¹⁰ They stressed the importance of prioritizing the well-being and emotional stability of patients and enhancing care by providing patients adequate time and support to process, comprehend, and discuss findings with their physician.

Proposed 2024 Medicare Quality Payment Program Requirements

The CMS proposed to increase the performance threshold in the quality payment program from 75 to 82 points for the 2024 Merit-based Incentive Payment System (MIPS) performance period, impacting the 2026 payment year.^2,3,11 As a result of this increase, there could be more MIPS-eligible clinicians receiving penalties, which could be a reduction of up to 9%. The AADA will firmly oppose any increase in the threshold and strongly urge CMS to maintain the 75-point threshold. The performance category weights for the 2024 performance year will remain unchanged from the 2023 performance year.^2,3,11

2024 Proposed Quality MIPS Measures Set—The CMS proposed to remove the topped-out MIPS measure 138 (coordination of care for melanoma).^2,3,11 Additionally, it proposed to remove MIPS measure 402 (tobacco use and help with quitting among adolescents) as a quality measure from MIPS because the agency believes it is duplicative of measure 226 (preventive care and screening: tobacco use: screening and cessation intervention).^2,3,11

MIPS Value Pathways—The CMS consolidated 2 previously established MIPS value pathways (MVPs): the Promoting Wellness MVP and the Optimizing Chronic Disease Management MVP.^2,3,11 Proposed new MVPs for 2024 include Focusing on Women’s Health; Quality Care for the Treatment of Ear, Nose, and Throat Disorders; Prevention and Treatment of Infectious Disorders Including Hepatitis C and HIV; Quality Care in Mental Health and Substance Use Disorders; and Rehabilitative Support for Musculoskeletal Care. Dermatology is not impacted; however, the CMS plans to sunset traditional MIPS and replace it with MVPs—the future of MIPS.^2,3,11 The AADA maintains that traditional MIPS should continue to be an option because MVPs have a limited number of measures for dermatologists.

Update on Reporting Suture Removal

There are 2 new CPT add-on codes—15853 and 15854—for the removal of sutures or staples not requiring anesthesia to be listed separately in addition to an appropriate E/M service. These add-on codes went into effect on January 1, 2023.¹² These codes were created with the intent to capture and ensure remuneration for practice expenses that are not included in a stand-alone E/M encounter that occur after a 0-day procedure (eg, services reported with CPT codes 11102–11107 and 11300–11313) for wound check and suture removal where appropriate. These new add-on codes do not have physician work RVUs assigned to them because they are only for practice expenses (eg, clinical staff time, disposable supplies, use of equipment); CPT code 15853 is reported for the removal of sutures or staples, and CPT code 15854 is reported when both sutures and staples are removed. These codes can only be reported if an E/M service also is reported for the patient encounter.¹²

Final Thoughts

The AADA is working with the House of Medicine and the medical specialty community to develop specific proposals to reform the Medicare payment system.⁴ The proposed 2024 MPFS was released on July 13, 2023, and final regulations are expected in the late fall of 2023. The AADA will continue to engage with the CMS, but it is important for physicians to learn about and support advocacy priorities and efforts as well as join forces to protect their practices. As health care professionals, we have unique insights into the challenges and needs of our patients and the health care system. Advocacy can take various forms, such as supporting or opposing specific legislations, participating in grassroots campaigns, engaging with policymakers, and/or joining professional organizations that advocate for health care–related issues. Get involved, stay informed, and stay engaged through dermatology medical societies; together we can make a difference.

Health care spending in the United States remained relatively flat from 2019 to 2021 and only increased 2.7% in 2021, reaching $4.3 billion or $12,914 per person. Physician services account for 15% of health care spending (Figure). Relative value units (RVUs) signify the time it took a physician to complete a task multiplied by a conversion factor (CF). When RVUs initially were created in 1992 by what is now the Centers for Medicare &Medicaid Services (CMS), the CF was $32.00. Thirty-one years later, the CF is $33.89 in 2023; however, it would be $66.00 if the CF had increased with inflation.¹ If the proposed 2024 Medicare physician fee schedule (MPFS) is adopted, the payment formula would decrease by 3.4% ($32.75) relative to the 2023 fee schedule ($33.89), which would be a 9% decrease relative to 2019 ($36.04).^2,3 This reduction is due to the budget neutrality adjustment required by changes in RVUs, implementation of the evaluation and management (E/M) add-on code G2211, and proposed increases in primary are services.^2,3 Since 2001, Medicare physician payment has declined by 26%.⁴ Adjustments to the CF typically are made based on 3 factors: (1) the Medicare Economic Index (MEI); (2) an expenditure target performance adjustment; and (3) miscellaneous adjustments, including those for budget neutrality required by law. Despite continued substantial increases in practice expenses, physicians’ reimbursement has remained flat while other service providers, such as those in skilled nursing facilities and hospitals, have received favorable payment increases compared to practice cost inflation and the Consumer Price Index.⁴

The CMS will not incorporate 2017 MEI cost weights for the RVUs in the MPFS rate setting for 2024 because all key measures of practice expenses in the MEI accelerated in 2022. Instead, the CMS is updating data on practice expense per hour to calculate payment for physician services with a survey for physician practices that launched on July 31, 2023.⁵ The American Medical Association contracted with Mathematica, an independent research company, to conduct a physician practice information survey that will be used to determine indirect practice expenses. Physicians should be on the lookout for emails regarding completion of these surveys and the appropriate financial expert in their practice should be contacted so the responses are accurate, as these data are key to future updates in the Medicare pay formula used to reimburse physicians.

Impact of Medicare Cuts

The recent congressional debt limit deal set spending caps for the next 2 fiscal years. Dermatology is facing an overall payment reduction of 1.87% (range, 1%–4%).^2,3 The impact will depend on the services offered in an individual practice; for example, payment for a punch biopsy (Current Procedural Terminology [CPT] code 11104) would decrease by 3.9%. Payment for benign destruction (CPT code 17110) would decrease by 2.8%, and payment for even simple E/M of an established patient (CPT code 99213) would decrease by 1.6%. Overall, there would be a reduction of 2.75% for dermatopathology services, with a decrease of 2% for CPT code 88305 global and decreases for the technical component of 1% and professional component of 3%.^2,3

Medicare cuts have reached a critical level, and physicians cannot continue to absorb the costs to own and operate their practices.⁴ This has led to health market consolidation, which in turn limits competition and patient access while driving up health care costs and driving down the quality of care. Small independent rural practices as well as those caring for historically marginalized patients will be disproportionately affected.

Proposed Addition of E/M Code G2211

In the calendar year (CY) 2021 final rule, the CMS tried to adopt a new add-on code—G2211—patients with a serious or complex condition that typically require referral and coordination of multispecialty care. Per the CMS, the primary policy goal of G2211 is to increase payments to primary care physicians and to reimburse them more appropriately for the care provided to patients with a serious or complex condition.^2,3 It can be reported in conjunction with all office and outpatient E/M visits to better account for additional resources associated with primary care, or similarly ongoing medical care related to a patient’s single, serious condition, or complex condition.³ Typically, G2211 would not be used by dermatologists, as this add-on code requires visit complexity inherent to E/M associated with medical care services that serve as the continuing focal point for all needed health care services and/or with medical care services that are part of ongoing care related to a patient’s single serious condition or a complex condition.^2,3

Initially, the CMS assumed that G2211 would be reported with 90% of all office and outpatient E/M visit claims, which would account for a considerable portion of total MPFS schedule spending; however, the House of Medicine disagreed and believed it would be 75%.^2,3 Given the extremely high utilization estimate, G2211 would have had a substantial effect on budget neutrality, accounting for an estimated increase of $3.3 billion and a corresponding 3.0% cut to the CY 2021 MPFS. Because of the potential payment reductions to physicians and a successful advocacy effort by organized medicine, including the American Academy of Dermatology Association (AADA), Congress delayed implementation of G2211 until CY 2024. Modifier -25 cannot be reported with G2211. The CMS revised its utilization assumptions from 90% of all E/M services to an initial utilization of 38% and then 54% when fully adopted. The proposed 2024 payment for G2211 is an additional $16.05.^2,3

Advancing Health Equity With Healthcare Common Procedure Coding System G Codes

The CMS is proposing coding and payment for several new services to help underserved populations, including addressing unmet health-related social needs that can potentially interfere with the diagnosis and treatment of medical conditions, which includes paying for certain caregiver training services as well as payment for community health integration services.^2,3 These are the first MPFS services designed to include care involving community health workers, who link underserved communities with critical health care and social services in the community. Additionally, the rule also proposes coding and payment for evaluating the risks related to social factors that affect a patient’s health, such as access to affordable quality health care, that can take place during an annual wellness visit or in combination with an E/M visit.^2,3 As dermatologists, we should be familiar with this set of G codes, as we will likely use them in practice for patients with transportation needs.

 

 

Advocacy Efforts on Medicare Payment Reform

Medicare physician payment reform needs to happen at a national level. Advocacy efforts by the AADA and other groups have been underway to mitigate the proposed 2024 cuts. The Strengthening Medicare for Patients and Providers Act (HR 2474) is a bill that was introduced by a bipartisan coalition of physicians to provide an inflation-based increase in Medicare payments in 2024 and beyond.⁶

Other Legislative Updates Affecting Dermatology

Modifier -25—Cigna’s policy requiring dermatologists to submit documentation to use modifier -25 when billing with E/M CPT codes 99212 through 99215 has been delayed indefinitely.⁷ If a payer denies a dermatologist payment, contact the AADA Patient Access and Payer Relations committee (privatepayer@aad.org) for assistance.

Telehealth and Digital Pathology—Recent legislation authorized extension of many of the Medicare telehealth and digital pathology flexibilities that were put in place during the COVID-19 public health emergency through December 31, 2024.^8,9 Seventeen newly approved CPT telemedicine codes for new and established patient audio-visual and audio-only visits recently were surveyed.^2,3 The data from the survey will be used as a key element in assigning a specific RVU to the CMS and will be included in the MPFS.

Thirty additional new digital pathology add-on CPT category III codes for 2024 were added to the ones from 2023.^2,3 These codes can be used to report additional clinical staff work and service requirements associated with digitizing glass microscope slides for primary diagnosis. They cannot be used for archival or educational purposes, clinical conferences, training, or validating artificial intelligence algorithms. Category III codes used for emerging technologies have no assigned RVUs or reimbursement.^2,3

The Cures Act—The Cures Act aims to ensure that patients have timely access to their health information.¹⁰ It requires all physicians to make their office notes, laboratory results, and other diagnostic reports available to patients as soon as the office receives them. The rules went into effect on April 5, 2021, with a limited definition of electronic health information; on October 6, 2022, the Cures Act rule expanded to include all electronic health information. The AADA has urged the Office of the National Coordinator for Health Information Technology to collaborate with stakeholder organizations to re-evaluate federal policies concerning the immediate release of electronic health information and information blocking, particularly in cases with life-altering diagnoses.¹⁰ They stressed the importance of prioritizing the well-being and emotional stability of patients and enhancing care by providing patients adequate time and support to process, comprehend, and discuss findings with their physician.

Proposed 2024 Medicare Quality Payment Program Requirements

The CMS proposed to increase the performance threshold in the quality payment program from 75 to 82 points for the 2024 Merit-based Incentive Payment System (MIPS) performance period, impacting the 2026 payment year.^2,3,11 As a result of this increase, there could be more MIPS-eligible clinicians receiving penalties, which could be a reduction of up to 9%. The AADA will firmly oppose any increase in the threshold and strongly urge CMS to maintain the 75-point threshold. The performance category weights for the 2024 performance year will remain unchanged from the 2023 performance year.^2,3,11

2024 Proposed Quality MIPS Measures Set—The CMS proposed to remove the topped-out MIPS measure 138 (coordination of care for melanoma).^2,3,11 Additionally, it proposed to remove MIPS measure 402 (tobacco use and help with quitting among adolescents) as a quality measure from MIPS because the agency believes it is duplicative of measure 226 (preventive care and screening: tobacco use: screening and cessation intervention).^2,3,11

MIPS Value Pathways—The CMS consolidated 2 previously established MIPS value pathways (MVPs): the Promoting Wellness MVP and the Optimizing Chronic Disease Management MVP.^2,3,11 Proposed new MVPs for 2024 include Focusing on Women’s Health; Quality Care for the Treatment of Ear, Nose, and Throat Disorders; Prevention and Treatment of Infectious Disorders Including Hepatitis C and HIV; Quality Care in Mental Health and Substance Use Disorders; and Rehabilitative Support for Musculoskeletal Care. Dermatology is not impacted; however, the CMS plans to sunset traditional MIPS and replace it with MVPs—the future of MIPS.^2,3,11 The AADA maintains that traditional MIPS should continue to be an option because MVPs have a limited number of measures for dermatologists.

Update on Reporting Suture Removal

There are 2 new CPT add-on codes—15853 and 15854—for the removal of sutures or staples not requiring anesthesia to be listed separately in addition to an appropriate E/M service. These add-on codes went into effect on January 1, 2023.¹² These codes were created with the intent to capture and ensure remuneration for practice expenses that are not included in a stand-alone E/M encounter that occur after a 0-day procedure (eg, services reported with CPT codes 11102–11107 and 11300–11313) for wound check and suture removal where appropriate. These new add-on codes do not have physician work RVUs assigned to them because they are only for practice expenses (eg, clinical staff time, disposable supplies, use of equipment); CPT code 15853 is reported for the removal of sutures or staples, and CPT code 15854 is reported when both sutures and staples are removed. These codes can only be reported if an E/M service also is reported for the patient encounter.¹²

Final Thoughts

The AADA is working with the House of Medicine and the medical specialty community to develop specific proposals to reform the Medicare payment system.⁴ The proposed 2024 MPFS was released on July 13, 2023, and final regulations are expected in the late fall of 2023. The AADA will continue to engage with the CMS, but it is important for physicians to learn about and support advocacy priorities and efforts as well as join forces to protect their practices. As health care professionals, we have unique insights into the challenges and needs of our patients and the health care system. Advocacy can take various forms, such as supporting or opposing specific legislations, participating in grassroots campaigns, engaging with policymakers, and/or joining professional organizations that advocate for health care–related issues. Get involved, stay informed, and stay engaged through dermatology medical societies; together we can make a difference.

Health care spending in the United States remained relatively flat from 2019 to 2021 and only increased 2.7% in 2021, reaching $4.3 billion or $12,914 per person. Physician services account for 15% of health care spending (Figure). Relative value units (RVUs) signify the time it took a physician to complete a task multiplied by a conversion factor (CF). When RVUs initially were created in 1992 by what is now the Centers for Medicare &Medicaid Services (CMS), the CF was $32.00. Thirty-one years later, the CF is $33.89 in 2023; however, it would be $66.00 if the CF had increased with inflation.¹ If the proposed 2024 Medicare physician fee schedule (MPFS) is adopted, the payment formula would decrease by 3.4% ($32.75) relative to the 2023 fee schedule ($33.89), which would be a 9% decrease relative to 2019 ($36.04).^2,3 This reduction is due to the budget neutrality adjustment required by changes in RVUs, implementation of the evaluation and management (E/M) add-on code G2211, and proposed increases in primary are services.^2,3 Since 2001, Medicare physician payment has declined by 26%.⁴ Adjustments to the CF typically are made based on 3 factors: (1) the Medicare Economic Index (MEI); (2) an expenditure target performance adjustment; and (3) miscellaneous adjustments, including those for budget neutrality required by law. Despite continued substantial increases in practice expenses, physicians’ reimbursement has remained flat while other service providers, such as those in skilled nursing facilities and hospitals, have received favorable payment increases compared to practice cost inflation and the Consumer Price Index.⁴

The CMS will not incorporate 2017 MEI cost weights for the RVUs in the MPFS rate setting for 2024 because all key measures of practice expenses in the MEI accelerated in 2022. Instead, the CMS is updating data on practice expense per hour to calculate payment for physician services with a survey for physician practices that launched on July 31, 2023.⁵ The American Medical Association contracted with Mathematica, an independent research company, to conduct a physician practice information survey that will be used to determine indirect practice expenses. Physicians should be on the lookout for emails regarding completion of these surveys and the appropriate financial expert in their practice should be contacted so the responses are accurate, as these data are key to future updates in the Medicare pay formula used to reimburse physicians.

Impact of Medicare Cuts

The recent congressional debt limit deal set spending caps for the next 2 fiscal years. Dermatology is facing an overall payment reduction of 1.87% (range, 1%–4%).^2,3 The impact will depend on the services offered in an individual practice; for example, payment for a punch biopsy (Current Procedural Terminology [CPT] code 11104) would decrease by 3.9%. Payment for benign destruction (CPT code 17110) would decrease by 2.8%, and payment for even simple E/M of an established patient (CPT code 99213) would decrease by 1.6%. Overall, there would be a reduction of 2.75% for dermatopathology services, with a decrease of 2% for CPT code 88305 global and decreases for the technical component of 1% and professional component of 3%.^2,3

Medicare cuts have reached a critical level, and physicians cannot continue to absorb the costs to own and operate their practices.⁴ This has led to health market consolidation, which in turn limits competition and patient access while driving up health care costs and driving down the quality of care. Small independent rural practices as well as those caring for historically marginalized patients will be disproportionately affected.

Proposed Addition of E/M Code G2211

In the calendar year (CY) 2021 final rule, the CMS tried to adopt a new add-on code—G2211—patients with a serious or complex condition that typically require referral and coordination of multispecialty care. Per the CMS, the primary policy goal of G2211 is to increase payments to primary care physicians and to reimburse them more appropriately for the care provided to patients with a serious or complex condition.^2,3 It can be reported in conjunction with all office and outpatient E/M visits to better account for additional resources associated with primary care, or similarly ongoing medical care related to a patient’s single, serious condition, or complex condition.³ Typically, G2211 would not be used by dermatologists, as this add-on code requires visit complexity inherent to E/M associated with medical care services that serve as the continuing focal point for all needed health care services and/or with medical care services that are part of ongoing care related to a patient’s single serious condition or a complex condition.^2,3

Initially, the CMS assumed that G2211 would be reported with 90% of all office and outpatient E/M visit claims, which would account for a considerable portion of total MPFS schedule spending; however, the House of Medicine disagreed and believed it would be 75%.^2,3 Given the extremely high utilization estimate, G2211 would have had a substantial effect on budget neutrality, accounting for an estimated increase of $3.3 billion and a corresponding 3.0% cut to the CY 2021 MPFS. Because of the potential payment reductions to physicians and a successful advocacy effort by organized medicine, including the American Academy of Dermatology Association (AADA), Congress delayed implementation of G2211 until CY 2024. Modifier -25 cannot be reported with G2211. The CMS revised its utilization assumptions from 90% of all E/M services to an initial utilization of 38% and then 54% when fully adopted. The proposed 2024 payment for G2211 is an additional $16.05.^2,3

Advancing Health Equity With Healthcare Common Procedure Coding System G Codes

The CMS is proposing coding and payment for several new services to help underserved populations, including addressing unmet health-related social needs that can potentially interfere with the diagnosis and treatment of medical conditions, which includes paying for certain caregiver training services as well as payment for community health integration services.^2,3 These are the first MPFS services designed to include care involving community health workers, who link underserved communities with critical health care and social services in the community. Additionally, the rule also proposes coding and payment for evaluating the risks related to social factors that affect a patient’s health, such as access to affordable quality health care, that can take place during an annual wellness visit or in combination with an E/M visit.^2,3 As dermatologists, we should be familiar with this set of G codes, as we will likely use them in practice for patients with transportation needs.

 

 

Advocacy Efforts on Medicare Payment Reform

Medicare physician payment reform needs to happen at a national level. Advocacy efforts by the AADA and other groups have been underway to mitigate the proposed 2024 cuts. The Strengthening Medicare for Patients and Providers Act (HR 2474) is a bill that was introduced by a bipartisan coalition of physicians to provide an inflation-based increase in Medicare payments in 2024 and beyond.⁶

Other Legislative Updates Affecting Dermatology

Modifier -25—Cigna’s policy requiring dermatologists to submit documentation to use modifier -25 when billing with E/M CPT codes 99212 through 99215 has been delayed indefinitely.⁷ If a payer denies a dermatologist payment, contact the AADA Patient Access and Payer Relations committee (privatepayer@aad.org) for assistance.

Telehealth and Digital Pathology—Recent legislation authorized extension of many of the Medicare telehealth and digital pathology flexibilities that were put in place during the COVID-19 public health emergency through December 31, 2024.^8,9 Seventeen newly approved CPT telemedicine codes for new and established patient audio-visual and audio-only visits recently were surveyed.^2,3 The data from the survey will be used as a key element in assigning a specific RVU to the CMS and will be included in the MPFS.

Thirty additional new digital pathology add-on CPT category III codes for 2024 were added to the ones from 2023.^2,3 These codes can be used to report additional clinical staff work and service requirements associated with digitizing glass microscope slides for primary diagnosis. They cannot be used for archival or educational purposes, clinical conferences, training, or validating artificial intelligence algorithms. Category III codes used for emerging technologies have no assigned RVUs or reimbursement.^2,3

The Cures Act—The Cures Act aims to ensure that patients have timely access to their health information.¹⁰ It requires all physicians to make their office notes, laboratory results, and other diagnostic reports available to patients as soon as the office receives them. The rules went into effect on April 5, 2021, with a limited definition of electronic health information; on October 6, 2022, the Cures Act rule expanded to include all electronic health information. The AADA has urged the Office of the National Coordinator for Health Information Technology to collaborate with stakeholder organizations to re-evaluate federal policies concerning the immediate release of electronic health information and information blocking, particularly in cases with life-altering diagnoses.¹⁰ They stressed the importance of prioritizing the well-being and emotional stability of patients and enhancing care by providing patients adequate time and support to process, comprehend, and discuss findings with their physician.

Proposed 2024 Medicare Quality Payment Program Requirements

The CMS proposed to increase the performance threshold in the quality payment program from 75 to 82 points for the 2024 Merit-based Incentive Payment System (MIPS) performance period, impacting the 2026 payment year.^2,3,11 As a result of this increase, there could be more MIPS-eligible clinicians receiving penalties, which could be a reduction of up to 9%. The AADA will firmly oppose any increase in the threshold and strongly urge CMS to maintain the 75-point threshold. The performance category weights for the 2024 performance year will remain unchanged from the 2023 performance year.^2,3,11

2024 Proposed Quality MIPS Measures Set—The CMS proposed to remove the topped-out MIPS measure 138 (coordination of care for melanoma).^2,3,11 Additionally, it proposed to remove MIPS measure 402 (tobacco use and help with quitting among adolescents) as a quality measure from MIPS because the agency believes it is duplicative of measure 226 (preventive care and screening: tobacco use: screening and cessation intervention).^2,3,11

MIPS Value Pathways—The CMS consolidated 2 previously established MIPS value pathways (MVPs): the Promoting Wellness MVP and the Optimizing Chronic Disease Management MVP.^2,3,11 Proposed new MVPs for 2024 include Focusing on Women’s Health; Quality Care for the Treatment of Ear, Nose, and Throat Disorders; Prevention and Treatment of Infectious Disorders Including Hepatitis C and HIV; Quality Care in Mental Health and Substance Use Disorders; and Rehabilitative Support for Musculoskeletal Care. Dermatology is not impacted; however, the CMS plans to sunset traditional MIPS and replace it with MVPs—the future of MIPS.^2,3,11 The AADA maintains that traditional MIPS should continue to be an option because MVPs have a limited number of measures for dermatologists.

Update on Reporting Suture Removal

There are 2 new CPT add-on codes—15853 and 15854—for the removal of sutures or staples not requiring anesthesia to be listed separately in addition to an appropriate E/M service. These add-on codes went into effect on January 1, 2023.¹² These codes were created with the intent to capture and ensure remuneration for practice expenses that are not included in a stand-alone E/M encounter that occur after a 0-day procedure (eg, services reported with CPT codes 11102–11107 and 11300–11313) for wound check and suture removal where appropriate. These new add-on codes do not have physician work RVUs assigned to them because they are only for practice expenses (eg, clinical staff time, disposable supplies, use of equipment); CPT code 15853 is reported for the removal of sutures or staples, and CPT code 15854 is reported when both sutures and staples are removed. These codes can only be reported if an E/M service also is reported for the patient encounter.¹²

Final Thoughts

The AADA is working with the House of Medicine and the medical specialty community to develop specific proposals to reform the Medicare payment system.⁴ The proposed 2024 MPFS was released on July 13, 2023, and final regulations are expected in the late fall of 2023. The AADA will continue to engage with the CMS, but it is important for physicians to learn about and support advocacy priorities and efforts as well as join forces to protect their practices. As health care professionals, we have unique insights into the challenges and needs of our patients and the health care system. Advocacy can take various forms, such as supporting or opposing specific legislations, participating in grassroots campaigns, engaging with policymakers, and/or joining professional organizations that advocate for health care–related issues. Get involved, stay informed, and stay engaged through dermatology medical societies; together we can make a difference.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

To the Editor:

Granulomatous dermatitis (GD) has been described as a rare side effect of MEK and BRAF inhibitor use in the treatment of BRAF V600E mutation–positive metastatic melanoma. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation. We present the case of a 52-year-old woman who developed GD while being treated with vemurafenib and cobimetinib for BRAF V600E mutation–positive metastatic cholangiocarcinoma.

A 52-year-old White woman presented with faint patches of nonpalpable violaceous mottling that extended distally to proximally from the ankles to the thighs on the medial aspects of both legs. She was diagnosed with cholangiocarcinoma 10 months prior, with metastases to the lung, liver, and sternum. She underwent treatment with gemcitabine and cisplatin therapy. Computed tomography after several treatment cycles revealed progressive disease with multiple pulmonary nodules as well as metastatic intrathoracic and abdominal adenopathy. Treatment with gemcitabine and cisplatin failed to produce a favorable response and was discontinued after 6 treatment cycles.

Genomic testing performed at the time of diagnosis revealed a positive mutation for BRAF V600E. The patient subsequently enrolled in a clinical trial and started treatment with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. She developed sun sensitivity and multiple sunburns after starting these therapies. The patient tolerated the next few cycles of therapy well with only moderate concerns of dry sensitive skin.

During the sixth cycle of therapy, she presented to dermatology after developing a rash. Over the next 2 weeks, similar lesions appeared on the arms. The patient denied the use of any new lotions, soaps, or other medications. Punch biopsies of the right forearm and right medial thigh revealed nonnecrotizing granulomas in the superficial dermis that extended into the subcutaneous adipose tissue (Figure 1). Surrounding chronic inflammation was scant, and the presence of rare eosinophils was noted (Figure 2). The histiocytes were highlighted by a CD68 immunohistochemical stain. An auramine-O special stain test was negative for acid-fast bacilli, and a Grocott methenamine-silver special stain test for fungal organisms was negative. These findings were consistent with GD. Computed tomography of the chest performed 2 months prior and 1 month after biopsy of the skin lesions revealed no axillary, mediastinal, or hilar lymphadenopathy. The calcium level at the time of skin biopsy was within reference range.

A topical steroid was prescribed; however, it was not utilized by the patient. Within 2 months of onset, the GD lesions resolved with no treatment. The GD lesions did not affect the patient’s enrollment in the clinical trial, and no dose reductions were made. Due to progressive disease with metastases to the brain, the patient eventually discontinued the clinical trial.

BRAF inhibitors are US Food and Drug Administration approved for the treatment of metastatic melanoma to deactivate the serine-threonine kinase BRAF gene mutation, which leads to decreased generation and survival of melanoma cells.^1,2 Vemurafenib, dabrafenib, and encorafenib are the only BRAF inhibitors approved in the United States.³ The most common side effects of vemurafenib include arthralgia, fatigue, rash, and photosensitivity.^1,4 There are 4 MEK inhibitors currently available in the United States: cobimetinib, trametinib, selumetinib and binimetinib. The addition of a MEK inhibitor to BRAF inhibitor therapy has shown increased patient response rates and prolonged survival in 3 phase 3 studies.^5-10

Response rates remain low in the treatment of advanced cholangiocarcinoma with standard chemotherapy. Recent research has explored if targeted therapies at the molecular level would be of benefit.¹¹ Our patient was enrolled in the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (TAPUR) trial, a phase 2, prospective, nonrandomized trial that matches eligible participants to US Food and Drug Administration–approved study medications based on specific data from their molecular testing results.¹² Some of the most common mutations in intrahepatic cholangiocarcinoma include HER2, KRAS, MET, and BRAF.^13-17 Our patient’s molecular test results were positive for a BRAF V600E–positive mutation, and she subsequently started therapy with vemurafenib and cobimetinib. The use of personalized genomic treatment approaches for BRAF V600E mutation–positive cholangiocarcinoma has produced a dramatic patient response to BRAF and MEK inhibitor combination therapies.^11,18-20

Drug-induced GD most likely is caused by vascular insults that lead to deposition of immune complexes in vessels causing inflammation and a consequent granulomatous infiltrate.^21,22 Although cordlike lesions in the subcutaneous tissue on the trunk commonly are reported, the presentation of GD can vary considerably. Other presentations include areas of violaceous or erythematous patches or plaques on the limbs, intertriginous areas, and upper trunk. Diffuse macular erythema or small flesh-colored papules also can be observed.²³

Granulomatous dermatitis secondary to drug reactions can have varying morphologies. The infiltrate often can have an interstitial appearance with the presence of lymphocytes, plasma cells, histiocytes, eosinophils, and multinucleated giant cells.²⁴ These findings can be confused with interstitial granuloma annulare. Other cases, such as in our patient, can have discrete granulomata formation with a sarcoidlike appearance. These naked granulomas lack surrounding inflammation and suggest a differential diagnosis of sarcoidosis and infection. Use of immune checkpoint inhibitors (CIs) and kinase inhibitors has been proven to cause sarcoidosislike reactions.²⁵ The development of granulomatous/sarcoidlike lesions associated with the use of BRAF and MEK inhibitors may clinically and radiographically mimic disease recurrence. An awareness of this type of reaction by clinicians and pathologists is important to ensure appropriate management in patients who develop GD.²⁶

Checkpoint inhibitor–induced GD that remains asymptomatic does not necessarily warrant treatment; however, corticosteroid use and elimination of CI therapies have resolved GD in prior cases. Responsiveness of the cancer to CI therapy and severity of GD symptoms should be considered before discontinuation of a CI trial.²⁵

One case report described complete resolution of a GD eruption without interruption of the scheduled BRAF and MEK inhibitor therapies for the treatment of metastatic melanoma. There was no reported use of a steroidal cream or other topical medication to aid in controlling the eruption.²⁷ The exact mechanism of how GD resolves while continuing therapy is unknown; however, it has been suggested that a GD eruption may be the consequence of a BRAF and MEK inhibitor–mediated immune response against a subclinical area of metastatic melanoma.²⁸ If the immune response successfully eliminates the subclinical tumor, one could postulate that the inflammatory response and granulomatous eruption would resolve. Future studies are necessary to further elucidate the exact mechanisms involved.

There have been several case reports of GD with vemurafenib treatment,^29,30 1 report of GD and erythema induratum with vemurafenib and cobimetinib treatment,³¹ 2 reports of GD with dabrafenib treatment,^27,30 and a few reports of GD with the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib,^28,32,33 all for the treatment of metastatic melanoma. Additionally, a report described a 3-year-old boy who developed GD secondary to vemurafenib for the treatment of Langerhans cell histiocytosis.³⁴ We present a unique case of BRAF and MEK inhibitor therapy–induced GD in the treatment of metastatic cholangiocarcinoma with vemurafenib and cobimetinib.

BRAF and MEK inhibitor therapy is used in patients with metastatic melanomas with a positive BRAF V600E mutation. Due to advancements in next-generation DNA sequencing, these therapies also are being tested in clinical trials for use in the treatment of other cancers with the same checkpoint mutation, such as metastatic cholangiocarcinoma. Cutaneous reactions frequently are documented side effects that occur during treatment with BRAF and MEK inhibitors; GD is an uncommon finding. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of other cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation.

To the Editor:

Granulomatous dermatitis (GD) has been described as a rare side effect of MEK and BRAF inhibitor use in the treatment of BRAF V600E mutation–positive metastatic melanoma. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation. We present the case of a 52-year-old woman who developed GD while being treated with vemurafenib and cobimetinib for BRAF V600E mutation–positive metastatic cholangiocarcinoma.

A 52-year-old White woman presented with faint patches of nonpalpable violaceous mottling that extended distally to proximally from the ankles to the thighs on the medial aspects of both legs. She was diagnosed with cholangiocarcinoma 10 months prior, with metastases to the lung, liver, and sternum. She underwent treatment with gemcitabine and cisplatin therapy. Computed tomography after several treatment cycles revealed progressive disease with multiple pulmonary nodules as well as metastatic intrathoracic and abdominal adenopathy. Treatment with gemcitabine and cisplatin failed to produce a favorable response and was discontinued after 6 treatment cycles.

Genomic testing performed at the time of diagnosis revealed a positive mutation for BRAF V600E. The patient subsequently enrolled in a clinical trial and started treatment with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. She developed sun sensitivity and multiple sunburns after starting these therapies. The patient tolerated the next few cycles of therapy well with only moderate concerns of dry sensitive skin.

During the sixth cycle of therapy, she presented to dermatology after developing a rash. Over the next 2 weeks, similar lesions appeared on the arms. The patient denied the use of any new lotions, soaps, or other medications. Punch biopsies of the right forearm and right medial thigh revealed nonnecrotizing granulomas in the superficial dermis that extended into the subcutaneous adipose tissue (Figure 1). Surrounding chronic inflammation was scant, and the presence of rare eosinophils was noted (Figure 2). The histiocytes were highlighted by a CD68 immunohistochemical stain. An auramine-O special stain test was negative for acid-fast bacilli, and a Grocott methenamine-silver special stain test for fungal organisms was negative. These findings were consistent with GD. Computed tomography of the chest performed 2 months prior and 1 month after biopsy of the skin lesions revealed no axillary, mediastinal, or hilar lymphadenopathy. The calcium level at the time of skin biopsy was within reference range.

A topical steroid was prescribed; however, it was not utilized by the patient. Within 2 months of onset, the GD lesions resolved with no treatment. The GD lesions did not affect the patient’s enrollment in the clinical trial, and no dose reductions were made. Due to progressive disease with metastases to the brain, the patient eventually discontinued the clinical trial.

BRAF inhibitors are US Food and Drug Administration approved for the treatment of metastatic melanoma to deactivate the serine-threonine kinase BRAF gene mutation, which leads to decreased generation and survival of melanoma cells.^1,2 Vemurafenib, dabrafenib, and encorafenib are the only BRAF inhibitors approved in the United States.³ The most common side effects of vemurafenib include arthralgia, fatigue, rash, and photosensitivity.^1,4 There are 4 MEK inhibitors currently available in the United States: cobimetinib, trametinib, selumetinib and binimetinib. The addition of a MEK inhibitor to BRAF inhibitor therapy has shown increased patient response rates and prolonged survival in 3 phase 3 studies.^5-10

Response rates remain low in the treatment of advanced cholangiocarcinoma with standard chemotherapy. Recent research has explored if targeted therapies at the molecular level would be of benefit.¹¹ Our patient was enrolled in the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (TAPUR) trial, a phase 2, prospective, nonrandomized trial that matches eligible participants to US Food and Drug Administration–approved study medications based on specific data from their molecular testing results.¹² Some of the most common mutations in intrahepatic cholangiocarcinoma include HER2, KRAS, MET, and BRAF.^13-17 Our patient’s molecular test results were positive for a BRAF V600E–positive mutation, and she subsequently started therapy with vemurafenib and cobimetinib. The use of personalized genomic treatment approaches for BRAF V600E mutation–positive cholangiocarcinoma has produced a dramatic patient response to BRAF and MEK inhibitor combination therapies.^11,18-20

Drug-induced GD most likely is caused by vascular insults that lead to deposition of immune complexes in vessels causing inflammation and a consequent granulomatous infiltrate.^21,22 Although cordlike lesions in the subcutaneous tissue on the trunk commonly are reported, the presentation of GD can vary considerably. Other presentations include areas of violaceous or erythematous patches or plaques on the limbs, intertriginous areas, and upper trunk. Diffuse macular erythema or small flesh-colored papules also can be observed.²³

Granulomatous dermatitis secondary to drug reactions can have varying morphologies. The infiltrate often can have an interstitial appearance with the presence of lymphocytes, plasma cells, histiocytes, eosinophils, and multinucleated giant cells.²⁴ These findings can be confused with interstitial granuloma annulare. Other cases, such as in our patient, can have discrete granulomata formation with a sarcoidlike appearance. These naked granulomas lack surrounding inflammation and suggest a differential diagnosis of sarcoidosis and infection. Use of immune checkpoint inhibitors (CIs) and kinase inhibitors has been proven to cause sarcoidosislike reactions.²⁵ The development of granulomatous/sarcoidlike lesions associated with the use of BRAF and MEK inhibitors may clinically and radiographically mimic disease recurrence. An awareness of this type of reaction by clinicians and pathologists is important to ensure appropriate management in patients who develop GD.²⁶

Checkpoint inhibitor–induced GD that remains asymptomatic does not necessarily warrant treatment; however, corticosteroid use and elimination of CI therapies have resolved GD in prior cases. Responsiveness of the cancer to CI therapy and severity of GD symptoms should be considered before discontinuation of a CI trial.²⁵

One case report described complete resolution of a GD eruption without interruption of the scheduled BRAF and MEK inhibitor therapies for the treatment of metastatic melanoma. There was no reported use of a steroidal cream or other topical medication to aid in controlling the eruption.²⁷ The exact mechanism of how GD resolves while continuing therapy is unknown; however, it has been suggested that a GD eruption may be the consequence of a BRAF and MEK inhibitor–mediated immune response against a subclinical area of metastatic melanoma.²⁸ If the immune response successfully eliminates the subclinical tumor, one could postulate that the inflammatory response and granulomatous eruption would resolve. Future studies are necessary to further elucidate the exact mechanisms involved.

There have been several case reports of GD with vemurafenib treatment,^29,30 1 report of GD and erythema induratum with vemurafenib and cobimetinib treatment,³¹ 2 reports of GD with dabrafenib treatment,^27,30 and a few reports of GD with the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib,^28,32,33 all for the treatment of metastatic melanoma. Additionally, a report described a 3-year-old boy who developed GD secondary to vemurafenib for the treatment of Langerhans cell histiocytosis.³⁴ We present a unique case of BRAF and MEK inhibitor therapy–induced GD in the treatment of metastatic cholangiocarcinoma with vemurafenib and cobimetinib.

BRAF and MEK inhibitor therapy is used in patients with metastatic melanomas with a positive BRAF V600E mutation. Due to advancements in next-generation DNA sequencing, these therapies also are being tested in clinical trials for use in the treatment of other cancers with the same checkpoint mutation, such as metastatic cholangiocarcinoma. Cutaneous reactions frequently are documented side effects that occur during treatment with BRAF and MEK inhibitors; GD is an uncommon finding. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of other cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation.

To the Editor:

Granulomatous dermatitis (GD) has been described as a rare side effect of MEK and BRAF inhibitor use in the treatment of BRAF V600E mutation–positive metastatic melanoma. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation. We present the case of a 52-year-old woman who developed GD while being treated with vemurafenib and cobimetinib for BRAF V600E mutation–positive metastatic cholangiocarcinoma.

A 52-year-old White woman presented with faint patches of nonpalpable violaceous mottling that extended distally to proximally from the ankles to the thighs on the medial aspects of both legs. She was diagnosed with cholangiocarcinoma 10 months prior, with metastases to the lung, liver, and sternum. She underwent treatment with gemcitabine and cisplatin therapy. Computed tomography after several treatment cycles revealed progressive disease with multiple pulmonary nodules as well as metastatic intrathoracic and abdominal adenopathy. Treatment with gemcitabine and cisplatin failed to produce a favorable response and was discontinued after 6 treatment cycles.

Genomic testing performed at the time of diagnosis revealed a positive mutation for BRAF V600E. The patient subsequently enrolled in a clinical trial and started treatment with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. She developed sun sensitivity and multiple sunburns after starting these therapies. The patient tolerated the next few cycles of therapy well with only moderate concerns of dry sensitive skin.

During the sixth cycle of therapy, she presented to dermatology after developing a rash. Over the next 2 weeks, similar lesions appeared on the arms. The patient denied the use of any new lotions, soaps, or other medications. Punch biopsies of the right forearm and right medial thigh revealed nonnecrotizing granulomas in the superficial dermis that extended into the subcutaneous adipose tissue (Figure 1). Surrounding chronic inflammation was scant, and the presence of rare eosinophils was noted (Figure 2). The histiocytes were highlighted by a CD68 immunohistochemical stain. An auramine-O special stain test was negative for acid-fast bacilli, and a Grocott methenamine-silver special stain test for fungal organisms was negative. These findings were consistent with GD. Computed tomography of the chest performed 2 months prior and 1 month after biopsy of the skin lesions revealed no axillary, mediastinal, or hilar lymphadenopathy. The calcium level at the time of skin biopsy was within reference range.

A topical steroid was prescribed; however, it was not utilized by the patient. Within 2 months of onset, the GD lesions resolved with no treatment. The GD lesions did not affect the patient’s enrollment in the clinical trial, and no dose reductions were made. Due to progressive disease with metastases to the brain, the patient eventually discontinued the clinical trial.

BRAF inhibitors are US Food and Drug Administration approved for the treatment of metastatic melanoma to deactivate the serine-threonine kinase BRAF gene mutation, which leads to decreased generation and survival of melanoma cells.^1,2 Vemurafenib, dabrafenib, and encorafenib are the only BRAF inhibitors approved in the United States.³ The most common side effects of vemurafenib include arthralgia, fatigue, rash, and photosensitivity.^1,4 There are 4 MEK inhibitors currently available in the United States: cobimetinib, trametinib, selumetinib and binimetinib. The addition of a MEK inhibitor to BRAF inhibitor therapy has shown increased patient response rates and prolonged survival in 3 phase 3 studies.^5-10

Response rates remain low in the treatment of advanced cholangiocarcinoma with standard chemotherapy. Recent research has explored if targeted therapies at the molecular level would be of benefit.¹¹ Our patient was enrolled in the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (TAPUR) trial, a phase 2, prospective, nonrandomized trial that matches eligible participants to US Food and Drug Administration–approved study medications based on specific data from their molecular testing results.¹² Some of the most common mutations in intrahepatic cholangiocarcinoma include HER2, KRAS, MET, and BRAF.^13-17 Our patient’s molecular test results were positive for a BRAF V600E–positive mutation, and she subsequently started therapy with vemurafenib and cobimetinib. The use of personalized genomic treatment approaches for BRAF V600E mutation–positive cholangiocarcinoma has produced a dramatic patient response to BRAF and MEK inhibitor combination therapies.^11,18-20

Drug-induced GD most likely is caused by vascular insults that lead to deposition of immune complexes in vessels causing inflammation and a consequent granulomatous infiltrate.^21,22 Although cordlike lesions in the subcutaneous tissue on the trunk commonly are reported, the presentation of GD can vary considerably. Other presentations include areas of violaceous or erythematous patches or plaques on the limbs, intertriginous areas, and upper trunk. Diffuse macular erythema or small flesh-colored papules also can be observed.²³

Granulomatous dermatitis secondary to drug reactions can have varying morphologies. The infiltrate often can have an interstitial appearance with the presence of lymphocytes, plasma cells, histiocytes, eosinophils, and multinucleated giant cells.²⁴ These findings can be confused with interstitial granuloma annulare. Other cases, such as in our patient, can have discrete granulomata formation with a sarcoidlike appearance. These naked granulomas lack surrounding inflammation and suggest a differential diagnosis of sarcoidosis and infection. Use of immune checkpoint inhibitors (CIs) and kinase inhibitors has been proven to cause sarcoidosislike reactions.²⁵ The development of granulomatous/sarcoidlike lesions associated with the use of BRAF and MEK inhibitors may clinically and radiographically mimic disease recurrence. An awareness of this type of reaction by clinicians and pathologists is important to ensure appropriate management in patients who develop GD.²⁶

Checkpoint inhibitor–induced GD that remains asymptomatic does not necessarily warrant treatment; however, corticosteroid use and elimination of CI therapies have resolved GD in prior cases. Responsiveness of the cancer to CI therapy and severity of GD symptoms should be considered before discontinuation of a CI trial.²⁵

One case report described complete resolution of a GD eruption without interruption of the scheduled BRAF and MEK inhibitor therapies for the treatment of metastatic melanoma. There was no reported use of a steroidal cream or other topical medication to aid in controlling the eruption.²⁷ The exact mechanism of how GD resolves while continuing therapy is unknown; however, it has been suggested that a GD eruption may be the consequence of a BRAF and MEK inhibitor–mediated immune response against a subclinical area of metastatic melanoma.²⁸ If the immune response successfully eliminates the subclinical tumor, one could postulate that the inflammatory response and granulomatous eruption would resolve. Future studies are necessary to further elucidate the exact mechanisms involved.

There have been several case reports of GD with vemurafenib treatment,^29,30 1 report of GD and erythema induratum with vemurafenib and cobimetinib treatment,³¹ 2 reports of GD with dabrafenib treatment,^27,30 and a few reports of GD with the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib,^28,32,33 all for the treatment of metastatic melanoma. Additionally, a report described a 3-year-old boy who developed GD secondary to vemurafenib for the treatment of Langerhans cell histiocytosis.³⁴ We present a unique case of BRAF and MEK inhibitor therapy–induced GD in the treatment of metastatic cholangiocarcinoma with vemurafenib and cobimetinib.

BRAF and MEK inhibitor therapy is used in patients with metastatic melanomas with a positive BRAF V600E mutation. Due to advancements in next-generation DNA sequencing, these therapies also are being tested in clinical trials for use in the treatment of other cancers with the same checkpoint mutation, such as metastatic cholangiocarcinoma. Cutaneous reactions frequently are documented side effects that occur during treatment with BRAF and MEK inhibitors; GD is an uncommon finding. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of other cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation.

The Diagnosis: Papular Acantholytic Dyskeratosis

The shave biopsy revealed suprabasal clefts associated with acantholytic and dyskeratotic cells as well as overlying hyperkeratosis. Direct immunofluorescence (DIF) was negative. Based on the combined clinical and histological findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD), a rare disease that clinically presents as small whitishgreyish papules with the potential to coalesce into larger plaques.^1,2 The condition predominantly manifests without symptoms, though pruritus and burning have been reported in affected sites. Most cases of PAD have been reported in older adults rather than in children or adolescents; it is more prevalent in women than in men. Lesions generally are localized to the penis, vulva, scrotum, inguinal folds, and perianal region.³ More specific terms have been used to describe this presentation such as papular acantholytic dyskeratosis of the anogenital region and papular acantholytic dyskeratosis of the genital-crural region. Histologic findings of PAD include epidermal acantholysis and dyskeratosis with hyperkeratosis and parakeratosis (quiz image).

The histologic differential diagnosis of PAD is broad due to its overlapping features with other diseases such as pemphigus vulgaris, Hailey-Hailey disease (HHD), Darier disease, and Grover disease. The acantholytic pathophysiology of these conditions involves dysfunction in cell adhesion markers. The correct diagnosis can be made by considering both the clinical location of involvement and histopathologic clues.

Pemphigus is a family of disorders involving mucocutaneous blistering of an autoimmune nature (Figure 1). Pemphigus vulgaris is the most prevalent variant of the pemphigus family, with symptomatically painful involvement of mucosal and cutaneous tissue. Autoantibodies to desmoglein 3 alone or both desmoglein 1 and 3 are present. Pemphigus vulgaris displays positive DIF findings with intercellular IgG and C3.

Hailey-Hailey disease (also known as benign familial pemphigus) is an autosomal-dominant disease that shares the acantholytic feature that is common in this class of diseases and caused by a defect in cell-cell adhesion as well as a loss of function in the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1. Blistering lesions typically appear in the neck, axillary, inguinal, or genital regions, and they can develop into crusted, exudate-filled lesions. No autoimmunity has been associated with this disease, unlike other diseases in the pemphigus family, and mutations in the ATP2C1 gene have been linked with dysregulation of cell-cell adhesion, particularly in cadherins and calcium-dependent cell adhesion processes. Histologically, HHD will show diffuse keratinocyte acantholysis with suprabasal clefting (Figure 2).⁴ Dyskeratosis is mild, if present at all, and dyskeratotic keratinocytes show a well-defined nucleus with cytoplasmic preservation. In contrast to HHD, PAD typically shows more dyskeratosis.

Darier disease (also known as keratosis follicularis) is an autosomal-dominant condition that normally presents with seborrheic eruptions in intertriginous areas, usually with onset during adolescence. Darier disease is caused by a loss-of-function mutation in the ATP2A2 gene found on chromosome 12q23-24.1 that encodes for the sarco(endo)plasmic reticulum calcium ATPase2 (SERCA2) enzymes involved in calcium-dependent transport of the endoplasmic reticulum within the cell. Due to calcium dysregulation, desmosomes are unable to carry out their function in cell-cell adhesion, resulting in keratinocyte acantholysis. Histopathology of Darier disease is identical to HHD but displays more dyskeratosis than HHD (Figure 3), possibly due to the endoplasmic reticulum calcium stores that are affected in Darier disease compared to the Golgi apparatus calcium stores that are implicated in HHD.5 The lowered endoplasmic reticulum calcium stores in Darier-White disease are associated with more pronounced dyskeratosis, which is seen histologically as corps ronds. Suprabasal hyperkeratosis also is found in Darier disease. The histopathologic findings of Darier disease and PAD can be identical, but the clinical presentations are distinct, with Darier disease typically manifesting as seborrheic eruptions appearing in adolescence and PAD presenting as small white papules in the anogenital or crural regions.

Grover disease (also referred to as transient acantholytic dermatosis) has an idiopathic pathophysiology. It clinically manifests with eruptions of erythematous, pruritic, truncal papules on the chest or back. Grover disease has a predilection for White men older than 50 years, and symptoms may be exacerbated in heat and diaphoretic conditions. Histologically, Grover disease may show acantholytic features seen in pemphigus vulgaris, HHD, and Darier disease; the pattern can only follow a specific disease or consist of a combination of all disease features (Figure 4). The acantholytic pattern of Grover disease was found to be similar to pemphigus vulgaris, Darier disease, pemphigus foliaceus, and HHD 47%, 18%, 9%, and 8% of the time, respectively. In 9% of cases, Grover disease will exhibit a mixed histopathology in which its acantholytic pattern will consist of a combination of features seen in the pemphigus family of diseases.6 Biopsy results showing mixed histologic patterns or a combination of different acantholytic features are suggestive of Grover disease over PAD. Moreover, the clinical distribution helps to differentiate Grover disease from PAD.

Because the histologic characteristics of these diseases overlap, certain nuances in clinical correlations and histology allow for distinction. In our patient, the diagnosis was most consistent with PAD based on the clinical manifestation of the disease and the biopsy results. Considering solely the clinical location of the lesions, Grover disease was a less likely diagnosis because our patient’s lesions were observed in the perianal region, not the truncal region as typically seen in Grover disease. Taking into account the DIF assay results in our patient, the pemphigus family of diseases also moved lower on the differential diagnosis. Finally, because the biopsy showed more dyskeratosis than would be present in HHD and also was inconsistent with the location and onset that would be expected to be seen in Darier disease, PAD was the most probable diagnosis. Interestingly, studies have shown mosaic mutations in ATP2A2 and ATP2C1 as possible causes of PAD, suggesting that this may be an allelic variant of Darier disease and HHD.7-9 No genetic testing was performed in our patient.

The Diagnosis: Papular Acantholytic Dyskeratosis

The shave biopsy revealed suprabasal clefts associated with acantholytic and dyskeratotic cells as well as overlying hyperkeratosis. Direct immunofluorescence (DIF) was negative. Based on the combined clinical and histological findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD), a rare disease that clinically presents as small whitishgreyish papules with the potential to coalesce into larger plaques.^1,2 The condition predominantly manifests without symptoms, though pruritus and burning have been reported in affected sites. Most cases of PAD have been reported in older adults rather than in children or adolescents; it is more prevalent in women than in men. Lesions generally are localized to the penis, vulva, scrotum, inguinal folds, and perianal region.³ More specific terms have been used to describe this presentation such as papular acantholytic dyskeratosis of the anogenital region and papular acantholytic dyskeratosis of the genital-crural region. Histologic findings of PAD include epidermal acantholysis and dyskeratosis with hyperkeratosis and parakeratosis (quiz image).

The histologic differential diagnosis of PAD is broad due to its overlapping features with other diseases such as pemphigus vulgaris, Hailey-Hailey disease (HHD), Darier disease, and Grover disease. The acantholytic pathophysiology of these conditions involves dysfunction in cell adhesion markers. The correct diagnosis can be made by considering both the clinical location of involvement and histopathologic clues.

Pemphigus is a family of disorders involving mucocutaneous blistering of an autoimmune nature (Figure 1). Pemphigus vulgaris is the most prevalent variant of the pemphigus family, with symptomatically painful involvement of mucosal and cutaneous tissue. Autoantibodies to desmoglein 3 alone or both desmoglein 1 and 3 are present. Pemphigus vulgaris displays positive DIF findings with intercellular IgG and C3.

Hailey-Hailey disease (also known as benign familial pemphigus) is an autosomal-dominant disease that shares the acantholytic feature that is common in this class of diseases and caused by a defect in cell-cell adhesion as well as a loss of function in the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1. Blistering lesions typically appear in the neck, axillary, inguinal, or genital regions, and they can develop into crusted, exudate-filled lesions. No autoimmunity has been associated with this disease, unlike other diseases in the pemphigus family, and mutations in the ATP2C1 gene have been linked with dysregulation of cell-cell adhesion, particularly in cadherins and calcium-dependent cell adhesion processes. Histologically, HHD will show diffuse keratinocyte acantholysis with suprabasal clefting (Figure 2).⁴ Dyskeratosis is mild, if present at all, and dyskeratotic keratinocytes show a well-defined nucleus with cytoplasmic preservation. In contrast to HHD, PAD typically shows more dyskeratosis.

Darier disease (also known as keratosis follicularis) is an autosomal-dominant condition that normally presents with seborrheic eruptions in intertriginous areas, usually with onset during adolescence. Darier disease is caused by a loss-of-function mutation in the ATP2A2 gene found on chromosome 12q23-24.1 that encodes for the sarco(endo)plasmic reticulum calcium ATPase2 (SERCA2) enzymes involved in calcium-dependent transport of the endoplasmic reticulum within the cell. Due to calcium dysregulation, desmosomes are unable to carry out their function in cell-cell adhesion, resulting in keratinocyte acantholysis. Histopathology of Darier disease is identical to HHD but displays more dyskeratosis than HHD (Figure 3), possibly due to the endoplasmic reticulum calcium stores that are affected in Darier disease compared to the Golgi apparatus calcium stores that are implicated in HHD.5 The lowered endoplasmic reticulum calcium stores in Darier-White disease are associated with more pronounced dyskeratosis, which is seen histologically as corps ronds. Suprabasal hyperkeratosis also is found in Darier disease. The histopathologic findings of Darier disease and PAD can be identical, but the clinical presentations are distinct, with Darier disease typically manifesting as seborrheic eruptions appearing in adolescence and PAD presenting as small white papules in the anogenital or crural regions.

Grover disease (also referred to as transient acantholytic dermatosis) has an idiopathic pathophysiology. It clinically manifests with eruptions of erythematous, pruritic, truncal papules on the chest or back. Grover disease has a predilection for White men older than 50 years, and symptoms may be exacerbated in heat and diaphoretic conditions. Histologically, Grover disease may show acantholytic features seen in pemphigus vulgaris, HHD, and Darier disease; the pattern can only follow a specific disease or consist of a combination of all disease features (Figure 4). The acantholytic pattern of Grover disease was found to be similar to pemphigus vulgaris, Darier disease, pemphigus foliaceus, and HHD 47%, 18%, 9%, and 8% of the time, respectively. In 9% of cases, Grover disease will exhibit a mixed histopathology in which its acantholytic pattern will consist of a combination of features seen in the pemphigus family of diseases.6 Biopsy results showing mixed histologic patterns or a combination of different acantholytic features are suggestive of Grover disease over PAD. Moreover, the clinical distribution helps to differentiate Grover disease from PAD.

Because the histologic characteristics of these diseases overlap, certain nuances in clinical correlations and histology allow for distinction. In our patient, the diagnosis was most consistent with PAD based on the clinical manifestation of the disease and the biopsy results. Considering solely the clinical location of the lesions, Grover disease was a less likely diagnosis because our patient’s lesions were observed in the perianal region, not the truncal region as typically seen in Grover disease. Taking into account the DIF assay results in our patient, the pemphigus family of diseases also moved lower on the differential diagnosis. Finally, because the biopsy showed more dyskeratosis than would be present in HHD and also was inconsistent with the location and onset that would be expected to be seen in Darier disease, PAD was the most probable diagnosis. Interestingly, studies have shown mosaic mutations in ATP2A2 and ATP2C1 as possible causes of PAD, suggesting that this may be an allelic variant of Darier disease and HHD.7-9 No genetic testing was performed in our patient.

The Diagnosis: Papular Acantholytic Dyskeratosis

The shave biopsy revealed suprabasal clefts associated with acantholytic and dyskeratotic cells as well as overlying hyperkeratosis. Direct immunofluorescence (DIF) was negative. Based on the combined clinical and histological findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD), a rare disease that clinically presents as small whitishgreyish papules with the potential to coalesce into larger plaques.^1,2 The condition predominantly manifests without symptoms, though pruritus and burning have been reported in affected sites. Most cases of PAD have been reported in older adults rather than in children or adolescents; it is more prevalent in women than in men. Lesions generally are localized to the penis, vulva, scrotum, inguinal folds, and perianal region.³ More specific terms have been used to describe this presentation such as papular acantholytic dyskeratosis of the anogenital region and papular acantholytic dyskeratosis of the genital-crural region. Histologic findings of PAD include epidermal acantholysis and dyskeratosis with hyperkeratosis and parakeratosis (quiz image).

The histologic differential diagnosis of PAD is broad due to its overlapping features with other diseases such as pemphigus vulgaris, Hailey-Hailey disease (HHD), Darier disease, and Grover disease. The acantholytic pathophysiology of these conditions involves dysfunction in cell adhesion markers. The correct diagnosis can be made by considering both the clinical location of involvement and histopathologic clues.

Pemphigus is a family of disorders involving mucocutaneous blistering of an autoimmune nature (Figure 1). Pemphigus vulgaris is the most prevalent variant of the pemphigus family, with symptomatically painful involvement of mucosal and cutaneous tissue. Autoantibodies to desmoglein 3 alone or both desmoglein 1 and 3 are present. Pemphigus vulgaris displays positive DIF findings with intercellular IgG and C3.

Hailey-Hailey disease (also known as benign familial pemphigus) is an autosomal-dominant disease that shares the acantholytic feature that is common in this class of diseases and caused by a defect in cell-cell adhesion as well as a loss of function in the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1. Blistering lesions typically appear in the neck, axillary, inguinal, or genital regions, and they can develop into crusted, exudate-filled lesions. No autoimmunity has been associated with this disease, unlike other diseases in the pemphigus family, and mutations in the ATP2C1 gene have been linked with dysregulation of cell-cell adhesion, particularly in cadherins and calcium-dependent cell adhesion processes. Histologically, HHD will show diffuse keratinocyte acantholysis with suprabasal clefting (Figure 2).⁴ Dyskeratosis is mild, if present at all, and dyskeratotic keratinocytes show a well-defined nucleus with cytoplasmic preservation. In contrast to HHD, PAD typically shows more dyskeratosis.

Darier disease (also known as keratosis follicularis) is an autosomal-dominant condition that normally presents with seborrheic eruptions in intertriginous areas, usually with onset during adolescence. Darier disease is caused by a loss-of-function mutation in the ATP2A2 gene found on chromosome 12q23-24.1 that encodes for the sarco(endo)plasmic reticulum calcium ATPase2 (SERCA2) enzymes involved in calcium-dependent transport of the endoplasmic reticulum within the cell. Due to calcium dysregulation, desmosomes are unable to carry out their function in cell-cell adhesion, resulting in keratinocyte acantholysis. Histopathology of Darier disease is identical to HHD but displays more dyskeratosis than HHD (Figure 3), possibly due to the endoplasmic reticulum calcium stores that are affected in Darier disease compared to the Golgi apparatus calcium stores that are implicated in HHD.5 The lowered endoplasmic reticulum calcium stores in Darier-White disease are associated with more pronounced dyskeratosis, which is seen histologically as corps ronds. Suprabasal hyperkeratosis also is found in Darier disease. The histopathologic findings of Darier disease and PAD can be identical, but the clinical presentations are distinct, with Darier disease typically manifesting as seborrheic eruptions appearing in adolescence and PAD presenting as small white papules in the anogenital or crural regions.

Grover disease (also referred to as transient acantholytic dermatosis) has an idiopathic pathophysiology. It clinically manifests with eruptions of erythematous, pruritic, truncal papules on the chest or back. Grover disease has a predilection for White men older than 50 years, and symptoms may be exacerbated in heat and diaphoretic conditions. Histologically, Grover disease may show acantholytic features seen in pemphigus vulgaris, HHD, and Darier disease; the pattern can only follow a specific disease or consist of a combination of all disease features (Figure 4). The acantholytic pattern of Grover disease was found to be similar to pemphigus vulgaris, Darier disease, pemphigus foliaceus, and HHD 47%, 18%, 9%, and 8% of the time, respectively. In 9% of cases, Grover disease will exhibit a mixed histopathology in which its acantholytic pattern will consist of a combination of features seen in the pemphigus family of diseases.6 Biopsy results showing mixed histologic patterns or a combination of different acantholytic features are suggestive of Grover disease over PAD. Moreover, the clinical distribution helps to differentiate Grover disease from PAD.

Because the histologic characteristics of these diseases overlap, certain nuances in clinical correlations and histology allow for distinction. In our patient, the diagnosis was most consistent with PAD based on the clinical manifestation of the disease and the biopsy results. Considering solely the clinical location of the lesions, Grover disease was a less likely diagnosis because our patient’s lesions were observed in the perianal region, not the truncal region as typically seen in Grover disease. Taking into account the DIF assay results in our patient, the pemphigus family of diseases also moved lower on the differential diagnosis. Finally, because the biopsy showed more dyskeratosis than would be present in HHD and also was inconsistent with the location and onset that would be expected to be seen in Darier disease, PAD was the most probable diagnosis. Interestingly, studies have shown mosaic mutations in ATP2A2 and ATP2C1 as possible causes of PAD, suggesting that this may be an allelic variant of Darier disease and HHD.7-9 No genetic testing was performed in our patient.

The Diagnosis: Congenital Cutaneous Langerhans Cell Histiocytosis

Although the infectious workup was positive for herpes simplex virus type 1 and cytomegalovirus antibodies, serologies for the rest of the TORCH (toxoplasmosis, other agents [syphilis, hepatitis B virus], rubella, cytomegalovirus) group of infections, as well as other bacterial, fungal, and viral infections, were negative. A skin biopsy from the right fifth toe showed a dense infiltrate of CD1a+ histiocytic cells with folded or kidney-shaped nuclei mixed with eosinophils, which was consistent with Langerhans cell histiocytosis (LCH) (Figure 1). Skin lesions were treated with hydrocortisone cream 2.5% and progressively faded over a few weeks.

Langerhans cell histiocytosis is a rare disorder with a variable clinical presentation depending on the sites affected and the extent of involvement. It can involve multiple organ systems, most commonly the skeletal system and the skin. Organ involvement is characterized by histiocyte infiltration. Acute disseminated multisystem disease most commonly is seen in children younger than 3 years.¹

Congenital cutaneous LCH presents with variable skin lesions ranging from papules to vesicles, pustules, and ulcers, with onset at birth or in the neonatal period. Various morphologic traits of skin lesions have been described; the most common presentation is multiple red to yellow-brown, crusted papules with accompanying hemorrhage or erosion.¹ Other cases have described an eczematous, seborrheic, diffuse eruption or erosive intertrigo. One case of a child with a solitary necrotic nodule on the scalp has been reported.²

Our patient presented with disseminated, nonblanching, purple to dark red papules and nodules of the skin and oral mucosa, as well as nail dystrophy (Figure 2). However, LCH in a neonate can mimic other causes of congenital papulonodular eruptions. Red-brown papules and nodules with or without crusting in a newborn can be mistaken for erythema toxicum neonatorum, transient neonatal pustular melanosis, congenital leukemia cutis, neonatal erythropoiesis, disseminated neonatal hemangiomatosis, infantile acropustulosis, or congenital TORCH infections such as rubella or syphilis. When LCH presents as vesicles or eroded papules or nodules in a newborn, the differential diagnosis includes incontinentia pigmenti and hereditary epidermolysis bullosa.

Langerhans cell histiocytosis may even present with a classic blueberry muffin rash that can lead clinicians to consider cutaneous metastasis from various hematologic malignancies or the more common TORCH infections. Several diagnostic tests can be performed to clarify the diagnosis, including bacterial and viral cultures and stains, serology, immunohistochemistry, flow cytometry, bone marrow aspiration, or skin biopsy.³ Langerhans cell histiocytosis is diagnosed with a combination of histology, immunohistochemistry, and clinical presentation; however, a skin biopsy is crucial. Tissue should be taken from the most easily accessible yet representative lesion. The characteristic appearance of LCH lesions is described as a dense infiltrate of histiocytic cells mixed with numerous eosinophils in the dermis.¹ Histiocytes usually have folded nuclei and eosinophilic cytoplasm or kidney-shaped nuclei with prominent nucleoli. Positive CD1a and/or CD207 (Langerin) staining of the cells is required for definitive diagnosis.⁴ After diagnosis, it is important to obtain baseline laboratory and radiographic studies to determine the extent of systemic involvement.

Treatment of congenital LCH is tailored to the extent of organ involvement. The dermatologic manifestations resolve without medications in many cases. However, true self-resolving LCH can only be diagnosed retrospectively after a full evaluation for other sites of disease. Disseminated disease can be life-threatening and requires more active management. In cases of skin-limited disease, therapies include topical steroids, nitrogen mustard, or imiquimod; surgical resection of isolated lesions; phototherapy; or systemic therapies such as methotrexate, 6-mercaptopurine, vinblastine/vincristine, cladribine, and/or cytarabine. Symptomatic patients initially are treated with methotrexate and 6-mercaptopurine.⁵ Asymptomatic infants with skin-limited involvement can be managed with topical treatments.

Our patient had skin-limited disease. Abdominal ultrasonography, skeletal survey, and magnetic resonance imaging of the brain revealed no abnormalities. The patient’s family was advised to monitor him for reoccurrence of the skin lesions and to continue close follow-up with hematology and dermatology. Although congenital LCH often is self-resolving, extensive skin involvement increases the risk for internal organ involvement for several years.⁶ These patients require long-term follow-up for potential musculoskeletal, ophthalmologic, endocrine, hepatic, and/or pulmonary disease.

The Diagnosis: Congenital Cutaneous Langerhans Cell Histiocytosis

Although the infectious workup was positive for herpes simplex virus type 1 and cytomegalovirus antibodies, serologies for the rest of the TORCH (toxoplasmosis, other agents [syphilis, hepatitis B virus], rubella, cytomegalovirus) group of infections, as well as other bacterial, fungal, and viral infections, were negative. A skin biopsy from the right fifth toe showed a dense infiltrate of CD1a+ histiocytic cells with folded or kidney-shaped nuclei mixed with eosinophils, which was consistent with Langerhans cell histiocytosis (LCH) (Figure 1). Skin lesions were treated with hydrocortisone cream 2.5% and progressively faded over a few weeks.

Langerhans cell histiocytosis is a rare disorder with a variable clinical presentation depending on the sites affected and the extent of involvement. It can involve multiple organ systems, most commonly the skeletal system and the skin. Organ involvement is characterized by histiocyte infiltration. Acute disseminated multisystem disease most commonly is seen in children younger than 3 years.¹

Congenital cutaneous LCH presents with variable skin lesions ranging from papules to vesicles, pustules, and ulcers, with onset at birth or in the neonatal period. Various morphologic traits of skin lesions have been described; the most common presentation is multiple red to yellow-brown, crusted papules with accompanying hemorrhage or erosion.¹ Other cases have described an eczematous, seborrheic, diffuse eruption or erosive intertrigo. One case of a child with a solitary necrotic nodule on the scalp has been reported.²

Our patient presented with disseminated, nonblanching, purple to dark red papules and nodules of the skin and oral mucosa, as well as nail dystrophy (Figure 2). However, LCH in a neonate can mimic other causes of congenital papulonodular eruptions. Red-brown papules and nodules with or without crusting in a newborn can be mistaken for erythema toxicum neonatorum, transient neonatal pustular melanosis, congenital leukemia cutis, neonatal erythropoiesis, disseminated neonatal hemangiomatosis, infantile acropustulosis, or congenital TORCH infections such as rubella or syphilis. When LCH presents as vesicles or eroded papules or nodules in a newborn, the differential diagnosis includes incontinentia pigmenti and hereditary epidermolysis bullosa.

Langerhans cell histiocytosis may even present with a classic blueberry muffin rash that can lead clinicians to consider cutaneous metastasis from various hematologic malignancies or the more common TORCH infections. Several diagnostic tests can be performed to clarify the diagnosis, including bacterial and viral cultures and stains, serology, immunohistochemistry, flow cytometry, bone marrow aspiration, or skin biopsy.³ Langerhans cell histiocytosis is diagnosed with a combination of histology, immunohistochemistry, and clinical presentation; however, a skin biopsy is crucial. Tissue should be taken from the most easily accessible yet representative lesion. The characteristic appearance of LCH lesions is described as a dense infiltrate of histiocytic cells mixed with numerous eosinophils in the dermis.¹ Histiocytes usually have folded nuclei and eosinophilic cytoplasm or kidney-shaped nuclei with prominent nucleoli. Positive CD1a and/or CD207 (Langerin) staining of the cells is required for definitive diagnosis.⁴ After diagnosis, it is important to obtain baseline laboratory and radiographic studies to determine the extent of systemic involvement.

Treatment of congenital LCH is tailored to the extent of organ involvement. The dermatologic manifestations resolve without medications in many cases. However, true self-resolving LCH can only be diagnosed retrospectively after a full evaluation for other sites of disease. Disseminated disease can be life-threatening and requires more active management. In cases of skin-limited disease, therapies include topical steroids, nitrogen mustard, or imiquimod; surgical resection of isolated lesions; phototherapy; or systemic therapies such as methotrexate, 6-mercaptopurine, vinblastine/vincristine, cladribine, and/or cytarabine. Symptomatic patients initially are treated with methotrexate and 6-mercaptopurine.⁵ Asymptomatic infants with skin-limited involvement can be managed with topical treatments.

Our patient had skin-limited disease. Abdominal ultrasonography, skeletal survey, and magnetic resonance imaging of the brain revealed no abnormalities. The patient’s family was advised to monitor him for reoccurrence of the skin lesions and to continue close follow-up with hematology and dermatology. Although congenital LCH often is self-resolving, extensive skin involvement increases the risk for internal organ involvement for several years.⁶ These patients require long-term follow-up for potential musculoskeletal, ophthalmologic, endocrine, hepatic, and/or pulmonary disease.

The Diagnosis: Congenital Cutaneous Langerhans Cell Histiocytosis

Although the infectious workup was positive for herpes simplex virus type 1 and cytomegalovirus antibodies, serologies for the rest of the TORCH (toxoplasmosis, other agents [syphilis, hepatitis B virus], rubella, cytomegalovirus) group of infections, as well as other bacterial, fungal, and viral infections, were negative. A skin biopsy from the right fifth toe showed a dense infiltrate of CD1a+ histiocytic cells with folded or kidney-shaped nuclei mixed with eosinophils, which was consistent with Langerhans cell histiocytosis (LCH) (Figure 1). Skin lesions were treated with hydrocortisone cream 2.5% and progressively faded over a few weeks.

Langerhans cell histiocytosis is a rare disorder with a variable clinical presentation depending on the sites affected and the extent of involvement. It can involve multiple organ systems, most commonly the skeletal system and the skin. Organ involvement is characterized by histiocyte infiltration. Acute disseminated multisystem disease most commonly is seen in children younger than 3 years.¹

Congenital cutaneous LCH presents with variable skin lesions ranging from papules to vesicles, pustules, and ulcers, with onset at birth or in the neonatal period. Various morphologic traits of skin lesions have been described; the most common presentation is multiple red to yellow-brown, crusted papules with accompanying hemorrhage or erosion.¹ Other cases have described an eczematous, seborrheic, diffuse eruption or erosive intertrigo. One case of a child with a solitary necrotic nodule on the scalp has been reported.²

Our patient presented with disseminated, nonblanching, purple to dark red papules and nodules of the skin and oral mucosa, as well as nail dystrophy (Figure 2). However, LCH in a neonate can mimic other causes of congenital papulonodular eruptions. Red-brown papules and nodules with or without crusting in a newborn can be mistaken for erythema toxicum neonatorum, transient neonatal pustular melanosis, congenital leukemia cutis, neonatal erythropoiesis, disseminated neonatal hemangiomatosis, infantile acropustulosis, or congenital TORCH infections such as rubella or syphilis. When LCH presents as vesicles or eroded papules or nodules in a newborn, the differential diagnosis includes incontinentia pigmenti and hereditary epidermolysis bullosa.

Langerhans cell histiocytosis may even present with a classic blueberry muffin rash that can lead clinicians to consider cutaneous metastasis from various hematologic malignancies or the more common TORCH infections. Several diagnostic tests can be performed to clarify the diagnosis, including bacterial and viral cultures and stains, serology, immunohistochemistry, flow cytometry, bone marrow aspiration, or skin biopsy.³ Langerhans cell histiocytosis is diagnosed with a combination of histology, immunohistochemistry, and clinical presentation; however, a skin biopsy is crucial. Tissue should be taken from the most easily accessible yet representative lesion. The characteristic appearance of LCH lesions is described as a dense infiltrate of histiocytic cells mixed with numerous eosinophils in the dermis.¹ Histiocytes usually have folded nuclei and eosinophilic cytoplasm or kidney-shaped nuclei with prominent nucleoli. Positive CD1a and/or CD207 (Langerin) staining of the cells is required for definitive diagnosis.⁴ After diagnosis, it is important to obtain baseline laboratory and radiographic studies to determine the extent of systemic involvement.

Treatment of congenital LCH is tailored to the extent of organ involvement. The dermatologic manifestations resolve without medications in many cases. However, true self-resolving LCH can only be diagnosed retrospectively after a full evaluation for other sites of disease. Disseminated disease can be life-threatening and requires more active management. In cases of skin-limited disease, therapies include topical steroids, nitrogen mustard, or imiquimod; surgical resection of isolated lesions; phototherapy; or systemic therapies such as methotrexate, 6-mercaptopurine, vinblastine/vincristine, cladribine, and/or cytarabine. Symptomatic patients initially are treated with methotrexate and 6-mercaptopurine.⁵ Asymptomatic infants with skin-limited involvement can be managed with topical treatments.

Our patient had skin-limited disease. Abdominal ultrasonography, skeletal survey, and magnetic resonance imaging of the brain revealed no abnormalities. The patient’s family was advised to monitor him for reoccurrence of the skin lesions and to continue close follow-up with hematology and dermatology. Although congenital LCH often is self-resolving, extensive skin involvement increases the risk for internal organ involvement for several years.⁶ These patients require long-term follow-up for potential musculoskeletal, ophthalmologic, endocrine, hepatic, and/or pulmonary disease.

To the Editor:

The term ectopic breast tissue serves as an umbrella term that encompasses breast tissue positioned in anatomically incorrect locations, including the subtypes of supernumerary and aberrant breasts.¹ However, the more frequently used term is accessory breast tissue (ABT).¹ Supernumerary breasts have diverse variations of a nipple, areola, and/or ductal tissue and can span in size from a small mole to a fully functioning breast. This breast type maintains structured ductal systems connected to the overlying skin and experiences regular changes during the reproductive cycle. In contrast, an aberrant breast is isolated breast tissue that does not contain organized ductal systems.¹ Accessory breast tissue is prevalent in up to 6.0% of the world population, with Japanese individuals being the most affected and White individuals being the least affected.¹

Accessory breasts typically are located along the milk line—the embryologic precursor to mammary glands and nipples, which extend from the axillae to the groin and regress from the caudal end spanning to the groin.² For this reason, incomplete regression of the mammary ridge results in ABT, most commonly in the axillary region.³ Accessory breast tissue usually is benign and is considered an anatomical variant; however, because the histomorphology is similar to mammary gland tissue, accessory breasts have the same proliferative potential as anatomically correct breasts and therefore can form fibroadenomas, cysts, abscesses, mastitis, or breast cancer.⁴ Accessory breast carcinomas comprise 0.3% to 0.6% of all breast malignancies.⁵ Certain genodermatoses (ie, Cowden syndrome) also may predispose patients to benign or malignant pathology in ABT.⁶ We present a rare case of accessory breast cancer in the inframammary region masquerading as a cyst. These findings were further supported by ultrasonography and mammography.

A 45-year-old White woman presented to our clinic for removal of a dermal mass underlying a supernumerary nipple at the left inframammary fold. Her medical history was noncontributory and was only remarkable for uterine fibroids. She developed pain and swelling in the left breast 1 year prior, which prompted her to seek medical attention from her primary care physician. Diagnostic mammography was negative for any concerning malignant nodules, and subsequent BRCA genetic testing also was negative. Six months after the diagnostic mammography, she continued to experience pain and swelling in the left breast and was then referred for diagnostic ultrasonography; 2 masses in the left breast suspected as infected cysts with rupture were identified (Figure 1). She was then referred to our dermatology clinic for evaluation and surgical extirpation of the suspected cyst underlying the accessory breast. The area subsequently was excised under local anesthesia, and a second similar but smaller mass also was identified adjacent to the initial growth. Dermatopathologic examination revealed an estrogen receptor– (Figure 2A) and progesterone receptor–positive (Figure 2B), ERBB2 (HER2/neu)–negative, nuclear grade III ductal carcinoma in situ (Figure 3).

Various ABT classification methods have been proposed with Brightmore⁷ categorizing polymastia into 8 subtypes: (1) complete breast; (2) glandular tissue and nipple; (3) glandular tissue and areola; (4) glandular tissue only; (5) nipple, areola, and fat; (6) nipple only; (7) areola only; and (8) patch of hair only. De Cholnokey⁸ focused on axillary polymastia, dividing it into 4 classes: (1) axillary tumor in milk line without nipple or areola; (2) axillary tumor with areola with or without pigmentation; (3) nipple or areola without underlying breast tissue; and (4) complete breast with nipple, areola, and glandular tissue. Fenench’s⁹ method is preferred and simply describes ABT as 2 subtypes: supernumerary and aberrant.^1,2,10 One study observed 6% of ABT cancers were the supernumerary type and 94% were the aberrant type.¹ Ductal lumen stagnation increases the risk for accessory breast carcinoma development.¹⁰ Men have a higher prevalence of cancer in ABT compared to anatomically correct breast tissue.¹¹

There currently is no standardized guideline for ABT cancer treatment. The initial clinical impression of cancer of ABT may be misdiagnosed as lymphadenopathy, abscesses, or lipomas.¹² The risk for misdiagnosis is higher for cancer of ABT compared to normal breast tissue and is associated with a poorer prognosis.¹ Despite multiple screening modalities, our patient’s initial breast cancer screenings proved unreliable. A mammogram failed to detect malignancy, likely secondary to the area of concern being out of the standard imaging field. Ultrasonography also was unreliable and led to misdiagnosis as an infected sebaceous cyst with rupture in our patient. Upon review of the ultrasound, concerns were raised by dermatology that the mass was more likely an epidermal inclusion cyst with rupture given the more superficial and sac-free nature of sebaceous cysts, which commonly are associated with steatocystoma multiplex.¹³ Definitive diagnosis of ductal carcinoma in situ was made with dermatopathologic examination.

Prophylactic surgical excision of ABT has been recommended, suggesting that excisional biopsy and histopathologic examination is the more appropriate method to rule out malignancy. Surgical treatment of ABT may omit any risk for malignant transformation and may provide psychological relief to patients for aesthetic reasons.^10,12,14 The risk and benefits of prophylactic excision of ABT has been compared to prophylactic mastectomy of anatomically correct breasts,¹⁵ with some clinicians considering this definitive procedure unnecessary except in high-risk patients with a strong genetic predisposition.^16,17

Accessory breast tissue should be viewed as an anatomical variant with the option of surgical removal for symptomatic concerns, such as firm nodules, discharge, and pain. Although ABT is rare and cancer in ABT is even more uncommon (<1% of all breast cancers),^5,11 clinicians should be suspicious of benign diagnostic reports when the clinical situation does not fit the proposed narrative.

To the Editor:

The term ectopic breast tissue serves as an umbrella term that encompasses breast tissue positioned in anatomically incorrect locations, including the subtypes of supernumerary and aberrant breasts.¹ However, the more frequently used term is accessory breast tissue (ABT).¹ Supernumerary breasts have diverse variations of a nipple, areola, and/or ductal tissue and can span in size from a small mole to a fully functioning breast. This breast type maintains structured ductal systems connected to the overlying skin and experiences regular changes during the reproductive cycle. In contrast, an aberrant breast is isolated breast tissue that does not contain organized ductal systems.¹ Accessory breast tissue is prevalent in up to 6.0% of the world population, with Japanese individuals being the most affected and White individuals being the least affected.¹

Accessory breasts typically are located along the milk line—the embryologic precursor to mammary glands and nipples, which extend from the axillae to the groin and regress from the caudal end spanning to the groin.² For this reason, incomplete regression of the mammary ridge results in ABT, most commonly in the axillary region.³ Accessory breast tissue usually is benign and is considered an anatomical variant; however, because the histomorphology is similar to mammary gland tissue, accessory breasts have the same proliferative potential as anatomically correct breasts and therefore can form fibroadenomas, cysts, abscesses, mastitis, or breast cancer.⁴ Accessory breast carcinomas comprise 0.3% to 0.6% of all breast malignancies.⁵ Certain genodermatoses (ie, Cowden syndrome) also may predispose patients to benign or malignant pathology in ABT.⁶ We present a rare case of accessory breast cancer in the inframammary region masquerading as a cyst. These findings were further supported by ultrasonography and mammography.

A 45-year-old White woman presented to our clinic for removal of a dermal mass underlying a supernumerary nipple at the left inframammary fold. Her medical history was noncontributory and was only remarkable for uterine fibroids. She developed pain and swelling in the left breast 1 year prior, which prompted her to seek medical attention from her primary care physician. Diagnostic mammography was negative for any concerning malignant nodules, and subsequent BRCA genetic testing also was negative. Six months after the diagnostic mammography, she continued to experience pain and swelling in the left breast and was then referred for diagnostic ultrasonography; 2 masses in the left breast suspected as infected cysts with rupture were identified (Figure 1). She was then referred to our dermatology clinic for evaluation and surgical extirpation of the suspected cyst underlying the accessory breast. The area subsequently was excised under local anesthesia, and a second similar but smaller mass also was identified adjacent to the initial growth. Dermatopathologic examination revealed an estrogen receptor– (Figure 2A) and progesterone receptor–positive (Figure 2B), ERBB2 (HER2/neu)–negative, nuclear grade III ductal carcinoma in situ (Figure 3).

Various ABT classification methods have been proposed with Brightmore⁷ categorizing polymastia into 8 subtypes: (1) complete breast; (2) glandular tissue and nipple; (3) glandular tissue and areola; (4) glandular tissue only; (5) nipple, areola, and fat; (6) nipple only; (7) areola only; and (8) patch of hair only. De Cholnokey⁸ focused on axillary polymastia, dividing it into 4 classes: (1) axillary tumor in milk line without nipple or areola; (2) axillary tumor with areola with or without pigmentation; (3) nipple or areola without underlying breast tissue; and (4) complete breast with nipple, areola, and glandular tissue. Fenench’s⁹ method is preferred and simply describes ABT as 2 subtypes: supernumerary and aberrant.^1,2,10 One study observed 6% of ABT cancers were the supernumerary type and 94% were the aberrant type.¹ Ductal lumen stagnation increases the risk for accessory breast carcinoma development.¹⁰ Men have a higher prevalence of cancer in ABT compared to anatomically correct breast tissue.¹¹

There currently is no standardized guideline for ABT cancer treatment. The initial clinical impression of cancer of ABT may be misdiagnosed as lymphadenopathy, abscesses, or lipomas.¹² The risk for misdiagnosis is higher for cancer of ABT compared to normal breast tissue and is associated with a poorer prognosis.¹ Despite multiple screening modalities, our patient’s initial breast cancer screenings proved unreliable. A mammogram failed to detect malignancy, likely secondary to the area of concern being out of the standard imaging field. Ultrasonography also was unreliable and led to misdiagnosis as an infected sebaceous cyst with rupture in our patient. Upon review of the ultrasound, concerns were raised by dermatology that the mass was more likely an epidermal inclusion cyst with rupture given the more superficial and sac-free nature of sebaceous cysts, which commonly are associated with steatocystoma multiplex.¹³ Definitive diagnosis of ductal carcinoma in situ was made with dermatopathologic examination.

Prophylactic surgical excision of ABT has been recommended, suggesting that excisional biopsy and histopathologic examination is the more appropriate method to rule out malignancy. Surgical treatment of ABT may omit any risk for malignant transformation and may provide psychological relief to patients for aesthetic reasons.^10,12,14 The risk and benefits of prophylactic excision of ABT has been compared to prophylactic mastectomy of anatomically correct breasts,¹⁵ with some clinicians considering this definitive procedure unnecessary except in high-risk patients with a strong genetic predisposition.^16,17

Accessory breast tissue should be viewed as an anatomical variant with the option of surgical removal for symptomatic concerns, such as firm nodules, discharge, and pain. Although ABT is rare and cancer in ABT is even more uncommon (<1% of all breast cancers),^5,11 clinicians should be suspicious of benign diagnostic reports when the clinical situation does not fit the proposed narrative.

To the Editor:

The term ectopic breast tissue serves as an umbrella term that encompasses breast tissue positioned in anatomically incorrect locations, including the subtypes of supernumerary and aberrant breasts.¹ However, the more frequently used term is accessory breast tissue (ABT).¹ Supernumerary breasts have diverse variations of a nipple, areola, and/or ductal tissue and can span in size from a small mole to a fully functioning breast. This breast type maintains structured ductal systems connected to the overlying skin and experiences regular changes during the reproductive cycle. In contrast, an aberrant breast is isolated breast tissue that does not contain organized ductal systems.¹ Accessory breast tissue is prevalent in up to 6.0% of the world population, with Japanese individuals being the most affected and White individuals being the least affected.¹

Accessory breasts typically are located along the milk line—the embryologic precursor to mammary glands and nipples, which extend from the axillae to the groin and regress from the caudal end spanning to the groin.² For this reason, incomplete regression of the mammary ridge results in ABT, most commonly in the axillary region.³ Accessory breast tissue usually is benign and is considered an anatomical variant; however, because the histomorphology is similar to mammary gland tissue, accessory breasts have the same proliferative potential as anatomically correct breasts and therefore can form fibroadenomas, cysts, abscesses, mastitis, or breast cancer.⁴ Accessory breast carcinomas comprise 0.3% to 0.6% of all breast malignancies.⁵ Certain genodermatoses (ie, Cowden syndrome) also may predispose patients to benign or malignant pathology in ABT.⁶ We present a rare case of accessory breast cancer in the inframammary region masquerading as a cyst. These findings were further supported by ultrasonography and mammography.

A 45-year-old White woman presented to our clinic for removal of a dermal mass underlying a supernumerary nipple at the left inframammary fold. Her medical history was noncontributory and was only remarkable for uterine fibroids. She developed pain and swelling in the left breast 1 year prior, which prompted her to seek medical attention from her primary care physician. Diagnostic mammography was negative for any concerning malignant nodules, and subsequent BRCA genetic testing also was negative. Six months after the diagnostic mammography, she continued to experience pain and swelling in the left breast and was then referred for diagnostic ultrasonography; 2 masses in the left breast suspected as infected cysts with rupture were identified (Figure 1). She was then referred to our dermatology clinic for evaluation and surgical extirpation of the suspected cyst underlying the accessory breast. The area subsequently was excised under local anesthesia, and a second similar but smaller mass also was identified adjacent to the initial growth. Dermatopathologic examination revealed an estrogen receptor– (Figure 2A) and progesterone receptor–positive (Figure 2B), ERBB2 (HER2/neu)–negative, nuclear grade III ductal carcinoma in situ (Figure 3).

Various ABT classification methods have been proposed with Brightmore⁷ categorizing polymastia into 8 subtypes: (1) complete breast; (2) glandular tissue and nipple; (3) glandular tissue and areola; (4) glandular tissue only; (5) nipple, areola, and fat; (6) nipple only; (7) areola only; and (8) patch of hair only. De Cholnokey⁸ focused on axillary polymastia, dividing it into 4 classes: (1) axillary tumor in milk line without nipple or areola; (2) axillary tumor with areola with or without pigmentation; (3) nipple or areola without underlying breast tissue; and (4) complete breast with nipple, areola, and glandular tissue. Fenench’s⁹ method is preferred and simply describes ABT as 2 subtypes: supernumerary and aberrant.^1,2,10 One study observed 6% of ABT cancers were the supernumerary type and 94% were the aberrant type.¹ Ductal lumen stagnation increases the risk for accessory breast carcinoma development.¹⁰ Men have a higher prevalence of cancer in ABT compared to anatomically correct breast tissue.¹¹

There currently is no standardized guideline for ABT cancer treatment. The initial clinical impression of cancer of ABT may be misdiagnosed as lymphadenopathy, abscesses, or lipomas.¹² The risk for misdiagnosis is higher for cancer of ABT compared to normal breast tissue and is associated with a poorer prognosis.¹ Despite multiple screening modalities, our patient’s initial breast cancer screenings proved unreliable. A mammogram failed to detect malignancy, likely secondary to the area of concern being out of the standard imaging field. Ultrasonography also was unreliable and led to misdiagnosis as an infected sebaceous cyst with rupture in our patient. Upon review of the ultrasound, concerns were raised by dermatology that the mass was more likely an epidermal inclusion cyst with rupture given the more superficial and sac-free nature of sebaceous cysts, which commonly are associated with steatocystoma multiplex.¹³ Definitive diagnosis of ductal carcinoma in situ was made with dermatopathologic examination.

Prophylactic surgical excision of ABT has been recommended, suggesting that excisional biopsy and histopathologic examination is the more appropriate method to rule out malignancy. Surgical treatment of ABT may omit any risk for malignant transformation and may provide psychological relief to patients for aesthetic reasons.^10,12,14 The risk and benefits of prophylactic excision of ABT has been compared to prophylactic mastectomy of anatomically correct breasts,¹⁵ with some clinicians considering this definitive procedure unnecessary except in high-risk patients with a strong genetic predisposition.^16,17

Accessory breast tissue should be viewed as an anatomical variant with the option of surgical removal for symptomatic concerns, such as firm nodules, discharge, and pain. Although ABT is rare and cancer in ABT is even more uncommon (<1% of all breast cancers),^5,11 clinicians should be suspicious of benign diagnostic reports when the clinical situation does not fit the proposed narrative.

The Diagnosis: Localized Cutaneous Argyria

The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.

Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.¹ Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.² Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.³

Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.¹ Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.³ Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.⁴

Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).^3,5,6

Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.⁷

Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.⁸

Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.³

Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.^3,8

Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.

The Diagnosis: Localized Cutaneous Argyria

The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.

Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.¹ Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.² Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.³

Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.¹ Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.³ Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.⁴

Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).^3,5,6

Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.⁷

Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.⁸

Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.³

Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.^3,8

Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.

The Diagnosis: Localized Cutaneous Argyria

The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.

Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.¹ Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.² Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.³

Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.¹ Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.³ Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.⁴

Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).^3,5,6

Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.⁷

Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.⁸

Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.³

Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.^3,8

Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.

The Diagnosis: Scrotal Calcinosis

Scrotal calcinosis is a rare benign disease that results from the deposition of calcium, magnesium, phosphate, and carbonate within the dermis and subcutaneous layer of the skin in the absence of underlying systemic disease or serum calcium and phosphorus abnormalities.^1,2 Lesions usually are asymptomatic but can be mildly painful or pruritic. They usually present in childhood or early adulthood as yellow-white firm nodules ranging in size from a few millimeters to a few centimeters that increase in size and number over time. Additionally, lesions can ulcerate and discharge a chalklike exudative material. Although benign in nature, the quality-of-life impact in patients with this condition can be substantial, specifically regarding cosmesis, which may cause patients to feel embarrassed and even avoid sexual activity. This condition rarely has been associated with infection.¹

Our patient elected to undergo surgical excision under local anesthesia, and the lesions were sent for histopathologic examination. His postoperative course was unremarkable, and he was pleased with the cosmetic result of the surgery (Figure 1). Histopathology revealed calcified deposits that appeared as intradermal basophilic nodules lacking an epithelial lining (Figure 2), consistent with the diagnosis of scrotal calcinosis.² No recurrence of the lesions was documented over the course of 18 months.

The pathogenesis of this condition is not clear. Most research supports scrotal calcinosis resulting from dystrophic calcification of epidermal inclusion cysts.³ There have been cases of scrotal calcinosis coinciding with epidermal inclusion cysts of the scrotum in varying stages of inflammation (some intact and some ruptured).² Some research also suggests dystrophic calcification of eccrine epithelial cysts and degenerated dartos muscle as the origin of scrotal calcinosis.³

The differential diagnosis for this case included calcified steatocystoma multiplex, eruptive xanthomas, nodular scabies, and epidermal inclusion cysts. Steatocystoma multiplex can be inherited in an autosomal-dominant fashion or can develop sporadically with mutations in the KRT17 gene.⁴ It is characterized by multiple sebum-filled, cystic lesions of the pilosebaceous unit that may become calcified. Calcified lesions appear as yellow, firm, irregularly shaped papules or nodules ranging from a few millimeters to centimeters in size. Cysts can develop anywhere on the body with a predilection for the chest, upper extremities, axillae, trunk, groin, and scrotum.⁴ Histologically, our patient’s lesions were not associated with the pilosebaceous unit. Additionally, our patient denied a family history of similar skin lesions, which made calcified steatocystoma multiplex an unlikely diagnosis.

Eruptive xanthomas result from localized deposition of lipids within the dermis, typically in the setting of dyslipidemia or poorly controlled diabetes mellitus. They commonly appear on the extremities or buttocks as pruritic crops of yellow-red papules or nodules that are a few millimeters in size. Although our patient has a history of hyperlipidemia, his lesions differed substantially from eruptive xanthomas in clinical presentation.

Nodular scabies is a manifestation of classic scabies that presents with intensely pruritic erythematous papules and nodules that are a few millimeters in size and commonly occur on the axillae, groin, and genitalia. Our patient’s skin lesions were not pruritic and differed in appearance from nodular scabies.

Although research indicates scrotal calcinosis may result from dystrophic calcification of epidermal inclusion cysts,² the latter present as dome-shaped, flesh-colored nodules with central pores representing the opening of hair follicles. Our patient lacked characteristic findings of epidermal inclusion cysts on histology.

The preferred treatment for scrotal calcinosis is surgical excision, which improves the aesthetic appearance, relieves itch, and removes ulcerative lesions.⁵ Additionally, surgical excision provides histological diagnostic confirmation. Recurrence with incomplete excision is possible; therefore, all lesions should be completely excised to reduce the risk for recurrence.³

The Diagnosis: Scrotal Calcinosis

Scrotal calcinosis is a rare benign disease that results from the deposition of calcium, magnesium, phosphate, and carbonate within the dermis and subcutaneous layer of the skin in the absence of underlying systemic disease or serum calcium and phosphorus abnormalities.^1,2 Lesions usually are asymptomatic but can be mildly painful or pruritic. They usually present in childhood or early adulthood as yellow-white firm nodules ranging in size from a few millimeters to a few centimeters that increase in size and number over time. Additionally, lesions can ulcerate and discharge a chalklike exudative material. Although benign in nature, the quality-of-life impact in patients with this condition can be substantial, specifically regarding cosmesis, which may cause patients to feel embarrassed and even avoid sexual activity. This condition rarely has been associated with infection.¹

Our patient elected to undergo surgical excision under local anesthesia, and the lesions were sent for histopathologic examination. His postoperative course was unremarkable, and he was pleased with the cosmetic result of the surgery (Figure 1). Histopathology revealed calcified deposits that appeared as intradermal basophilic nodules lacking an epithelial lining (Figure 2), consistent with the diagnosis of scrotal calcinosis.² No recurrence of the lesions was documented over the course of 18 months.

The pathogenesis of this condition is not clear. Most research supports scrotal calcinosis resulting from dystrophic calcification of epidermal inclusion cysts.³ There have been cases of scrotal calcinosis coinciding with epidermal inclusion cysts of the scrotum in varying stages of inflammation (some intact and some ruptured).² Some research also suggests dystrophic calcification of eccrine epithelial cysts and degenerated dartos muscle as the origin of scrotal calcinosis.³

The differential diagnosis for this case included calcified steatocystoma multiplex, eruptive xanthomas, nodular scabies, and epidermal inclusion cysts. Steatocystoma multiplex can be inherited in an autosomal-dominant fashion or can develop sporadically with mutations in the KRT17 gene.⁴ It is characterized by multiple sebum-filled, cystic lesions of the pilosebaceous unit that may become calcified. Calcified lesions appear as yellow, firm, irregularly shaped papules or nodules ranging from a few millimeters to centimeters in size. Cysts can develop anywhere on the body with a predilection for the chest, upper extremities, axillae, trunk, groin, and scrotum.⁴ Histologically, our patient’s lesions were not associated with the pilosebaceous unit. Additionally, our patient denied a family history of similar skin lesions, which made calcified steatocystoma multiplex an unlikely diagnosis.

Eruptive xanthomas result from localized deposition of lipids within the dermis, typically in the setting of dyslipidemia or poorly controlled diabetes mellitus. They commonly appear on the extremities or buttocks as pruritic crops of yellow-red papules or nodules that are a few millimeters in size. Although our patient has a history of hyperlipidemia, his lesions differed substantially from eruptive xanthomas in clinical presentation.

Nodular scabies is a manifestation of classic scabies that presents with intensely pruritic erythematous papules and nodules that are a few millimeters in size and commonly occur on the axillae, groin, and genitalia. Our patient’s skin lesions were not pruritic and differed in appearance from nodular scabies.

Although research indicates scrotal calcinosis may result from dystrophic calcification of epidermal inclusion cysts,² the latter present as dome-shaped, flesh-colored nodules with central pores representing the opening of hair follicles. Our patient lacked characteristic findings of epidermal inclusion cysts on histology.

The preferred treatment for scrotal calcinosis is surgical excision, which improves the aesthetic appearance, relieves itch, and removes ulcerative lesions.⁵ Additionally, surgical excision provides histological diagnostic confirmation. Recurrence with incomplete excision is possible; therefore, all lesions should be completely excised to reduce the risk for recurrence.³

The Diagnosis: Scrotal Calcinosis

Scrotal calcinosis is a rare benign disease that results from the deposition of calcium, magnesium, phosphate, and carbonate within the dermis and subcutaneous layer of the skin in the absence of underlying systemic disease or serum calcium and phosphorus abnormalities.^1,2 Lesions usually are asymptomatic but can be mildly painful or pruritic. They usually present in childhood or early adulthood as yellow-white firm nodules ranging in size from a few millimeters to a few centimeters that increase in size and number over time. Additionally, lesions can ulcerate and discharge a chalklike exudative material. Although benign in nature, the quality-of-life impact in patients with this condition can be substantial, specifically regarding cosmesis, which may cause patients to feel embarrassed and even avoid sexual activity. This condition rarely has been associated with infection.¹

Our patient elected to undergo surgical excision under local anesthesia, and the lesions were sent for histopathologic examination. His postoperative course was unremarkable, and he was pleased with the cosmetic result of the surgery (Figure 1). Histopathology revealed calcified deposits that appeared as intradermal basophilic nodules lacking an epithelial lining (Figure 2), consistent with the diagnosis of scrotal calcinosis.² No recurrence of the lesions was documented over the course of 18 months.

The pathogenesis of this condition is not clear. Most research supports scrotal calcinosis resulting from dystrophic calcification of epidermal inclusion cysts.³ There have been cases of scrotal calcinosis coinciding with epidermal inclusion cysts of the scrotum in varying stages of inflammation (some intact and some ruptured).² Some research also suggests dystrophic calcification of eccrine epithelial cysts and degenerated dartos muscle as the origin of scrotal calcinosis.³

The differential diagnosis for this case included calcified steatocystoma multiplex, eruptive xanthomas, nodular scabies, and epidermal inclusion cysts. Steatocystoma multiplex can be inherited in an autosomal-dominant fashion or can develop sporadically with mutations in the KRT17 gene.⁴ It is characterized by multiple sebum-filled, cystic lesions of the pilosebaceous unit that may become calcified. Calcified lesions appear as yellow, firm, irregularly shaped papules or nodules ranging from a few millimeters to centimeters in size. Cysts can develop anywhere on the body with a predilection for the chest, upper extremities, axillae, trunk, groin, and scrotum.⁴ Histologically, our patient’s lesions were not associated with the pilosebaceous unit. Additionally, our patient denied a family history of similar skin lesions, which made calcified steatocystoma multiplex an unlikely diagnosis.

Eruptive xanthomas result from localized deposition of lipids within the dermis, typically in the setting of dyslipidemia or poorly controlled diabetes mellitus. They commonly appear on the extremities or buttocks as pruritic crops of yellow-red papules or nodules that are a few millimeters in size. Although our patient has a history of hyperlipidemia, his lesions differed substantially from eruptive xanthomas in clinical presentation.

Nodular scabies is a manifestation of classic scabies that presents with intensely pruritic erythematous papules and nodules that are a few millimeters in size and commonly occur on the axillae, groin, and genitalia. Our patient’s skin lesions were not pruritic and differed in appearance from nodular scabies.

Although research indicates scrotal calcinosis may result from dystrophic calcification of epidermal inclusion cysts,² the latter present as dome-shaped, flesh-colored nodules with central pores representing the opening of hair follicles. Our patient lacked characteristic findings of epidermal inclusion cysts on histology.

The preferred treatment for scrotal calcinosis is surgical excision, which improves the aesthetic appearance, relieves itch, and removes ulcerative lesions.⁵ Additionally, surgical excision provides histological diagnostic confirmation. Recurrence with incomplete excision is possible; therefore, all lesions should be completely excised to reduce the risk for recurrence.³

The Diagnosis: Extragenital Lichen Sclerosus et Atrophicus

A punch biopsy of the lesion revealed epidermal hyperkeratosis, atrophy, follicular plugs with basal vacuolar degeneration, and homogenous dense fibrosis in the papillary dermis with a dense lymphocytic infiltrate beneath the fibrosis (Figure 1). Dermoscopic examination was remarkable for a distinctive rainbow pattern. Clinical, histopathologic, and dermoscopic findings led to the diagnosis of extragenital lichen sclerosus et atrophicus (LSEA). A potent corticosteroid cream was prescribed twice daily for 2 months, after which the lesions completely resolved. At 2-year follow-up, a relapse was not observed (Figure 2).

Lichen sclerosus et atrophicus is an inflammatory dermatosis that clinically presents as atrophic or hypertrophic plaques that may show pigmentation changes with anogenital and extragenital involvement. It is common among females and predominantly occurs in prepubescent girls and postmenopausal women. The exact etiology is unclear; however, it is hypothesized to occur secondary to autoimmunity with an underlying genetic predisposition. Local trauma, hormonal influences, and infections are other suspected etiologic factors. Genital lesions often lead to itching, pain, and dyspareunia, whereas extragenital lesions predominantly are asymptomatic. When symptomatic, itching usually is the main concern. Unlike genital LSEA, extragenital lesions are not associated with squamous cell carcinoma development. Reported dermoscopic features of LSEA are white structureless areas with scaling, comedolike openings, follicular plugs, white shiny streaks, blue-gray peppering, pigment network, and red-purple globules.¹ In our case, the dermoscopic finding of a rainbow pattern in LSEA is rare.² Although the mechanism behind this appearance unclear, it can be the result of the birefringence effect—local variations in refractive index—influenced by the direction of structures within the dermis such as collagen. In this case, there was diffuse and dense homogenous fibrosis in the superficial dermis that corresponded to dermoscopic white polygonal clods.

Extragenital LSEA commonly is located on the neck, shoulders, wrists, and upper trunk and manifests clinically as whitish papules coalescing into scarlike plaques. Of all patients who have LSEA, 20% have extragenital lesions, and most of these lesions are seen in patients who also have genital LSEA. Approximately 6% of all LSEA patients have extragenital LSEA without genital involvement.³

For experienced dermatologists, clinical symptoms and lesion characteristics usually are sufficient for diagnosis; however, a differential diagnosis of atypical lesions and isolated extragenital presentations such as morphea, lichen simplex chronicus, lichen planus, and vitiligo requires the correlation of clinical findings with histopathology and dermoscopy. Morphea, known as localized scleroderma, is an idiopathic inflammatory skin disease with sclerotic changes. It manifests as inflammatory plaques that vary in color from red to purple. If there is moderate sclerosis in the center of this plaque, the color progressively fades to white, leaving a purplish ring around the edges. Dermoscopic features of morphea are reported as areas of erythema; red-focused vessels of linear, irregular, or dotted morphology; white fibrotic beams; and pigmentary structures.² Lichen simplex chronicus is characterized by single or multiple dry and patchy skin lesions that are intensely pruritic. It commonly occurs on the neck, scalp, extremities, genital areas, and buttocks. Scratching the lesions leads to scarring, thickening of the skin, and increased frequency of itching. Histopathology of lichen simplex chronicus most frequently demonstrates a thickening of the epidermis and papillary dermis, irregularly elongated rete ridges, and fibroplasia with stellate or multinucleated fibroblasts completed by perivascular lymphocytic inflammation.⁴ Lichen planus presents with pruritic, polygonal, purple papules and/or plaques that can present in a variety of clinical forms, including atrophic and hypertrophic lichen planus.⁵ Lichen planus was an unlikely diagnosis for our patient due to the presence of patchy scarlike lesions and dermoscopic features that are well described in patients with LSEA. Lichen sclerosus et atrophicus presents with hypopigmented and/or hyperpigmented patches and plaques, distinguishing itself from vitiligo, which has flat lesions.

Topical steroids are the first-line therapeutic agents in the treatment of LSEA.6 Despite frequent use in this setting, common side effects such as localized scarring and atrophic degenerations have led to debate about their use. In our patient, the lesions resolved almost completely in 2 months, and no relapse was observed in the following 2 years. In the setting of topical steroid resistance, topical calcineurin inhibitors, UVA/UVB phototherapy, and topical tacrolimus can be used for treatment.⁶

The diagnosis of isolated extragenital LSEA may be a clinical challenge and generally requires further workup. When evaluating extragenital lesions, dermatologists should keep in mind extragenital LSEA as a differential diagnosis in the presence of a dermoscopic rainbow pattern arranged over white polygonal clods.

The Diagnosis: Extragenital Lichen Sclerosus et Atrophicus

A punch biopsy of the lesion revealed epidermal hyperkeratosis, atrophy, follicular plugs with basal vacuolar degeneration, and homogenous dense fibrosis in the papillary dermis with a dense lymphocytic infiltrate beneath the fibrosis (Figure 1). Dermoscopic examination was remarkable for a distinctive rainbow pattern. Clinical, histopathologic, and dermoscopic findings led to the diagnosis of extragenital lichen sclerosus et atrophicus (LSEA). A potent corticosteroid cream was prescribed twice daily for 2 months, after which the lesions completely resolved. At 2-year follow-up, a relapse was not observed (Figure 2).

Lichen sclerosus et atrophicus is an inflammatory dermatosis that clinically presents as atrophic or hypertrophic plaques that may show pigmentation changes with anogenital and extragenital involvement. It is common among females and predominantly occurs in prepubescent girls and postmenopausal women. The exact etiology is unclear; however, it is hypothesized to occur secondary to autoimmunity with an underlying genetic predisposition. Local trauma, hormonal influences, and infections are other suspected etiologic factors. Genital lesions often lead to itching, pain, and dyspareunia, whereas extragenital lesions predominantly are asymptomatic. When symptomatic, itching usually is the main concern. Unlike genital LSEA, extragenital lesions are not associated with squamous cell carcinoma development. Reported dermoscopic features of LSEA are white structureless areas with scaling, comedolike openings, follicular plugs, white shiny streaks, blue-gray peppering, pigment network, and red-purple globules.¹ In our case, the dermoscopic finding of a rainbow pattern in LSEA is rare.² Although the mechanism behind this appearance unclear, it can be the result of the birefringence effect—local variations in refractive index—influenced by the direction of structures within the dermis such as collagen. In this case, there was diffuse and dense homogenous fibrosis in the superficial dermis that corresponded to dermoscopic white polygonal clods.

Extragenital LSEA commonly is located on the neck, shoulders, wrists, and upper trunk and manifests clinically as whitish papules coalescing into scarlike plaques. Of all patients who have LSEA, 20% have extragenital lesions, and most of these lesions are seen in patients who also have genital LSEA. Approximately 6% of all LSEA patients have extragenital LSEA without genital involvement.³

For experienced dermatologists, clinical symptoms and lesion characteristics usually are sufficient for diagnosis; however, a differential diagnosis of atypical lesions and isolated extragenital presentations such as morphea, lichen simplex chronicus, lichen planus, and vitiligo requires the correlation of clinical findings with histopathology and dermoscopy. Morphea, known as localized scleroderma, is an idiopathic inflammatory skin disease with sclerotic changes. It manifests as inflammatory plaques that vary in color from red to purple. If there is moderate sclerosis in the center of this plaque, the color progressively fades to white, leaving a purplish ring around the edges. Dermoscopic features of morphea are reported as areas of erythema; red-focused vessels of linear, irregular, or dotted morphology; white fibrotic beams; and pigmentary structures.² Lichen simplex chronicus is characterized by single or multiple dry and patchy skin lesions that are intensely pruritic. It commonly occurs on the neck, scalp, extremities, genital areas, and buttocks. Scratching the lesions leads to scarring, thickening of the skin, and increased frequency of itching. Histopathology of lichen simplex chronicus most frequently demonstrates a thickening of the epidermis and papillary dermis, irregularly elongated rete ridges, and fibroplasia with stellate or multinucleated fibroblasts completed by perivascular lymphocytic inflammation.⁴ Lichen planus presents with pruritic, polygonal, purple papules and/or plaques that can present in a variety of clinical forms, including atrophic and hypertrophic lichen planus.⁵ Lichen planus was an unlikely diagnosis for our patient due to the presence of patchy scarlike lesions and dermoscopic features that are well described in patients with LSEA. Lichen sclerosus et atrophicus presents with hypopigmented and/or hyperpigmented patches and plaques, distinguishing itself from vitiligo, which has flat lesions.

Topical steroids are the first-line therapeutic agents in the treatment of LSEA.6 Despite frequent use in this setting, common side effects such as localized scarring and atrophic degenerations have led to debate about their use. In our patient, the lesions resolved almost completely in 2 months, and no relapse was observed in the following 2 years. In the setting of topical steroid resistance, topical calcineurin inhibitors, UVA/UVB phototherapy, and topical tacrolimus can be used for treatment.⁶

The diagnosis of isolated extragenital LSEA may be a clinical challenge and generally requires further workup. When evaluating extragenital lesions, dermatologists should keep in mind extragenital LSEA as a differential diagnosis in the presence of a dermoscopic rainbow pattern arranged over white polygonal clods.

The Diagnosis: Extragenital Lichen Sclerosus et Atrophicus

A punch biopsy of the lesion revealed epidermal hyperkeratosis, atrophy, follicular plugs with basal vacuolar degeneration, and homogenous dense fibrosis in the papillary dermis with a dense lymphocytic infiltrate beneath the fibrosis (Figure 1). Dermoscopic examination was remarkable for a distinctive rainbow pattern. Clinical, histopathologic, and dermoscopic findings led to the diagnosis of extragenital lichen sclerosus et atrophicus (LSEA). A potent corticosteroid cream was prescribed twice daily for 2 months, after which the lesions completely resolved. At 2-year follow-up, a relapse was not observed (Figure 2).

Lichen sclerosus et atrophicus is an inflammatory dermatosis that clinically presents as atrophic or hypertrophic plaques that may show pigmentation changes with anogenital and extragenital involvement. It is common among females and predominantly occurs in prepubescent girls and postmenopausal women. The exact etiology is unclear; however, it is hypothesized to occur secondary to autoimmunity with an underlying genetic predisposition. Local trauma, hormonal influences, and infections are other suspected etiologic factors. Genital lesions often lead to itching, pain, and dyspareunia, whereas extragenital lesions predominantly are asymptomatic. When symptomatic, itching usually is the main concern. Unlike genital LSEA, extragenital lesions are not associated with squamous cell carcinoma development. Reported dermoscopic features of LSEA are white structureless areas with scaling, comedolike openings, follicular plugs, white shiny streaks, blue-gray peppering, pigment network, and red-purple globules.¹ In our case, the dermoscopic finding of a rainbow pattern in LSEA is rare.² Although the mechanism behind this appearance unclear, it can be the result of the birefringence effect—local variations in refractive index—influenced by the direction of structures within the dermis such as collagen. In this case, there was diffuse and dense homogenous fibrosis in the superficial dermis that corresponded to dermoscopic white polygonal clods.

Extragenital LSEA commonly is located on the neck, shoulders, wrists, and upper trunk and manifests clinically as whitish papules coalescing into scarlike plaques. Of all patients who have LSEA, 20% have extragenital lesions, and most of these lesions are seen in patients who also have genital LSEA. Approximately 6% of all LSEA patients have extragenital LSEA without genital involvement.³

For experienced dermatologists, clinical symptoms and lesion characteristics usually are sufficient for diagnosis; however, a differential diagnosis of atypical lesions and isolated extragenital presentations such as morphea, lichen simplex chronicus, lichen planus, and vitiligo requires the correlation of clinical findings with histopathology and dermoscopy. Morphea, known as localized scleroderma, is an idiopathic inflammatory skin disease with sclerotic changes. It manifests as inflammatory plaques that vary in color from red to purple. If there is moderate sclerosis in the center of this plaque, the color progressively fades to white, leaving a purplish ring around the edges. Dermoscopic features of morphea are reported as areas of erythema; red-focused vessels of linear, irregular, or dotted morphology; white fibrotic beams; and pigmentary structures.² Lichen simplex chronicus is characterized by single or multiple dry and patchy skin lesions that are intensely pruritic. It commonly occurs on the neck, scalp, extremities, genital areas, and buttocks. Scratching the lesions leads to scarring, thickening of the skin, and increased frequency of itching. Histopathology of lichen simplex chronicus most frequently demonstrates a thickening of the epidermis and papillary dermis, irregularly elongated rete ridges, and fibroplasia with stellate or multinucleated fibroblasts completed by perivascular lymphocytic inflammation.⁴ Lichen planus presents with pruritic, polygonal, purple papules and/or plaques that can present in a variety of clinical forms, including atrophic and hypertrophic lichen planus.⁵ Lichen planus was an unlikely diagnosis for our patient due to the presence of patchy scarlike lesions and dermoscopic features that are well described in patients with LSEA. Lichen sclerosus et atrophicus presents with hypopigmented and/or hyperpigmented patches and plaques, distinguishing itself from vitiligo, which has flat lesions.

Topical steroids are the first-line therapeutic agents in the treatment of LSEA.6 Despite frequent use in this setting, common side effects such as localized scarring and atrophic degenerations have led to debate about their use. In our patient, the lesions resolved almost completely in 2 months, and no relapse was observed in the following 2 years. In the setting of topical steroid resistance, topical calcineurin inhibitors, UVA/UVB phototherapy, and topical tacrolimus can be used for treatment.⁶

The diagnosis of isolated extragenital LSEA may be a clinical challenge and generally requires further workup. When evaluating extragenital lesions, dermatologists should keep in mind extragenital LSEA as a differential diagnosis in the presence of a dermoscopic rainbow pattern arranged over white polygonal clods.

The Diagnosis: Diffuse Dermal Angiomatosis

Diffuse dermal angiomatosis (DDA) is an acquired reactive vascular proliferation in the spectrum of cutaneous reactive angioendotheliomatoses. Clinically, DDA presents as violaceous reticulated plaques, often with secondary ulceration and sometimes necrosis.1-3 Diffuse dermal angiomatosis more commonly presents in patients with a history of severe peripheral vascular disease, coagulopathies, or infection, and it frequently arises on the extremities. Diffuse dermal angiomatosis also has been shown to develop on the breasts, particularly in patients with pendulous breast tissue. Vascular proliferation in DDA is hypothesized to be from ischemia and hypoxia, leading to angiogenesis.^1-3 Diffuse dermal angiomatosis is characterized histologically by the presence of a diffuse proliferation of spindled endothelial cells distributed between the collagen bundles throughout the dermis (quiz image and Figure 1). Spindle-shaped endothelial cells exhibit a vacuolated cytoplasm. On immunohistochemistry, these dermal spindle cells classically stain positive for CD31, CD34, and erythroblast transformation specific–related gene (Erg) and stain negative for both human herpesvirus 8 (HHV-8) and factor XIIIa.

Cutaneous fibrous histiocytoma, more commonly referred to as dermatofibroma, is a common benign lesion that presents clinically as a solitary firm nodule most commonly on the extremities in areas of repetitive trauma or pressure. It classically exhibits dimpling of the overlaying skin with lateral pressure on the lesion, known as the dimple sign.⁴ Histologically, dermatofibromas share similar features to DDA and demonstrate the presence of bland-appearing spindle cells within the dermis between the collagen bundles, resulting in collagen trapping. However, a distinguishing histologic feature of a dermatofibroma in comparison to DDA is the presence of epidermal hyperplasia overlying the dermatofibroma, leading to tabled rete ridges (Figure 2). Spindle cells in dermatofibromas are fibroblasts and have a distinct immunophenotype that includes factor XIIIa positivity and negative staining for CD31, CD34, and Erg.^4,5

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant soft-tissue sarcoma that clinically presents as a firm, flesh-colored, dermal plaque on the trunk, proximal extremities, head, or neck.⁵ Histologically, DFSP can be distinguished from DDA by the high density of spindle cells that are arranged in a storiform pattern, extending and infiltrating the underlying subcutaneous fat in a honeycomblike pattern (Figure 3). Spindle cells in DFSP typically show expression of CD34 but are negative for CD31, Erg, and factor XIIIa.⁵

Kaposi sarcoma (KS) is an endothelial cell–driven angioproliferative neoplasm that is associated with HHV-8 infection.⁶ The clinical presentation of KS can range from isolated pink or purple papules and patches to more extensive ulcerated plaques or nodules. Histopathology exhibits proliferation of monomorphic spindled endothelial cells within the dermis staining positive for HHV-8, Erg, CD31, and CD34, in conjunction with extravasated erythrocytes arranged within slitlike vascular spaces (Figure 4). Additionally, KS classically exhibits aberrant endothelial cell proliferation and vessel formation around preexisting vessels, which is referred to as the promontory sign (Figure 4).

Angiosarcoma is a rare and highly aggressive vascular tumor arising from endothelial cells lining the blood vessels and lymphatics.^7,8 Clinically, angiosarcoma presents as ulcerated violaceous nodules or plaques on the head, neck, or trunk. Histologic evaluation of angiosarcoma reveals a complex and poorly demarcated vascular network dissecting between collagen bundles in the dermis (Figure 5). Multilayering of endothelial cells, papillary projections extending into the vessel lumina, and mitoses frequently are seen. On immunohistochemistry, endothelial cells demonstrate prominent cellular atypia and stain positive with CD31, CD34, and Erg.

The Diagnosis: Diffuse Dermal Angiomatosis

Diffuse dermal angiomatosis (DDA) is an acquired reactive vascular proliferation in the spectrum of cutaneous reactive angioendotheliomatoses. Clinically, DDA presents as violaceous reticulated plaques, often with secondary ulceration and sometimes necrosis.1-3 Diffuse dermal angiomatosis more commonly presents in patients with a history of severe peripheral vascular disease, coagulopathies, or infection, and it frequently arises on the extremities. Diffuse dermal angiomatosis also has been shown to develop on the breasts, particularly in patients with pendulous breast tissue. Vascular proliferation in DDA is hypothesized to be from ischemia and hypoxia, leading to angiogenesis.^1-3 Diffuse dermal angiomatosis is characterized histologically by the presence of a diffuse proliferation of spindled endothelial cells distributed between the collagen bundles throughout the dermis (quiz image and Figure 1). Spindle-shaped endothelial cells exhibit a vacuolated cytoplasm. On immunohistochemistry, these dermal spindle cells classically stain positive for CD31, CD34, and erythroblast transformation specific–related gene (Erg) and stain negative for both human herpesvirus 8 (HHV-8) and factor XIIIa.

Cutaneous fibrous histiocytoma, more commonly referred to as dermatofibroma, is a common benign lesion that presents clinically as a solitary firm nodule most commonly on the extremities in areas of repetitive trauma or pressure. It classically exhibits dimpling of the overlaying skin with lateral pressure on the lesion, known as the dimple sign.⁴ Histologically, dermatofibromas share similar features to DDA and demonstrate the presence of bland-appearing spindle cells within the dermis between the collagen bundles, resulting in collagen trapping. However, a distinguishing histologic feature of a dermatofibroma in comparison to DDA is the presence of epidermal hyperplasia overlying the dermatofibroma, leading to tabled rete ridges (Figure 2). Spindle cells in dermatofibromas are fibroblasts and have a distinct immunophenotype that includes factor XIIIa positivity and negative staining for CD31, CD34, and Erg.^4,5

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant soft-tissue sarcoma that clinically presents as a firm, flesh-colored, dermal plaque on the trunk, proximal extremities, head, or neck.⁵ Histologically, DFSP can be distinguished from DDA by the high density of spindle cells that are arranged in a storiform pattern, extending and infiltrating the underlying subcutaneous fat in a honeycomblike pattern (Figure 3). Spindle cells in DFSP typically show expression of CD34 but are negative for CD31, Erg, and factor XIIIa.⁵

Kaposi sarcoma (KS) is an endothelial cell–driven angioproliferative neoplasm that is associated with HHV-8 infection.⁶ The clinical presentation of KS can range from isolated pink or purple papules and patches to more extensive ulcerated plaques or nodules. Histopathology exhibits proliferation of monomorphic spindled endothelial cells within the dermis staining positive for HHV-8, Erg, CD31, and CD34, in conjunction with extravasated erythrocytes arranged within slitlike vascular spaces (Figure 4). Additionally, KS classically exhibits aberrant endothelial cell proliferation and vessel formation around preexisting vessels, which is referred to as the promontory sign (Figure 4).

Angiosarcoma is a rare and highly aggressive vascular tumor arising from endothelial cells lining the blood vessels and lymphatics.^7,8 Clinically, angiosarcoma presents as ulcerated violaceous nodules or plaques on the head, neck, or trunk. Histologic evaluation of angiosarcoma reveals a complex and poorly demarcated vascular network dissecting between collagen bundles in the dermis (Figure 5). Multilayering of endothelial cells, papillary projections extending into the vessel lumina, and mitoses frequently are seen. On immunohistochemistry, endothelial cells demonstrate prominent cellular atypia and stain positive with CD31, CD34, and Erg.

The Diagnosis: Diffuse Dermal Angiomatosis

Diffuse dermal angiomatosis (DDA) is an acquired reactive vascular proliferation in the spectrum of cutaneous reactive angioendotheliomatoses. Clinically, DDA presents as violaceous reticulated plaques, often with secondary ulceration and sometimes necrosis.1-3 Diffuse dermal angiomatosis more commonly presents in patients with a history of severe peripheral vascular disease, coagulopathies, or infection, and it frequently arises on the extremities. Diffuse dermal angiomatosis also has been shown to develop on the breasts, particularly in patients with pendulous breast tissue. Vascular proliferation in DDA is hypothesized to be from ischemia and hypoxia, leading to angiogenesis.^1-3 Diffuse dermal angiomatosis is characterized histologically by the presence of a diffuse proliferation of spindled endothelial cells distributed between the collagen bundles throughout the dermis (quiz image and Figure 1). Spindle-shaped endothelial cells exhibit a vacuolated cytoplasm. On immunohistochemistry, these dermal spindle cells classically stain positive for CD31, CD34, and erythroblast transformation specific–related gene (Erg) and stain negative for both human herpesvirus 8 (HHV-8) and factor XIIIa.

Cutaneous fibrous histiocytoma, more commonly referred to as dermatofibroma, is a common benign lesion that presents clinically as a solitary firm nodule most commonly on the extremities in areas of repetitive trauma or pressure. It classically exhibits dimpling of the overlaying skin with lateral pressure on the lesion, known as the dimple sign.⁴ Histologically, dermatofibromas share similar features to DDA and demonstrate the presence of bland-appearing spindle cells within the dermis between the collagen bundles, resulting in collagen trapping. However, a distinguishing histologic feature of a dermatofibroma in comparison to DDA is the presence of epidermal hyperplasia overlying the dermatofibroma, leading to tabled rete ridges (Figure 2). Spindle cells in dermatofibromas are fibroblasts and have a distinct immunophenotype that includes factor XIIIa positivity and negative staining for CD31, CD34, and Erg.^4,5

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant soft-tissue sarcoma that clinically presents as a firm, flesh-colored, dermal plaque on the trunk, proximal extremities, head, or neck.⁵ Histologically, DFSP can be distinguished from DDA by the high density of spindle cells that are arranged in a storiform pattern, extending and infiltrating the underlying subcutaneous fat in a honeycomblike pattern (Figure 3). Spindle cells in DFSP typically show expression of CD34 but are negative for CD31, Erg, and factor XIIIa.⁵

Kaposi sarcoma (KS) is an endothelial cell–driven angioproliferative neoplasm that is associated with HHV-8 infection.⁶ The clinical presentation of KS can range from isolated pink or purple papules and patches to more extensive ulcerated plaques or nodules. Histopathology exhibits proliferation of monomorphic spindled endothelial cells within the dermis staining positive for HHV-8, Erg, CD31, and CD34, in conjunction with extravasated erythrocytes arranged within slitlike vascular spaces (Figure 4). Additionally, KS classically exhibits aberrant endothelial cell proliferation and vessel formation around preexisting vessels, which is referred to as the promontory sign (Figure 4).

Angiosarcoma is a rare and highly aggressive vascular tumor arising from endothelial cells lining the blood vessels and lymphatics.^7,8 Clinically, angiosarcoma presents as ulcerated violaceous nodules or plaques on the head, neck, or trunk. Histologic evaluation of angiosarcoma reveals a complex and poorly demarcated vascular network dissecting between collagen bundles in the dermis (Figure 5). Multilayering of endothelial cells, papillary projections extending into the vessel lumina, and mitoses frequently are seen. On immunohistochemistry, endothelial cells demonstrate prominent cellular atypia and stain positive with CD31, CD34, and Erg.