MDedge Dermatology

THE DIAGNOSIS: Dermatofibroma

Histopathologic examination of the shave biopsy revealed fascicles of plump fibroblasts and histiocytes interposed between thick collagen bundles within the dermis, consistent with a diagnosis of dermatofibroma (DF). Dermatofibroma is a common benign skin tumor that classically manifests as brownish or reddish-brown firm papules or nodules that dimple when compressed. While the exact etiology of DF remains uncertain, it is believed to arise from a combined neoplastic and reactive fibroblastic proliferation process in response to stimuli, such as minor trauma or insect bites (as in our patient).¹

On histopathology, the most common findings associated with DF are dermal proliferation of spindle-shaped fibroblasts arranged in a storiform or whorled pattern.² In this patient, fascicles of plump fibroblasts and histiocytes were observed interspersed among thick collagen bundles within the dermis (Figure). Other histologic variants of DF include cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, monster cell, myxoid, keloidal, palisading, osteoclastic, and epithelioid.

On dermatoscopic examination, a pigment network is the most common feature, followed by a white scarlike patch, brown dots and globules, and vascular structures.² Atypical DF variants can manifest with diverse clinical morphologies; one example is giant DF, which exceeds 5 cm and may exhibit an ulcerated or pedunculated appearance, as seen in our case.³ In such cases, a thorough clinical examination coupled with histopathologic analysis becomes paramount for accurate diagnosis.

Most cases of DF do not require intervention unless there are cosmetic concerns or the lesions are symptomatic. Surgical excision is a common and effective treatment method but results in scarring. Intralesional steroid injection and cryotherapy are less aggressive treatment options but have limited efficacy. Lasers, including carbon dioxide and pulsed dye lasers, are infrequently used; however, recurrence is possible with any treatment modality.⁴ Local recurrence is common, occurring in 26% to 50% of cases, particularly in atypical dermatofibroma variants after treatment.⁵ Recurrence is more likely with primary lesions larger than 1 cm.⁵

Several conditions share clinical features with DF, necessitating a thorough differential diagnosis. Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive, malignant tumor with a propensity for recurrence. It manifests as a slow-growing, red-brown, indurated plaque with irregular nodularity. Immunohistochemical staining can be used to differentiate DF from DFSP, with DF typically expressing factor XIIIa and lacking CD34, whereas DFSP exhibits CD34 positivity and lacks factor XIIIa expression.⁶ Another diagnosis in the differential is fibrosarcoma, a malignant tumor of fibroblasts that manifests as a painless, enlarging, poorly defined mass on the lower extremities. Histopathologic features include atypical fibroblasts and collagen with proliferation of atypical spindle-shaped cells.

Other benign lesions to consider include neurofibroma, which may manifest as a firm nodule but is derived from nerve tissue. Clinically, neurofibromas can be differentiated by their association with neurofibromatosis and softer texture. Cutaneous squamous cell carcinoma also should be considered, as it is a malignant proliferation of cutaneous epithelium that clinically manifests as a hyperkeratotic papule or plaque.⁵

THE DIAGNOSIS: Dermatofibroma

Histopathologic examination of the shave biopsy revealed fascicles of plump fibroblasts and histiocytes interposed between thick collagen bundles within the dermis, consistent with a diagnosis of dermatofibroma (DF). Dermatofibroma is a common benign skin tumor that classically manifests as brownish or reddish-brown firm papules or nodules that dimple when compressed. While the exact etiology of DF remains uncertain, it is believed to arise from a combined neoplastic and reactive fibroblastic proliferation process in response to stimuli, such as minor trauma or insect bites (as in our patient).¹

On histopathology, the most common findings associated with DF are dermal proliferation of spindle-shaped fibroblasts arranged in a storiform or whorled pattern.² In this patient, fascicles of plump fibroblasts and histiocytes were observed interspersed among thick collagen bundles within the dermis (Figure). Other histologic variants of DF include cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, monster cell, myxoid, keloidal, palisading, osteoclastic, and epithelioid.

On dermatoscopic examination, a pigment network is the most common feature, followed by a white scarlike patch, brown dots and globules, and vascular structures.² Atypical DF variants can manifest with diverse clinical morphologies; one example is giant DF, which exceeds 5 cm and may exhibit an ulcerated or pedunculated appearance, as seen in our case.³ In such cases, a thorough clinical examination coupled with histopathologic analysis becomes paramount for accurate diagnosis.

Most cases of DF do not require intervention unless there are cosmetic concerns or the lesions are symptomatic. Surgical excision is a common and effective treatment method but results in scarring. Intralesional steroid injection and cryotherapy are less aggressive treatment options but have limited efficacy. Lasers, including carbon dioxide and pulsed dye lasers, are infrequently used; however, recurrence is possible with any treatment modality.⁴ Local recurrence is common, occurring in 26% to 50% of cases, particularly in atypical dermatofibroma variants after treatment.⁵ Recurrence is more likely with primary lesions larger than 1 cm.⁵

Several conditions share clinical features with DF, necessitating a thorough differential diagnosis. Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive, malignant tumor with a propensity for recurrence. It manifests as a slow-growing, red-brown, indurated plaque with irregular nodularity. Immunohistochemical staining can be used to differentiate DF from DFSP, with DF typically expressing factor XIIIa and lacking CD34, whereas DFSP exhibits CD34 positivity and lacks factor XIIIa expression.⁶ Another diagnosis in the differential is fibrosarcoma, a malignant tumor of fibroblasts that manifests as a painless, enlarging, poorly defined mass on the lower extremities. Histopathologic features include atypical fibroblasts and collagen with proliferation of atypical spindle-shaped cells.

Other benign lesions to consider include neurofibroma, which may manifest as a firm nodule but is derived from nerve tissue. Clinically, neurofibromas can be differentiated by their association with neurofibromatosis and softer texture. Cutaneous squamous cell carcinoma also should be considered, as it is a malignant proliferation of cutaneous epithelium that clinically manifests as a hyperkeratotic papule or plaque.⁵

THE DIAGNOSIS: Dermatofibroma

Histopathologic examination of the shave biopsy revealed fascicles of plump fibroblasts and histiocytes interposed between thick collagen bundles within the dermis, consistent with a diagnosis of dermatofibroma (DF). Dermatofibroma is a common benign skin tumor that classically manifests as brownish or reddish-brown firm papules or nodules that dimple when compressed. While the exact etiology of DF remains uncertain, it is believed to arise from a combined neoplastic and reactive fibroblastic proliferation process in response to stimuli, such as minor trauma or insect bites (as in our patient).¹

On histopathology, the most common findings associated with DF are dermal proliferation of spindle-shaped fibroblasts arranged in a storiform or whorled pattern.² In this patient, fascicles of plump fibroblasts and histiocytes were observed interspersed among thick collagen bundles within the dermis (Figure). Other histologic variants of DF include cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, monster cell, myxoid, keloidal, palisading, osteoclastic, and epithelioid.

On dermatoscopic examination, a pigment network is the most common feature, followed by a white scarlike patch, brown dots and globules, and vascular structures.² Atypical DF variants can manifest with diverse clinical morphologies; one example is giant DF, which exceeds 5 cm and may exhibit an ulcerated or pedunculated appearance, as seen in our case.³ In such cases, a thorough clinical examination coupled with histopathologic analysis becomes paramount for accurate diagnosis.

Most cases of DF do not require intervention unless there are cosmetic concerns or the lesions are symptomatic. Surgical excision is a common and effective treatment method but results in scarring. Intralesional steroid injection and cryotherapy are less aggressive treatment options but have limited efficacy. Lasers, including carbon dioxide and pulsed dye lasers, are infrequently used; however, recurrence is possible with any treatment modality.⁴ Local recurrence is common, occurring in 26% to 50% of cases, particularly in atypical dermatofibroma variants after treatment.⁵ Recurrence is more likely with primary lesions larger than 1 cm.⁵

Several conditions share clinical features with DF, necessitating a thorough differential diagnosis. Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive, malignant tumor with a propensity for recurrence. It manifests as a slow-growing, red-brown, indurated plaque with irregular nodularity. Immunohistochemical staining can be used to differentiate DF from DFSP, with DF typically expressing factor XIIIa and lacking CD34, whereas DFSP exhibits CD34 positivity and lacks factor XIIIa expression.⁶ Another diagnosis in the differential is fibrosarcoma, a malignant tumor of fibroblasts that manifests as a painless, enlarging, poorly defined mass on the lower extremities. Histopathologic features include atypical fibroblasts and collagen with proliferation of atypical spindle-shaped cells.

Other benign lesions to consider include neurofibroma, which may manifest as a firm nodule but is derived from nerve tissue. Clinically, neurofibromas can be differentiated by their association with neurofibromatosis and softer texture. Cutaneous squamous cell carcinoma also should be considered, as it is a malignant proliferation of cutaneous epithelium that clinically manifests as a hyperkeratotic papule or plaque.⁵

Effective staffing is central to delivering high-quality, efficient dermatologic care. In the current landscape of American medicine, dermatologists manage complex medical conditions, perform surgical procedures, and in some cases expand into elective aesthetic services. The ability to offer advanced clinical services is dependent on the performance of those who operate equipment and sustain daily operations.

The “perfect” hire is therefore not a luxury but a necessity for practice survival: with shrinking reimbursements and rising administrative burden, staff capability influences clinic efficiency, medicolegal risk, and patient experience and outcomes. A dysfunctional team can contribute to physician burnout, whereas a high‑functioning one enables dermatologists to practice at the top of their license by focusing on diagnosis and complex interventions while the office functions efficiently. In this article, we examine the anatomy of modern dermatology hiring and highlight the benefits of shifting from reactive staffing to proactive talent acquisition.

PHASE 1: THE PHILOSOPHY OF THE DERMATOLOGY-SPECIFIC PROFILE

Before drafting a job description, it is important to have an idea of what the ideal candidate embodies. A medical assistant in a high-volume Mohs surgery suite requires a vastly different temperament and skill set than an aesthetic coordinator in a boutique cosmetic practice. Here are some factors to consider when approaching your ideal hire.

The Hybridity of the Specialty

Dermatology is unique in that the same patient can be treated for a life-threatening melanoma and a bothersome wrinkle within the same afternoon. This requires staff who can pivot emotionally and technically. When looking for a new employee, prioritize the 4 pillars of the ideal dermatology assistant: clinical competency, a hospitality mindset, digital agility, and a “get it done” mindset.

Clinical Competency—A basic understanding of skin anatomy and common pathologies is vital, even for nonclinical roles. A front-desk employee who understands the urgency of a changing mole in a patient with melanoma vs a new acne cyst is a vital triage asset.

Hospitality Mindset—When operating a dermatology clinic with offerings in the elective space (ie, aesthetics), be aware that patients increasingly are viewing themselves as consumers in these spaces. Dermatologists should look for candidates who have experience in high-end service industries such as retail, hospitality, or concierge services. These individuals understand that the patient experience begins in the parking lot and ends with the follow-up call.

Digital Agility—We are in the midst of a technological revolution. Between AI-driven diagnostic assistance, teledermatology platforms, and integrated electronic medical record/billing systems, the modern employee has to be more than just computer literate—they must be digitally native (eg, able to troubleshoot a tablet-based consent form or explain a patient portal with ease).

“Get It Done” Mindset—In a fast-paced dermatology clinic, it is important to find someone who looks for work instead of waiting for orders; otherwise, you might find yourself spending more time directing your employees than getting your actual work done.

The Culture Fit vs Culture Add

Traditionally, practices have prioritized hiring for “culture fit”—that is, looking for individuals who think and behave like existing staff. Contemporary management theory, however, favors hiring for “culture add,” recruiting candidates who contribute perspectives and skills absent from the current team. For practices expanding into aesthetics or focusing on a specific aspect of dermatology, the practice needs employees who bring perspectives it lacks. Perhaps the candidate has a background in hospitality, or they are involved in community health initiatives. These “adds” broaden the practice’s reach and depth.

PHASE 2: THE STRATEGIC RECRUITMENT PROCESS

The days of putting up “Help Wanted” signs are over. To find elite talent, dermatologists must treat recruitment like a diagnostic workup: thorough, methodical, and evidence based. Follow these steps for a thoughtful progression in finding the right candidate for your practice.

Step 1: Crafting a Magnetic Job Description

Most job postings read like a dry list of tasks: Take vitals, room patients, call in prescriptions. These descriptions attract clock-punchers. To attract careerists, the vision must be sold. An effective job description should include 2 main components: the vision statement and the growth path.

The Vision Statement—Start by stating your practice’s mission. If you’re focused on building a practice that values concierge-style care with long visit times, say so: “Join a team dedicated to patient care, slowing down, and personalized services.”

The Growth Path—High-quality candidates want to focus on their career trajectory. During the interview, mention opportunities for laser certification, scribe training, or management tracks. For those on a path toward higher education, describe the breadth of clinical training and experience.

Step 2: The Tiered Interview Protocol

We recommend a 3-tiered approach to the interview process to ensure multiple data points are collected before an offer is made: a behavior screen, a “shadow day,” and a “no doctor” zone.

Tier 1: The Behavioral Screen (Remote)—Conduct a 20-minute video call focused purely on soft skills using questions from the STAR method (Situation, Task, Action, Result). For example, ask something like, “Tell me about a time you may have faced an unsatisfied client. How did you de-escalate the situation?” Pay attention to whether the candidate takes responsibility or places blame.

Tier 2: The Shadow Day (Working Interview)—This can be an important part of the hiring process. We recommend inviting top candidates for a paid half- or full-day trial to assess how they perform in a real-world clinical setting. For medical assistant candidates, evaluate their ability to remain task focused and efficient and observe how they handle situations such as the sight of blood or interactions with needle-phobic patients. For front-desk candidates, pay attention to how they prioritize competing responsibilities and their openness to learning and feedback. For all positions, observing interactions with both patients and team members can provide valuable insight into professionalism, communication skills, and overall fit within the practice.

Tier 3: The “No-Doctor” Zone (Optional)—Leave the candidate alone with the current staff, if only for a few minutes. This allows the employer to gauge not only the candidate’s behavior with a senior member of staff but also with other members of the team, allowing for demonstration of character. Ask the team to assess if this is someone they would want to spend a workday with. If the staff says no, that may affect your choice of hire as well.  

PHASE 3: THE OFFER AND THE LEGAL GUARDRAILS

After finding the unicorn candidate, the closing process must be professional and legally sound. Here are the steps we have found most helpful to take once a decision for a hire is made.

The Offer Letter as a Blueprint

An offer letter is more than a salary statement; it is a document of expectations. It should include the following components:

• Clear Compensation Structure: Base pay plus any performance-based incentives (eg, bonuses for retail skin care sales or conversion rates on cosmetic consultations).
• Specific Benefit Clauses: Paid time off, benefits such as health insurance and 401(k) matching if you are offering, and professional perks such as discounted treatments or skin care stipends.
• At-Will Statement: Ensure your legal counsel has reviewed your at-will employment clauses to protect the practice. This allows the employer to terminate an employee without legal liability and conversely gives the employee flexibility to leave the position if it does not fit their needs.
• Employee Manual: Once formally hired, make sure you have an employee handbook with your expectations and regulations—ranging from dress code and safety regulations to paid time off—clearly written. Be more specific than you think is necessary, which will prevent potential discrepancies down the road.  

Onboarding: The First 90 Days

The first 90 days of employment are the most volatile. Statistics show that the majority of staff turnover happens in this window.¹ To mitigate this, use the following 90-day success map:

• The Immersion Period (Days 1-30): The new hire should not be expected to produce. They are there to learn the culture of the clinic: the protocols for rooming, the vernacular for explaining procedures, and the standards for documentation.
• The Guided Execution Period (Days 31-60): They begin performing tasks under the direct supervision of a senior lead.
• The Independent Integration Period (Days 61-90): They take on a full load, with weekly check-ins to address friction points.

PHASE 4: RETENTION THROUGH ­PROFESSIONAL DEVELOPMENT

In dermatology practices, staff members frequently are approached by competitors, medical spas, and industry representatives to work for them. Retention is not just about the paycheck; it’s about the “professional home.” Staff members want to feel valued and have a responsible role in the workplace.

As dermatologists, we often are seen as the captain of the ship; however, the most successful practices operate as high-reliability organizations. In this type of practice, everyone from the janitorial staff to the senior associate is encouraged to speak up if there is a safety issue or an efficiency gap. Here are some techniques to foster this culture.

The Weekly Huddle—For practices that are just starting to expand, this is a great way to make sure that friction points and difficulties are addressed before becoming a larger issue. Gathering the staff for just 15 minutes in the morning before clinic begins can be a great way to address housekeeping issues, encourage staff to speak up about problems they may have identified, and provide a chance for everyone to feel heard.

The Educational Bend—Encourage staff to grow their wealth of knowledge, whether from industry-sponsored educational product events to formal certifications. A front desk assistant who then moves on to get their advanced degree may return to the practice as a nurse and become a valuable partner and asset. 

PHASE 5: LOOKING TOWARD THE FUTURE

As we look toward 2027 and beyond, the employee of the future may not be entirely human. We already are seeing the integration of AI scribes and automated billing auditors. Practices should look for candidates who aren’t afraid of AI but are excited by it. A medical assistant who can oversee an AI scribe while still maintaining eye contact and holding a patient’s hand during a painful injection is the gold standard.

Final Thoughts

Our medical school training prepares us for the “what” of dermatology, but it rarely prepares us for the “who.” As practice managers, we are thrust into the role of CEO, human resources director, and culture architect without a formal syllabus. By applying the same clinical rigor to the hiring process that we do to a complex diagnostic case, we can build teams that don’t just work for us but build with us. The goal is a practice where the physician can focus on the art and science of the skin, confident that every other aspect of the patient journey is being handled by a team that is as dedicated, ethical, and clinical as they are. Hiring is one of the most difficult procedures you will likely perform in your practice; it also is the one with the highest long-term success rate if performed with thoughtfulness, precision, and above all, kindness.

Effective staffing is central to delivering high-quality, efficient dermatologic care. In the current landscape of American medicine, dermatologists manage complex medical conditions, perform surgical procedures, and in some cases expand into elective aesthetic services. The ability to offer advanced clinical services is dependent on the performance of those who operate equipment and sustain daily operations.

The “perfect” hire is therefore not a luxury but a necessity for practice survival: with shrinking reimbursements and rising administrative burden, staff capability influences clinic efficiency, medicolegal risk, and patient experience and outcomes. A dysfunctional team can contribute to physician burnout, whereas a high‑functioning one enables dermatologists to practice at the top of their license by focusing on diagnosis and complex interventions while the office functions efficiently. In this article, we examine the anatomy of modern dermatology hiring and highlight the benefits of shifting from reactive staffing to proactive talent acquisition.

PHASE 1: THE PHILOSOPHY OF THE DERMATOLOGY-SPECIFIC PROFILE

Before drafting a job description, it is important to have an idea of what the ideal candidate embodies. A medical assistant in a high-volume Mohs surgery suite requires a vastly different temperament and skill set than an aesthetic coordinator in a boutique cosmetic practice. Here are some factors to consider when approaching your ideal hire.

The Hybridity of the Specialty

Dermatology is unique in that the same patient can be treated for a life-threatening melanoma and a bothersome wrinkle within the same afternoon. This requires staff who can pivot emotionally and technically. When looking for a new employee, prioritize the 4 pillars of the ideal dermatology assistant: clinical competency, a hospitality mindset, digital agility, and a “get it done” mindset.

Clinical Competency—A basic understanding of skin anatomy and common pathologies is vital, even for nonclinical roles. A front-desk employee who understands the urgency of a changing mole in a patient with melanoma vs a new acne cyst is a vital triage asset.

Hospitality Mindset—When operating a dermatology clinic with offerings in the elective space (ie, aesthetics), be aware that patients increasingly are viewing themselves as consumers in these spaces. Dermatologists should look for candidates who have experience in high-end service industries such as retail, hospitality, or concierge services. These individuals understand that the patient experience begins in the parking lot and ends with the follow-up call.

Digital Agility—We are in the midst of a technological revolution. Between AI-driven diagnostic assistance, teledermatology platforms, and integrated electronic medical record/billing systems, the modern employee has to be more than just computer literate—they must be digitally native (eg, able to troubleshoot a tablet-based consent form or explain a patient portal with ease).

“Get It Done” Mindset—In a fast-paced dermatology clinic, it is important to find someone who looks for work instead of waiting for orders; otherwise, you might find yourself spending more time directing your employees than getting your actual work done.

The Culture Fit vs Culture Add

Traditionally, practices have prioritized hiring for “culture fit”—that is, looking for individuals who think and behave like existing staff. Contemporary management theory, however, favors hiring for “culture add,” recruiting candidates who contribute perspectives and skills absent from the current team. For practices expanding into aesthetics or focusing on a specific aspect of dermatology, the practice needs employees who bring perspectives it lacks. Perhaps the candidate has a background in hospitality, or they are involved in community health initiatives. These “adds” broaden the practice’s reach and depth.

PHASE 2: THE STRATEGIC RECRUITMENT PROCESS

The days of putting up “Help Wanted” signs are over. To find elite talent, dermatologists must treat recruitment like a diagnostic workup: thorough, methodical, and evidence based. Follow these steps for a thoughtful progression in finding the right candidate for your practice.

Step 1: Crafting a Magnetic Job Description

Most job postings read like a dry list of tasks: Take vitals, room patients, call in prescriptions. These descriptions attract clock-punchers. To attract careerists, the vision must be sold. An effective job description should include 2 main components: the vision statement and the growth path.

The Vision Statement—Start by stating your practice’s mission. If you’re focused on building a practice that values concierge-style care with long visit times, say so: “Join a team dedicated to patient care, slowing down, and personalized services.”

The Growth Path—High-quality candidates want to focus on their career trajectory. During the interview, mention opportunities for laser certification, scribe training, or management tracks. For those on a path toward higher education, describe the breadth of clinical training and experience.

Step 2: The Tiered Interview Protocol

We recommend a 3-tiered approach to the interview process to ensure multiple data points are collected before an offer is made: a behavior screen, a “shadow day,” and a “no doctor” zone.

Tier 1: The Behavioral Screen (Remote)—Conduct a 20-minute video call focused purely on soft skills using questions from the STAR method (Situation, Task, Action, Result). For example, ask something like, “Tell me about a time you may have faced an unsatisfied client. How did you de-escalate the situation?” Pay attention to whether the candidate takes responsibility or places blame.

Tier 2: The Shadow Day (Working Interview)—This can be an important part of the hiring process. We recommend inviting top candidates for a paid half- or full-day trial to assess how they perform in a real-world clinical setting. For medical assistant candidates, evaluate their ability to remain task focused and efficient and observe how they handle situations such as the sight of blood or interactions with needle-phobic patients. For front-desk candidates, pay attention to how they prioritize competing responsibilities and their openness to learning and feedback. For all positions, observing interactions with both patients and team members can provide valuable insight into professionalism, communication skills, and overall fit within the practice.

Tier 3: The “No-Doctor” Zone (Optional)—Leave the candidate alone with the current staff, if only for a few minutes. This allows the employer to gauge not only the candidate’s behavior with a senior member of staff but also with other members of the team, allowing for demonstration of character. Ask the team to assess if this is someone they would want to spend a workday with. If the staff says no, that may affect your choice of hire as well.  

PHASE 3: THE OFFER AND THE LEGAL GUARDRAILS

After finding the unicorn candidate, the closing process must be professional and legally sound. Here are the steps we have found most helpful to take once a decision for a hire is made.

The Offer Letter as a Blueprint

An offer letter is more than a salary statement; it is a document of expectations. It should include the following components:

• Clear Compensation Structure: Base pay plus any performance-based incentives (eg, bonuses for retail skin care sales or conversion rates on cosmetic consultations).
• Specific Benefit Clauses: Paid time off, benefits such as health insurance and 401(k) matching if you are offering, and professional perks such as discounted treatments or skin care stipends.
• At-Will Statement: Ensure your legal counsel has reviewed your at-will employment clauses to protect the practice. This allows the employer to terminate an employee without legal liability and conversely gives the employee flexibility to leave the position if it does not fit their needs.
• Employee Manual: Once formally hired, make sure you have an employee handbook with your expectations and regulations—ranging from dress code and safety regulations to paid time off—clearly written. Be more specific than you think is necessary, which will prevent potential discrepancies down the road.  

Onboarding: The First 90 Days

The first 90 days of employment are the most volatile. Statistics show that the majority of staff turnover happens in this window.¹ To mitigate this, use the following 90-day success map:

• The Immersion Period (Days 1-30): The new hire should not be expected to produce. They are there to learn the culture of the clinic: the protocols for rooming, the vernacular for explaining procedures, and the standards for documentation.
• The Guided Execution Period (Days 31-60): They begin performing tasks under the direct supervision of a senior lead.
• The Independent Integration Period (Days 61-90): They take on a full load, with weekly check-ins to address friction points.

PHASE 4: RETENTION THROUGH ­PROFESSIONAL DEVELOPMENT

In dermatology practices, staff members frequently are approached by competitors, medical spas, and industry representatives to work for them. Retention is not just about the paycheck; it’s about the “professional home.” Staff members want to feel valued and have a responsible role in the workplace.

As dermatologists, we often are seen as the captain of the ship; however, the most successful practices operate as high-reliability organizations. In this type of practice, everyone from the janitorial staff to the senior associate is encouraged to speak up if there is a safety issue or an efficiency gap. Here are some techniques to foster this culture.

The Weekly Huddle—For practices that are just starting to expand, this is a great way to make sure that friction points and difficulties are addressed before becoming a larger issue. Gathering the staff for just 15 minutes in the morning before clinic begins can be a great way to address housekeeping issues, encourage staff to speak up about problems they may have identified, and provide a chance for everyone to feel heard.

The Educational Bend—Encourage staff to grow their wealth of knowledge, whether from industry-sponsored educational product events to formal certifications. A front desk assistant who then moves on to get their advanced degree may return to the practice as a nurse and become a valuable partner and asset. 

PHASE 5: LOOKING TOWARD THE FUTURE

As we look toward 2027 and beyond, the employee of the future may not be entirely human. We already are seeing the integration of AI scribes and automated billing auditors. Practices should look for candidates who aren’t afraid of AI but are excited by it. A medical assistant who can oversee an AI scribe while still maintaining eye contact and holding a patient’s hand during a painful injection is the gold standard.

Final Thoughts

Our medical school training prepares us for the “what” of dermatology, but it rarely prepares us for the “who.” As practice managers, we are thrust into the role of CEO, human resources director, and culture architect without a formal syllabus. By applying the same clinical rigor to the hiring process that we do to a complex diagnostic case, we can build teams that don’t just work for us but build with us. The goal is a practice where the physician can focus on the art and science of the skin, confident that every other aspect of the patient journey is being handled by a team that is as dedicated, ethical, and clinical as they are. Hiring is one of the most difficult procedures you will likely perform in your practice; it also is the one with the highest long-term success rate if performed with thoughtfulness, precision, and above all, kindness.

Effective staffing is central to delivering high-quality, efficient dermatologic care. In the current landscape of American medicine, dermatologists manage complex medical conditions, perform surgical procedures, and in some cases expand into elective aesthetic services. The ability to offer advanced clinical services is dependent on the performance of those who operate equipment and sustain daily operations.

The “perfect” hire is therefore not a luxury but a necessity for practice survival: with shrinking reimbursements and rising administrative burden, staff capability influences clinic efficiency, medicolegal risk, and patient experience and outcomes. A dysfunctional team can contribute to physician burnout, whereas a high‑functioning one enables dermatologists to practice at the top of their license by focusing on diagnosis and complex interventions while the office functions efficiently. In this article, we examine the anatomy of modern dermatology hiring and highlight the benefits of shifting from reactive staffing to proactive talent acquisition.

PHASE 1: THE PHILOSOPHY OF THE DERMATOLOGY-SPECIFIC PROFILE

Before drafting a job description, it is important to have an idea of what the ideal candidate embodies. A medical assistant in a high-volume Mohs surgery suite requires a vastly different temperament and skill set than an aesthetic coordinator in a boutique cosmetic practice. Here are some factors to consider when approaching your ideal hire.

The Hybridity of the Specialty

Dermatology is unique in that the same patient can be treated for a life-threatening melanoma and a bothersome wrinkle within the same afternoon. This requires staff who can pivot emotionally and technically. When looking for a new employee, prioritize the 4 pillars of the ideal dermatology assistant: clinical competency, a hospitality mindset, digital agility, and a “get it done” mindset.

Clinical Competency—A basic understanding of skin anatomy and common pathologies is vital, even for nonclinical roles. A front-desk employee who understands the urgency of a changing mole in a patient with melanoma vs a new acne cyst is a vital triage asset.

Hospitality Mindset—When operating a dermatology clinic with offerings in the elective space (ie, aesthetics), be aware that patients increasingly are viewing themselves as consumers in these spaces. Dermatologists should look for candidates who have experience in high-end service industries such as retail, hospitality, or concierge services. These individuals understand that the patient experience begins in the parking lot and ends with the follow-up call.

Digital Agility—We are in the midst of a technological revolution. Between AI-driven diagnostic assistance, teledermatology platforms, and integrated electronic medical record/billing systems, the modern employee has to be more than just computer literate—they must be digitally native (eg, able to troubleshoot a tablet-based consent form or explain a patient portal with ease).

“Get It Done” Mindset—In a fast-paced dermatology clinic, it is important to find someone who looks for work instead of waiting for orders; otherwise, you might find yourself spending more time directing your employees than getting your actual work done.

The Culture Fit vs Culture Add

Traditionally, practices have prioritized hiring for “culture fit”—that is, looking for individuals who think and behave like existing staff. Contemporary management theory, however, favors hiring for “culture add,” recruiting candidates who contribute perspectives and skills absent from the current team. For practices expanding into aesthetics or focusing on a specific aspect of dermatology, the practice needs employees who bring perspectives it lacks. Perhaps the candidate has a background in hospitality, or they are involved in community health initiatives. These “adds” broaden the practice’s reach and depth.

PHASE 2: THE STRATEGIC RECRUITMENT PROCESS

The days of putting up “Help Wanted” signs are over. To find elite talent, dermatologists must treat recruitment like a diagnostic workup: thorough, methodical, and evidence based. Follow these steps for a thoughtful progression in finding the right candidate for your practice.

Step 1: Crafting a Magnetic Job Description

Most job postings read like a dry list of tasks: Take vitals, room patients, call in prescriptions. These descriptions attract clock-punchers. To attract careerists, the vision must be sold. An effective job description should include 2 main components: the vision statement and the growth path.

The Vision Statement—Start by stating your practice’s mission. If you’re focused on building a practice that values concierge-style care with long visit times, say so: “Join a team dedicated to patient care, slowing down, and personalized services.”

The Growth Path—High-quality candidates want to focus on their career trajectory. During the interview, mention opportunities for laser certification, scribe training, or management tracks. For those on a path toward higher education, describe the breadth of clinical training and experience.

Step 2: The Tiered Interview Protocol

We recommend a 3-tiered approach to the interview process to ensure multiple data points are collected before an offer is made: a behavior screen, a “shadow day,” and a “no doctor” zone.

Tier 1: The Behavioral Screen (Remote)—Conduct a 20-minute video call focused purely on soft skills using questions from the STAR method (Situation, Task, Action, Result). For example, ask something like, “Tell me about a time you may have faced an unsatisfied client. How did you de-escalate the situation?” Pay attention to whether the candidate takes responsibility or places blame.

Tier 2: The Shadow Day (Working Interview)—This can be an important part of the hiring process. We recommend inviting top candidates for a paid half- or full-day trial to assess how they perform in a real-world clinical setting. For medical assistant candidates, evaluate their ability to remain task focused and efficient and observe how they handle situations such as the sight of blood or interactions with needle-phobic patients. For front-desk candidates, pay attention to how they prioritize competing responsibilities and their openness to learning and feedback. For all positions, observing interactions with both patients and team members can provide valuable insight into professionalism, communication skills, and overall fit within the practice.

Tier 3: The “No-Doctor” Zone (Optional)—Leave the candidate alone with the current staff, if only for a few minutes. This allows the employer to gauge not only the candidate’s behavior with a senior member of staff but also with other members of the team, allowing for demonstration of character. Ask the team to assess if this is someone they would want to spend a workday with. If the staff says no, that may affect your choice of hire as well.  

PHASE 3: THE OFFER AND THE LEGAL GUARDRAILS

After finding the unicorn candidate, the closing process must be professional and legally sound. Here are the steps we have found most helpful to take once a decision for a hire is made.

The Offer Letter as a Blueprint

An offer letter is more than a salary statement; it is a document of expectations. It should include the following components:

• Clear Compensation Structure: Base pay plus any performance-based incentives (eg, bonuses for retail skin care sales or conversion rates on cosmetic consultations).
• Specific Benefit Clauses: Paid time off, benefits such as health insurance and 401(k) matching if you are offering, and professional perks such as discounted treatments or skin care stipends.
• At-Will Statement: Ensure your legal counsel has reviewed your at-will employment clauses to protect the practice. This allows the employer to terminate an employee without legal liability and conversely gives the employee flexibility to leave the position if it does not fit their needs.
• Employee Manual: Once formally hired, make sure you have an employee handbook with your expectations and regulations—ranging from dress code and safety regulations to paid time off—clearly written. Be more specific than you think is necessary, which will prevent potential discrepancies down the road.  

Onboarding: The First 90 Days

The first 90 days of employment are the most volatile. Statistics show that the majority of staff turnover happens in this window.¹ To mitigate this, use the following 90-day success map:

• The Immersion Period (Days 1-30): The new hire should not be expected to produce. They are there to learn the culture of the clinic: the protocols for rooming, the vernacular for explaining procedures, and the standards for documentation.
• The Guided Execution Period (Days 31-60): They begin performing tasks under the direct supervision of a senior lead.
• The Independent Integration Period (Days 61-90): They take on a full load, with weekly check-ins to address friction points.

PHASE 4: RETENTION THROUGH ­PROFESSIONAL DEVELOPMENT

In dermatology practices, staff members frequently are approached by competitors, medical spas, and industry representatives to work for them. Retention is not just about the paycheck; it’s about the “professional home.” Staff members want to feel valued and have a responsible role in the workplace.

As dermatologists, we often are seen as the captain of the ship; however, the most successful practices operate as high-reliability organizations. In this type of practice, everyone from the janitorial staff to the senior associate is encouraged to speak up if there is a safety issue or an efficiency gap. Here are some techniques to foster this culture.

The Weekly Huddle—For practices that are just starting to expand, this is a great way to make sure that friction points and difficulties are addressed before becoming a larger issue. Gathering the staff for just 15 minutes in the morning before clinic begins can be a great way to address housekeeping issues, encourage staff to speak up about problems they may have identified, and provide a chance for everyone to feel heard.

The Educational Bend—Encourage staff to grow their wealth of knowledge, whether from industry-sponsored educational product events to formal certifications. A front desk assistant who then moves on to get their advanced degree may return to the practice as a nurse and become a valuable partner and asset. 

PHASE 5: LOOKING TOWARD THE FUTURE

As we look toward 2027 and beyond, the employee of the future may not be entirely human. We already are seeing the integration of AI scribes and automated billing auditors. Practices should look for candidates who aren’t afraid of AI but are excited by it. A medical assistant who can oversee an AI scribe while still maintaining eye contact and holding a patient’s hand during a painful injection is the gold standard.

Final Thoughts

Our medical school training prepares us for the “what” of dermatology, but it rarely prepares us for the “who.” As practice managers, we are thrust into the role of CEO, human resources director, and culture architect without a formal syllabus. By applying the same clinical rigor to the hiring process that we do to a complex diagnostic case, we can build teams that don’t just work for us but build with us. The goal is a practice where the physician can focus on the art and science of the skin, confident that every other aspect of the patient journey is being handled by a team that is as dedicated, ethical, and clinical as they are. Hiring is one of the most difficult procedures you will likely perform in your practice; it also is the one with the highest long-term success rate if performed with thoughtfulness, precision, and above all, kindness.

Recent data suggest that approximately 20% to 40% of patients treated with isotretinoin have recurrence of acne. How should dermatologists interpret these findings?

DR. BARBIERI: While isotretinoin is highly effective and capable of delivering long-term remission, we should be careful to avoid describing it as a “cure” when counseling patients. Importantly, when acne does recur, it is often milder, and about half of those who have acne recurrence can be managed with topicals alone. For those who do require a subsequent course of isotretinoin, we should view this as an outcome that can be expected to happen in about 1 in 10 treated with isotretinoin rather than a treatment failure.

How important is cumulative dose in preventing relapse, and should we be rethinking traditional dosing targets?

DR. BARBIERI: Cumulative dose is one of the most important factors in preventing recurrence. Multiple studies support that higher cumulative dose is a strong predictor of long-term clearance. In contrast, daily dose does not seem to be as important a factor. However, higher cumulative dose also means longer courses and more potential for adverse effects, including long-term skin and eye dryness. For this reason, I prefer to treat to clinical endpoints of clear skin for 2 to 3 months and at least 120 to 150 mg/kg cumulative dose to balance achieving high cumulative doses with potential adverse effects and risks. For those with fewer adverse effects or who prioritize long-term clearance, we might go a little longer and for those with more adverse effects, we might use a shorter course and accept a higher risk for recurrence. By taking this approach, we can individualize our dosing approach to each patient.

What factors most strongly predict relapse after a completed isotretinoin course?

DR. BARBIERI: Some demographic factors that have been associated with higher rates of recurrence include greater baseline severity and younger age at treatment. Women with a strong hormonal component to their acne, such as those with polyendocrine metabolic ovarian syndrome (formerly polycystic ovary syndrome), also may be more likely to have recurrence. With respect to clinical factors, increasing cumulative dose has been associated with reduced risk for recurrence in multiple studies, and treating until a clinical endpoint of clear skin for 2 to 3 months also may be predictive of long-term clearance.

When a patient relapses, how do you decide between topical therapy, hormonal treatment, or a second isotretinoin course?

DR. BARBIERI: It depends on relapse severity and patient goals. Mild recurrence often responds well to topical therapies such as retinoids, benzoyl peroxide, antibiotics, and clascoterone. About half of those with recurrence will be able to manage it with topical therapies alone. For those with more severe acne requiring systemic therapy, about half will decide on a repeat course of isotretinoin, which I often find works faster and better than the first course. For second courses, I will typically try to use micronized isotretinoin due to the more consistent pharmacokinetics. For women—especially those with signs of hyperandrogenism such as hirsutism, irregular periods, or flaring with menstrual cycle—hormonal therapy such as combined oral contraceptives or spironolactone can be a great option. Oral antibiotics also can be a consideration for those with recurrence, though we need to be thoughtful about antimicrobial stewardship and risks of long-term antibiotic use.

Are low-dose or shorter-course regimens contributing to higher relapse rates?

DR. BARBIERI: While there is some evidence that higher daily doses may be associated with lower risk for recurrence, when you control for cumulative dose, it doesn’t seem like daily dose has much influence. In contrast, cumulative dose has a large effect on frequency of long-term clearance. While I don’t think low-dose regimens are inherently problematic, if they result in shorter cumulative dose courses, that could increase the risk for recurrence.

How does hormonal acne influence long-term outcomes after isotretinoin?

DR. BARBIERI: While all acne is “hormonal,” those with a stronger hormonal pathogenesis, such as women with polyendocrine metabolic ovarian syndrome or other signs of hyperandrogenism, may have a higher likelihood of recurrence after treatment. In these patients, I often find hormonal therapy such as combined oral contraceptives or spironolactone to be highly effective, even if they haven't worked before.

Should maintenance therapy be routine after isotretinoin, and if so, what strategies are most effective?

DR. BARBIERI: Since many patients have a goal of long-term clearance after isotretinoin, I do not routinely recommend maintenance therapy, as this seems antithetical to this goal. However, for those who are very concerned about recurrence or who would like to be on a topical retinoid for other reasons, I will sometimes start a topical retinoid after treatment with isotretinoin.

How should dermatologists counsel patients about expectations with respect to relapse before starting isotretinoin?

DR. BARBIERI: We should be careful to set appropriate expectations with isotretinoin. I counsel patients that isotretinoin is an incredibly effective therapy for severe acne, with a high likelihood of long-term remission, but not a guaranteed permanent cure. Setting this expectation upfront reduces disappointment if acne does recur and improves shared decision-making.

Recent data suggest that approximately 20% to 40% of patients treated with isotretinoin have recurrence of acne. How should dermatologists interpret these findings?

DR. BARBIERI: While isotretinoin is highly effective and capable of delivering long-term remission, we should be careful to avoid describing it as a “cure” when counseling patients. Importantly, when acne does recur, it is often milder, and about half of those who have acne recurrence can be managed with topicals alone. For those who do require a subsequent course of isotretinoin, we should view this as an outcome that can be expected to happen in about 1 in 10 treated with isotretinoin rather than a treatment failure.

How important is cumulative dose in preventing relapse, and should we be rethinking traditional dosing targets?

DR. BARBIERI: Cumulative dose is one of the most important factors in preventing recurrence. Multiple studies support that higher cumulative dose is a strong predictor of long-term clearance. In contrast, daily dose does not seem to be as important a factor. However, higher cumulative dose also means longer courses and more potential for adverse effects, including long-term skin and eye dryness. For this reason, I prefer to treat to clinical endpoints of clear skin for 2 to 3 months and at least 120 to 150 mg/kg cumulative dose to balance achieving high cumulative doses with potential adverse effects and risks. For those with fewer adverse effects or who prioritize long-term clearance, we might go a little longer and for those with more adverse effects, we might use a shorter course and accept a higher risk for recurrence. By taking this approach, we can individualize our dosing approach to each patient.

What factors most strongly predict relapse after a completed isotretinoin course?

DR. BARBIERI: Some demographic factors that have been associated with higher rates of recurrence include greater baseline severity and younger age at treatment. Women with a strong hormonal component to their acne, such as those with polyendocrine metabolic ovarian syndrome (formerly polycystic ovary syndrome), also may be more likely to have recurrence. With respect to clinical factors, increasing cumulative dose has been associated with reduced risk for recurrence in multiple studies, and treating until a clinical endpoint of clear skin for 2 to 3 months also may be predictive of long-term clearance.

When a patient relapses, how do you decide between topical therapy, hormonal treatment, or a second isotretinoin course?

DR. BARBIERI: It depends on relapse severity and patient goals. Mild recurrence often responds well to topical therapies such as retinoids, benzoyl peroxide, antibiotics, and clascoterone. About half of those with recurrence will be able to manage it with topical therapies alone. For those with more severe acne requiring systemic therapy, about half will decide on a repeat course of isotretinoin, which I often find works faster and better than the first course. For second courses, I will typically try to use micronized isotretinoin due to the more consistent pharmacokinetics. For women—especially those with signs of hyperandrogenism such as hirsutism, irregular periods, or flaring with menstrual cycle—hormonal therapy such as combined oral contraceptives or spironolactone can be a great option. Oral antibiotics also can be a consideration for those with recurrence, though we need to be thoughtful about antimicrobial stewardship and risks of long-term antibiotic use.

Are low-dose or shorter-course regimens contributing to higher relapse rates?

DR. BARBIERI: While there is some evidence that higher daily doses may be associated with lower risk for recurrence, when you control for cumulative dose, it doesn’t seem like daily dose has much influence. In contrast, cumulative dose has a large effect on frequency of long-term clearance. While I don’t think low-dose regimens are inherently problematic, if they result in shorter cumulative dose courses, that could increase the risk for recurrence.

How does hormonal acne influence long-term outcomes after isotretinoin?

DR. BARBIERI: While all acne is “hormonal,” those with a stronger hormonal pathogenesis, such as women with polyendocrine metabolic ovarian syndrome or other signs of hyperandrogenism, may have a higher likelihood of recurrence after treatment. In these patients, I often find hormonal therapy such as combined oral contraceptives or spironolactone to be highly effective, even if they haven't worked before.

Should maintenance therapy be routine after isotretinoin, and if so, what strategies are most effective?

DR. BARBIERI: Since many patients have a goal of long-term clearance after isotretinoin, I do not routinely recommend maintenance therapy, as this seems antithetical to this goal. However, for those who are very concerned about recurrence or who would like to be on a topical retinoid for other reasons, I will sometimes start a topical retinoid after treatment with isotretinoin.

How should dermatologists counsel patients about expectations with respect to relapse before starting isotretinoin?

DR. BARBIERI: We should be careful to set appropriate expectations with isotretinoin. I counsel patients that isotretinoin is an incredibly effective therapy for severe acne, with a high likelihood of long-term remission, but not a guaranteed permanent cure. Setting this expectation upfront reduces disappointment if acne does recur and improves shared decision-making.

Recent data suggest that approximately 20% to 40% of patients treated with isotretinoin have recurrence of acne. How should dermatologists interpret these findings?

DR. BARBIERI: While isotretinoin is highly effective and capable of delivering long-term remission, we should be careful to avoid describing it as a “cure” when counseling patients. Importantly, when acne does recur, it is often milder, and about half of those who have acne recurrence can be managed with topicals alone. For those who do require a subsequent course of isotretinoin, we should view this as an outcome that can be expected to happen in about 1 in 10 treated with isotretinoin rather than a treatment failure.

How important is cumulative dose in preventing relapse, and should we be rethinking traditional dosing targets?

DR. BARBIERI: Cumulative dose is one of the most important factors in preventing recurrence. Multiple studies support that higher cumulative dose is a strong predictor of long-term clearance. In contrast, daily dose does not seem to be as important a factor. However, higher cumulative dose also means longer courses and more potential for adverse effects, including long-term skin and eye dryness. For this reason, I prefer to treat to clinical endpoints of clear skin for 2 to 3 months and at least 120 to 150 mg/kg cumulative dose to balance achieving high cumulative doses with potential adverse effects and risks. For those with fewer adverse effects or who prioritize long-term clearance, we might go a little longer and for those with more adverse effects, we might use a shorter course and accept a higher risk for recurrence. By taking this approach, we can individualize our dosing approach to each patient.

What factors most strongly predict relapse after a completed isotretinoin course?

DR. BARBIERI: Some demographic factors that have been associated with higher rates of recurrence include greater baseline severity and younger age at treatment. Women with a strong hormonal component to their acne, such as those with polyendocrine metabolic ovarian syndrome (formerly polycystic ovary syndrome), also may be more likely to have recurrence. With respect to clinical factors, increasing cumulative dose has been associated with reduced risk for recurrence in multiple studies, and treating until a clinical endpoint of clear skin for 2 to 3 months also may be predictive of long-term clearance.

When a patient relapses, how do you decide between topical therapy, hormonal treatment, or a second isotretinoin course?

DR. BARBIERI: It depends on relapse severity and patient goals. Mild recurrence often responds well to topical therapies such as retinoids, benzoyl peroxide, antibiotics, and clascoterone. About half of those with recurrence will be able to manage it with topical therapies alone. For those with more severe acne requiring systemic therapy, about half will decide on a repeat course of isotretinoin, which I often find works faster and better than the first course. For second courses, I will typically try to use micronized isotretinoin due to the more consistent pharmacokinetics. For women—especially those with signs of hyperandrogenism such as hirsutism, irregular periods, or flaring with menstrual cycle—hormonal therapy such as combined oral contraceptives or spironolactone can be a great option. Oral antibiotics also can be a consideration for those with recurrence, though we need to be thoughtful about antimicrobial stewardship and risks of long-term antibiotic use.

Are low-dose or shorter-course regimens contributing to higher relapse rates?

DR. BARBIERI: While there is some evidence that higher daily doses may be associated with lower risk for recurrence, when you control for cumulative dose, it doesn’t seem like daily dose has much influence. In contrast, cumulative dose has a large effect on frequency of long-term clearance. While I don’t think low-dose regimens are inherently problematic, if they result in shorter cumulative dose courses, that could increase the risk for recurrence.

How does hormonal acne influence long-term outcomes after isotretinoin?

DR. BARBIERI: While all acne is “hormonal,” those with a stronger hormonal pathogenesis, such as women with polyendocrine metabolic ovarian syndrome or other signs of hyperandrogenism, may have a higher likelihood of recurrence after treatment. In these patients, I often find hormonal therapy such as combined oral contraceptives or spironolactone to be highly effective, even if they haven't worked before.

Should maintenance therapy be routine after isotretinoin, and if so, what strategies are most effective?

DR. BARBIERI: Since many patients have a goal of long-term clearance after isotretinoin, I do not routinely recommend maintenance therapy, as this seems antithetical to this goal. However, for those who are very concerned about recurrence or who would like to be on a topical retinoid for other reasons, I will sometimes start a topical retinoid after treatment with isotretinoin.

How should dermatologists counsel patients about expectations with respect to relapse before starting isotretinoin?

DR. BARBIERI: We should be careful to set appropriate expectations with isotretinoin. I counsel patients that isotretinoin is an incredibly effective therapy for severe acne, with a high likelihood of long-term remission, but not a guaranteed permanent cure. Setting this expectation upfront reduces disappointment if acne does recur and improves shared decision-making.

Bullous pemphigoid (BP) is an autoimmune blistering disorder characterized by the development of tense subepidermal blisters and erosions primarily on the skin, commonly affecting the elderly.¹ It is attributed to autoantibodies targeting 2 hemidesmosomal components within the dermoepidermal junction—transmembrane collagen XVII (BP180/BPAG2) and plakin family protein BP230 (BPAG1)—resulting in blister formation due to loss of structural integrity.² Typically, patients present with pruritic urticarial plaques and tense bullae localized on flexural areas, but cutaneous manifestations vary and can be nonspecific. Histologically, a subepidermal blister with eosinophilic infiltration is characteristic, and detection of circulating autoantibodies against BP180 and BP230 antigens aids in diagnosis.^3,4

Drug-induced BP (DIBP) is a subset triggered by medications, including immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1) or its ligand, programmed death ligand-1 (PD-L1).^5,6 Often overexpressed in malignant tumors, PD-L1 inhibits host lymphocytic and apoptotic immune responses. Anti‒PD-1 and anti‒PD-L1 agents, designed to enhance the immune system’s ability to recognize and eliminate cancer cells,^7,8 have improved oncologic outcomes for various cancers, including urothelial cancer.^9-11 Before 2016, platinum-based chemotherapy was the mainstay for metastatic urothelial cancer management, but US Food and Drug Administration approval of 5 ICIs—nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab—­transformed treatment options.¹²Despite robust antitumor responses to ICIs, these medications are increasingly associated with immune-related adverse events (IRAEs), including DIBP, due to inhibition of negative regulators of immunity crucial for maintaining immunologic homeostasis.^13,14 Up to 30% to 40% of patients treated with PD-1 inhibitors experience dermatologic complications, such as lichenoid reactions, eczema, vitiligo, and pruritus,¹⁵ and patients undergoing treatment with the PD-1 inhibitor pembrolizumab are estimated to be 2.6 times more likely to develop a rash than those receiving standard chemotherapy.^16,17 The pathogenesis of DIBP involves autoreactive T-cell activation and subsequent autoantibody production against BP antigens.¹⁸ We present the case of DIBP secondary to pembrolizumab immunotherapy in a man with PD-L1–negative metastatic bladder cancer.

Case Report

An 81-year-old man with metastatic urothelial carcinoma presented to dermatology with a pruritic rash characterized by blisters of 5 months’ duration following treatment with pembrolizumab. He had a history of non–muscle invasive urothelial carcinoma and underwent intravesical bacillus Calmette-Guerin treatment. Thirty years later, after surveillance cystoscopies, the patient developed hematuria, which prompted pelvic ultrasonography and cystoscopy that revealed a tumor. Transurethral resection of the bladder tumor confirmed invasive, high-grade papillary urothelial carcinoma with vascular and muscle invasion (clinical stage T2NxMx). Due to elevated creatinine levels, neoadjuvant chemotherapy was contraindicated. Instead, the patient underwent cystoprostatectomy with ureteroileal conduit creation and pelvic lymphadenectomy one month later; final pathology revealed pT2aN0M0 disease with multifocal carcinoma in situ. At that time, there was no evidence of distant metastasis. Surveillance 5 months later identified pulmonary nodules that were confirmed as metastatic urothelial cancer by positron emission ­tomography/computed tomography (CT). The patient received 6 cycles of paclitaxel (175 mg/m² on day 1) and gemcitabine (1000 mg/m² on days 1 and 8 every 21 days), with progressive disease 16 months later. Despite 0% PD-L1 expression, pembrolizumab 400 mg intravenous (IV) treatment every 6 weeks was initiated 2 months later, and subsequent positron emission tomography/CT showed a positive response at 3 and 7 months after treatment initiation. After the patient’s sixth cycle of pembrolizumab, a generalized maculopapular rash involving approximately 50% of the body surface area led to discontinuation of pembrolizumab, initiation of multiple courses of prednisone and prednisolone, and a dermatology referral.

At the current presentation, the patient exhibited excoriated red patches on the abdomen, wrists, arms, upper chest, and legs (Figure 1). Tense blisters were observed on various areas, including the ear and arms. The provisional diagnosis was pembrolizumab-induced BP, supported by the clinical history, presentation, and an initial positive response to steroids. Treatment included topical triamcinolone 0.1% ointment and prednisone 40 mg daily. Biopsies revealed subepidermal blisters with underlying eosinophils on histopathology (Figure 2). Direct immunofluorescence showed strong linear basement membrane zone staining with IgG and C3, consistent with a diagnosis of BP.

One month later, the patient was given the first of two 1-g doses of rituximab, chosen as a treatment due to metastatic cancer history and ongoing severity of the DIBP. In addition, a slow prednisone taper was initiated. Atovaquone 1500 mg daily was ordered for Pneumocystis jirovecii prophylaxis. Following the first rituximab dose, the patient became clear of DIBP but required treatment for a chronic urinary tract infection, delaying the second rituximab dose. The prednisone taper continued, however, and the patient reported re-emergence of several blisters, followed by resolution of pruritus following the second rituximab dose. Bilateral pulmonary embolisms were noted on a restaging CT, attributed to the underlying malignancy and inflammation from DIBP. Doxycycline was initiated at 100 mg twice daily, and prednisone was slowly tapered (as tolerated by the patient’s symptoms) down to 2.5 mg daily approximately 6 months after rituximab initiation. The patient remains in clinical remission at last follow-up; however, considerations for further treatments have included intravenous immunoglobulin.

Comment

This case highlights major clinical challenges in the diagnosis and management of DIBP in a patient with metastatic urothelial carcinoma receiving ICI therapy. Our patient’s clinical course offers several high-yield lessons regarding diagnostic latency, treatment resistance, and a multidisciplinary approach to management.

Pruritus as a Precursor—Since an initial report in 2015, the emergence of DIBP postpembrolizumab has been well described in the literature.^19-22 Pruritus is frequently the earliest symptom, preceding bullous eruption. Similar to our case—in which DIBP developed 30 weeks after pembrolizumab initiation—the classic clinical presentation and formation of bullae often are delayed, typically occurring 28 and 39 weeks.

Beyond Corticosteroids to Manage Refractory DIBP—Our patient’s DIBP persisted despite multiple interventions, including pembrolizumab discontinuation, corticosteroid therapy, and rituximab administration. Although cases of DIBP in pembrolizumab-treated metastatic urothelial carcinoma patients have been reported, they did not exhibit similar treatment resistance.^23-25 As observed in our patient, immunotherapy discontinuation has been reported in at least 40% of all ICI-mediated cases of BP.¹⁴ Subsequent management involves low-dose oral corticosteroids and potent topical corticosteroids; the duration of steroid treatment varies widely, ranging from a few weeks to longer than 12 months, with no standardized approach.²⁶ In cases where ICI withdrawal and corticosteroids fail to produce a complete response, monoclonal antibodies such as rituximab, dupilumab, and omalizumab have been used as alternative treatments, with dupilumab recently receiving US Food and Drug Administration approval for moderate to severe BP.^27-31 These biologics selectively inhibit autoantibody formation and the inflammatory cascade, and research has pointed toward them as safe and effective options for refractory BP. Although robust randomized, controlled clinical trials on rituximab for DIBP still are lacking, prospective and retrospective cohort studies have shown promising results, including complete remission rates of 67% to 90%, along with a decline in circulating BP180-specific B lymphocytes, anti-BP180 IgG, and the expression of proinflammatory IL-15 and IL-6.³²

Despite receiving 2 doses of rituximab, our patient experienced recurrence of blisters when prednisone was tapered, prompting discussions about alternative tapering timelines and additional therapies such as doxycycline³³ or intravenous immunoglobulin,³⁴ which have emerged as steroid-sparing agents for BP following initial steroid therapy.

Systemic Barriers and the Need for Multidisciplinary Care—This case underscores systemic barriers within the health care system that impede prompt diagnosis and management of conditions such as DIBP. The 5-month delay between the patient’s referral to dermatology and the actual consultation, potentially due to shortages of dermatologists, highlights the need for more systematic urgent dermatologic referrals and streamlined diagnostic pathways in suspected cases of IRAEs. Diagnosis requires comprehensive evaluation, including skin biopsy for histopathologic examination and immunofluorescence studies. Ruling out alternative blistering disorders, such as epidermolysis bullosa acquisita, is crucial before confirming a BP diagnosis. Encouraging direct communication between referring physicians and consultants often can expedite the process, as a call from the referring physician can alert the consultant and speed up scheduling. Notably, the patient’s daughter, who was a patient of the dermatologist herself, played a crucial role in advocating for the dermatology referral. Although this should not be necessary, it highlights the pivotal role families can play in ensuring timely access to specialized care for challenging conditions such as BP.

Lastly, the refractory nature of the patient’s condition, coupled with concurrent chronic urinary tract infection and bilateral pulmonary embolisms, emphasizes the necessity of multidisciplinary collaboration among oncology, dermatology, and primary care in managing DIBP. Consulting experts on IRAEs and coordinating with the oncologist were essential for making informed treatment decisions and facilitating the timely exchange of clinical information.

Conclusion

This case underscores the importance of timely recognition and diagnosis of DIBP in patients undergoing ICI therapy but also highlights the need for individualized treatment approaches and multidisciplinary collaboration when managing adverse cutaneous reactions.

Bullous pemphigoid (BP) is an autoimmune blistering disorder characterized by the development of tense subepidermal blisters and erosions primarily on the skin, commonly affecting the elderly.¹ It is attributed to autoantibodies targeting 2 hemidesmosomal components within the dermoepidermal junction—transmembrane collagen XVII (BP180/BPAG2) and plakin family protein BP230 (BPAG1)—resulting in blister formation due to loss of structural integrity.² Typically, patients present with pruritic urticarial plaques and tense bullae localized on flexural areas, but cutaneous manifestations vary and can be nonspecific. Histologically, a subepidermal blister with eosinophilic infiltration is characteristic, and detection of circulating autoantibodies against BP180 and BP230 antigens aids in diagnosis.^3,4

Drug-induced BP (DIBP) is a subset triggered by medications, including immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1) or its ligand, programmed death ligand-1 (PD-L1).^5,6 Often overexpressed in malignant tumors, PD-L1 inhibits host lymphocytic and apoptotic immune responses. Anti‒PD-1 and anti‒PD-L1 agents, designed to enhance the immune system’s ability to recognize and eliminate cancer cells,^7,8 have improved oncologic outcomes for various cancers, including urothelial cancer.^9-11 Before 2016, platinum-based chemotherapy was the mainstay for metastatic urothelial cancer management, but US Food and Drug Administration approval of 5 ICIs—nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab—­transformed treatment options.¹²Despite robust antitumor responses to ICIs, these medications are increasingly associated with immune-related adverse events (IRAEs), including DIBP, due to inhibition of negative regulators of immunity crucial for maintaining immunologic homeostasis.^13,14 Up to 30% to 40% of patients treated with PD-1 inhibitors experience dermatologic complications, such as lichenoid reactions, eczema, vitiligo, and pruritus,¹⁵ and patients undergoing treatment with the PD-1 inhibitor pembrolizumab are estimated to be 2.6 times more likely to develop a rash than those receiving standard chemotherapy.^16,17 The pathogenesis of DIBP involves autoreactive T-cell activation and subsequent autoantibody production against BP antigens.¹⁸ We present the case of DIBP secondary to pembrolizumab immunotherapy in a man with PD-L1–negative metastatic bladder cancer.

Case Report

An 81-year-old man with metastatic urothelial carcinoma presented to dermatology with a pruritic rash characterized by blisters of 5 months’ duration following treatment with pembrolizumab. He had a history of non–muscle invasive urothelial carcinoma and underwent intravesical bacillus Calmette-Guerin treatment. Thirty years later, after surveillance cystoscopies, the patient developed hematuria, which prompted pelvic ultrasonography and cystoscopy that revealed a tumor. Transurethral resection of the bladder tumor confirmed invasive, high-grade papillary urothelial carcinoma with vascular and muscle invasion (clinical stage T2NxMx). Due to elevated creatinine levels, neoadjuvant chemotherapy was contraindicated. Instead, the patient underwent cystoprostatectomy with ureteroileal conduit creation and pelvic lymphadenectomy one month later; final pathology revealed pT2aN0M0 disease with multifocal carcinoma in situ. At that time, there was no evidence of distant metastasis. Surveillance 5 months later identified pulmonary nodules that were confirmed as metastatic urothelial cancer by positron emission ­tomography/computed tomography (CT). The patient received 6 cycles of paclitaxel (175 mg/m² on day 1) and gemcitabine (1000 mg/m² on days 1 and 8 every 21 days), with progressive disease 16 months later. Despite 0% PD-L1 expression, pembrolizumab 400 mg intravenous (IV) treatment every 6 weeks was initiated 2 months later, and subsequent positron emission tomography/CT showed a positive response at 3 and 7 months after treatment initiation. After the patient’s sixth cycle of pembrolizumab, a generalized maculopapular rash involving approximately 50% of the body surface area led to discontinuation of pembrolizumab, initiation of multiple courses of prednisone and prednisolone, and a dermatology referral.

At the current presentation, the patient exhibited excoriated red patches on the abdomen, wrists, arms, upper chest, and legs (Figure 1). Tense blisters were observed on various areas, including the ear and arms. The provisional diagnosis was pembrolizumab-induced BP, supported by the clinical history, presentation, and an initial positive response to steroids. Treatment included topical triamcinolone 0.1% ointment and prednisone 40 mg daily. Biopsies revealed subepidermal blisters with underlying eosinophils on histopathology (Figure 2). Direct immunofluorescence showed strong linear basement membrane zone staining with IgG and C3, consistent with a diagnosis of BP.

One month later, the patient was given the first of two 1-g doses of rituximab, chosen as a treatment due to metastatic cancer history and ongoing severity of the DIBP. In addition, a slow prednisone taper was initiated. Atovaquone 1500 mg daily was ordered for Pneumocystis jirovecii prophylaxis. Following the first rituximab dose, the patient became clear of DIBP but required treatment for a chronic urinary tract infection, delaying the second rituximab dose. The prednisone taper continued, however, and the patient reported re-emergence of several blisters, followed by resolution of pruritus following the second rituximab dose. Bilateral pulmonary embolisms were noted on a restaging CT, attributed to the underlying malignancy and inflammation from DIBP. Doxycycline was initiated at 100 mg twice daily, and prednisone was slowly tapered (as tolerated by the patient’s symptoms) down to 2.5 mg daily approximately 6 months after rituximab initiation. The patient remains in clinical remission at last follow-up; however, considerations for further treatments have included intravenous immunoglobulin.

Comment

This case highlights major clinical challenges in the diagnosis and management of DIBP in a patient with metastatic urothelial carcinoma receiving ICI therapy. Our patient’s clinical course offers several high-yield lessons regarding diagnostic latency, treatment resistance, and a multidisciplinary approach to management.

Pruritus as a Precursor—Since an initial report in 2015, the emergence of DIBP postpembrolizumab has been well described in the literature.^19-22 Pruritus is frequently the earliest symptom, preceding bullous eruption. Similar to our case—in which DIBP developed 30 weeks after pembrolizumab initiation—the classic clinical presentation and formation of bullae often are delayed, typically occurring 28 and 39 weeks.

Beyond Corticosteroids to Manage Refractory DIBP—Our patient’s DIBP persisted despite multiple interventions, including pembrolizumab discontinuation, corticosteroid therapy, and rituximab administration. Although cases of DIBP in pembrolizumab-treated metastatic urothelial carcinoma patients have been reported, they did not exhibit similar treatment resistance.^23-25 As observed in our patient, immunotherapy discontinuation has been reported in at least 40% of all ICI-mediated cases of BP.¹⁴ Subsequent management involves low-dose oral corticosteroids and potent topical corticosteroids; the duration of steroid treatment varies widely, ranging from a few weeks to longer than 12 months, with no standardized approach.²⁶ In cases where ICI withdrawal and corticosteroids fail to produce a complete response, monoclonal antibodies such as rituximab, dupilumab, and omalizumab have been used as alternative treatments, with dupilumab recently receiving US Food and Drug Administration approval for moderate to severe BP.^27-31 These biologics selectively inhibit autoantibody formation and the inflammatory cascade, and research has pointed toward them as safe and effective options for refractory BP. Although robust randomized, controlled clinical trials on rituximab for DIBP still are lacking, prospective and retrospective cohort studies have shown promising results, including complete remission rates of 67% to 90%, along with a decline in circulating BP180-specific B lymphocytes, anti-BP180 IgG, and the expression of proinflammatory IL-15 and IL-6.³²

Despite receiving 2 doses of rituximab, our patient experienced recurrence of blisters when prednisone was tapered, prompting discussions about alternative tapering timelines and additional therapies such as doxycycline³³ or intravenous immunoglobulin,³⁴ which have emerged as steroid-sparing agents for BP following initial steroid therapy.

Systemic Barriers and the Need for Multidisciplinary Care—This case underscores systemic barriers within the health care system that impede prompt diagnosis and management of conditions such as DIBP. The 5-month delay between the patient’s referral to dermatology and the actual consultation, potentially due to shortages of dermatologists, highlights the need for more systematic urgent dermatologic referrals and streamlined diagnostic pathways in suspected cases of IRAEs. Diagnosis requires comprehensive evaluation, including skin biopsy for histopathologic examination and immunofluorescence studies. Ruling out alternative blistering disorders, such as epidermolysis bullosa acquisita, is crucial before confirming a BP diagnosis. Encouraging direct communication between referring physicians and consultants often can expedite the process, as a call from the referring physician can alert the consultant and speed up scheduling. Notably, the patient’s daughter, who was a patient of the dermatologist herself, played a crucial role in advocating for the dermatology referral. Although this should not be necessary, it highlights the pivotal role families can play in ensuring timely access to specialized care for challenging conditions such as BP.

Lastly, the refractory nature of the patient’s condition, coupled with concurrent chronic urinary tract infection and bilateral pulmonary embolisms, emphasizes the necessity of multidisciplinary collaboration among oncology, dermatology, and primary care in managing DIBP. Consulting experts on IRAEs and coordinating with the oncologist were essential for making informed treatment decisions and facilitating the timely exchange of clinical information.

Conclusion

This case underscores the importance of timely recognition and diagnosis of DIBP in patients undergoing ICI therapy but also highlights the need for individualized treatment approaches and multidisciplinary collaboration when managing adverse cutaneous reactions.

Bullous pemphigoid (BP) is an autoimmune blistering disorder characterized by the development of tense subepidermal blisters and erosions primarily on the skin, commonly affecting the elderly.¹ It is attributed to autoantibodies targeting 2 hemidesmosomal components within the dermoepidermal junction—transmembrane collagen XVII (BP180/BPAG2) and plakin family protein BP230 (BPAG1)—resulting in blister formation due to loss of structural integrity.² Typically, patients present with pruritic urticarial plaques and tense bullae localized on flexural areas, but cutaneous manifestations vary and can be nonspecific. Histologically, a subepidermal blister with eosinophilic infiltration is characteristic, and detection of circulating autoantibodies against BP180 and BP230 antigens aids in diagnosis.^3,4

Drug-induced BP (DIBP) is a subset triggered by medications, including immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1) or its ligand, programmed death ligand-1 (PD-L1).^5,6 Often overexpressed in malignant tumors, PD-L1 inhibits host lymphocytic and apoptotic immune responses. Anti‒PD-1 and anti‒PD-L1 agents, designed to enhance the immune system’s ability to recognize and eliminate cancer cells,^7,8 have improved oncologic outcomes for various cancers, including urothelial cancer.^9-11 Before 2016, platinum-based chemotherapy was the mainstay for metastatic urothelial cancer management, but US Food and Drug Administration approval of 5 ICIs—nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab—­transformed treatment options.¹²Despite robust antitumor responses to ICIs, these medications are increasingly associated with immune-related adverse events (IRAEs), including DIBP, due to inhibition of negative regulators of immunity crucial for maintaining immunologic homeostasis.^13,14 Up to 30% to 40% of patients treated with PD-1 inhibitors experience dermatologic complications, such as lichenoid reactions, eczema, vitiligo, and pruritus,¹⁵ and patients undergoing treatment with the PD-1 inhibitor pembrolizumab are estimated to be 2.6 times more likely to develop a rash than those receiving standard chemotherapy.^16,17 The pathogenesis of DIBP involves autoreactive T-cell activation and subsequent autoantibody production against BP antigens.¹⁸ We present the case of DIBP secondary to pembrolizumab immunotherapy in a man with PD-L1–negative metastatic bladder cancer.

Case Report

An 81-year-old man with metastatic urothelial carcinoma presented to dermatology with a pruritic rash characterized by blisters of 5 months’ duration following treatment with pembrolizumab. He had a history of non–muscle invasive urothelial carcinoma and underwent intravesical bacillus Calmette-Guerin treatment. Thirty years later, after surveillance cystoscopies, the patient developed hematuria, which prompted pelvic ultrasonography and cystoscopy that revealed a tumor. Transurethral resection of the bladder tumor confirmed invasive, high-grade papillary urothelial carcinoma with vascular and muscle invasion (clinical stage T2NxMx). Due to elevated creatinine levels, neoadjuvant chemotherapy was contraindicated. Instead, the patient underwent cystoprostatectomy with ureteroileal conduit creation and pelvic lymphadenectomy one month later; final pathology revealed pT2aN0M0 disease with multifocal carcinoma in situ. At that time, there was no evidence of distant metastasis. Surveillance 5 months later identified pulmonary nodules that were confirmed as metastatic urothelial cancer by positron emission ­tomography/computed tomography (CT). The patient received 6 cycles of paclitaxel (175 mg/m² on day 1) and gemcitabine (1000 mg/m² on days 1 and 8 every 21 days), with progressive disease 16 months later. Despite 0% PD-L1 expression, pembrolizumab 400 mg intravenous (IV) treatment every 6 weeks was initiated 2 months later, and subsequent positron emission tomography/CT showed a positive response at 3 and 7 months after treatment initiation. After the patient’s sixth cycle of pembrolizumab, a generalized maculopapular rash involving approximately 50% of the body surface area led to discontinuation of pembrolizumab, initiation of multiple courses of prednisone and prednisolone, and a dermatology referral.

At the current presentation, the patient exhibited excoriated red patches on the abdomen, wrists, arms, upper chest, and legs (Figure 1). Tense blisters were observed on various areas, including the ear and arms. The provisional diagnosis was pembrolizumab-induced BP, supported by the clinical history, presentation, and an initial positive response to steroids. Treatment included topical triamcinolone 0.1% ointment and prednisone 40 mg daily. Biopsies revealed subepidermal blisters with underlying eosinophils on histopathology (Figure 2). Direct immunofluorescence showed strong linear basement membrane zone staining with IgG and C3, consistent with a diagnosis of BP.

One month later, the patient was given the first of two 1-g doses of rituximab, chosen as a treatment due to metastatic cancer history and ongoing severity of the DIBP. In addition, a slow prednisone taper was initiated. Atovaquone 1500 mg daily was ordered for Pneumocystis jirovecii prophylaxis. Following the first rituximab dose, the patient became clear of DIBP but required treatment for a chronic urinary tract infection, delaying the second rituximab dose. The prednisone taper continued, however, and the patient reported re-emergence of several blisters, followed by resolution of pruritus following the second rituximab dose. Bilateral pulmonary embolisms were noted on a restaging CT, attributed to the underlying malignancy and inflammation from DIBP. Doxycycline was initiated at 100 mg twice daily, and prednisone was slowly tapered (as tolerated by the patient’s symptoms) down to 2.5 mg daily approximately 6 months after rituximab initiation. The patient remains in clinical remission at last follow-up; however, considerations for further treatments have included intravenous immunoglobulin.

Comment

This case highlights major clinical challenges in the diagnosis and management of DIBP in a patient with metastatic urothelial carcinoma receiving ICI therapy. Our patient’s clinical course offers several high-yield lessons regarding diagnostic latency, treatment resistance, and a multidisciplinary approach to management.

Pruritus as a Precursor—Since an initial report in 2015, the emergence of DIBP postpembrolizumab has been well described in the literature.^19-22 Pruritus is frequently the earliest symptom, preceding bullous eruption. Similar to our case—in which DIBP developed 30 weeks after pembrolizumab initiation—the classic clinical presentation and formation of bullae often are delayed, typically occurring 28 and 39 weeks.

Beyond Corticosteroids to Manage Refractory DIBP—Our patient’s DIBP persisted despite multiple interventions, including pembrolizumab discontinuation, corticosteroid therapy, and rituximab administration. Although cases of DIBP in pembrolizumab-treated metastatic urothelial carcinoma patients have been reported, they did not exhibit similar treatment resistance.^23-25 As observed in our patient, immunotherapy discontinuation has been reported in at least 40% of all ICI-mediated cases of BP.¹⁴ Subsequent management involves low-dose oral corticosteroids and potent topical corticosteroids; the duration of steroid treatment varies widely, ranging from a few weeks to longer than 12 months, with no standardized approach.²⁶ In cases where ICI withdrawal and corticosteroids fail to produce a complete response, monoclonal antibodies such as rituximab, dupilumab, and omalizumab have been used as alternative treatments, with dupilumab recently receiving US Food and Drug Administration approval for moderate to severe BP.^27-31 These biologics selectively inhibit autoantibody formation and the inflammatory cascade, and research has pointed toward them as safe and effective options for refractory BP. Although robust randomized, controlled clinical trials on rituximab for DIBP still are lacking, prospective and retrospective cohort studies have shown promising results, including complete remission rates of 67% to 90%, along with a decline in circulating BP180-specific B lymphocytes, anti-BP180 IgG, and the expression of proinflammatory IL-15 and IL-6.³²

Despite receiving 2 doses of rituximab, our patient experienced recurrence of blisters when prednisone was tapered, prompting discussions about alternative tapering timelines and additional therapies such as doxycycline³³ or intravenous immunoglobulin,³⁴ which have emerged as steroid-sparing agents for BP following initial steroid therapy.

Systemic Barriers and the Need for Multidisciplinary Care—This case underscores systemic barriers within the health care system that impede prompt diagnosis and management of conditions such as DIBP. The 5-month delay between the patient’s referral to dermatology and the actual consultation, potentially due to shortages of dermatologists, highlights the need for more systematic urgent dermatologic referrals and streamlined diagnostic pathways in suspected cases of IRAEs. Diagnosis requires comprehensive evaluation, including skin biopsy for histopathologic examination and immunofluorescence studies. Ruling out alternative blistering disorders, such as epidermolysis bullosa acquisita, is crucial before confirming a BP diagnosis. Encouraging direct communication between referring physicians and consultants often can expedite the process, as a call from the referring physician can alert the consultant and speed up scheduling. Notably, the patient’s daughter, who was a patient of the dermatologist herself, played a crucial role in advocating for the dermatology referral. Although this should not be necessary, it highlights the pivotal role families can play in ensuring timely access to specialized care for challenging conditions such as BP.

Lastly, the refractory nature of the patient’s condition, coupled with concurrent chronic urinary tract infection and bilateral pulmonary embolisms, emphasizes the necessity of multidisciplinary collaboration among oncology, dermatology, and primary care in managing DIBP. Consulting experts on IRAEs and coordinating with the oncologist were essential for making informed treatment decisions and facilitating the timely exchange of clinical information.

Conclusion

This case underscores the importance of timely recognition and diagnosis of DIBP in patients undergoing ICI therapy but also highlights the need for individualized treatment approaches and multidisciplinary collaboration when managing adverse cutaneous reactions.

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer and ranks sixth in prevalence among all cancers in the United Kingdom.^1,2 The etiologic factors underlying cSCC are well established, with major efforts undertaken by governments and public health organizations over the past 2 decades to increase public awareness globally. Known risk factors for cSCC include chronic exposure to UV radiation, radiotherapy, chemical injury, and immunosuppression. The first 3 risk factors amplify risk by increasing accumulation of abnormal gene mutations. Immunosuppression hampers the immune system’s ability to eradicate cells bearing malignant genetic aberrations. Notable gene mutations implicated in cSCC include p53, p16, telomerase reverse transcriptase, NOTCH1, ROS1, mitogen-activated protein kinases, forkhead box M1, and cyclooxygenase 2, in addition to matrix metalloproteinases, which are most commonly associated with Marjolin ulcers.³

The incidence of cSCC continues to surge worldwide,^3,4 with more patients presenting with advanced stages of disease and a notable increase in those presenting with unresectable cSCC due to either locally advanced disease or distant metastases.⁵ Existing therapies for cSCC include surgical excision (including Mohs micrographic surgery); radiotherapy (indicated for cosmetic reasons, locally advanced disease, and/or patient factors); and systemic treatments, encompassing chemotherapy (eg, ­5-fluorouracil), and epidermal growth factor receptor inhibitors (indicated locally advanced disease or distant metastases).⁴

In recent years, immunotherapy has emerged as a potent and effective treatment modality for unresectable cSCC, both locally advanced and metastatic. The success of immunotherapy in cSCC treatment can be attributed to the unique tumor microenvironment of cSCC, which is characterized by high tumor mutational burden, increased density of tumor-infiltrating lymphocytes (TILs), and heightened programmed cell death ligand 1 (PD-L1) expression on neoplastic cells. The elevated TIL density enables a robust immune response, rendering checkpoint inhibitors particularly effective. Greater tumor mutational burden further augments this enhanced TIL activity, amplifying the response to checkpoint inhibitors. Additionally, heightened PD-L1 expression facilitates more effective unmasking by checkpoint inhibitors, thereby enhancing the immune response.⁶

Cemiplimab is a programmed cell death protein 1/PD-L1 that was approved by the US Food and Drug Administration in September 2018 for treatment of cSCC. It also gained a European Union endorsement in June 2019 and National Institute for Health and Care Excellence approval in August 2019 based on the highly promising results of a phase 2 trial that involved only 59 adult patients with metastatic cSCC.⁷ The trial reported an overall response rate (ORR) of 47%, durable disease control in 61% of patients, a median time to response of 1.9 months, and response duration exceeding 6 months in 57% of patients. The phase 2 trials reported an estimated 12-month progression-free survival (PFS) of 53% and an estimated 12-month overall survival (OS) of 81%.⁷

Despite the noteworthy response statistics demonstrated by these studies, it is imperative to recognize that immunotherapies, while potent, are not without challenges. They can precipitate severe immune-related adverse events (AEs), including myocarditis, adrenal failure, and pneumonitis, which can negatively impact patient health outcomes and lead to early treatment cessation. The initial trials reported high-grade AEs such as pneumonitis, pleural effusion, and, notably 11 total deaths, with 8 (72.7%) attributed to disease progression and 3 (27.3%) to AEs.⁷ Additionally, cost and access to immunotherapy are inherent limitations of the treatment; immunotherapy agents are expensive, and not all centers or patients are able to access them.

The aim of this study was to assess the efficacy of cemiplimab in patients with inoperable cSCC, including locally advanced and metastatic disease, treated at a tertiary referral center in the United Kingdom, and to compare outcomes with the pivotal phase 2 trial that supported regulatory approval of cemiplimab.⁷ The primary objective was ORR, with secondary objectives including PFS, OS, and AEs.

Methods

The patients included in this study had unresectable cSCC and therefore were not candidates for surgery or radiotherapy. Patient demographics are presented in Table 1. The main indications for cemiplimab in place of surgery or radiotherapy included local recurrence, locally advanced disease involving deep structures, advanced nodal disease, and distant metastatic disease. Patients meeting these criteria and the following inclusion criteria for cemiplimab treatment from November 2018 through March 2023 at a single tertiary referral center were included in the study:

• Age 18 years or older
• Histologically confirmed cSCC with locoregional recurrence after surgery or radiotherapy, or histologically confirmed advanced or metastatic disease deemed to be inoperable
• Eastern Cooperative Oncology Group performance status of 0 to 2

All enrolled patients received intravenous infusions of cemiplimab 3 times weekly at a dosage of 350 mg. Treatment was continued until complete response, unacceptable toxicity, or disease progression, with a maximum duration of 2 years or 35 cycles. Patients underwent regular follow-up, typically 3 weeks preceding each treatment cycle. Monitoring adhered to the Common Terminology Criteria for Adverse Events, version 4.0, as outlined by the National Cancer Institute.⁸ Response to treatment was reported according to the guidelines stipulated by the Response Evaluation Criteria in Solid Tumours, version 1.1.⁹ Written informed consent was obtained for all patients.

Comprehensive patient demographics, histologic profiles, and clinical data were meticulously captured on a retrospective basis. The primary objective centered on elucidating the ORR. Secondary objectives encompassed evaluating PFS, OS, and a comprehensive analysis of AEs. Progression-free survival and OS were calculated by generating Kaplan-Meier curves using Python 3.9 (Python Software Foundation).

Results

Patient Characteristics—From November 2018 through March 2023, a cohort of 31 patients with inoperable cSCC underwent treatment with cemiplimab at our tertiary referral center. The median duration of follow-up was 13 months. Clinical characteristics are outlined in the Table 2. Four (12.9%) patients successfully completed the full 2-year treatment course. Nine (29.0%) continued to receive cemiplimab therapy at the conclusion of this study in March 2023, with treatment courses ranging from 2 to 11 months since initiation. Ten (32.3%) patients discontinued treatment due to AEs, while 5 (16.1%) regrettably ceased treatment due to mortality. Two (6.5%) patients terminated treatment due to the COVID-19 pandemic, and 1 (3.2%) discontinued treatment as a result of disease progression.

Clinical Efficacy—Of the 31 enrolled patients, a substantial proportion experienced positive clinical outcomes, with 20 (64.5%) achieving complete response and 6 (19.4%) achieving partial response. A total of 26 patients achieved a response on cemiplimab, with an ORR of 83.9% (95% CI, 66.3%-94.6%). Regrettably, 2 (6.5%) patients experienced disease progression, while 3 (9.7%) died before response to cemiplimab could be assessed. Following a median follow-up period of 13 months, the median PFS and OS remained unreached, emphasizing the efficacy of cemiplimab in treating inoperable cSCC (Figures 1 and 2).

In our cohort, 2-year PFS was 57.5% (95% CI, 33.9%-75.5%) with cemiplimab and 2-year OS was 70.6% (95% CI, 46.5%-85.4%). For PFS, we observed the steepest drops at onset and at the 23-month mark (Figure 1), while for OS we observed the steepest drop at the 38-month mark (Figure 2). Clinically, we observed cemiplimab causing near-complete regression of previously large, ulcerating, fungating cSCC in patients who responded to cemiplimab, mirroring results seen elsewhere.⁷

Adverse Events and Treatment Cessation—A substantial proportion of patients (24/31 [77.4%]) reported AEs during treatment. Notably, treatment discontinuation was necessary in 10 (32.3%) patients due to a range of AEs, including myocarditis, atrial flutter, pneumonitis, nephritis, derangement of liver function tests, and arthritis. Additional relevant side effects included adrenal insufficiency (3/31 [9.7%]), fatigue (3/31 [9.7%]), diarrhea (2/31 [6.5%]), and type 1 diabetes 1/31 [3.2%]). These outcomes emphasize the importance of vigilance and monitoring when administering cemiplimab in the context of advanced cSCC.

Comment

Historically, advanced cSCC has had a bleak prognosis. The nature of the disease generally meant these patients could not be operated on due to metastatic spread or local invasion, and radiotherapy was not curative. The only option remaining was palliation, but new therapies have shown promise due to specific inherent characteristics of advanced cSCC; for example, the characteristic high mutation burden prevalent in advanced cSCC has paved the way for the emergence of immunotherapy as a promising avenue for intervention.¹⁰ Cemiplimab in particular has emerged as a feasible treatment for patients who would otherwise be confined to palliation. Our findings derived from a local cohort reinforce this notion, with a remarkable 83.9% (26/31) exhibiting a favorable response to cemiplimab. Although this local sample of 31 patients is small in absolute terms, in the context of the trial with 59 participants⁷ that gained global approval for the use of cemiplimab, our study adds a substantial amount of data to the growing body of evidence on the long-term efficacy of cemiplimab. Notably, our results emphasize the potential applicability of cemiplimab among elderly patients and individuals with lower performance statuses: populations historically excluded from immunotherapeutic considerations.

Immunotherapeutic AEs and Tolerance­—As anticipated with immunotherapeutic agents, cemiplimab is associated with AEs that also are seen in its counterparts.¹¹ A total of 77.4% (24/31) of our cohort reported immune-related AEs, although the severity warranted treatment discontinuation in only 10 (10/24 [41.7%]) patients, representing less than half of those who encountered side effects and less than a third of the entire cohort. Furthermore, most of these immune-related AEs were managed effectively with short courses of oral steroids, further substantiating the notion that cemiplimab is generally well tolerated across patients of diverse performance statuses. Even for patients who discontinued treatment early due to immune-related side effects, benefits persisted despite the partial course of cemiplimab. Of the 10 patients who discontinued treatment due to immune AEs, 6 (60%) demonstrated stable complete response, 2 (20%) experienced relapse after stopping cemiplimab, and 2 (20%) demonstrated a partial response with stable disease.

Challenges in the Most Vulnerable Patient—Of the 5 recorded mortalities, 2 (40%) were attributed to disease progression, while 3 (60%) occurred before response assessment could be undertaken. The 3 patients who died prior to response evaluation were among the most medically fragile in the cohort, characterized by extensive metastatic cSCC and major comorbidities that, in isolation, posed life-threatening risks. For individuals grappling with widespread metastatic cSCC and substantial life-threatening comorbidities, it is plausible that the necessary physiologic resilience necessary for cemiplimab therapy may be absent. We hypothesize that an immune reconstitution syndrome–like response may be responsible for this early mortality, and these patients may lack the necessary physiological resilience to tolerate this response. This subset of patients warrants careful consideration when considering therapy with cemiplimab.

Conclusion

In summary, our results underscore the efficacy of cemiplimab, as it supported a response in more than three-quarters of our patient cohort. Additionally, the associated AEs, similar to those with other programmed cell death protein 1 inhibitors, generally were manageable with medical intervention. Our findings corroborate earlier studies that have demonstrated the therapeutic potential of cemiplimab in advanced, inoperable cSCC management. In addition to efficacy, our results also suggest that cemiplimab holds promise as a therapeutic option for patients who might not be amenable to the stresses of general anesthesia, surgery, or prolonged hospitalization, although cemiplimab should likely be used with caution in patients with severe, life-threatening medical comorbidities and/or concurrent severe illness. Furthermore, our data demonstrate that the benefits persist not only beyond the completion of the full 2-year course, but also after partial treatment courses discontinued due to patient-specific factors. Future studies would be useful to better understand and optimize dose and duration of cemiplimab treatment to maximize therapeutic effectiveness while minimizing risk of immune-related AEs. Among individuals confronting advanced, inoperable cSCC, cemiplimab is emerging as a viable and beneficial intervention.

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer and ranks sixth in prevalence among all cancers in the United Kingdom.^1,2 The etiologic factors underlying cSCC are well established, with major efforts undertaken by governments and public health organizations over the past 2 decades to increase public awareness globally. Known risk factors for cSCC include chronic exposure to UV radiation, radiotherapy, chemical injury, and immunosuppression. The first 3 risk factors amplify risk by increasing accumulation of abnormal gene mutations. Immunosuppression hampers the immune system’s ability to eradicate cells bearing malignant genetic aberrations. Notable gene mutations implicated in cSCC include p53, p16, telomerase reverse transcriptase, NOTCH1, ROS1, mitogen-activated protein kinases, forkhead box M1, and cyclooxygenase 2, in addition to matrix metalloproteinases, which are most commonly associated with Marjolin ulcers.³

The incidence of cSCC continues to surge worldwide,^3,4 with more patients presenting with advanced stages of disease and a notable increase in those presenting with unresectable cSCC due to either locally advanced disease or distant metastases.⁵ Existing therapies for cSCC include surgical excision (including Mohs micrographic surgery); radiotherapy (indicated for cosmetic reasons, locally advanced disease, and/or patient factors); and systemic treatments, encompassing chemotherapy (eg, ­5-fluorouracil), and epidermal growth factor receptor inhibitors (indicated locally advanced disease or distant metastases).⁴

In recent years, immunotherapy has emerged as a potent and effective treatment modality for unresectable cSCC, both locally advanced and metastatic. The success of immunotherapy in cSCC treatment can be attributed to the unique tumor microenvironment of cSCC, which is characterized by high tumor mutational burden, increased density of tumor-infiltrating lymphocytes (TILs), and heightened programmed cell death ligand 1 (PD-L1) expression on neoplastic cells. The elevated TIL density enables a robust immune response, rendering checkpoint inhibitors particularly effective. Greater tumor mutational burden further augments this enhanced TIL activity, amplifying the response to checkpoint inhibitors. Additionally, heightened PD-L1 expression facilitates more effective unmasking by checkpoint inhibitors, thereby enhancing the immune response.⁶

Cemiplimab is a programmed cell death protein 1/PD-L1 that was approved by the US Food and Drug Administration in September 2018 for treatment of cSCC. It also gained a European Union endorsement in June 2019 and National Institute for Health and Care Excellence approval in August 2019 based on the highly promising results of a phase 2 trial that involved only 59 adult patients with metastatic cSCC.⁷ The trial reported an overall response rate (ORR) of 47%, durable disease control in 61% of patients, a median time to response of 1.9 months, and response duration exceeding 6 months in 57% of patients. The phase 2 trials reported an estimated 12-month progression-free survival (PFS) of 53% and an estimated 12-month overall survival (OS) of 81%.⁷

Despite the noteworthy response statistics demonstrated by these studies, it is imperative to recognize that immunotherapies, while potent, are not without challenges. They can precipitate severe immune-related adverse events (AEs), including myocarditis, adrenal failure, and pneumonitis, which can negatively impact patient health outcomes and lead to early treatment cessation. The initial trials reported high-grade AEs such as pneumonitis, pleural effusion, and, notably 11 total deaths, with 8 (72.7%) attributed to disease progression and 3 (27.3%) to AEs.⁷ Additionally, cost and access to immunotherapy are inherent limitations of the treatment; immunotherapy agents are expensive, and not all centers or patients are able to access them.

The aim of this study was to assess the efficacy of cemiplimab in patients with inoperable cSCC, including locally advanced and metastatic disease, treated at a tertiary referral center in the United Kingdom, and to compare outcomes with the pivotal phase 2 trial that supported regulatory approval of cemiplimab.⁷ The primary objective was ORR, with secondary objectives including PFS, OS, and AEs.

Methods

The patients included in this study had unresectable cSCC and therefore were not candidates for surgery or radiotherapy. Patient demographics are presented in Table 1. The main indications for cemiplimab in place of surgery or radiotherapy included local recurrence, locally advanced disease involving deep structures, advanced nodal disease, and distant metastatic disease. Patients meeting these criteria and the following inclusion criteria for cemiplimab treatment from November 2018 through March 2023 at a single tertiary referral center were included in the study:

• Age 18 years or older
• Histologically confirmed cSCC with locoregional recurrence after surgery or radiotherapy, or histologically confirmed advanced or metastatic disease deemed to be inoperable
• Eastern Cooperative Oncology Group performance status of 0 to 2

All enrolled patients received intravenous infusions of cemiplimab 3 times weekly at a dosage of 350 mg. Treatment was continued until complete response, unacceptable toxicity, or disease progression, with a maximum duration of 2 years or 35 cycles. Patients underwent regular follow-up, typically 3 weeks preceding each treatment cycle. Monitoring adhered to the Common Terminology Criteria for Adverse Events, version 4.0, as outlined by the National Cancer Institute.⁸ Response to treatment was reported according to the guidelines stipulated by the Response Evaluation Criteria in Solid Tumours, version 1.1.⁹ Written informed consent was obtained for all patients.

Comprehensive patient demographics, histologic profiles, and clinical data were meticulously captured on a retrospective basis. The primary objective centered on elucidating the ORR. Secondary objectives encompassed evaluating PFS, OS, and a comprehensive analysis of AEs. Progression-free survival and OS were calculated by generating Kaplan-Meier curves using Python 3.9 (Python Software Foundation).

Results

Patient Characteristics—From November 2018 through March 2023, a cohort of 31 patients with inoperable cSCC underwent treatment with cemiplimab at our tertiary referral center. The median duration of follow-up was 13 months. Clinical characteristics are outlined in the Table 2. Four (12.9%) patients successfully completed the full 2-year treatment course. Nine (29.0%) continued to receive cemiplimab therapy at the conclusion of this study in March 2023, with treatment courses ranging from 2 to 11 months since initiation. Ten (32.3%) patients discontinued treatment due to AEs, while 5 (16.1%) regrettably ceased treatment due to mortality. Two (6.5%) patients terminated treatment due to the COVID-19 pandemic, and 1 (3.2%) discontinued treatment as a result of disease progression.

Clinical Efficacy—Of the 31 enrolled patients, a substantial proportion experienced positive clinical outcomes, with 20 (64.5%) achieving complete response and 6 (19.4%) achieving partial response. A total of 26 patients achieved a response on cemiplimab, with an ORR of 83.9% (95% CI, 66.3%-94.6%). Regrettably, 2 (6.5%) patients experienced disease progression, while 3 (9.7%) died before response to cemiplimab could be assessed. Following a median follow-up period of 13 months, the median PFS and OS remained unreached, emphasizing the efficacy of cemiplimab in treating inoperable cSCC (Figures 1 and 2).

In our cohort, 2-year PFS was 57.5% (95% CI, 33.9%-75.5%) with cemiplimab and 2-year OS was 70.6% (95% CI, 46.5%-85.4%). For PFS, we observed the steepest drops at onset and at the 23-month mark (Figure 1), while for OS we observed the steepest drop at the 38-month mark (Figure 2). Clinically, we observed cemiplimab causing near-complete regression of previously large, ulcerating, fungating cSCC in patients who responded to cemiplimab, mirroring results seen elsewhere.⁷

Adverse Events and Treatment Cessation—A substantial proportion of patients (24/31 [77.4%]) reported AEs during treatment. Notably, treatment discontinuation was necessary in 10 (32.3%) patients due to a range of AEs, including myocarditis, atrial flutter, pneumonitis, nephritis, derangement of liver function tests, and arthritis. Additional relevant side effects included adrenal insufficiency (3/31 [9.7%]), fatigue (3/31 [9.7%]), diarrhea (2/31 [6.5%]), and type 1 diabetes 1/31 [3.2%]). These outcomes emphasize the importance of vigilance and monitoring when administering cemiplimab in the context of advanced cSCC.

Comment

Historically, advanced cSCC has had a bleak prognosis. The nature of the disease generally meant these patients could not be operated on due to metastatic spread or local invasion, and radiotherapy was not curative. The only option remaining was palliation, but new therapies have shown promise due to specific inherent characteristics of advanced cSCC; for example, the characteristic high mutation burden prevalent in advanced cSCC has paved the way for the emergence of immunotherapy as a promising avenue for intervention.¹⁰ Cemiplimab in particular has emerged as a feasible treatment for patients who would otherwise be confined to palliation. Our findings derived from a local cohort reinforce this notion, with a remarkable 83.9% (26/31) exhibiting a favorable response to cemiplimab. Although this local sample of 31 patients is small in absolute terms, in the context of the trial with 59 participants⁷ that gained global approval for the use of cemiplimab, our study adds a substantial amount of data to the growing body of evidence on the long-term efficacy of cemiplimab. Notably, our results emphasize the potential applicability of cemiplimab among elderly patients and individuals with lower performance statuses: populations historically excluded from immunotherapeutic considerations.

Immunotherapeutic AEs and Tolerance­—As anticipated with immunotherapeutic agents, cemiplimab is associated with AEs that also are seen in its counterparts.¹¹ A total of 77.4% (24/31) of our cohort reported immune-related AEs, although the severity warranted treatment discontinuation in only 10 (10/24 [41.7%]) patients, representing less than half of those who encountered side effects and less than a third of the entire cohort. Furthermore, most of these immune-related AEs were managed effectively with short courses of oral steroids, further substantiating the notion that cemiplimab is generally well tolerated across patients of diverse performance statuses. Even for patients who discontinued treatment early due to immune-related side effects, benefits persisted despite the partial course of cemiplimab. Of the 10 patients who discontinued treatment due to immune AEs, 6 (60%) demonstrated stable complete response, 2 (20%) experienced relapse after stopping cemiplimab, and 2 (20%) demonstrated a partial response with stable disease.

Challenges in the Most Vulnerable Patient—Of the 5 recorded mortalities, 2 (40%) were attributed to disease progression, while 3 (60%) occurred before response assessment could be undertaken. The 3 patients who died prior to response evaluation were among the most medically fragile in the cohort, characterized by extensive metastatic cSCC and major comorbidities that, in isolation, posed life-threatening risks. For individuals grappling with widespread metastatic cSCC and substantial life-threatening comorbidities, it is plausible that the necessary physiologic resilience necessary for cemiplimab therapy may be absent. We hypothesize that an immune reconstitution syndrome–like response may be responsible for this early mortality, and these patients may lack the necessary physiological resilience to tolerate this response. This subset of patients warrants careful consideration when considering therapy with cemiplimab.

Conclusion

In summary, our results underscore the efficacy of cemiplimab, as it supported a response in more than three-quarters of our patient cohort. Additionally, the associated AEs, similar to those with other programmed cell death protein 1 inhibitors, generally were manageable with medical intervention. Our findings corroborate earlier studies that have demonstrated the therapeutic potential of cemiplimab in advanced, inoperable cSCC management. In addition to efficacy, our results also suggest that cemiplimab holds promise as a therapeutic option for patients who might not be amenable to the stresses of general anesthesia, surgery, or prolonged hospitalization, although cemiplimab should likely be used with caution in patients with severe, life-threatening medical comorbidities and/or concurrent severe illness. Furthermore, our data demonstrate that the benefits persist not only beyond the completion of the full 2-year course, but also after partial treatment courses discontinued due to patient-specific factors. Future studies would be useful to better understand and optimize dose and duration of cemiplimab treatment to maximize therapeutic effectiveness while minimizing risk of immune-related AEs. Among individuals confronting advanced, inoperable cSCC, cemiplimab is emerging as a viable and beneficial intervention.

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer and ranks sixth in prevalence among all cancers in the United Kingdom.^1,2 The etiologic factors underlying cSCC are well established, with major efforts undertaken by governments and public health organizations over the past 2 decades to increase public awareness globally. Known risk factors for cSCC include chronic exposure to UV radiation, radiotherapy, chemical injury, and immunosuppression. The first 3 risk factors amplify risk by increasing accumulation of abnormal gene mutations. Immunosuppression hampers the immune system’s ability to eradicate cells bearing malignant genetic aberrations. Notable gene mutations implicated in cSCC include p53, p16, telomerase reverse transcriptase, NOTCH1, ROS1, mitogen-activated protein kinases, forkhead box M1, and cyclooxygenase 2, in addition to matrix metalloproteinases, which are most commonly associated with Marjolin ulcers.³

The incidence of cSCC continues to surge worldwide,^3,4 with more patients presenting with advanced stages of disease and a notable increase in those presenting with unresectable cSCC due to either locally advanced disease or distant metastases.⁵ Existing therapies for cSCC include surgical excision (including Mohs micrographic surgery); radiotherapy (indicated for cosmetic reasons, locally advanced disease, and/or patient factors); and systemic treatments, encompassing chemotherapy (eg, ­5-fluorouracil), and epidermal growth factor receptor inhibitors (indicated locally advanced disease or distant metastases).⁴

In recent years, immunotherapy has emerged as a potent and effective treatment modality for unresectable cSCC, both locally advanced and metastatic. The success of immunotherapy in cSCC treatment can be attributed to the unique tumor microenvironment of cSCC, which is characterized by high tumor mutational burden, increased density of tumor-infiltrating lymphocytes (TILs), and heightened programmed cell death ligand 1 (PD-L1) expression on neoplastic cells. The elevated TIL density enables a robust immune response, rendering checkpoint inhibitors particularly effective. Greater tumor mutational burden further augments this enhanced TIL activity, amplifying the response to checkpoint inhibitors. Additionally, heightened PD-L1 expression facilitates more effective unmasking by checkpoint inhibitors, thereby enhancing the immune response.⁶

Cemiplimab is a programmed cell death protein 1/PD-L1 that was approved by the US Food and Drug Administration in September 2018 for treatment of cSCC. It also gained a European Union endorsement in June 2019 and National Institute for Health and Care Excellence approval in August 2019 based on the highly promising results of a phase 2 trial that involved only 59 adult patients with metastatic cSCC.⁷ The trial reported an overall response rate (ORR) of 47%, durable disease control in 61% of patients, a median time to response of 1.9 months, and response duration exceeding 6 months in 57% of patients. The phase 2 trials reported an estimated 12-month progression-free survival (PFS) of 53% and an estimated 12-month overall survival (OS) of 81%.⁷

Despite the noteworthy response statistics demonstrated by these studies, it is imperative to recognize that immunotherapies, while potent, are not without challenges. They can precipitate severe immune-related adverse events (AEs), including myocarditis, adrenal failure, and pneumonitis, which can negatively impact patient health outcomes and lead to early treatment cessation. The initial trials reported high-grade AEs such as pneumonitis, pleural effusion, and, notably 11 total deaths, with 8 (72.7%) attributed to disease progression and 3 (27.3%) to AEs.⁷ Additionally, cost and access to immunotherapy are inherent limitations of the treatment; immunotherapy agents are expensive, and not all centers or patients are able to access them.

The aim of this study was to assess the efficacy of cemiplimab in patients with inoperable cSCC, including locally advanced and metastatic disease, treated at a tertiary referral center in the United Kingdom, and to compare outcomes with the pivotal phase 2 trial that supported regulatory approval of cemiplimab.⁷ The primary objective was ORR, with secondary objectives including PFS, OS, and AEs.

Methods

The patients included in this study had unresectable cSCC and therefore were not candidates for surgery or radiotherapy. Patient demographics are presented in Table 1. The main indications for cemiplimab in place of surgery or radiotherapy included local recurrence, locally advanced disease involving deep structures, advanced nodal disease, and distant metastatic disease. Patients meeting these criteria and the following inclusion criteria for cemiplimab treatment from November 2018 through March 2023 at a single tertiary referral center were included in the study:

• Age 18 years or older
• Histologically confirmed cSCC with locoregional recurrence after surgery or radiotherapy, or histologically confirmed advanced or metastatic disease deemed to be inoperable
• Eastern Cooperative Oncology Group performance status of 0 to 2

All enrolled patients received intravenous infusions of cemiplimab 3 times weekly at a dosage of 350 mg. Treatment was continued until complete response, unacceptable toxicity, or disease progression, with a maximum duration of 2 years or 35 cycles. Patients underwent regular follow-up, typically 3 weeks preceding each treatment cycle. Monitoring adhered to the Common Terminology Criteria for Adverse Events, version 4.0, as outlined by the National Cancer Institute.⁸ Response to treatment was reported according to the guidelines stipulated by the Response Evaluation Criteria in Solid Tumours, version 1.1.⁹ Written informed consent was obtained for all patients.

Comprehensive patient demographics, histologic profiles, and clinical data were meticulously captured on a retrospective basis. The primary objective centered on elucidating the ORR. Secondary objectives encompassed evaluating PFS, OS, and a comprehensive analysis of AEs. Progression-free survival and OS were calculated by generating Kaplan-Meier curves using Python 3.9 (Python Software Foundation).

Results

Patient Characteristics—From November 2018 through March 2023, a cohort of 31 patients with inoperable cSCC underwent treatment with cemiplimab at our tertiary referral center. The median duration of follow-up was 13 months. Clinical characteristics are outlined in the Table 2. Four (12.9%) patients successfully completed the full 2-year treatment course. Nine (29.0%) continued to receive cemiplimab therapy at the conclusion of this study in March 2023, with treatment courses ranging from 2 to 11 months since initiation. Ten (32.3%) patients discontinued treatment due to AEs, while 5 (16.1%) regrettably ceased treatment due to mortality. Two (6.5%) patients terminated treatment due to the COVID-19 pandemic, and 1 (3.2%) discontinued treatment as a result of disease progression.

Clinical Efficacy—Of the 31 enrolled patients, a substantial proportion experienced positive clinical outcomes, with 20 (64.5%) achieving complete response and 6 (19.4%) achieving partial response. A total of 26 patients achieved a response on cemiplimab, with an ORR of 83.9% (95% CI, 66.3%-94.6%). Regrettably, 2 (6.5%) patients experienced disease progression, while 3 (9.7%) died before response to cemiplimab could be assessed. Following a median follow-up period of 13 months, the median PFS and OS remained unreached, emphasizing the efficacy of cemiplimab in treating inoperable cSCC (Figures 1 and 2).

In our cohort, 2-year PFS was 57.5% (95% CI, 33.9%-75.5%) with cemiplimab and 2-year OS was 70.6% (95% CI, 46.5%-85.4%). For PFS, we observed the steepest drops at onset and at the 23-month mark (Figure 1), while for OS we observed the steepest drop at the 38-month mark (Figure 2). Clinically, we observed cemiplimab causing near-complete regression of previously large, ulcerating, fungating cSCC in patients who responded to cemiplimab, mirroring results seen elsewhere.⁷

Adverse Events and Treatment Cessation—A substantial proportion of patients (24/31 [77.4%]) reported AEs during treatment. Notably, treatment discontinuation was necessary in 10 (32.3%) patients due to a range of AEs, including myocarditis, atrial flutter, pneumonitis, nephritis, derangement of liver function tests, and arthritis. Additional relevant side effects included adrenal insufficiency (3/31 [9.7%]), fatigue (3/31 [9.7%]), diarrhea (2/31 [6.5%]), and type 1 diabetes 1/31 [3.2%]). These outcomes emphasize the importance of vigilance and monitoring when administering cemiplimab in the context of advanced cSCC.

Comment

Historically, advanced cSCC has had a bleak prognosis. The nature of the disease generally meant these patients could not be operated on due to metastatic spread or local invasion, and radiotherapy was not curative. The only option remaining was palliation, but new therapies have shown promise due to specific inherent characteristics of advanced cSCC; for example, the characteristic high mutation burden prevalent in advanced cSCC has paved the way for the emergence of immunotherapy as a promising avenue for intervention.¹⁰ Cemiplimab in particular has emerged as a feasible treatment for patients who would otherwise be confined to palliation. Our findings derived from a local cohort reinforce this notion, with a remarkable 83.9% (26/31) exhibiting a favorable response to cemiplimab. Although this local sample of 31 patients is small in absolute terms, in the context of the trial with 59 participants⁷ that gained global approval for the use of cemiplimab, our study adds a substantial amount of data to the growing body of evidence on the long-term efficacy of cemiplimab. Notably, our results emphasize the potential applicability of cemiplimab among elderly patients and individuals with lower performance statuses: populations historically excluded from immunotherapeutic considerations.

Immunotherapeutic AEs and Tolerance­—As anticipated with immunotherapeutic agents, cemiplimab is associated with AEs that also are seen in its counterparts.¹¹ A total of 77.4% (24/31) of our cohort reported immune-related AEs, although the severity warranted treatment discontinuation in only 10 (10/24 [41.7%]) patients, representing less than half of those who encountered side effects and less than a third of the entire cohort. Furthermore, most of these immune-related AEs were managed effectively with short courses of oral steroids, further substantiating the notion that cemiplimab is generally well tolerated across patients of diverse performance statuses. Even for patients who discontinued treatment early due to immune-related side effects, benefits persisted despite the partial course of cemiplimab. Of the 10 patients who discontinued treatment due to immune AEs, 6 (60%) demonstrated stable complete response, 2 (20%) experienced relapse after stopping cemiplimab, and 2 (20%) demonstrated a partial response with stable disease.

Challenges in the Most Vulnerable Patient—Of the 5 recorded mortalities, 2 (40%) were attributed to disease progression, while 3 (60%) occurred before response assessment could be undertaken. The 3 patients who died prior to response evaluation were among the most medically fragile in the cohort, characterized by extensive metastatic cSCC and major comorbidities that, in isolation, posed life-threatening risks. For individuals grappling with widespread metastatic cSCC and substantial life-threatening comorbidities, it is plausible that the necessary physiologic resilience necessary for cemiplimab therapy may be absent. We hypothesize that an immune reconstitution syndrome–like response may be responsible for this early mortality, and these patients may lack the necessary physiological resilience to tolerate this response. This subset of patients warrants careful consideration when considering therapy with cemiplimab.

Conclusion

In summary, our results underscore the efficacy of cemiplimab, as it supported a response in more than three-quarters of our patient cohort. Additionally, the associated AEs, similar to those with other programmed cell death protein 1 inhibitors, generally were manageable with medical intervention. Our findings corroborate earlier studies that have demonstrated the therapeutic potential of cemiplimab in advanced, inoperable cSCC management. In addition to efficacy, our results also suggest that cemiplimab holds promise as a therapeutic option for patients who might not be amenable to the stresses of general anesthesia, surgery, or prolonged hospitalization, although cemiplimab should likely be used with caution in patients with severe, life-threatening medical comorbidities and/or concurrent severe illness. Furthermore, our data demonstrate that the benefits persist not only beyond the completion of the full 2-year course, but also after partial treatment courses discontinued due to patient-specific factors. Future studies would be useful to better understand and optimize dose and duration of cemiplimab treatment to maximize therapeutic effectiveness while minimizing risk of immune-related AEs. Among individuals confronting advanced, inoperable cSCC, cemiplimab is emerging as a viable and beneficial intervention.

Compared to later-onset procedures, early diagnosis of melanoma using affordable skin biopsies can result in better patient outcomes, lower health care expenditures, and enhanced psychological well-being.¹ Numerous research and economic evaluations that highlight the possible advantages of early intervention in melanoma care lend support to this strategy. In health care systems, the cost of early identification and screening for skin cancer is a critical factor.¹ There has been debate in the literature regarding performing more frequent biopsies earlier for skin cancers, which may greatly improve patient outcomes at the expense of increased financial cost, compared with performing fewer biopsies, which reduces costs at the potential expense of managing later-onset melanoma.^1,2 We sought to summarize the current literature and address some considerations that may help bring more clarity to this topic.

According to a study of a large health care system, the average cost of a skin cancer screening visit was $150, of which $105 (70%) went toward the costs of the office visit and $45 (30%) went toward the costs of the biopsy.¹ In the changing health care landscape, it is crucial to take into account the possible compounded savings from early diagnosis and treatment. While biopsies do involve some expenses, consideration of immunotherapy costs for advanced melanoma also should be considered, as they provide an alternative viewpoint on the financial effects of melanoma treatment.² The use of new systemic treatments such as immunotherapy has led to a notable rise in Medicare users’ first-year melanoma treatment expenses. The average expense of treating stage IV melanoma rose from $47,739 in 2007 through 2012 to $117,450 in 2018 through 2019. This sharp rise highlights how much more expensive treating advanced melanoma is than performing biopsies for early detection and treatment. Hundreds of biopsies might be carried out for the cost of a single advanced melanoma therapy, possibly identifying several cases at an earlier, more manageable stage.²

Patient quality of life and survival rates also can be considerably improved by early melanoma detection through screening.³ Compared to patients with later-stage diagnoses, those with early-stage melanoma reported a higher overall quality of life. Better physical functioning and reduced levels of anxiety and sadness were linked to early identification using skin biopsies. Patients with more advanced melanoma who had later-onset procedures, on the other hand, experience worsening psychological symptoms and physical health.³

A cost-effectiveness analysis using a Markov cohort model compared the long-term economic impact of early detection and primary prevention of melanoma. It found that daily use of sunscreen could prevent a substantial number of new skin tumors and melanoma deaths and reduce health care costs when compared to early detection strategies such as performing extra biopsies.⁴ There already are programs across the United States that aim to educate the public on the importance of wearing sunscreen; this has, in turn, reduced the prevalence of skin cancer in certain communities. Primary prevention resulted in just 1364 new melanomas and more than $430 million in expenditures per 100,000 individuals, whereas early diagnosis produced 2446 new melanomas and more than $660 million in economic expenses per 100,000 individuals.⁴ It is imperative to acknowledge that skin biopsies remain a vital tool for the early identification of melanoma, particularly in high-risk groups.

By using technologies such as teledermoscopy, the cost-effectiveness of skin cancer referral and consultation can be further enhanced; for example, teledermoscopy for skin cancer referral and triage would result in faster clinical resolution at an average cost of $54.64 per case. This method may reduce the need for redundant in-person consultations and increase the effectiveness of melanoma identification.⁵

Large-scale public health initiatives in skin cancer prevention and early detection have the potential to be very effective, as evidenced by the War on Melanoma project at Oregon Health & Science University (Portland, Oregon). This all-encompassing strategy, which uses cutting-edge technologies, public education, and health care professional training, has improved melanoma outcomes and decreased health care expenditures with encouraging results.⁶

A few tactics can be used to best balance the costs of later-onset procedures and early skin biopsies. These include using advanced technologies such as teledermoscopy and dermoscopy, provider training to increase diagnostic accuracy, public health campaigns to raise awareness and promote prevention, and a comprehensive strategy combining targeted early detection strategies with primary prevention.^5,6 Health care systems can optimize the financial efficiency and clinical results of melanoma treatment by putting these principles into practice.

Compared to later-onset melanoma procedures, early skin biopsies typically are more cost-effective, produce better patient outcomes, and offer psychological advantages, even if they may have a higher initial cost. Health care systems can optimize the trade-off between early detection and cost effectiveness in melanoma management by putting sophisticated technology to use, enhancing provider training, and implementing focused screening programs.^5,6 To support evidence-based policies and guidelines, future research should assess the long-term economic impact of different melanoma prevention and detection measures.

Compared to later-onset procedures, early diagnosis of melanoma using affordable skin biopsies can result in better patient outcomes, lower health care expenditures, and enhanced psychological well-being.¹ Numerous research and economic evaluations that highlight the possible advantages of early intervention in melanoma care lend support to this strategy. In health care systems, the cost of early identification and screening for skin cancer is a critical factor.¹ There has been debate in the literature regarding performing more frequent biopsies earlier for skin cancers, which may greatly improve patient outcomes at the expense of increased financial cost, compared with performing fewer biopsies, which reduces costs at the potential expense of managing later-onset melanoma.^1,2 We sought to summarize the current literature and address some considerations that may help bring more clarity to this topic.

According to a study of a large health care system, the average cost of a skin cancer screening visit was $150, of which $105 (70%) went toward the costs of the office visit and $45 (30%) went toward the costs of the biopsy.¹ In the changing health care landscape, it is crucial to take into account the possible compounded savings from early diagnosis and treatment. While biopsies do involve some expenses, consideration of immunotherapy costs for advanced melanoma also should be considered, as they provide an alternative viewpoint on the financial effects of melanoma treatment.² The use of new systemic treatments such as immunotherapy has led to a notable rise in Medicare users’ first-year melanoma treatment expenses. The average expense of treating stage IV melanoma rose from $47,739 in 2007 through 2012 to $117,450 in 2018 through 2019. This sharp rise highlights how much more expensive treating advanced melanoma is than performing biopsies for early detection and treatment. Hundreds of biopsies might be carried out for the cost of a single advanced melanoma therapy, possibly identifying several cases at an earlier, more manageable stage.²

Patient quality of life and survival rates also can be considerably improved by early melanoma detection through screening.³ Compared to patients with later-stage diagnoses, those with early-stage melanoma reported a higher overall quality of life. Better physical functioning and reduced levels of anxiety and sadness were linked to early identification using skin biopsies. Patients with more advanced melanoma who had later-onset procedures, on the other hand, experience worsening psychological symptoms and physical health.³

A cost-effectiveness analysis using a Markov cohort model compared the long-term economic impact of early detection and primary prevention of melanoma. It found that daily use of sunscreen could prevent a substantial number of new skin tumors and melanoma deaths and reduce health care costs when compared to early detection strategies such as performing extra biopsies.⁴ There already are programs across the United States that aim to educate the public on the importance of wearing sunscreen; this has, in turn, reduced the prevalence of skin cancer in certain communities. Primary prevention resulted in just 1364 new melanomas and more than $430 million in expenditures per 100,000 individuals, whereas early diagnosis produced 2446 new melanomas and more than $660 million in economic expenses per 100,000 individuals.⁴ It is imperative to acknowledge that skin biopsies remain a vital tool for the early identification of melanoma, particularly in high-risk groups.

By using technologies such as teledermoscopy, the cost-effectiveness of skin cancer referral and consultation can be further enhanced; for example, teledermoscopy for skin cancer referral and triage would result in faster clinical resolution at an average cost of $54.64 per case. This method may reduce the need for redundant in-person consultations and increase the effectiveness of melanoma identification.⁵

Large-scale public health initiatives in skin cancer prevention and early detection have the potential to be very effective, as evidenced by the War on Melanoma project at Oregon Health & Science University (Portland, Oregon). This all-encompassing strategy, which uses cutting-edge technologies, public education, and health care professional training, has improved melanoma outcomes and decreased health care expenditures with encouraging results.⁶

A few tactics can be used to best balance the costs of later-onset procedures and early skin biopsies. These include using advanced technologies such as teledermoscopy and dermoscopy, provider training to increase diagnostic accuracy, public health campaigns to raise awareness and promote prevention, and a comprehensive strategy combining targeted early detection strategies with primary prevention.^5,6 Health care systems can optimize the financial efficiency and clinical results of melanoma treatment by putting these principles into practice.

Compared to later-onset melanoma procedures, early skin biopsies typically are more cost-effective, produce better patient outcomes, and offer psychological advantages, even if they may have a higher initial cost. Health care systems can optimize the trade-off between early detection and cost effectiveness in melanoma management by putting sophisticated technology to use, enhancing provider training, and implementing focused screening programs.^5,6 To support evidence-based policies and guidelines, future research should assess the long-term economic impact of different melanoma prevention and detection measures.

Compared to later-onset procedures, early diagnosis of melanoma using affordable skin biopsies can result in better patient outcomes, lower health care expenditures, and enhanced psychological well-being.¹ Numerous research and economic evaluations that highlight the possible advantages of early intervention in melanoma care lend support to this strategy. In health care systems, the cost of early identification and screening for skin cancer is a critical factor.¹ There has been debate in the literature regarding performing more frequent biopsies earlier for skin cancers, which may greatly improve patient outcomes at the expense of increased financial cost, compared with performing fewer biopsies, which reduces costs at the potential expense of managing later-onset melanoma.^1,2 We sought to summarize the current literature and address some considerations that may help bring more clarity to this topic.

According to a study of a large health care system, the average cost of a skin cancer screening visit was $150, of which $105 (70%) went toward the costs of the office visit and $45 (30%) went toward the costs of the biopsy.¹ In the changing health care landscape, it is crucial to take into account the possible compounded savings from early diagnosis and treatment. While biopsies do involve some expenses, consideration of immunotherapy costs for advanced melanoma also should be considered, as they provide an alternative viewpoint on the financial effects of melanoma treatment.² The use of new systemic treatments such as immunotherapy has led to a notable rise in Medicare users’ first-year melanoma treatment expenses. The average expense of treating stage IV melanoma rose from $47,739 in 2007 through 2012 to $117,450 in 2018 through 2019. This sharp rise highlights how much more expensive treating advanced melanoma is than performing biopsies for early detection and treatment. Hundreds of biopsies might be carried out for the cost of a single advanced melanoma therapy, possibly identifying several cases at an earlier, more manageable stage.²

Patient quality of life and survival rates also can be considerably improved by early melanoma detection through screening.³ Compared to patients with later-stage diagnoses, those with early-stage melanoma reported a higher overall quality of life. Better physical functioning and reduced levels of anxiety and sadness were linked to early identification using skin biopsies. Patients with more advanced melanoma who had later-onset procedures, on the other hand, experience worsening psychological symptoms and physical health.³

A cost-effectiveness analysis using a Markov cohort model compared the long-term economic impact of early detection and primary prevention of melanoma. It found that daily use of sunscreen could prevent a substantial number of new skin tumors and melanoma deaths and reduce health care costs when compared to early detection strategies such as performing extra biopsies.⁴ There already are programs across the United States that aim to educate the public on the importance of wearing sunscreen; this has, in turn, reduced the prevalence of skin cancer in certain communities. Primary prevention resulted in just 1364 new melanomas and more than $430 million in expenditures per 100,000 individuals, whereas early diagnosis produced 2446 new melanomas and more than $660 million in economic expenses per 100,000 individuals.⁴ It is imperative to acknowledge that skin biopsies remain a vital tool for the early identification of melanoma, particularly in high-risk groups.

By using technologies such as teledermoscopy, the cost-effectiveness of skin cancer referral and consultation can be further enhanced; for example, teledermoscopy for skin cancer referral and triage would result in faster clinical resolution at an average cost of $54.64 per case. This method may reduce the need for redundant in-person consultations and increase the effectiveness of melanoma identification.⁵

Large-scale public health initiatives in skin cancer prevention and early detection have the potential to be very effective, as evidenced by the War on Melanoma project at Oregon Health & Science University (Portland, Oregon). This all-encompassing strategy, which uses cutting-edge technologies, public education, and health care professional training, has improved melanoma outcomes and decreased health care expenditures with encouraging results.⁶

A few tactics can be used to best balance the costs of later-onset procedures and early skin biopsies. These include using advanced technologies such as teledermoscopy and dermoscopy, provider training to increase diagnostic accuracy, public health campaigns to raise awareness and promote prevention, and a comprehensive strategy combining targeted early detection strategies with primary prevention.^5,6 Health care systems can optimize the financial efficiency and clinical results of melanoma treatment by putting these principles into practice.

Compared to later-onset melanoma procedures, early skin biopsies typically are more cost-effective, produce better patient outcomes, and offer psychological advantages, even if they may have a higher initial cost. Health care systems can optimize the trade-off between early detection and cost effectiveness in melanoma management by putting sophisticated technology to use, enhancing provider training, and implementing focused screening programs.^5,6 To support evidence-based policies and guidelines, future research should assess the long-term economic impact of different melanoma prevention and detection measures.

A 72-year-old man with a history of multiple cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), presented to the dermatology clinic for a regularly scheduled full-body skin examination. His family history was negative for malignancy, but due to his personal history of both primary internal cancers and skin cancers, the patient previously had been referred by dermatology to a medical geneticist for evaluation. He tested positive for a pathogenic POT1 (protection of telomeres 1) variant associated with tumor predisposition, which most often is associated with cutaneous melanoma, chronic lymphocytic leukemia (CLL), angiosarcoma, and gliomas.¹

At the current presentation, physical examination revealed a small, asymmetric, pink papule on the superior thoracic spine. A biopsy of the lesion was performed (Figure 1). Pathology demonstrated cornifying cystic structures with a granulomatous response at the surface of the tumor, ductal differentiation with depth, and infiltrative strands and cords of hyperchromatic cells within a collagenous stroma at the base of the specimen (Figures 2A and 2B). One unusual finding was the presence of prominent clear-cell change within the superficial portion of the neoplasm (Figure 2C). Immunohistochemical stains revealed strong p63 and p40 positivity. Epithelial membrane antigen staining was positive in the hyperchromatic strands and cords with depth but not in the clear-cell superficial portion. Similarly, periodic acid–Schiff–positive material increased within tumor cells in proportion to depth of infiltration. Additional immunohistochemical staining showed carcinoembryonic antigen was largely negative (with rare positivity in a few ductal lumina), with negative results for S100, SOX10, CD117, BerEP4, factor XIIIa, CD34, and cytokeratin 7 (Figures 2D and 2E).

The differential diagnoses included trichilemmal carcinoma (which may manifest with CD34 expression),² clear cell BCC, adenoid cystic carcinoma (tubular variant), sebaceous carcinoma, and eccrine carcinoma. Importantly, the patient was under continuous oncologic surveillance, with no evidence of a primary internal tumor to suggest metastasis. Despite negative carcinoembryonic antigen staining, the immunohistochemical and histopathologic findings fit best with a primary cutaneous malignant eccrine tumor, specifically microcystic adnexal carcinoma (MAC), in which p63 typically stains peripheral cells but solid variants have been described.³

Eccrine carcinoma is exceedingly rare, reported in 0.01% of diagnosed cutaneous malignancies, and demonstrates overlapping features to other malignant eccrine tumors. It possesses an inconsistent immunohistochemical staining profile, making the distinction from other malignant sweat gland tumors challenging.⁴ Given that the morphologic features were otherwise classic for MAC in our patient, we favored a clear-cell variant.

Sixteen years prior to the current presentation, our patient presented to urology with a history of prostatitis and increasing prostate-specific antigen levels. Biopsies were negative until prostate-specific antigen reached 13 ng/mL, confirming stage 1A prostate cancer. The patient subsequently underwent a robot-assisted radical prostatectomy. At age 63 years, dysphagia that was unresponsive to antibiotics led to a tonsillar biopsy revealing T2N2bM0 stage IVA SCC of the right tonsil with confirmed HPV type 16 with extracapsular extension. The patient underwent transoral robotic radical tonsillectomy and right neck dissection, followed by adjuvant chemoradiation consisting of intensity-modulated radiation therapy (IMRT) to a total dose of 63 Gy in 33 fractions, with concurrent weekly cisplatin. At age 67 years, dyspepsia, dysphagia, pyrosis, and gastroesophageal reflux prompted endoscopy, revealing T1aNxMx esophageal adenocarcinoma. Three months later, the patient underwent laparoscopic-assisted esophagectomy, with no recurrence. At age 68 years, an atypical intramelanocytic proliferation was found on the left cheek and was treated with Mohs micrographic surgery.

At age 71 years, acral lentiginous malignant melanoma (Breslow thickness 0.8 mm; Clark level IV; American Joint Committee on Cancer T1b) was diagnosed on the left plantar foot and treated with Mohs micrographic surgery. Sentinel lymph node biopsy was negative. Squamous cell carcinoma in situ on the frontal scalp and nodular BCC on the right upper back also were diagnosed.

While there are no guidelines for surveillance of individuals with POT1, recommendations were given in consensus from a medical genetics team,¹ including comprehensive monitoring—specifically baseline imaging utilizing brain and full-body magnetic resonance imaging. Furthermore, considering the crucial role of POT1 in maintaining telomeres, it was advised to measure telomere length as part of the surveillance process. Given the patient’s susceptibility to CLL, routine complete blood count assessments were recommended. Additionally, we advised close monitoring for seizures and consideration of genetic testing in first-degree relatives.

Literature Review

Given our patient’s history of multiple skin cancers, including the most recent MAC, we sought to conduct a review of the literature to evaluate existing skin cancer associations and reports for patients with known POT1 mutations to guide recommendations for dermatologic surveillance (Table). A search of PubMed articles indexed for MEDLINE through April 2023 using the terms microcystic adnexal carcinoma, POT1, melanoma, basal cell carcinoma, squamous cell carcinoma, and skin cancer yielded no reported cases of MAC associated with POT1 mutations. POT1 is one of 6 proteins (TERF1, TERF2, RAP1, TIN2, TPP1, and POT1) belonging to the shelterin complex, which plays a crucial role in telomeric DNA remodeling and regulation of telomere length.⁵ Mutation in the POT1 gene disrupts the shelterin complex, causing telomeres to become elongated and unstable, resulting in chromosomal abnormalities and promoting cancer development.⁵

While our literature review did not reveal any associations between the shelterin complex genes and MAC, mutations in the POT1 gene have been studied in other types of skin cancer, particularly melanoma.¹ One of the earliest studies was conducted in 2014 by Shi et al,⁶ in which whole-exome sequencing was performed on families with a history of melanoma. Multiple POT1 gene pathogenic variants associated with increased telomere length and fragility were identified in unrelated families. Subsequent studies have confirmed POT1 variants in melanoma-prone families,⁷ supporting an association between increased telomere length and melanoma risk^8-11; however, other studies have yielded nonsignificant findings.^12,13 Further investigation also has identified morphologic characteristics consistent with POT1 mutation, including spitzoid morphology.¹⁴

The association between POT1 mutations and nonmelanoma skin cancers has been relatively understudied. While a few studies have explored this link, results have shown mixed findings. Some studies have suggested a potential role for POT1 mutations in cutaneous SCC risk,¹⁵ while other studies have shown no significant associations for both BCC and SCC risk and telomere gene mutations.¹⁶ Additionally, mRNA levels of POT1 were upregulated in BCC cases compared to normal tissue in a gene expression.¹⁷

Comment

In the literature, POT1 mutations are well established as high-penetrance alterations associated with melanoma.^9,18,19 However, the correlation between POT1 and other forms of skin cancer is not yet delineated. Recent insights suggest that POT1 mutations play a major role in promoting melanoma progression through telomere elongation, an established driver of melanoma progression, thereby extending the proliferative capacity of incipient cancer cells.²⁰ This notion is supported by observations of increased telomere length in melanomaprone families with POT1 mutations. Given this association, research has focused on examining the relationship between telomere length and skin cancer.

Several studies have examined the relationship between telomere length and the risk for various types of skin cancer, including melanoma, BCC, and SCC. Prior investigations have suggested that shorter telomere length is associated with a decreased risk for melanoma and an increased risk for BCC, while no significant association has been observed for SCC.¹⁶ However, subsequent reports analyzing POT1 variants have failed to reveal any conclusive associations between BCC and SCC and telomere length.^16,21

In contrast, other genetic variants associated with melanoma susceptibility have demonstrated notable associations with BCC and SCC; for instance, the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene, which is the first gene linked to high-risk familial melanoma, exhibits an increased presence of mutations in individuals with BCC and SCC.²² Similarly, the MC1R (melanocortin 1 receptor) variant, a gene involved in human pigmentation and known to increase the risk for melanoma, carries a statistically significantly higher risk for BCC (summary odds ratio, 1.39; 95% CI, 1.15-1.69) and SCC (summary odds ratio, 1.61; 95% CI, 1.35-1.91) when at least one variant is present and an even greater risk with 2 or more variants.²³

Considering the potential importance of POT1 mutations and their association with melanoma, as well as the inconsistencies surrounding POT1 mutations and their associations with BCC and SCC, further research may clarify the impact of POT1 mutations on the development and progression of different types of skin cancers and improve understanding of the complex interplay among telomere length, genetic variants, and skin cancer susceptibility. Given the established risk for melanoma with POT1 mutations, regular dermatology surveillance seems prudent. Dermatologists should consider referring patients with multiple skin cancers (especially melanoma) and any strong family history of internal malignancies to genetic testing for POT1. Though melanoma, CLL, angiosarcoma, and gliomas are the most commonly associated malignancies with POT1 mutations, as our case demonstrates, presentations can be heterogeneous, and the spectrum of malignancies associated with POT1 may be more expansive than previously thought.

For our patient, the current surveillance plan is fullbody skin examinations every 3 months. Given no prior family history of malignancies, presumably our patient’s case was a spontaneous mutation. Interestingly, despite his many primary cancer diagnoses and metastases, our patient has responded well to all treatments without recurrence. It is unclear if these characteristics and treatment successes are features of POT1associated cancers. Further research is needed to refine recommendations for screening and management of patients with identified POT1 mutations.

Conclusion

This case report highlights a rare occurrence of MAC in a patient with a POT1 mutation. Given the limited research conducted on investigating POT1 mutations and skin cancer, it is important to consider various forms of skin cancer, in addition to melanoma, when treating patients with a POT1 mutation.

A 72-year-old man with a history of multiple cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), presented to the dermatology clinic for a regularly scheduled full-body skin examination. His family history was negative for malignancy, but due to his personal history of both primary internal cancers and skin cancers, the patient previously had been referred by dermatology to a medical geneticist for evaluation. He tested positive for a pathogenic POT1 (protection of telomeres 1) variant associated with tumor predisposition, which most often is associated with cutaneous melanoma, chronic lymphocytic leukemia (CLL), angiosarcoma, and gliomas.¹

At the current presentation, physical examination revealed a small, asymmetric, pink papule on the superior thoracic spine. A biopsy of the lesion was performed (Figure 1). Pathology demonstrated cornifying cystic structures with a granulomatous response at the surface of the tumor, ductal differentiation with depth, and infiltrative strands and cords of hyperchromatic cells within a collagenous stroma at the base of the specimen (Figures 2A and 2B). One unusual finding was the presence of prominent clear-cell change within the superficial portion of the neoplasm (Figure 2C). Immunohistochemical stains revealed strong p63 and p40 positivity. Epithelial membrane antigen staining was positive in the hyperchromatic strands and cords with depth but not in the clear-cell superficial portion. Similarly, periodic acid–Schiff–positive material increased within tumor cells in proportion to depth of infiltration. Additional immunohistochemical staining showed carcinoembryonic antigen was largely negative (with rare positivity in a few ductal lumina), with negative results for S100, SOX10, CD117, BerEP4, factor XIIIa, CD34, and cytokeratin 7 (Figures 2D and 2E).

The differential diagnoses included trichilemmal carcinoma (which may manifest with CD34 expression),² clear cell BCC, adenoid cystic carcinoma (tubular variant), sebaceous carcinoma, and eccrine carcinoma. Importantly, the patient was under continuous oncologic surveillance, with no evidence of a primary internal tumor to suggest metastasis. Despite negative carcinoembryonic antigen staining, the immunohistochemical and histopathologic findings fit best with a primary cutaneous malignant eccrine tumor, specifically microcystic adnexal carcinoma (MAC), in which p63 typically stains peripheral cells but solid variants have been described.³

Eccrine carcinoma is exceedingly rare, reported in 0.01% of diagnosed cutaneous malignancies, and demonstrates overlapping features to other malignant eccrine tumors. It possesses an inconsistent immunohistochemical staining profile, making the distinction from other malignant sweat gland tumors challenging.⁴ Given that the morphologic features were otherwise classic for MAC in our patient, we favored a clear-cell variant.

Sixteen years prior to the current presentation, our patient presented to urology with a history of prostatitis and increasing prostate-specific antigen levels. Biopsies were negative until prostate-specific antigen reached 13 ng/mL, confirming stage 1A prostate cancer. The patient subsequently underwent a robot-assisted radical prostatectomy. At age 63 years, dysphagia that was unresponsive to antibiotics led to a tonsillar biopsy revealing T2N2bM0 stage IVA SCC of the right tonsil with confirmed HPV type 16 with extracapsular extension. The patient underwent transoral robotic radical tonsillectomy and right neck dissection, followed by adjuvant chemoradiation consisting of intensity-modulated radiation therapy (IMRT) to a total dose of 63 Gy in 33 fractions, with concurrent weekly cisplatin. At age 67 years, dyspepsia, dysphagia, pyrosis, and gastroesophageal reflux prompted endoscopy, revealing T1aNxMx esophageal adenocarcinoma. Three months later, the patient underwent laparoscopic-assisted esophagectomy, with no recurrence. At age 68 years, an atypical intramelanocytic proliferation was found on the left cheek and was treated with Mohs micrographic surgery.

At age 71 years, acral lentiginous malignant melanoma (Breslow thickness 0.8 mm; Clark level IV; American Joint Committee on Cancer T1b) was diagnosed on the left plantar foot and treated with Mohs micrographic surgery. Sentinel lymph node biopsy was negative. Squamous cell carcinoma in situ on the frontal scalp and nodular BCC on the right upper back also were diagnosed.

While there are no guidelines for surveillance of individuals with POT1, recommendations were given in consensus from a medical genetics team,¹ including comprehensive monitoring—specifically baseline imaging utilizing brain and full-body magnetic resonance imaging. Furthermore, considering the crucial role of POT1 in maintaining telomeres, it was advised to measure telomere length as part of the surveillance process. Given the patient’s susceptibility to CLL, routine complete blood count assessments were recommended. Additionally, we advised close monitoring for seizures and consideration of genetic testing in first-degree relatives.

Literature Review

Given our patient’s history of multiple skin cancers, including the most recent MAC, we sought to conduct a review of the literature to evaluate existing skin cancer associations and reports for patients with known POT1 mutations to guide recommendations for dermatologic surveillance (Table). A search of PubMed articles indexed for MEDLINE through April 2023 using the terms microcystic adnexal carcinoma, POT1, melanoma, basal cell carcinoma, squamous cell carcinoma, and skin cancer yielded no reported cases of MAC associated with POT1 mutations. POT1 is one of 6 proteins (TERF1, TERF2, RAP1, TIN2, TPP1, and POT1) belonging to the shelterin complex, which plays a crucial role in telomeric DNA remodeling and regulation of telomere length.⁵ Mutation in the POT1 gene disrupts the shelterin complex, causing telomeres to become elongated and unstable, resulting in chromosomal abnormalities and promoting cancer development.⁵

While our literature review did not reveal any associations between the shelterin complex genes and MAC, mutations in the POT1 gene have been studied in other types of skin cancer, particularly melanoma.¹ One of the earliest studies was conducted in 2014 by Shi et al,⁶ in which whole-exome sequencing was performed on families with a history of melanoma. Multiple POT1 gene pathogenic variants associated with increased telomere length and fragility were identified in unrelated families. Subsequent studies have confirmed POT1 variants in melanoma-prone families,⁷ supporting an association between increased telomere length and melanoma risk^8-11; however, other studies have yielded nonsignificant findings.^12,13 Further investigation also has identified morphologic characteristics consistent with POT1 mutation, including spitzoid morphology.¹⁴

The association between POT1 mutations and nonmelanoma skin cancers has been relatively understudied. While a few studies have explored this link, results have shown mixed findings. Some studies have suggested a potential role for POT1 mutations in cutaneous SCC risk,¹⁵ while other studies have shown no significant associations for both BCC and SCC risk and telomere gene mutations.¹⁶ Additionally, mRNA levels of POT1 were upregulated in BCC cases compared to normal tissue in a gene expression.¹⁷

Comment

In the literature, POT1 mutations are well established as high-penetrance alterations associated with melanoma.^9,18,19 However, the correlation between POT1 and other forms of skin cancer is not yet delineated. Recent insights suggest that POT1 mutations play a major role in promoting melanoma progression through telomere elongation, an established driver of melanoma progression, thereby extending the proliferative capacity of incipient cancer cells.²⁰ This notion is supported by observations of increased telomere length in melanomaprone families with POT1 mutations. Given this association, research has focused on examining the relationship between telomere length and skin cancer.

Several studies have examined the relationship between telomere length and the risk for various types of skin cancer, including melanoma, BCC, and SCC. Prior investigations have suggested that shorter telomere length is associated with a decreased risk for melanoma and an increased risk for BCC, while no significant association has been observed for SCC.¹⁶ However, subsequent reports analyzing POT1 variants have failed to reveal any conclusive associations between BCC and SCC and telomere length.^16,21

In contrast, other genetic variants associated with melanoma susceptibility have demonstrated notable associations with BCC and SCC; for instance, the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene, which is the first gene linked to high-risk familial melanoma, exhibits an increased presence of mutations in individuals with BCC and SCC.²² Similarly, the MC1R (melanocortin 1 receptor) variant, a gene involved in human pigmentation and known to increase the risk for melanoma, carries a statistically significantly higher risk for BCC (summary odds ratio, 1.39; 95% CI, 1.15-1.69) and SCC (summary odds ratio, 1.61; 95% CI, 1.35-1.91) when at least one variant is present and an even greater risk with 2 or more variants.²³

Considering the potential importance of POT1 mutations and their association with melanoma, as well as the inconsistencies surrounding POT1 mutations and their associations with BCC and SCC, further research may clarify the impact of POT1 mutations on the development and progression of different types of skin cancers and improve understanding of the complex interplay among telomere length, genetic variants, and skin cancer susceptibility. Given the established risk for melanoma with POT1 mutations, regular dermatology surveillance seems prudent. Dermatologists should consider referring patients with multiple skin cancers (especially melanoma) and any strong family history of internal malignancies to genetic testing for POT1. Though melanoma, CLL, angiosarcoma, and gliomas are the most commonly associated malignancies with POT1 mutations, as our case demonstrates, presentations can be heterogeneous, and the spectrum of malignancies associated with POT1 may be more expansive than previously thought.

For our patient, the current surveillance plan is fullbody skin examinations every 3 months. Given no prior family history of malignancies, presumably our patient’s case was a spontaneous mutation. Interestingly, despite his many primary cancer diagnoses and metastases, our patient has responded well to all treatments without recurrence. It is unclear if these characteristics and treatment successes are features of POT1associated cancers. Further research is needed to refine recommendations for screening and management of patients with identified POT1 mutations.

Conclusion

This case report highlights a rare occurrence of MAC in a patient with a POT1 mutation. Given the limited research conducted on investigating POT1 mutations and skin cancer, it is important to consider various forms of skin cancer, in addition to melanoma, when treating patients with a POT1 mutation.

A 72-year-old man with a history of multiple cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), presented to the dermatology clinic for a regularly scheduled full-body skin examination. His family history was negative for malignancy, but due to his personal history of both primary internal cancers and skin cancers, the patient previously had been referred by dermatology to a medical geneticist for evaluation. He tested positive for a pathogenic POT1 (protection of telomeres 1) variant associated with tumor predisposition, which most often is associated with cutaneous melanoma, chronic lymphocytic leukemia (CLL), angiosarcoma, and gliomas.¹

At the current presentation, physical examination revealed a small, asymmetric, pink papule on the superior thoracic spine. A biopsy of the lesion was performed (Figure 1). Pathology demonstrated cornifying cystic structures with a granulomatous response at the surface of the tumor, ductal differentiation with depth, and infiltrative strands and cords of hyperchromatic cells within a collagenous stroma at the base of the specimen (Figures 2A and 2B). One unusual finding was the presence of prominent clear-cell change within the superficial portion of the neoplasm (Figure 2C). Immunohistochemical stains revealed strong p63 and p40 positivity. Epithelial membrane antigen staining was positive in the hyperchromatic strands and cords with depth but not in the clear-cell superficial portion. Similarly, periodic acid–Schiff–positive material increased within tumor cells in proportion to depth of infiltration. Additional immunohistochemical staining showed carcinoembryonic antigen was largely negative (with rare positivity in a few ductal lumina), with negative results for S100, SOX10, CD117, BerEP4, factor XIIIa, CD34, and cytokeratin 7 (Figures 2D and 2E).

The differential diagnoses included trichilemmal carcinoma (which may manifest with CD34 expression),² clear cell BCC, adenoid cystic carcinoma (tubular variant), sebaceous carcinoma, and eccrine carcinoma. Importantly, the patient was under continuous oncologic surveillance, with no evidence of a primary internal tumor to suggest metastasis. Despite negative carcinoembryonic antigen staining, the immunohistochemical and histopathologic findings fit best with a primary cutaneous malignant eccrine tumor, specifically microcystic adnexal carcinoma (MAC), in which p63 typically stains peripheral cells but solid variants have been described.³

Eccrine carcinoma is exceedingly rare, reported in 0.01% of diagnosed cutaneous malignancies, and demonstrates overlapping features to other malignant eccrine tumors. It possesses an inconsistent immunohistochemical staining profile, making the distinction from other malignant sweat gland tumors challenging.⁴ Given that the morphologic features were otherwise classic for MAC in our patient, we favored a clear-cell variant.

Sixteen years prior to the current presentation, our patient presented to urology with a history of prostatitis and increasing prostate-specific antigen levels. Biopsies were negative until prostate-specific antigen reached 13 ng/mL, confirming stage 1A prostate cancer. The patient subsequently underwent a robot-assisted radical prostatectomy. At age 63 years, dysphagia that was unresponsive to antibiotics led to a tonsillar biopsy revealing T2N2bM0 stage IVA SCC of the right tonsil with confirmed HPV type 16 with extracapsular extension. The patient underwent transoral robotic radical tonsillectomy and right neck dissection, followed by adjuvant chemoradiation consisting of intensity-modulated radiation therapy (IMRT) to a total dose of 63 Gy in 33 fractions, with concurrent weekly cisplatin. At age 67 years, dyspepsia, dysphagia, pyrosis, and gastroesophageal reflux prompted endoscopy, revealing T1aNxMx esophageal adenocarcinoma. Three months later, the patient underwent laparoscopic-assisted esophagectomy, with no recurrence. At age 68 years, an atypical intramelanocytic proliferation was found on the left cheek and was treated with Mohs micrographic surgery.

At age 71 years, acral lentiginous malignant melanoma (Breslow thickness 0.8 mm; Clark level IV; American Joint Committee on Cancer T1b) was diagnosed on the left plantar foot and treated with Mohs micrographic surgery. Sentinel lymph node biopsy was negative. Squamous cell carcinoma in situ on the frontal scalp and nodular BCC on the right upper back also were diagnosed.

While there are no guidelines for surveillance of individuals with POT1, recommendations were given in consensus from a medical genetics team,¹ including comprehensive monitoring—specifically baseline imaging utilizing brain and full-body magnetic resonance imaging. Furthermore, considering the crucial role of POT1 in maintaining telomeres, it was advised to measure telomere length as part of the surveillance process. Given the patient’s susceptibility to CLL, routine complete blood count assessments were recommended. Additionally, we advised close monitoring for seizures and consideration of genetic testing in first-degree relatives.

Literature Review

Given our patient’s history of multiple skin cancers, including the most recent MAC, we sought to conduct a review of the literature to evaluate existing skin cancer associations and reports for patients with known POT1 mutations to guide recommendations for dermatologic surveillance (Table). A search of PubMed articles indexed for MEDLINE through April 2023 using the terms microcystic adnexal carcinoma, POT1, melanoma, basal cell carcinoma, squamous cell carcinoma, and skin cancer yielded no reported cases of MAC associated with POT1 mutations. POT1 is one of 6 proteins (TERF1, TERF2, RAP1, TIN2, TPP1, and POT1) belonging to the shelterin complex, which plays a crucial role in telomeric DNA remodeling and regulation of telomere length.⁵ Mutation in the POT1 gene disrupts the shelterin complex, causing telomeres to become elongated and unstable, resulting in chromosomal abnormalities and promoting cancer development.⁵

While our literature review did not reveal any associations between the shelterin complex genes and MAC, mutations in the POT1 gene have been studied in other types of skin cancer, particularly melanoma.¹ One of the earliest studies was conducted in 2014 by Shi et al,⁶ in which whole-exome sequencing was performed on families with a history of melanoma. Multiple POT1 gene pathogenic variants associated with increased telomere length and fragility were identified in unrelated families. Subsequent studies have confirmed POT1 variants in melanoma-prone families,⁷ supporting an association between increased telomere length and melanoma risk^8-11; however, other studies have yielded nonsignificant findings.^12,13 Further investigation also has identified morphologic characteristics consistent with POT1 mutation, including spitzoid morphology.¹⁴

The association between POT1 mutations and nonmelanoma skin cancers has been relatively understudied. While a few studies have explored this link, results have shown mixed findings. Some studies have suggested a potential role for POT1 mutations in cutaneous SCC risk,¹⁵ while other studies have shown no significant associations for both BCC and SCC risk and telomere gene mutations.¹⁶ Additionally, mRNA levels of POT1 were upregulated in BCC cases compared to normal tissue in a gene expression.¹⁷

Comment

In the literature, POT1 mutations are well established as high-penetrance alterations associated with melanoma.^9,18,19 However, the correlation between POT1 and other forms of skin cancer is not yet delineated. Recent insights suggest that POT1 mutations play a major role in promoting melanoma progression through telomere elongation, an established driver of melanoma progression, thereby extending the proliferative capacity of incipient cancer cells.²⁰ This notion is supported by observations of increased telomere length in melanomaprone families with POT1 mutations. Given this association, research has focused on examining the relationship between telomere length and skin cancer.

Several studies have examined the relationship between telomere length and the risk for various types of skin cancer, including melanoma, BCC, and SCC. Prior investigations have suggested that shorter telomere length is associated with a decreased risk for melanoma and an increased risk for BCC, while no significant association has been observed for SCC.¹⁶ However, subsequent reports analyzing POT1 variants have failed to reveal any conclusive associations between BCC and SCC and telomere length.^16,21

In contrast, other genetic variants associated with melanoma susceptibility have demonstrated notable associations with BCC and SCC; for instance, the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene, which is the first gene linked to high-risk familial melanoma, exhibits an increased presence of mutations in individuals with BCC and SCC.²² Similarly, the MC1R (melanocortin 1 receptor) variant, a gene involved in human pigmentation and known to increase the risk for melanoma, carries a statistically significantly higher risk for BCC (summary odds ratio, 1.39; 95% CI, 1.15-1.69) and SCC (summary odds ratio, 1.61; 95% CI, 1.35-1.91) when at least one variant is present and an even greater risk with 2 or more variants.²³

Considering the potential importance of POT1 mutations and their association with melanoma, as well as the inconsistencies surrounding POT1 mutations and their associations with BCC and SCC, further research may clarify the impact of POT1 mutations on the development and progression of different types of skin cancers and improve understanding of the complex interplay among telomere length, genetic variants, and skin cancer susceptibility. Given the established risk for melanoma with POT1 mutations, regular dermatology surveillance seems prudent. Dermatologists should consider referring patients with multiple skin cancers (especially melanoma) and any strong family history of internal malignancies to genetic testing for POT1. Though melanoma, CLL, angiosarcoma, and gliomas are the most commonly associated malignancies with POT1 mutations, as our case demonstrates, presentations can be heterogeneous, and the spectrum of malignancies associated with POT1 may be more expansive than previously thought.

For our patient, the current surveillance plan is fullbody skin examinations every 3 months. Given no prior family history of malignancies, presumably our patient’s case was a spontaneous mutation. Interestingly, despite his many primary cancer diagnoses and metastases, our patient has responded well to all treatments without recurrence. It is unclear if these characteristics and treatment successes are features of POT1associated cancers. Further research is needed to refine recommendations for screening and management of patients with identified POT1 mutations.

Conclusion

This case report highlights a rare occurrence of MAC in a patient with a POT1 mutation. Given the limited research conducted on investigating POT1 mutations and skin cancer, it is important to consider various forms of skin cancer, in addition to melanoma, when treating patients with a POT1 mutation.

THE DIAGNOSIS: Mycobacteria infection

Despite the initial biopsy for tissue culture showing no growth, a subsequent biopsy performed 1 month later yielded a positive result. Mycobacterium marinum was identified through organism genome sequencing. The patient was further treated by infectious disease with clarithromycin and ethambutol, with complete resolution of the lesions.

Although initial staining with acid-fast bacilli and tissue culture were negative, we suspected a diagnosis of mycobacterial infection with sporotrichoid spread of multiple nodular and ulcerated lesions that was unresponsive to antibiotics. Performing a tissue culture is crucial for diagnosing mycobacterial skin and soft-tissue infections, as an acid-fast bacilli stain alone cannot distinguish between different mycobacterial species. Lowenstein-Jensen agar is a selective medium specifically used for the culture and isolation of Mycobacterium species. The strict temperature requirement of 30 °C to 32 °C (86-89.6 °F) for the growth of this organism suggests that the infection predominantly affects the limbs, which tend to have a slightly lower temperature compared to the core of the body.¹ In our case, the histologic findings and clinical history suggested granulomatous involvement due to fungi or mycobacteria.

Cutaneous leishmaniasis is characterized by ulcers with possible accompanying nodular lymphangitis; however, the patient did not have relevant travel history. Leishmaniasis results from a parasite transmitted by a sandfly, with most cases occurring in Afghanistan, Algeria, Brazil, Iran, Pakistan, Peru, Saudi Arabia, and Syria.²

Ecthyma gangrenosum is characterized by tender necrotic plaques seen predominantly in immunocompromised patients and is associated with Pseudomonas aeruginosa bacteremia.³ Our patient had lesions present for a duration of 5 months, which is inconsistent with the more rapidly progressing course of ecthyma gangrenosum.

Leukocytoclastic vasculitis may manifest with palpable purpura of the lower extremities. An infectious trigger, such as Mycobacterium, may lead to a leukocytoclastic vasculitis. The histopathologic findings classically demonstrate neutrophil deposition in vessel walls, deposition of fibrin in the vessel lumen, and nuclear debris.⁴

Despite the presence of granulomatous changes in our patient, the presentation of ulcerated nodules in a sporotrichoid pattern on one extremity suggests a diagnosis of infectious etiology rather than sarcoidosis.

THE DIAGNOSIS: Mycobacteria infection

Despite the initial biopsy for tissue culture showing no growth, a subsequent biopsy performed 1 month later yielded a positive result. Mycobacterium marinum was identified through organism genome sequencing. The patient was further treated by infectious disease with clarithromycin and ethambutol, with complete resolution of the lesions.

Although initial staining with acid-fast bacilli and tissue culture were negative, we suspected a diagnosis of mycobacterial infection with sporotrichoid spread of multiple nodular and ulcerated lesions that was unresponsive to antibiotics. Performing a tissue culture is crucial for diagnosing mycobacterial skin and soft-tissue infections, as an acid-fast bacilli stain alone cannot distinguish between different mycobacterial species. Lowenstein-Jensen agar is a selective medium specifically used for the culture and isolation of Mycobacterium species. The strict temperature requirement of 30 °C to 32 °C (86-89.6 °F) for the growth of this organism suggests that the infection predominantly affects the limbs, which tend to have a slightly lower temperature compared to the core of the body.¹ In our case, the histologic findings and clinical history suggested granulomatous involvement due to fungi or mycobacteria.

Cutaneous leishmaniasis is characterized by ulcers with possible accompanying nodular lymphangitis; however, the patient did not have relevant travel history. Leishmaniasis results from a parasite transmitted by a sandfly, with most cases occurring in Afghanistan, Algeria, Brazil, Iran, Pakistan, Peru, Saudi Arabia, and Syria.²

Ecthyma gangrenosum is characterized by tender necrotic plaques seen predominantly in immunocompromised patients and is associated with Pseudomonas aeruginosa bacteremia.³ Our patient had lesions present for a duration of 5 months, which is inconsistent with the more rapidly progressing course of ecthyma gangrenosum.

Leukocytoclastic vasculitis may manifest with palpable purpura of the lower extremities. An infectious trigger, such as Mycobacterium, may lead to a leukocytoclastic vasculitis. The histopathologic findings classically demonstrate neutrophil deposition in vessel walls, deposition of fibrin in the vessel lumen, and nuclear debris.⁴

Despite the presence of granulomatous changes in our patient, the presentation of ulcerated nodules in a sporotrichoid pattern on one extremity suggests a diagnosis of infectious etiology rather than sarcoidosis.

THE DIAGNOSIS: Mycobacteria infection

Despite the initial biopsy for tissue culture showing no growth, a subsequent biopsy performed 1 month later yielded a positive result. Mycobacterium marinum was identified through organism genome sequencing. The patient was further treated by infectious disease with clarithromycin and ethambutol, with complete resolution of the lesions.

Although initial staining with acid-fast bacilli and tissue culture were negative, we suspected a diagnosis of mycobacterial infection with sporotrichoid spread of multiple nodular and ulcerated lesions that was unresponsive to antibiotics. Performing a tissue culture is crucial for diagnosing mycobacterial skin and soft-tissue infections, as an acid-fast bacilli stain alone cannot distinguish between different mycobacterial species. Lowenstein-Jensen agar is a selective medium specifically used for the culture and isolation of Mycobacterium species. The strict temperature requirement of 30 °C to 32 °C (86-89.6 °F) for the growth of this organism suggests that the infection predominantly affects the limbs, which tend to have a slightly lower temperature compared to the core of the body.¹ In our case, the histologic findings and clinical history suggested granulomatous involvement due to fungi or mycobacteria.

Cutaneous leishmaniasis is characterized by ulcers with possible accompanying nodular lymphangitis; however, the patient did not have relevant travel history. Leishmaniasis results from a parasite transmitted by a sandfly, with most cases occurring in Afghanistan, Algeria, Brazil, Iran, Pakistan, Peru, Saudi Arabia, and Syria.²

Ecthyma gangrenosum is characterized by tender necrotic plaques seen predominantly in immunocompromised patients and is associated with Pseudomonas aeruginosa bacteremia.³ Our patient had lesions present for a duration of 5 months, which is inconsistent with the more rapidly progressing course of ecthyma gangrenosum.

Leukocytoclastic vasculitis may manifest with palpable purpura of the lower extremities. An infectious trigger, such as Mycobacterium, may lead to a leukocytoclastic vasculitis. The histopathologic findings classically demonstrate neutrophil deposition in vessel walls, deposition of fibrin in the vessel lumen, and nuclear debris.⁴

Despite the presence of granulomatous changes in our patient, the presentation of ulcerated nodules in a sporotrichoid pattern on one extremity suggests a diagnosis of infectious etiology rather than sarcoidosis.

THE DIAGNOSIS: Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign, inflammatory vascular proliferation with lymphocytic and eosinophilic infiltration. Bleeding and pruritus associated with ALHE can substantially affect a patient’s quality of life, necessitating correct diagnosis and effective treatment.¹ The etiopathogenesis of ALHE is poorly understood, and it often is attributed to an underlying vascular malformation or local trauma. Vascular proliferation due to hyperestrogenemia could explain why pregnancy is considered a predisposing factor for ALHE.^1,2

Angiolymphoid hyperplasia with eosinophilia typically manifests with solitary or multiple pink to red-brown, dome-shaped papules or nodules occurring most frequently on the head and neck. Lesions may be either asymptomatic or associated with pruritus, pain, and spontaneous bleeding.¹ Dermoscopy is crucial to diagnosis. The most frequent dermoscopic findings include a polymorphic vascular pattern such as dotted and linear irregular vessels over a pink background, white lines, white dots, white structureless areas, and red-purple lacunae.^2,3 Histopathology will demonstrate a vascular proliferation with plump epithelioid endothelial cells showing abundant eosinophilic cytoplasm, accompanied by a variable lymphocytic and eosinophilic inflammatory infiltrate (Figure 1).¹

In our case, dermoscopic-histopathologic correlation suggested that the polymorphic vascular pattern and clods on a pink background corresponded to thin- and thick-walled vessels containing plump endothelial cells and intraluminal erythrocytes within the superficial and deep dermis. White structures could represent underlying fibrosis and altered dermal collagen due to vascular proliferation. The brown pigment network and peripheral brownish pigmentation were most likely secondary to increased melanin and accentuation of the pigment network in the setting of Fitzpatrick skin types IV to V, although pruritic trauma with postinflammatory hyperpigmentation may also have contributed, making dermoscopic-histopathologic correlation challenging.

Surgical excision is considered the primary treatment modality for ALHE, with the lowest recurrence rates.¹ Alternative therapeutic options include intralesional steroids, cryotherapy, sclerotherapy, radiofrequency, pulsed dye laser, and carbon dioxide laser, with varying efficacy reported.¹ Our patient was treated with a combination of a long-pulse Nd:YAG laser (pulse width of 30 ms) to target the vascular component, followed by a single session with an ablative Er:YAG laser. After 4 weeks, healing with good cosmetic results was observed (Figure 2). At 6-month follow-up, there was no recurrence of the lesions.

Kimura disease, often considered the closest differential diagnosis for ALHE, is a rare lymphoproliferative fibroinflammatory condition. Patients present with subcutaneous nodules on the head and neck, often associated with lymphadenopathy. Elevated serum IgE levels and peripheral blood eosinophilia are common.¹ Another consideration in the differential diagnosis is cutaneous bacillary angiomatosis caused by Bartonella species, a vascular proliferative condition that mostly affects individuals with HIV, transplant recipients, and those taking immunosuppressive medications.⁴ Pyogenic granuloma, also known as lobular capillary haemangioma, is another benign vascular proliferation that resembles ALHE. Clinically, it manifests as a solitary, painless, flesh-colored to erythematous papulonodule; however, multiple grouped lesions also can occur. The lesions often are associated with bleeding and erosions.⁵ Epithelioid hemangioendothelioma is a rare vascular tumor most frequently manifesting in the liver, lungs, or bones, and very rarely is limited to skin. Cutaneous epithelioid hemangioendothelioma mimics ALHE and may manifest as a solitary erythematous mass, multiple dome-shaped masses, or dermal nodules.⁶

THE DIAGNOSIS: Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign, inflammatory vascular proliferation with lymphocytic and eosinophilic infiltration. Bleeding and pruritus associated with ALHE can substantially affect a patient’s quality of life, necessitating correct diagnosis and effective treatment.¹ The etiopathogenesis of ALHE is poorly understood, and it often is attributed to an underlying vascular malformation or local trauma. Vascular proliferation due to hyperestrogenemia could explain why pregnancy is considered a predisposing factor for ALHE.^1,2

Angiolymphoid hyperplasia with eosinophilia typically manifests with solitary or multiple pink to red-brown, dome-shaped papules or nodules occurring most frequently on the head and neck. Lesions may be either asymptomatic or associated with pruritus, pain, and spontaneous bleeding.¹ Dermoscopy is crucial to diagnosis. The most frequent dermoscopic findings include a polymorphic vascular pattern such as dotted and linear irregular vessels over a pink background, white lines, white dots, white structureless areas, and red-purple lacunae.^2,3 Histopathology will demonstrate a vascular proliferation with plump epithelioid endothelial cells showing abundant eosinophilic cytoplasm, accompanied by a variable lymphocytic and eosinophilic inflammatory infiltrate (Figure 1).¹

In our case, dermoscopic-histopathologic correlation suggested that the polymorphic vascular pattern and clods on a pink background corresponded to thin- and thick-walled vessels containing plump endothelial cells and intraluminal erythrocytes within the superficial and deep dermis. White structures could represent underlying fibrosis and altered dermal collagen due to vascular proliferation. The brown pigment network and peripheral brownish pigmentation were most likely secondary to increased melanin and accentuation of the pigment network in the setting of Fitzpatrick skin types IV to V, although pruritic trauma with postinflammatory hyperpigmentation may also have contributed, making dermoscopic-histopathologic correlation challenging.

Surgical excision is considered the primary treatment modality for ALHE, with the lowest recurrence rates.¹ Alternative therapeutic options include intralesional steroids, cryotherapy, sclerotherapy, radiofrequency, pulsed dye laser, and carbon dioxide laser, with varying efficacy reported.¹ Our patient was treated with a combination of a long-pulse Nd:YAG laser (pulse width of 30 ms) to target the vascular component, followed by a single session with an ablative Er:YAG laser. After 4 weeks, healing with good cosmetic results was observed (Figure 2). At 6-month follow-up, there was no recurrence of the lesions.

Kimura disease, often considered the closest differential diagnosis for ALHE, is a rare lymphoproliferative fibroinflammatory condition. Patients present with subcutaneous nodules on the head and neck, often associated with lymphadenopathy. Elevated serum IgE levels and peripheral blood eosinophilia are common.¹ Another consideration in the differential diagnosis is cutaneous bacillary angiomatosis caused by Bartonella species, a vascular proliferative condition that mostly affects individuals with HIV, transplant recipients, and those taking immunosuppressive medications.⁴ Pyogenic granuloma, also known as lobular capillary haemangioma, is another benign vascular proliferation that resembles ALHE. Clinically, it manifests as a solitary, painless, flesh-colored to erythematous papulonodule; however, multiple grouped lesions also can occur. The lesions often are associated with bleeding and erosions.⁵ Epithelioid hemangioendothelioma is a rare vascular tumor most frequently manifesting in the liver, lungs, or bones, and very rarely is limited to skin. Cutaneous epithelioid hemangioendothelioma mimics ALHE and may manifest as a solitary erythematous mass, multiple dome-shaped masses, or dermal nodules.⁶

THE DIAGNOSIS: Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign, inflammatory vascular proliferation with lymphocytic and eosinophilic infiltration. Bleeding and pruritus associated with ALHE can substantially affect a patient’s quality of life, necessitating correct diagnosis and effective treatment.¹ The etiopathogenesis of ALHE is poorly understood, and it often is attributed to an underlying vascular malformation or local trauma. Vascular proliferation due to hyperestrogenemia could explain why pregnancy is considered a predisposing factor for ALHE.^1,2

Angiolymphoid hyperplasia with eosinophilia typically manifests with solitary or multiple pink to red-brown, dome-shaped papules or nodules occurring most frequently on the head and neck. Lesions may be either asymptomatic or associated with pruritus, pain, and spontaneous bleeding.¹ Dermoscopy is crucial to diagnosis. The most frequent dermoscopic findings include a polymorphic vascular pattern such as dotted and linear irregular vessels over a pink background, white lines, white dots, white structureless areas, and red-purple lacunae.^2,3 Histopathology will demonstrate a vascular proliferation with plump epithelioid endothelial cells showing abundant eosinophilic cytoplasm, accompanied by a variable lymphocytic and eosinophilic inflammatory infiltrate (Figure 1).¹

In our case, dermoscopic-histopathologic correlation suggested that the polymorphic vascular pattern and clods on a pink background corresponded to thin- and thick-walled vessels containing plump endothelial cells and intraluminal erythrocytes within the superficial and deep dermis. White structures could represent underlying fibrosis and altered dermal collagen due to vascular proliferation. The brown pigment network and peripheral brownish pigmentation were most likely secondary to increased melanin and accentuation of the pigment network in the setting of Fitzpatrick skin types IV to V, although pruritic trauma with postinflammatory hyperpigmentation may also have contributed, making dermoscopic-histopathologic correlation challenging.

Surgical excision is considered the primary treatment modality for ALHE, with the lowest recurrence rates.¹ Alternative therapeutic options include intralesional steroids, cryotherapy, sclerotherapy, radiofrequency, pulsed dye laser, and carbon dioxide laser, with varying efficacy reported.¹ Our patient was treated with a combination of a long-pulse Nd:YAG laser (pulse width of 30 ms) to target the vascular component, followed by a single session with an ablative Er:YAG laser. After 4 weeks, healing with good cosmetic results was observed (Figure 2). At 6-month follow-up, there was no recurrence of the lesions.

Kimura disease, often considered the closest differential diagnosis for ALHE, is a rare lymphoproliferative fibroinflammatory condition. Patients present with subcutaneous nodules on the head and neck, often associated with lymphadenopathy. Elevated serum IgE levels and peripheral blood eosinophilia are common.¹ Another consideration in the differential diagnosis is cutaneous bacillary angiomatosis caused by Bartonella species, a vascular proliferative condition that mostly affects individuals with HIV, transplant recipients, and those taking immunosuppressive medications.⁴ Pyogenic granuloma, also known as lobular capillary haemangioma, is another benign vascular proliferation that resembles ALHE. Clinically, it manifests as a solitary, painless, flesh-colored to erythematous papulonodule; however, multiple grouped lesions also can occur. The lesions often are associated with bleeding and erosions.⁵ Epithelioid hemangioendothelioma is a rare vascular tumor most frequently manifesting in the liver, lungs, or bones, and very rarely is limited to skin. Cutaneous epithelioid hemangioendothelioma mimics ALHE and may manifest as a solitary erythematous mass, multiple dome-shaped masses, or dermal nodules.⁶

Horse flies (Tabanidae) are hematophagous dipteran insects that feed on the blood of their hosts, including humans.¹ Their bites can cause minor cutaneous reactions (eg, urticaria) or, rarely, severe reactions such as anaphylaxis. They also are vectors of tularemia, which may manifest with cutaneous ulcers and systemic illness. In this article, we discuss identifying features of horse flies as well as clinical manifestations from bite reactions, symptomatic and emergency management, and strategies for prevention and control.

Morphology and Geographic Distribution

Horse flies, which can grow as large as 30 mm, can be identified by their brown or black bodies and characteristic large heads and proboscises, wing venation, large calypters, pulvilliform empodium between large pulvilli, and lack of bristles on the body.² Occasionally, their bodies may be gray, yellow, green, or blue, but this is less likely than in the other species of the Tabanidae family. Short hairs are present on the head and thorax. The eyes are large and often patterned, multicolored, and bright, though they also can exhibit shades of dark brown, gray, or black. There is variation in the appearance of male vs female horse flies: females have eyes that are widely spaced apart, while males have eyes that are closer together.² It is important to note the difference between male and female horseflies, as hematophagy is exhibited only by females.¹

Horse flies are found worldwide, with the exception of Hawaii, Greenland, and Iceland.^3,4 They are especially prevalent in warm and moist regions, as these conditions are optimal for breeding.^3-5 They tend to be active during the day and inactive at night due to a preference for sunlight and warmth.⁶ Due to this preference, horse flies’ seasonal activity depends on the climate; for many regions, activity persists from summer to early autumn.⁷

Clinical Manifestations and Treatment

Female horse flies use their mouthparts to pierce the host’s skin, inject saliva, and suck blood. The saliva contains anticoagulant properties. The bites are painful for the host, and various reactions can occur, including large urticarial wheals or papules at the site of the bite. Treatment for these minor cutaneous reactions is largely symptomatic. The bite site should be washed with soap and water; ice can be applied to help reduce inflammation.⁸ Oral antihistamines may be administered to reduce pruritus and treat urticaria. Topical steroids also can be prescribed for symptomatic relief. Acetaminophen and nonsteroidal anti-inflammatory drugs can be administered for pain control.⁸

While most cases of horse fly bites are minor, there have been reports of anaphylaxis.⁹ Horse fly bite–induced anaphylaxis can manifest as generalized itching, urticaria, and angioedema within minutes of being bitten. This may be followed by pharyngeal constriction, shortness of breath, nausea, vomiting, shivers, perspiration, and loss of consciousness.⁹ Anaphylaxis symptoms should be treated with immediate administration of intramuscular epinephrine.¹⁰

Pathogen Transmission, Prevention, and Control

Although horse flies have been found to carry numerous viruses, bacteria, and protozoa that affect other mammals, there is not enough evidence to suggest that they are vectors of transmission for humans for most diseases.^11,12 In particular, West Nile virus and Borrelia burgdorferi both have been found in horse flies, but there are no reports of transmission of these diseases to humans through their bites.¹²

Horse flies, their close cousins deer flies (specifically Chrysops discalis), and ticks are known vectors of Francisella tularensis.¹³ These bacteria cause tularemia, which can manifest with symptoms such as fever, headache, and malaise. Ulceroglandular tularemia is the most common manifestation, in which the patient develops a cutaneous ulceration at the site of the horse fly bite and exhibits associated tender regional lymphadenopathy.¹⁴ Exudative conjunctivitis, exudative pharyngitis, abdominal pain, diarrhea, vomiting, and severe bilateral pneumonia also are common symptoms. The most severe form of tularemia is systemic or typhoidal tularemia, which can manifest with fever, septic shock, and hepatosplenomegaly.¹⁴ The current treatment of choice for all forms of tularemia is intravenous gentamicin, with a recommended dosage of 5 mg/kg/d for 7 to 14 days; streptomycin is an acceptable alternative.^14-16 Ciprofloxacin is used less commonly and is reserved for milder disease. Incision and drainage of the affected lymph nodes also may be necessary.¹⁴ It is important to promptly identify and treat tularemia, as the mortality rate can be as high as 50% for untreated disease, especially in patients with systemic symptoms. Even after treatment, many patients exhibit residual scarring at the site of the ulcer, as well as lung, kidney, and muscle damage.¹⁴

It is advised to avoid contact with horse flies due to the range of symptom severity caused by their bites, but avoidance and control can be difficult. Malaise traps, consisting of a tent and polyester netting, can be used to capture the insects.¹⁷ Octenol has been shown to be effective for attracting horse flies and can be applied to the trap in order to increase its effectiveness.¹⁸ A Manitoba horse fly trap is a modified version of the Malaise trap that contains a suspended dark sphere to further attract horse flies.¹⁹ Patients also should be instructed to wear long-sleeved shirts and pants when outdoors in areas with horse flies to avoid contact, and application of DEET (N,N-diethylmeta-toluamide), picaridin, citronella, or geraniol-based repellents also can be effective in reducing exposure.²⁰

Final Thoughts

Horse flies are large, blood‑feeding dipteran insects whose bites usually produce painful local reactions. Although most bites are benign, they rarely can cause anaphylaxis, and certain Tabanidae insects can transmit Francisella tularensis; therefore, clinicians should consider the risk for tularemia infection in patients presenting with horse fly bites and start appropriate antibiotic therapy when indicated. Due to the risks, prevention of bites and reduction of contact with horse flies via protective clothing, repellents, and trapping methods is recommended. Patients should be advised on bite care and to seek urgent care for systemic symptoms or rapidly progressive local signs.

Horse flies (Tabanidae) are hematophagous dipteran insects that feed on the blood of their hosts, including humans.¹ Their bites can cause minor cutaneous reactions (eg, urticaria) or, rarely, severe reactions such as anaphylaxis. They also are vectors of tularemia, which may manifest with cutaneous ulcers and systemic illness. In this article, we discuss identifying features of horse flies as well as clinical manifestations from bite reactions, symptomatic and emergency management, and strategies for prevention and control.

Morphology and Geographic Distribution

Horse flies, which can grow as large as 30 mm, can be identified by their brown or black bodies and characteristic large heads and proboscises, wing venation, large calypters, pulvilliform empodium between large pulvilli, and lack of bristles on the body.² Occasionally, their bodies may be gray, yellow, green, or blue, but this is less likely than in the other species of the Tabanidae family. Short hairs are present on the head and thorax. The eyes are large and often patterned, multicolored, and bright, though they also can exhibit shades of dark brown, gray, or black. There is variation in the appearance of male vs female horse flies: females have eyes that are widely spaced apart, while males have eyes that are closer together.² It is important to note the difference between male and female horseflies, as hematophagy is exhibited only by females.¹

Horse flies are found worldwide, with the exception of Hawaii, Greenland, and Iceland.^3,4 They are especially prevalent in warm and moist regions, as these conditions are optimal for breeding.^3-5 They tend to be active during the day and inactive at night due to a preference for sunlight and warmth.⁶ Due to this preference, horse flies’ seasonal activity depends on the climate; for many regions, activity persists from summer to early autumn.⁷

Clinical Manifestations and Treatment

Female horse flies use their mouthparts to pierce the host’s skin, inject saliva, and suck blood. The saliva contains anticoagulant properties. The bites are painful for the host, and various reactions can occur, including large urticarial wheals or papules at the site of the bite. Treatment for these minor cutaneous reactions is largely symptomatic. The bite site should be washed with soap and water; ice can be applied to help reduce inflammation.⁸ Oral antihistamines may be administered to reduce pruritus and treat urticaria. Topical steroids also can be prescribed for symptomatic relief. Acetaminophen and nonsteroidal anti-inflammatory drugs can be administered for pain control.⁸

While most cases of horse fly bites are minor, there have been reports of anaphylaxis.⁹ Horse fly bite–induced anaphylaxis can manifest as generalized itching, urticaria, and angioedema within minutes of being bitten. This may be followed by pharyngeal constriction, shortness of breath, nausea, vomiting, shivers, perspiration, and loss of consciousness.⁹ Anaphylaxis symptoms should be treated with immediate administration of intramuscular epinephrine.¹⁰

Pathogen Transmission, Prevention, and Control

Although horse flies have been found to carry numerous viruses, bacteria, and protozoa that affect other mammals, there is not enough evidence to suggest that they are vectors of transmission for humans for most diseases.^11,12 In particular, West Nile virus and Borrelia burgdorferi both have been found in horse flies, but there are no reports of transmission of these diseases to humans through their bites.¹²

Horse flies, their close cousins deer flies (specifically Chrysops discalis), and ticks are known vectors of Francisella tularensis.¹³ These bacteria cause tularemia, which can manifest with symptoms such as fever, headache, and malaise. Ulceroglandular tularemia is the most common manifestation, in which the patient develops a cutaneous ulceration at the site of the horse fly bite and exhibits associated tender regional lymphadenopathy.¹⁴ Exudative conjunctivitis, exudative pharyngitis, abdominal pain, diarrhea, vomiting, and severe bilateral pneumonia also are common symptoms. The most severe form of tularemia is systemic or typhoidal tularemia, which can manifest with fever, septic shock, and hepatosplenomegaly.¹⁴ The current treatment of choice for all forms of tularemia is intravenous gentamicin, with a recommended dosage of 5 mg/kg/d for 7 to 14 days; streptomycin is an acceptable alternative.^14-16 Ciprofloxacin is used less commonly and is reserved for milder disease. Incision and drainage of the affected lymph nodes also may be necessary.¹⁴ It is important to promptly identify and treat tularemia, as the mortality rate can be as high as 50% for untreated disease, especially in patients with systemic symptoms. Even after treatment, many patients exhibit residual scarring at the site of the ulcer, as well as lung, kidney, and muscle damage.¹⁴

It is advised to avoid contact with horse flies due to the range of symptom severity caused by their bites, but avoidance and control can be difficult. Malaise traps, consisting of a tent and polyester netting, can be used to capture the insects.¹⁷ Octenol has been shown to be effective for attracting horse flies and can be applied to the trap in order to increase its effectiveness.¹⁸ A Manitoba horse fly trap is a modified version of the Malaise trap that contains a suspended dark sphere to further attract horse flies.¹⁹ Patients also should be instructed to wear long-sleeved shirts and pants when outdoors in areas with horse flies to avoid contact, and application of DEET (N,N-diethylmeta-toluamide), picaridin, citronella, or geraniol-based repellents also can be effective in reducing exposure.²⁰

Final Thoughts

Horse flies are large, blood‑feeding dipteran insects whose bites usually produce painful local reactions. Although most bites are benign, they rarely can cause anaphylaxis, and certain Tabanidae insects can transmit Francisella tularensis; therefore, clinicians should consider the risk for tularemia infection in patients presenting with horse fly bites and start appropriate antibiotic therapy when indicated. Due to the risks, prevention of bites and reduction of contact with horse flies via protective clothing, repellents, and trapping methods is recommended. Patients should be advised on bite care and to seek urgent care for systemic symptoms or rapidly progressive local signs.

Horse flies (Tabanidae) are hematophagous dipteran insects that feed on the blood of their hosts, including humans.¹ Their bites can cause minor cutaneous reactions (eg, urticaria) or, rarely, severe reactions such as anaphylaxis. They also are vectors of tularemia, which may manifest with cutaneous ulcers and systemic illness. In this article, we discuss identifying features of horse flies as well as clinical manifestations from bite reactions, symptomatic and emergency management, and strategies for prevention and control.

Morphology and Geographic Distribution

Horse flies, which can grow as large as 30 mm, can be identified by their brown or black bodies and characteristic large heads and proboscises, wing venation, large calypters, pulvilliform empodium between large pulvilli, and lack of bristles on the body.² Occasionally, their bodies may be gray, yellow, green, or blue, but this is less likely than in the other species of the Tabanidae family. Short hairs are present on the head and thorax. The eyes are large and often patterned, multicolored, and bright, though they also can exhibit shades of dark brown, gray, or black. There is variation in the appearance of male vs female horse flies: females have eyes that are widely spaced apart, while males have eyes that are closer together.² It is important to note the difference between male and female horseflies, as hematophagy is exhibited only by females.¹

Horse flies are found worldwide, with the exception of Hawaii, Greenland, and Iceland.^3,4 They are especially prevalent in warm and moist regions, as these conditions are optimal for breeding.^3-5 They tend to be active during the day and inactive at night due to a preference for sunlight and warmth.⁶ Due to this preference, horse flies’ seasonal activity depends on the climate; for many regions, activity persists from summer to early autumn.⁷

Clinical Manifestations and Treatment

Female horse flies use their mouthparts to pierce the host’s skin, inject saliva, and suck blood. The saliva contains anticoagulant properties. The bites are painful for the host, and various reactions can occur, including large urticarial wheals or papules at the site of the bite. Treatment for these minor cutaneous reactions is largely symptomatic. The bite site should be washed with soap and water; ice can be applied to help reduce inflammation.⁸ Oral antihistamines may be administered to reduce pruritus and treat urticaria. Topical steroids also can be prescribed for symptomatic relief. Acetaminophen and nonsteroidal anti-inflammatory drugs can be administered for pain control.⁸

While most cases of horse fly bites are minor, there have been reports of anaphylaxis.⁹ Horse fly bite–induced anaphylaxis can manifest as generalized itching, urticaria, and angioedema within minutes of being bitten. This may be followed by pharyngeal constriction, shortness of breath, nausea, vomiting, shivers, perspiration, and loss of consciousness.⁹ Anaphylaxis symptoms should be treated with immediate administration of intramuscular epinephrine.¹⁰

Pathogen Transmission, Prevention, and Control

Although horse flies have been found to carry numerous viruses, bacteria, and protozoa that affect other mammals, there is not enough evidence to suggest that they are vectors of transmission for humans for most diseases.^11,12 In particular, West Nile virus and Borrelia burgdorferi both have been found in horse flies, but there are no reports of transmission of these diseases to humans through their bites.¹²

Horse flies, their close cousins deer flies (specifically Chrysops discalis), and ticks are known vectors of Francisella tularensis.¹³ These bacteria cause tularemia, which can manifest with symptoms such as fever, headache, and malaise. Ulceroglandular tularemia is the most common manifestation, in which the patient develops a cutaneous ulceration at the site of the horse fly bite and exhibits associated tender regional lymphadenopathy.¹⁴ Exudative conjunctivitis, exudative pharyngitis, abdominal pain, diarrhea, vomiting, and severe bilateral pneumonia also are common symptoms. The most severe form of tularemia is systemic or typhoidal tularemia, which can manifest with fever, septic shock, and hepatosplenomegaly.¹⁴ The current treatment of choice for all forms of tularemia is intravenous gentamicin, with a recommended dosage of 5 mg/kg/d for 7 to 14 days; streptomycin is an acceptable alternative.^14-16 Ciprofloxacin is used less commonly and is reserved for milder disease. Incision and drainage of the affected lymph nodes also may be necessary.¹⁴ It is important to promptly identify and treat tularemia, as the mortality rate can be as high as 50% for untreated disease, especially in patients with systemic symptoms. Even after treatment, many patients exhibit residual scarring at the site of the ulcer, as well as lung, kidney, and muscle damage.¹⁴

It is advised to avoid contact with horse flies due to the range of symptom severity caused by their bites, but avoidance and control can be difficult. Malaise traps, consisting of a tent and polyester netting, can be used to capture the insects.¹⁷ Octenol has been shown to be effective for attracting horse flies and can be applied to the trap in order to increase its effectiveness.¹⁸ A Manitoba horse fly trap is a modified version of the Malaise trap that contains a suspended dark sphere to further attract horse flies.¹⁹ Patients also should be instructed to wear long-sleeved shirts and pants when outdoors in areas with horse flies to avoid contact, and application of DEET (N,N-diethylmeta-toluamide), picaridin, citronella, or geraniol-based repellents also can be effective in reducing exposure.²⁰

Final Thoughts

Horse flies are large, blood‑feeding dipteran insects whose bites usually produce painful local reactions. Although most bites are benign, they rarely can cause anaphylaxis, and certain Tabanidae insects can transmit Francisella tularensis; therefore, clinicians should consider the risk for tularemia infection in patients presenting with horse fly bites and start appropriate antibiotic therapy when indicated. Due to the risks, prevention of bites and reduction of contact with horse flies via protective clothing, repellents, and trapping methods is recommended. Patients should be advised on bite care and to seek urgent care for systemic symptoms or rapidly progressive local signs.