Nonmelanoma Skin Cancer

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

Cutaneous T-cell lymphoma (CTCL) is a diverse group of skin-homing T-cell neoplasms with a wide array of clinical presentations, immunohistopathologic subtypes, and prognoses. The age-adjusted incidence of CTCL in the United States is 6.4 per million individuals.¹ In the early stages of CTCL, the malignant lymphocytes are isolated to the skin, while more advanced disease involves metastatic spread to the lymphatic and peripheral blood compartments. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising roughly 50% of all cases. The etiology of CTCL and MF remains poorly understood and no unifying driver mutation has been identified.² However, recent sequencing efforts have revealed recurrent genomics alterations primarily in 3 pathways: constitutive T-cell activation, resistance to apoptosis/cell-cycle dysregulation, and DNA structural/gene expression dysregulation.^3-8 These studies, among others, support the assertion that CTCL may be an epigenetic phenomenon.^9-14

Most patients with MF will experience an indolent course of skin-limited disease with a favorable prognosis and a 5-year survival rate of 88%.^15-17 A large study of patients with MF (N=525) followed for more than 40 years determined that approximately 20% of early-stage (IA-IIA) patients with MF progress to develop tumors, metastasis to the lymphatic tissue, and/or leukemic blood disease.¹⁸

Cutaneous T-cell lymphoma is a chronic disease, and most treatment responses are partial and short-lived. Allogenic hematopoietic transplantation is the only potentially curative option, and all other therapies are aimed at arresting progression and achieving remission.¹⁹ Skin-directed therapies include topical steroids, topical nitrogen mustard, phototherapy, and radiation. Systemic therapies such as oral retinoids, chemotherapy, and immunotherapy may be used alone or in combination with skin-directed therapies based on the overall disease stage and clinical presentation. Unfortunately, complete response (CR) to therapy is rare and fleeting, and most patients require multiple sequential treatments over their lifetimes.²⁰

Across all stages of CTCL, there is a therapeutic push to combination and immune-based therapies to achieve more durable responses. The imidazoquinolines are a family of toll-like receptor (TLR) agonists including imiquimod (TLR7) and resiquimod (TLR7 and TLR8). Imiquimod (IMQ) is a topical immunomodulator, which increases the local cytotoxic helper T-cell profile (T_H1 marked by IFN-α, tumor necrosis factor α, IL-1α, IL-6, and IL-8), thereby enhancing both humoral and innate immune responses targeting tumor cells.^21-23 Several small studies evaluating topical TLR agonists have documented efficacy in patients with early and advanced stages of CTCL.^24-34

Skin-directed chemotherapy using 5-fluorouracil (5-FU) has shown activity against many cutaneous malignancies. 5-Fluorouracil is an antimetabolite drug that inhibits thymidylate synthase, resulting in interrupted DNA and RNA synthesis and leading to an apoptotic cell death (Figure 1). It has been administered via intravenous, oral (prodrug), intralesional (IL), and topical routes with well-documented success in treating cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and precancerous actinic keratosis.³⁵ As a topical, 5-FU has been shown to provide a good response in 6 patients with early MF.³⁶ In late-stage MF, 5-FU has been used in combination with methotrexate as an infusion.³⁷ We present a single-center case series of 9 patients with CTCL who received combination IL 5-FU and IMQ cream 5%.

Methods

Patient Selection—Patients were selected from our multidisciplinary CTCL subspecialty clinic at the Inova Schar Cancer Institute (Fairfax, Virginia). Patients with single to few recalcitrant CTCL plaques or tumors that were symptomatic or otherwise bothersome were included. All patients had at least 2 prior skin-directed therapies that failed, and many had advanced-stage disease requiring systemic therapy. All patients provided verbal consent.

Study Materials and Evaluations—Patients received IL injections of 5-FU 50 mg/mL. The volume injected was approximately 0.2 cc per cubic centimeter of lesion tissue. Injections were repeated at 2- to 3-week intervals until the target lesions achieved an acute hemorrhagic phase characterized by erosion, flattening, and crust formation. The total number of serial injections administered ranged from 1 to 5. The patients concomitantly treated all lesions with IMQ cream 5% daily for a duration of 2 to 3 months.

Medical photography and physical examination were performed every 2 to 3 weeks until the hemorrhagic phase resolved and treated sites re-epithelialized. Index lesions were assessed using the Composite Assessment of Index Lesion Severity (CAILS) score by a single investigator for all patients.³⁸ Scores were retrospectively assigned using the investigator’s detailed physical examination descriptions and extensive medical photography. Any hyperpigmentation was scored as residual disease, despite the fair interpretation of it as procedure-related postinflammatory dyspigmentation. Complete response was strictly defined as a CAILS score of 0. The patients were screened for possible systemic effects of IMQ, including the presence of fever, chills, fatigue, and myalgia. Patients were evaluated every 6 to 12 weeks as a standing follow-up.

Statistical Analysis—Reductions were calculated using local regression from baseline to the 4- to 7-week follow-up. Patients with multiple lesions had their CAILS score averaged at ea

Results

Nine patients aged 28 to 91 years (median age, 66 years) with CTCL stages IA to IVA2, who had lesions located throughout their body, achieved CR; 3 patients were female (Table 1). The most common phenotype was CD8⁺ (n=3). All patients had at least 2 prior skin-directed therapies at treatment sites that failed, and 1 patient had 7 prior treatments that failed. Prior treatments included a variety of modalities, including all standard-of-care options and enrollment in clinical trials. One patient died from pneumonia following CR (Table 2). Seven patients had previously received systemic therapy for CTCL, and 1 patient was stable on romidepsin during our study. In patients who received more than 1 injection of 5-FU—1 injection: 3 patients; 2 injections: 3 patients; 3 injections: 1 patient; 4 injections: 1 patient; 5 injections: 1 patient—injections were spaced by 2 to 3 weeks. There was 1 patient who initially had an inadequate dosing of IL 5-FU and was restarted 14 months later; this was the patient with 5 total injections. This occurred in one of the first patients in the study, who presented with a facial lesion. The investigator used approximately 0.02 cc per cubic centimeter (dose reduction of nearly 90%), which was inadequate and did not achieve the requisite hemorrhagic phase.

Treatment was well tolerated overall. In all cases, a hemorrhagic phase was achieved, characterized by erosion and crusting that was rated as mildly uncomfortable by 7 patients and moderately uncomfortable by 2 patients. In total, 15 lesions in all 9 patients achieved a CR within 24 weeks of the final injection. The longest treatment course required 12 weeks of therapy with IMQ and 5 IL injections of 5-FU. The fastest CR was achieved in patient 6 within 6 weeks following a single IL injection of 5-FU and 2 applications of IMQ. The average time to CR was 14.78 weeks (95% CI, 1.75-27.81)(Figure 2), and the time to CR ranged from 4 to 24 weeks. On average, patients achieved more than 50% reduction in CAILS score by 3.53 weeks (95% CI, 1.55-5.51) and nearly a 4-fold (74.7%) reduction at the time of initial follow-up (occurring at 4–7 weeks). By 7 weeks, patient 3 had the most modest improvement in CAILS score with a 2.75-fold reduction, while patient 5 had the largest decrease with a 5-fold reduction. Figure 3 shows representative clinical photographs of 2 patients before and after treatment, with all patients having similar results.

Comment

Cutaneous T-cell lymphoma is a chronic skin cancer with a pattern of limited response to therapy and frequent recurrence. Currently available skin-directed therapies function as temporizing measures rather than curative treatments. Immunotherapy offers the promise of lasting disease control even after cessation of treatment, as it may essentially awaken cutaneous immune surveillance to malignant lymphocytes.

Several small observational studies have evaluated topical IMQ and TLR agonist therapy in CTCL. The construct of prior reports varies widely, including many different pretreatments, dosing schemes, and follow-up periods.^24-33 Dosing intervals with IMQ ranged from daily to 3 times per week and treatment duration from 2 weeks to 1 year. Complete response rates from 50% to 100% were reported, and partial responses were observed in all but 1 patient, with recurrence-free follow-up ranging from 6 months to 8 years. Comparatively, combining IL 5-FU and IMQ appears to be at least as effective as IMQ alone or in other sequential treatments and combinations.^24-33

Resiquimod, an experimental TLR7/8 agonist, has shown promising results in CTCL. Rook et al³⁴ conducted a phase 1 trial of topical resiquimod in 12 early-stage patients with CTCL, all of whom responded to therapy. Two patients achieved CR, and 9 achieved a partial response, including 5 patients with the folliculotropic subtype. Interestingly, an abscopal effect was observed in 92% (11/12) of patients. Molecular evidence of reduction of the malignant clone was observed in 90% of patients via high-throughput sequencing of lesional tissue.³⁴ These exciting findings suggest that topical immune therapy with TLR agonists may achieve robust, sustained, and possibly global disease control in CTCL.

Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced T_H1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.

In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.

Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al³⁶ reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.

Conclusion

Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.

Cutaneous T-cell lymphoma (CTCL) is a diverse group of skin-homing T-cell neoplasms with a wide array of clinical presentations, immunohistopathologic subtypes, and prognoses. The age-adjusted incidence of CTCL in the United States is 6.4 per million individuals.¹ In the early stages of CTCL, the malignant lymphocytes are isolated to the skin, while more advanced disease involves metastatic spread to the lymphatic and peripheral blood compartments. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising roughly 50% of all cases. The etiology of CTCL and MF remains poorly understood and no unifying driver mutation has been identified.² However, recent sequencing efforts have revealed recurrent genomics alterations primarily in 3 pathways: constitutive T-cell activation, resistance to apoptosis/cell-cycle dysregulation, and DNA structural/gene expression dysregulation.^3-8 These studies, among others, support the assertion that CTCL may be an epigenetic phenomenon.^9-14

Most patients with MF will experience an indolent course of skin-limited disease with a favorable prognosis and a 5-year survival rate of 88%.^15-17 A large study of patients with MF (N=525) followed for more than 40 years determined that approximately 20% of early-stage (IA-IIA) patients with MF progress to develop tumors, metastasis to the lymphatic tissue, and/or leukemic blood disease.¹⁸

Cutaneous T-cell lymphoma is a chronic disease, and most treatment responses are partial and short-lived. Allogenic hematopoietic transplantation is the only potentially curative option, and all other therapies are aimed at arresting progression and achieving remission.¹⁹ Skin-directed therapies include topical steroids, topical nitrogen mustard, phototherapy, and radiation. Systemic therapies such as oral retinoids, chemotherapy, and immunotherapy may be used alone or in combination with skin-directed therapies based on the overall disease stage and clinical presentation. Unfortunately, complete response (CR) to therapy is rare and fleeting, and most patients require multiple sequential treatments over their lifetimes.²⁰

Across all stages of CTCL, there is a therapeutic push to combination and immune-based therapies to achieve more durable responses. The imidazoquinolines are a family of toll-like receptor (TLR) agonists including imiquimod (TLR7) and resiquimod (TLR7 and TLR8). Imiquimod (IMQ) is a topical immunomodulator, which increases the local cytotoxic helper T-cell profile (T_H1 marked by IFN-α, tumor necrosis factor α, IL-1α, IL-6, and IL-8), thereby enhancing both humoral and innate immune responses targeting tumor cells.^21-23 Several small studies evaluating topical TLR agonists have documented efficacy in patients with early and advanced stages of CTCL.^24-34

Skin-directed chemotherapy using 5-fluorouracil (5-FU) has shown activity against many cutaneous malignancies. 5-Fluorouracil is an antimetabolite drug that inhibits thymidylate synthase, resulting in interrupted DNA and RNA synthesis and leading to an apoptotic cell death (Figure 1). It has been administered via intravenous, oral (prodrug), intralesional (IL), and topical routes with well-documented success in treating cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and precancerous actinic keratosis.³⁵ As a topical, 5-FU has been shown to provide a good response in 6 patients with early MF.³⁶ In late-stage MF, 5-FU has been used in combination with methotrexate as an infusion.³⁷ We present a single-center case series of 9 patients with CTCL who received combination IL 5-FU and IMQ cream 5%.

Methods

Patient Selection—Patients were selected from our multidisciplinary CTCL subspecialty clinic at the Inova Schar Cancer Institute (Fairfax, Virginia). Patients with single to few recalcitrant CTCL plaques or tumors that were symptomatic or otherwise bothersome were included. All patients had at least 2 prior skin-directed therapies that failed, and many had advanced-stage disease requiring systemic therapy. All patients provided verbal consent.

Study Materials and Evaluations—Patients received IL injections of 5-FU 50 mg/mL. The volume injected was approximately 0.2 cc per cubic centimeter of lesion tissue. Injections were repeated at 2- to 3-week intervals until the target lesions achieved an acute hemorrhagic phase characterized by erosion, flattening, and crust formation. The total number of serial injections administered ranged from 1 to 5. The patients concomitantly treated all lesions with IMQ cream 5% daily for a duration of 2 to 3 months.

Medical photography and physical examination were performed every 2 to 3 weeks until the hemorrhagic phase resolved and treated sites re-epithelialized. Index lesions were assessed using the Composite Assessment of Index Lesion Severity (CAILS) score by a single investigator for all patients.³⁸ Scores were retrospectively assigned using the investigator’s detailed physical examination descriptions and extensive medical photography. Any hyperpigmentation was scored as residual disease, despite the fair interpretation of it as procedure-related postinflammatory dyspigmentation. Complete response was strictly defined as a CAILS score of 0. The patients were screened for possible systemic effects of IMQ, including the presence of fever, chills, fatigue, and myalgia. Patients were evaluated every 6 to 12 weeks as a standing follow-up.

Statistical Analysis—Reductions were calculated using local regression from baseline to the 4- to 7-week follow-up. Patients with multiple lesions had their CAILS score averaged at ea

Results

Nine patients aged 28 to 91 years (median age, 66 years) with CTCL stages IA to IVA2, who had lesions located throughout their body, achieved CR; 3 patients were female (Table 1). The most common phenotype was CD8⁺ (n=3). All patients had at least 2 prior skin-directed therapies at treatment sites that failed, and 1 patient had 7 prior treatments that failed. Prior treatments included a variety of modalities, including all standard-of-care options and enrollment in clinical trials. One patient died from pneumonia following CR (Table 2). Seven patients had previously received systemic therapy for CTCL, and 1 patient was stable on romidepsin during our study. In patients who received more than 1 injection of 5-FU—1 injection: 3 patients; 2 injections: 3 patients; 3 injections: 1 patient; 4 injections: 1 patient; 5 injections: 1 patient—injections were spaced by 2 to 3 weeks. There was 1 patient who initially had an inadequate dosing of IL 5-FU and was restarted 14 months later; this was the patient with 5 total injections. This occurred in one of the first patients in the study, who presented with a facial lesion. The investigator used approximately 0.02 cc per cubic centimeter (dose reduction of nearly 90%), which was inadequate and did not achieve the requisite hemorrhagic phase.

Treatment was well tolerated overall. In all cases, a hemorrhagic phase was achieved, characterized by erosion and crusting that was rated as mildly uncomfortable by 7 patients and moderately uncomfortable by 2 patients. In total, 15 lesions in all 9 patients achieved a CR within 24 weeks of the final injection. The longest treatment course required 12 weeks of therapy with IMQ and 5 IL injections of 5-FU. The fastest CR was achieved in patient 6 within 6 weeks following a single IL injection of 5-FU and 2 applications of IMQ. The average time to CR was 14.78 weeks (95% CI, 1.75-27.81)(Figure 2), and the time to CR ranged from 4 to 24 weeks. On average, patients achieved more than 50% reduction in CAILS score by 3.53 weeks (95% CI, 1.55-5.51) and nearly a 4-fold (74.7%) reduction at the time of initial follow-up (occurring at 4–7 weeks). By 7 weeks, patient 3 had the most modest improvement in CAILS score with a 2.75-fold reduction, while patient 5 had the largest decrease with a 5-fold reduction. Figure 3 shows representative clinical photographs of 2 patients before and after treatment, with all patients having similar results.

Comment

Cutaneous T-cell lymphoma is a chronic skin cancer with a pattern of limited response to therapy and frequent recurrence. Currently available skin-directed therapies function as temporizing measures rather than curative treatments. Immunotherapy offers the promise of lasting disease control even after cessation of treatment, as it may essentially awaken cutaneous immune surveillance to malignant lymphocytes.

Several small observational studies have evaluated topical IMQ and TLR agonist therapy in CTCL. The construct of prior reports varies widely, including many different pretreatments, dosing schemes, and follow-up periods.^24-33 Dosing intervals with IMQ ranged from daily to 3 times per week and treatment duration from 2 weeks to 1 year. Complete response rates from 50% to 100% were reported, and partial responses were observed in all but 1 patient, with recurrence-free follow-up ranging from 6 months to 8 years. Comparatively, combining IL 5-FU and IMQ appears to be at least as effective as IMQ alone or in other sequential treatments and combinations.^24-33

Resiquimod, an experimental TLR7/8 agonist, has shown promising results in CTCL. Rook et al³⁴ conducted a phase 1 trial of topical resiquimod in 12 early-stage patients with CTCL, all of whom responded to therapy. Two patients achieved CR, and 9 achieved a partial response, including 5 patients with the folliculotropic subtype. Interestingly, an abscopal effect was observed in 92% (11/12) of patients. Molecular evidence of reduction of the malignant clone was observed in 90% of patients via high-throughput sequencing of lesional tissue.³⁴ These exciting findings suggest that topical immune therapy with TLR agonists may achieve robust, sustained, and possibly global disease control in CTCL.

Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced T_H1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.

In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.

Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al³⁶ reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.

Conclusion

Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.

Cutaneous T-cell lymphoma (CTCL) is a diverse group of skin-homing T-cell neoplasms with a wide array of clinical presentations, immunohistopathologic subtypes, and prognoses. The age-adjusted incidence of CTCL in the United States is 6.4 per million individuals.¹ In the early stages of CTCL, the malignant lymphocytes are isolated to the skin, while more advanced disease involves metastatic spread to the lymphatic and peripheral blood compartments. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising roughly 50% of all cases. The etiology of CTCL and MF remains poorly understood and no unifying driver mutation has been identified.² However, recent sequencing efforts have revealed recurrent genomics alterations primarily in 3 pathways: constitutive T-cell activation, resistance to apoptosis/cell-cycle dysregulation, and DNA structural/gene expression dysregulation.^3-8 These studies, among others, support the assertion that CTCL may be an epigenetic phenomenon.^9-14

Most patients with MF will experience an indolent course of skin-limited disease with a favorable prognosis and a 5-year survival rate of 88%.^15-17 A large study of patients with MF (N=525) followed for more than 40 years determined that approximately 20% of early-stage (IA-IIA) patients with MF progress to develop tumors, metastasis to the lymphatic tissue, and/or leukemic blood disease.¹⁸

Cutaneous T-cell lymphoma is a chronic disease, and most treatment responses are partial and short-lived. Allogenic hematopoietic transplantation is the only potentially curative option, and all other therapies are aimed at arresting progression and achieving remission.¹⁹ Skin-directed therapies include topical steroids, topical nitrogen mustard, phototherapy, and radiation. Systemic therapies such as oral retinoids, chemotherapy, and immunotherapy may be used alone or in combination with skin-directed therapies based on the overall disease stage and clinical presentation. Unfortunately, complete response (CR) to therapy is rare and fleeting, and most patients require multiple sequential treatments over their lifetimes.²⁰

Across all stages of CTCL, there is a therapeutic push to combination and immune-based therapies to achieve more durable responses. The imidazoquinolines are a family of toll-like receptor (TLR) agonists including imiquimod (TLR7) and resiquimod (TLR7 and TLR8). Imiquimod (IMQ) is a topical immunomodulator, which increases the local cytotoxic helper T-cell profile (T_H1 marked by IFN-α, tumor necrosis factor α, IL-1α, IL-6, and IL-8), thereby enhancing both humoral and innate immune responses targeting tumor cells.^21-23 Several small studies evaluating topical TLR agonists have documented efficacy in patients with early and advanced stages of CTCL.^24-34

Skin-directed chemotherapy using 5-fluorouracil (5-FU) has shown activity against many cutaneous malignancies. 5-Fluorouracil is an antimetabolite drug that inhibits thymidylate synthase, resulting in interrupted DNA and RNA synthesis and leading to an apoptotic cell death (Figure 1). It has been administered via intravenous, oral (prodrug), intralesional (IL), and topical routes with well-documented success in treating cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and precancerous actinic keratosis.³⁵ As a topical, 5-FU has been shown to provide a good response in 6 patients with early MF.³⁶ In late-stage MF, 5-FU has been used in combination with methotrexate as an infusion.³⁷ We present a single-center case series of 9 patients with CTCL who received combination IL 5-FU and IMQ cream 5%.

Methods

Patient Selection—Patients were selected from our multidisciplinary CTCL subspecialty clinic at the Inova Schar Cancer Institute (Fairfax, Virginia). Patients with single to few recalcitrant CTCL plaques or tumors that were symptomatic or otherwise bothersome were included. All patients had at least 2 prior skin-directed therapies that failed, and many had advanced-stage disease requiring systemic therapy. All patients provided verbal consent.

Study Materials and Evaluations—Patients received IL injections of 5-FU 50 mg/mL. The volume injected was approximately 0.2 cc per cubic centimeter of lesion tissue. Injections were repeated at 2- to 3-week intervals until the target lesions achieved an acute hemorrhagic phase characterized by erosion, flattening, and crust formation. The total number of serial injections administered ranged from 1 to 5. The patients concomitantly treated all lesions with IMQ cream 5% daily for a duration of 2 to 3 months.

Medical photography and physical examination were performed every 2 to 3 weeks until the hemorrhagic phase resolved and treated sites re-epithelialized. Index lesions were assessed using the Composite Assessment of Index Lesion Severity (CAILS) score by a single investigator for all patients.³⁸ Scores were retrospectively assigned using the investigator’s detailed physical examination descriptions and extensive medical photography. Any hyperpigmentation was scored as residual disease, despite the fair interpretation of it as procedure-related postinflammatory dyspigmentation. Complete response was strictly defined as a CAILS score of 0. The patients were screened for possible systemic effects of IMQ, including the presence of fever, chills, fatigue, and myalgia. Patients were evaluated every 6 to 12 weeks as a standing follow-up.

Statistical Analysis—Reductions were calculated using local regression from baseline to the 4- to 7-week follow-up. Patients with multiple lesions had their CAILS score averaged at ea

Results

Nine patients aged 28 to 91 years (median age, 66 years) with CTCL stages IA to IVA2, who had lesions located throughout their body, achieved CR; 3 patients were female (Table 1). The most common phenotype was CD8⁺ (n=3). All patients had at least 2 prior skin-directed therapies at treatment sites that failed, and 1 patient had 7 prior treatments that failed. Prior treatments included a variety of modalities, including all standard-of-care options and enrollment in clinical trials. One patient died from pneumonia following CR (Table 2). Seven patients had previously received systemic therapy for CTCL, and 1 patient was stable on romidepsin during our study. In patients who received more than 1 injection of 5-FU—1 injection: 3 patients; 2 injections: 3 patients; 3 injections: 1 patient; 4 injections: 1 patient; 5 injections: 1 patient—injections were spaced by 2 to 3 weeks. There was 1 patient who initially had an inadequate dosing of IL 5-FU and was restarted 14 months later; this was the patient with 5 total injections. This occurred in one of the first patients in the study, who presented with a facial lesion. The investigator used approximately 0.02 cc per cubic centimeter (dose reduction of nearly 90%), which was inadequate and did not achieve the requisite hemorrhagic phase.

Treatment was well tolerated overall. In all cases, a hemorrhagic phase was achieved, characterized by erosion and crusting that was rated as mildly uncomfortable by 7 patients and moderately uncomfortable by 2 patients. In total, 15 lesions in all 9 patients achieved a CR within 24 weeks of the final injection. The longest treatment course required 12 weeks of therapy with IMQ and 5 IL injections of 5-FU. The fastest CR was achieved in patient 6 within 6 weeks following a single IL injection of 5-FU and 2 applications of IMQ. The average time to CR was 14.78 weeks (95% CI, 1.75-27.81)(Figure 2), and the time to CR ranged from 4 to 24 weeks. On average, patients achieved more than 50% reduction in CAILS score by 3.53 weeks (95% CI, 1.55-5.51) and nearly a 4-fold (74.7%) reduction at the time of initial follow-up (occurring at 4–7 weeks). By 7 weeks, patient 3 had the most modest improvement in CAILS score with a 2.75-fold reduction, while patient 5 had the largest decrease with a 5-fold reduction. Figure 3 shows representative clinical photographs of 2 patients before and after treatment, with all patients having similar results.

Comment

Cutaneous T-cell lymphoma is a chronic skin cancer with a pattern of limited response to therapy and frequent recurrence. Currently available skin-directed therapies function as temporizing measures rather than curative treatments. Immunotherapy offers the promise of lasting disease control even after cessation of treatment, as it may essentially awaken cutaneous immune surveillance to malignant lymphocytes.

Several small observational studies have evaluated topical IMQ and TLR agonist therapy in CTCL. The construct of prior reports varies widely, including many different pretreatments, dosing schemes, and follow-up periods.^24-33 Dosing intervals with IMQ ranged from daily to 3 times per week and treatment duration from 2 weeks to 1 year. Complete response rates from 50% to 100% were reported, and partial responses were observed in all but 1 patient, with recurrence-free follow-up ranging from 6 months to 8 years. Comparatively, combining IL 5-FU and IMQ appears to be at least as effective as IMQ alone or in other sequential treatments and combinations.^24-33

Resiquimod, an experimental TLR7/8 agonist, has shown promising results in CTCL. Rook et al³⁴ conducted a phase 1 trial of topical resiquimod in 12 early-stage patients with CTCL, all of whom responded to therapy. Two patients achieved CR, and 9 achieved a partial response, including 5 patients with the folliculotropic subtype. Interestingly, an abscopal effect was observed in 92% (11/12) of patients. Molecular evidence of reduction of the malignant clone was observed in 90% of patients via high-throughput sequencing of lesional tissue.³⁴ These exciting findings suggest that topical immune therapy with TLR agonists may achieve robust, sustained, and possibly global disease control in CTCL.

Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced T_H1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.

In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.

Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al³⁶ reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.

Conclusion

Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.

SAN DIEGO – After Arisa E. Ortiz, MD, and colleagues published results of a multicenter study reporting that one treatment with the long-pulsed 1,064-nm Nd:YAG laser cleared nonaggressive basal cell carcinoma (BCC) on the trunk and extremities in 90% of patients, she heard from colleagues who were skeptical of the approach.

Maybe it’s just the biopsy alone that’s clearing these tumors, some told her. Others postulated that since the energy was delivered with a 5- to 6-mm spot size at a fluence of 125-140 J/cm² and a 7- to 10-ms pulse duration, bulk heating likely disrupted the tumors. However, treatments were generally well tolerated, required no anesthesia, and caused no significant adverse events.

“It’s almost scarless,” Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, said at the annual Masters of Aesthetics Symposium. “Sometimes the treatment does leave a mark, but I think the scars are always acceptable. We do have good histologic evidence that we can penetrate 2.15 mm, which is a lot deeper than what the pulsed-dye laser or other superficial wavelengths are able to penetrate.”

Data is well powered to reject the null hypothesis that laser treatment does not have an effect on nodular and superficial BCC lesions, she continued, noting that it is at least comparable if not superior with clearance rates reported for methyl aminolevulinate–PDT (73%), imiquimod cream (83%), and fluorouracil cream (80%). “Maybe we’re not specifically targeting the vasculature [with this approach], but we did some optical coherence tomography imaging and saw that the blood vessels in the tumor were coagulated while the vasculature in the surrounding normal skin were spared,” said Dr. Ortiz, who is also vice president of the American Society for Laser Medicine and Surgery.

In a more recent analysis, she and her colleagues retrospectively analyzed long-term outcomes in 11 patients with BCC who had 16 lesions treated with the 1,064-nm Nd:YAG laser. At a mean of 9 months, 100% of lesions remained clear as determined by clinical observation.

In a subsequent, as yet unpublished study, she and her collaborators followed 34 patients with BCC one year following laser treatment. “Of these, 33 had no recurrence at 1-year follow-up,” Dr. Ortiz said, noting that the one patient with a recurrence was on a biologic agent for Crohn’s disease.

One key advantage of using the long-pulsed 1,064-nm Nd:YAG laser for nonaggressive BCC is the potential for one treatment visit. “They don’t have to come back for suture removal,” she said. “It’s a quick procedure, takes only about 5 minutes. There’s no limitation on activity and there’s minimal wound care, light ointment, and a band-aid; that’s it.”

In addition, she said, there is a lower risk of complications, infections, and bleeding, and there is minimal scarring. It is “also an alternative for treating patients with multiple tumors or those who are poor surgical candidates, such as the elderly and those with Gorlin syndrome.”

Dr. Ortiz avoids treating aggressive subtypes “because we don’t know what margin to treat,” she added. “Avoid the face. I do make some exceptions for patients if they’re elderly or if they’ve had multiple tumors. Monitor for recurrence like you would using any other modality.”

She uses lidocaine without epinephrine to avoid vasoconstriction and treats with the 1,064-nm Nd:YAG laser as follows: a 5-mm spot size, a fluence of 140 J/cm², and a pulse duration of 8 ms, with no cooling, which are the settings for the Excel V Laser System, she noted. “If you’re using a different Nd:YAG laser, your pulse duration may vary. I do let the device cool in between pulses to avoid bulk heating.”

The immediate endpoint to strive for is slight greying and slight contraction, and the procedure is covered by insurance, billed as malignant destruction/EDC (CPT codes 17260-17266 trunk and 17280-17283 face). “I do biopsy prior to treatment,” she said. “I like the biopsy to be healed when I’m using the laser, so I’ll treat them about a month later.”

As for future directions, Dr. Ortiz and colleagues plan to evaluate the use of gold nanoparticles to more selectively target BCC during treatment with the 1,064-nm Nd:YAG laser. For now, she sees no downside of the procedure for proper candidates. “I do think that patients really like it,” she said. “It’s effective and easy.”

Dr. Ortiz disclosed having financial relationships with several pharmaceutical and device companies. She is also cochair of the MOAS.





 

SAN DIEGO – After Arisa E. Ortiz, MD, and colleagues published results of a multicenter study reporting that one treatment with the long-pulsed 1,064-nm Nd:YAG laser cleared nonaggressive basal cell carcinoma (BCC) on the trunk and extremities in 90% of patients, she heard from colleagues who were skeptical of the approach.

Maybe it’s just the biopsy alone that’s clearing these tumors, some told her. Others postulated that since the energy was delivered with a 5- to 6-mm spot size at a fluence of 125-140 J/cm² and a 7- to 10-ms pulse duration, bulk heating likely disrupted the tumors. However, treatments were generally well tolerated, required no anesthesia, and caused no significant adverse events.

“It’s almost scarless,” Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, said at the annual Masters of Aesthetics Symposium. “Sometimes the treatment does leave a mark, but I think the scars are always acceptable. We do have good histologic evidence that we can penetrate 2.15 mm, which is a lot deeper than what the pulsed-dye laser or other superficial wavelengths are able to penetrate.”

Data is well powered to reject the null hypothesis that laser treatment does not have an effect on nodular and superficial BCC lesions, she continued, noting that it is at least comparable if not superior with clearance rates reported for methyl aminolevulinate–PDT (73%), imiquimod cream (83%), and fluorouracil cream (80%). “Maybe we’re not specifically targeting the vasculature [with this approach], but we did some optical coherence tomography imaging and saw that the blood vessels in the tumor were coagulated while the vasculature in the surrounding normal skin were spared,” said Dr. Ortiz, who is also vice president of the American Society for Laser Medicine and Surgery.

In a more recent analysis, she and her colleagues retrospectively analyzed long-term outcomes in 11 patients with BCC who had 16 lesions treated with the 1,064-nm Nd:YAG laser. At a mean of 9 months, 100% of lesions remained clear as determined by clinical observation.

In a subsequent, as yet unpublished study, she and her collaborators followed 34 patients with BCC one year following laser treatment. “Of these, 33 had no recurrence at 1-year follow-up,” Dr. Ortiz said, noting that the one patient with a recurrence was on a biologic agent for Crohn’s disease.

One key advantage of using the long-pulsed 1,064-nm Nd:YAG laser for nonaggressive BCC is the potential for one treatment visit. “They don’t have to come back for suture removal,” she said. “It’s a quick procedure, takes only about 5 minutes. There’s no limitation on activity and there’s minimal wound care, light ointment, and a band-aid; that’s it.”

In addition, she said, there is a lower risk of complications, infections, and bleeding, and there is minimal scarring. It is “also an alternative for treating patients with multiple tumors or those who are poor surgical candidates, such as the elderly and those with Gorlin syndrome.”

Dr. Ortiz avoids treating aggressive subtypes “because we don’t know what margin to treat,” she added. “Avoid the face. I do make some exceptions for patients if they’re elderly or if they’ve had multiple tumors. Monitor for recurrence like you would using any other modality.”

She uses lidocaine without epinephrine to avoid vasoconstriction and treats with the 1,064-nm Nd:YAG laser as follows: a 5-mm spot size, a fluence of 140 J/cm², and a pulse duration of 8 ms, with no cooling, which are the settings for the Excel V Laser System, she noted. “If you’re using a different Nd:YAG laser, your pulse duration may vary. I do let the device cool in between pulses to avoid bulk heating.”

The immediate endpoint to strive for is slight greying and slight contraction, and the procedure is covered by insurance, billed as malignant destruction/EDC (CPT codes 17260-17266 trunk and 17280-17283 face). “I do biopsy prior to treatment,” she said. “I like the biopsy to be healed when I’m using the laser, so I’ll treat them about a month later.”

As for future directions, Dr. Ortiz and colleagues plan to evaluate the use of gold nanoparticles to more selectively target BCC during treatment with the 1,064-nm Nd:YAG laser. For now, she sees no downside of the procedure for proper candidates. “I do think that patients really like it,” she said. “It’s effective and easy.”

Dr. Ortiz disclosed having financial relationships with several pharmaceutical and device companies. She is also cochair of the MOAS.





 

SAN DIEGO – After Arisa E. Ortiz, MD, and colleagues published results of a multicenter study reporting that one treatment with the long-pulsed 1,064-nm Nd:YAG laser cleared nonaggressive basal cell carcinoma (BCC) on the trunk and extremities in 90% of patients, she heard from colleagues who were skeptical of the approach.

Maybe it’s just the biopsy alone that’s clearing these tumors, some told her. Others postulated that since the energy was delivered with a 5- to 6-mm spot size at a fluence of 125-140 J/cm² and a 7- to 10-ms pulse duration, bulk heating likely disrupted the tumors. However, treatments were generally well tolerated, required no anesthesia, and caused no significant adverse events.

“It’s almost scarless,” Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, said at the annual Masters of Aesthetics Symposium. “Sometimes the treatment does leave a mark, but I think the scars are always acceptable. We do have good histologic evidence that we can penetrate 2.15 mm, which is a lot deeper than what the pulsed-dye laser or other superficial wavelengths are able to penetrate.”

Data is well powered to reject the null hypothesis that laser treatment does not have an effect on nodular and superficial BCC lesions, she continued, noting that it is at least comparable if not superior with clearance rates reported for methyl aminolevulinate–PDT (73%), imiquimod cream (83%), and fluorouracil cream (80%). “Maybe we’re not specifically targeting the vasculature [with this approach], but we did some optical coherence tomography imaging and saw that the blood vessels in the tumor were coagulated while the vasculature in the surrounding normal skin were spared,” said Dr. Ortiz, who is also vice president of the American Society for Laser Medicine and Surgery.

In a more recent analysis, she and her colleagues retrospectively analyzed long-term outcomes in 11 patients with BCC who had 16 lesions treated with the 1,064-nm Nd:YAG laser. At a mean of 9 months, 100% of lesions remained clear as determined by clinical observation.

In a subsequent, as yet unpublished study, she and her collaborators followed 34 patients with BCC one year following laser treatment. “Of these, 33 had no recurrence at 1-year follow-up,” Dr. Ortiz said, noting that the one patient with a recurrence was on a biologic agent for Crohn’s disease.

One key advantage of using the long-pulsed 1,064-nm Nd:YAG laser for nonaggressive BCC is the potential for one treatment visit. “They don’t have to come back for suture removal,” she said. “It’s a quick procedure, takes only about 5 minutes. There’s no limitation on activity and there’s minimal wound care, light ointment, and a band-aid; that’s it.”

In addition, she said, there is a lower risk of complications, infections, and bleeding, and there is minimal scarring. It is “also an alternative for treating patients with multiple tumors or those who are poor surgical candidates, such as the elderly and those with Gorlin syndrome.”

Dr. Ortiz avoids treating aggressive subtypes “because we don’t know what margin to treat,” she added. “Avoid the face. I do make some exceptions for patients if they’re elderly or if they’ve had multiple tumors. Monitor for recurrence like you would using any other modality.”

She uses lidocaine without epinephrine to avoid vasoconstriction and treats with the 1,064-nm Nd:YAG laser as follows: a 5-mm spot size, a fluence of 140 J/cm², and a pulse duration of 8 ms, with no cooling, which are the settings for the Excel V Laser System, she noted. “If you’re using a different Nd:YAG laser, your pulse duration may vary. I do let the device cool in between pulses to avoid bulk heating.”

The immediate endpoint to strive for is slight greying and slight contraction, and the procedure is covered by insurance, billed as malignant destruction/EDC (CPT codes 17260-17266 trunk and 17280-17283 face). “I do biopsy prior to treatment,” she said. “I like the biopsy to be healed when I’m using the laser, so I’ll treat them about a month later.”

As for future directions, Dr. Ortiz and colleagues plan to evaluate the use of gold nanoparticles to more selectively target BCC during treatment with the 1,064-nm Nd:YAG laser. For now, she sees no downside of the procedure for proper candidates. “I do think that patients really like it,” she said. “It’s effective and easy.”

Dr. Ortiz disclosed having financial relationships with several pharmaceutical and device companies. She is also cochair of the MOAS.





 

A California woman developed skin cancer after getting a cut during a manicure. Now, she and her doctor are spreading the word about her ordeal as a lesson that speed and persistence in seeking treatment are the keys that make her type of cancer – squamous cell carcinoma – completely curable.

“She cut me, and the cut wasn’t just a regular cuticle cut. She cut me deep, and that was one of the first times that happened to me,” Grace Garcia, 50, told TODAY.com, recalling the November 2021 incident.

Ms. Garcia had been getting her nails done regularly for 20 years, she said, but happened to go to a different salon than her usual spot because she couldn’t get an appointment during the busy pre-Thanksgiving season. She doesn’t recall whether the technician opened packaging that signals unused tools.

She put antibiotic ointment on the cut, but it didn’t heal after a few days. Eventually, the skin closed and a darkened bump formed. It was painful. She went to her doctor, who said it was a “callus from writing,” she told TODAY.com. But it was on her ring finger, which didn’t seem connected to writing. Her doctor said to keep an eye on it. 

Five months after the cut occurred, she mentioned it during a gynecology appointment and was referred to a dermatologist, who also advised keeping an eye on it. A wart developed. She went back to her primary care physician and then to another dermatologist. The spot was biopsied.

Squamous cell carcinoma is a common type of skin cancer, according to the American Academy of Dermatology. It can have many causes, but the cause in Ms. Garcia’s case was both very common and very rare: human papillomavirus, or HPV. HPV is a virus that infects millions of people every year, but it’s not a typical cause of skin cancer.

“It’s pretty rare for several reasons. Generally speaking, the strains that cause cancer from an HPV standpoint tend to be more sexually transmitted,” dermatologist Teo Soleymani told TODAY.com. “In Grace’s case, she had an injury, which became the portal of entry. So that thick skin that we have on our hands and feet that acts as a natural barrier against infections and things like that was no longer the case, and the virus was able to infect her skin.”

Dr. Soleymani said Ms. Garcia’s persistence to get answers likely saved her from losing a finger.

“Your outcomes are entirely dictated by how early you catch them, and very often they’re completely curable,” he said. “Her persistence – not only was she able to have a great outcome, she probably saved herself from having her finger amputated.”

A California woman developed skin cancer after getting a cut during a manicure. Now, she and her doctor are spreading the word about her ordeal as a lesson that speed and persistence in seeking treatment are the keys that make her type of cancer – squamous cell carcinoma – completely curable.

“She cut me, and the cut wasn’t just a regular cuticle cut. She cut me deep, and that was one of the first times that happened to me,” Grace Garcia, 50, told TODAY.com, recalling the November 2021 incident.

Ms. Garcia had been getting her nails done regularly for 20 years, she said, but happened to go to a different salon than her usual spot because she couldn’t get an appointment during the busy pre-Thanksgiving season. She doesn’t recall whether the technician opened packaging that signals unused tools.

She put antibiotic ointment on the cut, but it didn’t heal after a few days. Eventually, the skin closed and a darkened bump formed. It was painful. She went to her doctor, who said it was a “callus from writing,” she told TODAY.com. But it was on her ring finger, which didn’t seem connected to writing. Her doctor said to keep an eye on it. 

Five months after the cut occurred, she mentioned it during a gynecology appointment and was referred to a dermatologist, who also advised keeping an eye on it. A wart developed. She went back to her primary care physician and then to another dermatologist. The spot was biopsied.

Squamous cell carcinoma is a common type of skin cancer, according to the American Academy of Dermatology. It can have many causes, but the cause in Ms. Garcia’s case was both very common and very rare: human papillomavirus, or HPV. HPV is a virus that infects millions of people every year, but it’s not a typical cause of skin cancer.

“It’s pretty rare for several reasons. Generally speaking, the strains that cause cancer from an HPV standpoint tend to be more sexually transmitted,” dermatologist Teo Soleymani told TODAY.com. “In Grace’s case, she had an injury, which became the portal of entry. So that thick skin that we have on our hands and feet that acts as a natural barrier against infections and things like that was no longer the case, and the virus was able to infect her skin.”

Dr. Soleymani said Ms. Garcia’s persistence to get answers likely saved her from losing a finger.

“Your outcomes are entirely dictated by how early you catch them, and very often they’re completely curable,” he said. “Her persistence – not only was she able to have a great outcome, she probably saved herself from having her finger amputated.”

A California woman developed skin cancer after getting a cut during a manicure. Now, she and her doctor are spreading the word about her ordeal as a lesson that speed and persistence in seeking treatment are the keys that make her type of cancer – squamous cell carcinoma – completely curable.

“She cut me, and the cut wasn’t just a regular cuticle cut. She cut me deep, and that was one of the first times that happened to me,” Grace Garcia, 50, told TODAY.com, recalling the November 2021 incident.

Ms. Garcia had been getting her nails done regularly for 20 years, she said, but happened to go to a different salon than her usual spot because she couldn’t get an appointment during the busy pre-Thanksgiving season. She doesn’t recall whether the technician opened packaging that signals unused tools.

She put antibiotic ointment on the cut, but it didn’t heal after a few days. Eventually, the skin closed and a darkened bump formed. It was painful. She went to her doctor, who said it was a “callus from writing,” she told TODAY.com. But it was on her ring finger, which didn’t seem connected to writing. Her doctor said to keep an eye on it. 

Five months after the cut occurred, she mentioned it during a gynecology appointment and was referred to a dermatologist, who also advised keeping an eye on it. A wart developed. She went back to her primary care physician and then to another dermatologist. The spot was biopsied.

Squamous cell carcinoma is a common type of skin cancer, according to the American Academy of Dermatology. It can have many causes, but the cause in Ms. Garcia’s case was both very common and very rare: human papillomavirus, or HPV. HPV is a virus that infects millions of people every year, but it’s not a typical cause of skin cancer.

“It’s pretty rare for several reasons. Generally speaking, the strains that cause cancer from an HPV standpoint tend to be more sexually transmitted,” dermatologist Teo Soleymani told TODAY.com. “In Grace’s case, she had an injury, which became the portal of entry. So that thick skin that we have on our hands and feet that acts as a natural barrier against infections and things like that was no longer the case, and the virus was able to infect her skin.”

Dr. Soleymani said Ms. Garcia’s persistence to get answers likely saved her from losing a finger.

“Your outcomes are entirely dictated by how early you catch them, and very often they’re completely curable,” he said. “Her persistence – not only was she able to have a great outcome, she probably saved herself from having her finger amputated.”

To the Editor:

Surgical wounds on the lower leg are challenging to manage because venous stasis, bacterial colonization, and high tension may contribute to protracted healing. Advances in technology led to the development of novel, polymer-based wound-healing modalities that hold promise for the management of these wounds.

A 75-year-old man presented with a well-differentiated squamous cell carcinoma with a 3-mm depth of invasion on the left pretibial region. His comorbidities were notable for hypertension, hypercholesterolemia, varicose veins, myocardial infarction, peripheral vascular disease, and a 32 pack-year cigarette smoking history. Current medications included clopidogrel bisulfate and warfarin sodium to manage a recently placed coronary artery stent.

The tumor was cleared after 2 stages of Mohs micrographic surgery with excision down to tibialis anterior fascia (Figure 1A). The resultant defect measured 43×33 mm in area and 9 mm in depth (wound size, 12,771 mm³). Reconstructive options were discussed, including random-pattern flap repair and skin graft. Given the patient’s risk of bleeding, the decision was made to forego a flap repair. Additionally, the patient was a heavy smoker and could not comply with the wound care and elevation and ambulation restrictions required for optimal skin graft care. Therefore, a decision was made to proceed with secondary intention healing using a methacrylate polymer powder dressing.

After achieving hemostasis, a novel 10-mg sterile, biologically inert methacrylate polymer powder dressing was poured over the wound in a uniform layer to fill and seal the entire wound surface (Figure 1B). Sterile normal saline 0.1 mL was sprayed onto the powder to activate particle aggregation. No secondary dressing was used, and the patient was permitted to get the dressing wet after 48 hours.

The dressing was changed in a similar fashion 4 weeks after application, following gentle debridement with gauze and normal saline. Eight weeks after surgery, the wound exhibited healthy granulation tissue and measured 5×6 mm in area and 2 mm in depth (wound size, 60 mm³), which represented a 99.5% reduction in wound size (Figure 1C). The dressing was not painful, and there were no reported adverse effects. The patient continued to smoke and ambulate fully throughout this period. No antibiotics were used.

Methacrylate polymer powder dressings are a novel and sophisticated dressing modality with great promise for the management of surgical wounds on the lower limb. The dressing is a sterile powder consisting of 84.8% poly-2-hydroxyethylmethacrylate, 14.9% poly-2-hydroxypropylmethacrylate, and 0.3% sodium deoxycholate. These hydrophilic polymers have a covalent methacrylate backbone with a hydroxyl aliphatic side chain. When saline or wound exudate contacts the powder, the spheres hydrate and nonreversibly aggregate to form a moist, flexible dressing that conforms to the topography of the wound and seals it (Figure 2).¹

Once the spheres have aggregated, they are designed to orient in a honeycomb formation with 4- to 10-nm openings that serve as capillary channels (Figure 3). This porous architecture of the polymer is essential for adequate moisture management. It allows for vapor transpiration at a rate of 12 L/m² per day, which ensures the capillary flow from the moist wound surface is evenly distributed through the dressing, contributing to its 68% water content. Notably, this approximately three-fifths water composition is similar to the water makeup of human skin. Optimized moisture management is theorized to enhance epithelial migration, stimulate angiogenesis, retain growth factors, promote autolytic debridement, and maintain ideal voltage and oxygen gradients for wound healing. The risk for infection is not increased by the existence of these pores, as their small size does not allow for bacterial migration.¹

This case demonstrates the effectiveness of using a methacrylate polymer powder dressing to promote timely wound healing in a poorly vascularized lower leg surgical wound. The low maintenance, user-friendly dressing was changed at monthly intervals, which spared the patient the inconvenience and pain associated with the repeated application of more conventional primary and secondary dressings. The dressing was well tolerated and resulted in a 99.5% reduction in wound size. Further studies are needed to investigate the utility of this promising technology.

To the Editor:

Surgical wounds on the lower leg are challenging to manage because venous stasis, bacterial colonization, and high tension may contribute to protracted healing. Advances in technology led to the development of novel, polymer-based wound-healing modalities that hold promise for the management of these wounds.

A 75-year-old man presented with a well-differentiated squamous cell carcinoma with a 3-mm depth of invasion on the left pretibial region. His comorbidities were notable for hypertension, hypercholesterolemia, varicose veins, myocardial infarction, peripheral vascular disease, and a 32 pack-year cigarette smoking history. Current medications included clopidogrel bisulfate and warfarin sodium to manage a recently placed coronary artery stent.

The tumor was cleared after 2 stages of Mohs micrographic surgery with excision down to tibialis anterior fascia (Figure 1A). The resultant defect measured 43×33 mm in area and 9 mm in depth (wound size, 12,771 mm³). Reconstructive options were discussed, including random-pattern flap repair and skin graft. Given the patient’s risk of bleeding, the decision was made to forego a flap repair. Additionally, the patient was a heavy smoker and could not comply with the wound care and elevation and ambulation restrictions required for optimal skin graft care. Therefore, a decision was made to proceed with secondary intention healing using a methacrylate polymer powder dressing.

After achieving hemostasis, a novel 10-mg sterile, biologically inert methacrylate polymer powder dressing was poured over the wound in a uniform layer to fill and seal the entire wound surface (Figure 1B). Sterile normal saline 0.1 mL was sprayed onto the powder to activate particle aggregation. No secondary dressing was used, and the patient was permitted to get the dressing wet after 48 hours.

The dressing was changed in a similar fashion 4 weeks after application, following gentle debridement with gauze and normal saline. Eight weeks after surgery, the wound exhibited healthy granulation tissue and measured 5×6 mm in area and 2 mm in depth (wound size, 60 mm³), which represented a 99.5% reduction in wound size (Figure 1C). The dressing was not painful, and there were no reported adverse effects. The patient continued to smoke and ambulate fully throughout this period. No antibiotics were used.

Methacrylate polymer powder dressings are a novel and sophisticated dressing modality with great promise for the management of surgical wounds on the lower limb. The dressing is a sterile powder consisting of 84.8% poly-2-hydroxyethylmethacrylate, 14.9% poly-2-hydroxypropylmethacrylate, and 0.3% sodium deoxycholate. These hydrophilic polymers have a covalent methacrylate backbone with a hydroxyl aliphatic side chain. When saline or wound exudate contacts the powder, the spheres hydrate and nonreversibly aggregate to form a moist, flexible dressing that conforms to the topography of the wound and seals it (Figure 2).¹

Once the spheres have aggregated, they are designed to orient in a honeycomb formation with 4- to 10-nm openings that serve as capillary channels (Figure 3). This porous architecture of the polymer is essential for adequate moisture management. It allows for vapor transpiration at a rate of 12 L/m² per day, which ensures the capillary flow from the moist wound surface is evenly distributed through the dressing, contributing to its 68% water content. Notably, this approximately three-fifths water composition is similar to the water makeup of human skin. Optimized moisture management is theorized to enhance epithelial migration, stimulate angiogenesis, retain growth factors, promote autolytic debridement, and maintain ideal voltage and oxygen gradients for wound healing. The risk for infection is not increased by the existence of these pores, as their small size does not allow for bacterial migration.¹

This case demonstrates the effectiveness of using a methacrylate polymer powder dressing to promote timely wound healing in a poorly vascularized lower leg surgical wound. The low maintenance, user-friendly dressing was changed at monthly intervals, which spared the patient the inconvenience and pain associated with the repeated application of more conventional primary and secondary dressings. The dressing was well tolerated and resulted in a 99.5% reduction in wound size. Further studies are needed to investigate the utility of this promising technology.

To the Editor:

Surgical wounds on the lower leg are challenging to manage because venous stasis, bacterial colonization, and high tension may contribute to protracted healing. Advances in technology led to the development of novel, polymer-based wound-healing modalities that hold promise for the management of these wounds.

A 75-year-old man presented with a well-differentiated squamous cell carcinoma with a 3-mm depth of invasion on the left pretibial region. His comorbidities were notable for hypertension, hypercholesterolemia, varicose veins, myocardial infarction, peripheral vascular disease, and a 32 pack-year cigarette smoking history. Current medications included clopidogrel bisulfate and warfarin sodium to manage a recently placed coronary artery stent.

The tumor was cleared after 2 stages of Mohs micrographic surgery with excision down to tibialis anterior fascia (Figure 1A). The resultant defect measured 43×33 mm in area and 9 mm in depth (wound size, 12,771 mm³). Reconstructive options were discussed, including random-pattern flap repair and skin graft. Given the patient’s risk of bleeding, the decision was made to forego a flap repair. Additionally, the patient was a heavy smoker and could not comply with the wound care and elevation and ambulation restrictions required for optimal skin graft care. Therefore, a decision was made to proceed with secondary intention healing using a methacrylate polymer powder dressing.

After achieving hemostasis, a novel 10-mg sterile, biologically inert methacrylate polymer powder dressing was poured over the wound in a uniform layer to fill and seal the entire wound surface (Figure 1B). Sterile normal saline 0.1 mL was sprayed onto the powder to activate particle aggregation. No secondary dressing was used, and the patient was permitted to get the dressing wet after 48 hours.

The dressing was changed in a similar fashion 4 weeks after application, following gentle debridement with gauze and normal saline. Eight weeks after surgery, the wound exhibited healthy granulation tissue and measured 5×6 mm in area and 2 mm in depth (wound size, 60 mm³), which represented a 99.5% reduction in wound size (Figure 1C). The dressing was not painful, and there were no reported adverse effects. The patient continued to smoke and ambulate fully throughout this period. No antibiotics were used.

Methacrylate polymer powder dressings are a novel and sophisticated dressing modality with great promise for the management of surgical wounds on the lower limb. The dressing is a sterile powder consisting of 84.8% poly-2-hydroxyethylmethacrylate, 14.9% poly-2-hydroxypropylmethacrylate, and 0.3% sodium deoxycholate. These hydrophilic polymers have a covalent methacrylate backbone with a hydroxyl aliphatic side chain. When saline or wound exudate contacts the powder, the spheres hydrate and nonreversibly aggregate to form a moist, flexible dressing that conforms to the topography of the wound and seals it (Figure 2).¹

Once the spheres have aggregated, they are designed to orient in a honeycomb formation with 4- to 10-nm openings that serve as capillary channels (Figure 3). This porous architecture of the polymer is essential for adequate moisture management. It allows for vapor transpiration at a rate of 12 L/m² per day, which ensures the capillary flow from the moist wound surface is evenly distributed through the dressing, contributing to its 68% water content. Notably, this approximately three-fifths water composition is similar to the water makeup of human skin. Optimized moisture management is theorized to enhance epithelial migration, stimulate angiogenesis, retain growth factors, promote autolytic debridement, and maintain ideal voltage and oxygen gradients for wound healing. The risk for infection is not increased by the existence of these pores, as their small size does not allow for bacterial migration.¹

This case demonstrates the effectiveness of using a methacrylate polymer powder dressing to promote timely wound healing in a poorly vascularized lower leg surgical wound. The low maintenance, user-friendly dressing was changed at monthly intervals, which spared the patient the inconvenience and pain associated with the repeated application of more conventional primary and secondary dressings. The dressing was well tolerated and resulted in a 99.5% reduction in wound size. Further studies are needed to investigate the utility of this promising technology.

Overall survival has improved in patients with Kaposi’s sarcoma since the introduction of antiretroviral therapy (ART), but those with HIV infection can expect to live shorter lives than their uninfected counterparts, based on the first such analysis of the American College of Surgeons’ National Cancer Database.

One-year overall survival for all patients with Kaposi’s sarcoma (KS), 74.9% in 2004-2007, rose by 6.4 percentage points to 81.3% in 2016-2018, with the use of ART for HIV starting in 2008. Two-year survival was up by an even larger 8.3 percentage points: 68.0% to 76.3%, said Amar D. Desai of New Jersey Medical School, Newark, and Shari R. Lipner, MD, of Weill Cornell Medicine, New York.

Since HIV-infected patients represented a much lower 46.7% of the Kaposi’s population in 2016-2018 than in 2004-2007 (70.5%), “better outcomes for all KS patients likely reflects advancements in ART, preventing many HIV+ patients from progressing to AIDS, changes in clinical practice with earlier treatment start, and more off-label treatments,” they wrote in the Journal of the American Academy of Dermatology.

Overall survival rates for the 10,027 patients with KS with data available in the National Cancer Database were 77.9% at 1 year and 72.4% at 2 years. HIV status had a significant (P < .0074) effect over the entire study period: One-year survival rates were 88.9% for HIV-negative and 74.5% for HIV-positive patients, and 2-year rates were 83.0% (HIV-negative) and 69.3% (HIV-positive), the investigators reported in what they called “the largest analysis since the advent of antiretroviral therapy for HIV in 2008.”

The improvement in overall survival, along with the continued differences in survival between HIV infected and noninfected patients, indicate that “dermatologists, as part of a multidisciplinary team including oncologists and infectious disease physicians, can play significant roles in early KS diagnosis,” Mr. Desai and Dr. Lipner said.

Mr. Desai had no conflicts of interest to report. Dr. Lipner has served as a consultant for Ortho-Dermatologics, Hoth Therapeutics, and BelleTorus Corporation.

Overall survival has improved in patients with Kaposi’s sarcoma since the introduction of antiretroviral therapy (ART), but those with HIV infection can expect to live shorter lives than their uninfected counterparts, based on the first such analysis of the American College of Surgeons’ National Cancer Database.

One-year overall survival for all patients with Kaposi’s sarcoma (KS), 74.9% in 2004-2007, rose by 6.4 percentage points to 81.3% in 2016-2018, with the use of ART for HIV starting in 2008. Two-year survival was up by an even larger 8.3 percentage points: 68.0% to 76.3%, said Amar D. Desai of New Jersey Medical School, Newark, and Shari R. Lipner, MD, of Weill Cornell Medicine, New York.

Since HIV-infected patients represented a much lower 46.7% of the Kaposi’s population in 2016-2018 than in 2004-2007 (70.5%), “better outcomes for all KS patients likely reflects advancements in ART, preventing many HIV+ patients from progressing to AIDS, changes in clinical practice with earlier treatment start, and more off-label treatments,” they wrote in the Journal of the American Academy of Dermatology.

Overall survival rates for the 10,027 patients with KS with data available in the National Cancer Database were 77.9% at 1 year and 72.4% at 2 years. HIV status had a significant (P < .0074) effect over the entire study period: One-year survival rates were 88.9% for HIV-negative and 74.5% for HIV-positive patients, and 2-year rates were 83.0% (HIV-negative) and 69.3% (HIV-positive), the investigators reported in what they called “the largest analysis since the advent of antiretroviral therapy for HIV in 2008.”

The improvement in overall survival, along with the continued differences in survival between HIV infected and noninfected patients, indicate that “dermatologists, as part of a multidisciplinary team including oncologists and infectious disease physicians, can play significant roles in early KS diagnosis,” Mr. Desai and Dr. Lipner said.

Mr. Desai had no conflicts of interest to report. Dr. Lipner has served as a consultant for Ortho-Dermatologics, Hoth Therapeutics, and BelleTorus Corporation.

Overall survival has improved in patients with Kaposi’s sarcoma since the introduction of antiretroviral therapy (ART), but those with HIV infection can expect to live shorter lives than their uninfected counterparts, based on the first such analysis of the American College of Surgeons’ National Cancer Database.

One-year overall survival for all patients with Kaposi’s sarcoma (KS), 74.9% in 2004-2007, rose by 6.4 percentage points to 81.3% in 2016-2018, with the use of ART for HIV starting in 2008. Two-year survival was up by an even larger 8.3 percentage points: 68.0% to 76.3%, said Amar D. Desai of New Jersey Medical School, Newark, and Shari R. Lipner, MD, of Weill Cornell Medicine, New York.

Since HIV-infected patients represented a much lower 46.7% of the Kaposi’s population in 2016-2018 than in 2004-2007 (70.5%), “better outcomes for all KS patients likely reflects advancements in ART, preventing many HIV+ patients from progressing to AIDS, changes in clinical practice with earlier treatment start, and more off-label treatments,” they wrote in the Journal of the American Academy of Dermatology.

Overall survival rates for the 10,027 patients with KS with data available in the National Cancer Database were 77.9% at 1 year and 72.4% at 2 years. HIV status had a significant (P < .0074) effect over the entire study period: One-year survival rates were 88.9% for HIV-negative and 74.5% for HIV-positive patients, and 2-year rates were 83.0% (HIV-negative) and 69.3% (HIV-positive), the investigators reported in what they called “the largest analysis since the advent of antiretroviral therapy for HIV in 2008.”

The improvement in overall survival, along with the continued differences in survival between HIV infected and noninfected patients, indicate that “dermatologists, as part of a multidisciplinary team including oncologists and infectious disease physicians, can play significant roles in early KS diagnosis,” Mr. Desai and Dr. Lipner said.

Mr. Desai had no conflicts of interest to report. Dr. Lipner has served as a consultant for Ortho-Dermatologics, Hoth Therapeutics, and BelleTorus Corporation.

To the Editor:

Angiosarcoma is a malignancy of the vascular endothelium that most commonly presents on the skin.¹ Patients diagnosed with cutaneous angiosarcoma, which is a rare and aggressive malignancy, have a 5-year survival rate of approximately 30%.^2,3 Angiosarcoma can be seen in the setting of chronic lymphedema; radiation therapy; and sporadically in elderly patients, where it is commonly seen on the head and neck. Presentation on the head and neck has been associated with worse outcomes, with a projected overall 10-year survival rate of 13.8%; the survival rate is lower if the tumor is surgically unresectable or larger in size. Metastasis can occur via both lymphatic and hematogenous routes, with pulmonary and hepatic metastases most frequently observed.¹ Prognostications of poor outcomes for patients with head and neck cutaneous angiosarcoma via a 5-year survival rate were identified in a meta-analysis and included the following: patient age older than 70 years, larger tumors, tumor location of scalp vs face, nonsurgical treatments, and lack of clear margins on histology.²

Treatment of angiosarcoma historically has encompassed both surgical resection and adjuvant radiation therapy with suboptimal success. Evidence supporting various treatment regimens remains sparse due to the low incidence of the neoplasm. Although surgical resection is the only documented curative treatment, cutaneous angiosarcomas frequently are found to have positive surgical margins and require adjuvant radiation. Use of high-dose radiation (>50 Gy) with application over a wide treatment area such as total scalp irradiation is recommended.⁴ Although radiation has been found to diminish local recurrence rates, it has not substantially affected rates of distant disease recurrence.¹ Cytotoxic chemotherapy has clinical utility in minimizing progression, but standard regimens afford a progression-free survival of only months.³ Adjuvant treatment with paclitaxel has been shown to have improved efficacy in scalp angiosarcoma vs other visceral sites, showing a nonprogression rate of 42% at 4 months after treatment.⁵ More recently, targeted chemotherapeutics, including the vascular endothelial growth factor inhibitor bevacizumab and tyrosine kinase inhibitor sorafenib, have shown some survival benefit, but it is unclear if these agents are superior to traditional cytotoxic agents.^4,6-10 A phase 2 study of paclitaxel administered weekly with or without bevacizumab showed similar progression-free survival and overall survival, albeit at the expense of added toxicity experienced by participants in the combined group.¹⁰

The addition of the nonselective β-adrenergic blocker propranolol to the treatment armamentarium, which was pursued due to its utility in the treatment of benign infantile hemangioma and demonstrated ability to limit the expression of adrenergic receptors in angiosarcoma, has gained clinical attention for possible augmentation of cutaneous angiosarcoma therapy.^11-14 Propranolol has been shown to reduce metastasis in other neoplasms—both vascular and nonvascular—and may play a role as an adjuvant treatment to current therapies in angiosarcoma.^15-20 We report a patient with cutaneous angiosarcoma (T2 classification) with disease-free survival of nearly 6 years without evidence of recurrence in the setting of continuous propranolol use supplementary to chemotherapy and radiation.

A 78-year-old man with a history of multiple basal cell carcinomas, hypertension, and remote smoking history presented to the dermatology clinic with an enlarging red-brown plaque on the scalp of 2 months’ duration. The lesion had grown rapidly to involve the forehead, right temple, preauricular region, and parietal scalp. At presentation, the tumor measured more than 20 cm in diameter at its greatest point (Figure 1). Physical examination revealed a 6-mm purple nodule within the lesion on the patient’s right parietal scalp. No clinical lymphadenopathy was appreciated at the time of diagnosis. Punch biopsies of the right parietal scalp nodule and right temple patch showed findings consistent with angiosarcoma with diffuse cytoplasmic staining of CD31 in atypical endothelial cells and no staining for human herpesvirus 8 (Figure 2). Concurrent computed tomography of the head showed thickening of the right epidermis, dermis, and deeper scalp tissues, but there was no evidence of skull involvement. Computed tomography of the thorax, abdomen, and pelvis showed no evidence of metastatic disease. After a diagnostic workup, the patient was diagnosed with T2bN0M0 angiosarcoma.

The lesion was determined to be nonresectable due to the extent of the patient’s cutaneous disease. The patient was started on a regimen of paclitaxel, scalp radiation, and oral propranolol. Propranolol 40 mg twice daily was initiated at the time of diagnosis with a plan to continue indefinitely. Starting 1 month after staging, the patient completed 10 weekly cycles of paclitaxel, and he was treated with 60 Gy of scalp radiation in 30 fractions, starting with the second cycle of paclitaxel. He tolerated both well with no reported adverse events. Repeat computed tomography performed 1 month after completion of chemotherapy and radiation showed no evidence of a mass or fluid collection in subcutaneous scalp tissues and no evidence of metastatic disease. This correlated with an observed clinical regression at 1 month and complete clinical response at 5 months with residual hemosiderin and radiation changes. The area of prior disease involvement subsequently evolved from violet to dusky gray in appearance to an eventual complete resolution 26 months after diagnosis, accompanied by atrophic radiation-induced sequelae (Figure 3).

The patient’s postchemotherapy course was complicated by hospitalization for a suspected malignant pleural effusion. Analysis revealed growing ground-glass opacities and nodules in the right lower lung lobe. A thoracentesis with cytology studies was negative for malignancy. Continued monitoring over 19 months demonstrated eventual resolution of those findings. He experienced notable complication from local radiation therapy to the scalp with chronic cutaneous ulceration refractory to wound care and surgical intervention. The patient did not exhibit additional signs or symptoms concerning for recurrence or metastasis and was followed by dermatology and oncology until he died nearly 5 years after initial diagnosis due to complications from acute hypoxic respiratory failure secondary to COVID-19. The last imaging obtained showed no convincing evidence of metastasis, though spinal imaging within a month of his death showed lesions favored to represent benign angiomatous growths. His survival after diagnosis ultimately reached 57 months without confirmed disease recurrence and cause of death unrelated to malignancy history, which is a markedly long documented survival for this extent of disease.

Cutaneous angiosarcoma is an aggressive yet rare malignancy without effective treatments for prolonging survival or eradicating disease. Cutaneous angiosarcoma of the head and neck has a reported 10-year survival rate of 13.8%.¹ Although angiosarcoma in any location holds a bleak prognosis, cutaneous angiosarcoma of the scalp with a T2 classification has a 2-year survival rate of 0%. Moreover, even if remission is achieved, disease is highly recurrent, typically within months with the current standard of care.^3,21,22

Emerging evidence for the possible role of β-adrenergic receptor blockade in the treatment of malignant vascular neoplasms is promising. Microarrays from a host of vascular growths have demonstrated expression of β-adrenergic receptors in 77% of sampled angiosarcoma specimens in addition to strong expression in infantile hemangiomas, hemangiomas, hemangioendotheliomas, and vascular malformations.¹⁹ Research findings have further verified the validity of this approach with the demonstration of b₁-, b₂-, and b₃- adrenergic receptor expression by angiosarcoma cell lines. Propranolol subsequently was shown to effectively target proliferation of these cells and induce apoptosis in a dose-dependent manner and moreover be synergistic in effect with other chemotherapies.¹⁵ Several genes have exhibited differential expression between control tumor cells and propranolol-treated cells. Specifically, target genes including AXL (a receptor tyrosine kinase associated with cell adhesion, proliferation, and apoptosis and found to upregulated in melanoma and leukemia) and ERBB receptor feedback inhibitor 1 (receptor tyrosine kinase, with ERBB family members commonly overexpressed or mutated in the setting malignancy) have been posited as possible explanatory factors in the observed angiosarcoma response to propranolol.²³

Several cases describing propranolol use as an adjunctive therapy for angiosarcoma suggest a beneficial role in clinical medicine. One case report described propranolol monotherapy for lesion to our patient, with a resultant reduction in Ki-67 as a measure of proliferative index within 1 week of initiating propranolol therapy.¹³ Propranolol also has been shown to halt or slow progression of metastatic disease in visceral and metastatic angiosarcomas.^12-14 In combination with oral etoposide and cyclophosphamide, maintenance propranolol therapy in 7 cases of advanced cutaneous angiosarcoma resulted in 1 complete response and 3 very good partial responses, with a median progression-free survival of 11 months.¹¹ Larger-scale studies have not been published, but the growing number of case reports and case series warrants further investigation of the utility of propranolol as an adjunct to current therapies in advanced angiosarcoma.

To the Editor:

Angiosarcoma is a malignancy of the vascular endothelium that most commonly presents on the skin.¹ Patients diagnosed with cutaneous angiosarcoma, which is a rare and aggressive malignancy, have a 5-year survival rate of approximately 30%.^2,3 Angiosarcoma can be seen in the setting of chronic lymphedema; radiation therapy; and sporadically in elderly patients, where it is commonly seen on the head and neck. Presentation on the head and neck has been associated with worse outcomes, with a projected overall 10-year survival rate of 13.8%; the survival rate is lower if the tumor is surgically unresectable or larger in size. Metastasis can occur via both lymphatic and hematogenous routes, with pulmonary and hepatic metastases most frequently observed.¹ Prognostications of poor outcomes for patients with head and neck cutaneous angiosarcoma via a 5-year survival rate were identified in a meta-analysis and included the following: patient age older than 70 years, larger tumors, tumor location of scalp vs face, nonsurgical treatments, and lack of clear margins on histology.²

Treatment of angiosarcoma historically has encompassed both surgical resection and adjuvant radiation therapy with suboptimal success. Evidence supporting various treatment regimens remains sparse due to the low incidence of the neoplasm. Although surgical resection is the only documented curative treatment, cutaneous angiosarcomas frequently are found to have positive surgical margins and require adjuvant radiation. Use of high-dose radiation (>50 Gy) with application over a wide treatment area such as total scalp irradiation is recommended.⁴ Although radiation has been found to diminish local recurrence rates, it has not substantially affected rates of distant disease recurrence.¹ Cytotoxic chemotherapy has clinical utility in minimizing progression, but standard regimens afford a progression-free survival of only months.³ Adjuvant treatment with paclitaxel has been shown to have improved efficacy in scalp angiosarcoma vs other visceral sites, showing a nonprogression rate of 42% at 4 months after treatment.⁵ More recently, targeted chemotherapeutics, including the vascular endothelial growth factor inhibitor bevacizumab and tyrosine kinase inhibitor sorafenib, have shown some survival benefit, but it is unclear if these agents are superior to traditional cytotoxic agents.^4,6-10 A phase 2 study of paclitaxel administered weekly with or without bevacizumab showed similar progression-free survival and overall survival, albeit at the expense of added toxicity experienced by participants in the combined group.¹⁰

The addition of the nonselective β-adrenergic blocker propranolol to the treatment armamentarium, which was pursued due to its utility in the treatment of benign infantile hemangioma and demonstrated ability to limit the expression of adrenergic receptors in angiosarcoma, has gained clinical attention for possible augmentation of cutaneous angiosarcoma therapy.^11-14 Propranolol has been shown to reduce metastasis in other neoplasms—both vascular and nonvascular—and may play a role as an adjuvant treatment to current therapies in angiosarcoma.^15-20 We report a patient with cutaneous angiosarcoma (T2 classification) with disease-free survival of nearly 6 years without evidence of recurrence in the setting of continuous propranolol use supplementary to chemotherapy and radiation.

A 78-year-old man with a history of multiple basal cell carcinomas, hypertension, and remote smoking history presented to the dermatology clinic with an enlarging red-brown plaque on the scalp of 2 months’ duration. The lesion had grown rapidly to involve the forehead, right temple, preauricular region, and parietal scalp. At presentation, the tumor measured more than 20 cm in diameter at its greatest point (Figure 1). Physical examination revealed a 6-mm purple nodule within the lesion on the patient’s right parietal scalp. No clinical lymphadenopathy was appreciated at the time of diagnosis. Punch biopsies of the right parietal scalp nodule and right temple patch showed findings consistent with angiosarcoma with diffuse cytoplasmic staining of CD31 in atypical endothelial cells and no staining for human herpesvirus 8 (Figure 2). Concurrent computed tomography of the head showed thickening of the right epidermis, dermis, and deeper scalp tissues, but there was no evidence of skull involvement. Computed tomography of the thorax, abdomen, and pelvis showed no evidence of metastatic disease. After a diagnostic workup, the patient was diagnosed with T2bN0M0 angiosarcoma.

The lesion was determined to be nonresectable due to the extent of the patient’s cutaneous disease. The patient was started on a regimen of paclitaxel, scalp radiation, and oral propranolol. Propranolol 40 mg twice daily was initiated at the time of diagnosis with a plan to continue indefinitely. Starting 1 month after staging, the patient completed 10 weekly cycles of paclitaxel, and he was treated with 60 Gy of scalp radiation in 30 fractions, starting with the second cycle of paclitaxel. He tolerated both well with no reported adverse events. Repeat computed tomography performed 1 month after completion of chemotherapy and radiation showed no evidence of a mass or fluid collection in subcutaneous scalp tissues and no evidence of metastatic disease. This correlated with an observed clinical regression at 1 month and complete clinical response at 5 months with residual hemosiderin and radiation changes. The area of prior disease involvement subsequently evolved from violet to dusky gray in appearance to an eventual complete resolution 26 months after diagnosis, accompanied by atrophic radiation-induced sequelae (Figure 3).

The patient’s postchemotherapy course was complicated by hospitalization for a suspected malignant pleural effusion. Analysis revealed growing ground-glass opacities and nodules in the right lower lung lobe. A thoracentesis with cytology studies was negative for malignancy. Continued monitoring over 19 months demonstrated eventual resolution of those findings. He experienced notable complication from local radiation therapy to the scalp with chronic cutaneous ulceration refractory to wound care and surgical intervention. The patient did not exhibit additional signs or symptoms concerning for recurrence or metastasis and was followed by dermatology and oncology until he died nearly 5 years after initial diagnosis due to complications from acute hypoxic respiratory failure secondary to COVID-19. The last imaging obtained showed no convincing evidence of metastasis, though spinal imaging within a month of his death showed lesions favored to represent benign angiomatous growths. His survival after diagnosis ultimately reached 57 months without confirmed disease recurrence and cause of death unrelated to malignancy history, which is a markedly long documented survival for this extent of disease.

Cutaneous angiosarcoma is an aggressive yet rare malignancy without effective treatments for prolonging survival or eradicating disease. Cutaneous angiosarcoma of the head and neck has a reported 10-year survival rate of 13.8%.¹ Although angiosarcoma in any location holds a bleak prognosis, cutaneous angiosarcoma of the scalp with a T2 classification has a 2-year survival rate of 0%. Moreover, even if remission is achieved, disease is highly recurrent, typically within months with the current standard of care.^3,21,22

Emerging evidence for the possible role of β-adrenergic receptor blockade in the treatment of malignant vascular neoplasms is promising. Microarrays from a host of vascular growths have demonstrated expression of β-adrenergic receptors in 77% of sampled angiosarcoma specimens in addition to strong expression in infantile hemangiomas, hemangiomas, hemangioendotheliomas, and vascular malformations.¹⁹ Research findings have further verified the validity of this approach with the demonstration of b₁-, b₂-, and b₃- adrenergic receptor expression by angiosarcoma cell lines. Propranolol subsequently was shown to effectively target proliferation of these cells and induce apoptosis in a dose-dependent manner and moreover be synergistic in effect with other chemotherapies.¹⁵ Several genes have exhibited differential expression between control tumor cells and propranolol-treated cells. Specifically, target genes including AXL (a receptor tyrosine kinase associated with cell adhesion, proliferation, and apoptosis and found to upregulated in melanoma and leukemia) and ERBB receptor feedback inhibitor 1 (receptor tyrosine kinase, with ERBB family members commonly overexpressed or mutated in the setting malignancy) have been posited as possible explanatory factors in the observed angiosarcoma response to propranolol.²³

Several cases describing propranolol use as an adjunctive therapy for angiosarcoma suggest a beneficial role in clinical medicine. One case report described propranolol monotherapy for lesion to our patient, with a resultant reduction in Ki-67 as a measure of proliferative index within 1 week of initiating propranolol therapy.¹³ Propranolol also has been shown to halt or slow progression of metastatic disease in visceral and metastatic angiosarcomas.^12-14 In combination with oral etoposide and cyclophosphamide, maintenance propranolol therapy in 7 cases of advanced cutaneous angiosarcoma resulted in 1 complete response and 3 very good partial responses, with a median progression-free survival of 11 months.¹¹ Larger-scale studies have not been published, but the growing number of case reports and case series warrants further investigation of the utility of propranolol as an adjunct to current therapies in advanced angiosarcoma.

To the Editor:

Angiosarcoma is a malignancy of the vascular endothelium that most commonly presents on the skin.¹ Patients diagnosed with cutaneous angiosarcoma, which is a rare and aggressive malignancy, have a 5-year survival rate of approximately 30%.^2,3 Angiosarcoma can be seen in the setting of chronic lymphedema; radiation therapy; and sporadically in elderly patients, where it is commonly seen on the head and neck. Presentation on the head and neck has been associated with worse outcomes, with a projected overall 10-year survival rate of 13.8%; the survival rate is lower if the tumor is surgically unresectable or larger in size. Metastasis can occur via both lymphatic and hematogenous routes, with pulmonary and hepatic metastases most frequently observed.¹ Prognostications of poor outcomes for patients with head and neck cutaneous angiosarcoma via a 5-year survival rate were identified in a meta-analysis and included the following: patient age older than 70 years, larger tumors, tumor location of scalp vs face, nonsurgical treatments, and lack of clear margins on histology.²

Treatment of angiosarcoma historically has encompassed both surgical resection and adjuvant radiation therapy with suboptimal success. Evidence supporting various treatment regimens remains sparse due to the low incidence of the neoplasm. Although surgical resection is the only documented curative treatment, cutaneous angiosarcomas frequently are found to have positive surgical margins and require adjuvant radiation. Use of high-dose radiation (>50 Gy) with application over a wide treatment area such as total scalp irradiation is recommended.⁴ Although radiation has been found to diminish local recurrence rates, it has not substantially affected rates of distant disease recurrence.¹ Cytotoxic chemotherapy has clinical utility in minimizing progression, but standard regimens afford a progression-free survival of only months.³ Adjuvant treatment with paclitaxel has been shown to have improved efficacy in scalp angiosarcoma vs other visceral sites, showing a nonprogression rate of 42% at 4 months after treatment.⁵ More recently, targeted chemotherapeutics, including the vascular endothelial growth factor inhibitor bevacizumab and tyrosine kinase inhibitor sorafenib, have shown some survival benefit, but it is unclear if these agents are superior to traditional cytotoxic agents.^4,6-10 A phase 2 study of paclitaxel administered weekly with or without bevacizumab showed similar progression-free survival and overall survival, albeit at the expense of added toxicity experienced by participants in the combined group.¹⁰

The addition of the nonselective β-adrenergic blocker propranolol to the treatment armamentarium, which was pursued due to its utility in the treatment of benign infantile hemangioma and demonstrated ability to limit the expression of adrenergic receptors in angiosarcoma, has gained clinical attention for possible augmentation of cutaneous angiosarcoma therapy.^11-14 Propranolol has been shown to reduce metastasis in other neoplasms—both vascular and nonvascular—and may play a role as an adjuvant treatment to current therapies in angiosarcoma.^15-20 We report a patient with cutaneous angiosarcoma (T2 classification) with disease-free survival of nearly 6 years without evidence of recurrence in the setting of continuous propranolol use supplementary to chemotherapy and radiation.

A 78-year-old man with a history of multiple basal cell carcinomas, hypertension, and remote smoking history presented to the dermatology clinic with an enlarging red-brown plaque on the scalp of 2 months’ duration. The lesion had grown rapidly to involve the forehead, right temple, preauricular region, and parietal scalp. At presentation, the tumor measured more than 20 cm in diameter at its greatest point (Figure 1). Physical examination revealed a 6-mm purple nodule within the lesion on the patient’s right parietal scalp. No clinical lymphadenopathy was appreciated at the time of diagnosis. Punch biopsies of the right parietal scalp nodule and right temple patch showed findings consistent with angiosarcoma with diffuse cytoplasmic staining of CD31 in atypical endothelial cells and no staining for human herpesvirus 8 (Figure 2). Concurrent computed tomography of the head showed thickening of the right epidermis, dermis, and deeper scalp tissues, but there was no evidence of skull involvement. Computed tomography of the thorax, abdomen, and pelvis showed no evidence of metastatic disease. After a diagnostic workup, the patient was diagnosed with T2bN0M0 angiosarcoma.

The lesion was determined to be nonresectable due to the extent of the patient’s cutaneous disease. The patient was started on a regimen of paclitaxel, scalp radiation, and oral propranolol. Propranolol 40 mg twice daily was initiated at the time of diagnosis with a plan to continue indefinitely. Starting 1 month after staging, the patient completed 10 weekly cycles of paclitaxel, and he was treated with 60 Gy of scalp radiation in 30 fractions, starting with the second cycle of paclitaxel. He tolerated both well with no reported adverse events. Repeat computed tomography performed 1 month after completion of chemotherapy and radiation showed no evidence of a mass or fluid collection in subcutaneous scalp tissues and no evidence of metastatic disease. This correlated with an observed clinical regression at 1 month and complete clinical response at 5 months with residual hemosiderin and radiation changes. The area of prior disease involvement subsequently evolved from violet to dusky gray in appearance to an eventual complete resolution 26 months after diagnosis, accompanied by atrophic radiation-induced sequelae (Figure 3).

The patient’s postchemotherapy course was complicated by hospitalization for a suspected malignant pleural effusion. Analysis revealed growing ground-glass opacities and nodules in the right lower lung lobe. A thoracentesis with cytology studies was negative for malignancy. Continued monitoring over 19 months demonstrated eventual resolution of those findings. He experienced notable complication from local radiation therapy to the scalp with chronic cutaneous ulceration refractory to wound care and surgical intervention. The patient did not exhibit additional signs or symptoms concerning for recurrence or metastasis and was followed by dermatology and oncology until he died nearly 5 years after initial diagnosis due to complications from acute hypoxic respiratory failure secondary to COVID-19. The last imaging obtained showed no convincing evidence of metastasis, though spinal imaging within a month of his death showed lesions favored to represent benign angiomatous growths. His survival after diagnosis ultimately reached 57 months without confirmed disease recurrence and cause of death unrelated to malignancy history, which is a markedly long documented survival for this extent of disease.

Cutaneous angiosarcoma is an aggressive yet rare malignancy without effective treatments for prolonging survival or eradicating disease. Cutaneous angiosarcoma of the head and neck has a reported 10-year survival rate of 13.8%.¹ Although angiosarcoma in any location holds a bleak prognosis, cutaneous angiosarcoma of the scalp with a T2 classification has a 2-year survival rate of 0%. Moreover, even if remission is achieved, disease is highly recurrent, typically within months with the current standard of care.^3,21,22

Emerging evidence for the possible role of β-adrenergic receptor blockade in the treatment of malignant vascular neoplasms is promising. Microarrays from a host of vascular growths have demonstrated expression of β-adrenergic receptors in 77% of sampled angiosarcoma specimens in addition to strong expression in infantile hemangiomas, hemangiomas, hemangioendotheliomas, and vascular malformations.¹⁹ Research findings have further verified the validity of this approach with the demonstration of b₁-, b₂-, and b₃- adrenergic receptor expression by angiosarcoma cell lines. Propranolol subsequently was shown to effectively target proliferation of these cells and induce apoptosis in a dose-dependent manner and moreover be synergistic in effect with other chemotherapies.¹⁵ Several genes have exhibited differential expression between control tumor cells and propranolol-treated cells. Specifically, target genes including AXL (a receptor tyrosine kinase associated with cell adhesion, proliferation, and apoptosis and found to upregulated in melanoma and leukemia) and ERBB receptor feedback inhibitor 1 (receptor tyrosine kinase, with ERBB family members commonly overexpressed or mutated in the setting malignancy) have been posited as possible explanatory factors in the observed angiosarcoma response to propranolol.²³

Several cases describing propranolol use as an adjunctive therapy for angiosarcoma suggest a beneficial role in clinical medicine. One case report described propranolol monotherapy for lesion to our patient, with a resultant reduction in Ki-67 as a measure of proliferative index within 1 week of initiating propranolol therapy.¹³ Propranolol also has been shown to halt or slow progression of metastatic disease in visceral and metastatic angiosarcomas.^12-14 In combination with oral etoposide and cyclophosphamide, maintenance propranolol therapy in 7 cases of advanced cutaneous angiosarcoma resulted in 1 complete response and 3 very good partial responses, with a median progression-free survival of 11 months.¹¹ Larger-scale studies have not been published, but the growing number of case reports and case series warrants further investigation of the utility of propranolol as an adjunct to current therapies in advanced angiosarcoma.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, and cutaneous melanoma is projected to be the fifth most common form of cancer in 2022, with increasing incidence and high potential for mortality.^1-3 Estimates indicate that 35% to 45% of all cancers in White patients are cutaneous, with 4% to 5% occurring in Hispanic patients, 2% to 4% in Asian patients, and 1% to 2% in Black patients.⁴ Of the keratinocyte carcinomas, basal cell carcinoma (BCC) is the most prevalent, projected to affect approximately 33% to 39% of White males and 23% to 28% of White females in the United States during their lifetimes. Squamous cell carcinoma (SCC) is the second most common skin malignancy, with a lifetime risk of 9% to 14% for White males and 4% to 9% for White females in the United States.⁵ The incidence of melanoma continues to increase, with approximately 99,780 new cases expected in the United States in 2022.¹

UV-induced DNA damage plays a key role in the pathogenesis and development of various skin malignancies.⁶ UV radiation from sunlight or tanning devices causes photocarcinogenesis due to molecular and cellular effects, including the generation of reactive oxygen species, DNA damage due to the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone, melanogenesis, apoptosis, and the increased expression of harmful genes and proteins.⁶ The summation of this damage can result in skin malignancies, including NMSC and melanoma.^6,7 Dietary antioxidants theoretically help prevent oxidative reactions from occurring within the body, and it has been suggested that intake of dietary antioxidants may decrease DNA damage and prevent tumorigenesis secondary to UV radiation.⁸ Antioxidants exist naturally in the body but can be acquired exogenously. Investigators have studied dietary antioxidants in preventing skin cancer formation with promising results in the laboratory setting.^8-11 Recently, more robust human studies have been initiated to further delineate this relationship. We present clinical evidence of several frequently utilized antioxidant vitamins and their effects on melanoma and NMSC.

Antioxidants

Vitamin A—Vitamin A is a fat-soluble vitamin found in animal sources, including fish, liver, and eggs. Carotenoids, such as beta carotene, are provitamin A plant derivatives found in fruits and vegetables that are converted into biologically active retinol and retinoic acid.¹² Retinols play a key role in cellular growth and differentiation and are thought to be protective against skin cancer via the inactivation of free radicals and immunologic enhancement due to their antiproliferative, antioxidative, and antiapoptotic effects.^13-16 Animal studies have demonstrated this protective effect and the ability of retinoids to suppress carcinogenesis; however, human studies reveal conflicting results.^17,18

Greenberg et al¹⁹ investigated the use of beta carotene in preventing the formation of NMSC. Patients (N=1805) were randomized to receive 50 mg of beta carotene daily or placebo. Over a 5-year period, there was no significant reduction in the occurrence of NMSC (relative risk [RR], 1.05; 95% CI, 0.91-1.22).¹⁹ Frieling et al²⁰ conducted a similar randomized, double-blind, placebo-controlled trial investigating beta carotene for primary prevention of NMSC in 22,071 healthy male physicians. The study group received 50 mg of beta carotene every other day for 12 years’ duration, and there was no significant effect on the incidence of first NMSC development (RR, 0.98; 95% CI, 0.92-1.05).²⁰

A case-control study by Naldi et al²¹ found an inverse association between vitamin A intake and development of melanoma. Study participants were stratified into quartiles based on level of dietary intake and found an odds ratio (OR) of 0.71 for beta carotene (95% CI, 0.50-1.02), 0.57 for retinol (95% CI, 0.39-0.83), and 0.51 for total vitamin A (95% CI, 0.35-0.75) when comparing the upper quartile of vitamin A intake to the lower quartile. Upper-quartile cutoff values of vitamin A intake were 214 µg/d for beta carotene, 149 µg/d for retinol, and 359 µg/d for total vitamin A.²¹ More recently, a meta-analysis by Zhang et al²² pooled data from 8 case-control studies and 2 prospective studies. Intake of retinol but not total vitamin A or beta carotene was associated with a reduced risk for development of melanoma (retinol: OR, 0.80; 95% CI, 0.69-0.92; total vitamin A: OR, 0.86; 95% CI, 0.59-1.25; beta carotene: OR, 0.87; 95% CI, 0.62-1.20).²² Feskanich et al²³ demonstrated similar findings with use of food-frequency questionnaires in White women, suggesting that retinol intake from food combined with supplements may be protective for women who were otherwise at a low risk for melanoma based on nondietary factors. These factors included painful or blistering sunburns during childhood, history of more than 6 sunburns, more than 3 moles on the left arm, having red or blonde hair, and having a parent or sibling with melanoma (P=.01). However, this relationship did not hold true when looking at women at an intermediate or high risk for melanoma (P=.16 and P=.46).²³

When looking at high-risk patients, such as transplant patients, oral retinoids have been beneficial in preventing NMSC.^24-27 Bavinck et al²⁴ investigated 44 renal transplant patients with a history of more than 10 NMSCs treated with 30 mg of acitretin daily vs placebo. Patients receiving oral retinoid supplementation developed fewer NMSCs over a 6-month treatment period (P=.01).²⁴ Similarly, George et al²⁵ investigated acitretin in renal transplant patients and found a statistically significant decrease in number of SCCs in patients on supplementation (P=.002). Solomon-Cohen et al²⁶ performed a retrospective case-crossover study in solid organ transplant recipients and found that those treated with 10 mg of acitretin daily for 2 years had a significant reduction in the number of new keratinocyte carcinomas (P=.002). Other investigators have demonstrated similar results, and in 2006, Otley et al²⁷ proposed standardized dosing of acitretin for chemoprevention in high-risk patients, including patients developing 5 to 10 NMSCs per year, solid organ transplant recipients, and those with syndromes associated with the development of NMSC.^28,29 Overall, in the general population, vitamin A and related compounds have not demonstrated a significant association with decreased development of NMSC; however, oral retinoids have proven useful for high-risk patients. Furthermore, several studies have suggested a negative association between vitamin A levels and the incidence of melanoma, specifically in the retinol formulation. 

Vitamin B₃—Nicotinamide (also known as niacinamide) is a water-soluble form of vitamin B₃ and is obtained from animal-based and plant-based foods, such as meat, fish, and legumes.³⁰ Nicotinamide plays a key role in cellular metabolism, cellular signaling, and DNA repair, including protection from UV damage within keratinocytes.^31,32 Early mouse models demonstrated decreased formation of skin tumors in mice treated with topical or oral nicotinamide.^32,33 A number of human studies have revealed similar results.^34-36

Chen et al³⁴ conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).³⁴ Drago et al³⁵ specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.³⁵

Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.^34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.^31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.^31,37

Vitamin B₉—Folate, the natural form of vitamin B₉, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.^38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.³⁸ Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.^38,40 Donnenfeld et al⁴¹ conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.⁴¹ Similar effects were observed by Fung et al,⁴² who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).⁴² Fung et al⁴³ also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al⁴⁰ conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.⁴⁰ In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.

Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.^44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.⁴⁴ Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.^46-48 Despite these findings, minimal photoprotective effects have been found in the human population.

Kune et al⁴⁹ performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).⁴⁹ In addition, Vural et al⁵⁰ analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).⁵¹ More recently, Heinen et al⁵² performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).⁵² Similarly, Fung et al⁴² performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).

The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.⁵³ Feskanich et al²³ examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.

Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.⁵⁴ Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.⁵⁴ Vitamin D receptors are expressed on keratinocytes and melanocytes.⁵⁵ Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.⁵⁶ In a mouse model, Ellison et al⁵⁶ found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.

Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.^57-60 Eide et al⁵⁷ studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).⁵⁷ An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.⁵⁸ This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).⁵⁸ Furthermore, Park et al⁶⁰ looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.^59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al⁶³ performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.

Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.⁶⁴ It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.^65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.^64,65

Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.^67,68 Human studies have not consistently shown these effects. Vural et al⁵⁰ investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,⁴² which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted. 

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, and cutaneous melanoma is projected to be the fifth most common form of cancer in 2022, with increasing incidence and high potential for mortality.^1-3 Estimates indicate that 35% to 45% of all cancers in White patients are cutaneous, with 4% to 5% occurring in Hispanic patients, 2% to 4% in Asian patients, and 1% to 2% in Black patients.⁴ Of the keratinocyte carcinomas, basal cell carcinoma (BCC) is the most prevalent, projected to affect approximately 33% to 39% of White males and 23% to 28% of White females in the United States during their lifetimes. Squamous cell carcinoma (SCC) is the second most common skin malignancy, with a lifetime risk of 9% to 14% for White males and 4% to 9% for White females in the United States.⁵ The incidence of melanoma continues to increase, with approximately 99,780 new cases expected in the United States in 2022.¹

UV-induced DNA damage plays a key role in the pathogenesis and development of various skin malignancies.⁶ UV radiation from sunlight or tanning devices causes photocarcinogenesis due to molecular and cellular effects, including the generation of reactive oxygen species, DNA damage due to the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone, melanogenesis, apoptosis, and the increased expression of harmful genes and proteins.⁶ The summation of this damage can result in skin malignancies, including NMSC and melanoma.^6,7 Dietary antioxidants theoretically help prevent oxidative reactions from occurring within the body, and it has been suggested that intake of dietary antioxidants may decrease DNA damage and prevent tumorigenesis secondary to UV radiation.⁸ Antioxidants exist naturally in the body but can be acquired exogenously. Investigators have studied dietary antioxidants in preventing skin cancer formation with promising results in the laboratory setting.^8-11 Recently, more robust human studies have been initiated to further delineate this relationship. We present clinical evidence of several frequently utilized antioxidant vitamins and their effects on melanoma and NMSC.

Antioxidants

Vitamin A—Vitamin A is a fat-soluble vitamin found in animal sources, including fish, liver, and eggs. Carotenoids, such as beta carotene, are provitamin A plant derivatives found in fruits and vegetables that are converted into biologically active retinol and retinoic acid.¹² Retinols play a key role in cellular growth and differentiation and are thought to be protective against skin cancer via the inactivation of free radicals and immunologic enhancement due to their antiproliferative, antioxidative, and antiapoptotic effects.^13-16 Animal studies have demonstrated this protective effect and the ability of retinoids to suppress carcinogenesis; however, human studies reveal conflicting results.^17,18

Greenberg et al¹⁹ investigated the use of beta carotene in preventing the formation of NMSC. Patients (N=1805) were randomized to receive 50 mg of beta carotene daily or placebo. Over a 5-year period, there was no significant reduction in the occurrence of NMSC (relative risk [RR], 1.05; 95% CI, 0.91-1.22).¹⁹ Frieling et al²⁰ conducted a similar randomized, double-blind, placebo-controlled trial investigating beta carotene for primary prevention of NMSC in 22,071 healthy male physicians. The study group received 50 mg of beta carotene every other day for 12 years’ duration, and there was no significant effect on the incidence of first NMSC development (RR, 0.98; 95% CI, 0.92-1.05).²⁰

A case-control study by Naldi et al²¹ found an inverse association between vitamin A intake and development of melanoma. Study participants were stratified into quartiles based on level of dietary intake and found an odds ratio (OR) of 0.71 for beta carotene (95% CI, 0.50-1.02), 0.57 for retinol (95% CI, 0.39-0.83), and 0.51 for total vitamin A (95% CI, 0.35-0.75) when comparing the upper quartile of vitamin A intake to the lower quartile. Upper-quartile cutoff values of vitamin A intake were 214 µg/d for beta carotene, 149 µg/d for retinol, and 359 µg/d for total vitamin A.²¹ More recently, a meta-analysis by Zhang et al²² pooled data from 8 case-control studies and 2 prospective studies. Intake of retinol but not total vitamin A or beta carotene was associated with a reduced risk for development of melanoma (retinol: OR, 0.80; 95% CI, 0.69-0.92; total vitamin A: OR, 0.86; 95% CI, 0.59-1.25; beta carotene: OR, 0.87; 95% CI, 0.62-1.20).²² Feskanich et al²³ demonstrated similar findings with use of food-frequency questionnaires in White women, suggesting that retinol intake from food combined with supplements may be protective for women who were otherwise at a low risk for melanoma based on nondietary factors. These factors included painful or blistering sunburns during childhood, history of more than 6 sunburns, more than 3 moles on the left arm, having red or blonde hair, and having a parent or sibling with melanoma (P=.01). However, this relationship did not hold true when looking at women at an intermediate or high risk for melanoma (P=.16 and P=.46).²³

When looking at high-risk patients, such as transplant patients, oral retinoids have been beneficial in preventing NMSC.^24-27 Bavinck et al²⁴ investigated 44 renal transplant patients with a history of more than 10 NMSCs treated with 30 mg of acitretin daily vs placebo. Patients receiving oral retinoid supplementation developed fewer NMSCs over a 6-month treatment period (P=.01).²⁴ Similarly, George et al²⁵ investigated acitretin in renal transplant patients and found a statistically significant decrease in number of SCCs in patients on supplementation (P=.002). Solomon-Cohen et al²⁶ performed a retrospective case-crossover study in solid organ transplant recipients and found that those treated with 10 mg of acitretin daily for 2 years had a significant reduction in the number of new keratinocyte carcinomas (P=.002). Other investigators have demonstrated similar results, and in 2006, Otley et al²⁷ proposed standardized dosing of acitretin for chemoprevention in high-risk patients, including patients developing 5 to 10 NMSCs per year, solid organ transplant recipients, and those with syndromes associated with the development of NMSC.^28,29 Overall, in the general population, vitamin A and related compounds have not demonstrated a significant association with decreased development of NMSC; however, oral retinoids have proven useful for high-risk patients. Furthermore, several studies have suggested a negative association between vitamin A levels and the incidence of melanoma, specifically in the retinol formulation. 

Vitamin B₃—Nicotinamide (also known as niacinamide) is a water-soluble form of vitamin B₃ and is obtained from animal-based and plant-based foods, such as meat, fish, and legumes.³⁰ Nicotinamide plays a key role in cellular metabolism, cellular signaling, and DNA repair, including protection from UV damage within keratinocytes.^31,32 Early mouse models demonstrated decreased formation of skin tumors in mice treated with topical or oral nicotinamide.^32,33 A number of human studies have revealed similar results.^34-36

Chen et al³⁴ conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).³⁴ Drago et al³⁵ specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.³⁵

Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.^34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.^31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.^31,37

Vitamin B₉—Folate, the natural form of vitamin B₉, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.^38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.³⁸ Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.^38,40 Donnenfeld et al⁴¹ conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.⁴¹ Similar effects were observed by Fung et al,⁴² who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).⁴² Fung et al⁴³ also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al⁴⁰ conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.⁴⁰ In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.

Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.^44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.⁴⁴ Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.^46-48 Despite these findings, minimal photoprotective effects have been found in the human population.

Kune et al⁴⁹ performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).⁴⁹ In addition, Vural et al⁵⁰ analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).⁵¹ More recently, Heinen et al⁵² performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).⁵² Similarly, Fung et al⁴² performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).

The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.⁵³ Feskanich et al²³ examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.

Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.⁵⁴ Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.⁵⁴ Vitamin D receptors are expressed on keratinocytes and melanocytes.⁵⁵ Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.⁵⁶ In a mouse model, Ellison et al⁵⁶ found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.

Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.^57-60 Eide et al⁵⁷ studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).⁵⁷ An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.⁵⁸ This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).⁵⁸ Furthermore, Park et al⁶⁰ looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.^59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al⁶³ performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.

Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.⁶⁴ It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.^65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.^64,65

Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.^67,68 Human studies have not consistently shown these effects. Vural et al⁵⁰ investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,⁴² which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted. 

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, and cutaneous melanoma is projected to be the fifth most common form of cancer in 2022, with increasing incidence and high potential for mortality.^1-3 Estimates indicate that 35% to 45% of all cancers in White patients are cutaneous, with 4% to 5% occurring in Hispanic patients, 2% to 4% in Asian patients, and 1% to 2% in Black patients.⁴ Of the keratinocyte carcinomas, basal cell carcinoma (BCC) is the most prevalent, projected to affect approximately 33% to 39% of White males and 23% to 28% of White females in the United States during their lifetimes. Squamous cell carcinoma (SCC) is the second most common skin malignancy, with a lifetime risk of 9% to 14% for White males and 4% to 9% for White females in the United States.⁵ The incidence of melanoma continues to increase, with approximately 99,780 new cases expected in the United States in 2022.¹

UV-induced DNA damage plays a key role in the pathogenesis and development of various skin malignancies.⁶ UV radiation from sunlight or tanning devices causes photocarcinogenesis due to molecular and cellular effects, including the generation of reactive oxygen species, DNA damage due to the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone, melanogenesis, apoptosis, and the increased expression of harmful genes and proteins.⁶ The summation of this damage can result in skin malignancies, including NMSC and melanoma.^6,7 Dietary antioxidants theoretically help prevent oxidative reactions from occurring within the body, and it has been suggested that intake of dietary antioxidants may decrease DNA damage and prevent tumorigenesis secondary to UV radiation.⁸ Antioxidants exist naturally in the body but can be acquired exogenously. Investigators have studied dietary antioxidants in preventing skin cancer formation with promising results in the laboratory setting.^8-11 Recently, more robust human studies have been initiated to further delineate this relationship. We present clinical evidence of several frequently utilized antioxidant vitamins and their effects on melanoma and NMSC.

Antioxidants

Vitamin A—Vitamin A is a fat-soluble vitamin found in animal sources, including fish, liver, and eggs. Carotenoids, such as beta carotene, are provitamin A plant derivatives found in fruits and vegetables that are converted into biologically active retinol and retinoic acid.¹² Retinols play a key role in cellular growth and differentiation and are thought to be protective against skin cancer via the inactivation of free radicals and immunologic enhancement due to their antiproliferative, antioxidative, and antiapoptotic effects.^13-16 Animal studies have demonstrated this protective effect and the ability of retinoids to suppress carcinogenesis; however, human studies reveal conflicting results.^17,18

Greenberg et al¹⁹ investigated the use of beta carotene in preventing the formation of NMSC. Patients (N=1805) were randomized to receive 50 mg of beta carotene daily or placebo. Over a 5-year period, there was no significant reduction in the occurrence of NMSC (relative risk [RR], 1.05; 95% CI, 0.91-1.22).¹⁹ Frieling et al²⁰ conducted a similar randomized, double-blind, placebo-controlled trial investigating beta carotene for primary prevention of NMSC in 22,071 healthy male physicians. The study group received 50 mg of beta carotene every other day for 12 years’ duration, and there was no significant effect on the incidence of first NMSC development (RR, 0.98; 95% CI, 0.92-1.05).²⁰

A case-control study by Naldi et al²¹ found an inverse association between vitamin A intake and development of melanoma. Study participants were stratified into quartiles based on level of dietary intake and found an odds ratio (OR) of 0.71 for beta carotene (95% CI, 0.50-1.02), 0.57 for retinol (95% CI, 0.39-0.83), and 0.51 for total vitamin A (95% CI, 0.35-0.75) when comparing the upper quartile of vitamin A intake to the lower quartile. Upper-quartile cutoff values of vitamin A intake were 214 µg/d for beta carotene, 149 µg/d for retinol, and 359 µg/d for total vitamin A.²¹ More recently, a meta-analysis by Zhang et al²² pooled data from 8 case-control studies and 2 prospective studies. Intake of retinol but not total vitamin A or beta carotene was associated with a reduced risk for development of melanoma (retinol: OR, 0.80; 95% CI, 0.69-0.92; total vitamin A: OR, 0.86; 95% CI, 0.59-1.25; beta carotene: OR, 0.87; 95% CI, 0.62-1.20).²² Feskanich et al²³ demonstrated similar findings with use of food-frequency questionnaires in White women, suggesting that retinol intake from food combined with supplements may be protective for women who were otherwise at a low risk for melanoma based on nondietary factors. These factors included painful or blistering sunburns during childhood, history of more than 6 sunburns, more than 3 moles on the left arm, having red or blonde hair, and having a parent or sibling with melanoma (P=.01). However, this relationship did not hold true when looking at women at an intermediate or high risk for melanoma (P=.16 and P=.46).²³

When looking at high-risk patients, such as transplant patients, oral retinoids have been beneficial in preventing NMSC.^24-27 Bavinck et al²⁴ investigated 44 renal transplant patients with a history of more than 10 NMSCs treated with 30 mg of acitretin daily vs placebo. Patients receiving oral retinoid supplementation developed fewer NMSCs over a 6-month treatment period (P=.01).²⁴ Similarly, George et al²⁵ investigated acitretin in renal transplant patients and found a statistically significant decrease in number of SCCs in patients on supplementation (P=.002). Solomon-Cohen et al²⁶ performed a retrospective case-crossover study in solid organ transplant recipients and found that those treated with 10 mg of acitretin daily for 2 years had a significant reduction in the number of new keratinocyte carcinomas (P=.002). Other investigators have demonstrated similar results, and in 2006, Otley et al²⁷ proposed standardized dosing of acitretin for chemoprevention in high-risk patients, including patients developing 5 to 10 NMSCs per year, solid organ transplant recipients, and those with syndromes associated with the development of NMSC.^28,29 Overall, in the general population, vitamin A and related compounds have not demonstrated a significant association with decreased development of NMSC; however, oral retinoids have proven useful for high-risk patients. Furthermore, several studies have suggested a negative association between vitamin A levels and the incidence of melanoma, specifically in the retinol formulation. 

Vitamin B₃—Nicotinamide (also known as niacinamide) is a water-soluble form of vitamin B₃ and is obtained from animal-based and plant-based foods, such as meat, fish, and legumes.³⁰ Nicotinamide plays a key role in cellular metabolism, cellular signaling, and DNA repair, including protection from UV damage within keratinocytes.^31,32 Early mouse models demonstrated decreased formation of skin tumors in mice treated with topical or oral nicotinamide.^32,33 A number of human studies have revealed similar results.^34-36

Chen et al³⁴ conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).³⁴ Drago et al³⁵ specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.³⁵

Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.^34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.^31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.^31,37

Vitamin B₉—Folate, the natural form of vitamin B₉, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.^38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.³⁸ Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.^38,40 Donnenfeld et al⁴¹ conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.⁴¹ Similar effects were observed by Fung et al,⁴² who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).⁴² Fung et al⁴³ also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al⁴⁰ conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.⁴⁰ In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.

Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.^44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.⁴⁴ Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.^46-48 Despite these findings, minimal photoprotective effects have been found in the human population.

Kune et al⁴⁹ performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).⁴⁹ In addition, Vural et al⁵⁰ analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).⁵¹ More recently, Heinen et al⁵² performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).⁵² Similarly, Fung et al⁴² performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).

The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.⁵³ Feskanich et al²³ examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.

Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.⁵⁴ Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.⁵⁴ Vitamin D receptors are expressed on keratinocytes and melanocytes.⁵⁵ Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.⁵⁶ In a mouse model, Ellison et al⁵⁶ found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.

Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.^57-60 Eide et al⁵⁷ studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).⁵⁷ An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.⁵⁸ This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).⁵⁸ Furthermore, Park et al⁶⁰ looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.^59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al⁶³ performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.

Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.⁶⁴ It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.^65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.^64,65

Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.^67,68 Human studies have not consistently shown these effects. Vural et al⁵⁰ investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,⁴² which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted. 

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly.¹ Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon type IV hypersensitivity reaction reported most commonly in association with β-lactam antibiotics and other medications.² Treatment of SDRIFE generally involves withdrawing the inciting medication; however, in SDRIFE secondary to oncologic therapies, medication withdrawal may not be feasible or desirable. We present 2 cases of SDRIFE secondary to EGFR inhibitors in which treatment was continued alongside supportive skin-directed therapies. We also review the literature.

Case Reports

Patient 1—A 65-year-old man with stage IV non–small cell lung cancer presented to the dermatology clinic with an eruption of 2 months’ duration that began in the periumbilical area and spread to the perianal area within 2 weeks of starting treatment with lazertinib and amivantamab. Physical examination was notable for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 periumbilical erythema and erosions as well as symmetric red-brown patches with linear erosions in the gluteal cleft (Figure 1) and Grade 2 facial papulopustular rash. Herpes simplex virus polymerase chain reaction and bacterial culture were negative. A skin biopsy from the left buttock revealed dermal edema and a perivascular lymphocytic infiltrate compatible with SDRIFE. Triamcinolone ointment 0.1% twice daily was initiated, then uptitrated to betamethasone ointment 0.05% twice daily with moderate improvement. The patient had a treatment interruption due to malignancy complications, at which time his skin improved, with recurrence of the eruption after treatment re-initiation. He resumed skin-directed treatment and was maintained on betamethasone ointment 0.05% and tacrolimus ointment 0.1% twice daily on alternating days. This treatment was continued for 4 months before the patient died from complications of the malignancy.

Patient 2—A 68-year-old woman with stage IV lung adenocarcinoma presented to the dermatology clinic with a rash of 3 weeks’ duration. Treatment with osimertinib was initiated 8 months prior to presentation, and there were no recent medication changes. Physical examination revealed CTCAE Grade 2 erythematous patches in the inguinal folds (Figure 2A), inframammary folds (Figure 2B), and on the nasal tip, as well as Grade 2 paronychia. The patient was managed with hydrocortisone cream 1% twice daily, and osimertinib was continued. At follow-up 4 weeks later, the erythema had faded to hyperpigmentation in affected areas with resolution of symptoms. No further treatment was required.

Comment

Supportive oncodermatologists and dermatology hospitalists should be aware of SDRIFE as an uncommon but increasingly recognized cutaneous AE of EGFR inhibitors. Other cases of SDRIFE secondary to EGFR inhibition are described in the Table.^2-5 Although SDRIFE typically is treated by discontinuation of the offending agent, in all reported cases of EGFR inhibitor–associated SDRIFE the rash was CTCAE Grade 2, meaning that it did not interfere with instrumental activities of daily living. In 5 of 6 cases, EGFR therapy was continued while skin-directed therapies were used for symptom management.

Presentation of SDRIFE—Symmetrical drug-related intertriginous and flexural exanthema is characterized by a symmetric, sharply demarcated erythema in the inguinal, gluteal, or perianal area with at least 1 other flexural localization involved in the absence of systemic signs. It is observed most frequently at initial exposure or re-exposure to a medication. Onset typically is within a few hours to a few days after exposure to a medication.⁶ Interestingly, in this case series, half of reported SDRIFE cases developed 8 months or more after EGFR inhibitor initiation.

Pathophysiology of SDRIFE—The mechanism of SDRIFE has not been clearly elucidated; it generally is accepted to be a delayed-type hypersensitivity drug reaction, though other proposed pathophysiologic mechanisms for the distribution of SDRIFE include recall phenomenon or predisposing anatomic factors such as temperature, humidity, and apocrine or eccrine gland density.^6,7 Epidermal growth factor receptor plays a critical role in regulating differentiation and proliferation of epidermal keratinocytes, hair follicles, and the sweat gland apparatus. Additionally, it has been hypothesized that EGFR inhibitor use may affect the microflora of the skin and that EGFR inhibitors directly affect the immune system, as demonstrated in an experiment showing EGFR inhibitor–treated mice had enhanced skin inflammation and contact hypersensitivity responses.⁸ How these disparate mechanisms may interact to produce SDRIFE and the reason for the notably delayed presentation of SDRIFE in half of the cases we reviewed is not known. Other delayed cutaneous AEs of EGFR inhibitor therapy, such as paronychia, are thought to be secondary to development of skin fragility and decreased keratinocyte proliferation with secondary infection.¹ It is conceivable that a combination of proliferative, immunologic, and microbiome-related factors may each be playing a role in EGFR inhibitor–related SDRIFE.

Dermatology Inpatient Considerations—As seen in our cases, dermatologists can play a valuable role in diagnosing, grading, and managing cutaneous AEs associated with the administration of oncologic therapies. The array of cutaneous AEs has grown as cancer treatment options have expanded from conventional antimetabolite agents to kinase inhibitors and immune checkpoint inhibitors. Dermatologists may play an important role in differentiating the etiology of a skin finding (eg, infectious vs inflammatory) and can identify serious or dose-limiting reactions, such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). If cutaneous AEs appear to occur secondary to administration of a chemotherapeutic agent, use of the National Cancer Institute CTCAE should be employed. For certain AEs (eg, alopecia, acneiform rashes, bullous dermatitis), specific grading has been developed based on a combination of body surface area involved, psychosocial impact, symptoms, and other associated morbidity.⁹

In management of chemotherapy-associated cutaneous AEs, dermatologists are likely to be the members of the health care team most comfortable with prescribing high-potency anti-inflammatory topical medications. Dermatologic consultation for management of cutaneous AEs has been shown to both reduce the need for systemic immunosuppression and limit interruptions in oncologic treatment.¹⁰

Conclusion

Epidermal growth factor receptor inhibitors commonly are prescribed for colorectal cancer, non–small cell lung cancer, and squamous cell carcinoma of the head and neck. They are associated with a variety of cutaneous AEs, including acneiform eruptions, paronychia, and xerosis, which rarely necessitate stopping EGFR inhibitor therapy. Our cases support an approach to managing EGFR inhibitor–related SDRIFE that does not involve discontinuation of the offending agent. Further studies are needed on the best supportive topical and systemic regimens for EGFR inhibitor–associated SDRIFE.

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly.¹ Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon type IV hypersensitivity reaction reported most commonly in association with β-lactam antibiotics and other medications.² Treatment of SDRIFE generally involves withdrawing the inciting medication; however, in SDRIFE secondary to oncologic therapies, medication withdrawal may not be feasible or desirable. We present 2 cases of SDRIFE secondary to EGFR inhibitors in which treatment was continued alongside supportive skin-directed therapies. We also review the literature.

Case Reports

Patient 1—A 65-year-old man with stage IV non–small cell lung cancer presented to the dermatology clinic with an eruption of 2 months’ duration that began in the periumbilical area and spread to the perianal area within 2 weeks of starting treatment with lazertinib and amivantamab. Physical examination was notable for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 periumbilical erythema and erosions as well as symmetric red-brown patches with linear erosions in the gluteal cleft (Figure 1) and Grade 2 facial papulopustular rash. Herpes simplex virus polymerase chain reaction and bacterial culture were negative. A skin biopsy from the left buttock revealed dermal edema and a perivascular lymphocytic infiltrate compatible with SDRIFE. Triamcinolone ointment 0.1% twice daily was initiated, then uptitrated to betamethasone ointment 0.05% twice daily with moderate improvement. The patient had a treatment interruption due to malignancy complications, at which time his skin improved, with recurrence of the eruption after treatment re-initiation. He resumed skin-directed treatment and was maintained on betamethasone ointment 0.05% and tacrolimus ointment 0.1% twice daily on alternating days. This treatment was continued for 4 months before the patient died from complications of the malignancy.

Patient 2—A 68-year-old woman with stage IV lung adenocarcinoma presented to the dermatology clinic with a rash of 3 weeks’ duration. Treatment with osimertinib was initiated 8 months prior to presentation, and there were no recent medication changes. Physical examination revealed CTCAE Grade 2 erythematous patches in the inguinal folds (Figure 2A), inframammary folds (Figure 2B), and on the nasal tip, as well as Grade 2 paronychia. The patient was managed with hydrocortisone cream 1% twice daily, and osimertinib was continued. At follow-up 4 weeks later, the erythema had faded to hyperpigmentation in affected areas with resolution of symptoms. No further treatment was required.

Comment

Supportive oncodermatologists and dermatology hospitalists should be aware of SDRIFE as an uncommon but increasingly recognized cutaneous AE of EGFR inhibitors. Other cases of SDRIFE secondary to EGFR inhibition are described in the Table.^2-5 Although SDRIFE typically is treated by discontinuation of the offending agent, in all reported cases of EGFR inhibitor–associated SDRIFE the rash was CTCAE Grade 2, meaning that it did not interfere with instrumental activities of daily living. In 5 of 6 cases, EGFR therapy was continued while skin-directed therapies were used for symptom management.

Presentation of SDRIFE—Symmetrical drug-related intertriginous and flexural exanthema is characterized by a symmetric, sharply demarcated erythema in the inguinal, gluteal, or perianal area with at least 1 other flexural localization involved in the absence of systemic signs. It is observed most frequently at initial exposure or re-exposure to a medication. Onset typically is within a few hours to a few days after exposure to a medication.⁶ Interestingly, in this case series, half of reported SDRIFE cases developed 8 months or more after EGFR inhibitor initiation.

Pathophysiology of SDRIFE—The mechanism of SDRIFE has not been clearly elucidated; it generally is accepted to be a delayed-type hypersensitivity drug reaction, though other proposed pathophysiologic mechanisms for the distribution of SDRIFE include recall phenomenon or predisposing anatomic factors such as temperature, humidity, and apocrine or eccrine gland density.^6,7 Epidermal growth factor receptor plays a critical role in regulating differentiation and proliferation of epidermal keratinocytes, hair follicles, and the sweat gland apparatus. Additionally, it has been hypothesized that EGFR inhibitor use may affect the microflora of the skin and that EGFR inhibitors directly affect the immune system, as demonstrated in an experiment showing EGFR inhibitor–treated mice had enhanced skin inflammation and contact hypersensitivity responses.⁸ How these disparate mechanisms may interact to produce SDRIFE and the reason for the notably delayed presentation of SDRIFE in half of the cases we reviewed is not known. Other delayed cutaneous AEs of EGFR inhibitor therapy, such as paronychia, are thought to be secondary to development of skin fragility and decreased keratinocyte proliferation with secondary infection.¹ It is conceivable that a combination of proliferative, immunologic, and microbiome-related factors may each be playing a role in EGFR inhibitor–related SDRIFE.

Dermatology Inpatient Considerations—As seen in our cases, dermatologists can play a valuable role in diagnosing, grading, and managing cutaneous AEs associated with the administration of oncologic therapies. The array of cutaneous AEs has grown as cancer treatment options have expanded from conventional antimetabolite agents to kinase inhibitors and immune checkpoint inhibitors. Dermatologists may play an important role in differentiating the etiology of a skin finding (eg, infectious vs inflammatory) and can identify serious or dose-limiting reactions, such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). If cutaneous AEs appear to occur secondary to administration of a chemotherapeutic agent, use of the National Cancer Institute CTCAE should be employed. For certain AEs (eg, alopecia, acneiform rashes, bullous dermatitis), specific grading has been developed based on a combination of body surface area involved, psychosocial impact, symptoms, and other associated morbidity.⁹

In management of chemotherapy-associated cutaneous AEs, dermatologists are likely to be the members of the health care team most comfortable with prescribing high-potency anti-inflammatory topical medications. Dermatologic consultation for management of cutaneous AEs has been shown to both reduce the need for systemic immunosuppression and limit interruptions in oncologic treatment.¹⁰

Conclusion

Epidermal growth factor receptor inhibitors commonly are prescribed for colorectal cancer, non–small cell lung cancer, and squamous cell carcinoma of the head and neck. They are associated with a variety of cutaneous AEs, including acneiform eruptions, paronychia, and xerosis, which rarely necessitate stopping EGFR inhibitor therapy. Our cases support an approach to managing EGFR inhibitor–related SDRIFE that does not involve discontinuation of the offending agent. Further studies are needed on the best supportive topical and systemic regimens for EGFR inhibitor–associated SDRIFE.

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly.¹ Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon type IV hypersensitivity reaction reported most commonly in association with β-lactam antibiotics and other medications.² Treatment of SDRIFE generally involves withdrawing the inciting medication; however, in SDRIFE secondary to oncologic therapies, medication withdrawal may not be feasible or desirable. We present 2 cases of SDRIFE secondary to EGFR inhibitors in which treatment was continued alongside supportive skin-directed therapies. We also review the literature.

Case Reports

Patient 1—A 65-year-old man with stage IV non–small cell lung cancer presented to the dermatology clinic with an eruption of 2 months’ duration that began in the periumbilical area and spread to the perianal area within 2 weeks of starting treatment with lazertinib and amivantamab. Physical examination was notable for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 periumbilical erythema and erosions as well as symmetric red-brown patches with linear erosions in the gluteal cleft (Figure 1) and Grade 2 facial papulopustular rash. Herpes simplex virus polymerase chain reaction and bacterial culture were negative. A skin biopsy from the left buttock revealed dermal edema and a perivascular lymphocytic infiltrate compatible with SDRIFE. Triamcinolone ointment 0.1% twice daily was initiated, then uptitrated to betamethasone ointment 0.05% twice daily with moderate improvement. The patient had a treatment interruption due to malignancy complications, at which time his skin improved, with recurrence of the eruption after treatment re-initiation. He resumed skin-directed treatment and was maintained on betamethasone ointment 0.05% and tacrolimus ointment 0.1% twice daily on alternating days. This treatment was continued for 4 months before the patient died from complications of the malignancy.

Patient 2—A 68-year-old woman with stage IV lung adenocarcinoma presented to the dermatology clinic with a rash of 3 weeks’ duration. Treatment with osimertinib was initiated 8 months prior to presentation, and there were no recent medication changes. Physical examination revealed CTCAE Grade 2 erythematous patches in the inguinal folds (Figure 2A), inframammary folds (Figure 2B), and on the nasal tip, as well as Grade 2 paronychia. The patient was managed with hydrocortisone cream 1% twice daily, and osimertinib was continued. At follow-up 4 weeks later, the erythema had faded to hyperpigmentation in affected areas with resolution of symptoms. No further treatment was required.

Comment

Supportive oncodermatologists and dermatology hospitalists should be aware of SDRIFE as an uncommon but increasingly recognized cutaneous AE of EGFR inhibitors. Other cases of SDRIFE secondary to EGFR inhibition are described in the Table.^2-5 Although SDRIFE typically is treated by discontinuation of the offending agent, in all reported cases of EGFR inhibitor–associated SDRIFE the rash was CTCAE Grade 2, meaning that it did not interfere with instrumental activities of daily living. In 5 of 6 cases, EGFR therapy was continued while skin-directed therapies were used for symptom management.

Presentation of SDRIFE—Symmetrical drug-related intertriginous and flexural exanthema is characterized by a symmetric, sharply demarcated erythema in the inguinal, gluteal, or perianal area with at least 1 other flexural localization involved in the absence of systemic signs. It is observed most frequently at initial exposure or re-exposure to a medication. Onset typically is within a few hours to a few days after exposure to a medication.⁶ Interestingly, in this case series, half of reported SDRIFE cases developed 8 months or more after EGFR inhibitor initiation.

Pathophysiology of SDRIFE—The mechanism of SDRIFE has not been clearly elucidated; it generally is accepted to be a delayed-type hypersensitivity drug reaction, though other proposed pathophysiologic mechanisms for the distribution of SDRIFE include recall phenomenon or predisposing anatomic factors such as temperature, humidity, and apocrine or eccrine gland density.^6,7 Epidermal growth factor receptor plays a critical role in regulating differentiation and proliferation of epidermal keratinocytes, hair follicles, and the sweat gland apparatus. Additionally, it has been hypothesized that EGFR inhibitor use may affect the microflora of the skin and that EGFR inhibitors directly affect the immune system, as demonstrated in an experiment showing EGFR inhibitor–treated mice had enhanced skin inflammation and contact hypersensitivity responses.⁸ How these disparate mechanisms may interact to produce SDRIFE and the reason for the notably delayed presentation of SDRIFE in half of the cases we reviewed is not known. Other delayed cutaneous AEs of EGFR inhibitor therapy, such as paronychia, are thought to be secondary to development of skin fragility and decreased keratinocyte proliferation with secondary infection.¹ It is conceivable that a combination of proliferative, immunologic, and microbiome-related factors may each be playing a role in EGFR inhibitor–related SDRIFE.

Dermatology Inpatient Considerations—As seen in our cases, dermatologists can play a valuable role in diagnosing, grading, and managing cutaneous AEs associated with the administration of oncologic therapies. The array of cutaneous AEs has grown as cancer treatment options have expanded from conventional antimetabolite agents to kinase inhibitors and immune checkpoint inhibitors. Dermatologists may play an important role in differentiating the etiology of a skin finding (eg, infectious vs inflammatory) and can identify serious or dose-limiting reactions, such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). If cutaneous AEs appear to occur secondary to administration of a chemotherapeutic agent, use of the National Cancer Institute CTCAE should be employed. For certain AEs (eg, alopecia, acneiform rashes, bullous dermatitis), specific grading has been developed based on a combination of body surface area involved, psychosocial impact, symptoms, and other associated morbidity.⁹

In management of chemotherapy-associated cutaneous AEs, dermatologists are likely to be the members of the health care team most comfortable with prescribing high-potency anti-inflammatory topical medications. Dermatologic consultation for management of cutaneous AEs has been shown to both reduce the need for systemic immunosuppression and limit interruptions in oncologic treatment.¹⁰

Conclusion

Epidermal growth factor receptor inhibitors commonly are prescribed for colorectal cancer, non–small cell lung cancer, and squamous cell carcinoma of the head and neck. They are associated with a variety of cutaneous AEs, including acneiform eruptions, paronychia, and xerosis, which rarely necessitate stopping EGFR inhibitor therapy. Our cases support an approach to managing EGFR inhibitor–related SDRIFE that does not involve discontinuation of the offending agent. Further studies are needed on the best supportive topical and systemic regimens for EGFR inhibitor–associated SDRIFE.