Nonmelanoma Skin Cancer

Practice Gap

Common donor sites for split-thickness skin grafts (STSGs) include the abdomen, buttocks, inner upper arms and forearms, and thighs. Challenges associated with donor site wounds in these areas include slow healing times and poor scar cosmesis. Although the scalp is not commonly considered when selecting a STSG donor site, harvesting from this area yields optimal results to improve these shortcomings.

Tools

A Weck knife facilitates STSG harvesting in an operationally timely, convenient fashion from larger donor sites up to 5.5 cm in width, such as the scalp, using adjustable thickness control guards.

The Technique

The donor site is lubricated with a sterile mineral oil. An assistant provides tension, leading the trajectory of the Weck knife with a guard. Small, gentle, back-and-forth strokes are made with the Weck knife to harvest the graft, which is then meshed with a No. 15 blade by placing the belly of the blade on the tissue and rolling it to-and-fro. The recipient site cartilage is fenestrated with a 2-mm punch biopsy.

A 48-year-old man underwent Mohs micrographic surgery for treatment of a primary basal cell carcinoma of the left helix, resulting in a 2.5×1.3-cm defect after 2 stages. A Weck knife with a 0.012-in guard was used to harvest an STSG from the postauricular scalp (Figure, A), and the graft was inset to the recipient wound bed. Hemostasis at the scalp donor site was achieved through application of pressure and sterile gauze that was saturated with local 1% lidocaine anesthesia containing 1:400,000 epinephrine. Both recipient and donor sites were dressed with tie-over bolsters that were sutured into place. At 2-week follow-up, the donor site was fully reepithelialized and hair regrowth obscured the defect (Figure, B).

Practice Implications

Our case demonstrates the advantages of the scalp as an STSG donor site with prompt healing time and excellent cosmesis. Because grafts are harvested at a depth superficial to the hair follicle, the hair regrows to conceal the donor site scar. Additionally, the robust blood supply of the scalp and hair follicle density optimize healing time. The location of the donor site at the postauricular scalp facilitates accessibility for wound care by the patient. Electrocautery or chemical styptics used for hemostasis may traumatize the hair follicles and risk causing alopecia; therefore, as demonstrated in our case, the preferred method to achieve hemostasis is the use of pressure or application of sterile gauze that has been saturated with local 1% lidocaine anesthesia containing 1:400,000 epinephrine, followed by a pressure dressing provided by a sutured bolster.

Our case also demonstrates the utility of the Weck knife, which was introduced in 1968 as a modification of existing instruments to improve the ease of harvesting STSGs by appending a fixed handle and interchangeable depth gauges to a straight razor.^1,2 The Weck knife can obtain grafts up to 5.5 cm in width (length may be as long as anatomically available), often circumventing the need to overlap grafts of smaller widths for repair of larger defects. Furthermore, grafts are harvested at a depth superficial to the hair follicle, averting donor site alopecia. These characteristics make the technique an ideal option for harvesting grafts from the scalp and other large donor sites.

Limitations of the Weck knife technique include the inability to harvest grafts from small donor sites in difficult-to-access anatomic regions or from areas with notable 3-dimensional structure. For harvesting such grafts, we prefer the DermaBlade (AccuTec Blades). Furthermore, assistance for providing tension along the trajectory of the Weck blade with a guard is optimal when performing the procedure. For practices not already utilizing a Weck knife, the technique necessitates additional training and cost. Nonetheless, for STSGs in which large donor site surface area, adjustable thickness, and convenient and timely operational technique are desired, the Weck knife should be considered as part of the dermatologic surgeon’s armamentarium.

Practice Gap

Common donor sites for split-thickness skin grafts (STSGs) include the abdomen, buttocks, inner upper arms and forearms, and thighs. Challenges associated with donor site wounds in these areas include slow healing times and poor scar cosmesis. Although the scalp is not commonly considered when selecting a STSG donor site, harvesting from this area yields optimal results to improve these shortcomings.

Tools

A Weck knife facilitates STSG harvesting in an operationally timely, convenient fashion from larger donor sites up to 5.5 cm in width, such as the scalp, using adjustable thickness control guards.

The Technique

The donor site is lubricated with a sterile mineral oil. An assistant provides tension, leading the trajectory of the Weck knife with a guard. Small, gentle, back-and-forth strokes are made with the Weck knife to harvest the graft, which is then meshed with a No. 15 blade by placing the belly of the blade on the tissue and rolling it to-and-fro. The recipient site cartilage is fenestrated with a 2-mm punch biopsy.

A 48-year-old man underwent Mohs micrographic surgery for treatment of a primary basal cell carcinoma of the left helix, resulting in a 2.5×1.3-cm defect after 2 stages. A Weck knife with a 0.012-in guard was used to harvest an STSG from the postauricular scalp (Figure, A), and the graft was inset to the recipient wound bed. Hemostasis at the scalp donor site was achieved through application of pressure and sterile gauze that was saturated with local 1% lidocaine anesthesia containing 1:400,000 epinephrine. Both recipient and donor sites were dressed with tie-over bolsters that were sutured into place. At 2-week follow-up, the donor site was fully reepithelialized and hair regrowth obscured the defect (Figure, B).

Practice Implications

Our case demonstrates the advantages of the scalp as an STSG donor site with prompt healing time and excellent cosmesis. Because grafts are harvested at a depth superficial to the hair follicle, the hair regrows to conceal the donor site scar. Additionally, the robust blood supply of the scalp and hair follicle density optimize healing time. The location of the donor site at the postauricular scalp facilitates accessibility for wound care by the patient. Electrocautery or chemical styptics used for hemostasis may traumatize the hair follicles and risk causing alopecia; therefore, as demonstrated in our case, the preferred method to achieve hemostasis is the use of pressure or application of sterile gauze that has been saturated with local 1% lidocaine anesthesia containing 1:400,000 epinephrine, followed by a pressure dressing provided by a sutured bolster.

Our case also demonstrates the utility of the Weck knife, which was introduced in 1968 as a modification of existing instruments to improve the ease of harvesting STSGs by appending a fixed handle and interchangeable depth gauges to a straight razor.^1,2 The Weck knife can obtain grafts up to 5.5 cm in width (length may be as long as anatomically available), often circumventing the need to overlap grafts of smaller widths for repair of larger defects. Furthermore, grafts are harvested at a depth superficial to the hair follicle, averting donor site alopecia. These characteristics make the technique an ideal option for harvesting grafts from the scalp and other large donor sites.

Limitations of the Weck knife technique include the inability to harvest grafts from small donor sites in difficult-to-access anatomic regions or from areas with notable 3-dimensional structure. For harvesting such grafts, we prefer the DermaBlade (AccuTec Blades). Furthermore, assistance for providing tension along the trajectory of the Weck blade with a guard is optimal when performing the procedure. For practices not already utilizing a Weck knife, the technique necessitates additional training and cost. Nonetheless, for STSGs in which large donor site surface area, adjustable thickness, and convenient and timely operational technique are desired, the Weck knife should be considered as part of the dermatologic surgeon’s armamentarium.

Practice Gap

Common donor sites for split-thickness skin grafts (STSGs) include the abdomen, buttocks, inner upper arms and forearms, and thighs. Challenges associated with donor site wounds in these areas include slow healing times and poor scar cosmesis. Although the scalp is not commonly considered when selecting a STSG donor site, harvesting from this area yields optimal results to improve these shortcomings.

Tools

A Weck knife facilitates STSG harvesting in an operationally timely, convenient fashion from larger donor sites up to 5.5 cm in width, such as the scalp, using adjustable thickness control guards.

The Technique

The donor site is lubricated with a sterile mineral oil. An assistant provides tension, leading the trajectory of the Weck knife with a guard. Small, gentle, back-and-forth strokes are made with the Weck knife to harvest the graft, which is then meshed with a No. 15 blade by placing the belly of the blade on the tissue and rolling it to-and-fro. The recipient site cartilage is fenestrated with a 2-mm punch biopsy.

A 48-year-old man underwent Mohs micrographic surgery for treatment of a primary basal cell carcinoma of the left helix, resulting in a 2.5×1.3-cm defect after 2 stages. A Weck knife with a 0.012-in guard was used to harvest an STSG from the postauricular scalp (Figure, A), and the graft was inset to the recipient wound bed. Hemostasis at the scalp donor site was achieved through application of pressure and sterile gauze that was saturated with local 1% lidocaine anesthesia containing 1:400,000 epinephrine. Both recipient and donor sites were dressed with tie-over bolsters that were sutured into place. At 2-week follow-up, the donor site was fully reepithelialized and hair regrowth obscured the defect (Figure, B).

Practice Implications

Our case demonstrates the advantages of the scalp as an STSG donor site with prompt healing time and excellent cosmesis. Because grafts are harvested at a depth superficial to the hair follicle, the hair regrows to conceal the donor site scar. Additionally, the robust blood supply of the scalp and hair follicle density optimize healing time. The location of the donor site at the postauricular scalp facilitates accessibility for wound care by the patient. Electrocautery or chemical styptics used for hemostasis may traumatize the hair follicles and risk causing alopecia; therefore, as demonstrated in our case, the preferred method to achieve hemostasis is the use of pressure or application of sterile gauze that has been saturated with local 1% lidocaine anesthesia containing 1:400,000 epinephrine, followed by a pressure dressing provided by a sutured bolster.

Our case also demonstrates the utility of the Weck knife, which was introduced in 1968 as a modification of existing instruments to improve the ease of harvesting STSGs by appending a fixed handle and interchangeable depth gauges to a straight razor.^1,2 The Weck knife can obtain grafts up to 5.5 cm in width (length may be as long as anatomically available), often circumventing the need to overlap grafts of smaller widths for repair of larger defects. Furthermore, grafts are harvested at a depth superficial to the hair follicle, averting donor site alopecia. These characteristics make the technique an ideal option for harvesting grafts from the scalp and other large donor sites.

Limitations of the Weck knife technique include the inability to harvest grafts from small donor sites in difficult-to-access anatomic regions or from areas with notable 3-dimensional structure. For harvesting such grafts, we prefer the DermaBlade (AccuTec Blades). Furthermore, assistance for providing tension along the trajectory of the Weck blade with a guard is optimal when performing the procedure. For practices not already utilizing a Weck knife, the technique necessitates additional training and cost. Nonetheless, for STSGs in which large donor site surface area, adjustable thickness, and convenient and timely operational technique are desired, the Weck knife should be considered as part of the dermatologic surgeon’s armamentarium.

Vandetanib is a once-daily oral multikinase inhibitor that targets the rearranged during transfection (RET) tyrosine kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor. It has shown efficacy at doses of 300 mg daily in the treatment of progressive medullary thyroid cancer and has shown promise in non–small cell lung cancer and breast cancer. Vandetanib’s toxicity profile includes QT prolongation, diarrhea, and rash.^1-3 Cutaneous involvement has been described in the literature as a photodistributed drug reaction with both erythema multiforme (EM) and Stevens-Johnson syndrome (SJS)–like eruptions, phototoxicity, and photoallergy (Table).^4-12 Photoinduction is the common thread, but various mechanisms have been proposed, including drug deposition within the dermis and direct toxicity to keratinocytes; however, an understanding of the varied presentation is lacking.

We present 3 cases of vandetanib photoinduced cutaneous toxicities and review the literature on this novel kinase inhibitor. This discussion highlights the spectrum of photosensitivity reactions to vandetanib among patients with varying histologic and clinical presentations.

Case Reports

Patient 1A
74-year-old woman with a history of recurrent metastatic squamous cell carcinoma of the cervix and Fitzpatrick skin type III presented with erythematous, well-demarcated, photodistributed, eczematous papules that were coalescing into plaques on the scalp, hands, and face. The rash appeared sharply demarcated at the wrists bilaterally and principally involved the dorsal sun-exposed areas of her hands (Figure 1). The rash also involved the face and the V of the neck with sharp demarcation. Two weeks prior to onset, she initiated a phase 1 trial of oral vandetanib 100 mg twice daily and oral everolimus 5 mg daily. She did not recall practicing sun protection or experiencing increased sun exposure after starting that trial. The patient demonstrated symptom improvement with desonide cream, hydrocortisone cream 2.5%, and over-the-counter analgesic cream while continuing with the study drugs. However, she developed new, warm, painful papules on the hands and face. Phototesting and biopsy were not performed, and the etiology of the photosensitivity was unknown.

The patient was counseled about regular sun protection and was prescribed triamcinolone cream 0.1% for the arms and hydrocortisone cream 2.5% for the affected facial areas. Therapy with vandetanib and everolimus was continued without dose reduction or further cutaneous eruptions.

Patient 2
A 54-year-old man with a history of progressive medullary thyroid carcinoma and Fitzpatrick skin type II presented with erythematous, well-demarcated, photodistributed, edematous plaques and bullae of the head and neck, bilateral dorsal hands, and bilateral palms of 2 weeks’ duration. The rash spared the upper back and chest with a well-demarcated border (Figure 2A). There were ulcerations and erosions at the base of the neck and the dorsal hands (Figure 2B). He also had conjunctivitis but uninvolved oral and genital mucosae.

Two weeks before the rash appeared, oral vandetanib 300 mg daily was initiated. The patient initially noted some dry skin, which progressed to an eruption involving the face and neck and later the hands with palmar blistering and desquamation. Medication cessation for 1 month led to moderate improvement of the rash on the face and neck. He had not been practicing sun protection but did wear a baseball cap when outside. The patient did not recall an incidence of increased sun exposure. He underwent a skin biopsy of the right dorsal hand, which revealed interface dermatitis with dyskeratosis and subepidermal and intraepidermal bullae (Figure 3). The biopsy findings were most consistent with a phototoxic eruption. Phototesting was not performed.

Patient 3
A 73-year-old man with a history of metastatic lung carcinoma and Fitzpatrick skin type II presented with a rash on the scalp, face, and arms of 2.5 weeks’ duration. There was sharp demarcation at the edges of sun-exposed skin, and no bullae were noted (Figure 4). Prior to presentation, the patient started a 4-week phase 1 trial with vandetanib 300 mg daily and everolimus 10 mg daily. He did not recall any episodes of increased sun exposure. A punch biopsy of the arm showed an interface dermatitis suggestive of a phototoxic reaction. Phototesting was not performed to further clarify if there was a diminished minimal erythema dose with UVA or UVB radiation. Both drugs were discontinued, strict photoprotection was practiced, and triamcinolone cream 0.1% was initiated with resolution of rash. Vandetanib and everolimus were resumed at initial doses with strict photoprotection, and the rash has not recurred.

Comment

Adverse Events Associated With Vandetanib
Vandetanib is a novel multikinase inhibitor that targets RET tyrosine kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor.^1,2 It currently is approved by the US Food and Drug Administration for the treatment of progressive medullary thyroid cancer and is being used in clinical trials for non–small cell lung cancer, glioma, advanced biliary tract cancer, breast cancer, and other advanced solid malignancies. Frequently reported adverse events (AEs) include QT prolongation, diarrhea, and rash.^1-3 In a large phase 3 trial, 45% of patients had a rash; of these, 4% were grade 3 and above.³ The most common reasons for dose decrease or cessation were diarrhea and rash (1% and 1.3%, respectively).¹³ Outside of a trial setting, 75% (45/60) of patients in one French study reported a cutaneous AE, with photosensitivity noted in 22% (13/60). Thus, cutaneous reactions tend to be a common occurrence for patients on this drug, requiring diligent dermatologic examinations.¹⁴ In one meta-analysis comprising 9 studies with a total of 2961 patients, the incidence of all-grade rash was 46.1% (95% CI, 40.6%-51.8%), and it was concluded that vandetanib has the highest association of all-grade rash among the anti–vascular endothelial growth factor tyrosine kinase inhibitors. In this meta-analysis, the specific diagnosis of AEs was not further classified.¹⁵ In another cohort of vandetanib-treated patients, as many as 37% (28/63) of patients had photosensitivity, with no clarification of the etiology.¹⁶

Photoallergic vs Phototoxic Reactions
Photosensitivity reactions are cutaneous reactions that occur from UV light exposure, typically in conjunction with a photosensitizing agent. Photosensitivity reactions can be further classified into phototoxic and photoallergic reactions, which can be distinguished by histopathologic evaluation and history. Although phototoxic reactions will cause keratinocyte necrosis similar to a sunburn, photoallergic reactions will cause epidermal spongiosis similar to allergic contact dermatitis or eczema. Also, phototoxic reactions appear within 1 to 2 days of UV exposure and often are painful, whereas photoallergic reactions can be delayed for 2 to 3 weeks and usually are pruritic. Photosensitivity reactions related to vandetanib have been reported and are summarized in the Table.^4-12

Although reported cutaneous reactions to vandetanib thus far in the literature were reported as photoinduced reactions, there have been isolated case reports of other eruptions including cutaneous pigmentation⁵ and one case of SJS.⁹ According to a PubMed search of articles indexed for MEDLINE using the terms vandetanib and rash, we found that there are a variety of clinical findings, but most of the reported photosensitivity cases were phototoxic. Fava et al⁷ and Goldstein et al¹² both reported 1 photoallergic reaction each, plus patient 1 in our case series was noted to have a photoallergic reaction. Phototoxic reactions were reported in 4 patients (including our patient 2) who had dyskeratotic keratinocytes and vacuolar degeneration of the basal layer on histopathology.^4,8 Fava et al⁷ described a lichenoid infiltrate with spongiosis consistent with a photoallergic reaction, but Chang et al⁴ and Bota et al¹¹ described a lichenoid infiltrate with dyskeratotic cells. Also, Giacchero et al¹⁶ described a photosensitivity reaction in 28 of 63 patients. Although only 6 patients had biopsies performed, the range of photosensitivity reactions was demonstrated with lichenoid, dyskeratotic, and spongiotic reactions. However, the cases were not further defined as photoallergic or phototoxic.¹⁶ Vandetanib also has been associated with cutaneous blue pigmentation after likely phototoxic reactions. Pigment changes occurred after photosensitivity, but the clinical presentation of photosensitivity was not further characterized.^5,16

Classic Drug Eruptions
Two patients were described as having classic drug eruptions—EM¹⁰ and SJS⁹—in photodistributed locations. Histologically, these entities are identical to phototoxic reactions, resulting in epidermal necrosis and an interface dermatitis, but the presence of targetoid lesions on the palms prompted the diagnosis of photodistributed EM and SJS in both cases.^9,10 Unique to the SJS case was oral involvement.⁹

Distinguishing between a phototoxic reaction and photodistributed EM or SJS may be inconsequential if both can be prevented with photoprotection. Rechallenging patients with vandetanib while practicing photoprotection would help to clarify the mechanism, though this course is not always practical.

Mechanism of Action
As seen in our case series, cutaneous reactions occurred only on sun-exposed surfaces, and patients presented with sharp cutoff points that spared non–sun-exposed areas. Although clinically organized as a subtype of photosensitivity, the phototoxicity mechanism of action is considered a direct toxic effect on keratinocytes, which explains the histopathologic finding of dyskeratotic cells and the clinical spectrum of sunburn reaction, phototoxic EM, and SJS. UVA1 induces 2 photoproducts of vandetanib via a UVA1-mediated debromination process,¹⁷ but these photoproducts are not responsible for epidermal dyskeratosis.¹⁸ It was subsequently demonstrated that keratinocyte death was induced by apoptosis through photoinduced DNA cleavage and the formation of an aryl radical, which can induce further DNA damage.¹⁸ Caro-Gutierrez et al¹⁰ demonstrated a lowered minimal erythema dose in their patient with vandetanib-induced phototoxic EM.

Conversely, photoallergic reactions are considered immune-mediated delayed-type hypersensitivity reactions.^4,7,11 Although the mechanism of a photoallergic reaction remains unclear, it is possible that vandetanib or a metabolite (in susceptible patients) induces an immune-mediated delayed-type hypersensitivity reaction with repeated exposure to the compound, which may explain the varied timing of photoallergic onset, including the events featured in the Bota et al¹¹ case that occurred several months after drug initiation.

Conclusion

Considering the high prevalence of cutaneous AEs, especially varied photosensitivity reactions, these cases emphasize the importance of sun protection to help prevent dose reduction or drug cessation among patients taking vandetanib therapy.

Vandetanib is a once-daily oral multikinase inhibitor that targets the rearranged during transfection (RET) tyrosine kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor. It has shown efficacy at doses of 300 mg daily in the treatment of progressive medullary thyroid cancer and has shown promise in non–small cell lung cancer and breast cancer. Vandetanib’s toxicity profile includes QT prolongation, diarrhea, and rash.^1-3 Cutaneous involvement has been described in the literature as a photodistributed drug reaction with both erythema multiforme (EM) and Stevens-Johnson syndrome (SJS)–like eruptions, phototoxicity, and photoallergy (Table).^4-12 Photoinduction is the common thread, but various mechanisms have been proposed, including drug deposition within the dermis and direct toxicity to keratinocytes; however, an understanding of the varied presentation is lacking.

We present 3 cases of vandetanib photoinduced cutaneous toxicities and review the literature on this novel kinase inhibitor. This discussion highlights the spectrum of photosensitivity reactions to vandetanib among patients with varying histologic and clinical presentations.

Case Reports

Patient 1A
74-year-old woman with a history of recurrent metastatic squamous cell carcinoma of the cervix and Fitzpatrick skin type III presented with erythematous, well-demarcated, photodistributed, eczematous papules that were coalescing into plaques on the scalp, hands, and face. The rash appeared sharply demarcated at the wrists bilaterally and principally involved the dorsal sun-exposed areas of her hands (Figure 1). The rash also involved the face and the V of the neck with sharp demarcation. Two weeks prior to onset, she initiated a phase 1 trial of oral vandetanib 100 mg twice daily and oral everolimus 5 mg daily. She did not recall practicing sun protection or experiencing increased sun exposure after starting that trial. The patient demonstrated symptom improvement with desonide cream, hydrocortisone cream 2.5%, and over-the-counter analgesic cream while continuing with the study drugs. However, she developed new, warm, painful papules on the hands and face. Phototesting and biopsy were not performed, and the etiology of the photosensitivity was unknown.

The patient was counseled about regular sun protection and was prescribed triamcinolone cream 0.1% for the arms and hydrocortisone cream 2.5% for the affected facial areas. Therapy with vandetanib and everolimus was continued without dose reduction or further cutaneous eruptions.

Patient 2
A 54-year-old man with a history of progressive medullary thyroid carcinoma and Fitzpatrick skin type II presented with erythematous, well-demarcated, photodistributed, edematous plaques and bullae of the head and neck, bilateral dorsal hands, and bilateral palms of 2 weeks’ duration. The rash spared the upper back and chest with a well-demarcated border (Figure 2A). There were ulcerations and erosions at the base of the neck and the dorsal hands (Figure 2B). He also had conjunctivitis but uninvolved oral and genital mucosae.

Two weeks before the rash appeared, oral vandetanib 300 mg daily was initiated. The patient initially noted some dry skin, which progressed to an eruption involving the face and neck and later the hands with palmar blistering and desquamation. Medication cessation for 1 month led to moderate improvement of the rash on the face and neck. He had not been practicing sun protection but did wear a baseball cap when outside. The patient did not recall an incidence of increased sun exposure. He underwent a skin biopsy of the right dorsal hand, which revealed interface dermatitis with dyskeratosis and subepidermal and intraepidermal bullae (Figure 3). The biopsy findings were most consistent with a phototoxic eruption. Phototesting was not performed.

Patient 3
A 73-year-old man with a history of metastatic lung carcinoma and Fitzpatrick skin type II presented with a rash on the scalp, face, and arms of 2.5 weeks’ duration. There was sharp demarcation at the edges of sun-exposed skin, and no bullae were noted (Figure 4). Prior to presentation, the patient started a 4-week phase 1 trial with vandetanib 300 mg daily and everolimus 10 mg daily. He did not recall any episodes of increased sun exposure. A punch biopsy of the arm showed an interface dermatitis suggestive of a phototoxic reaction. Phototesting was not performed to further clarify if there was a diminished minimal erythema dose with UVA or UVB radiation. Both drugs were discontinued, strict photoprotection was practiced, and triamcinolone cream 0.1% was initiated with resolution of rash. Vandetanib and everolimus were resumed at initial doses with strict photoprotection, and the rash has not recurred.

Comment

Adverse Events Associated With Vandetanib
Vandetanib is a novel multikinase inhibitor that targets RET tyrosine kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor.^1,2 It currently is approved by the US Food and Drug Administration for the treatment of progressive medullary thyroid cancer and is being used in clinical trials for non–small cell lung cancer, glioma, advanced biliary tract cancer, breast cancer, and other advanced solid malignancies. Frequently reported adverse events (AEs) include QT prolongation, diarrhea, and rash.^1-3 In a large phase 3 trial, 45% of patients had a rash; of these, 4% were grade 3 and above.³ The most common reasons for dose decrease or cessation were diarrhea and rash (1% and 1.3%, respectively).¹³ Outside of a trial setting, 75% (45/60) of patients in one French study reported a cutaneous AE, with photosensitivity noted in 22% (13/60). Thus, cutaneous reactions tend to be a common occurrence for patients on this drug, requiring diligent dermatologic examinations.¹⁴ In one meta-analysis comprising 9 studies with a total of 2961 patients, the incidence of all-grade rash was 46.1% (95% CI, 40.6%-51.8%), and it was concluded that vandetanib has the highest association of all-grade rash among the anti–vascular endothelial growth factor tyrosine kinase inhibitors. In this meta-analysis, the specific diagnosis of AEs was not further classified.¹⁵ In another cohort of vandetanib-treated patients, as many as 37% (28/63) of patients had photosensitivity, with no clarification of the etiology.¹⁶

Photoallergic vs Phototoxic Reactions
Photosensitivity reactions are cutaneous reactions that occur from UV light exposure, typically in conjunction with a photosensitizing agent. Photosensitivity reactions can be further classified into phototoxic and photoallergic reactions, which can be distinguished by histopathologic evaluation and history. Although phototoxic reactions will cause keratinocyte necrosis similar to a sunburn, photoallergic reactions will cause epidermal spongiosis similar to allergic contact dermatitis or eczema. Also, phototoxic reactions appear within 1 to 2 days of UV exposure and often are painful, whereas photoallergic reactions can be delayed for 2 to 3 weeks and usually are pruritic. Photosensitivity reactions related to vandetanib have been reported and are summarized in the Table.^4-12

Although reported cutaneous reactions to vandetanib thus far in the literature were reported as photoinduced reactions, there have been isolated case reports of other eruptions including cutaneous pigmentation⁵ and one case of SJS.⁹ According to a PubMed search of articles indexed for MEDLINE using the terms vandetanib and rash, we found that there are a variety of clinical findings, but most of the reported photosensitivity cases were phototoxic. Fava et al⁷ and Goldstein et al¹² both reported 1 photoallergic reaction each, plus patient 1 in our case series was noted to have a photoallergic reaction. Phototoxic reactions were reported in 4 patients (including our patient 2) who had dyskeratotic keratinocytes and vacuolar degeneration of the basal layer on histopathology.^4,8 Fava et al⁷ described a lichenoid infiltrate with spongiosis consistent with a photoallergic reaction, but Chang et al⁴ and Bota et al¹¹ described a lichenoid infiltrate with dyskeratotic cells. Also, Giacchero et al¹⁶ described a photosensitivity reaction in 28 of 63 patients. Although only 6 patients had biopsies performed, the range of photosensitivity reactions was demonstrated with lichenoid, dyskeratotic, and spongiotic reactions. However, the cases were not further defined as photoallergic or phototoxic.¹⁶ Vandetanib also has been associated with cutaneous blue pigmentation after likely phototoxic reactions. Pigment changes occurred after photosensitivity, but the clinical presentation of photosensitivity was not further characterized.^5,16

Classic Drug Eruptions
Two patients were described as having classic drug eruptions—EM¹⁰ and SJS⁹—in photodistributed locations. Histologically, these entities are identical to phototoxic reactions, resulting in epidermal necrosis and an interface dermatitis, but the presence of targetoid lesions on the palms prompted the diagnosis of photodistributed EM and SJS in both cases.^9,10 Unique to the SJS case was oral involvement.⁹

Distinguishing between a phototoxic reaction and photodistributed EM or SJS may be inconsequential if both can be prevented with photoprotection. Rechallenging patients with vandetanib while practicing photoprotection would help to clarify the mechanism, though this course is not always practical.

Mechanism of Action
As seen in our case series, cutaneous reactions occurred only on sun-exposed surfaces, and patients presented with sharp cutoff points that spared non–sun-exposed areas. Although clinically organized as a subtype of photosensitivity, the phototoxicity mechanism of action is considered a direct toxic effect on keratinocytes, which explains the histopathologic finding of dyskeratotic cells and the clinical spectrum of sunburn reaction, phototoxic EM, and SJS. UVA1 induces 2 photoproducts of vandetanib via a UVA1-mediated debromination process,¹⁷ but these photoproducts are not responsible for epidermal dyskeratosis.¹⁸ It was subsequently demonstrated that keratinocyte death was induced by apoptosis through photoinduced DNA cleavage and the formation of an aryl radical, which can induce further DNA damage.¹⁸ Caro-Gutierrez et al¹⁰ demonstrated a lowered minimal erythema dose in their patient with vandetanib-induced phototoxic EM.

Conversely, photoallergic reactions are considered immune-mediated delayed-type hypersensitivity reactions.^4,7,11 Although the mechanism of a photoallergic reaction remains unclear, it is possible that vandetanib or a metabolite (in susceptible patients) induces an immune-mediated delayed-type hypersensitivity reaction with repeated exposure to the compound, which may explain the varied timing of photoallergic onset, including the events featured in the Bota et al¹¹ case that occurred several months after drug initiation.

Conclusion

Considering the high prevalence of cutaneous AEs, especially varied photosensitivity reactions, these cases emphasize the importance of sun protection to help prevent dose reduction or drug cessation among patients taking vandetanib therapy.

Vandetanib is a once-daily oral multikinase inhibitor that targets the rearranged during transfection (RET) tyrosine kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor. It has shown efficacy at doses of 300 mg daily in the treatment of progressive medullary thyroid cancer and has shown promise in non–small cell lung cancer and breast cancer. Vandetanib’s toxicity profile includes QT prolongation, diarrhea, and rash.^1-3 Cutaneous involvement has been described in the literature as a photodistributed drug reaction with both erythema multiforme (EM) and Stevens-Johnson syndrome (SJS)–like eruptions, phototoxicity, and photoallergy (Table).^4-12 Photoinduction is the common thread, but various mechanisms have been proposed, including drug deposition within the dermis and direct toxicity to keratinocytes; however, an understanding of the varied presentation is lacking.

We present 3 cases of vandetanib photoinduced cutaneous toxicities and review the literature on this novel kinase inhibitor. This discussion highlights the spectrum of photosensitivity reactions to vandetanib among patients with varying histologic and clinical presentations.

Case Reports

Patient 1A
74-year-old woman with a history of recurrent metastatic squamous cell carcinoma of the cervix and Fitzpatrick skin type III presented with erythematous, well-demarcated, photodistributed, eczematous papules that were coalescing into plaques on the scalp, hands, and face. The rash appeared sharply demarcated at the wrists bilaterally and principally involved the dorsal sun-exposed areas of her hands (Figure 1). The rash also involved the face and the V of the neck with sharp demarcation. Two weeks prior to onset, she initiated a phase 1 trial of oral vandetanib 100 mg twice daily and oral everolimus 5 mg daily. She did not recall practicing sun protection or experiencing increased sun exposure after starting that trial. The patient demonstrated symptom improvement with desonide cream, hydrocortisone cream 2.5%, and over-the-counter analgesic cream while continuing with the study drugs. However, she developed new, warm, painful papules on the hands and face. Phototesting and biopsy were not performed, and the etiology of the photosensitivity was unknown.

The patient was counseled about regular sun protection and was prescribed triamcinolone cream 0.1% for the arms and hydrocortisone cream 2.5% for the affected facial areas. Therapy with vandetanib and everolimus was continued without dose reduction or further cutaneous eruptions.

Patient 2
A 54-year-old man with a history of progressive medullary thyroid carcinoma and Fitzpatrick skin type II presented with erythematous, well-demarcated, photodistributed, edematous plaques and bullae of the head and neck, bilateral dorsal hands, and bilateral palms of 2 weeks’ duration. The rash spared the upper back and chest with a well-demarcated border (Figure 2A). There were ulcerations and erosions at the base of the neck and the dorsal hands (Figure 2B). He also had conjunctivitis but uninvolved oral and genital mucosae.

Two weeks before the rash appeared, oral vandetanib 300 mg daily was initiated. The patient initially noted some dry skin, which progressed to an eruption involving the face and neck and later the hands with palmar blistering and desquamation. Medication cessation for 1 month led to moderate improvement of the rash on the face and neck. He had not been practicing sun protection but did wear a baseball cap when outside. The patient did not recall an incidence of increased sun exposure. He underwent a skin biopsy of the right dorsal hand, which revealed interface dermatitis with dyskeratosis and subepidermal and intraepidermal bullae (Figure 3). The biopsy findings were most consistent with a phototoxic eruption. Phototesting was not performed.

Patient 3
A 73-year-old man with a history of metastatic lung carcinoma and Fitzpatrick skin type II presented with a rash on the scalp, face, and arms of 2.5 weeks’ duration. There was sharp demarcation at the edges of sun-exposed skin, and no bullae were noted (Figure 4). Prior to presentation, the patient started a 4-week phase 1 trial with vandetanib 300 mg daily and everolimus 10 mg daily. He did not recall any episodes of increased sun exposure. A punch biopsy of the arm showed an interface dermatitis suggestive of a phototoxic reaction. Phototesting was not performed to further clarify if there was a diminished minimal erythema dose with UVA or UVB radiation. Both drugs were discontinued, strict photoprotection was practiced, and triamcinolone cream 0.1% was initiated with resolution of rash. Vandetanib and everolimus were resumed at initial doses with strict photoprotection, and the rash has not recurred.

Comment

Adverse Events Associated With Vandetanib
Vandetanib is a novel multikinase inhibitor that targets RET tyrosine kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor.^1,2 It currently is approved by the US Food and Drug Administration for the treatment of progressive medullary thyroid cancer and is being used in clinical trials for non–small cell lung cancer, glioma, advanced biliary tract cancer, breast cancer, and other advanced solid malignancies. Frequently reported adverse events (AEs) include QT prolongation, diarrhea, and rash.^1-3 In a large phase 3 trial, 45% of patients had a rash; of these, 4% were grade 3 and above.³ The most common reasons for dose decrease or cessation were diarrhea and rash (1% and 1.3%, respectively).¹³ Outside of a trial setting, 75% (45/60) of patients in one French study reported a cutaneous AE, with photosensitivity noted in 22% (13/60). Thus, cutaneous reactions tend to be a common occurrence for patients on this drug, requiring diligent dermatologic examinations.¹⁴ In one meta-analysis comprising 9 studies with a total of 2961 patients, the incidence of all-grade rash was 46.1% (95% CI, 40.6%-51.8%), and it was concluded that vandetanib has the highest association of all-grade rash among the anti–vascular endothelial growth factor tyrosine kinase inhibitors. In this meta-analysis, the specific diagnosis of AEs was not further classified.¹⁵ In another cohort of vandetanib-treated patients, as many as 37% (28/63) of patients had photosensitivity, with no clarification of the etiology.¹⁶

Photoallergic vs Phototoxic Reactions
Photosensitivity reactions are cutaneous reactions that occur from UV light exposure, typically in conjunction with a photosensitizing agent. Photosensitivity reactions can be further classified into phototoxic and photoallergic reactions, which can be distinguished by histopathologic evaluation and history. Although phototoxic reactions will cause keratinocyte necrosis similar to a sunburn, photoallergic reactions will cause epidermal spongiosis similar to allergic contact dermatitis or eczema. Also, phototoxic reactions appear within 1 to 2 days of UV exposure and often are painful, whereas photoallergic reactions can be delayed for 2 to 3 weeks and usually are pruritic. Photosensitivity reactions related to vandetanib have been reported and are summarized in the Table.^4-12

Although reported cutaneous reactions to vandetanib thus far in the literature were reported as photoinduced reactions, there have been isolated case reports of other eruptions including cutaneous pigmentation⁵ and one case of SJS.⁹ According to a PubMed search of articles indexed for MEDLINE using the terms vandetanib and rash, we found that there are a variety of clinical findings, but most of the reported photosensitivity cases were phototoxic. Fava et al⁷ and Goldstein et al¹² both reported 1 photoallergic reaction each, plus patient 1 in our case series was noted to have a photoallergic reaction. Phototoxic reactions were reported in 4 patients (including our patient 2) who had dyskeratotic keratinocytes and vacuolar degeneration of the basal layer on histopathology.^4,8 Fava et al⁷ described a lichenoid infiltrate with spongiosis consistent with a photoallergic reaction, but Chang et al⁴ and Bota et al¹¹ described a lichenoid infiltrate with dyskeratotic cells. Also, Giacchero et al¹⁶ described a photosensitivity reaction in 28 of 63 patients. Although only 6 patients had biopsies performed, the range of photosensitivity reactions was demonstrated with lichenoid, dyskeratotic, and spongiotic reactions. However, the cases were not further defined as photoallergic or phototoxic.¹⁶ Vandetanib also has been associated with cutaneous blue pigmentation after likely phototoxic reactions. Pigment changes occurred after photosensitivity, but the clinical presentation of photosensitivity was not further characterized.^5,16

Classic Drug Eruptions
Two patients were described as having classic drug eruptions—EM¹⁰ and SJS⁹—in photodistributed locations. Histologically, these entities are identical to phototoxic reactions, resulting in epidermal necrosis and an interface dermatitis, but the presence of targetoid lesions on the palms prompted the diagnosis of photodistributed EM and SJS in both cases.^9,10 Unique to the SJS case was oral involvement.⁹

Distinguishing between a phototoxic reaction and photodistributed EM or SJS may be inconsequential if both can be prevented with photoprotection. Rechallenging patients with vandetanib while practicing photoprotection would help to clarify the mechanism, though this course is not always practical.

Mechanism of Action
As seen in our case series, cutaneous reactions occurred only on sun-exposed surfaces, and patients presented with sharp cutoff points that spared non–sun-exposed areas. Although clinically organized as a subtype of photosensitivity, the phototoxicity mechanism of action is considered a direct toxic effect on keratinocytes, which explains the histopathologic finding of dyskeratotic cells and the clinical spectrum of sunburn reaction, phototoxic EM, and SJS. UVA1 induces 2 photoproducts of vandetanib via a UVA1-mediated debromination process,¹⁷ but these photoproducts are not responsible for epidermal dyskeratosis.¹⁸ It was subsequently demonstrated that keratinocyte death was induced by apoptosis through photoinduced DNA cleavage and the formation of an aryl radical, which can induce further DNA damage.¹⁸ Caro-Gutierrez et al¹⁰ demonstrated a lowered minimal erythema dose in their patient with vandetanib-induced phototoxic EM.

Conversely, photoallergic reactions are considered immune-mediated delayed-type hypersensitivity reactions.^4,7,11 Although the mechanism of a photoallergic reaction remains unclear, it is possible that vandetanib or a metabolite (in susceptible patients) induces an immune-mediated delayed-type hypersensitivity reaction with repeated exposure to the compound, which may explain the varied timing of photoallergic onset, including the events featured in the Bota et al¹¹ case that occurred several months after drug initiation.

Conclusion

Considering the high prevalence of cutaneous AEs, especially varied photosensitivity reactions, these cases emphasize the importance of sun protection to help prevent dose reduction or drug cessation among patients taking vandetanib therapy.

Use of aspirin or nonaspirin NSAIDs was not associated with a reduced risk of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), in a large, prospective cohort study of Australian residents.

Fuse/Thinkstock

“Overall, we observed weak and inconsistent inverse associations between use of these medications and incidence of either BCC or SCC,” wrote Nirmala Pandeya, PhD, of the University of Queensland (Australia) and coauthors. “While we did observe a modest reduction in risk of BCC associated with NSAID use among people with high risk of skin cancer ... no statistically significant associations were seen with aspirin use,” they added. The study was published in the British Journal of Dermatology.

While reviews of observational studies have suggested that NSAIDs may have “a potential benefit” in reducing the incidence of BCC and SCC, the results have varied, they noted.

To investigate the potential chemopreventive effects of NSAID use on skin cancer, the investigators used data from the QSkin Sun and Health Study, a prospective cohort of 43,764 residents of Queensland, Australia. Those eligible for the study had a white ethnic background and no history of melanoma; 34,630 participants were available for analysis, their median age was 57 years, and 55% were women

Almost 15,600 (45%) were classified as “high risk” because they had had at least one skin cancer excision or more than five actinic lesions treated; 18,828 participants were classified as “average to low risk;” and data were unavailable for 206 participants. One‐third of the participants in the high-risk group (5,398) used aspirin; of these individuals, 39% (2,132) used aspirin more than once a week (defined as “frequent” users). Also, 60% (9,236) used NSAIDs, and of those, 24% (2,229) were frequent users.

During a median follow-up of 3 years, 3,421 of those in the study (10%) developed one or more BCC, and 1,470 (4%) developed one or more SCC.


Compared with never users, frequent NSAID use in the high-risk group was modestly associated with a reduced risk of BCC (hazard ratio, 0.84; 95% confidence interval, 0.71-0.99), but not with SCC. Aspirin use was weakly associated with a reduced risk of SCC (HR, 0.77; 95% CI, 0.64-0.93) but only among infrequent users and was not associated with BCC risk. In the average- to low-risk group, there was no association with either NSAIDs or aspirin and BCC or SCC occurrence.

The authors noted limitations of their study, including its reliance on self-reported NSAID use and a lack of detail in regard to usage dose and duration. In addition, though the investigators controlled for all likely confounders, “the possibility of some residual confounding cannot be excluded.”

The QSkin Study was funded by a grant from the National Health and Medical Research Council of Australia (NHMRC). The authors declared no conflicts of interest.

SOURCE: Pandeya N et al. Br J Dermatol. 2019 Mar 28. doi: 10.1111/bjd.17938.

Use of aspirin or nonaspirin NSAIDs was not associated with a reduced risk of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), in a large, prospective cohort study of Australian residents.

Fuse/Thinkstock

“Overall, we observed weak and inconsistent inverse associations between use of these medications and incidence of either BCC or SCC,” wrote Nirmala Pandeya, PhD, of the University of Queensland (Australia) and coauthors. “While we did observe a modest reduction in risk of BCC associated with NSAID use among people with high risk of skin cancer ... no statistically significant associations were seen with aspirin use,” they added. The study was published in the British Journal of Dermatology.

While reviews of observational studies have suggested that NSAIDs may have “a potential benefit” in reducing the incidence of BCC and SCC, the results have varied, they noted.

To investigate the potential chemopreventive effects of NSAID use on skin cancer, the investigators used data from the QSkin Sun and Health Study, a prospective cohort of 43,764 residents of Queensland, Australia. Those eligible for the study had a white ethnic background and no history of melanoma; 34,630 participants were available for analysis, their median age was 57 years, and 55% were women

Almost 15,600 (45%) were classified as “high risk” because they had had at least one skin cancer excision or more than five actinic lesions treated; 18,828 participants were classified as “average to low risk;” and data were unavailable for 206 participants. One‐third of the participants in the high-risk group (5,398) used aspirin; of these individuals, 39% (2,132) used aspirin more than once a week (defined as “frequent” users). Also, 60% (9,236) used NSAIDs, and of those, 24% (2,229) were frequent users.

During a median follow-up of 3 years, 3,421 of those in the study (10%) developed one or more BCC, and 1,470 (4%) developed one or more SCC.


Compared with never users, frequent NSAID use in the high-risk group was modestly associated with a reduced risk of BCC (hazard ratio, 0.84; 95% confidence interval, 0.71-0.99), but not with SCC. Aspirin use was weakly associated with a reduced risk of SCC (HR, 0.77; 95% CI, 0.64-0.93) but only among infrequent users and was not associated with BCC risk. In the average- to low-risk group, there was no association with either NSAIDs or aspirin and BCC or SCC occurrence.

The authors noted limitations of their study, including its reliance on self-reported NSAID use and a lack of detail in regard to usage dose and duration. In addition, though the investigators controlled for all likely confounders, “the possibility of some residual confounding cannot be excluded.”

The QSkin Study was funded by a grant from the National Health and Medical Research Council of Australia (NHMRC). The authors declared no conflicts of interest.

SOURCE: Pandeya N et al. Br J Dermatol. 2019 Mar 28. doi: 10.1111/bjd.17938.

Use of aspirin or nonaspirin NSAIDs was not associated with a reduced risk of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), in a large, prospective cohort study of Australian residents.

Fuse/Thinkstock

“Overall, we observed weak and inconsistent inverse associations between use of these medications and incidence of either BCC or SCC,” wrote Nirmala Pandeya, PhD, of the University of Queensland (Australia) and coauthors. “While we did observe a modest reduction in risk of BCC associated with NSAID use among people with high risk of skin cancer ... no statistically significant associations were seen with aspirin use,” they added. The study was published in the British Journal of Dermatology.

While reviews of observational studies have suggested that NSAIDs may have “a potential benefit” in reducing the incidence of BCC and SCC, the results have varied, they noted.

To investigate the potential chemopreventive effects of NSAID use on skin cancer, the investigators used data from the QSkin Sun and Health Study, a prospective cohort of 43,764 residents of Queensland, Australia. Those eligible for the study had a white ethnic background and no history of melanoma; 34,630 participants were available for analysis, their median age was 57 years, and 55% were women

Almost 15,600 (45%) were classified as “high risk” because they had had at least one skin cancer excision or more than five actinic lesions treated; 18,828 participants were classified as “average to low risk;” and data were unavailable for 206 participants. One‐third of the participants in the high-risk group (5,398) used aspirin; of these individuals, 39% (2,132) used aspirin more than once a week (defined as “frequent” users). Also, 60% (9,236) used NSAIDs, and of those, 24% (2,229) were frequent users.

During a median follow-up of 3 years, 3,421 of those in the study (10%) developed one or more BCC, and 1,470 (4%) developed one or more SCC.


Compared with never users, frequent NSAID use in the high-risk group was modestly associated with a reduced risk of BCC (hazard ratio, 0.84; 95% confidence interval, 0.71-0.99), but not with SCC. Aspirin use was weakly associated with a reduced risk of SCC (HR, 0.77; 95% CI, 0.64-0.93) but only among infrequent users and was not associated with BCC risk. In the average- to low-risk group, there was no association with either NSAIDs or aspirin and BCC or SCC occurrence.

The authors noted limitations of their study, including its reliance on self-reported NSAID use and a lack of detail in regard to usage dose and duration. In addition, though the investigators controlled for all likely confounders, “the possibility of some residual confounding cannot be excluded.”

The QSkin Study was funded by a grant from the National Health and Medical Research Council of Australia (NHMRC). The authors declared no conflicts of interest.

SOURCE: Pandeya N et al. Br J Dermatol. 2019 Mar 28. doi: 10.1111/bjd.17938.

CHICAGO – Compared with that of calcineurin inhibitors, belatacept appears to be associated with a lower risk of keratinocyte carcinomas in solid organ transplant patients, based on results from a single-center analysis presented at the annual meeting of the Society for Investigative Dermatology.

“Belatacept may offer a better risk-benefit profile in regards to skin cancer,” reported Michael Wang, a medical student who conducted this research in collaboration with the senior author, Oscar Colegio, MD, PhD, an associate professor of dermatology, pathology, and surgery at Yale University, New Haven, Conn.

Belatacept, a CTLA-4 fusion protein, has been compared with calcineurin inhibitors in two previous studies. The results were equivocal in one, and the other found no difference in risk and could not rule out the possibility that skin cancer risk was even higher on belatacept.

This single-center chart review included 110 kidney transplant patients, median age 58 years, who were switched from a calcineurin inhibitor, such as cyclosporine or tacrolimus, to belatacept. Ultimately, the study was limited to the 66 patients with at least 2 years of dermatologic follow-up both before and after the switch from a calcineurin inhibitor.

The primary outcome was the number of keratinocyte carcinomas overall and, specifically, the number of squamous cell carcinomas (SCCs) before and after the switch. Over the course of this study there were 128 cutaneous malignancies, 83 of which were SCCs.

When patients were on a calcineurin inhibitor, the risk of keratinocyte carcinomas increased incrementally by 2.6 events per 100 patients per year of follow-up, and the risk of SCCs increased by 1.7 events per 100 patients per year of follow-up. In the first 6 months after the switch to belatacept, there was no change in the rising trajectory of skin cancers, but rates declined thereafter.

Relative to rates prior to and 6 months after the switch, “the incidence of SCCs decreased at a rate of 5.9 events per 100 patients per year (P = .0068), and the incidence of keratinocyte carcinomas decreased by 7.1 events per 100 patients per year (P = .003),” Mr. Wang reported. He noted, however, that the incidence of basal cell carcinomas and melanomas following the switch remained unchanged.

When patients switched to belatacept were compared with another group of patients who remained on a calcineurin inhibitor after developing a SCC, the hazard ratio for a new SCC was 0.42, indicating a greater than 50% reduction in risk.

In patients on calcineurin inhibitors, the risk of keratinocyte carcinomas appears to be related to a direct effect of these agents on keratinocyte dedifferentiation. Belatacept is not believed to have any direct effects on keratinocytes, according to Mr. Wang.

As the chart review was retrospective and limited to a single center, “we hope [the findings] will encourage a prospective trial,” Mr. Wang said.

SOURCE: Wang M. SID 2019, Abstract 532.

CHICAGO – Compared with that of calcineurin inhibitors, belatacept appears to be associated with a lower risk of keratinocyte carcinomas in solid organ transplant patients, based on results from a single-center analysis presented at the annual meeting of the Society for Investigative Dermatology.

“Belatacept may offer a better risk-benefit profile in regards to skin cancer,” reported Michael Wang, a medical student who conducted this research in collaboration with the senior author, Oscar Colegio, MD, PhD, an associate professor of dermatology, pathology, and surgery at Yale University, New Haven, Conn.

Belatacept, a CTLA-4 fusion protein, has been compared with calcineurin inhibitors in two previous studies. The results were equivocal in one, and the other found no difference in risk and could not rule out the possibility that skin cancer risk was even higher on belatacept.

This single-center chart review included 110 kidney transplant patients, median age 58 years, who were switched from a calcineurin inhibitor, such as cyclosporine or tacrolimus, to belatacept. Ultimately, the study was limited to the 66 patients with at least 2 years of dermatologic follow-up both before and after the switch from a calcineurin inhibitor.

The primary outcome was the number of keratinocyte carcinomas overall and, specifically, the number of squamous cell carcinomas (SCCs) before and after the switch. Over the course of this study there were 128 cutaneous malignancies, 83 of which were SCCs.

When patients were on a calcineurin inhibitor, the risk of keratinocyte carcinomas increased incrementally by 2.6 events per 100 patients per year of follow-up, and the risk of SCCs increased by 1.7 events per 100 patients per year of follow-up. In the first 6 months after the switch to belatacept, there was no change in the rising trajectory of skin cancers, but rates declined thereafter.

Relative to rates prior to and 6 months after the switch, “the incidence of SCCs decreased at a rate of 5.9 events per 100 patients per year (P = .0068), and the incidence of keratinocyte carcinomas decreased by 7.1 events per 100 patients per year (P = .003),” Mr. Wang reported. He noted, however, that the incidence of basal cell carcinomas and melanomas following the switch remained unchanged.

When patients switched to belatacept were compared with another group of patients who remained on a calcineurin inhibitor after developing a SCC, the hazard ratio for a new SCC was 0.42, indicating a greater than 50% reduction in risk.

In patients on calcineurin inhibitors, the risk of keratinocyte carcinomas appears to be related to a direct effect of these agents on keratinocyte dedifferentiation. Belatacept is not believed to have any direct effects on keratinocytes, according to Mr. Wang.

As the chart review was retrospective and limited to a single center, “we hope [the findings] will encourage a prospective trial,” Mr. Wang said.

SOURCE: Wang M. SID 2019, Abstract 532.

CHICAGO – Compared with that of calcineurin inhibitors, belatacept appears to be associated with a lower risk of keratinocyte carcinomas in solid organ transplant patients, based on results from a single-center analysis presented at the annual meeting of the Society for Investigative Dermatology.

“Belatacept may offer a better risk-benefit profile in regards to skin cancer,” reported Michael Wang, a medical student who conducted this research in collaboration with the senior author, Oscar Colegio, MD, PhD, an associate professor of dermatology, pathology, and surgery at Yale University, New Haven, Conn.

Belatacept, a CTLA-4 fusion protein, has been compared with calcineurin inhibitors in two previous studies. The results were equivocal in one, and the other found no difference in risk and could not rule out the possibility that skin cancer risk was even higher on belatacept.

This single-center chart review included 110 kidney transplant patients, median age 58 years, who were switched from a calcineurin inhibitor, such as cyclosporine or tacrolimus, to belatacept. Ultimately, the study was limited to the 66 patients with at least 2 years of dermatologic follow-up both before and after the switch from a calcineurin inhibitor.

The primary outcome was the number of keratinocyte carcinomas overall and, specifically, the number of squamous cell carcinomas (SCCs) before and after the switch. Over the course of this study there were 128 cutaneous malignancies, 83 of which were SCCs.

When patients were on a calcineurin inhibitor, the risk of keratinocyte carcinomas increased incrementally by 2.6 events per 100 patients per year of follow-up, and the risk of SCCs increased by 1.7 events per 100 patients per year of follow-up. In the first 6 months after the switch to belatacept, there was no change in the rising trajectory of skin cancers, but rates declined thereafter.

Relative to rates prior to and 6 months after the switch, “the incidence of SCCs decreased at a rate of 5.9 events per 100 patients per year (P = .0068), and the incidence of keratinocyte carcinomas decreased by 7.1 events per 100 patients per year (P = .003),” Mr. Wang reported. He noted, however, that the incidence of basal cell carcinomas and melanomas following the switch remained unchanged.

When patients switched to belatacept were compared with another group of patients who remained on a calcineurin inhibitor after developing a SCC, the hazard ratio for a new SCC was 0.42, indicating a greater than 50% reduction in risk.

In patients on calcineurin inhibitors, the risk of keratinocyte carcinomas appears to be related to a direct effect of these agents on keratinocyte dedifferentiation. Belatacept is not believed to have any direct effects on keratinocytes, according to Mr. Wang.

As the chart review was retrospective and limited to a single center, “we hope [the findings] will encourage a prospective trial,” Mr. Wang said.

SOURCE: Wang M. SID 2019, Abstract 532.

CHICAGO – Because of the very substantial risk of metastatic spread, baseline imaging should be performed in all patients with Merkel cell carcinoma (MCC), including those without palpable lymph nodes, according to results of an analysis of a large MCC registry presented at the annual meeting of the Society for Investigative Dermatology.

Ted Bosworth/MDedge News

The results were a “surprise,” according to Neha Singh, a researcher in the division of dermatology at the University of Washington, Seattle. She contended that many treatment guidelines for MCC, including imaging at the time of diagnosis, are borrowed from those developed for melanoma but should not be.

“MCC is much more frequently metastatic to regional and distant sites than melanoma, so current melanoma guidelines may not be appropriate for use with MCC,” she said. According to the data she cited, 41% of MCC patients, versus 14% of melanoma patients, already have metastatic disease at the time of diagnosis.

The presence of more aggressive disease and the need for scanning was confirmed in the analysis of the MCC Registry in Seattle, which contains 1,439 patients. Of 586 patients who met inclusion criteria for this analysis, 493 MCC patients had no palpable lymph nodes at the time of diagnosis. Yet, 60 (12%) proved to already have regional or distant metastases on the basis of scans.

This contrasts starkly with melanoma data, according to Ms. Singh. Guidelines from the National Comprehensive Cancer Network (NCCN) do not recommend scans in melanoma patients without palpable lymph nodes based on evidence that only 1% of these will be upstaged by imaging. This figure was judged too small to justify routine scans, she said.

In melanoma patients with palpable lymph nodes, NCCN guidelines do recommend imaging at diagnosis because upstaging is common, and the same is true in MCC, Ms. Singh noted. In the Seattle registry, 10 (11%) of the 93 patients with palpable lymph nodes were upstaged for distant metastases found on imaging.

In those without palpable lymph nodes, “even a small tumor does not guarantee the absence of distant metastases,” Ms. Singh cautioned. Although the median tumor size in this group was 2.3 cm, tumors of less than 1 cm were still associated with distant disease.

The likelihood of distant disease in MCC patients without palpable lymph nodes might be even greater than that identified in this analysis. At least some of the patients in this series were evaluated with CT rather than PET imaging, which is more sensitive. Ms. Singh reported that no stratification to determine rates of distant disease by imaging type have yet been undertaken in this dataset.

Based on these findings, guidelines for MCC should include consideration of baseline imaging in all patients, Ms. Singh said. In making this point, she also emphasized the guidelines for melanoma should not be considered transferable to MCC.

“Why is this important?” Ms. Singh asked. Understaging MCC “may lead to inadequate surgery, overaggressive local therapy, and a potential delay to effective systemic therapy.”

CHICAGO – Because of the very substantial risk of metastatic spread, baseline imaging should be performed in all patients with Merkel cell carcinoma (MCC), including those without palpable lymph nodes, according to results of an analysis of a large MCC registry presented at the annual meeting of the Society for Investigative Dermatology.

Ted Bosworth/MDedge News

The results were a “surprise,” according to Neha Singh, a researcher in the division of dermatology at the University of Washington, Seattle. She contended that many treatment guidelines for MCC, including imaging at the time of diagnosis, are borrowed from those developed for melanoma but should not be.

“MCC is much more frequently metastatic to regional and distant sites than melanoma, so current melanoma guidelines may not be appropriate for use with MCC,” she said. According to the data she cited, 41% of MCC patients, versus 14% of melanoma patients, already have metastatic disease at the time of diagnosis.

The presence of more aggressive disease and the need for scanning was confirmed in the analysis of the MCC Registry in Seattle, which contains 1,439 patients. Of 586 patients who met inclusion criteria for this analysis, 493 MCC patients had no palpable lymph nodes at the time of diagnosis. Yet, 60 (12%) proved to already have regional or distant metastases on the basis of scans.

This contrasts starkly with melanoma data, according to Ms. Singh. Guidelines from the National Comprehensive Cancer Network (NCCN) do not recommend scans in melanoma patients without palpable lymph nodes based on evidence that only 1% of these will be upstaged by imaging. This figure was judged too small to justify routine scans, she said.

In melanoma patients with palpable lymph nodes, NCCN guidelines do recommend imaging at diagnosis because upstaging is common, and the same is true in MCC, Ms. Singh noted. In the Seattle registry, 10 (11%) of the 93 patients with palpable lymph nodes were upstaged for distant metastases found on imaging.

In those without palpable lymph nodes, “even a small tumor does not guarantee the absence of distant metastases,” Ms. Singh cautioned. Although the median tumor size in this group was 2.3 cm, tumors of less than 1 cm were still associated with distant disease.

The likelihood of distant disease in MCC patients without palpable lymph nodes might be even greater than that identified in this analysis. At least some of the patients in this series were evaluated with CT rather than PET imaging, which is more sensitive. Ms. Singh reported that no stratification to determine rates of distant disease by imaging type have yet been undertaken in this dataset.

Based on these findings, guidelines for MCC should include consideration of baseline imaging in all patients, Ms. Singh said. In making this point, she also emphasized the guidelines for melanoma should not be considered transferable to MCC.

“Why is this important?” Ms. Singh asked. Understaging MCC “may lead to inadequate surgery, overaggressive local therapy, and a potential delay to effective systemic therapy.”

CHICAGO – Because of the very substantial risk of metastatic spread, baseline imaging should be performed in all patients with Merkel cell carcinoma (MCC), including those without palpable lymph nodes, according to results of an analysis of a large MCC registry presented at the annual meeting of the Society for Investigative Dermatology.

Ted Bosworth/MDedge News

The results were a “surprise,” according to Neha Singh, a researcher in the division of dermatology at the University of Washington, Seattle. She contended that many treatment guidelines for MCC, including imaging at the time of diagnosis, are borrowed from those developed for melanoma but should not be.

“MCC is much more frequently metastatic to regional and distant sites than melanoma, so current melanoma guidelines may not be appropriate for use with MCC,” she said. According to the data she cited, 41% of MCC patients, versus 14% of melanoma patients, already have metastatic disease at the time of diagnosis.

The presence of more aggressive disease and the need for scanning was confirmed in the analysis of the MCC Registry in Seattle, which contains 1,439 patients. Of 586 patients who met inclusion criteria for this analysis, 493 MCC patients had no palpable lymph nodes at the time of diagnosis. Yet, 60 (12%) proved to already have regional or distant metastases on the basis of scans.

This contrasts starkly with melanoma data, according to Ms. Singh. Guidelines from the National Comprehensive Cancer Network (NCCN) do not recommend scans in melanoma patients without palpable lymph nodes based on evidence that only 1% of these will be upstaged by imaging. This figure was judged too small to justify routine scans, she said.

In melanoma patients with palpable lymph nodes, NCCN guidelines do recommend imaging at diagnosis because upstaging is common, and the same is true in MCC, Ms. Singh noted. In the Seattle registry, 10 (11%) of the 93 patients with palpable lymph nodes were upstaged for distant metastases found on imaging.

In those without palpable lymph nodes, “even a small tumor does not guarantee the absence of distant metastases,” Ms. Singh cautioned. Although the median tumor size in this group was 2.3 cm, tumors of less than 1 cm were still associated with distant disease.

The likelihood of distant disease in MCC patients without palpable lymph nodes might be even greater than that identified in this analysis. At least some of the patients in this series were evaluated with CT rather than PET imaging, which is more sensitive. Ms. Singh reported that no stratification to determine rates of distant disease by imaging type have yet been undertaken in this dataset.

Based on these findings, guidelines for MCC should include consideration of baseline imaging in all patients, Ms. Singh said. In making this point, she also emphasized the guidelines for melanoma should not be considered transferable to MCC.

“Why is this important?” Ms. Singh asked. Understaging MCC “may lead to inadequate surgery, overaggressive local therapy, and a potential delay to effective systemic therapy.”

An atypical case of cutaneous mantle cell lymphoma (MCL) with histomorphological features mimicking subcutaneous panniculitis-like T-cell lymphoma (SPTCL) highlights a “potential pitfall,” according to investigators.

This unusual case stresses the importance of molecular cytogenetics and/or immunohistochemistry for panniculitis-type lymphomas, reported lead author Caroline Laggis, MD of the University of Utah, Salt Lake City, and colleagues.

“While morphologic features of SPTCL, specifically rimming of adipocytes by neoplastic lymphoid cells, have been documented in other types of lymphomas, this case is exceptional in that the morphologic features of SPTCL are showed in secondary cutaneous involvement by MCL,” the investigators wrote. Their report is in Journal of Cutaneous Pathology.

The patient was a 69-year-old man who presented with 2-year history of night sweats and fever of unknown origin, and, closer to presentation, weight loss and tender bumps under the skin of his pelvic region.

Subsequent computed tomography and excisional lymph node biopsy led to a diagnosis of MCL, with a Mantle Cell Lymphoma International Prognostic Index of 5, suggesting aggressive, intermediate-risk disease. Further imaging showed involvement of the nasopharynx, and cervical and mediastinal lymph nodes.

Bendamustine and rituximab chemotherapy was given unremarkably until the final cycle, at which point the patient presented with tender subcutaneous nodules on his lower legs. Histopathology from punch biopsies revealed “a dense infiltrate of monomorphic, mitotically active lymphoid cells with infiltration between the deep dermal collagen and the adipocytes in subcutaneous fat,” the investigators wrote, noting that the infiltrative cells were blastoid and 70% expressed cyclin D1, supporting cutaneous involvement of his systemic MCL.

Treatment was switched to ibrutinib and selinexor via a clinical trial, which led to temporary improvement of leg lesions; when the lesions returned, biopsy was performed with the same histopathological result. Lenalidomide and rituximab were started, but without success, and disease spread to the central nervous system.

Another biopsy of the skin lesions again supported cutaneous MCL, with tumor cells rimming individual adipocytes.

Because of this atypical morphology, fluorescence in situ hybridization (FISH) was conducted, revealing t(11;14)(q13:32) positivity, thereby “confirming the diagnosis of cutaneous involvement by systemic MCL,” the investigators wrote.

Genomic sequencing revealed abnormalities of “ataxia-telangiectasia mutated, mechanistic target of rapamycin kinase (mTOR), BCL6 corepressor, and FAS-associated factor 1, as well as the expected mutation in IGH-CCND1, leading to cyclin D1 upregulation.”

Subsequent treatment was unsuccessful, and the patient died from his disease.

“The complex and central role that mTOR plays in adipose homeostasis may link our tumor to its preference to the adipose tissue, although further investigation is warranted regarding specific genomic alterations in lymphomas and the implications these mutations have in the involvement of tumor cells with cutaneous and adipose environments,” the investigators wrote.

The investigators did not report conflicts of interest.

SOURCE: Laggis C et al. 2019 Apr 8. doi:10.1111/cup.13471.

An atypical case of cutaneous mantle cell lymphoma (MCL) with histomorphological features mimicking subcutaneous panniculitis-like T-cell lymphoma (SPTCL) highlights a “potential pitfall,” according to investigators.

This unusual case stresses the importance of molecular cytogenetics and/or immunohistochemistry for panniculitis-type lymphomas, reported lead author Caroline Laggis, MD of the University of Utah, Salt Lake City, and colleagues.

“While morphologic features of SPTCL, specifically rimming of adipocytes by neoplastic lymphoid cells, have been documented in other types of lymphomas, this case is exceptional in that the morphologic features of SPTCL are showed in secondary cutaneous involvement by MCL,” the investigators wrote. Their report is in Journal of Cutaneous Pathology.

The patient was a 69-year-old man who presented with 2-year history of night sweats and fever of unknown origin, and, closer to presentation, weight loss and tender bumps under the skin of his pelvic region.

Subsequent computed tomography and excisional lymph node biopsy led to a diagnosis of MCL, with a Mantle Cell Lymphoma International Prognostic Index of 5, suggesting aggressive, intermediate-risk disease. Further imaging showed involvement of the nasopharynx, and cervical and mediastinal lymph nodes.

Bendamustine and rituximab chemotherapy was given unremarkably until the final cycle, at which point the patient presented with tender subcutaneous nodules on his lower legs. Histopathology from punch biopsies revealed “a dense infiltrate of monomorphic, mitotically active lymphoid cells with infiltration between the deep dermal collagen and the adipocytes in subcutaneous fat,” the investigators wrote, noting that the infiltrative cells were blastoid and 70% expressed cyclin D1, supporting cutaneous involvement of his systemic MCL.

Treatment was switched to ibrutinib and selinexor via a clinical trial, which led to temporary improvement of leg lesions; when the lesions returned, biopsy was performed with the same histopathological result. Lenalidomide and rituximab were started, but without success, and disease spread to the central nervous system.

Another biopsy of the skin lesions again supported cutaneous MCL, with tumor cells rimming individual adipocytes.

Because of this atypical morphology, fluorescence in situ hybridization (FISH) was conducted, revealing t(11;14)(q13:32) positivity, thereby “confirming the diagnosis of cutaneous involvement by systemic MCL,” the investigators wrote.

Genomic sequencing revealed abnormalities of “ataxia-telangiectasia mutated, mechanistic target of rapamycin kinase (mTOR), BCL6 corepressor, and FAS-associated factor 1, as well as the expected mutation in IGH-CCND1, leading to cyclin D1 upregulation.”

Subsequent treatment was unsuccessful, and the patient died from his disease.

“The complex and central role that mTOR plays in adipose homeostasis may link our tumor to its preference to the adipose tissue, although further investigation is warranted regarding specific genomic alterations in lymphomas and the implications these mutations have in the involvement of tumor cells with cutaneous and adipose environments,” the investigators wrote.

The investigators did not report conflicts of interest.

SOURCE: Laggis C et al. 2019 Apr 8. doi:10.1111/cup.13471.

An atypical case of cutaneous mantle cell lymphoma (MCL) with histomorphological features mimicking subcutaneous panniculitis-like T-cell lymphoma (SPTCL) highlights a “potential pitfall,” according to investigators.

This unusual case stresses the importance of molecular cytogenetics and/or immunohistochemistry for panniculitis-type lymphomas, reported lead author Caroline Laggis, MD of the University of Utah, Salt Lake City, and colleagues.

“While morphologic features of SPTCL, specifically rimming of adipocytes by neoplastic lymphoid cells, have been documented in other types of lymphomas, this case is exceptional in that the morphologic features of SPTCL are showed in secondary cutaneous involvement by MCL,” the investigators wrote. Their report is in Journal of Cutaneous Pathology.

The patient was a 69-year-old man who presented with 2-year history of night sweats and fever of unknown origin, and, closer to presentation, weight loss and tender bumps under the skin of his pelvic region.

Subsequent computed tomography and excisional lymph node biopsy led to a diagnosis of MCL, with a Mantle Cell Lymphoma International Prognostic Index of 5, suggesting aggressive, intermediate-risk disease. Further imaging showed involvement of the nasopharynx, and cervical and mediastinal lymph nodes.

Bendamustine and rituximab chemotherapy was given unremarkably until the final cycle, at which point the patient presented with tender subcutaneous nodules on his lower legs. Histopathology from punch biopsies revealed “a dense infiltrate of monomorphic, mitotically active lymphoid cells with infiltration between the deep dermal collagen and the adipocytes in subcutaneous fat,” the investigators wrote, noting that the infiltrative cells were blastoid and 70% expressed cyclin D1, supporting cutaneous involvement of his systemic MCL.

Treatment was switched to ibrutinib and selinexor via a clinical trial, which led to temporary improvement of leg lesions; when the lesions returned, biopsy was performed with the same histopathological result. Lenalidomide and rituximab were started, but without success, and disease spread to the central nervous system.

Another biopsy of the skin lesions again supported cutaneous MCL, with tumor cells rimming individual adipocytes.

Because of this atypical morphology, fluorescence in situ hybridization (FISH) was conducted, revealing t(11;14)(q13:32) positivity, thereby “confirming the diagnosis of cutaneous involvement by systemic MCL,” the investigators wrote.

Genomic sequencing revealed abnormalities of “ataxia-telangiectasia mutated, mechanistic target of rapamycin kinase (mTOR), BCL6 corepressor, and FAS-associated factor 1, as well as the expected mutation in IGH-CCND1, leading to cyclin D1 upregulation.”

Subsequent treatment was unsuccessful, and the patient died from his disease.

“The complex and central role that mTOR plays in adipose homeostasis may link our tumor to its preference to the adipose tissue, although further investigation is warranted regarding specific genomic alterations in lymphomas and the implications these mutations have in the involvement of tumor cells with cutaneous and adipose environments,” the investigators wrote.

The investigators did not report conflicts of interest.

SOURCE: Laggis C et al. 2019 Apr 8. doi:10.1111/cup.13471.

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

The Diagnosis: Merkel Cell Carcinoma 

An excisional biopsy revealed that the dermis was mostly replaced by a malignant neoplastic infiltrate morphologically resembling small cell carcinoma (Figure 1). The cells had uniform hyperchromatic nuclei with fairly even chromatin and generally inconspicuous nucleoli. There was a tendency for smudgy artifacts at the periphery of the infiltrate, and the cells had relatively scant cytoplasm with slight streaming. Occasional apoptotic forms were present. Immunohistochemistry showed strong dotlike staining with cytokeratin 20 and moderate positivity with synaptophysin and chromogranin A (Figure 2). Unusually, there also was weak staining in a few tumor cells with thyroid transcription factor 1, a marker usually indicative of small cell carcinoma of the lungs that typically is negative in Merkel cell carcinoma (MCC). A second thyroid transcription factor 1 monoclonal antibody used in a double immunostain for lung adenocarcinomas was completely negative. This second antibody is more specific but less sensitive than the stand-alone version. The skin biopsy results confirmed the diagnosis of MCC. Given the patient's frailty and comorbidities, wide local excision was not performed and the patient was referred to radiation oncology. He died several months later from metastatic MCC. 

Merkel cell carcinoma is an uncommon skin malignancy that can be easily mistaken for other conditions if the clinician is not familiar with its typical presentation. It most commonly is found on the head and neck in elderly individuals, most often aged 60 to 80 years,¹ with a notable history of sun exposure and/or immunosuppression. It is an aggressive skin cancer that originally was thought to be due to pathogenic changes of Merkel cells,² which are specialized touch receptors located at the dermoepidermal junction of the skin; however, newer evidence has suggested that MCC arises from malignant changes to skin stem cells.³ It shares more characteristics with extracutaneous neuroendocrine tumors and is more aptly labeled by pathologists as a primary neuroendocrine carcinoma of the skin.⁴  

The frequency of MCC is highest in Australia, likely due to intense sun exposure, where the age-adjusted incidence rate reported in Queensland was 1.6 per 100,000 individuals from 2006 to 2010.⁵ The lowest incidence rates were reported in Finland (0.11 and 0.12 per 100,000 males and females, respectively)⁶ and Denmark (2.2 cases per million person-years).⁷ The clinical features of MCC are summarized by the mnemonic AEIOU: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin.⁸ In a 2008 study of 195 patients, 89% of primary MCC lesions met 3 or more criteria, 32% met 4 or more criteria, and 7% met all 5 criteria.⁸  

The classic presentation of MCC is a pink-red to violaceous nodule on the head or neck in an elderly patient, but there is a need to maintain suspicion of malignancy when examining a presumed infected cystic lesion, especially when a round of antibiotics has not ameliorated the symptoms. According to Heath et al,⁸ of 106 patients treated for MCC, 56% of first clinical impressions were benign. A PubMed and Scopus search was performed with the MeSH headings Merkel cell carcinoma +/- presentation to uncover similar unusual presentations between 1970 and the present day. Merkel cell carcinoma has been misdiagnosed as seemingly benign lesions including lipoma,⁹ allergic contact dermatitis,¹⁰ and atheroma.¹¹ The differential diagnosis of MCC also includes cysts, amelanotic melanoma, basal cell carcinoma, dermatofibrosarcoma protuberans, squamous cell carcinoma, fungal kerion, leiomyosarcoma, neurothekeoma, abscesses, and cutaneous lymphoma.  

Merkel cell polyomavirus has been implicated in the malignant transformation of MCC. It is a small, human, nonenveloped, double-stranded DNA virus1 and is found in approximately 70% to 80% of MCC cases.¹² Merkel cell polyomavirus is a respiratory tract pathogen that is acquired by immunocompetent infants; it integrates itself into the host's genome and then enters a long latency period to later reactivate in immunocompromised adults.¹³ 

Wide local excision down to fascia is the mainstay of treatment of MCC, with recommended margins of 1 to 2 cm.¹⁴ Mohs micrographic surgery also can be considered.¹⁵ Similar to other neuroendocrine tumors, MCC is considered a radiosensitive tumor; radiation likely improves local control and is recommended in early-stage disease.^16,17 It also has been described as the sole treatment modality in patients who are not candidates for surgery. The role of chemotherapy is more controversial, as responses do not appear to be long-lasting but should be considered in patients with advanced disease.^14,18 There have been major advances in immunotherapy with the recent approvals of avelumab, an anti-PD-L1 inhibitor,¹⁹ and pembrolizumab,²⁰ an anti-PD-1 inhibitor, for metastatic MCC. Clinical trials for MCC using kinase inhibitors and somatostatin analogues currently are ongoing.²¹  

Several studies have demonstrated high rates of occult nodal disease in clinically node-negative patients, which has led to widespread use of sentinel lymph node biopsies^.22,23 A sentinel lymph node biopsy is recommended at the time of surgery to aid with treatment decisions and prognosis.²⁴  

Merkel cell carcinoma is highly aggressive, and more than one-third of patients die from their disease, making it twice as lethal as melanoma. Overall survival rates remain low (5-year overall survival, 0%-18%) for advanced disease.⁵ Unfortunately, progression to metastasis is common and most often occurs within 2 years of diagnosis.^17,25 Follow-up after treatment of MCC is crucial, with the 2019 National Comprehensive Cancer Network (NCCN) guidelines suggesting a physical examination with complete skin and complete lymph node examination every 3 to 6 months for 3 years and every 6 to 12 months thereafter.¹⁵ 

This case is an important reminder to include MCC in the differential diagnosis of presumed infected cysts, particularly on sun-exposed sites in elderly patients, as our patient was treated with antibiotics twice without improvement. An infected cyst with a lack of response to antibiotics should alert clinicians to the potential of malignancy.  

The Diagnosis: Merkel Cell Carcinoma 

An excisional biopsy revealed that the dermis was mostly replaced by a malignant neoplastic infiltrate morphologically resembling small cell carcinoma (Figure 1). The cells had uniform hyperchromatic nuclei with fairly even chromatin and generally inconspicuous nucleoli. There was a tendency for smudgy artifacts at the periphery of the infiltrate, and the cells had relatively scant cytoplasm with slight streaming. Occasional apoptotic forms were present. Immunohistochemistry showed strong dotlike staining with cytokeratin 20 and moderate positivity with synaptophysin and chromogranin A (Figure 2). Unusually, there also was weak staining in a few tumor cells with thyroid transcription factor 1, a marker usually indicative of small cell carcinoma of the lungs that typically is negative in Merkel cell carcinoma (MCC). A second thyroid transcription factor 1 monoclonal antibody used in a double immunostain for lung adenocarcinomas was completely negative. This second antibody is more specific but less sensitive than the stand-alone version. The skin biopsy results confirmed the diagnosis of MCC. Given the patient's frailty and comorbidities, wide local excision was not performed and the patient was referred to radiation oncology. He died several months later from metastatic MCC. 

Merkel cell carcinoma is an uncommon skin malignancy that can be easily mistaken for other conditions if the clinician is not familiar with its typical presentation. It most commonly is found on the head and neck in elderly individuals, most often aged 60 to 80 years,¹ with a notable history of sun exposure and/or immunosuppression. It is an aggressive skin cancer that originally was thought to be due to pathogenic changes of Merkel cells,² which are specialized touch receptors located at the dermoepidermal junction of the skin; however, newer evidence has suggested that MCC arises from malignant changes to skin stem cells.³ It shares more characteristics with extracutaneous neuroendocrine tumors and is more aptly labeled by pathologists as a primary neuroendocrine carcinoma of the skin.⁴  

The frequency of MCC is highest in Australia, likely due to intense sun exposure, where the age-adjusted incidence rate reported in Queensland was 1.6 per 100,000 individuals from 2006 to 2010.⁵ The lowest incidence rates were reported in Finland (0.11 and 0.12 per 100,000 males and females, respectively)⁶ and Denmark (2.2 cases per million person-years).⁷ The clinical features of MCC are summarized by the mnemonic AEIOU: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin.⁸ In a 2008 study of 195 patients, 89% of primary MCC lesions met 3 or more criteria, 32% met 4 or more criteria, and 7% met all 5 criteria.⁸  

The classic presentation of MCC is a pink-red to violaceous nodule on the head or neck in an elderly patient, but there is a need to maintain suspicion of malignancy when examining a presumed infected cystic lesion, especially when a round of antibiotics has not ameliorated the symptoms. According to Heath et al,⁸ of 106 patients treated for MCC, 56% of first clinical impressions were benign. A PubMed and Scopus search was performed with the MeSH headings Merkel cell carcinoma +/- presentation to uncover similar unusual presentations between 1970 and the present day. Merkel cell carcinoma has been misdiagnosed as seemingly benign lesions including lipoma,⁹ allergic contact dermatitis,¹⁰ and atheroma.¹¹ The differential diagnosis of MCC also includes cysts, amelanotic melanoma, basal cell carcinoma, dermatofibrosarcoma protuberans, squamous cell carcinoma, fungal kerion, leiomyosarcoma, neurothekeoma, abscesses, and cutaneous lymphoma.  

Merkel cell polyomavirus has been implicated in the malignant transformation of MCC. It is a small, human, nonenveloped, double-stranded DNA virus1 and is found in approximately 70% to 80% of MCC cases.¹² Merkel cell polyomavirus is a respiratory tract pathogen that is acquired by immunocompetent infants; it integrates itself into the host's genome and then enters a long latency period to later reactivate in immunocompromised adults.¹³ 

Wide local excision down to fascia is the mainstay of treatment of MCC, with recommended margins of 1 to 2 cm.¹⁴ Mohs micrographic surgery also can be considered.¹⁵ Similar to other neuroendocrine tumors, MCC is considered a radiosensitive tumor; radiation likely improves local control and is recommended in early-stage disease.^16,17 It also has been described as the sole treatment modality in patients who are not candidates for surgery. The role of chemotherapy is more controversial, as responses do not appear to be long-lasting but should be considered in patients with advanced disease.^14,18 There have been major advances in immunotherapy with the recent approvals of avelumab, an anti-PD-L1 inhibitor,¹⁹ and pembrolizumab,²⁰ an anti-PD-1 inhibitor, for metastatic MCC. Clinical trials for MCC using kinase inhibitors and somatostatin analogues currently are ongoing.²¹  

Several studies have demonstrated high rates of occult nodal disease in clinically node-negative patients, which has led to widespread use of sentinel lymph node biopsies^.22,23 A sentinel lymph node biopsy is recommended at the time of surgery to aid with treatment decisions and prognosis.²⁴  

Merkel cell carcinoma is highly aggressive, and more than one-third of patients die from their disease, making it twice as lethal as melanoma. Overall survival rates remain low (5-year overall survival, 0%-18%) for advanced disease.⁵ Unfortunately, progression to metastasis is common and most often occurs within 2 years of diagnosis.^17,25 Follow-up after treatment of MCC is crucial, with the 2019 National Comprehensive Cancer Network (NCCN) guidelines suggesting a physical examination with complete skin and complete lymph node examination every 3 to 6 months for 3 years and every 6 to 12 months thereafter.¹⁵ 

This case is an important reminder to include MCC in the differential diagnosis of presumed infected cysts, particularly on sun-exposed sites in elderly patients, as our patient was treated with antibiotics twice without improvement. An infected cyst with a lack of response to antibiotics should alert clinicians to the potential of malignancy.  

The Diagnosis: Merkel Cell Carcinoma 

An excisional biopsy revealed that the dermis was mostly replaced by a malignant neoplastic infiltrate morphologically resembling small cell carcinoma (Figure 1). The cells had uniform hyperchromatic nuclei with fairly even chromatin and generally inconspicuous nucleoli. There was a tendency for smudgy artifacts at the periphery of the infiltrate, and the cells had relatively scant cytoplasm with slight streaming. Occasional apoptotic forms were present. Immunohistochemistry showed strong dotlike staining with cytokeratin 20 and moderate positivity with synaptophysin and chromogranin A (Figure 2). Unusually, there also was weak staining in a few tumor cells with thyroid transcription factor 1, a marker usually indicative of small cell carcinoma of the lungs that typically is negative in Merkel cell carcinoma (MCC). A second thyroid transcription factor 1 monoclonal antibody used in a double immunostain for lung adenocarcinomas was completely negative. This second antibody is more specific but less sensitive than the stand-alone version. The skin biopsy results confirmed the diagnosis of MCC. Given the patient's frailty and comorbidities, wide local excision was not performed and the patient was referred to radiation oncology. He died several months later from metastatic MCC. 

Merkel cell carcinoma is an uncommon skin malignancy that can be easily mistaken for other conditions if the clinician is not familiar with its typical presentation. It most commonly is found on the head and neck in elderly individuals, most often aged 60 to 80 years,¹ with a notable history of sun exposure and/or immunosuppression. It is an aggressive skin cancer that originally was thought to be due to pathogenic changes of Merkel cells,² which are specialized touch receptors located at the dermoepidermal junction of the skin; however, newer evidence has suggested that MCC arises from malignant changes to skin stem cells.³ It shares more characteristics with extracutaneous neuroendocrine tumors and is more aptly labeled by pathologists as a primary neuroendocrine carcinoma of the skin.⁴  

The frequency of MCC is highest in Australia, likely due to intense sun exposure, where the age-adjusted incidence rate reported in Queensland was 1.6 per 100,000 individuals from 2006 to 2010.⁵ The lowest incidence rates were reported in Finland (0.11 and 0.12 per 100,000 males and females, respectively)⁶ and Denmark (2.2 cases per million person-years).⁷ The clinical features of MCC are summarized by the mnemonic AEIOU: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin.⁸ In a 2008 study of 195 patients, 89% of primary MCC lesions met 3 or more criteria, 32% met 4 or more criteria, and 7% met all 5 criteria.⁸  

The classic presentation of MCC is a pink-red to violaceous nodule on the head or neck in an elderly patient, but there is a need to maintain suspicion of malignancy when examining a presumed infected cystic lesion, especially when a round of antibiotics has not ameliorated the symptoms. According to Heath et al,⁸ of 106 patients treated for MCC, 56% of first clinical impressions were benign. A PubMed and Scopus search was performed with the MeSH headings Merkel cell carcinoma +/- presentation to uncover similar unusual presentations between 1970 and the present day. Merkel cell carcinoma has been misdiagnosed as seemingly benign lesions including lipoma,⁹ allergic contact dermatitis,¹⁰ and atheroma.¹¹ The differential diagnosis of MCC also includes cysts, amelanotic melanoma, basal cell carcinoma, dermatofibrosarcoma protuberans, squamous cell carcinoma, fungal kerion, leiomyosarcoma, neurothekeoma, abscesses, and cutaneous lymphoma.  

Merkel cell polyomavirus has been implicated in the malignant transformation of MCC. It is a small, human, nonenveloped, double-stranded DNA virus1 and is found in approximately 70% to 80% of MCC cases.¹² Merkel cell polyomavirus is a respiratory tract pathogen that is acquired by immunocompetent infants; it integrates itself into the host's genome and then enters a long latency period to later reactivate in immunocompromised adults.¹³ 

Wide local excision down to fascia is the mainstay of treatment of MCC, with recommended margins of 1 to 2 cm.¹⁴ Mohs micrographic surgery also can be considered.¹⁵ Similar to other neuroendocrine tumors, MCC is considered a radiosensitive tumor; radiation likely improves local control and is recommended in early-stage disease.^16,17 It also has been described as the sole treatment modality in patients who are not candidates for surgery. The role of chemotherapy is more controversial, as responses do not appear to be long-lasting but should be considered in patients with advanced disease.^14,18 There have been major advances in immunotherapy with the recent approvals of avelumab, an anti-PD-L1 inhibitor,¹⁹ and pembrolizumab,²⁰ an anti-PD-1 inhibitor, for metastatic MCC. Clinical trials for MCC using kinase inhibitors and somatostatin analogues currently are ongoing.²¹  

Several studies have demonstrated high rates of occult nodal disease in clinically node-negative patients, which has led to widespread use of sentinel lymph node biopsies^.22,23 A sentinel lymph node biopsy is recommended at the time of surgery to aid with treatment decisions and prognosis.²⁴  

Merkel cell carcinoma is highly aggressive, and more than one-third of patients die from their disease, making it twice as lethal as melanoma. Overall survival rates remain low (5-year overall survival, 0%-18%) for advanced disease.⁵ Unfortunately, progression to metastasis is common and most often occurs within 2 years of diagnosis.^17,25 Follow-up after treatment of MCC is crucial, with the 2019 National Comprehensive Cancer Network (NCCN) guidelines suggesting a physical examination with complete skin and complete lymph node examination every 3 to 6 months for 3 years and every 6 to 12 months thereafter.¹⁵ 

This case is an important reminder to include MCC in the differential diagnosis of presumed infected cysts, particularly on sun-exposed sites in elderly patients, as our patient was treated with antibiotics twice without improvement. An infected cyst with a lack of response to antibiotics should alert clinicians to the potential of malignancy.  

BALTIMORE – Ultrasound can be a very effective way to track early nodal metastasis in patients with high-stage cutaneous squamous cell carcinomas, and at a fraction of the cost of other imaging modalities.

Bogdanhoda/Thinkstock

The technique shows not only abnormal variations in the shape of nodes, but changes in the core and outer density, and vascular patterns, Emily Ruiz, MD, said at the annual meeting of the American College of Mohs Surgery. And over a 2-year surveillance period, this costs thousands less than radiation-based imaging.

Dr. Ruiz, director of the High-Risk Skin Cancer Clinic at Dana-Farber/Brigham and Women’s Cancer Center, Boston, said the standard imaging technique at that center used to be serial CT scans performed at diagnosis and every 6 months thereafter, for 2 years. But recently, the protocol changed: Ultrasound is now the preferred technique.

“The big problem with CT in this earlier disease, is that it can only identify the nodes that are enlarged, and doesn’t tell us anything about the etiology. Ultrasound, on the other hand, looks at a number of different features of the node.”

Tracking high-risk squamous cell carcinoma patients is a must, she said. “About 4% of people diagnosed with high-risk SCC will develop nodal metastases, and 1.5% of those will die from disease-specific death,” most often from locoregional disease. “So it’s critical to identify nodal diseases early as possible. Earlier identification leads to better outcomes.” Ultrasound simply provides more information about nodal metastasis, Dr. Ruiz added.

Michele G. Sullivan/MDedge News

Cost is another consideration, Dr. Ruiz said. Five CT scans conducted over the recommended 2 years of follow-up will run about $5,000. Five scans with magnetic resonance imaging come in at about $6,500. PET CT is, of course, the most expensive, racking up a national average cost of $28,500 for five scans.

Ultrasound is amazingly inexpensive, Dr. Ruiz said. The national average cost of one scan is around $180, bringing the 2-year cost of five surveillance scans to $900.

Finally, clinicians and patients should consider the potential impact of repeated radiation exposure. “This can really add up over the follow-up period. Because there’s a 10-year latency period for these cancers, this might not be an issue for our older patients, but it really is something to consider in younger ones. “

However, she acknowledged that it’s not a completely rosy picture.

“Ultrasound is very user dependent, but we do think that by putting this in the hands of dermatologists with special training, we can solve this issue. In Europe, ultrasound’s very high sensitivity and specificity, combined with clinical exams, really improves disease detection.”

Unfortunately, at this point, anyone who wants to learn the technique has to go to Europe. “I trained in Germany, where I took a standard 3-day course, did 250 supervised scans, and completed an exam. I realize that’s unrealistic for most people,” she said. But a training protocol is being developed at Brigham and Women’s, under the auspices of the institution’s imaging experts, who felt that 3 days and 250 supervised scans was excessive. The Brigham and Women’s program comprises 8 hours of didactic training and at least 30 supervised scans with at least three abnormalities correctly identified, and will be put into place soon, Dr. Ruiz said.

The biggest obstacle to large-scale adoption of this protocol is data – there are not a lot, at least now.

“We are working on that, too. In conjunction with the Skin Cancer Foundation, we’re launching a prospective study. We want to recruit 80 patients with T2B/T3 cutaneous SCCs. They get both and ultrasound and a CT scan at diagnosis and every 6 months for 2 years,” she said.

[email protected]

BALTIMORE – Ultrasound can be a very effective way to track early nodal metastasis in patients with high-stage cutaneous squamous cell carcinomas, and at a fraction of the cost of other imaging modalities.

Bogdanhoda/Thinkstock

The technique shows not only abnormal variations in the shape of nodes, but changes in the core and outer density, and vascular patterns, Emily Ruiz, MD, said at the annual meeting of the American College of Mohs Surgery. And over a 2-year surveillance period, this costs thousands less than radiation-based imaging.

Dr. Ruiz, director of the High-Risk Skin Cancer Clinic at Dana-Farber/Brigham and Women’s Cancer Center, Boston, said the standard imaging technique at that center used to be serial CT scans performed at diagnosis and every 6 months thereafter, for 2 years. But recently, the protocol changed: Ultrasound is now the preferred technique.

“The big problem with CT in this earlier disease, is that it can only identify the nodes that are enlarged, and doesn’t tell us anything about the etiology. Ultrasound, on the other hand, looks at a number of different features of the node.”

Tracking high-risk squamous cell carcinoma patients is a must, she said. “About 4% of people diagnosed with high-risk SCC will develop nodal metastases, and 1.5% of those will die from disease-specific death,” most often from locoregional disease. “So it’s critical to identify nodal diseases early as possible. Earlier identification leads to better outcomes.” Ultrasound simply provides more information about nodal metastasis, Dr. Ruiz added.

Michele G. Sullivan/MDedge News

Cost is another consideration, Dr. Ruiz said. Five CT scans conducted over the recommended 2 years of follow-up will run about $5,000. Five scans with magnetic resonance imaging come in at about $6,500. PET CT is, of course, the most expensive, racking up a national average cost of $28,500 for five scans.

Ultrasound is amazingly inexpensive, Dr. Ruiz said. The national average cost of one scan is around $180, bringing the 2-year cost of five surveillance scans to $900.

Finally, clinicians and patients should consider the potential impact of repeated radiation exposure. “This can really add up over the follow-up period. Because there’s a 10-year latency period for these cancers, this might not be an issue for our older patients, but it really is something to consider in younger ones. “

However, she acknowledged that it’s not a completely rosy picture.

“Ultrasound is very user dependent, but we do think that by putting this in the hands of dermatologists with special training, we can solve this issue. In Europe, ultrasound’s very high sensitivity and specificity, combined with clinical exams, really improves disease detection.”

Unfortunately, at this point, anyone who wants to learn the technique has to go to Europe. “I trained in Germany, where I took a standard 3-day course, did 250 supervised scans, and completed an exam. I realize that’s unrealistic for most people,” she said. But a training protocol is being developed at Brigham and Women’s, under the auspices of the institution’s imaging experts, who felt that 3 days and 250 supervised scans was excessive. The Brigham and Women’s program comprises 8 hours of didactic training and at least 30 supervised scans with at least three abnormalities correctly identified, and will be put into place soon, Dr. Ruiz said.

The biggest obstacle to large-scale adoption of this protocol is data – there are not a lot, at least now.

“We are working on that, too. In conjunction with the Skin Cancer Foundation, we’re launching a prospective study. We want to recruit 80 patients with T2B/T3 cutaneous SCCs. They get both and ultrasound and a CT scan at diagnosis and every 6 months for 2 years,” she said.

[email protected]

BALTIMORE – Ultrasound can be a very effective way to track early nodal metastasis in patients with high-stage cutaneous squamous cell carcinomas, and at a fraction of the cost of other imaging modalities.

Bogdanhoda/Thinkstock

The technique shows not only abnormal variations in the shape of nodes, but changes in the core and outer density, and vascular patterns, Emily Ruiz, MD, said at the annual meeting of the American College of Mohs Surgery. And over a 2-year surveillance period, this costs thousands less than radiation-based imaging.

Dr. Ruiz, director of the High-Risk Skin Cancer Clinic at Dana-Farber/Brigham and Women’s Cancer Center, Boston, said the standard imaging technique at that center used to be serial CT scans performed at diagnosis and every 6 months thereafter, for 2 years. But recently, the protocol changed: Ultrasound is now the preferred technique.

“The big problem with CT in this earlier disease, is that it can only identify the nodes that are enlarged, and doesn’t tell us anything about the etiology. Ultrasound, on the other hand, looks at a number of different features of the node.”

Tracking high-risk squamous cell carcinoma patients is a must, she said. “About 4% of people diagnosed with high-risk SCC will develop nodal metastases, and 1.5% of those will die from disease-specific death,” most often from locoregional disease. “So it’s critical to identify nodal diseases early as possible. Earlier identification leads to better outcomes.” Ultrasound simply provides more information about nodal metastasis, Dr. Ruiz added.

Michele G. Sullivan/MDedge News

Cost is another consideration, Dr. Ruiz said. Five CT scans conducted over the recommended 2 years of follow-up will run about $5,000. Five scans with magnetic resonance imaging come in at about $6,500. PET CT is, of course, the most expensive, racking up a national average cost of $28,500 for five scans.

Ultrasound is amazingly inexpensive, Dr. Ruiz said. The national average cost of one scan is around $180, bringing the 2-year cost of five surveillance scans to $900.

Finally, clinicians and patients should consider the potential impact of repeated radiation exposure. “This can really add up over the follow-up period. Because there’s a 10-year latency period for these cancers, this might not be an issue for our older patients, but it really is something to consider in younger ones. “

However, she acknowledged that it’s not a completely rosy picture.

“Ultrasound is very user dependent, but we do think that by putting this in the hands of dermatologists with special training, we can solve this issue. In Europe, ultrasound’s very high sensitivity and specificity, combined with clinical exams, really improves disease detection.”

Unfortunately, at this point, anyone who wants to learn the technique has to go to Europe. “I trained in Germany, where I took a standard 3-day course, did 250 supervised scans, and completed an exam. I realize that’s unrealistic for most people,” she said. But a training protocol is being developed at Brigham and Women’s, under the auspices of the institution’s imaging experts, who felt that 3 days and 250 supervised scans was excessive. The Brigham and Women’s program comprises 8 hours of didactic training and at least 30 supervised scans with at least three abnormalities correctly identified, and will be put into place soon, Dr. Ruiz said.

The biggest obstacle to large-scale adoption of this protocol is data – there are not a lot, at least now.

“We are working on that, too. In conjunction with the Skin Cancer Foundation, we’re launching a prospective study. We want to recruit 80 patients with T2B/T3 cutaneous SCCs. They get both and ultrasound and a CT scan at diagnosis and every 6 months for 2 years,” she said.

[email protected]

Isolated limb perfusion (ILP) for the adjuvant treatment of melanoma involves isolating the blood flow of a limb from the rest of the body to allow for high concentrations of chemotherapeutic agents locally. Chemotherapy with nitrogen mustard is the preferred chemotherapeutic agent in ILP for the adjuvant treatment of locally advanced melanoma.¹ Systemic exposure to nitrogen mustard has shown to be carcinogenic, and its topical application has been associated with the development of actinic keratosis, basal cell carcinoma (BCC), and squamous cell carcinoma.^2,3 However, the long-term effects of ILP with nitrogen mustard are not well defined. In 1998, one of the authors (R.L.M.) described a patient with melanoma of the left leg that was treated with ILP with nitrogen mustard who subsequently developed numerous BCCs on the same leg.⁴ This same patient has since been successfully managed with only topical chemotherapeutic agents for the last 21 years.

An 86-year-old man with a history of melanoma underwent wide resection, lymph node dissection, and adjuvant ILP with nitrogen mustard for the treatment of melanoma of the medial left thigh approximately 50 years ago. He denied any prior radiation treatment. He subsequently presented years later to our dermatology clinic with many biopsy-proven superficial and nodular BCCs of the left leg over the course of the last 30 years. On physical examination, the patient had several pink papules and macules on the left lower leg (Figure). The patient had previously undergone multiple invasive excisions with grafting for the treatment of BCCs by a plastic surgeon prior to presentation to our clinic but has since had many years of control under our care with only topical chemotherapeutic agents. His current medication regimen consists of 5-fluorouracil twice daily, which he tolerates without serious side effects. He also has used imiquimod in the past.

Treatment modalities for NMSC include surgical excision with defined margins, Mohs micrographic surgery, radiotherapy, electrodesiccation and curettage, cryotherapy, photodynamic therapy, and topical therapy. Our patient experienced such a high volume of superficial BCCs that the decision was made to avoid frequent surgical procedures and to treat with topical chemotherapeutic agents. He had an excellent response to topical 5-fluorouracil, and the treatment has been well tolerated. This case is valuable for clinicians, as it demonstrates that topical chemotherapy can be a well-tolerated option for patients who present with frequent superficial BCCs to prevent numerous invasive surgical treatments.

Isolated limb perfusion (ILP) for the adjuvant treatment of melanoma involves isolating the blood flow of a limb from the rest of the body to allow for high concentrations of chemotherapeutic agents locally. Chemotherapy with nitrogen mustard is the preferred chemotherapeutic agent in ILP for the adjuvant treatment of locally advanced melanoma.¹ Systemic exposure to nitrogen mustard has shown to be carcinogenic, and its topical application has been associated with the development of actinic keratosis, basal cell carcinoma (BCC), and squamous cell carcinoma.^2,3 However, the long-term effects of ILP with nitrogen mustard are not well defined. In 1998, one of the authors (R.L.M.) described a patient with melanoma of the left leg that was treated with ILP with nitrogen mustard who subsequently developed numerous BCCs on the same leg.⁴ This same patient has since been successfully managed with only topical chemotherapeutic agents for the last 21 years.

An 86-year-old man with a history of melanoma underwent wide resection, lymph node dissection, and adjuvant ILP with nitrogen mustard for the treatment of melanoma of the medial left thigh approximately 50 years ago. He denied any prior radiation treatment. He subsequently presented years later to our dermatology clinic with many biopsy-proven superficial and nodular BCCs of the left leg over the course of the last 30 years. On physical examination, the patient had several pink papules and macules on the left lower leg (Figure). The patient had previously undergone multiple invasive excisions with grafting for the treatment of BCCs by a plastic surgeon prior to presentation to our clinic but has since had many years of control under our care with only topical chemotherapeutic agents. His current medication regimen consists of 5-fluorouracil twice daily, which he tolerates without serious side effects. He also has used imiquimod in the past.

Treatment modalities for NMSC include surgical excision with defined margins, Mohs micrographic surgery, radiotherapy, electrodesiccation and curettage, cryotherapy, photodynamic therapy, and topical therapy. Our patient experienced such a high volume of superficial BCCs that the decision was made to avoid frequent surgical procedures and to treat with topical chemotherapeutic agents. He had an excellent response to topical 5-fluorouracil, and the treatment has been well tolerated. This case is valuable for clinicians, as it demonstrates that topical chemotherapy can be a well-tolerated option for patients who present with frequent superficial BCCs to prevent numerous invasive surgical treatments.

Isolated limb perfusion (ILP) for the adjuvant treatment of melanoma involves isolating the blood flow of a limb from the rest of the body to allow for high concentrations of chemotherapeutic agents locally. Chemotherapy with nitrogen mustard is the preferred chemotherapeutic agent in ILP for the adjuvant treatment of locally advanced melanoma.¹ Systemic exposure to nitrogen mustard has shown to be carcinogenic, and its topical application has been associated with the development of actinic keratosis, basal cell carcinoma (BCC), and squamous cell carcinoma.^2,3 However, the long-term effects of ILP with nitrogen mustard are not well defined. In 1998, one of the authors (R.L.M.) described a patient with melanoma of the left leg that was treated with ILP with nitrogen mustard who subsequently developed numerous BCCs on the same leg.⁴ This same patient has since been successfully managed with only topical chemotherapeutic agents for the last 21 years.

An 86-year-old man with a history of melanoma underwent wide resection, lymph node dissection, and adjuvant ILP with nitrogen mustard for the treatment of melanoma of the medial left thigh approximately 50 years ago. He denied any prior radiation treatment. He subsequently presented years later to our dermatology clinic with many biopsy-proven superficial and nodular BCCs of the left leg over the course of the last 30 years. On physical examination, the patient had several pink papules and macules on the left lower leg (Figure). The patient had previously undergone multiple invasive excisions with grafting for the treatment of BCCs by a plastic surgeon prior to presentation to our clinic but has since had many years of control under our care with only topical chemotherapeutic agents. His current medication regimen consists of 5-fluorouracil twice daily, which he tolerates without serious side effects. He also has used imiquimod in the past.

Treatment modalities for NMSC include surgical excision with defined margins, Mohs micrographic surgery, radiotherapy, electrodesiccation and curettage, cryotherapy, photodynamic therapy, and topical therapy. Our patient experienced such a high volume of superficial BCCs that the decision was made to avoid frequent surgical procedures and to treat with topical chemotherapeutic agents. He had an excellent response to topical 5-fluorouracil, and the treatment has been well tolerated. This case is valuable for clinicians, as it demonstrates that topical chemotherapy can be a well-tolerated option for patients who present with frequent superficial BCCs to prevent numerous invasive surgical treatments.