Cutis

It’s time for the American Contact Dermatitis Society (ACDS) Allergen of the Year! For 2021, the esteemed award goes to acetophenone azine (AA). If you have never heard of this chemical, you are not alone. Acetophenone azine has been identified in foam materials made of the copolymer ethyl-vinyl acetate (EVA). Contact allergy to AA initially was reported in 2016.¹ There are only a few European and Canadian case reports and one case series of AA contact allergy in the literature, all of which are associated with foam shin pads or shin guards, shoe insoles, and/or flip-flops.^2-6 Acetophenone azine is an important emerging allergen, and in this column, we will introduce you to AA and the sneaky places it can lurk and cause allergic contact dermatitis (ACD). We also highlight diagnosis, management, and patch testing for AA contact allergy.

AA Contact Allergy in the Literature

The first case of AA contact allergy was reported in Europe in 2016 when a 13-year-old male soccer player developed severe lower leg dermatitis and later generalized dermatitis associated with wearing foam shin guards.¹ Patch testing to standard and supplemental trays was negative or not relevant; however, the patient exhibited strong reactions when patch tested directly to a piece of the shin guard soaked in acetone, water, and ethanol. Additional testing with AA diluted in acetone, water, and petrolatum resulted in positive patch test reactions to acetone dilutions of 1%, 0.1%, 0.01%, and 0.001% and aqueous solutions of 1% and 0.1%. Chromatographic analyses with high-performance liquid chromatography (HPLC) of shin guard extracts confirmed the culprit allergen to be AA.¹

In the following months, the same clinic saw 2 more cases of AA contact allergy.² An 11-year-old male soccer player developed lower leg dermatitis and later generalized dermatitis from wearing shin guards. Months later, he also developed dermatitis on the soles of the feet, which was attributed to wearing flip-flops. Patch tests to pieces of the shin guards and flip-flops were positive; AA in acetone 0.1% and 0.01% also was positive. As you might expect, HPLC again confirmed the presence of AA in the shin guards and flip-flops. The third patient was a 12-year-old boy with dermatitis on the soles of both feet; later he also developed a generalized dermatitis. Patch testing to pieces of the insoles of his sneakers and AA in acetone 0.1% and 0.01% was positive. Again, HPLC was positive for the presence of AA in the insoles of his sneakers.²

Several more cases of AA contact allergy have been reported in the literature. A 29-year-old European male hockey player demonstrated contact allergy to the gray foam of his shin pads as well as localized leg dermatitis followed by generalized dermatitis (are you noticing a trend yet?), and later dermatitis on the soles of the feet with positive patch-test reactions to pieces of his shin pads and shoe insoles as well as AA 0.1% and 0.01% in acetone.³ A 6-year-old Canadian male soccer player presented with leg dermatitis and later generalized dermatitis and dermatitis on the soles of the feet with positive reactions to pieces of his shin pads and shoe insoles as well as to AA 1% and 0.1% in petrolatum.⁴ A 17-year-old British male (another trend, all males so far!) hockey player developed dermatitis localized to the legs and positive patch tests to the worn foam inner lining of his shin pads as well as to AA 0.1%, 0.01%, and 0.001% in acetone.⁵Finally, Darrigade et al⁶ published a case series of 6 European children with AA contact allergy associated with shin pads and shoes; all had localized leg dermatitis, and some had generalized dermatitis. Patch testing to pieces of shin pads and shoe parts as well as to AA 0.1% in petrolatum and/or acetone showed with positive reactions to the foam pieces and AA in all 6 patients.

What’s the Deal With AA?

Acetophenone azine (also known as methylphenylketazine or bis[1-phenylethylidene]hydrazine) is composed of 2 acetophenone structures and a hydrazine moiety. It has been identified in EVA foam, which can be found in sports equipment such as shin pads or shin guards, shoes, and flip-flops. Raison-Peyron et al¹ confirmed the presence of AA in EVA foam but reported that they did not know the exact reason for its presence. The authors theorized that AA might be a catalyst during EVA polymerization and also noted that it has antimicrobial and antihelminthic activity.¹ Several authors noted that AA could be a by-product of EVA synthesis and that sports equipment manufacturers might not be aware of its presence in EVA.^2,4-6 Some noted that AA concentration was higher in shin guards than in shoe insoles; they thought this explained why patients reacted first to their shin guards and were perhaps even initially sensitized to the shin guards, as well as why shoe insole contact allergy commonly was reported later or only after allergy to shin guards had already developed.^4,6

Differential Diagnosis of Shin Pad or Shin Guard Dermatitis

We would be remiss if we did not mention the appropriate differential diagnosis when shin pad or shin guard dermatitis is identified. In fact, in most cases, shin guard dermatitis results from irritant contact dermatitis from friction, heat, and/or perspiration. Acetophenone azine contact allergy is not the most likely diagnosis when your sports-savvy, shin guard–wearing patient presents with anterior lower leg dermatitis. However, when conservative therapy (eg, barrier between the shin guard and the skin, control or management of perspiration, topical corticosteroid therapy) fails, patch testing to evaluate for ACD is indicated.

Management of AA Contact Allergy

As astute readers of this column are already aware, treatment of ACD requires strict allergen avoidance. You will find that we have the same recommendations for AA contact allergy. Given that there are only a handful of cases in the literature, there are limited recommendations on practical allergen avoidance other than “don’t wear the problem shin guards, shoe insoles, or flip-flops.” However, Darrigade et al⁶ recommended wearing polyurethane shin guards and leather insoles as alternatives when AA contact allergy is suspected or confirmed. They also made it clear that thick socks worn between shin guards and the skin often are not good enough to avoid ACD because the relevant allergens may achieve skin contact despite the barrier.⁶

Patch Testing for AA Contact Allergy

Historically, ACD to shin guards or shin pads, insoles of shoes, and even flip-flops has been associated with rubber-related chemicals such as mercapto mix, thiuram mix, N-isopropyl-N’-phenyl-p-phenylenediamine, thioureas, and carbamates, as well as dyes, benzoyl peroxide, and urea formaldehyde or phenol formaldehyde resins.¹ Most of these chemicals can be tested with standard screening series or supplemental series. Patients with contact allergy to AA may have negative patch testing to screening series and/or supplemental series and may have strong positive reactions to pieces of suspected foam shin pads or shin guards, shoes, and/or flip-flops. Although Koumaki et al⁵ recommended patch testing for AA contact allergy with AA 0.1% in acetone, Besner Morin et al⁴ mentioned that petrolatum may be a more desirable vehicle because it could maintain stability for a longer period of time. In fact, a 2021 article highlighting the American Contact Dermatitis Society Allergen of the Year recommends testing with either AA 0.1% in acetone or AA 0.1% in petrolatum.⁷ Unfortunately, AA is not commercially available for purchase at the time of publication. We are hopeful that this will change in the near future.

Final Interpretation

Acetophenone azine is an emerging allergen commonly identified in EVA foam and attributed to contact allergy to shin guards or pads, soles of shoes, and flip-flops. Most cases have been reported in Europe and Canada and have been identified in young male athletes. In addition to standard patch testing, athletes with lower leg dermatitis and/or dermatitis of the soles of the feet should undergo patch testing with AA 0.1% in acetone or petrolatum and pieces of the equipment and/or footwear.

It’s time for the American Contact Dermatitis Society (ACDS) Allergen of the Year! For 2021, the esteemed award goes to acetophenone azine (AA). If you have never heard of this chemical, you are not alone. Acetophenone azine has been identified in foam materials made of the copolymer ethyl-vinyl acetate (EVA). Contact allergy to AA initially was reported in 2016.¹ There are only a few European and Canadian case reports and one case series of AA contact allergy in the literature, all of which are associated with foam shin pads or shin guards, shoe insoles, and/or flip-flops.^2-6 Acetophenone azine is an important emerging allergen, and in this column, we will introduce you to AA and the sneaky places it can lurk and cause allergic contact dermatitis (ACD). We also highlight diagnosis, management, and patch testing for AA contact allergy.

AA Contact Allergy in the Literature

The first case of AA contact allergy was reported in Europe in 2016 when a 13-year-old male soccer player developed severe lower leg dermatitis and later generalized dermatitis associated with wearing foam shin guards.¹ Patch testing to standard and supplemental trays was negative or not relevant; however, the patient exhibited strong reactions when patch tested directly to a piece of the shin guard soaked in acetone, water, and ethanol. Additional testing with AA diluted in acetone, water, and petrolatum resulted in positive patch test reactions to acetone dilutions of 1%, 0.1%, 0.01%, and 0.001% and aqueous solutions of 1% and 0.1%. Chromatographic analyses with high-performance liquid chromatography (HPLC) of shin guard extracts confirmed the culprit allergen to be AA.¹

In the following months, the same clinic saw 2 more cases of AA contact allergy.² An 11-year-old male soccer player developed lower leg dermatitis and later generalized dermatitis from wearing shin guards. Months later, he also developed dermatitis on the soles of the feet, which was attributed to wearing flip-flops. Patch tests to pieces of the shin guards and flip-flops were positive; AA in acetone 0.1% and 0.01% also was positive. As you might expect, HPLC again confirmed the presence of AA in the shin guards and flip-flops. The third patient was a 12-year-old boy with dermatitis on the soles of both feet; later he also developed a generalized dermatitis. Patch testing to pieces of the insoles of his sneakers and AA in acetone 0.1% and 0.01% was positive. Again, HPLC was positive for the presence of AA in the insoles of his sneakers.²

Several more cases of AA contact allergy have been reported in the literature. A 29-year-old European male hockey player demonstrated contact allergy to the gray foam of his shin pads as well as localized leg dermatitis followed by generalized dermatitis (are you noticing a trend yet?), and later dermatitis on the soles of the feet with positive patch-test reactions to pieces of his shin pads and shoe insoles as well as AA 0.1% and 0.01% in acetone.³ A 6-year-old Canadian male soccer player presented with leg dermatitis and later generalized dermatitis and dermatitis on the soles of the feet with positive reactions to pieces of his shin pads and shoe insoles as well as to AA 1% and 0.1% in petrolatum.⁴ A 17-year-old British male (another trend, all males so far!) hockey player developed dermatitis localized to the legs and positive patch tests to the worn foam inner lining of his shin pads as well as to AA 0.1%, 0.01%, and 0.001% in acetone.⁵Finally, Darrigade et al⁶ published a case series of 6 European children with AA contact allergy associated with shin pads and shoes; all had localized leg dermatitis, and some had generalized dermatitis. Patch testing to pieces of shin pads and shoe parts as well as to AA 0.1% in petrolatum and/or acetone showed with positive reactions to the foam pieces and AA in all 6 patients.

What’s the Deal With AA?

Acetophenone azine (also known as methylphenylketazine or bis[1-phenylethylidene]hydrazine) is composed of 2 acetophenone structures and a hydrazine moiety. It has been identified in EVA foam, which can be found in sports equipment such as shin pads or shin guards, shoes, and flip-flops. Raison-Peyron et al¹ confirmed the presence of AA in EVA foam but reported that they did not know the exact reason for its presence. The authors theorized that AA might be a catalyst during EVA polymerization and also noted that it has antimicrobial and antihelminthic activity.¹ Several authors noted that AA could be a by-product of EVA synthesis and that sports equipment manufacturers might not be aware of its presence in EVA.^2,4-6 Some noted that AA concentration was higher in shin guards than in shoe insoles; they thought this explained why patients reacted first to their shin guards and were perhaps even initially sensitized to the shin guards, as well as why shoe insole contact allergy commonly was reported later or only after allergy to shin guards had already developed.^4,6

Differential Diagnosis of Shin Pad or Shin Guard Dermatitis

We would be remiss if we did not mention the appropriate differential diagnosis when shin pad or shin guard dermatitis is identified. In fact, in most cases, shin guard dermatitis results from irritant contact dermatitis from friction, heat, and/or perspiration. Acetophenone azine contact allergy is not the most likely diagnosis when your sports-savvy, shin guard–wearing patient presents with anterior lower leg dermatitis. However, when conservative therapy (eg, barrier between the shin guard and the skin, control or management of perspiration, topical corticosteroid therapy) fails, patch testing to evaluate for ACD is indicated.

Management of AA Contact Allergy

As astute readers of this column are already aware, treatment of ACD requires strict allergen avoidance. You will find that we have the same recommendations for AA contact allergy. Given that there are only a handful of cases in the literature, there are limited recommendations on practical allergen avoidance other than “don’t wear the problem shin guards, shoe insoles, or flip-flops.” However, Darrigade et al⁶ recommended wearing polyurethane shin guards and leather insoles as alternatives when AA contact allergy is suspected or confirmed. They also made it clear that thick socks worn between shin guards and the skin often are not good enough to avoid ACD because the relevant allergens may achieve skin contact despite the barrier.⁶

Patch Testing for AA Contact Allergy

Historically, ACD to shin guards or shin pads, insoles of shoes, and even flip-flops has been associated with rubber-related chemicals such as mercapto mix, thiuram mix, N-isopropyl-N’-phenyl-p-phenylenediamine, thioureas, and carbamates, as well as dyes, benzoyl peroxide, and urea formaldehyde or phenol formaldehyde resins.¹ Most of these chemicals can be tested with standard screening series or supplemental series. Patients with contact allergy to AA may have negative patch testing to screening series and/or supplemental series and may have strong positive reactions to pieces of suspected foam shin pads or shin guards, shoes, and/or flip-flops. Although Koumaki et al⁵ recommended patch testing for AA contact allergy with AA 0.1% in acetone, Besner Morin et al⁴ mentioned that petrolatum may be a more desirable vehicle because it could maintain stability for a longer period of time. In fact, a 2021 article highlighting the American Contact Dermatitis Society Allergen of the Year recommends testing with either AA 0.1% in acetone or AA 0.1% in petrolatum.⁷ Unfortunately, AA is not commercially available for purchase at the time of publication. We are hopeful that this will change in the near future.

Final Interpretation

Acetophenone azine is an emerging allergen commonly identified in EVA foam and attributed to contact allergy to shin guards or pads, soles of shoes, and flip-flops. Most cases have been reported in Europe and Canada and have been identified in young male athletes. In addition to standard patch testing, athletes with lower leg dermatitis and/or dermatitis of the soles of the feet should undergo patch testing with AA 0.1% in acetone or petrolatum and pieces of the equipment and/or footwear.

It’s time for the American Contact Dermatitis Society (ACDS) Allergen of the Year! For 2021, the esteemed award goes to acetophenone azine (AA). If you have never heard of this chemical, you are not alone. Acetophenone azine has been identified in foam materials made of the copolymer ethyl-vinyl acetate (EVA). Contact allergy to AA initially was reported in 2016.¹ There are only a few European and Canadian case reports and one case series of AA contact allergy in the literature, all of which are associated with foam shin pads or shin guards, shoe insoles, and/or flip-flops.^2-6 Acetophenone azine is an important emerging allergen, and in this column, we will introduce you to AA and the sneaky places it can lurk and cause allergic contact dermatitis (ACD). We also highlight diagnosis, management, and patch testing for AA contact allergy.

AA Contact Allergy in the Literature

The first case of AA contact allergy was reported in Europe in 2016 when a 13-year-old male soccer player developed severe lower leg dermatitis and later generalized dermatitis associated with wearing foam shin guards.¹ Patch testing to standard and supplemental trays was negative or not relevant; however, the patient exhibited strong reactions when patch tested directly to a piece of the shin guard soaked in acetone, water, and ethanol. Additional testing with AA diluted in acetone, water, and petrolatum resulted in positive patch test reactions to acetone dilutions of 1%, 0.1%, 0.01%, and 0.001% and aqueous solutions of 1% and 0.1%. Chromatographic analyses with high-performance liquid chromatography (HPLC) of shin guard extracts confirmed the culprit allergen to be AA.¹

In the following months, the same clinic saw 2 more cases of AA contact allergy.² An 11-year-old male soccer player developed lower leg dermatitis and later generalized dermatitis from wearing shin guards. Months later, he also developed dermatitis on the soles of the feet, which was attributed to wearing flip-flops. Patch tests to pieces of the shin guards and flip-flops were positive; AA in acetone 0.1% and 0.01% also was positive. As you might expect, HPLC again confirmed the presence of AA in the shin guards and flip-flops. The third patient was a 12-year-old boy with dermatitis on the soles of both feet; later he also developed a generalized dermatitis. Patch testing to pieces of the insoles of his sneakers and AA in acetone 0.1% and 0.01% was positive. Again, HPLC was positive for the presence of AA in the insoles of his sneakers.²

Several more cases of AA contact allergy have been reported in the literature. A 29-year-old European male hockey player demonstrated contact allergy to the gray foam of his shin pads as well as localized leg dermatitis followed by generalized dermatitis (are you noticing a trend yet?), and later dermatitis on the soles of the feet with positive patch-test reactions to pieces of his shin pads and shoe insoles as well as AA 0.1% and 0.01% in acetone.³ A 6-year-old Canadian male soccer player presented with leg dermatitis and later generalized dermatitis and dermatitis on the soles of the feet with positive reactions to pieces of his shin pads and shoe insoles as well as to AA 1% and 0.1% in petrolatum.⁴ A 17-year-old British male (another trend, all males so far!) hockey player developed dermatitis localized to the legs and positive patch tests to the worn foam inner lining of his shin pads as well as to AA 0.1%, 0.01%, and 0.001% in acetone.⁵Finally, Darrigade et al⁶ published a case series of 6 European children with AA contact allergy associated with shin pads and shoes; all had localized leg dermatitis, and some had generalized dermatitis. Patch testing to pieces of shin pads and shoe parts as well as to AA 0.1% in petrolatum and/or acetone showed with positive reactions to the foam pieces and AA in all 6 patients.

What’s the Deal With AA?

Acetophenone azine (also known as methylphenylketazine or bis[1-phenylethylidene]hydrazine) is composed of 2 acetophenone structures and a hydrazine moiety. It has been identified in EVA foam, which can be found in sports equipment such as shin pads or shin guards, shoes, and flip-flops. Raison-Peyron et al¹ confirmed the presence of AA in EVA foam but reported that they did not know the exact reason for its presence. The authors theorized that AA might be a catalyst during EVA polymerization and also noted that it has antimicrobial and antihelminthic activity.¹ Several authors noted that AA could be a by-product of EVA synthesis and that sports equipment manufacturers might not be aware of its presence in EVA.^2,4-6 Some noted that AA concentration was higher in shin guards than in shoe insoles; they thought this explained why patients reacted first to their shin guards and were perhaps even initially sensitized to the shin guards, as well as why shoe insole contact allergy commonly was reported later or only after allergy to shin guards had already developed.^4,6

Differential Diagnosis of Shin Pad or Shin Guard Dermatitis

We would be remiss if we did not mention the appropriate differential diagnosis when shin pad or shin guard dermatitis is identified. In fact, in most cases, shin guard dermatitis results from irritant contact dermatitis from friction, heat, and/or perspiration. Acetophenone azine contact allergy is not the most likely diagnosis when your sports-savvy, shin guard–wearing patient presents with anterior lower leg dermatitis. However, when conservative therapy (eg, barrier between the shin guard and the skin, control or management of perspiration, topical corticosteroid therapy) fails, patch testing to evaluate for ACD is indicated.

Management of AA Contact Allergy

As astute readers of this column are already aware, treatment of ACD requires strict allergen avoidance. You will find that we have the same recommendations for AA contact allergy. Given that there are only a handful of cases in the literature, there are limited recommendations on practical allergen avoidance other than “don’t wear the problem shin guards, shoe insoles, or flip-flops.” However, Darrigade et al⁶ recommended wearing polyurethane shin guards and leather insoles as alternatives when AA contact allergy is suspected or confirmed. They also made it clear that thick socks worn between shin guards and the skin often are not good enough to avoid ACD because the relevant allergens may achieve skin contact despite the barrier.⁶

Patch Testing for AA Contact Allergy

Historically, ACD to shin guards or shin pads, insoles of shoes, and even flip-flops has been associated with rubber-related chemicals such as mercapto mix, thiuram mix, N-isopropyl-N’-phenyl-p-phenylenediamine, thioureas, and carbamates, as well as dyes, benzoyl peroxide, and urea formaldehyde or phenol formaldehyde resins.¹ Most of these chemicals can be tested with standard screening series or supplemental series. Patients with contact allergy to AA may have negative patch testing to screening series and/or supplemental series and may have strong positive reactions to pieces of suspected foam shin pads or shin guards, shoes, and/or flip-flops. Although Koumaki et al⁵ recommended patch testing for AA contact allergy with AA 0.1% in acetone, Besner Morin et al⁴ mentioned that petrolatum may be a more desirable vehicle because it could maintain stability for a longer period of time. In fact, a 2021 article highlighting the American Contact Dermatitis Society Allergen of the Year recommends testing with either AA 0.1% in acetone or AA 0.1% in petrolatum.⁷ Unfortunately, AA is not commercially available for purchase at the time of publication. We are hopeful that this will change in the near future.

Final Interpretation

Acetophenone azine is an emerging allergen commonly identified in EVA foam and attributed to contact allergy to shin guards or pads, soles of shoes, and flip-flops. Most cases have been reported in Europe and Canada and have been identified in young male athletes. In addition to standard patch testing, athletes with lower leg dermatitis and/or dermatitis of the soles of the feet should undergo patch testing with AA 0.1% in acetone or petrolatum and pieces of the equipment and/or footwear.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major challenges to both clinicians and pathologists.¹ Clinically, the lesions may appear as subtle bland papules, nodules, or plaques. They can be easily mistaken for benign growths, leading to a delayed diagnosis. Consequently, most DMMs at the time of diagnosis tend to be thick, with a mean Breslow depth ranging from 2.0 to 6.5 mm.² Histopathologic evaluation has its difficulties. At scanning magnification, these tumors may show low cellularity, mimicking a benign proliferation. It is well recognized that S-100 and other tumor markers lack specificity for DMM, which can be positive in a range of neural tumors and other cell types.² In some amelanotic tumors, DMM becomes virtually indistinguishable from benign peripheral sheath tumors such as neurofribroma.³

Desmoplastic melanoma is exceedingly uncommon in the United States, with an estimated annual incidence rate of 2.0 cases per million.² Typical locations of presentation include sun-exposed skin, with the head and neck regions representing more than half of reported cases.² Desmoplastic melanoma largely is a disease of fair-skinned patients, with 95.5% of cases in the United States occurring in white non-Hispanic individuals. Advancing age, male gender, and head and neck location are associated with an increased risk for DMM-specific death.² It is important that new or changing lesions in the correct cohort and location are biopsied promptly. We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor.

Case Report

A 51-year-old White man with a history of prostate cancer, a personal and family history of melanoma, and benign neurofibromas presented with a 6-mm, pink, well-demarcated, soft papule on the left lateral neck (Figure 1). The lesion had been stable for many years but began growing more rapidly 1 to 2 years prior to presentation. The lesion was asymptomatic, and he denied changes in color or texture. There also was no bleeding or ulceration. A review of systems was unremarkable. A shave biopsy of the lesion revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma on low power (Figure 2). However, overlying the tumor was a confluent proliferation positive for MART-1 and S-100, which was consistent with a diagnosis of melanoma in situ (Figure 3). Higher-power evaluation of the dermal proliferation showed both bland and hyperchromatic spindled and epithelioid cells (Figure 4), with rare mitotic figures highlighted by PHH3, an uncommon finding in neurofibromas (Figure 5). The dermal spindle cells were positive for S-100 and p75 and negative for Melan-A. Epithelial membrane antigen highlighted a faint sheath surrounding the dermal component. Ki-67 revealed a mildly increased proliferative index in the dermal component. The diagnosis of DMM was made after outside dermatopathology consultation was in agreement. However, the possibility of a melanoma in situ growing in association with an underlying neurofibroma remained a diagnostic consideration histologically. The lesion was widely excised.

Comment

Differential for DMM
Early DMMs may not show sufficient cytologic atypia to permit obvious distinction from neurofibromas, which becomes problematic when encountering a spindle cell proliferation within severely sun-damaged skin, or even more so when an intraepidermal population of melanocytes is situated above a dermal population of slender, spindled, S-100–positive cells, as seen in our patient.⁴ For these challenging scenarios, Yeh and McCalmont⁴ have proposed evaluating for a CD34 “fingerprint” pattern. This pattern typically is widespread in neurofibroma but absent or limited in DMM, and it is a useful adjunct in the differential diagnosis when conventional immunohistochemistry has little contribution.

There are several case reports in the literature of DMM mimicking other benign or malignant proliferations. In 2012, Jou et al⁵ described a case of a 62-year-old White man who presented with an oral nodule consistent with fibrous inflammatory hyperplasia clinically. Incisional biopsy later confirmed the diagnosis of amelanotic DMM.⁵ Similar case reports have been described in which the diagnosis of DMM was later found to resemble a sarcoma and malignant peripheral nerve sheath tumor.^6,7

Diagnosis of DMM
The prototypical DMM is an asymmetrical and deeply infiltrative spindle cell lesion in severely sun-damaged skin. By definition, the individual melanocytes are separated by connective tissue components, giving the tumor a paucicellular appearance.¹ Although the low cellularity can give a deceptively bland scanning aspect, on high-power examination there usually are identifiable atypical spindled cells with enlarged, elongated, and hyperchromatic nuclei. S-100 typically is diffusely positive in DMM, though occasional cases show more limited staining.⁸ Other commonly used and more specific markers of melanocytic differentiation, including HMB45 and Melan-A, typically are negative in the paucicellular spindle cell components.⁹ Desmoplastic melanoma can be further categorized by the degree of fibrosis within a particular tumor. If fibrosis is prominent throughout the entire tumor, it is named pure DMM. On the other hand, fibrosis may only represent a portion of an otherwise nondesmoplastic melanoma, which is known as combined DMM.¹⁰

Conclusion

We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically. Although a bland-appearing lesion, key clinical features prompting a biopsy in our patient included recent growth of the lesion, a personal history of melanoma, the patient’s fair skin type, a history of heavy sun exposure, and the location of the lesion. According to Busam,¹¹ an associated melanoma in situ component is identified in 80% to 85% of DMM cases. Detection of a melanoma in situ component associated with a malignant spindle cell tumor can help establish the diagnosis of DMM. In the absence of melanoma in situ, a strong diffuse immunoreactivity for S-100 and lack of epithelial markers support the diagnosis.¹¹ After review of the literature, our case likely represents DMM as opposed to a melanoma in situ developing within a neurofibroma.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major challenges to both clinicians and pathologists.¹ Clinically, the lesions may appear as subtle bland papules, nodules, or plaques. They can be easily mistaken for benign growths, leading to a delayed diagnosis. Consequently, most DMMs at the time of diagnosis tend to be thick, with a mean Breslow depth ranging from 2.0 to 6.5 mm.² Histopathologic evaluation has its difficulties. At scanning magnification, these tumors may show low cellularity, mimicking a benign proliferation. It is well recognized that S-100 and other tumor markers lack specificity for DMM, which can be positive in a range of neural tumors and other cell types.² In some amelanotic tumors, DMM becomes virtually indistinguishable from benign peripheral sheath tumors such as neurofribroma.³

Desmoplastic melanoma is exceedingly uncommon in the United States, with an estimated annual incidence rate of 2.0 cases per million.² Typical locations of presentation include sun-exposed skin, with the head and neck regions representing more than half of reported cases.² Desmoplastic melanoma largely is a disease of fair-skinned patients, with 95.5% of cases in the United States occurring in white non-Hispanic individuals. Advancing age, male gender, and head and neck location are associated with an increased risk for DMM-specific death.² It is important that new or changing lesions in the correct cohort and location are biopsied promptly. We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor.

Case Report

A 51-year-old White man with a history of prostate cancer, a personal and family history of melanoma, and benign neurofibromas presented with a 6-mm, pink, well-demarcated, soft papule on the left lateral neck (Figure 1). The lesion had been stable for many years but began growing more rapidly 1 to 2 years prior to presentation. The lesion was asymptomatic, and he denied changes in color or texture. There also was no bleeding or ulceration. A review of systems was unremarkable. A shave biopsy of the lesion revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma on low power (Figure 2). However, overlying the tumor was a confluent proliferation positive for MART-1 and S-100, which was consistent with a diagnosis of melanoma in situ (Figure 3). Higher-power evaluation of the dermal proliferation showed both bland and hyperchromatic spindled and epithelioid cells (Figure 4), with rare mitotic figures highlighted by PHH3, an uncommon finding in neurofibromas (Figure 5). The dermal spindle cells were positive for S-100 and p75 and negative for Melan-A. Epithelial membrane antigen highlighted a faint sheath surrounding the dermal component. Ki-67 revealed a mildly increased proliferative index in the dermal component. The diagnosis of DMM was made after outside dermatopathology consultation was in agreement. However, the possibility of a melanoma in situ growing in association with an underlying neurofibroma remained a diagnostic consideration histologically. The lesion was widely excised.

Comment

Differential for DMM
Early DMMs may not show sufficient cytologic atypia to permit obvious distinction from neurofibromas, which becomes problematic when encountering a spindle cell proliferation within severely sun-damaged skin, or even more so when an intraepidermal population of melanocytes is situated above a dermal population of slender, spindled, S-100–positive cells, as seen in our patient.⁴ For these challenging scenarios, Yeh and McCalmont⁴ have proposed evaluating for a CD34 “fingerprint” pattern. This pattern typically is widespread in neurofibroma but absent or limited in DMM, and it is a useful adjunct in the differential diagnosis when conventional immunohistochemistry has little contribution.

There are several case reports in the literature of DMM mimicking other benign or malignant proliferations. In 2012, Jou et al⁵ described a case of a 62-year-old White man who presented with an oral nodule consistent with fibrous inflammatory hyperplasia clinically. Incisional biopsy later confirmed the diagnosis of amelanotic DMM.⁵ Similar case reports have been described in which the diagnosis of DMM was later found to resemble a sarcoma and malignant peripheral nerve sheath tumor.^6,7

Diagnosis of DMM
The prototypical DMM is an asymmetrical and deeply infiltrative spindle cell lesion in severely sun-damaged skin. By definition, the individual melanocytes are separated by connective tissue components, giving the tumor a paucicellular appearance.¹ Although the low cellularity can give a deceptively bland scanning aspect, on high-power examination there usually are identifiable atypical spindled cells with enlarged, elongated, and hyperchromatic nuclei. S-100 typically is diffusely positive in DMM, though occasional cases show more limited staining.⁸ Other commonly used and more specific markers of melanocytic differentiation, including HMB45 and Melan-A, typically are negative in the paucicellular spindle cell components.⁹ Desmoplastic melanoma can be further categorized by the degree of fibrosis within a particular tumor. If fibrosis is prominent throughout the entire tumor, it is named pure DMM. On the other hand, fibrosis may only represent a portion of an otherwise nondesmoplastic melanoma, which is known as combined DMM.¹⁰

Conclusion

We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically. Although a bland-appearing lesion, key clinical features prompting a biopsy in our patient included recent growth of the lesion, a personal history of melanoma, the patient’s fair skin type, a history of heavy sun exposure, and the location of the lesion. According to Busam,¹¹ an associated melanoma in situ component is identified in 80% to 85% of DMM cases. Detection of a melanoma in situ component associated with a malignant spindle cell tumor can help establish the diagnosis of DMM. In the absence of melanoma in situ, a strong diffuse immunoreactivity for S-100 and lack of epithelial markers support the diagnosis.¹¹ After review of the literature, our case likely represents DMM as opposed to a melanoma in situ developing within a neurofibroma.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major challenges to both clinicians and pathologists.¹ Clinically, the lesions may appear as subtle bland papules, nodules, or plaques. They can be easily mistaken for benign growths, leading to a delayed diagnosis. Consequently, most DMMs at the time of diagnosis tend to be thick, with a mean Breslow depth ranging from 2.0 to 6.5 mm.² Histopathologic evaluation has its difficulties. At scanning magnification, these tumors may show low cellularity, mimicking a benign proliferation. It is well recognized that S-100 and other tumor markers lack specificity for DMM, which can be positive in a range of neural tumors and other cell types.² In some amelanotic tumors, DMM becomes virtually indistinguishable from benign peripheral sheath tumors such as neurofribroma.³

Desmoplastic melanoma is exceedingly uncommon in the United States, with an estimated annual incidence rate of 2.0 cases per million.² Typical locations of presentation include sun-exposed skin, with the head and neck regions representing more than half of reported cases.² Desmoplastic melanoma largely is a disease of fair-skinned patients, with 95.5% of cases in the United States occurring in white non-Hispanic individuals. Advancing age, male gender, and head and neck location are associated with an increased risk for DMM-specific death.² It is important that new or changing lesions in the correct cohort and location are biopsied promptly. We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor.

Case Report

A 51-year-old White man with a history of prostate cancer, a personal and family history of melanoma, and benign neurofibromas presented with a 6-mm, pink, well-demarcated, soft papule on the left lateral neck (Figure 1). The lesion had been stable for many years but began growing more rapidly 1 to 2 years prior to presentation. The lesion was asymptomatic, and he denied changes in color or texture. There also was no bleeding or ulceration. A review of systems was unremarkable. A shave biopsy of the lesion revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma on low power (Figure 2). However, overlying the tumor was a confluent proliferation positive for MART-1 and S-100, which was consistent with a diagnosis of melanoma in situ (Figure 3). Higher-power evaluation of the dermal proliferation showed both bland and hyperchromatic spindled and epithelioid cells (Figure 4), with rare mitotic figures highlighted by PHH3, an uncommon finding in neurofibromas (Figure 5). The dermal spindle cells were positive for S-100 and p75 and negative for Melan-A. Epithelial membrane antigen highlighted a faint sheath surrounding the dermal component. Ki-67 revealed a mildly increased proliferative index in the dermal component. The diagnosis of DMM was made after outside dermatopathology consultation was in agreement. However, the possibility of a melanoma in situ growing in association with an underlying neurofibroma remained a diagnostic consideration histologically. The lesion was widely excised.

Comment

Differential for DMM
Early DMMs may not show sufficient cytologic atypia to permit obvious distinction from neurofibromas, which becomes problematic when encountering a spindle cell proliferation within severely sun-damaged skin, or even more so when an intraepidermal population of melanocytes is situated above a dermal population of slender, spindled, S-100–positive cells, as seen in our patient.⁴ For these challenging scenarios, Yeh and McCalmont⁴ have proposed evaluating for a CD34 “fingerprint” pattern. This pattern typically is widespread in neurofibroma but absent or limited in DMM, and it is a useful adjunct in the differential diagnosis when conventional immunohistochemistry has little contribution.

There are several case reports in the literature of DMM mimicking other benign or malignant proliferations. In 2012, Jou et al⁵ described a case of a 62-year-old White man who presented with an oral nodule consistent with fibrous inflammatory hyperplasia clinically. Incisional biopsy later confirmed the diagnosis of amelanotic DMM.⁵ Similar case reports have been described in which the diagnosis of DMM was later found to resemble a sarcoma and malignant peripheral nerve sheath tumor.^6,7

Diagnosis of DMM
The prototypical DMM is an asymmetrical and deeply infiltrative spindle cell lesion in severely sun-damaged skin. By definition, the individual melanocytes are separated by connective tissue components, giving the tumor a paucicellular appearance.¹ Although the low cellularity can give a deceptively bland scanning aspect, on high-power examination there usually are identifiable atypical spindled cells with enlarged, elongated, and hyperchromatic nuclei. S-100 typically is diffusely positive in DMM, though occasional cases show more limited staining.⁸ Other commonly used and more specific markers of melanocytic differentiation, including HMB45 and Melan-A, typically are negative in the paucicellular spindle cell components.⁹ Desmoplastic melanoma can be further categorized by the degree of fibrosis within a particular tumor. If fibrosis is prominent throughout the entire tumor, it is named pure DMM. On the other hand, fibrosis may only represent a portion of an otherwise nondesmoplastic melanoma, which is known as combined DMM.¹⁰

Conclusion

We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically. Although a bland-appearing lesion, key clinical features prompting a biopsy in our patient included recent growth of the lesion, a personal history of melanoma, the patient’s fair skin type, a history of heavy sun exposure, and the location of the lesion. According to Busam,¹¹ an associated melanoma in situ component is identified in 80% to 85% of DMM cases. Detection of a melanoma in situ component associated with a malignant spindle cell tumor can help establish the diagnosis of DMM. In the absence of melanoma in situ, a strong diffuse immunoreactivity for S-100 and lack of epithelial markers support the diagnosis.¹¹ After review of the literature, our case likely represents DMM as opposed to a melanoma in situ developing within a neurofibroma.

What is West Nile virus? How is it contracted, and who can become infected?

West Nile virus (WNV) is a single-stranded RNA virus of the Flaviviridae family and Flavivirus genus, a lineage that also includes the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses.¹ Birds serve as the reservoir hosts of WNV, and mosquitoes acquire the virus during feeding.² West Nile virus then is transmitted to humans primarily by bites from Culex mosquitoes, which are especially prevalent in wooded areas during peak mosquito season (summer through early fall in North America).¹ Mosquitoes also can infect horses; however, humans and horses are dead-end hosts, meaning they do not pass the virus on to other biting mosquitoes.³ There also have been rare reports of transmission of WNV through blood and donation as well as mother-to-baby transmission.²

What is the epidemiology of WNV in the United States?

Since the introduction of WNV to the United States in 1999, it has become an important public health concern, with 48,183 cases and 2163 deaths reported since 1999.^2,3 In 2018, Nebraska had the highest number of cases of WNV (n=251), followed by California (n=217), North Dakota (n=204), Illinois (n=176), and South Dakota (n=169).³ West Nile virus is endemic to all 48 contiguous states and Canada, though the Great Plains region is especially affected by WNV due to several factors, such as a greater percentage of rural land, forests, and irrigated areas.⁴ The Great Plains region also has been thought to be an ecological niche for a more virulent species (Culex tarsalis) compared to other regions in the United States.⁵

The annual incidence of WNV in the United States peaked in 2003 at 9862 cases (up from 62 cases in 1999), then declined gradually until 2008 to 2011, during which the incidence was stable at 700 to 1100 new cases per year. However, there was a resurgence of cases (n=5674) in 2012 that steadied at around 2200 cases annually in subsequent years.⁶ Although there likely are several factors affecting WNV incidence trends in the United States, interannual changes in temperature and precipitation have been described. An increased mean annual temperature (from September through October, the end of peak mosquito season) and an increased temperature in winter months (from January through March, prior to peak mosquito season) have both been associated with an increased incidence of WNV.⁷ An increased temperature is thought to increase population numbers of mosquitoes both by increasing reproductive rates and creating ideal breeding environments via pooled water areas.⁸ Depending on the region, both above average and below average precipitation levels in the United States can increase WNV incidence the following year.^7,9

What are the signs and symptoms of WNV infection?

Up to 80% of those infected with WNV are asymptomatic.³ After an incubation period of roughly 2 to 14 days, the remaining 20% may develop symptoms of West Nile fever (WNF), typically a self-limited illness that consists of 3 to 10 days of nonspecific symptoms such as fever, headache, fatigue, muscle pain and/or weakness, eye pain, gastrointestinal tract upset, and a macular rash that usually presents on the trunk or extremities.^1,3 Less than 1% of patients affected by WNV develop neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis.¹⁰ West Nile virus neuroinvasive disease can cause permanent neurologic sequelae such as muscle weakness, confusion, memory loss, and fatigue; it carries a mortality rate of 10% to 30%, which is mainly dependent on older age and immunosuppression status.^1,10

What is the reported spectrum of cutaneous findings in WNV?

Of the roughly 20% of patients infected with WNV that develop WNF, approximately 25% to 50% will develop an associated rash.¹ It most commonly is described as a morbilliform or maculopapular rash located on the chest, back, and arms, usually sparing the palms and soles, though 1 case report noted involvement with these areas (Figure).^11,12 It typically appears 5 days after symptom onset, can be associated with defervescence, and lasts less than a week.^1,13 Pruritus and dysesthesia are sometimes present.¹³ Other rare presentations that have been reported include an ill-defined pseudovesicular rash with erythematous papules on the palms and pink, scaly, psoriasiform papules on the feet and thighs, as well as neuroinvasive WNV leading to purpura fulminans.^14,15 A diffuse, erythematous, petechial rash on the face, neck, trunk, and extremities was reported in a pediatric patient, but there have been no reports of a petechial rash associated with WNV in adult patients.¹⁶ These findings suggest some potential variability in the presentation of the WNV rash.

What role does the presence of rash play diagnostically and prognostically?

The rash of WNV has been implicated as a potential prognostic factor in predicting more favorable outcomes.¹⁷ Using 2002 data from the Illinois Department of Public Health and 2003 data from the Colorado Department of Public Health, Huhn and Dworkin¹⁷ found the age-adjusted risk of encephalitis and death to be decreased in WNV patients with a rash (relative risk, 0.44; 95% CI, 0.21-0.92). The reasons for this are not definitively known, but we hypothesize that the rash may prompt patients to seek earlier medical attention or indicate a more robust immune response. Additionally, a rash in WNV more commonly is seen in younger patients, whereas WNV neuroinvasive disease is more common in older patients, who also tend to have worse outcomes.¹⁰ One study found rash to be the only symptom that demonstrated a significant association with seropositivity (overall risk=6.35; P<.05; 95% CI, 3.75-10.80) by multivariate analysis.¹⁸

How is WNV diagnosed? What are the downsides to WNV testing?

Given that the presenting symptoms of WNV and WNF are nonspecific, it becomes challenging to arrive at the diagnosis based solely on physical examination. As such, the patient’s clinical and epidemiologic history, such as timing, pattern, and appearance of the rash or recent history of mosquito bites, is key to arriving at the correct diagnosis. With clinical suspicion, possible diagnostic tests include an IgM enzyme-linked immunosorbent assay (ELISA) for WNV, a plaque reduction neutralization test (PNRT), and blood polymerase chain reaction (PCR).

An ELISA is a confirmatory test to detect IgM antibodies to WNV in the serum. Because IgM seroconversion typically occurs between days 4 and 10 of symptom onset, there is a high probability of initial false-negative testing within the first 8 days after symptom onset.^19,20 Clinical understanding of this fact is imperative, as an initial negative ELISA does not rule out WNV, and a retest is warranted if clinical suspicion is high. In addition to a high initial false-negative rate with ELISA, there are several other limitations to note. IgM antibodies remain elevated for 1 to 3 months or possibly up to a year in immunocompromised patients.¹ Due to this, false positives may be present if there was a recent prior infection. Enzyme-linked immunosorbent assay may not distinguish from different flaviviruses, including the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses. Seropositivity has been estimated in some states, including 1999 data from New York (2.6%), 2003 data from Nebraska (9.5%), and 2012-2014 data from Connecticut (8.5%).^21-23 Regional variance may be expected, as there also were significant differences in WNV seropositivity between different regions in Nebraska (P<.001).²³

Because ELISA testing for WNV has readily apparent flaws, other tests have been utilized in its diagnosis. The PNRT is the most specific test, and it works by measuring neutralizing antibody titers for different flaviviruses. It has the ability to determine cross-reactivity with other flaviviruses; however, it does not discriminate between a current infection and a prior infection or prior flavivirus vaccine (ie, yellow fever vaccine). Despite this, a positive PNRT can lend credibility to a positive ELISA test and determine specificity for WNV for those with no prior flavivirus exposure.²⁴ According to the Centers for Disease Control and Prevention (CDC), this test can be performed by the CDC or in reference laboratories designated by the CDC.³ Additionally, some state health laboratories may perform PRNTs.

Viral detection with PCR currently is used to screen blood donations and may be beneficial for immunocompromised patients that lack the ability to form a robust antibody response or if a patient presents early, as PCR works best within the first week of symptom onset.¹ Tilley et al²⁵ showed that a combination of PCR and ELISA were able to accurately predict 94.2% of patients (180/191) with documented WNV on a first blood sample compared to 45% and 58.1% for only viral detection or ELISA, respectively. Based on costs from a Midwest academic center, antibody detection tests are around $100 while PCR may range from $500 to $1000 and is only performed in reference laboratories. Although these tests remain in the repertoire for WNV diagnosis, financial stewardship is important.

If there are symptoms of photophobia, phonophobia, nuchal rigidity, loss of consciousness, or marked personality changes, a lumbar puncture for WNV IgM in the cerebrospinal fluid can be performed. As with most viral infections, cerebrospinal fluid findings normally include an elevated protein and lymphocyte count, but neutrophils may be predominantly elevated if the infection is early in its course.²⁶

What are the management options?

To date, there is no curative treatment for WNV, and management is largely supportive. For WNF, over-the-counter pain medications may be helpful to reduce fever and pain. If more severe disease develops, hospitalization for further supportive care may be needed.²⁷ If meningitis or encephalitis is suspected, broad-spectrum antibiotics may need to be started until other common etiologies are ruled out.²⁸

How can you prevent WNV infection?

Disease prevention largely consists of educating the public to avoid heavily wooded areas, especially in areas of high prevalence and during peak months, and to use protective clothing and insect repellant that has been approved by the Environmental Protection Agency.³ Insect repellants approved by the Environmental Protection Agency contain ingredients such as DEET (N, N-diethyl-meta-toluamide), picaridin, IR3535 (ethyl butylacetylaminopropionate), and oil of lemon eucalyptus, which have been proven safe and effective.²⁹ Patients also can protect their homes by using window screens and promptly repairing screens with holes.³

What is the differential diagnosis for WNV?

The differential diagnosis for fever with generalized maculopapular rash broadly ranges from viral etiologies (eg, WNV, Zika, measles), to tick bites (eg, Rocky Mountain spotted fever, ehrlichiosis), to drug-induced rashes. A detailed patient history inquiring on recent sick contacts, travel (WNV in the Midwest, ehrlichiosis in the Southeast), environmental exposures (ticks, mosquitoes), and new medications (typically 7–10 days after starting) is imperative to narrow the differential.³⁰ In addition, the distribution, timing, and clinical characteristics of the rash may aid in diagnosis, along with an appropriately correlated clinical picture. West Nile virus likely will present in the summer in mid central geographic locations and often develops on the trunk and extremities as a blanching, generalized, maculopapular rash around 5 days after symptom onset or with defervescence.¹

What is West Nile virus? How is it contracted, and who can become infected?

West Nile virus (WNV) is a single-stranded RNA virus of the Flaviviridae family and Flavivirus genus, a lineage that also includes the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses.¹ Birds serve as the reservoir hosts of WNV, and mosquitoes acquire the virus during feeding.² West Nile virus then is transmitted to humans primarily by bites from Culex mosquitoes, which are especially prevalent in wooded areas during peak mosquito season (summer through early fall in North America).¹ Mosquitoes also can infect horses; however, humans and horses are dead-end hosts, meaning they do not pass the virus on to other biting mosquitoes.³ There also have been rare reports of transmission of WNV through blood and donation as well as mother-to-baby transmission.²

What is the epidemiology of WNV in the United States?

Since the introduction of WNV to the United States in 1999, it has become an important public health concern, with 48,183 cases and 2163 deaths reported since 1999.^2,3 In 2018, Nebraska had the highest number of cases of WNV (n=251), followed by California (n=217), North Dakota (n=204), Illinois (n=176), and South Dakota (n=169).³ West Nile virus is endemic to all 48 contiguous states and Canada, though the Great Plains region is especially affected by WNV due to several factors, such as a greater percentage of rural land, forests, and irrigated areas.⁴ The Great Plains region also has been thought to be an ecological niche for a more virulent species (Culex tarsalis) compared to other regions in the United States.⁵

The annual incidence of WNV in the United States peaked in 2003 at 9862 cases (up from 62 cases in 1999), then declined gradually until 2008 to 2011, during which the incidence was stable at 700 to 1100 new cases per year. However, there was a resurgence of cases (n=5674) in 2012 that steadied at around 2200 cases annually in subsequent years.⁶ Although there likely are several factors affecting WNV incidence trends in the United States, interannual changes in temperature and precipitation have been described. An increased mean annual temperature (from September through October, the end of peak mosquito season) and an increased temperature in winter months (from January through March, prior to peak mosquito season) have both been associated with an increased incidence of WNV.⁷ An increased temperature is thought to increase population numbers of mosquitoes both by increasing reproductive rates and creating ideal breeding environments via pooled water areas.⁸ Depending on the region, both above average and below average precipitation levels in the United States can increase WNV incidence the following year.^7,9

What are the signs and symptoms of WNV infection?

Up to 80% of those infected with WNV are asymptomatic.³ After an incubation period of roughly 2 to 14 days, the remaining 20% may develop symptoms of West Nile fever (WNF), typically a self-limited illness that consists of 3 to 10 days of nonspecific symptoms such as fever, headache, fatigue, muscle pain and/or weakness, eye pain, gastrointestinal tract upset, and a macular rash that usually presents on the trunk or extremities.^1,3 Less than 1% of patients affected by WNV develop neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis.¹⁰ West Nile virus neuroinvasive disease can cause permanent neurologic sequelae such as muscle weakness, confusion, memory loss, and fatigue; it carries a mortality rate of 10% to 30%, which is mainly dependent on older age and immunosuppression status.^1,10

What is the reported spectrum of cutaneous findings in WNV?

Of the roughly 20% of patients infected with WNV that develop WNF, approximately 25% to 50% will develop an associated rash.¹ It most commonly is described as a morbilliform or maculopapular rash located on the chest, back, and arms, usually sparing the palms and soles, though 1 case report noted involvement with these areas (Figure).^11,12 It typically appears 5 days after symptom onset, can be associated with defervescence, and lasts less than a week.^1,13 Pruritus and dysesthesia are sometimes present.¹³ Other rare presentations that have been reported include an ill-defined pseudovesicular rash with erythematous papules on the palms and pink, scaly, psoriasiform papules on the feet and thighs, as well as neuroinvasive WNV leading to purpura fulminans.^14,15 A diffuse, erythematous, petechial rash on the face, neck, trunk, and extremities was reported in a pediatric patient, but there have been no reports of a petechial rash associated with WNV in adult patients.¹⁶ These findings suggest some potential variability in the presentation of the WNV rash.

What role does the presence of rash play diagnostically and prognostically?

The rash of WNV has been implicated as a potential prognostic factor in predicting more favorable outcomes.¹⁷ Using 2002 data from the Illinois Department of Public Health and 2003 data from the Colorado Department of Public Health, Huhn and Dworkin¹⁷ found the age-adjusted risk of encephalitis and death to be decreased in WNV patients with a rash (relative risk, 0.44; 95% CI, 0.21-0.92). The reasons for this are not definitively known, but we hypothesize that the rash may prompt patients to seek earlier medical attention or indicate a more robust immune response. Additionally, a rash in WNV more commonly is seen in younger patients, whereas WNV neuroinvasive disease is more common in older patients, who also tend to have worse outcomes.¹⁰ One study found rash to be the only symptom that demonstrated a significant association with seropositivity (overall risk=6.35; P<.05; 95% CI, 3.75-10.80) by multivariate analysis.¹⁸

How is WNV diagnosed? What are the downsides to WNV testing?

Given that the presenting symptoms of WNV and WNF are nonspecific, it becomes challenging to arrive at the diagnosis based solely on physical examination. As such, the patient’s clinical and epidemiologic history, such as timing, pattern, and appearance of the rash or recent history of mosquito bites, is key to arriving at the correct diagnosis. With clinical suspicion, possible diagnostic tests include an IgM enzyme-linked immunosorbent assay (ELISA) for WNV, a plaque reduction neutralization test (PNRT), and blood polymerase chain reaction (PCR).

An ELISA is a confirmatory test to detect IgM antibodies to WNV in the serum. Because IgM seroconversion typically occurs between days 4 and 10 of symptom onset, there is a high probability of initial false-negative testing within the first 8 days after symptom onset.^19,20 Clinical understanding of this fact is imperative, as an initial negative ELISA does not rule out WNV, and a retest is warranted if clinical suspicion is high. In addition to a high initial false-negative rate with ELISA, there are several other limitations to note. IgM antibodies remain elevated for 1 to 3 months or possibly up to a year in immunocompromised patients.¹ Due to this, false positives may be present if there was a recent prior infection. Enzyme-linked immunosorbent assay may not distinguish from different flaviviruses, including the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses. Seropositivity has been estimated in some states, including 1999 data from New York (2.6%), 2003 data from Nebraska (9.5%), and 2012-2014 data from Connecticut (8.5%).^21-23 Regional variance may be expected, as there also were significant differences in WNV seropositivity between different regions in Nebraska (P<.001).²³

Because ELISA testing for WNV has readily apparent flaws, other tests have been utilized in its diagnosis. The PNRT is the most specific test, and it works by measuring neutralizing antibody titers for different flaviviruses. It has the ability to determine cross-reactivity with other flaviviruses; however, it does not discriminate between a current infection and a prior infection or prior flavivirus vaccine (ie, yellow fever vaccine). Despite this, a positive PNRT can lend credibility to a positive ELISA test and determine specificity for WNV for those with no prior flavivirus exposure.²⁴ According to the Centers for Disease Control and Prevention (CDC), this test can be performed by the CDC or in reference laboratories designated by the CDC.³ Additionally, some state health laboratories may perform PRNTs.

Viral detection with PCR currently is used to screen blood donations and may be beneficial for immunocompromised patients that lack the ability to form a robust antibody response or if a patient presents early, as PCR works best within the first week of symptom onset.¹ Tilley et al²⁵ showed that a combination of PCR and ELISA were able to accurately predict 94.2% of patients (180/191) with documented WNV on a first blood sample compared to 45% and 58.1% for only viral detection or ELISA, respectively. Based on costs from a Midwest academic center, antibody detection tests are around $100 while PCR may range from $500 to $1000 and is only performed in reference laboratories. Although these tests remain in the repertoire for WNV diagnosis, financial stewardship is important.

If there are symptoms of photophobia, phonophobia, nuchal rigidity, loss of consciousness, or marked personality changes, a lumbar puncture for WNV IgM in the cerebrospinal fluid can be performed. As with most viral infections, cerebrospinal fluid findings normally include an elevated protein and lymphocyte count, but neutrophils may be predominantly elevated if the infection is early in its course.²⁶

What are the management options?

To date, there is no curative treatment for WNV, and management is largely supportive. For WNF, over-the-counter pain medications may be helpful to reduce fever and pain. If more severe disease develops, hospitalization for further supportive care may be needed.²⁷ If meningitis or encephalitis is suspected, broad-spectrum antibiotics may need to be started until other common etiologies are ruled out.²⁸

How can you prevent WNV infection?

Disease prevention largely consists of educating the public to avoid heavily wooded areas, especially in areas of high prevalence and during peak months, and to use protective clothing and insect repellant that has been approved by the Environmental Protection Agency.³ Insect repellants approved by the Environmental Protection Agency contain ingredients such as DEET (N, N-diethyl-meta-toluamide), picaridin, IR3535 (ethyl butylacetylaminopropionate), and oil of lemon eucalyptus, which have been proven safe and effective.²⁹ Patients also can protect their homes by using window screens and promptly repairing screens with holes.³

What is the differential diagnosis for WNV?

The differential diagnosis for fever with generalized maculopapular rash broadly ranges from viral etiologies (eg, WNV, Zika, measles), to tick bites (eg, Rocky Mountain spotted fever, ehrlichiosis), to drug-induced rashes. A detailed patient history inquiring on recent sick contacts, travel (WNV in the Midwest, ehrlichiosis in the Southeast), environmental exposures (ticks, mosquitoes), and new medications (typically 7–10 days after starting) is imperative to narrow the differential.³⁰ In addition, the distribution, timing, and clinical characteristics of the rash may aid in diagnosis, along with an appropriately correlated clinical picture. West Nile virus likely will present in the summer in mid central geographic locations and often develops on the trunk and extremities as a blanching, generalized, maculopapular rash around 5 days after symptom onset or with defervescence.¹

What is West Nile virus? How is it contracted, and who can become infected?

West Nile virus (WNV) is a single-stranded RNA virus of the Flaviviridae family and Flavivirus genus, a lineage that also includes the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses.¹ Birds serve as the reservoir hosts of WNV, and mosquitoes acquire the virus during feeding.² West Nile virus then is transmitted to humans primarily by bites from Culex mosquitoes, which are especially prevalent in wooded areas during peak mosquito season (summer through early fall in North America).¹ Mosquitoes also can infect horses; however, humans and horses are dead-end hosts, meaning they do not pass the virus on to other biting mosquitoes.³ There also have been rare reports of transmission of WNV through blood and donation as well as mother-to-baby transmission.²

What is the epidemiology of WNV in the United States?

Since the introduction of WNV to the United States in 1999, it has become an important public health concern, with 48,183 cases and 2163 deaths reported since 1999.^2,3 In 2018, Nebraska had the highest number of cases of WNV (n=251), followed by California (n=217), North Dakota (n=204), Illinois (n=176), and South Dakota (n=169).³ West Nile virus is endemic to all 48 contiguous states and Canada, though the Great Plains region is especially affected by WNV due to several factors, such as a greater percentage of rural land, forests, and irrigated areas.⁴ The Great Plains region also has been thought to be an ecological niche for a more virulent species (Culex tarsalis) compared to other regions in the United States.⁵

The annual incidence of WNV in the United States peaked in 2003 at 9862 cases (up from 62 cases in 1999), then declined gradually until 2008 to 2011, during which the incidence was stable at 700 to 1100 new cases per year. However, there was a resurgence of cases (n=5674) in 2012 that steadied at around 2200 cases annually in subsequent years.⁶ Although there likely are several factors affecting WNV incidence trends in the United States, interannual changes in temperature and precipitation have been described. An increased mean annual temperature (from September through October, the end of peak mosquito season) and an increased temperature in winter months (from January through March, prior to peak mosquito season) have both been associated with an increased incidence of WNV.⁷ An increased temperature is thought to increase population numbers of mosquitoes both by increasing reproductive rates and creating ideal breeding environments via pooled water areas.⁸ Depending on the region, both above average and below average precipitation levels in the United States can increase WNV incidence the following year.^7,9

What are the signs and symptoms of WNV infection?

Up to 80% of those infected with WNV are asymptomatic.³ After an incubation period of roughly 2 to 14 days, the remaining 20% may develop symptoms of West Nile fever (WNF), typically a self-limited illness that consists of 3 to 10 days of nonspecific symptoms such as fever, headache, fatigue, muscle pain and/or weakness, eye pain, gastrointestinal tract upset, and a macular rash that usually presents on the trunk or extremities.^1,3 Less than 1% of patients affected by WNV develop neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis.¹⁰ West Nile virus neuroinvasive disease can cause permanent neurologic sequelae such as muscle weakness, confusion, memory loss, and fatigue; it carries a mortality rate of 10% to 30%, which is mainly dependent on older age and immunosuppression status.^1,10

What is the reported spectrum of cutaneous findings in WNV?

Of the roughly 20% of patients infected with WNV that develop WNF, approximately 25% to 50% will develop an associated rash.¹ It most commonly is described as a morbilliform or maculopapular rash located on the chest, back, and arms, usually sparing the palms and soles, though 1 case report noted involvement with these areas (Figure).^11,12 It typically appears 5 days after symptom onset, can be associated with defervescence, and lasts less than a week.^1,13 Pruritus and dysesthesia are sometimes present.¹³ Other rare presentations that have been reported include an ill-defined pseudovesicular rash with erythematous papules on the palms and pink, scaly, psoriasiform papules on the feet and thighs, as well as neuroinvasive WNV leading to purpura fulminans.^14,15 A diffuse, erythematous, petechial rash on the face, neck, trunk, and extremities was reported in a pediatric patient, but there have been no reports of a petechial rash associated with WNV in adult patients.¹⁶ These findings suggest some potential variability in the presentation of the WNV rash.

What role does the presence of rash play diagnostically and prognostically?

The rash of WNV has been implicated as a potential prognostic factor in predicting more favorable outcomes.¹⁷ Using 2002 data from the Illinois Department of Public Health and 2003 data from the Colorado Department of Public Health, Huhn and Dworkin¹⁷ found the age-adjusted risk of encephalitis and death to be decreased in WNV patients with a rash (relative risk, 0.44; 95% CI, 0.21-0.92). The reasons for this are not definitively known, but we hypothesize that the rash may prompt patients to seek earlier medical attention or indicate a more robust immune response. Additionally, a rash in WNV more commonly is seen in younger patients, whereas WNV neuroinvasive disease is more common in older patients, who also tend to have worse outcomes.¹⁰ One study found rash to be the only symptom that demonstrated a significant association with seropositivity (overall risk=6.35; P<.05; 95% CI, 3.75-10.80) by multivariate analysis.¹⁸

How is WNV diagnosed? What are the downsides to WNV testing?

Given that the presenting symptoms of WNV and WNF are nonspecific, it becomes challenging to arrive at the diagnosis based solely on physical examination. As such, the patient’s clinical and epidemiologic history, such as timing, pattern, and appearance of the rash or recent history of mosquito bites, is key to arriving at the correct diagnosis. With clinical suspicion, possible diagnostic tests include an IgM enzyme-linked immunosorbent assay (ELISA) for WNV, a plaque reduction neutralization test (PNRT), and blood polymerase chain reaction (PCR).

An ELISA is a confirmatory test to detect IgM antibodies to WNV in the serum. Because IgM seroconversion typically occurs between days 4 and 10 of symptom onset, there is a high probability of initial false-negative testing within the first 8 days after symptom onset.^19,20 Clinical understanding of this fact is imperative, as an initial negative ELISA does not rule out WNV, and a retest is warranted if clinical suspicion is high. In addition to a high initial false-negative rate with ELISA, there are several other limitations to note. IgM antibodies remain elevated for 1 to 3 months or possibly up to a year in immunocompromised patients.¹ Due to this, false positives may be present if there was a recent prior infection. Enzyme-linked immunosorbent assay may not distinguish from different flaviviruses, including the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses. Seropositivity has been estimated in some states, including 1999 data from New York (2.6%), 2003 data from Nebraska (9.5%), and 2012-2014 data from Connecticut (8.5%).^21-23 Regional variance may be expected, as there also were significant differences in WNV seropositivity between different regions in Nebraska (P<.001).²³

Because ELISA testing for WNV has readily apparent flaws, other tests have been utilized in its diagnosis. The PNRT is the most specific test, and it works by measuring neutralizing antibody titers for different flaviviruses. It has the ability to determine cross-reactivity with other flaviviruses; however, it does not discriminate between a current infection and a prior infection or prior flavivirus vaccine (ie, yellow fever vaccine). Despite this, a positive PNRT can lend credibility to a positive ELISA test and determine specificity for WNV for those with no prior flavivirus exposure.²⁴ According to the Centers for Disease Control and Prevention (CDC), this test can be performed by the CDC or in reference laboratories designated by the CDC.³ Additionally, some state health laboratories may perform PRNTs.

Viral detection with PCR currently is used to screen blood donations and may be beneficial for immunocompromised patients that lack the ability to form a robust antibody response or if a patient presents early, as PCR works best within the first week of symptom onset.¹ Tilley et al²⁵ showed that a combination of PCR and ELISA were able to accurately predict 94.2% of patients (180/191) with documented WNV on a first blood sample compared to 45% and 58.1% for only viral detection or ELISA, respectively. Based on costs from a Midwest academic center, antibody detection tests are around $100 while PCR may range from $500 to $1000 and is only performed in reference laboratories. Although these tests remain in the repertoire for WNV diagnosis, financial stewardship is important.

If there are symptoms of photophobia, phonophobia, nuchal rigidity, loss of consciousness, or marked personality changes, a lumbar puncture for WNV IgM in the cerebrospinal fluid can be performed. As with most viral infections, cerebrospinal fluid findings normally include an elevated protein and lymphocyte count, but neutrophils may be predominantly elevated if the infection is early in its course.²⁶

What are the management options?

To date, there is no curative treatment for WNV, and management is largely supportive. For WNF, over-the-counter pain medications may be helpful to reduce fever and pain. If more severe disease develops, hospitalization for further supportive care may be needed.²⁷ If meningitis or encephalitis is suspected, broad-spectrum antibiotics may need to be started until other common etiologies are ruled out.²⁸

How can you prevent WNV infection?

Disease prevention largely consists of educating the public to avoid heavily wooded areas, especially in areas of high prevalence and during peak months, and to use protective clothing and insect repellant that has been approved by the Environmental Protection Agency.³ Insect repellants approved by the Environmental Protection Agency contain ingredients such as DEET (N, N-diethyl-meta-toluamide), picaridin, IR3535 (ethyl butylacetylaminopropionate), and oil of lemon eucalyptus, which have been proven safe and effective.²⁹ Patients also can protect their homes by using window screens and promptly repairing screens with holes.³

What is the differential diagnosis for WNV?

The differential diagnosis for fever with generalized maculopapular rash broadly ranges from viral etiologies (eg, WNV, Zika, measles), to tick bites (eg, Rocky Mountain spotted fever, ehrlichiosis), to drug-induced rashes. A detailed patient history inquiring on recent sick contacts, travel (WNV in the Midwest, ehrlichiosis in the Southeast), environmental exposures (ticks, mosquitoes), and new medications (typically 7–10 days after starting) is imperative to narrow the differential.³⁰ In addition, the distribution, timing, and clinical characteristics of the rash may aid in diagnosis, along with an appropriately correlated clinical picture. West Nile virus likely will present in the summer in mid central geographic locations and often develops on the trunk and extremities as a blanching, generalized, maculopapular rash around 5 days after symptom onset or with defervescence.¹

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma  

Microscopic analysis showed a dense proliferation of mononuclear cells filling and expanding the dermis with focal epidermotropism (Figure 1). Immunohistochemistry demonstrated strong and diffuse staining for CD3, CD4, and CD30 (Figure 2) and lack of staining for anaplastic lymphoma kinase (ALK). Workup to exclude systemic disease was initiated and included unremarkable computed tomography (CT) of the neck, chest, abdomen, and pelvis along with no abnormal cells on bone marrow biopsy. Complete blood cell count, basic metabolic panel, and lactate dehydrogenase were within reference range. Given the lack of evidence for systemic involvement, a diagnosis of primary cutaneous anaplastic large cell lymphoma (PC-ALCL) was made. The treatment plan for our patient with a solitary lesion was localized radiation therapy. 

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass a spectrum of conditions, with premalignant lymphomatoid papulosis (LyP) at one extreme and the malignant PC-ALCL on the other.¹ The diagnosis of PC-ALCL is made by clinicopathologic correlation, and lesions typically present abruptly as solitary or grouped nodules with a tendency to ulcerate over time. Spontaneous regression has been reported, but relapse in the skin is frequent.² 

A representative, typically excisional, biopsy should be performed if the clinician suspects PC-ALCL. Histologic criteria include a dense dermal infiltrate of large pleomorphic cells and the expression of CD30 in at least 75% of tumor cells.³ Primary cutaneous anaplastic large cell lymphoma typically lacks the ALK gene translocation with the nucleophosmin gene, NPM, that is common in systemic disease; however, a small subset of PC-ALCL may be ALK positive and indicate a higher chance of transformation into systemic disease.²

 The extent of the lymphoma should be staged to exclude the possibility of systemic disease. This assessment includes a complete physical examination; laboratory investigation, including complete blood cell count with differential and blood chemistries; and radiography. A positron emission tomography-CT scan of the neck, chest, abdomen, and pelvis, or a whole-body integrated positron emission tomography-CT are sufficient for the radiographic examination.³ 

The initial choice of treatment for solitary or localized PC-ALCL is localized radiation therapy or low-dose methotrexate. Targeted therapy such as brentuximab has been shown to be effective for those with multifocal systemic involvement or refractory disease.² Cure rates from radiation therapy alone approach 95%.³ It is important to highlight radiation therapy as the initial management plan to increase awareness and to avoid inappropriate treatment of PC-ALCL with traditional chemotherapy. 

Large lesions of LyP may appear similar to PC-ALCL on histopathology, making the two entities difficult to distinguish. However, in contrast to PC-ALCL, LyP classically has a different clinical course characterized by waxing and waning crops of lesions that typically are smaller (<1 cm) than those of PC-ALCL.² Large cell transformation of mycosis fungoides is another entity to consider, but these patients usually have a known history of mycosis fungoides.⁴ 

Keratoacanthomas, considered to be a variant of a well-differentiated squamous cell carcinoma, present as rapidly enlarging crateriform nodules with a keratotic core. They usually are found on the head and neck or sun-exposed areas of the extremities and may regress spontaneously.⁵ Histology will show atypical, highly differentiated squamous epithelia. Merkel cell carcinoma also has a predilection for the head and neck in older patients and may present as a rapidly growing nodule. However, histology will show an aggressive tumor with small round blue cells, and immunohistochemistry will show the characteristic paranuclear dot staining for CK20 along with staining for various neuroendocrine markers. Similarly, atypical fibroxanthoma is a low-grade sarcoma that also presents on the head and neck of elderly sun-damaged patients.⁵ Histology will show dermal proliferation of spindle cells that often extend up against the epidermis along with pleomorphism and atypical mitoses. Basal cell carcinoma is a common tumor that can present on the head and neck in sun-damaged patients. Nodular basal cell carcinomas can enlarge and ulcerate, but growth is seen over years rather than weeks.⁵ Histology characteristically will show tumor islands composed of basaloid cells with peripheral palisading and clefting between the tumor islands and the stroma.  

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma  

Microscopic analysis showed a dense proliferation of mononuclear cells filling and expanding the dermis with focal epidermotropism (Figure 1). Immunohistochemistry demonstrated strong and diffuse staining for CD3, CD4, and CD30 (Figure 2) and lack of staining for anaplastic lymphoma kinase (ALK). Workup to exclude systemic disease was initiated and included unremarkable computed tomography (CT) of the neck, chest, abdomen, and pelvis along with no abnormal cells on bone marrow biopsy. Complete blood cell count, basic metabolic panel, and lactate dehydrogenase were within reference range. Given the lack of evidence for systemic involvement, a diagnosis of primary cutaneous anaplastic large cell lymphoma (PC-ALCL) was made. The treatment plan for our patient with a solitary lesion was localized radiation therapy. 

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass a spectrum of conditions, with premalignant lymphomatoid papulosis (LyP) at one extreme and the malignant PC-ALCL on the other.¹ The diagnosis of PC-ALCL is made by clinicopathologic correlation, and lesions typically present abruptly as solitary or grouped nodules with a tendency to ulcerate over time. Spontaneous regression has been reported, but relapse in the skin is frequent.² 

A representative, typically excisional, biopsy should be performed if the clinician suspects PC-ALCL. Histologic criteria include a dense dermal infiltrate of large pleomorphic cells and the expression of CD30 in at least 75% of tumor cells.³ Primary cutaneous anaplastic large cell lymphoma typically lacks the ALK gene translocation with the nucleophosmin gene, NPM, that is common in systemic disease; however, a small subset of PC-ALCL may be ALK positive and indicate a higher chance of transformation into systemic disease.²

 The extent of the lymphoma should be staged to exclude the possibility of systemic disease. This assessment includes a complete physical examination; laboratory investigation, including complete blood cell count with differential and blood chemistries; and radiography. A positron emission tomography-CT scan of the neck, chest, abdomen, and pelvis, or a whole-body integrated positron emission tomography-CT are sufficient for the radiographic examination.³ 

The initial choice of treatment for solitary or localized PC-ALCL is localized radiation therapy or low-dose methotrexate. Targeted therapy such as brentuximab has been shown to be effective for those with multifocal systemic involvement or refractory disease.² Cure rates from radiation therapy alone approach 95%.³ It is important to highlight radiation therapy as the initial management plan to increase awareness and to avoid inappropriate treatment of PC-ALCL with traditional chemotherapy. 

Large lesions of LyP may appear similar to PC-ALCL on histopathology, making the two entities difficult to distinguish. However, in contrast to PC-ALCL, LyP classically has a different clinical course characterized by waxing and waning crops of lesions that typically are smaller (<1 cm) than those of PC-ALCL.² Large cell transformation of mycosis fungoides is another entity to consider, but these patients usually have a known history of mycosis fungoides.⁴ 

Keratoacanthomas, considered to be a variant of a well-differentiated squamous cell carcinoma, present as rapidly enlarging crateriform nodules with a keratotic core. They usually are found on the head and neck or sun-exposed areas of the extremities and may regress spontaneously.⁵ Histology will show atypical, highly differentiated squamous epithelia. Merkel cell carcinoma also has a predilection for the head and neck in older patients and may present as a rapidly growing nodule. However, histology will show an aggressive tumor with small round blue cells, and immunohistochemistry will show the characteristic paranuclear dot staining for CK20 along with staining for various neuroendocrine markers. Similarly, atypical fibroxanthoma is a low-grade sarcoma that also presents on the head and neck of elderly sun-damaged patients.⁵ Histology will show dermal proliferation of spindle cells that often extend up against the epidermis along with pleomorphism and atypical mitoses. Basal cell carcinoma is a common tumor that can present on the head and neck in sun-damaged patients. Nodular basal cell carcinomas can enlarge and ulcerate, but growth is seen over years rather than weeks.⁵ Histology characteristically will show tumor islands composed of basaloid cells with peripheral palisading and clefting between the tumor islands and the stroma.  

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma  

Microscopic analysis showed a dense proliferation of mononuclear cells filling and expanding the dermis with focal epidermotropism (Figure 1). Immunohistochemistry demonstrated strong and diffuse staining for CD3, CD4, and CD30 (Figure 2) and lack of staining for anaplastic lymphoma kinase (ALK). Workup to exclude systemic disease was initiated and included unremarkable computed tomography (CT) of the neck, chest, abdomen, and pelvis along with no abnormal cells on bone marrow biopsy. Complete blood cell count, basic metabolic panel, and lactate dehydrogenase were within reference range. Given the lack of evidence for systemic involvement, a diagnosis of primary cutaneous anaplastic large cell lymphoma (PC-ALCL) was made. The treatment plan for our patient with a solitary lesion was localized radiation therapy. 

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass a spectrum of conditions, with premalignant lymphomatoid papulosis (LyP) at one extreme and the malignant PC-ALCL on the other.¹ The diagnosis of PC-ALCL is made by clinicopathologic correlation, and lesions typically present abruptly as solitary or grouped nodules with a tendency to ulcerate over time. Spontaneous regression has been reported, but relapse in the skin is frequent.² 

A representative, typically excisional, biopsy should be performed if the clinician suspects PC-ALCL. Histologic criteria include a dense dermal infiltrate of large pleomorphic cells and the expression of CD30 in at least 75% of tumor cells.³ Primary cutaneous anaplastic large cell lymphoma typically lacks the ALK gene translocation with the nucleophosmin gene, NPM, that is common in systemic disease; however, a small subset of PC-ALCL may be ALK positive and indicate a higher chance of transformation into systemic disease.²

 The extent of the lymphoma should be staged to exclude the possibility of systemic disease. This assessment includes a complete physical examination; laboratory investigation, including complete blood cell count with differential and blood chemistries; and radiography. A positron emission tomography-CT scan of the neck, chest, abdomen, and pelvis, or a whole-body integrated positron emission tomography-CT are sufficient for the radiographic examination.³ 

The initial choice of treatment for solitary or localized PC-ALCL is localized radiation therapy or low-dose methotrexate. Targeted therapy such as brentuximab has been shown to be effective for those with multifocal systemic involvement or refractory disease.² Cure rates from radiation therapy alone approach 95%.³ It is important to highlight radiation therapy as the initial management plan to increase awareness and to avoid inappropriate treatment of PC-ALCL with traditional chemotherapy. 

Large lesions of LyP may appear similar to PC-ALCL on histopathology, making the two entities difficult to distinguish. However, in contrast to PC-ALCL, LyP classically has a different clinical course characterized by waxing and waning crops of lesions that typically are smaller (<1 cm) than those of PC-ALCL.² Large cell transformation of mycosis fungoides is another entity to consider, but these patients usually have a known history of mycosis fungoides.⁴ 

Keratoacanthomas, considered to be a variant of a well-differentiated squamous cell carcinoma, present as rapidly enlarging crateriform nodules with a keratotic core. They usually are found on the head and neck or sun-exposed areas of the extremities and may regress spontaneously.⁵ Histology will show atypical, highly differentiated squamous epithelia. Merkel cell carcinoma also has a predilection for the head and neck in older patients and may present as a rapidly growing nodule. However, histology will show an aggressive tumor with small round blue cells, and immunohistochemistry will show the characteristic paranuclear dot staining for CK20 along with staining for various neuroendocrine markers. Similarly, atypical fibroxanthoma is a low-grade sarcoma that also presents on the head and neck of elderly sun-damaged patients.⁵ Histology will show dermal proliferation of spindle cells that often extend up against the epidermis along with pleomorphism and atypical mitoses. Basal cell carcinoma is a common tumor that can present on the head and neck in sun-damaged patients. Nodular basal cell carcinomas can enlarge and ulcerate, but growth is seen over years rather than weeks.⁵ Histology characteristically will show tumor islands composed of basaloid cells with peripheral palisading and clefting between the tumor islands and the stroma.  

Guidelines on Skin Cancer Surgeries During the COVID-19 Pandemic

At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention issued recommendations to decrease the spread of SARS-CoV-2 and optimize the use of personal protective equipment (PPE) for frontline workers.¹ In the field of dermatologic surgery, the American College of Mohs Surgery, the National Comprehensive Cancer Network, the American Society for Dermatologic Surgery, and the American Academy of Dermatology made recommendations to postpone nonessential and nonurgent procedures.^2-4 The initial guidelines of the American College of Mohs Surgery advised cancellation of all elective surgeries and deferred treatment of most cases of basal cell carcinoma for as long as 3 months; low-risk squamous cell carcinoma (SCC) and melanoma in situ treatment was deferred for as long as 2 or 3 months.³ Additional recommendations were made to reserve inpatient visits for suspicious lesions and high-risk cancers, postpone other nonessential and nonurgent appointments, and utilize telemedicine whenever possible.⁵

These recommendations led to great uncertainty and stress for patients and providers. Although numerous important variables, such as patient risk factors, severity of disease, availability of PPE and staff, and patient-to-provider transmission were considered when creating these guidelines, the patient’s experience likely was not a contributing factor.

COVID-19 Transmission During Mohs Surgery

There have been concerns that surgeons performing Mohs micrographic surgery (MMS) might be at an increased risk for COVID-19, given their close contact with high-risk sites (ie, nose, mouth) and cautery-generated aerosols; most of the estimated transmission risk associated with MMS has been based on head and neck surgery experience and publications.^6-8 Tee and colleagues⁹ recently published their institution’s MMS COVID-19 preventive measures, which, to their knowledge, have prevented all intraoperative transmission of SARS-CoV-2, even in disease-positive patients. Currently, evidence is lacking to support a high risk for SARS-CoV-2 transmission during MMS when proper PPE and personal hygiene measures as well as strict infection control protocols—presurgical COVID-19 testing in high-risk cases, COVID-19 screening optimization, visitor restrictions, and appropriate disinfection between patients—are in place.

The Impact of Postponing Treatment on Patients

Although studies have focused on the effects of the COVID-19 pandemic on physicians practicing MMS,¹⁰ little is known about the effects of delays in skin cancer treatment on patients. A survey conducted in the United Kingdom investigating the patient’s perspective found that patients expressed worry and concern about the possibility that their MMS would be postponed and greatly appreciated continuation of treatment during the pandemic.¹¹

Other medical specialties have reported their patient experiences during the pandemic. In a study examining patient perception of postponed surgical treatment of pelvic floor disorders due to COVID-19, nearly half of survey respondents were unhappy with the delay in receiving care. Furthermore, patients who reported being unhappy were more likely to report feelings of isolation and anxiety because their surgery was postponed.¹² In another study involving patients with lung cancer, 9.1% (N=15) of patients postponed their treatment during the COVID-19 pandemic because of pandemic-related anxiety.¹³

With the goal of improving care at our institution, we conducted a brief institutional review board–approved survey to evaluate how postponing MMS treatment due to the COVID-19 pandemic affected patients. All MMS patients undergoing surgery in June 2020 and July 2020 (N=99) were asked to complete our voluntary and anonymous 23-question survey in person during their procedure. We obtained 88 responses (response rate, 89%). Twenty percent of surveyed patients (n=18) reported that their MMS had been postponed; 78% of those whose MMS was postponed (n=14) indicated some level of anxiety during the waiting period. It was unclear which patients had their treatment postponed based on national guidelines and which ones elected to postpone surgery.

Tips for Health Care Providers

Patient-provider communication highlighting specific skin cancer risk and the risk vs benefit of postponing treatment might reduce anxiety and stress during the waiting period.¹⁴ A study found that COVID-19 posed a bigger threat than most noninvasive skin cancers; therefore, the authors of that study concluded that treatment for most skin cancers could be safely postponed.¹⁵ Specifically, those authors recommended prioritizing treatment for Merkel cell carcinoma, invasive SCC, and melanoma with positive margins or macroscopic residual disease. They proposed that all other skin cancers, including basal cell carcinoma, SCC in situ, and melanoma with negative margins and no macroscopic residual disease, could be safely delayed for as long as 3 months.¹⁵

For patients with multiple risk factors for COVID-19–related morbidity or mortality, delaying skin cancer treatment likely has less risk than contracting the virus.¹⁵ This information should be communicated with patients. Investigation of specific patient concerns is warranted, and case-by-case evaluation of patients’ risk factors and skin cancer risk should be considered.

Based on the current, though limited, literature, delaying medical treatment can have a negative impact on the patient experience. Furthermore, proper precautions have been shown to limit intraoperative transmission of SARS-CoV-2 during MMS, but research is lacking. Practitioners should utilize shared decision-making and evaluate a given patient’s risk factors and concerns when deciding whether to postpone treatment. We encourage other institutions to evaluate the effects that delaying MMS has had on their patients, as further studies would improve understanding of patients’ experiences during a pandemic and potentially influence future dermatology guidelines.

Guidelines on Skin Cancer Surgeries During the COVID-19 Pandemic

At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention issued recommendations to decrease the spread of SARS-CoV-2 and optimize the use of personal protective equipment (PPE) for frontline workers.¹ In the field of dermatologic surgery, the American College of Mohs Surgery, the National Comprehensive Cancer Network, the American Society for Dermatologic Surgery, and the American Academy of Dermatology made recommendations to postpone nonessential and nonurgent procedures.^2-4 The initial guidelines of the American College of Mohs Surgery advised cancellation of all elective surgeries and deferred treatment of most cases of basal cell carcinoma for as long as 3 months; low-risk squamous cell carcinoma (SCC) and melanoma in situ treatment was deferred for as long as 2 or 3 months.³ Additional recommendations were made to reserve inpatient visits for suspicious lesions and high-risk cancers, postpone other nonessential and nonurgent appointments, and utilize telemedicine whenever possible.⁵

These recommendations led to great uncertainty and stress for patients and providers. Although numerous important variables, such as patient risk factors, severity of disease, availability of PPE and staff, and patient-to-provider transmission were considered when creating these guidelines, the patient’s experience likely was not a contributing factor.

COVID-19 Transmission During Mohs Surgery

There have been concerns that surgeons performing Mohs micrographic surgery (MMS) might be at an increased risk for COVID-19, given their close contact with high-risk sites (ie, nose, mouth) and cautery-generated aerosols; most of the estimated transmission risk associated with MMS has been based on head and neck surgery experience and publications.^6-8 Tee and colleagues⁹ recently published their institution’s MMS COVID-19 preventive measures, which, to their knowledge, have prevented all intraoperative transmission of SARS-CoV-2, even in disease-positive patients. Currently, evidence is lacking to support a high risk for SARS-CoV-2 transmission during MMS when proper PPE and personal hygiene measures as well as strict infection control protocols—presurgical COVID-19 testing in high-risk cases, COVID-19 screening optimization, visitor restrictions, and appropriate disinfection between patients—are in place.

The Impact of Postponing Treatment on Patients

Although studies have focused on the effects of the COVID-19 pandemic on physicians practicing MMS,¹⁰ little is known about the effects of delays in skin cancer treatment on patients. A survey conducted in the United Kingdom investigating the patient’s perspective found that patients expressed worry and concern about the possibility that their MMS would be postponed and greatly appreciated continuation of treatment during the pandemic.¹¹

Other medical specialties have reported their patient experiences during the pandemic. In a study examining patient perception of postponed surgical treatment of pelvic floor disorders due to COVID-19, nearly half of survey respondents were unhappy with the delay in receiving care. Furthermore, patients who reported being unhappy were more likely to report feelings of isolation and anxiety because their surgery was postponed.¹² In another study involving patients with lung cancer, 9.1% (N=15) of patients postponed their treatment during the COVID-19 pandemic because of pandemic-related anxiety.¹³

With the goal of improving care at our institution, we conducted a brief institutional review board–approved survey to evaluate how postponing MMS treatment due to the COVID-19 pandemic affected patients. All MMS patients undergoing surgery in June 2020 and July 2020 (N=99) were asked to complete our voluntary and anonymous 23-question survey in person during their procedure. We obtained 88 responses (response rate, 89%). Twenty percent of surveyed patients (n=18) reported that their MMS had been postponed; 78% of those whose MMS was postponed (n=14) indicated some level of anxiety during the waiting period. It was unclear which patients had their treatment postponed based on national guidelines and which ones elected to postpone surgery.

Tips for Health Care Providers

Patient-provider communication highlighting specific skin cancer risk and the risk vs benefit of postponing treatment might reduce anxiety and stress during the waiting period.¹⁴ A study found that COVID-19 posed a bigger threat than most noninvasive skin cancers; therefore, the authors of that study concluded that treatment for most skin cancers could be safely postponed.¹⁵ Specifically, those authors recommended prioritizing treatment for Merkel cell carcinoma, invasive SCC, and melanoma with positive margins or macroscopic residual disease. They proposed that all other skin cancers, including basal cell carcinoma, SCC in situ, and melanoma with negative margins and no macroscopic residual disease, could be safely delayed for as long as 3 months.¹⁵

For patients with multiple risk factors for COVID-19–related morbidity or mortality, delaying skin cancer treatment likely has less risk than contracting the virus.¹⁵ This information should be communicated with patients. Investigation of specific patient concerns is warranted, and case-by-case evaluation of patients’ risk factors and skin cancer risk should be considered.

Based on the current, though limited, literature, delaying medical treatment can have a negative impact on the patient experience. Furthermore, proper precautions have been shown to limit intraoperative transmission of SARS-CoV-2 during MMS, but research is lacking. Practitioners should utilize shared decision-making and evaluate a given patient’s risk factors and concerns when deciding whether to postpone treatment. We encourage other institutions to evaluate the effects that delaying MMS has had on their patients, as further studies would improve understanding of patients’ experiences during a pandemic and potentially influence future dermatology guidelines.

Guidelines on Skin Cancer Surgeries During the COVID-19 Pandemic

At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention issued recommendations to decrease the spread of SARS-CoV-2 and optimize the use of personal protective equipment (PPE) for frontline workers.¹ In the field of dermatologic surgery, the American College of Mohs Surgery, the National Comprehensive Cancer Network, the American Society for Dermatologic Surgery, and the American Academy of Dermatology made recommendations to postpone nonessential and nonurgent procedures.^2-4 The initial guidelines of the American College of Mohs Surgery advised cancellation of all elective surgeries and deferred treatment of most cases of basal cell carcinoma for as long as 3 months; low-risk squamous cell carcinoma (SCC) and melanoma in situ treatment was deferred for as long as 2 or 3 months.³ Additional recommendations were made to reserve inpatient visits for suspicious lesions and high-risk cancers, postpone other nonessential and nonurgent appointments, and utilize telemedicine whenever possible.⁵

These recommendations led to great uncertainty and stress for patients and providers. Although numerous important variables, such as patient risk factors, severity of disease, availability of PPE and staff, and patient-to-provider transmission were considered when creating these guidelines, the patient’s experience likely was not a contributing factor.

COVID-19 Transmission During Mohs Surgery

There have been concerns that surgeons performing Mohs micrographic surgery (MMS) might be at an increased risk for COVID-19, given their close contact with high-risk sites (ie, nose, mouth) and cautery-generated aerosols; most of the estimated transmission risk associated with MMS has been based on head and neck surgery experience and publications.^6-8 Tee and colleagues⁹ recently published their institution’s MMS COVID-19 preventive measures, which, to their knowledge, have prevented all intraoperative transmission of SARS-CoV-2, even in disease-positive patients. Currently, evidence is lacking to support a high risk for SARS-CoV-2 transmission during MMS when proper PPE and personal hygiene measures as well as strict infection control protocols—presurgical COVID-19 testing in high-risk cases, COVID-19 screening optimization, visitor restrictions, and appropriate disinfection between patients—are in place.

The Impact of Postponing Treatment on Patients

Although studies have focused on the effects of the COVID-19 pandemic on physicians practicing MMS,¹⁰ little is known about the effects of delays in skin cancer treatment on patients. A survey conducted in the United Kingdom investigating the patient’s perspective found that patients expressed worry and concern about the possibility that their MMS would be postponed and greatly appreciated continuation of treatment during the pandemic.¹¹

Other medical specialties have reported their patient experiences during the pandemic. In a study examining patient perception of postponed surgical treatment of pelvic floor disorders due to COVID-19, nearly half of survey respondents were unhappy with the delay in receiving care. Furthermore, patients who reported being unhappy were more likely to report feelings of isolation and anxiety because their surgery was postponed.¹² In another study involving patients with lung cancer, 9.1% (N=15) of patients postponed their treatment during the COVID-19 pandemic because of pandemic-related anxiety.¹³

With the goal of improving care at our institution, we conducted a brief institutional review board–approved survey to evaluate how postponing MMS treatment due to the COVID-19 pandemic affected patients. All MMS patients undergoing surgery in June 2020 and July 2020 (N=99) were asked to complete our voluntary and anonymous 23-question survey in person during their procedure. We obtained 88 responses (response rate, 89%). Twenty percent of surveyed patients (n=18) reported that their MMS had been postponed; 78% of those whose MMS was postponed (n=14) indicated some level of anxiety during the waiting period. It was unclear which patients had their treatment postponed based on national guidelines and which ones elected to postpone surgery.

Tips for Health Care Providers

Patient-provider communication highlighting specific skin cancer risk and the risk vs benefit of postponing treatment might reduce anxiety and stress during the waiting period.¹⁴ A study found that COVID-19 posed a bigger threat than most noninvasive skin cancers; therefore, the authors of that study concluded that treatment for most skin cancers could be safely postponed.¹⁵ Specifically, those authors recommended prioritizing treatment for Merkel cell carcinoma, invasive SCC, and melanoma with positive margins or macroscopic residual disease. They proposed that all other skin cancers, including basal cell carcinoma, SCC in situ, and melanoma with negative margins and no macroscopic residual disease, could be safely delayed for as long as 3 months.¹⁵

For patients with multiple risk factors for COVID-19–related morbidity or mortality, delaying skin cancer treatment likely has less risk than contracting the virus.¹⁵ This information should be communicated with patients. Investigation of specific patient concerns is warranted, and case-by-case evaluation of patients’ risk factors and skin cancer risk should be considered.

Based on the current, though limited, literature, delaying medical treatment can have a negative impact on the patient experience. Furthermore, proper precautions have been shown to limit intraoperative transmission of SARS-CoV-2 during MMS, but research is lacking. Practitioners should utilize shared decision-making and evaluate a given patient’s risk factors and concerns when deciding whether to postpone treatment. We encourage other institutions to evaluate the effects that delaying MMS has had on their patients, as further studies would improve understanding of patients’ experiences during a pandemic and potentially influence future dermatology guidelines.

According to National Institutes of Health estimates, more than 90,000 new cases of melanoma were diagnosed in 2018.¹ Overall 5-year survival for patients with melanoma exceeds 90%, but individual survival estimates are highly dependent on stage at diagnosis, and survival decreases markedly with metastasis. Therefore, early and accurate diagnosis is critical.

Diagnosis of melanocytic neoplasms usually is performed by dermatopathologists through microscopic examination of stained tissue biopsy sections, a technically simple and effective method that enables a definitive diagnosis of benign nevus or malignant melanoma to be made in most cases. However, approximately 15% of all biopsied melanocytic lesions will exhibit some degree of histopathologic ambiguity,^2-4 meaning that some of their microscopic features will be characteristic of a benign nevus while others will suggest the possibility of malignant melanoma. Diagnostic interpretations often vary in these cases, even among experts, and a definitive diagnosis of benign or malignant may be difficult to achieve by microscopy alone.^2-4 Because of the marked reduction in survival once a melanoma has metastasized, these diagnostically ambiguous lesions often are treated as possible malignant melanomas with complete surgical excision (or re-excision). However, some experts suggest that many histopathologically ambiguous melanocytic neoplasms are, in fact, benign,⁵ a notion supported by epidemiologic evidence.^6,7 Therefore, excision of many ambiguous melanocytic neoplasms might be avoided if definitive diagnosis could be achieved.

A gene expression signature was developed and validated for use as an adjunct to traditional methods of differentiating malignant melanocytic neoplasms from their benign counterparts.^8-11 This test quantifies the RNA transcripts produced by 14 genes known to be overexpressed in malignant melanomas by comparison to benign nevi. These values are then combined algorithmically with measurements of 9 reference genes to produce an objective numerical score that is classified as benign, malignant, or indeterminate. When used by board-certified dermatopathologists and dermatologists confronting ambiguous melanocytic lesions, the test produces substantial increases in definitive diagnoses and prompts changes in treatment recommendations.^12,13 However, the long-term consequences of foregoing surgical excision of melanocytic neoplasms that are diagnostically ambiguous but classified as benign by this test have not yet been formally assessed. In the current study, prospectively tested patients whose ambiguous melanocytic neoplasms were classified as benign by the gene expression signature were followed for up to 4.5 years to evaluate the long-term safety of treatment decisions aligned with benign test results.

Methods

Study Population
As part of a prior study,¹² US-based dermatopathologists submitted tissue sections from biopsied melanocytic neoplasms determined to be diagnostically ambiguous by histopathology for analysis with the gene expression signature (Myriad Genetics, Inc). Diagnostically ambiguous lesions were those lesions that were described as ambiguous, uncertain, equivocal, indeterminate, or other synonymous terms by the submitting dermatopathologist and therefore lacked a confident diagnosis of benign or malignant prior to testing. Patients initially were tested between May 2014 and August 2014, with samples submitted through a prospective clinical experience study designed to assess the impact of the test on diagnosis and treatment decisions. This study was performed under an institutional review board waiver of consent (Quorum #33403/1).

Patients were eligible for inclusion in the current study if their biopsy specimens (1) had an uncertain preliminary diagnosis according to the submitting dermatopathologist (pretest diagnosis of indeterminate); (2) received a negative (benign) score from the gene expression test; (3) were treated as benign by the dermatologist(s) involved in follow-up care; and (4) were submitted by a single site (St. Joseph Medical Center, Houston, Texas). Although a single dermatopathology site was used for this study, multiple dermatologists were involved in the final treatment of these patients. Patients with benign scores who received additional intervention were excluded, as they may have a lower rate of adverse events (ie, metastasis) than those who did not receive intervention and would therefore skew the analysis population. A total of 25 patients from the prior study met these inclusion criteria. The previously collected¹² pretest and posttest de-identified data were compiled from the commercial laboratory databases, and the patients were followed from the time of testing via medical record review performed by the dermatology providers at participating sites. Clinical follow-up data were collected using study-specific case report forms (CRFs) that captured the following: (1) the dates and results of clinical follow-up visits; (2) the type(s) of treatment and interventions (if any) performed at those visits; (3) the specific indication for any intervention performed; (4) any evidence of persistent, locally recurrent, and/or distant melanocytic neoplasia (whether definitively attributable to the tested lesion or not); and (5) death from any cause. The CRF assigned interventions to 1 of 5 categories: excision, excision with sentinel lymph node biopsy, referral to dermatologic or other surgeon, examination only (without surgical intervention), and other. Selection of other required a free-text description of the treatment and indications. Pertinent information not otherwise captured by the CRF also was recordable as free text.

Gene Expression Testing
Gene expression testing was carried out at the time of specimen submission in the prior study¹² as described previously.¹⁴ Briefly, formalin-fixed, paraffin-embedded, unstained tissue sections and/or tissue blocks were submitted for testing along with a single hematoxylin and eosin–stained slide used to identify and designate the representative portion(s) of the lesion to be tested. These areas were macrodissected from unstained tissue sections and pooled for RNA extraction. Expression of 14 biomarker genes and 9 reference genes was measured via quantitative reverse transcription–polymerase chain reaction, performed in triplicate for each individual gene. The assay score was generated through application of a weighted algorithm to the expression values generated through quantitative reverse transcription–polymerase chain reaction. Scores were plotted on a scale ranging from −16.7 to 11.1, with scores from 0.0 to 11.1 classified as malignant, scores from −16.7 to −2.1 as benign, and scores from −2.1 to −0.1 as indeterminate.

Statistical Analysis
Demographic and other baseline characteristics of the patient population were summarized. Follow-up time was calculated as the interval between the date a patient’s gene expression test result was first issued to the provider and the date of the patient’s last recorded visit during the study period. All patient dermatology office visits within the designated follow-up period were documented, with a nonstandard number of visits and follow-up time across all study patients. Statistical analyses were conducted using SAS software (SAS Institute Inc), R software version 3.5.0 (R Foundation for Statistical Computing), and IBM SPSS Statistics software (IBM SPSS Statistics for Windows, Version 25).

Results

Patient Sample
A total of 25 ambiguous melanocytic neoplasms from 25 patients met the study inclusion criteria of a benign gene expression result with subsequent treatment as a benign neoplasm during follow-up. The patient sample statistics are summarized in Table 1. Most patients were younger than 65 years, with an average age at the time of biopsy of 48.4 years. All 25 neoplasms produced negative (benign) gene expression signature scores, all were diagnosed as benign nevi posttest by the submitting dermatopathologist, and all patients were initially treated in accordance with the benign diagnosis by the dermatologist(s) involved in clinical follow-up care. Prior to testing with the gene expression signature, most of these histopathologically indeterminate lesions received differential diagnoses, the most common of which were dysplastic nevus (84%), melanoma arising from a nevus (72%), and superficial spreading melanoma (64%; eTable). After testing with the gene expression signature and receiving a benign score, most lesions received a single differential diagnosis of dysplastic nevus (88%).

Follow-up and Survival
Clinical follow-up time ranged from 0.6 to 53.3 months, with a mean duration (SD) of 38.5 (16.6) months, and patients attended an average of 4 postbiopsy dermatology appointments (mean [SD], 4.6 [3.6]). According to the participating dermatology care providers, none of the 25 patients developed any indication during follow-up that the diagnosis of benign nevus was inaccurate. No patient had evidence of locally recurrent or metastatic melanoma, and none died during the study period.

Treatment/Interventions
The treatment recorded in the CRF was examination only for 21 of 25 patients, excision for 3, and other for 1 (Table 2). Because the explanation for the selection of other in this case described an excision performed at the same anatomic location as the biopsy, this treatment also was considered an excision for purposes of the study analyses. The 3 excisions all occurred at the first postbiopsy dermatology encounter. Across all follow-up visits, no additional surgical interventions occurred (Table 2).

The third excision (case 3) involved a 32-year-old woman with a pigmented lesion on the abdomen (Table 3; Figure, E and F). The clinical description was irregular-appearing black papule, nevus with atypia, and the histopathologic differential diagnosis again included dysplastic nevus, superficial spreading melanoma, and melanoma arising within a preexisting nevus. The gene expression signature result was benign (score, −7.2), and the final diagnosis issued within the accompanying pathology report was nevus with moderate junctional dysplasia. Despite the benign diagnosis, excision was performed 89 days after test result availability, with apparent residual pigmentation as the specified indication. As with the other 2 cases, the treating dermatologist confirmed that neither clinical features nor follow-up events suggested malignancy.

Comment

This study followed a cohort of 25 patients with histopathologically ambiguous melanocytic neoplasms that were classified as benign by a diagnostic gene expression test with the intent of determining the outcomes of patients whose treatment aligned with their benign test result. All patients initially were managed according to their test result. During an average posttest clinical follow-up time of more than 3 years (38.5 months), the 25 biopsied lesions, most of which received a differential diagnosis of dysplastic nevus, were regarded as benign nevi by their dermatologists, and the vast majority (88%) received no further surgical intervention. Three patients underwent subsequent excision of the biopsied lesion, with patient or physician preference as the indication in each instance. None of the 25 patients developed evidence of local recurrence, metastasis, or other findings that prompted doubt of the benign diagnosis. The absence of adverse events during clinical follow-up, particularly given that most lesions were not subjected to further intervention, supports use of the gene expression test as a safe and effective adjunct to the diagnosis and treatment of ambiguous melanocytic neoplasms by dermatologists and dermatopathologists.

Ambiguous melanocytic neoplasms evaluated without the aid of molecular adjuncts often result in equivocal or less-than-definitive diagnoses, and further surgical intervention is commonly undertaken to mitigate against the possibility of a missed melanoma.¹³ In this study, treatment that was aligned with the benign test result allowed most patients to avoid further surgical intervention, which suggests that adjunctive use of the gene signature can contribute to reductions in the physical and economic burdens imposed by unnecessary surgical interventions.^15,16 Moreover, any means of increasing accurate and definitive diagnoses may produce an immediate impact on health outcomes by reducing the anxiety that uncertainty often provokes in patients and health care providers alike.

Study Limitations
This study must be interpreted within the context of its limitations. Obtaining meaningful patient outcome data is a common challenge in health care research due to the requisite length of follow-up and sometimes the lack of definitive evidence of adverse events. This is particularly difficult for melanocytic neoplasms because of an apparent inclination for patients with benign diagnoses to abandon follow-up and an increasing tendency for even minimal diagnostic uncertainty to prompt complete excision. Additionally, the only definitive clinical outcome for melanocytic neoplasms is distant metastasis, which (fortunately for patients) is relatively rare. Not surprisingly, studies documenting clinical outcomes of patients with ambiguous melanocytic neoplasms tested prospectively with diagnostic adjuncts are scarce, and this study’s sample size and clinical follow-up compare favorably with the few that exist.^17,18 Although most melanomas declare themselves through recurrence or metastasis within several years of initial biopsy,^1,19 some are clinically dormant for as long as 10 years after initial detection.^20,21 This may be particularly true for the small or early-stage lesions that now comprise the majority of biopsied neoplasms, and such events would go undetected by this study and many others. It also must be recognized that uneventful follow-up, regardless of duration, cannot prove that a biopsied melanocytic neoplasm was benign. Although only 5 patients had a follow-up time of less than 2 years (the time frame in which most recurrence or metastasis will occur), it cannot be definitively proven that a minimum of 2 years recurrence- or metastasis-free survival indicates a benign lesion. Many early-stage malignant melanomas are eradicated by complete excision or even by the initial biopsy if margins are uninvolved.

Because these limitations are intrinsic to melanocytic neoplasms and current management strategies, they pertain to all investigations seeking insights into biological potential through clinical outcomes. Similarly, all current diagnostic tools and procedures have the potential for sampling error, including histopathology. The rarity of adverse outcomes (recurrence and metastasis) in patients with benign test results within this cohort indicates that false-negative results are uncommon, which is further evidenced by a similar rarity of adverse events in prior studies of the gene expression signature.^8-10,22 A particular strength of this study is that most of the ambiguous melanocytic neoplasms followed did not undergo excision after the initial biopsy, an increasingly uncommon situation that may increase their likelihood to be informative.

It must be emphasized that the gene expression test, similar to other diagnostic adjuncts, is neither a replacement for histopathologic interpretation nor a substitute for judgment. As with all tests, it can produce false-positive and false-negative results. Therefore, it should always be interpreted within the constellation of the many other data points that must be considered when making a distinction between benign nevus and malignant melanoma, including but not limited to patient age, family and personal history of melanoma, anatomic location, clinical features, and histopathologic findings. As is the case for many diseases, careful consideration of all relevant input is necessary to minimize the risk of misdiagnosis that might occur should any single data point prove inaccurate, including the results of adjunctive molecular tests.

Conclusion

Ancillary methods are emerging as useful tools for the diagnostic evaluation of melanocytic neoplasms that cannot be assigned definitive diagnoses using traditional techniques alone. This study suggests that patients with ambiguous melanocytic neoplasms may benefit from diagnoses and treatment decisions aligned with the results of a gene expression test, and that for those with a benign result, simple observation may be a safe alternative to surgical excision. This expands upon prior observations of the test’s influence on diagnoses and treatment decisions and supports its role as part of dermatopathologists’ and dermatologists’ decision-making process for histopathologically ambiguous melanocytic lesions.

According to National Institutes of Health estimates, more than 90,000 new cases of melanoma were diagnosed in 2018.¹ Overall 5-year survival for patients with melanoma exceeds 90%, but individual survival estimates are highly dependent on stage at diagnosis, and survival decreases markedly with metastasis. Therefore, early and accurate diagnosis is critical.

Diagnosis of melanocytic neoplasms usually is performed by dermatopathologists through microscopic examination of stained tissue biopsy sections, a technically simple and effective method that enables a definitive diagnosis of benign nevus or malignant melanoma to be made in most cases. However, approximately 15% of all biopsied melanocytic lesions will exhibit some degree of histopathologic ambiguity,^2-4 meaning that some of their microscopic features will be characteristic of a benign nevus while others will suggest the possibility of malignant melanoma. Diagnostic interpretations often vary in these cases, even among experts, and a definitive diagnosis of benign or malignant may be difficult to achieve by microscopy alone.^2-4 Because of the marked reduction in survival once a melanoma has metastasized, these diagnostically ambiguous lesions often are treated as possible malignant melanomas with complete surgical excision (or re-excision). However, some experts suggest that many histopathologically ambiguous melanocytic neoplasms are, in fact, benign,⁵ a notion supported by epidemiologic evidence.^6,7 Therefore, excision of many ambiguous melanocytic neoplasms might be avoided if definitive diagnosis could be achieved.

A gene expression signature was developed and validated for use as an adjunct to traditional methods of differentiating malignant melanocytic neoplasms from their benign counterparts.^8-11 This test quantifies the RNA transcripts produced by 14 genes known to be overexpressed in malignant melanomas by comparison to benign nevi. These values are then combined algorithmically with measurements of 9 reference genes to produce an objective numerical score that is classified as benign, malignant, or indeterminate. When used by board-certified dermatopathologists and dermatologists confronting ambiguous melanocytic lesions, the test produces substantial increases in definitive diagnoses and prompts changes in treatment recommendations.^12,13 However, the long-term consequences of foregoing surgical excision of melanocytic neoplasms that are diagnostically ambiguous but classified as benign by this test have not yet been formally assessed. In the current study, prospectively tested patients whose ambiguous melanocytic neoplasms were classified as benign by the gene expression signature were followed for up to 4.5 years to evaluate the long-term safety of treatment decisions aligned with benign test results.

Methods

Study Population
As part of a prior study,¹² US-based dermatopathologists submitted tissue sections from biopsied melanocytic neoplasms determined to be diagnostically ambiguous by histopathology for analysis with the gene expression signature (Myriad Genetics, Inc). Diagnostically ambiguous lesions were those lesions that were described as ambiguous, uncertain, equivocal, indeterminate, or other synonymous terms by the submitting dermatopathologist and therefore lacked a confident diagnosis of benign or malignant prior to testing. Patients initially were tested between May 2014 and August 2014, with samples submitted through a prospective clinical experience study designed to assess the impact of the test on diagnosis and treatment decisions. This study was performed under an institutional review board waiver of consent (Quorum #33403/1).

Patients were eligible for inclusion in the current study if their biopsy specimens (1) had an uncertain preliminary diagnosis according to the submitting dermatopathologist (pretest diagnosis of indeterminate); (2) received a negative (benign) score from the gene expression test; (3) were treated as benign by the dermatologist(s) involved in follow-up care; and (4) were submitted by a single site (St. Joseph Medical Center, Houston, Texas). Although a single dermatopathology site was used for this study, multiple dermatologists were involved in the final treatment of these patients. Patients with benign scores who received additional intervention were excluded, as they may have a lower rate of adverse events (ie, metastasis) than those who did not receive intervention and would therefore skew the analysis population. A total of 25 patients from the prior study met these inclusion criteria. The previously collected¹² pretest and posttest de-identified data were compiled from the commercial laboratory databases, and the patients were followed from the time of testing via medical record review performed by the dermatology providers at participating sites. Clinical follow-up data were collected using study-specific case report forms (CRFs) that captured the following: (1) the dates and results of clinical follow-up visits; (2) the type(s) of treatment and interventions (if any) performed at those visits; (3) the specific indication for any intervention performed; (4) any evidence of persistent, locally recurrent, and/or distant melanocytic neoplasia (whether definitively attributable to the tested lesion or not); and (5) death from any cause. The CRF assigned interventions to 1 of 5 categories: excision, excision with sentinel lymph node biopsy, referral to dermatologic or other surgeon, examination only (without surgical intervention), and other. Selection of other required a free-text description of the treatment and indications. Pertinent information not otherwise captured by the CRF also was recordable as free text.

Gene Expression Testing
Gene expression testing was carried out at the time of specimen submission in the prior study¹² as described previously.¹⁴ Briefly, formalin-fixed, paraffin-embedded, unstained tissue sections and/or tissue blocks were submitted for testing along with a single hematoxylin and eosin–stained slide used to identify and designate the representative portion(s) of the lesion to be tested. These areas were macrodissected from unstained tissue sections and pooled for RNA extraction. Expression of 14 biomarker genes and 9 reference genes was measured via quantitative reverse transcription–polymerase chain reaction, performed in triplicate for each individual gene. The assay score was generated through application of a weighted algorithm to the expression values generated through quantitative reverse transcription–polymerase chain reaction. Scores were plotted on a scale ranging from −16.7 to 11.1, with scores from 0.0 to 11.1 classified as malignant, scores from −16.7 to −2.1 as benign, and scores from −2.1 to −0.1 as indeterminate.

Statistical Analysis
Demographic and other baseline characteristics of the patient population were summarized. Follow-up time was calculated as the interval between the date a patient’s gene expression test result was first issued to the provider and the date of the patient’s last recorded visit during the study period. All patient dermatology office visits within the designated follow-up period were documented, with a nonstandard number of visits and follow-up time across all study patients. Statistical analyses were conducted using SAS software (SAS Institute Inc), R software version 3.5.0 (R Foundation for Statistical Computing), and IBM SPSS Statistics software (IBM SPSS Statistics for Windows, Version 25).

Results

Patient Sample
A total of 25 ambiguous melanocytic neoplasms from 25 patients met the study inclusion criteria of a benign gene expression result with subsequent treatment as a benign neoplasm during follow-up. The patient sample statistics are summarized in Table 1. Most patients were younger than 65 years, with an average age at the time of biopsy of 48.4 years. All 25 neoplasms produced negative (benign) gene expression signature scores, all were diagnosed as benign nevi posttest by the submitting dermatopathologist, and all patients were initially treated in accordance with the benign diagnosis by the dermatologist(s) involved in clinical follow-up care. Prior to testing with the gene expression signature, most of these histopathologically indeterminate lesions received differential diagnoses, the most common of which were dysplastic nevus (84%), melanoma arising from a nevus (72%), and superficial spreading melanoma (64%; eTable). After testing with the gene expression signature and receiving a benign score, most lesions received a single differential diagnosis of dysplastic nevus (88%).

Follow-up and Survival
Clinical follow-up time ranged from 0.6 to 53.3 months, with a mean duration (SD) of 38.5 (16.6) months, and patients attended an average of 4 postbiopsy dermatology appointments (mean [SD], 4.6 [3.6]). According to the participating dermatology care providers, none of the 25 patients developed any indication during follow-up that the diagnosis of benign nevus was inaccurate. No patient had evidence of locally recurrent or metastatic melanoma, and none died during the study period.

Treatment/Interventions
The treatment recorded in the CRF was examination only for 21 of 25 patients, excision for 3, and other for 1 (Table 2). Because the explanation for the selection of other in this case described an excision performed at the same anatomic location as the biopsy, this treatment also was considered an excision for purposes of the study analyses. The 3 excisions all occurred at the first postbiopsy dermatology encounter. Across all follow-up visits, no additional surgical interventions occurred (Table 2).

The third excision (case 3) involved a 32-year-old woman with a pigmented lesion on the abdomen (Table 3; Figure, E and F). The clinical description was irregular-appearing black papule, nevus with atypia, and the histopathologic differential diagnosis again included dysplastic nevus, superficial spreading melanoma, and melanoma arising within a preexisting nevus. The gene expression signature result was benign (score, −7.2), and the final diagnosis issued within the accompanying pathology report was nevus with moderate junctional dysplasia. Despite the benign diagnosis, excision was performed 89 days after test result availability, with apparent residual pigmentation as the specified indication. As with the other 2 cases, the treating dermatologist confirmed that neither clinical features nor follow-up events suggested malignancy.

Comment

This study followed a cohort of 25 patients with histopathologically ambiguous melanocytic neoplasms that were classified as benign by a diagnostic gene expression test with the intent of determining the outcomes of patients whose treatment aligned with their benign test result. All patients initially were managed according to their test result. During an average posttest clinical follow-up time of more than 3 years (38.5 months), the 25 biopsied lesions, most of which received a differential diagnosis of dysplastic nevus, were regarded as benign nevi by their dermatologists, and the vast majority (88%) received no further surgical intervention. Three patients underwent subsequent excision of the biopsied lesion, with patient or physician preference as the indication in each instance. None of the 25 patients developed evidence of local recurrence, metastasis, or other findings that prompted doubt of the benign diagnosis. The absence of adverse events during clinical follow-up, particularly given that most lesions were not subjected to further intervention, supports use of the gene expression test as a safe and effective adjunct to the diagnosis and treatment of ambiguous melanocytic neoplasms by dermatologists and dermatopathologists.

Ambiguous melanocytic neoplasms evaluated without the aid of molecular adjuncts often result in equivocal or less-than-definitive diagnoses, and further surgical intervention is commonly undertaken to mitigate against the possibility of a missed melanoma.¹³ In this study, treatment that was aligned with the benign test result allowed most patients to avoid further surgical intervention, which suggests that adjunctive use of the gene signature can contribute to reductions in the physical and economic burdens imposed by unnecessary surgical interventions.^15,16 Moreover, any means of increasing accurate and definitive diagnoses may produce an immediate impact on health outcomes by reducing the anxiety that uncertainty often provokes in patients and health care providers alike.

Study Limitations
This study must be interpreted within the context of its limitations. Obtaining meaningful patient outcome data is a common challenge in health care research due to the requisite length of follow-up and sometimes the lack of definitive evidence of adverse events. This is particularly difficult for melanocytic neoplasms because of an apparent inclination for patients with benign diagnoses to abandon follow-up and an increasing tendency for even minimal diagnostic uncertainty to prompt complete excision. Additionally, the only definitive clinical outcome for melanocytic neoplasms is distant metastasis, which (fortunately for patients) is relatively rare. Not surprisingly, studies documenting clinical outcomes of patients with ambiguous melanocytic neoplasms tested prospectively with diagnostic adjuncts are scarce, and this study’s sample size and clinical follow-up compare favorably with the few that exist.^17,18 Although most melanomas declare themselves through recurrence or metastasis within several years of initial biopsy,^1,19 some are clinically dormant for as long as 10 years after initial detection.^20,21 This may be particularly true for the small or early-stage lesions that now comprise the majority of biopsied neoplasms, and such events would go undetected by this study and many others. It also must be recognized that uneventful follow-up, regardless of duration, cannot prove that a biopsied melanocytic neoplasm was benign. Although only 5 patients had a follow-up time of less than 2 years (the time frame in which most recurrence or metastasis will occur), it cannot be definitively proven that a minimum of 2 years recurrence- or metastasis-free survival indicates a benign lesion. Many early-stage malignant melanomas are eradicated by complete excision or even by the initial biopsy if margins are uninvolved.

Because these limitations are intrinsic to melanocytic neoplasms and current management strategies, they pertain to all investigations seeking insights into biological potential through clinical outcomes. Similarly, all current diagnostic tools and procedures have the potential for sampling error, including histopathology. The rarity of adverse outcomes (recurrence and metastasis) in patients with benign test results within this cohort indicates that false-negative results are uncommon, which is further evidenced by a similar rarity of adverse events in prior studies of the gene expression signature.^8-10,22 A particular strength of this study is that most of the ambiguous melanocytic neoplasms followed did not undergo excision after the initial biopsy, an increasingly uncommon situation that may increase their likelihood to be informative.

It must be emphasized that the gene expression test, similar to other diagnostic adjuncts, is neither a replacement for histopathologic interpretation nor a substitute for judgment. As with all tests, it can produce false-positive and false-negative results. Therefore, it should always be interpreted within the constellation of the many other data points that must be considered when making a distinction between benign nevus and malignant melanoma, including but not limited to patient age, family and personal history of melanoma, anatomic location, clinical features, and histopathologic findings. As is the case for many diseases, careful consideration of all relevant input is necessary to minimize the risk of misdiagnosis that might occur should any single data point prove inaccurate, including the results of adjunctive molecular tests.

Conclusion

Ancillary methods are emerging as useful tools for the diagnostic evaluation of melanocytic neoplasms that cannot be assigned definitive diagnoses using traditional techniques alone. This study suggests that patients with ambiguous melanocytic neoplasms may benefit from diagnoses and treatment decisions aligned with the results of a gene expression test, and that for those with a benign result, simple observation may be a safe alternative to surgical excision. This expands upon prior observations of the test’s influence on diagnoses and treatment decisions and supports its role as part of dermatopathologists’ and dermatologists’ decision-making process for histopathologically ambiguous melanocytic lesions.

According to National Institutes of Health estimates, more than 90,000 new cases of melanoma were diagnosed in 2018.¹ Overall 5-year survival for patients with melanoma exceeds 90%, but individual survival estimates are highly dependent on stage at diagnosis, and survival decreases markedly with metastasis. Therefore, early and accurate diagnosis is critical.

Diagnosis of melanocytic neoplasms usually is performed by dermatopathologists through microscopic examination of stained tissue biopsy sections, a technically simple and effective method that enables a definitive diagnosis of benign nevus or malignant melanoma to be made in most cases. However, approximately 15% of all biopsied melanocytic lesions will exhibit some degree of histopathologic ambiguity,^2-4 meaning that some of their microscopic features will be characteristic of a benign nevus while others will suggest the possibility of malignant melanoma. Diagnostic interpretations often vary in these cases, even among experts, and a definitive diagnosis of benign or malignant may be difficult to achieve by microscopy alone.^2-4 Because of the marked reduction in survival once a melanoma has metastasized, these diagnostically ambiguous lesions often are treated as possible malignant melanomas with complete surgical excision (or re-excision). However, some experts suggest that many histopathologically ambiguous melanocytic neoplasms are, in fact, benign,⁵ a notion supported by epidemiologic evidence.^6,7 Therefore, excision of many ambiguous melanocytic neoplasms might be avoided if definitive diagnosis could be achieved.

A gene expression signature was developed and validated for use as an adjunct to traditional methods of differentiating malignant melanocytic neoplasms from their benign counterparts.^8-11 This test quantifies the RNA transcripts produced by 14 genes known to be overexpressed in malignant melanomas by comparison to benign nevi. These values are then combined algorithmically with measurements of 9 reference genes to produce an objective numerical score that is classified as benign, malignant, or indeterminate. When used by board-certified dermatopathologists and dermatologists confronting ambiguous melanocytic lesions, the test produces substantial increases in definitive diagnoses and prompts changes in treatment recommendations.^12,13 However, the long-term consequences of foregoing surgical excision of melanocytic neoplasms that are diagnostically ambiguous but classified as benign by this test have not yet been formally assessed. In the current study, prospectively tested patients whose ambiguous melanocytic neoplasms were classified as benign by the gene expression signature were followed for up to 4.5 years to evaluate the long-term safety of treatment decisions aligned with benign test results.

Methods

Study Population
As part of a prior study,¹² US-based dermatopathologists submitted tissue sections from biopsied melanocytic neoplasms determined to be diagnostically ambiguous by histopathology for analysis with the gene expression signature (Myriad Genetics, Inc). Diagnostically ambiguous lesions were those lesions that were described as ambiguous, uncertain, equivocal, indeterminate, or other synonymous terms by the submitting dermatopathologist and therefore lacked a confident diagnosis of benign or malignant prior to testing. Patients initially were tested between May 2014 and August 2014, with samples submitted through a prospective clinical experience study designed to assess the impact of the test on diagnosis and treatment decisions. This study was performed under an institutional review board waiver of consent (Quorum #33403/1).

Patients were eligible for inclusion in the current study if their biopsy specimens (1) had an uncertain preliminary diagnosis according to the submitting dermatopathologist (pretest diagnosis of indeterminate); (2) received a negative (benign) score from the gene expression test; (3) were treated as benign by the dermatologist(s) involved in follow-up care; and (4) were submitted by a single site (St. Joseph Medical Center, Houston, Texas). Although a single dermatopathology site was used for this study, multiple dermatologists were involved in the final treatment of these patients. Patients with benign scores who received additional intervention were excluded, as they may have a lower rate of adverse events (ie, metastasis) than those who did not receive intervention and would therefore skew the analysis population. A total of 25 patients from the prior study met these inclusion criteria. The previously collected¹² pretest and posttest de-identified data were compiled from the commercial laboratory databases, and the patients were followed from the time of testing via medical record review performed by the dermatology providers at participating sites. Clinical follow-up data were collected using study-specific case report forms (CRFs) that captured the following: (1) the dates and results of clinical follow-up visits; (2) the type(s) of treatment and interventions (if any) performed at those visits; (3) the specific indication for any intervention performed; (4) any evidence of persistent, locally recurrent, and/or distant melanocytic neoplasia (whether definitively attributable to the tested lesion or not); and (5) death from any cause. The CRF assigned interventions to 1 of 5 categories: excision, excision with sentinel lymph node biopsy, referral to dermatologic or other surgeon, examination only (without surgical intervention), and other. Selection of other required a free-text description of the treatment and indications. Pertinent information not otherwise captured by the CRF also was recordable as free text.

Gene Expression Testing
Gene expression testing was carried out at the time of specimen submission in the prior study¹² as described previously.¹⁴ Briefly, formalin-fixed, paraffin-embedded, unstained tissue sections and/or tissue blocks were submitted for testing along with a single hematoxylin and eosin–stained slide used to identify and designate the representative portion(s) of the lesion to be tested. These areas were macrodissected from unstained tissue sections and pooled for RNA extraction. Expression of 14 biomarker genes and 9 reference genes was measured via quantitative reverse transcription–polymerase chain reaction, performed in triplicate for each individual gene. The assay score was generated through application of a weighted algorithm to the expression values generated through quantitative reverse transcription–polymerase chain reaction. Scores were plotted on a scale ranging from −16.7 to 11.1, with scores from 0.0 to 11.1 classified as malignant, scores from −16.7 to −2.1 as benign, and scores from −2.1 to −0.1 as indeterminate.

Statistical Analysis
Demographic and other baseline characteristics of the patient population were summarized. Follow-up time was calculated as the interval between the date a patient’s gene expression test result was first issued to the provider and the date of the patient’s last recorded visit during the study period. All patient dermatology office visits within the designated follow-up period were documented, with a nonstandard number of visits and follow-up time across all study patients. Statistical analyses were conducted using SAS software (SAS Institute Inc), R software version 3.5.0 (R Foundation for Statistical Computing), and IBM SPSS Statistics software (IBM SPSS Statistics for Windows, Version 25).

Results

Patient Sample
A total of 25 ambiguous melanocytic neoplasms from 25 patients met the study inclusion criteria of a benign gene expression result with subsequent treatment as a benign neoplasm during follow-up. The patient sample statistics are summarized in Table 1. Most patients were younger than 65 years, with an average age at the time of biopsy of 48.4 years. All 25 neoplasms produced negative (benign) gene expression signature scores, all were diagnosed as benign nevi posttest by the submitting dermatopathologist, and all patients were initially treated in accordance with the benign diagnosis by the dermatologist(s) involved in clinical follow-up care. Prior to testing with the gene expression signature, most of these histopathologically indeterminate lesions received differential diagnoses, the most common of which were dysplastic nevus (84%), melanoma arising from a nevus (72%), and superficial spreading melanoma (64%; eTable). After testing with the gene expression signature and receiving a benign score, most lesions received a single differential diagnosis of dysplastic nevus (88%).

Follow-up and Survival
Clinical follow-up time ranged from 0.6 to 53.3 months, with a mean duration (SD) of 38.5 (16.6) months, and patients attended an average of 4 postbiopsy dermatology appointments (mean [SD], 4.6 [3.6]). According to the participating dermatology care providers, none of the 25 patients developed any indication during follow-up that the diagnosis of benign nevus was inaccurate. No patient had evidence of locally recurrent or metastatic melanoma, and none died during the study period.

Treatment/Interventions
The treatment recorded in the CRF was examination only for 21 of 25 patients, excision for 3, and other for 1 (Table 2). Because the explanation for the selection of other in this case described an excision performed at the same anatomic location as the biopsy, this treatment also was considered an excision for purposes of the study analyses. The 3 excisions all occurred at the first postbiopsy dermatology encounter. Across all follow-up visits, no additional surgical interventions occurred (Table 2).

The third excision (case 3) involved a 32-year-old woman with a pigmented lesion on the abdomen (Table 3; Figure, E and F). The clinical description was irregular-appearing black papule, nevus with atypia, and the histopathologic differential diagnosis again included dysplastic nevus, superficial spreading melanoma, and melanoma arising within a preexisting nevus. The gene expression signature result was benign (score, −7.2), and the final diagnosis issued within the accompanying pathology report was nevus with moderate junctional dysplasia. Despite the benign diagnosis, excision was performed 89 days after test result availability, with apparent residual pigmentation as the specified indication. As with the other 2 cases, the treating dermatologist confirmed that neither clinical features nor follow-up events suggested malignancy.

Comment

This study followed a cohort of 25 patients with histopathologically ambiguous melanocytic neoplasms that were classified as benign by a diagnostic gene expression test with the intent of determining the outcomes of patients whose treatment aligned with their benign test result. All patients initially were managed according to their test result. During an average posttest clinical follow-up time of more than 3 years (38.5 months), the 25 biopsied lesions, most of which received a differential diagnosis of dysplastic nevus, were regarded as benign nevi by their dermatologists, and the vast majority (88%) received no further surgical intervention. Three patients underwent subsequent excision of the biopsied lesion, with patient or physician preference as the indication in each instance. None of the 25 patients developed evidence of local recurrence, metastasis, or other findings that prompted doubt of the benign diagnosis. The absence of adverse events during clinical follow-up, particularly given that most lesions were not subjected to further intervention, supports use of the gene expression test as a safe and effective adjunct to the diagnosis and treatment of ambiguous melanocytic neoplasms by dermatologists and dermatopathologists.

Ambiguous melanocytic neoplasms evaluated without the aid of molecular adjuncts often result in equivocal or less-than-definitive diagnoses, and further surgical intervention is commonly undertaken to mitigate against the possibility of a missed melanoma.¹³ In this study, treatment that was aligned with the benign test result allowed most patients to avoid further surgical intervention, which suggests that adjunctive use of the gene signature can contribute to reductions in the physical and economic burdens imposed by unnecessary surgical interventions.^15,16 Moreover, any means of increasing accurate and definitive diagnoses may produce an immediate impact on health outcomes by reducing the anxiety that uncertainty often provokes in patients and health care providers alike.

Study Limitations
This study must be interpreted within the context of its limitations. Obtaining meaningful patient outcome data is a common challenge in health care research due to the requisite length of follow-up and sometimes the lack of definitive evidence of adverse events. This is particularly difficult for melanocytic neoplasms because of an apparent inclination for patients with benign diagnoses to abandon follow-up and an increasing tendency for even minimal diagnostic uncertainty to prompt complete excision. Additionally, the only definitive clinical outcome for melanocytic neoplasms is distant metastasis, which (fortunately for patients) is relatively rare. Not surprisingly, studies documenting clinical outcomes of patients with ambiguous melanocytic neoplasms tested prospectively with diagnostic adjuncts are scarce, and this study’s sample size and clinical follow-up compare favorably with the few that exist.^17,18 Although most melanomas declare themselves through recurrence or metastasis within several years of initial biopsy,^1,19 some are clinically dormant for as long as 10 years after initial detection.^20,21 This may be particularly true for the small or early-stage lesions that now comprise the majority of biopsied neoplasms, and such events would go undetected by this study and many others. It also must be recognized that uneventful follow-up, regardless of duration, cannot prove that a biopsied melanocytic neoplasm was benign. Although only 5 patients had a follow-up time of less than 2 years (the time frame in which most recurrence or metastasis will occur), it cannot be definitively proven that a minimum of 2 years recurrence- or metastasis-free survival indicates a benign lesion. Many early-stage malignant melanomas are eradicated by complete excision or even by the initial biopsy if margins are uninvolved.

Because these limitations are intrinsic to melanocytic neoplasms and current management strategies, they pertain to all investigations seeking insights into biological potential through clinical outcomes. Similarly, all current diagnostic tools and procedures have the potential for sampling error, including histopathology. The rarity of adverse outcomes (recurrence and metastasis) in patients with benign test results within this cohort indicates that false-negative results are uncommon, which is further evidenced by a similar rarity of adverse events in prior studies of the gene expression signature.^8-10,22 A particular strength of this study is that most of the ambiguous melanocytic neoplasms followed did not undergo excision after the initial biopsy, an increasingly uncommon situation that may increase their likelihood to be informative.

It must be emphasized that the gene expression test, similar to other diagnostic adjuncts, is neither a replacement for histopathologic interpretation nor a substitute for judgment. As with all tests, it can produce false-positive and false-negative results. Therefore, it should always be interpreted within the constellation of the many other data points that must be considered when making a distinction between benign nevus and malignant melanoma, including but not limited to patient age, family and personal history of melanoma, anatomic location, clinical features, and histopathologic findings. As is the case for many diseases, careful consideration of all relevant input is necessary to minimize the risk of misdiagnosis that might occur should any single data point prove inaccurate, including the results of adjunctive molecular tests.

Conclusion

Ancillary methods are emerging as useful tools for the diagnostic evaluation of melanocytic neoplasms that cannot be assigned definitive diagnoses using traditional techniques alone. This study suggests that patients with ambiguous melanocytic neoplasms may benefit from diagnoses and treatment decisions aligned with the results of a gene expression test, and that for those with a benign result, simple observation may be a safe alternative to surgical excision. This expands upon prior observations of the test’s influence on diagnoses and treatment decisions and supports its role as part of dermatopathologists’ and dermatologists’ decision-making process for histopathologically ambiguous melanocytic lesions.

Recent advances in the immunopathogenesis and therapy of cutaneous T-cell lymphoma (CTCL) have shown great promise for the care of patients with mycosis fungoides (MF) and Sézary syndrome (SS).^1-3 Research into the tumor microenvironment, microbiome, and molecular genetics may yield further information as we strive to develop MF/SS therapy from the bench to the bedside.³ Although progress has been made on multiple fronts in MF, some important—particularly epidemiologic and clinical—questions remain unanswered.

Racial disparities are well known to exist in CTCLs, particularly MF and SS.^4-7 The incidence of MF and SS in the United States is higher in African American/Black patients than in White patients⁴; in addition, MF has an earlier age at onset in Black patients compared with White patients.^4,5 Gender disparities also exist, with relatively more Black females than males affected with MF^4-6; in particular, early-onset MF (ie, <40 years of age) is more common in Black females than Black males.^6,7 According to Surveillance, Epidemiology, and End Results (SEER) data⁴ and the US National Cancer Database,⁵ African American/Black patients with MF have worse outcomes compared with other races (shorter overall survival and higher mortality) and also exhibit higher stages of disease at presentation (stage IIb or higher).⁵ Black race also was found to be a predictor of poor overall survival after accounting for disease characteristics, socioeconomicfactors, and types of treatment. The factors responsible for these racial disparities remain unclear.

A fortuitous collision of interests and technology may have helped to shed light on some of the reasons for these racial disparities in MF. Nearly 2 decades ago, high-quality, whole-body digital cutaneous photography was implemented by the Dermatology Service at Memorial Sloan Kettering Cancer Center Dermatology Service (New York, New York).⁸ Although the standardized 20-pose positioning images initially were used for the follow-up evaluation of patients with multiple nevi and melanomas, we incorporated the same photography technique into our multidisciplinary Cutaneous Lymphoma Clinic at Memorial Sloan Kettering Cancer Center. The multiplicity and clinical heterogeneity of MF lesions is well known, as is the fact that individual MF lesions may develop, respond to therapy, or change independently of other lesions in a given patient. We regularly reviewed these digital images with patients during their visits to assess treatment responses, discussed the need for changes in therapy in the face of progressive disease, and provided encouragement and positive reinforcement for those who improved with time-consuming regimens (eg, phototherapy).

Ultimately, as we became more familiar with looking at images in skin of color, we recognized different clinical features among our Black patients. In the literature, hypopigmented MF is a variant that typically is characterized by CD8⁺-predominant T cells and is seen more frequently in dark-skinned patients.⁹ In contrast, hyperpigmented MF has been considered a relatively rare presentation of MF.¹⁰ However, using only clinical and demographic information, we were able to identify 2 very different prognostic groups: those with hypopigmented lesions and those with only hyperpigmented and/or erythematous skin lesions.¹¹ In our retrospective review of 157 African American/Black MF patients at our institution—122 with early-stage and 35 with late-stage MF—45% of patients had hypopigmented lesions vs 52% with hyperpigmented and/or erythematous lesions but no hypopigmentation. Those with hypopigmentation had superior outcomes, with better overall survival (P=.002) and progression-free survival (P=.014). In addition, more than 80% of patients who progressed or died from disease had hyperpigmented and/or erythematous lesions without hypopigmentation.¹¹

Sometimes we have to go backward to go forward. Going from the bedside to the bench in our Black MF/SS patients—initially through the clinical recognition of prognostically different lesions, and then through clinicopathologic correlation with immunophenotyping and molecular studies—should provide important clues. Further investigation of Black patients who share similar pigmentary phenotypes of MF also may shed light on the pathogenetic mechanisms responsible for these prognostically significant skin findings. Through these efforts, we hope to identify higher-risk patients, which ultimately will lead to earlier intervention, more effective therapeutic regimens, and improved outcomes.

Recent advances in the immunopathogenesis and therapy of cutaneous T-cell lymphoma (CTCL) have shown great promise for the care of patients with mycosis fungoides (MF) and Sézary syndrome (SS).^1-3 Research into the tumor microenvironment, microbiome, and molecular genetics may yield further information as we strive to develop MF/SS therapy from the bench to the bedside.³ Although progress has been made on multiple fronts in MF, some important—particularly epidemiologic and clinical—questions remain unanswered.

Racial disparities are well known to exist in CTCLs, particularly MF and SS.^4-7 The incidence of MF and SS in the United States is higher in African American/Black patients than in White patients⁴; in addition, MF has an earlier age at onset in Black patients compared with White patients.^4,5 Gender disparities also exist, with relatively more Black females than males affected with MF^4-6; in particular, early-onset MF (ie, <40 years of age) is more common in Black females than Black males.^6,7 According to Surveillance, Epidemiology, and End Results (SEER) data⁴ and the US National Cancer Database,⁵ African American/Black patients with MF have worse outcomes compared with other races (shorter overall survival and higher mortality) and also exhibit higher stages of disease at presentation (stage IIb or higher).⁵ Black race also was found to be a predictor of poor overall survival after accounting for disease characteristics, socioeconomicfactors, and types of treatment. The factors responsible for these racial disparities remain unclear.

A fortuitous collision of interests and technology may have helped to shed light on some of the reasons for these racial disparities in MF. Nearly 2 decades ago, high-quality, whole-body digital cutaneous photography was implemented by the Dermatology Service at Memorial Sloan Kettering Cancer Center Dermatology Service (New York, New York).⁸ Although the standardized 20-pose positioning images initially were used for the follow-up evaluation of patients with multiple nevi and melanomas, we incorporated the same photography technique into our multidisciplinary Cutaneous Lymphoma Clinic at Memorial Sloan Kettering Cancer Center. The multiplicity and clinical heterogeneity of MF lesions is well known, as is the fact that individual MF lesions may develop, respond to therapy, or change independently of other lesions in a given patient. We regularly reviewed these digital images with patients during their visits to assess treatment responses, discussed the need for changes in therapy in the face of progressive disease, and provided encouragement and positive reinforcement for those who improved with time-consuming regimens (eg, phototherapy).

Ultimately, as we became more familiar with looking at images in skin of color, we recognized different clinical features among our Black patients. In the literature, hypopigmented MF is a variant that typically is characterized by CD8⁺-predominant T cells and is seen more frequently in dark-skinned patients.⁹ In contrast, hyperpigmented MF has been considered a relatively rare presentation of MF.¹⁰ However, using only clinical and demographic information, we were able to identify 2 very different prognostic groups: those with hypopigmented lesions and those with only hyperpigmented and/or erythematous skin lesions.¹¹ In our retrospective review of 157 African American/Black MF patients at our institution—122 with early-stage and 35 with late-stage MF—45% of patients had hypopigmented lesions vs 52% with hyperpigmented and/or erythematous lesions but no hypopigmentation. Those with hypopigmentation had superior outcomes, with better overall survival (P=.002) and progression-free survival (P=.014). In addition, more than 80% of patients who progressed or died from disease had hyperpigmented and/or erythematous lesions without hypopigmentation.¹¹

Sometimes we have to go backward to go forward. Going from the bedside to the bench in our Black MF/SS patients—initially through the clinical recognition of prognostically different lesions, and then through clinicopathologic correlation with immunophenotyping and molecular studies—should provide important clues. Further investigation of Black patients who share similar pigmentary phenotypes of MF also may shed light on the pathogenetic mechanisms responsible for these prognostically significant skin findings. Through these efforts, we hope to identify higher-risk patients, which ultimately will lead to earlier intervention, more effective therapeutic regimens, and improved outcomes.

Recent advances in the immunopathogenesis and therapy of cutaneous T-cell lymphoma (CTCL) have shown great promise for the care of patients with mycosis fungoides (MF) and Sézary syndrome (SS).^1-3 Research into the tumor microenvironment, microbiome, and molecular genetics may yield further information as we strive to develop MF/SS therapy from the bench to the bedside.³ Although progress has been made on multiple fronts in MF, some important—particularly epidemiologic and clinical—questions remain unanswered.

Racial disparities are well known to exist in CTCLs, particularly MF and SS.^4-7 The incidence of MF and SS in the United States is higher in African American/Black patients than in White patients⁴; in addition, MF has an earlier age at onset in Black patients compared with White patients.^4,5 Gender disparities also exist, with relatively more Black females than males affected with MF^4-6; in particular, early-onset MF (ie, <40 years of age) is more common in Black females than Black males.^6,7 According to Surveillance, Epidemiology, and End Results (SEER) data⁴ and the US National Cancer Database,⁵ African American/Black patients with MF have worse outcomes compared with other races (shorter overall survival and higher mortality) and also exhibit higher stages of disease at presentation (stage IIb or higher).⁵ Black race also was found to be a predictor of poor overall survival after accounting for disease characteristics, socioeconomicfactors, and types of treatment. The factors responsible for these racial disparities remain unclear.

A fortuitous collision of interests and technology may have helped to shed light on some of the reasons for these racial disparities in MF. Nearly 2 decades ago, high-quality, whole-body digital cutaneous photography was implemented by the Dermatology Service at Memorial Sloan Kettering Cancer Center Dermatology Service (New York, New York).⁸ Although the standardized 20-pose positioning images initially were used for the follow-up evaluation of patients with multiple nevi and melanomas, we incorporated the same photography technique into our multidisciplinary Cutaneous Lymphoma Clinic at Memorial Sloan Kettering Cancer Center. The multiplicity and clinical heterogeneity of MF lesions is well known, as is the fact that individual MF lesions may develop, respond to therapy, or change independently of other lesions in a given patient. We regularly reviewed these digital images with patients during their visits to assess treatment responses, discussed the need for changes in therapy in the face of progressive disease, and provided encouragement and positive reinforcement for those who improved with time-consuming regimens (eg, phototherapy).

Ultimately, as we became more familiar with looking at images in skin of color, we recognized different clinical features among our Black patients. In the literature, hypopigmented MF is a variant that typically is characterized by CD8⁺-predominant T cells and is seen more frequently in dark-skinned patients.⁹ In contrast, hyperpigmented MF has been considered a relatively rare presentation of MF.¹⁰ However, using only clinical and demographic information, we were able to identify 2 very different prognostic groups: those with hypopigmented lesions and those with only hyperpigmented and/or erythematous skin lesions.¹¹ In our retrospective review of 157 African American/Black MF patients at our institution—122 with early-stage and 35 with late-stage MF—45% of patients had hypopigmented lesions vs 52% with hyperpigmented and/or erythematous lesions but no hypopigmentation. Those with hypopigmentation had superior outcomes, with better overall survival (P=.002) and progression-free survival (P=.014). In addition, more than 80% of patients who progressed or died from disease had hyperpigmented and/or erythematous lesions without hypopigmentation.¹¹

Sometimes we have to go backward to go forward. Going from the bedside to the bench in our Black MF/SS patients—initially through the clinical recognition of prognostically different lesions, and then through clinicopathologic correlation with immunophenotyping and molecular studies—should provide important clues. Further investigation of Black patients who share similar pigmentary phenotypes of MF also may shed light on the pathogenetic mechanisms responsible for these prognostically significant skin findings. Through these efforts, we hope to identify higher-risk patients, which ultimately will lead to earlier intervention, more effective therapeutic regimens, and improved outcomes.

Practice Gap

Reconstruction of a lip defect poses challenges to the dermatologic surgeon. The lip is a free margin, where excess tension can cause noticeable distortion in facial aesthetics. Distortion of that free margin might not only disrupt the appearance of the lip but affect function by impairing oral competency and mobility; therefore, when choosing a method of reconstruction, the surgeon must take free margin distortion into account. Misalignment of the vermilion border upon reconstruction will cause a poor aesthetic result in the absence of free margin distortion. When a surgical defect involves more than one cosmetic subunit of the lip, great care must be taken to repair each subunit individually to achieve the best cosmetic and functional results.

The suitability of traditional approaches to reconstruction of a defect that crosses the vermilion border—healing by secondary intention, primary linear repair, full-thickness wedge repair, partial-thickness wedge repair, and combined cutaneous and mucosal advancement¹—depends on the depth of the lesion.

Clinical Presentation

A 66-year-old woman with a 4×6-mm, invasive, well-differentiated squamous cell carcinoma of the left lower lip was referred for Mohs micrographic surgery. Removal of the tumor required 2 stages to obtain clear margins, leaving a 1.0×1.2-cm defect that crossed the vermilion border (Figure, A). How would you repair this defect?

Selecting a Technique to Close the Surgical Defect

For this patient, we had several options to consider in approaching closure, including several that we rejected. Because the defect crossed cosmetic subunit boundaries, healing by secondary intention was avoided, as it would cause contraction, obliterate the vermilion border, and result in poor functional and cosmetic results. We decided against primary closure, even with careful attention to reapproximation of the vermilion border, because the width of the defect would have required a large Burow triangle that extended into the oral cavity. For defects less than one-third the width of the lip, full-thickness wedge repair can yield excellent cosmetic results but, in this case, would decrease the oral aperture and was deemed too extensive a procedure for a relatively shallow defect.²

Instead, we chose to perform repair with V to Y advancement of skin below the cutaneous defect, up to the location of the absent vermilion border, combined with small, horizontal, linear closure of the mucosal portion of the defect. This approach is a variation of a repair described by Jin et al,³ who described using 2 opposing V-Y advancement flaps to repair defects of the lip. This repair has provided excellent cosmetic results for a small series of our patients, preserving the oral aperture and maintaining the important aesthetic location of the vermilion border. In addition, the technique makes it unnecessary for the patient to undergo a much larger repair, such as a full- or partial-thickness wedge when the initial defect is relatively shallow.

Closure Technique

It is essential to properly outline the vermilion border of the lip before initiating the repair, ideally before any infiltration of local anesthesia if the surgeon anticipates that tumor extirpation might cross the vermilion border.

Repair
Closing then proceeds as follows:

• The cutaneous portion of the defect is drawn out in standard V to Y fashion, carrying the incision through the dermis and into subcutaneous tissue. The pedicle of the flap is maintained at the base of the island, serving as the blood supply to the flap.

• The periphery of the flap and surrounding tissue is undermined to facilitate movement superiorly into the cutaneous portion of the defect.

• A single buried vertical mattress suture can be placed at the advancing border of the island, holding it in place at the anticipated location of the vermilion border. The secondary defect created by the advancing V is closed to help push the island into place and prevent downward tension on the free margin of the lip.

• The remaining defect of the vermilion lip is closed by removing Burow triangles at the horizontal edges on each side of the remaining defect (Figure, B). The triangles are removed completely within the mucosal lip, with the inferior edge of the triangle placed at the vermilion border.

• The defect is closed in a primary linear horizontal fashion, using buried vertical mattress sutures and cutaneous approximation.

The final appearance of the sutured defect yields a small lateral extension at the superior edge of the V to Y closure, giving the appearance of wings on the Y, prompting us to term the closure V-to-flying-Y (Figure, C).

Although the limited portion of the mucosal lip that is closed in this fashion might appear thinner than the remaining lip, it generally yields a cosmetically acceptable result in the properly selected patient. Our experience also has shown an improvement in this difference in the months following repair. A full mucosal advancement flap might result in a more uniform appearance of the lower lip, but it is a larger and more difficult procedure for the patient to endure. Additionally, a full mucosal advancement flap risks uniformly creating a much thinner lip.

Postoperative Course
Sutures were removed 1 week postoperatively. Proper location of the vermilion border, without distortion of the free margin, was demonstrated. At 11-month follow-up, excellent cosmetic and functional results were noted (Figure, D).

Practice Implications

This repair (1) demonstrates an elegant method of closing a relatively shallow defect that crosses the vermilion border and (2) allows the surgeon to address each cosmetic subunit individually. We have found that this repair provides excellent cosmetic and functional results, with little morbidity.

The lip is a common site of nonmelanoma squamous cell carcinoma. Poorly planned closing after excision of the tumor risks notable impairment of function or cosmetic distortion. When a defect of the lip crosses cosmetic subunits, it is helpful to repair each subunit individually. V-to-flying-Y closure is an effective method to close defects that cross the vermilion border, resulting in well-preserved cosmetic appearance and function.

Practice Gap

Reconstruction of a lip defect poses challenges to the dermatologic surgeon. The lip is a free margin, where excess tension can cause noticeable distortion in facial aesthetics. Distortion of that free margin might not only disrupt the appearance of the lip but affect function by impairing oral competency and mobility; therefore, when choosing a method of reconstruction, the surgeon must take free margin distortion into account. Misalignment of the vermilion border upon reconstruction will cause a poor aesthetic result in the absence of free margin distortion. When a surgical defect involves more than one cosmetic subunit of the lip, great care must be taken to repair each subunit individually to achieve the best cosmetic and functional results.

The suitability of traditional approaches to reconstruction of a defect that crosses the vermilion border—healing by secondary intention, primary linear repair, full-thickness wedge repair, partial-thickness wedge repair, and combined cutaneous and mucosal advancement¹—depends on the depth of the lesion.

Clinical Presentation

A 66-year-old woman with a 4×6-mm, invasive, well-differentiated squamous cell carcinoma of the left lower lip was referred for Mohs micrographic surgery. Removal of the tumor required 2 stages to obtain clear margins, leaving a 1.0×1.2-cm defect that crossed the vermilion border (Figure, A). How would you repair this defect?

Selecting a Technique to Close the Surgical Defect

For this patient, we had several options to consider in approaching closure, including several that we rejected. Because the defect crossed cosmetic subunit boundaries, healing by secondary intention was avoided, as it would cause contraction, obliterate the vermilion border, and result in poor functional and cosmetic results. We decided against primary closure, even with careful attention to reapproximation of the vermilion border, because the width of the defect would have required a large Burow triangle that extended into the oral cavity. For defects less than one-third the width of the lip, full-thickness wedge repair can yield excellent cosmetic results but, in this case, would decrease the oral aperture and was deemed too extensive a procedure for a relatively shallow defect.²

Instead, we chose to perform repair with V to Y advancement of skin below the cutaneous defect, up to the location of the absent vermilion border, combined with small, horizontal, linear closure of the mucosal portion of the defect. This approach is a variation of a repair described by Jin et al,³ who described using 2 opposing V-Y advancement flaps to repair defects of the lip. This repair has provided excellent cosmetic results for a small series of our patients, preserving the oral aperture and maintaining the important aesthetic location of the vermilion border. In addition, the technique makes it unnecessary for the patient to undergo a much larger repair, such as a full- or partial-thickness wedge when the initial defect is relatively shallow.

Closure Technique

It is essential to properly outline the vermilion border of the lip before initiating the repair, ideally before any infiltration of local anesthesia if the surgeon anticipates that tumor extirpation might cross the vermilion border.

Repair
Closing then proceeds as follows:

• The cutaneous portion of the defect is drawn out in standard V to Y fashion, carrying the incision through the dermis and into subcutaneous tissue. The pedicle of the flap is maintained at the base of the island, serving as the blood supply to the flap.

• The periphery of the flap and surrounding tissue is undermined to facilitate movement superiorly into the cutaneous portion of the defect.

• A single buried vertical mattress suture can be placed at the advancing border of the island, holding it in place at the anticipated location of the vermilion border. The secondary defect created by the advancing V is closed to help push the island into place and prevent downward tension on the free margin of the lip.

• The remaining defect of the vermilion lip is closed by removing Burow triangles at the horizontal edges on each side of the remaining defect (Figure, B). The triangles are removed completely within the mucosal lip, with the inferior edge of the triangle placed at the vermilion border.

• The defect is closed in a primary linear horizontal fashion, using buried vertical mattress sutures and cutaneous approximation.

The final appearance of the sutured defect yields a small lateral extension at the superior edge of the V to Y closure, giving the appearance of wings on the Y, prompting us to term the closure V-to-flying-Y (Figure, C).

Although the limited portion of the mucosal lip that is closed in this fashion might appear thinner than the remaining lip, it generally yields a cosmetically acceptable result in the properly selected patient. Our experience also has shown an improvement in this difference in the months following repair. A full mucosal advancement flap might result in a more uniform appearance of the lower lip, but it is a larger and more difficult procedure for the patient to endure. Additionally, a full mucosal advancement flap risks uniformly creating a much thinner lip.

Postoperative Course
Sutures were removed 1 week postoperatively. Proper location of the vermilion border, without distortion of the free margin, was demonstrated. At 11-month follow-up, excellent cosmetic and functional results were noted (Figure, D).

Practice Implications

This repair (1) demonstrates an elegant method of closing a relatively shallow defect that crosses the vermilion border and (2) allows the surgeon to address each cosmetic subunit individually. We have found that this repair provides excellent cosmetic and functional results, with little morbidity.

The lip is a common site of nonmelanoma squamous cell carcinoma. Poorly planned closing after excision of the tumor risks notable impairment of function or cosmetic distortion. When a defect of the lip crosses cosmetic subunits, it is helpful to repair each subunit individually. V-to-flying-Y closure is an effective method to close defects that cross the vermilion border, resulting in well-preserved cosmetic appearance and function.

Practice Gap

Reconstruction of a lip defect poses challenges to the dermatologic surgeon. The lip is a free margin, where excess tension can cause noticeable distortion in facial aesthetics. Distortion of that free margin might not only disrupt the appearance of the lip but affect function by impairing oral competency and mobility; therefore, when choosing a method of reconstruction, the surgeon must take free margin distortion into account. Misalignment of the vermilion border upon reconstruction will cause a poor aesthetic result in the absence of free margin distortion. When a surgical defect involves more than one cosmetic subunit of the lip, great care must be taken to repair each subunit individually to achieve the best cosmetic and functional results.

The suitability of traditional approaches to reconstruction of a defect that crosses the vermilion border—healing by secondary intention, primary linear repair, full-thickness wedge repair, partial-thickness wedge repair, and combined cutaneous and mucosal advancement¹—depends on the depth of the lesion.

Clinical Presentation

A 66-year-old woman with a 4×6-mm, invasive, well-differentiated squamous cell carcinoma of the left lower lip was referred for Mohs micrographic surgery. Removal of the tumor required 2 stages to obtain clear margins, leaving a 1.0×1.2-cm defect that crossed the vermilion border (Figure, A). How would you repair this defect?

Selecting a Technique to Close the Surgical Defect

For this patient, we had several options to consider in approaching closure, including several that we rejected. Because the defect crossed cosmetic subunit boundaries, healing by secondary intention was avoided, as it would cause contraction, obliterate the vermilion border, and result in poor functional and cosmetic results. We decided against primary closure, even with careful attention to reapproximation of the vermilion border, because the width of the defect would have required a large Burow triangle that extended into the oral cavity. For defects less than one-third the width of the lip, full-thickness wedge repair can yield excellent cosmetic results but, in this case, would decrease the oral aperture and was deemed too extensive a procedure for a relatively shallow defect.²

Instead, we chose to perform repair with V to Y advancement of skin below the cutaneous defect, up to the location of the absent vermilion border, combined with small, horizontal, linear closure of the mucosal portion of the defect. This approach is a variation of a repair described by Jin et al,³ who described using 2 opposing V-Y advancement flaps to repair defects of the lip. This repair has provided excellent cosmetic results for a small series of our patients, preserving the oral aperture and maintaining the important aesthetic location of the vermilion border. In addition, the technique makes it unnecessary for the patient to undergo a much larger repair, such as a full- or partial-thickness wedge when the initial defect is relatively shallow.

Closure Technique

It is essential to properly outline the vermilion border of the lip before initiating the repair, ideally before any infiltration of local anesthesia if the surgeon anticipates that tumor extirpation might cross the vermilion border.

Repair
Closing then proceeds as follows:

• The cutaneous portion of the defect is drawn out in standard V to Y fashion, carrying the incision through the dermis and into subcutaneous tissue. The pedicle of the flap is maintained at the base of the island, serving as the blood supply to the flap.

• The periphery of the flap and surrounding tissue is undermined to facilitate movement superiorly into the cutaneous portion of the defect.

• A single buried vertical mattress suture can be placed at the advancing border of the island, holding it in place at the anticipated location of the vermilion border. The secondary defect created by the advancing V is closed to help push the island into place and prevent downward tension on the free margin of the lip.

• The remaining defect of the vermilion lip is closed by removing Burow triangles at the horizontal edges on each side of the remaining defect (Figure, B). The triangles are removed completely within the mucosal lip, with the inferior edge of the triangle placed at the vermilion border.

• The defect is closed in a primary linear horizontal fashion, using buried vertical mattress sutures and cutaneous approximation.

The final appearance of the sutured defect yields a small lateral extension at the superior edge of the V to Y closure, giving the appearance of wings on the Y, prompting us to term the closure V-to-flying-Y (Figure, C).

Although the limited portion of the mucosal lip that is closed in this fashion might appear thinner than the remaining lip, it generally yields a cosmetically acceptable result in the properly selected patient. Our experience also has shown an improvement in this difference in the months following repair. A full mucosal advancement flap might result in a more uniform appearance of the lower lip, but it is a larger and more difficult procedure for the patient to endure. Additionally, a full mucosal advancement flap risks uniformly creating a much thinner lip.

Postoperative Course
Sutures were removed 1 week postoperatively. Proper location of the vermilion border, without distortion of the free margin, was demonstrated. At 11-month follow-up, excellent cosmetic and functional results were noted (Figure, D).

Practice Implications

This repair (1) demonstrates an elegant method of closing a relatively shallow defect that crosses the vermilion border and (2) allows the surgeon to address each cosmetic subunit individually. We have found that this repair provides excellent cosmetic and functional results, with little morbidity.

The lip is a common site of nonmelanoma squamous cell carcinoma. Poorly planned closing after excision of the tumor risks notable impairment of function or cosmetic distortion. When a defect of the lip crosses cosmetic subunits, it is helpful to repair each subunit individually. V-to-flying-Y closure is an effective method to close defects that cross the vermilion border, resulting in well-preserved cosmetic appearance and function.

Intentional tanning—through sun exposure and tanning beds—is an easily avoidable contributor to skin cancer development and an important area for public education. Since the advent of social media, a correlation between social media use and increased indoor tanning behaviors has been reported.¹ In 2010, 11.3% of US adults aged 18 to 29 years reported using a tanning bed in the last 12 months.² The American Academy of Dermatology first published their “Position Statement on Indoor Tanning” in 1998, endorsing a ban on the sale of indoor tanning equipment for nonmedical purposes.³

Although there has been no outright ban on indoor tanning, regulations have been put in place in many states—including Texas, where (as of 2013) a person younger than 18 years must have written consent from their parent(s) to use a tanning bed. Despite efforts of organizations including the American Academy of Dermatology and the government to educate the public on skin cancer prevention and sun safety, the skin cancer rate has been steadily increasing over the last 20 years.

There is a constant campaign among dermatologists to educate their patients on how to reduce or avoid the risk for skin cancer, including the use of sunscreen and avoidance of tanning. Adolescents and young adults are an especially important demographic to reach and educate because increased UV light exposure during these years leads to a greatly increased risk for skin cancer later in life.⁴ Data on the overall prevalence of tanning and the demographics of participation in tanning activities are important to capture and can be used to efficiently target higher-risk populations.

In this study, we aimed to investigate the attitudes and behaviors of adolescents and young adults regarding sun protection and tanning. We also aimed to determine which avenues, including social media, would be most effective at educating about skin cancer awareness and sun protection to the higher-risk younger population.

Materials and Methods

We developed an institutional review board–approved protocol for the prospective collection of data from registered patients at the dermatology clinic of the Mays Cancer Center at the University of Texas Health at San Antonio. A paper survey containing 15 rating-scale questions was administered to 60 patients aged 13 to 27 years. Surveys were administered during intake, prior to the patients’ visit with a dermatologist; all visits were of a functional (not cosmetic) nature. Data collection spanned June to August 2018. Survey results were entered into Research Electronic Data Capture (REDCap) software for qualitative analysis.

Results

Sixty patients responded to the survey. The mean age of respondents was 19.5 years. No surveys were excluded from the data set. Table 1 provides baseline characteristics of respondents. Some respondents left questions unanswered, resulting in questions with fewer than 60 responses.

Among respondents to the survey, 70% (42/60) reported it is very important to protect their skin from sun exposure, and 30% (18/60) reported it is somewhat important. Regarding sunscreen use, 70% (42/60) indicated they use sunscreen only before outdoor activities, 12% (7/60) use sunscreen daily, and 17% (10/60) never use sunscreen. Of those who use sunscreen, 52% (28/54) do so to prevent skin damage and aging and 44% (24/54) to prevent skin cancer. Twenty-three percent (13/56) of respondents reported finding tanned skin attractive; 26% (14/55) reported wanting to be tan. Looking at race, 28% (10/36) of Whites, 25% (5/20) of Spanish/Hispanic/Latinos, and 22% (2/9) of Asians found tanned skin attractive; no Black respondents found tanned skin attractive.

Regarding tanning, 12% (7/57) reported using a tanning bed in their lifetime and 4% (2/57) in the last year; 34% (19/56) reported deliberately tanning outdoors; and 9% (5/56) reported using sunless or spray-on tanning. Dermatologists (75% [42/56]), primary care physicians (69.6% [39/56]), and parents (46.4% [26/56]) were perceived as more effective sources of skin care education; among media modalities, television (33.9% [19/56]), Instagram (30.4% [17/60]), and YouTube (23.2% [13/60]) were perceived as more effective sources of skin care education (Table 2).

Comment

Perceptions of Tanning
Almost one-quarter of respondents found tanned skin attractive, which might reflect a shift from prior generations. Compared to the 11% of respondents in the 2010 survey,² only 3.5% (2/57) of our respondents reported using a tanning bed in the last year, which could reflect the results of recent Texas legislation restricting the use of tanning beds by adolescents.

An alarming number of respondents reported going outdoors with the intention of tanning; although it appears that indoor tanning education has been successful, this finding shows that there is still a need for sun protection education because outdoor tanning is not a suitable alternative. A small number of respondents reported getting a sunless or spray-on tan, which is a risk-free alternative to indoor tanning.

Despite all respondents stating that protecting skin from the sun is important, most respondents surveyed do not use sunscreen daily. More respondents use sunscreen to prevent damage and aging than to prevent skin cancer. Young people might be more alarmed by the threat of early aging and losing their “youthful appearance” than by the possibility of developing skin cancer in the distant future. This discrepancy might indicate a lack of knowledge and be an important focus for future education efforts.

Perceptions of Trustworthiness of Education Sources
Our findings show dermatologists and primary care physicians are important educators on skin protection. Primary care physicians should remain vigilant to recognize at-risk patients who would benefit from skin protection education, especially those who do not see a dermatologist. Education of young people focusing on their concern over maintaining a youthful appearance instead of the possibility of developing skin cancer in the future might be more effective.

Although education provided by a physician is effective, using media—particularly social media—might be more efficient. Television, Instagram, and YouTube were listed by respondents as the 3 most preferred media outlets for skin health education, which shows important areas of focus for future advertising. Facebook was listed at a surprisingly low level, possibly showing the change in use of certain social media websites among this age group. According to the Pew Research Center, the most widely used social media apps among young adults aged 18 to 29 years are YouTube (91%), Facebook (63%), Instagram (67%), and Snapchat (62%). More than half of the same demographic visit Facebook (74%), Instagram (63%), Snapchat (61%), and YouTube (51%) daily.⁵ Although respondents to our survey were not specifically asked about the frequency of their use of social media and our data set includes patients younger than 18 years, we know that social media use has been increasing over the last decade among adolescents.¹ Therefore, we assume that more than one-half of respondents to our survey use their reported social media platforms daily.

Social media is an underused medium for skin cancer prevention education and can reach those who do not regularly see a dermatologist. Unlike printed pamphlets and posters, advertisements through social media can use metrics such as age, race, gender, and interests to target high-risk individuals.

Study Limitations
This was a single-site study of currently enrolled dermatology patients who might be more aware of skin protection than the general population because they are being treated by a dermatologist. Survey questions regarding demographics, required by our institution, could not effectively differentiate Hispanic and White patients. Respondents could have been subject to the Hawthorne effect—awareness that their behavior is being observed—when responding to the survey because it was administered in the office prior to being seen by a dermatologist.

Intentional tanning—through sun exposure and tanning beds—is an easily avoidable contributor to skin cancer development and an important area for public education. Since the advent of social media, a correlation between social media use and increased indoor tanning behaviors has been reported.¹ In 2010, 11.3% of US adults aged 18 to 29 years reported using a tanning bed in the last 12 months.² The American Academy of Dermatology first published their “Position Statement on Indoor Tanning” in 1998, endorsing a ban on the sale of indoor tanning equipment for nonmedical purposes.³

Although there has been no outright ban on indoor tanning, regulations have been put in place in many states—including Texas, where (as of 2013) a person younger than 18 years must have written consent from their parent(s) to use a tanning bed. Despite efforts of organizations including the American Academy of Dermatology and the government to educate the public on skin cancer prevention and sun safety, the skin cancer rate has been steadily increasing over the last 20 years.

There is a constant campaign among dermatologists to educate their patients on how to reduce or avoid the risk for skin cancer, including the use of sunscreen and avoidance of tanning. Adolescents and young adults are an especially important demographic to reach and educate because increased UV light exposure during these years leads to a greatly increased risk for skin cancer later in life.⁴ Data on the overall prevalence of tanning and the demographics of participation in tanning activities are important to capture and can be used to efficiently target higher-risk populations.

In this study, we aimed to investigate the attitudes and behaviors of adolescents and young adults regarding sun protection and tanning. We also aimed to determine which avenues, including social media, would be most effective at educating about skin cancer awareness and sun protection to the higher-risk younger population.

Materials and Methods

We developed an institutional review board–approved protocol for the prospective collection of data from registered patients at the dermatology clinic of the Mays Cancer Center at the University of Texas Health at San Antonio. A paper survey containing 15 rating-scale questions was administered to 60 patients aged 13 to 27 years. Surveys were administered during intake, prior to the patients’ visit with a dermatologist; all visits were of a functional (not cosmetic) nature. Data collection spanned June to August 2018. Survey results were entered into Research Electronic Data Capture (REDCap) software for qualitative analysis.

Results

Sixty patients responded to the survey. The mean age of respondents was 19.5 years. No surveys were excluded from the data set. Table 1 provides baseline characteristics of respondents. Some respondents left questions unanswered, resulting in questions with fewer than 60 responses.

Among respondents to the survey, 70% (42/60) reported it is very important to protect their skin from sun exposure, and 30% (18/60) reported it is somewhat important. Regarding sunscreen use, 70% (42/60) indicated they use sunscreen only before outdoor activities, 12% (7/60) use sunscreen daily, and 17% (10/60) never use sunscreen. Of those who use sunscreen, 52% (28/54) do so to prevent skin damage and aging and 44% (24/54) to prevent skin cancer. Twenty-three percent (13/56) of respondents reported finding tanned skin attractive; 26% (14/55) reported wanting to be tan. Looking at race, 28% (10/36) of Whites, 25% (5/20) of Spanish/Hispanic/Latinos, and 22% (2/9) of Asians found tanned skin attractive; no Black respondents found tanned skin attractive.

Regarding tanning, 12% (7/57) reported using a tanning bed in their lifetime and 4% (2/57) in the last year; 34% (19/56) reported deliberately tanning outdoors; and 9% (5/56) reported using sunless or spray-on tanning. Dermatologists (75% [42/56]), primary care physicians (69.6% [39/56]), and parents (46.4% [26/56]) were perceived as more effective sources of skin care education; among media modalities, television (33.9% [19/56]), Instagram (30.4% [17/60]), and YouTube (23.2% [13/60]) were perceived as more effective sources of skin care education (Table 2).

Comment

Perceptions of Tanning
Almost one-quarter of respondents found tanned skin attractive, which might reflect a shift from prior generations. Compared to the 11% of respondents in the 2010 survey,² only 3.5% (2/57) of our respondents reported using a tanning bed in the last year, which could reflect the results of recent Texas legislation restricting the use of tanning beds by adolescents.

An alarming number of respondents reported going outdoors with the intention of tanning; although it appears that indoor tanning education has been successful, this finding shows that there is still a need for sun protection education because outdoor tanning is not a suitable alternative. A small number of respondents reported getting a sunless or spray-on tan, which is a risk-free alternative to indoor tanning.

Despite all respondents stating that protecting skin from the sun is important, most respondents surveyed do not use sunscreen daily. More respondents use sunscreen to prevent damage and aging than to prevent skin cancer. Young people might be more alarmed by the threat of early aging and losing their “youthful appearance” than by the possibility of developing skin cancer in the distant future. This discrepancy might indicate a lack of knowledge and be an important focus for future education efforts.

Perceptions of Trustworthiness of Education Sources
Our findings show dermatologists and primary care physicians are important educators on skin protection. Primary care physicians should remain vigilant to recognize at-risk patients who would benefit from skin protection education, especially those who do not see a dermatologist. Education of young people focusing on their concern over maintaining a youthful appearance instead of the possibility of developing skin cancer in the future might be more effective.

Although education provided by a physician is effective, using media—particularly social media—might be more efficient. Television, Instagram, and YouTube were listed by respondents as the 3 most preferred media outlets for skin health education, which shows important areas of focus for future advertising. Facebook was listed at a surprisingly low level, possibly showing the change in use of certain social media websites among this age group. According to the Pew Research Center, the most widely used social media apps among young adults aged 18 to 29 years are YouTube (91%), Facebook (63%), Instagram (67%), and Snapchat (62%). More than half of the same demographic visit Facebook (74%), Instagram (63%), Snapchat (61%), and YouTube (51%) daily.⁵ Although respondents to our survey were not specifically asked about the frequency of their use of social media and our data set includes patients younger than 18 years, we know that social media use has been increasing over the last decade among adolescents.¹ Therefore, we assume that more than one-half of respondents to our survey use their reported social media platforms daily.

Social media is an underused medium for skin cancer prevention education and can reach those who do not regularly see a dermatologist. Unlike printed pamphlets and posters, advertisements through social media can use metrics such as age, race, gender, and interests to target high-risk individuals.

Study Limitations
This was a single-site study of currently enrolled dermatology patients who might be more aware of skin protection than the general population because they are being treated by a dermatologist. Survey questions regarding demographics, required by our institution, could not effectively differentiate Hispanic and White patients. Respondents could have been subject to the Hawthorne effect—awareness that their behavior is being observed—when responding to the survey because it was administered in the office prior to being seen by a dermatologist.

Intentional tanning—through sun exposure and tanning beds—is an easily avoidable contributor to skin cancer development and an important area for public education. Since the advent of social media, a correlation between social media use and increased indoor tanning behaviors has been reported.¹ In 2010, 11.3% of US adults aged 18 to 29 years reported using a tanning bed in the last 12 months.² The American Academy of Dermatology first published their “Position Statement on Indoor Tanning” in 1998, endorsing a ban on the sale of indoor tanning equipment for nonmedical purposes.³

Although there has been no outright ban on indoor tanning, regulations have been put in place in many states—including Texas, where (as of 2013) a person younger than 18 years must have written consent from their parent(s) to use a tanning bed. Despite efforts of organizations including the American Academy of Dermatology and the government to educate the public on skin cancer prevention and sun safety, the skin cancer rate has been steadily increasing over the last 20 years.

There is a constant campaign among dermatologists to educate their patients on how to reduce or avoid the risk for skin cancer, including the use of sunscreen and avoidance of tanning. Adolescents and young adults are an especially important demographic to reach and educate because increased UV light exposure during these years leads to a greatly increased risk for skin cancer later in life.⁴ Data on the overall prevalence of tanning and the demographics of participation in tanning activities are important to capture and can be used to efficiently target higher-risk populations.

In this study, we aimed to investigate the attitudes and behaviors of adolescents and young adults regarding sun protection and tanning. We also aimed to determine which avenues, including social media, would be most effective at educating about skin cancer awareness and sun protection to the higher-risk younger population.

Materials and Methods

We developed an institutional review board–approved protocol for the prospective collection of data from registered patients at the dermatology clinic of the Mays Cancer Center at the University of Texas Health at San Antonio. A paper survey containing 15 rating-scale questions was administered to 60 patients aged 13 to 27 years. Surveys were administered during intake, prior to the patients’ visit with a dermatologist; all visits were of a functional (not cosmetic) nature. Data collection spanned June to August 2018. Survey results were entered into Research Electronic Data Capture (REDCap) software for qualitative analysis.

Results

Sixty patients responded to the survey. The mean age of respondents was 19.5 years. No surveys were excluded from the data set. Table 1 provides baseline characteristics of respondents. Some respondents left questions unanswered, resulting in questions with fewer than 60 responses.

Among respondents to the survey, 70% (42/60) reported it is very important to protect their skin from sun exposure, and 30% (18/60) reported it is somewhat important. Regarding sunscreen use, 70% (42/60) indicated they use sunscreen only before outdoor activities, 12% (7/60) use sunscreen daily, and 17% (10/60) never use sunscreen. Of those who use sunscreen, 52% (28/54) do so to prevent skin damage and aging and 44% (24/54) to prevent skin cancer. Twenty-three percent (13/56) of respondents reported finding tanned skin attractive; 26% (14/55) reported wanting to be tan. Looking at race, 28% (10/36) of Whites, 25% (5/20) of Spanish/Hispanic/Latinos, and 22% (2/9) of Asians found tanned skin attractive; no Black respondents found tanned skin attractive.

Regarding tanning, 12% (7/57) reported using a tanning bed in their lifetime and 4% (2/57) in the last year; 34% (19/56) reported deliberately tanning outdoors; and 9% (5/56) reported using sunless or spray-on tanning. Dermatologists (75% [42/56]), primary care physicians (69.6% [39/56]), and parents (46.4% [26/56]) were perceived as more effective sources of skin care education; among media modalities, television (33.9% [19/56]), Instagram (30.4% [17/60]), and YouTube (23.2% [13/60]) were perceived as more effective sources of skin care education (Table 2).

Comment

Perceptions of Tanning
Almost one-quarter of respondents found tanned skin attractive, which might reflect a shift from prior generations. Compared to the 11% of respondents in the 2010 survey,² only 3.5% (2/57) of our respondents reported using a tanning bed in the last year, which could reflect the results of recent Texas legislation restricting the use of tanning beds by adolescents.

An alarming number of respondents reported going outdoors with the intention of tanning; although it appears that indoor tanning education has been successful, this finding shows that there is still a need for sun protection education because outdoor tanning is not a suitable alternative. A small number of respondents reported getting a sunless or spray-on tan, which is a risk-free alternative to indoor tanning.

Despite all respondents stating that protecting skin from the sun is important, most respondents surveyed do not use sunscreen daily. More respondents use sunscreen to prevent damage and aging than to prevent skin cancer. Young people might be more alarmed by the threat of early aging and losing their “youthful appearance” than by the possibility of developing skin cancer in the distant future. This discrepancy might indicate a lack of knowledge and be an important focus for future education efforts.

Perceptions of Trustworthiness of Education Sources
Our findings show dermatologists and primary care physicians are important educators on skin protection. Primary care physicians should remain vigilant to recognize at-risk patients who would benefit from skin protection education, especially those who do not see a dermatologist. Education of young people focusing on their concern over maintaining a youthful appearance instead of the possibility of developing skin cancer in the future might be more effective.

Although education provided by a physician is effective, using media—particularly social media—might be more efficient. Television, Instagram, and YouTube were listed by respondents as the 3 most preferred media outlets for skin health education, which shows important areas of focus for future advertising. Facebook was listed at a surprisingly low level, possibly showing the change in use of certain social media websites among this age group. According to the Pew Research Center, the most widely used social media apps among young adults aged 18 to 29 years are YouTube (91%), Facebook (63%), Instagram (67%), and Snapchat (62%). More than half of the same demographic visit Facebook (74%), Instagram (63%), Snapchat (61%), and YouTube (51%) daily.⁵ Although respondents to our survey were not specifically asked about the frequency of their use of social media and our data set includes patients younger than 18 years, we know that social media use has been increasing over the last decade among adolescents.¹ Therefore, we assume that more than one-half of respondents to our survey use their reported social media platforms daily.

Social media is an underused medium for skin cancer prevention education and can reach those who do not regularly see a dermatologist. Unlike printed pamphlets and posters, advertisements through social media can use metrics such as age, race, gender, and interests to target high-risk individuals.

Study Limitations
This was a single-site study of currently enrolled dermatology patients who might be more aware of skin protection than the general population because they are being treated by a dermatologist. Survey questions regarding demographics, required by our institution, could not effectively differentiate Hispanic and White patients. Respondents could have been subject to the Hawthorne effect—awareness that their behavior is being observed—when responding to the survey because it was administered in the office prior to being seen by a dermatologist.