MDedge Dermatology

The lip is commonly affected by skin cancer because of increased sun exposure and actinic damage, with basal cell carcinoma typically occurring on the upper lip and squamous cell carcinoma (SCC) on the lower lip. The risk for metastatic spread of SCC on the lip is higher than cutaneous SCC on other facial locations but lower than SCC of the oral mucosa.^1,2 If the tumor is operable and the patient has no contraindications to surgery, Mohs micrographic surgery is the preferred treatment, as it allows for maximal healthy tissue preservation and has the lowest recurrence rates.^1-3 Once the tumor is removed and margins are confirmed to be negative, one must consider the options for defect closure, including healing by secondary intention, primary/direct closure, full-thickness skin grafts, local flaps, or free flaps.⁴ Secondary intention may lead to wound contracture and suboptimal functional and cosmetic outcomes. Primary wedge closure can be utilized for optimal functional and cosmetic outcomes when the defect involves less than one-third of the horizontal width of the vermilion. For larger defects, the surgeon must consider a flap or graft. Skin grafts are less favorable than local flaps because they may have different skin color, texture, and hair-bearing properties than the recipient area.^3,5 In addition, grafts require a separate donor site, which means more pain, recovery time, and risk for complications for the patient.³ Free flaps similarly utilize tissue and blood supply from a donor site to repair major tissue loss. Radial forearm free flaps commonly are used for large lip defects but are more extensive, risky, and costly compared to local flaps for smaller defects under local anesthesia or nerve blocks.^6,7 With these considerations, a local lip flap often is the most ideal repair method.

When performing a local lip flap, it is important to consider the functional and aesthetic aspects of the lips. The lower face is more susceptible to distortion and wound contraction after defect repair because it lacks a substantial supportive fibrous network. The dynamics of opposing lip elevator and depressor muscles make the lips a visual focal point and a crucial structure for facial expression, mastication, oral continence, speech phonation, and mouth opening and closing.^2,4,8,9 Aesthetics and symmetry of the lips also are a large part of facial recognition and self-image.⁹

Lip defects are classified as partial thickness involving skin and muscle or full thickness involving skin, muscle, and mucosa. Partial-thickness wounds less than one-third the width of the horizontal lip can be repaired with a primary wedge resection or left to heal by secondary intention if the defect only involves the superficial vermilion.² For defects larger than one-third the width of the horizontal lip, local flaps are favored to allow for closely matched skin and lip mucosa to fill in the defect.⁹ Full-thickness defects are further classified based on defect width compared to total lip width (ie, less than one-third, between one-third and two-thirds, and greater than two-thirds) as well as location (ie, medial, lateral, upper lip, lower lip).^2,10

There are several local lip flap reconstruction options available, and choosing one is based on defect size and location. We provide a succinct review of the indications, risks, and benefits of commonly utilized flaps (Table), as well as artist renderings of all of the flaps (Figure).

Courtesy of Brinda Chellappan, MD (Galveston, Texas).

Vermilion Flaps

Vermilion flaps are used to close partial-thickness defects of the vermilion border, an area that poses unique obstacles of repair with blending distant tissues to match the surroundings.⁸ Goldstein¹¹ developed an adjacent ipsilateral vermilion flap utilizing an arterialized myocutaneous flap for reconstruction of vermilion defects.Later, this technique was modified by Sawada et al¹² into a bilateral adjacent advancement flap for closure of central vermilion defects and may be preferred for defects 2 cm in size or larger. Bilateral flaps are smaller and therefore more viable than unilateral or larger flaps, allowing for a more aesthetic alignment of the vermilion border and preservation of muscle activity because muscle fibers are not cut. This technique also allows for more efficient stretching or medial advancement of the tissue while generating less tension on the distal flap portions. Burow triangles can be utilized if necessary for improved aesthetic outcome.¹

Mucosal Advancement and Split Myomucosal Advancement Flap

The mucosal advancement technique can be considered for tumors that do not involve the adjacent cutaneous skin or the orbicularis oris muscle; thus, the reconstruction involves only the superficial vermilion area.^7,13 Mucosal incisions are made at the gingivobuccal sulcus, and the mucosal flap is elevated off the orbicularis oris muscle and advanced into the defect.¹⁰ A plane of dissection is maintained while preserving the labial artery. Undermining effectively advances wet mucosa into the dry mucosal lip to create a neovermilion. However, the reconstructed lip often appears thinner and will possibly be a different shade compared to the adjacent native lip. These discrepancies become more evident with deeper defects.⁷

There is a risk for cosmetic distortion and scar contraction with advancing the entire mucosa. Eirís et al¹³ described a solution—a bilateral mucosal rotation flap in which the primary incision is made along the entire vermilion border and tissue is undermined to allow advancement of the mucosa. Because the wound closure tension lays across the entire lip, there is less risk for scar contraction, even if the flap movement is unequal on either side of the defect.¹³

Although mucosal advancement flaps are a classic choice for reconstruction following a vermilion defect, other techniques, such as primary closure, should be considered in elderly patients and patients taking anticoagulants because of the risks for flap necrosis, swelling, bruising, hematoma, and dysesthesia, as well as a decrease in the anterior-posterior dimension of the lip. These risks can be attributed to trauma of surrounding tissue and stress secondary to longer overall operating times.¹⁴

Split myomucosal advancement flaps are used in similar scenarios as myomucosal advancement flaps but for larger red lip defects that are less than 50% the length of the upper or lower lip. Split myomucosal advancement flaps utilize an axial flap based on the labial artery, which provides robust vascular supply to the reconstructed area. This vascularity, along with lateral motor innervation of the orbicularis oris, allows for split myomucosal advancement flaps to restore the resected volume, preserve lip function, and minimize postoperative microstomia.⁷

V-Y Advancement Flaps

V-Y advancement flaps are based on a subcutaneous tissue pedicle and are optimal for partial- and full-thickness defects larger than 1 cm on the lateral upper lips, whereas bilateral V-Y advancement flaps are recommended for central lip defects.^15-17 Advantages of V-Y advancement flaps are preserved facial symmetry and maintenance of the oral sphincter and facial nerve function. The undermining portions allow for advancement of a skin flap of similar thickness and contour into the upper or lower lip.¹⁵ Disadvantages include facial asymmetry with larger defects involving the melolabial fold as well as paresthesia after closure. However, in one study, no paresthesia was reported more than 12 months postprocedure.⁴ The biggest disadvantage of the V-Y advancement flap is the kite-shaped scar and possible trapdoor deformity.^5,15 When working medially, the addition of the pincer modification helps avoid blunting of the philtrum and recreates a Cupid’s bow by curling the lateral flap edges medially to resemble a teardrop shape.¹⁷ V-Y advancement flaps for defects of skin and adipose tissue less than 5 mm in size have the highest need for revision surgery; thus, defects of this small size should be repaired primarily.⁴

When using a V-Y advancement flap to correct large defects, there are 3 common complications that may arise: fullness medial to the commissure, a depressed vermilion lip, and a standing cutaneous deformity along the trailing edge of the flap where the Y is formed upon closure of the donor site. To decrease the fullness, a skin excision from the inferior border of the flap along the vermiliocutaneous border can be made to debulk the area. A vermilion advancement can be used to optimize the vermiliocutaneous junction. Potential standing cutaneous deformity is addressed by excising a small ellipse of skin oriented along the axis of the relaxed skin tension lines.¹⁵

Abbé-Estlander Flap

The Abbé-Estlander flap (also known as a transoral cross-lip flap) is a full-thickness myocutaneous interpolation flap with blood supply from the labial artery. It is used for lower lip tumors that have deep invasion into muscle and are 30% to 60% of the horizontal lip.^8,9 Abbé transposition flaps are used for defects medial to the oral commissure and are best suited for philtrum reconstruction, whereas Estlander flaps are for defects that involve the oral commissure.^9,18 Interpolation flaps usually are performed in 2 stages, but some dermatologic surgeons have reported success with single-stage procedures.¹ The second-stage division usually is performed 2 to 3 weeks after flap insetting to allow time for neovascularization, which is crucial for pedicle survival.^8,9,19

Advantages of this type of flap are the preservation of orbicularis oris strength and a functional and aesthetic result with minimal change in appearance for defects sized from one-third to two-thirds the width of the lip.²⁰ This aesthetic effect is particularly notable when the donor flap is taken from the mediolateral upper lip, allowing the scarred area to blend into the nasolabial fold.⁸ Disadvantages of this flap are a risk for microstomia, lip vermilion misalignment, and lip adhesion.²¹ It is important that patients are educated on the need for multiple surgeries when using this type of flap, as patients favor single-step procedures.¹ The Abbé flap requires 2 surgeries, whereas the Estlander flap requires only 1. However, patients commonly require commissuroplasty with the Estlander flap alone.²¹

Gillies Fan Flap, Karapandzic Flap, Bernard-Webster Flap, and Bernard-Burrow-Webster Flap

The Gillies fan flap, Karapandzic flap, Bernard-Webster (BW) flap, and modified Bernard-Burrow-Webster flap are the likely choices for repair of lip defects that encompass more than two-thirds of the lip.^9,10,22 The Karapandzic and BW flaps are the 2 most frequently used for reconstruction of larger lower lip defects and only require 1 surgery.

Upper lip full-thickness defects that are too big for an Abbé-Estlander flap are closed with the Gillies fan flap.¹⁸ These defects involve 70% to 80% of the horizontal lip.⁹ The Gillies fan flap design redistributes the remaining lip to provide similar tissue quality and texture to fill the large defects.^9,23 Compared to Karapandzic and Bernard flaps, Gillies fan incision closures are hidden well in the nasolabial folds, and the degree of microstomy is decreased because of the rotation of the flaps. However, rotation of medial cheek flaps can distort the orbicular muscular fibers and the anatomy of the commissure, which may require repair with commissurotomy. Drawbacks include a risk for denervation that can result in temporary oral sphincter incompetence.²³ The bilateral Gillies fan flap carries a risk for microstomy as well as misalignment of the lip vermilion and round commissures.²¹

The Karapandzic flap is similar to the Gillies fan flap but only involves the skin and mucosa.⁹ This flap can be used for lateral or medial upper lip defects greater than one-third the width of the entire lip. This single-procedure flap allows for labial continuity, preserved sensation, and motor function; however, microstomia and misalignment of the oral commissure are common.^1,18,21 In a retrospective study by Nicholas et al,⁴ the only flap reported to have a poor functional outcome was the Karapandzic flap, with 3 patients reporting altered sensation and 1 patient reporting persistent stiffness while smiling.

The BW flap can be applied for extensive full-thickness defects greater than one-third the lower lip and for defects with limited residual lip. This flap also can be used in cases where only skin is excised, as the flap does not depend on reminiscent lip tissue for reconstruction of the new lower lip. Sensory function is maintained given adequate visualization and preservation of the local vascular, nervous, and muscular systems. Disadvantages of the BW flap include an incision notch in the region of the lower lip; blunting of the alveolobuccal sulcus; and functional deficits, such as lip incontinence to liquids during the postoperative period.²¹

The Bernard-Burrow-Webster flap is used for large lower lip defects and preserves the oral commissures by advancing adjacent cheek tissue and remaining lip tissue medially.¹⁰ It allows for larger site mobilization, but it is possible to see some resulting oral incontinence.^1,10 The Burow wedge flap is a variant of the advancement flap, with the Burow triangle located lateral to the oral commissure. Caution must be taken to avoid intraoperative bleeding from the labial and angular arteries. In addition, there also may be downward displacement of the vermilion border.⁵

How to Choose a Flap

The orbicularis oris is a circular muscle that surrounds both the upper and lower lips. It is pulled into an oval, allowing for sphincter function by radially oriented muscles, all of which are innervated by the facial nerve. Other key anatomical structures of the lips include the tubercle (vermilion prominence), Cupid’s bow and philtrum, nasolabial folds, white roll, hair-bearing area, and vermilion border. The lips are divided into cutaneous, mucosal, and vermilion parts, with the vermilion area divided into dry/external and wet/internal areas. Sensation to the upper lip is provided by the maxillary division of the trigeminal nerve via the infraorbital nerve. The lower lip is innervated by the mandibular division of the trigeminal nerve via the inferior alveolar nerve. The labial artery, a branch of the facial artery, is responsible for blood supply to the lips.^3,9 Because of the complex anatomy of the lips, careful reconstruction is crucial for functional and aesthetic preservation.

There are a variety of lip defect repairs, but all local flaps aim to preserve aesthetics and function. The Table summarizes the key risks and benefits of each flap. Local flap techniques can be used in combination for more complex defects.³ For example, Nadiminti et al¹⁹ described the combination of the Abbé flap and V-Y advancement flap to restore function and create a new symmetric nasolabial fold. Dermatologic surgeons will determine the most suitable technique based on tumor location, tumor stage or depth of invasion (partial or full thickness), and preservation of function and aesthetics.¹

Other factors to consider when choosing a local flap are the patient’s age, tissue laxity, dentition/need for dentures, and any prior treatments.⁷ Scar revision surgery may be needed after reconstruction, especially with longer vertical scars in areas without other rhytides. In addition, paresthesia is common after Mohs micrographic surgery of the face; however, new neural networks are created postoperatively, and most paresthesia resolves within 1 year of the repair.⁴ Dermabrasion and Z-plasty also may be considered, as they have been shown to be successful in improving final outcomes.⁹ Overall, local flaps have risks for infection, flap necrosis, and bleeding, though the incidence is low in reconstructions of the face.

Final Thoughts

There are several mechanisms to repair upper and lower lip defects resulting from surgical removal of cutaneous cancers. This review of specific flaps used in lip reconstruction provides a comprehensive overview of indications, advantages, and disadvantages of available lip flaps.

The lip is commonly affected by skin cancer because of increased sun exposure and actinic damage, with basal cell carcinoma typically occurring on the upper lip and squamous cell carcinoma (SCC) on the lower lip. The risk for metastatic spread of SCC on the lip is higher than cutaneous SCC on other facial locations but lower than SCC of the oral mucosa.^1,2 If the tumor is operable and the patient has no contraindications to surgery, Mohs micrographic surgery is the preferred treatment, as it allows for maximal healthy tissue preservation and has the lowest recurrence rates.^1-3 Once the tumor is removed and margins are confirmed to be negative, one must consider the options for defect closure, including healing by secondary intention, primary/direct closure, full-thickness skin grafts, local flaps, or free flaps.⁴ Secondary intention may lead to wound contracture and suboptimal functional and cosmetic outcomes. Primary wedge closure can be utilized for optimal functional and cosmetic outcomes when the defect involves less than one-third of the horizontal width of the vermilion. For larger defects, the surgeon must consider a flap or graft. Skin grafts are less favorable than local flaps because they may have different skin color, texture, and hair-bearing properties than the recipient area.^3,5 In addition, grafts require a separate donor site, which means more pain, recovery time, and risk for complications for the patient.³ Free flaps similarly utilize tissue and blood supply from a donor site to repair major tissue loss. Radial forearm free flaps commonly are used for large lip defects but are more extensive, risky, and costly compared to local flaps for smaller defects under local anesthesia or nerve blocks.^6,7 With these considerations, a local lip flap often is the most ideal repair method.

When performing a local lip flap, it is important to consider the functional and aesthetic aspects of the lips. The lower face is more susceptible to distortion and wound contraction after defect repair because it lacks a substantial supportive fibrous network. The dynamics of opposing lip elevator and depressor muscles make the lips a visual focal point and a crucial structure for facial expression, mastication, oral continence, speech phonation, and mouth opening and closing.^2,4,8,9 Aesthetics and symmetry of the lips also are a large part of facial recognition and self-image.⁹

Lip defects are classified as partial thickness involving skin and muscle or full thickness involving skin, muscle, and mucosa. Partial-thickness wounds less than one-third the width of the horizontal lip can be repaired with a primary wedge resection or left to heal by secondary intention if the defect only involves the superficial vermilion.² For defects larger than one-third the width of the horizontal lip, local flaps are favored to allow for closely matched skin and lip mucosa to fill in the defect.⁹ Full-thickness defects are further classified based on defect width compared to total lip width (ie, less than one-third, between one-third and two-thirds, and greater than two-thirds) as well as location (ie, medial, lateral, upper lip, lower lip).^2,10

There are several local lip flap reconstruction options available, and choosing one is based on defect size and location. We provide a succinct review of the indications, risks, and benefits of commonly utilized flaps (Table), as well as artist renderings of all of the flaps (Figure).

Courtesy of Brinda Chellappan, MD (Galveston, Texas).

Vermilion Flaps

Vermilion flaps are used to close partial-thickness defects of the vermilion border, an area that poses unique obstacles of repair with blending distant tissues to match the surroundings.⁸ Goldstein¹¹ developed an adjacent ipsilateral vermilion flap utilizing an arterialized myocutaneous flap for reconstruction of vermilion defects.Later, this technique was modified by Sawada et al¹² into a bilateral adjacent advancement flap for closure of central vermilion defects and may be preferred for defects 2 cm in size or larger. Bilateral flaps are smaller and therefore more viable than unilateral or larger flaps, allowing for a more aesthetic alignment of the vermilion border and preservation of muscle activity because muscle fibers are not cut. This technique also allows for more efficient stretching or medial advancement of the tissue while generating less tension on the distal flap portions. Burow triangles can be utilized if necessary for improved aesthetic outcome.¹

Mucosal Advancement and Split Myomucosal Advancement Flap

The mucosal advancement technique can be considered for tumors that do not involve the adjacent cutaneous skin or the orbicularis oris muscle; thus, the reconstruction involves only the superficial vermilion area.^7,13 Mucosal incisions are made at the gingivobuccal sulcus, and the mucosal flap is elevated off the orbicularis oris muscle and advanced into the defect.¹⁰ A plane of dissection is maintained while preserving the labial artery. Undermining effectively advances wet mucosa into the dry mucosal lip to create a neovermilion. However, the reconstructed lip often appears thinner and will possibly be a different shade compared to the adjacent native lip. These discrepancies become more evident with deeper defects.⁷

There is a risk for cosmetic distortion and scar contraction with advancing the entire mucosa. Eirís et al¹³ described a solution—a bilateral mucosal rotation flap in which the primary incision is made along the entire vermilion border and tissue is undermined to allow advancement of the mucosa. Because the wound closure tension lays across the entire lip, there is less risk for scar contraction, even if the flap movement is unequal on either side of the defect.¹³

Although mucosal advancement flaps are a classic choice for reconstruction following a vermilion defect, other techniques, such as primary closure, should be considered in elderly patients and patients taking anticoagulants because of the risks for flap necrosis, swelling, bruising, hematoma, and dysesthesia, as well as a decrease in the anterior-posterior dimension of the lip. These risks can be attributed to trauma of surrounding tissue and stress secondary to longer overall operating times.¹⁴

Split myomucosal advancement flaps are used in similar scenarios as myomucosal advancement flaps but for larger red lip defects that are less than 50% the length of the upper or lower lip. Split myomucosal advancement flaps utilize an axial flap based on the labial artery, which provides robust vascular supply to the reconstructed area. This vascularity, along with lateral motor innervation of the orbicularis oris, allows for split myomucosal advancement flaps to restore the resected volume, preserve lip function, and minimize postoperative microstomia.⁷

V-Y Advancement Flaps

V-Y advancement flaps are based on a subcutaneous tissue pedicle and are optimal for partial- and full-thickness defects larger than 1 cm on the lateral upper lips, whereas bilateral V-Y advancement flaps are recommended for central lip defects.^15-17 Advantages of V-Y advancement flaps are preserved facial symmetry and maintenance of the oral sphincter and facial nerve function. The undermining portions allow for advancement of a skin flap of similar thickness and contour into the upper or lower lip.¹⁵ Disadvantages include facial asymmetry with larger defects involving the melolabial fold as well as paresthesia after closure. However, in one study, no paresthesia was reported more than 12 months postprocedure.⁴ The biggest disadvantage of the V-Y advancement flap is the kite-shaped scar and possible trapdoor deformity.^5,15 When working medially, the addition of the pincer modification helps avoid blunting of the philtrum and recreates a Cupid’s bow by curling the lateral flap edges medially to resemble a teardrop shape.¹⁷ V-Y advancement flaps for defects of skin and adipose tissue less than 5 mm in size have the highest need for revision surgery; thus, defects of this small size should be repaired primarily.⁴

When using a V-Y advancement flap to correct large defects, there are 3 common complications that may arise: fullness medial to the commissure, a depressed vermilion lip, and a standing cutaneous deformity along the trailing edge of the flap where the Y is formed upon closure of the donor site. To decrease the fullness, a skin excision from the inferior border of the flap along the vermiliocutaneous border can be made to debulk the area. A vermilion advancement can be used to optimize the vermiliocutaneous junction. Potential standing cutaneous deformity is addressed by excising a small ellipse of skin oriented along the axis of the relaxed skin tension lines.¹⁵

Abbé-Estlander Flap

The Abbé-Estlander flap (also known as a transoral cross-lip flap) is a full-thickness myocutaneous interpolation flap with blood supply from the labial artery. It is used for lower lip tumors that have deep invasion into muscle and are 30% to 60% of the horizontal lip.^8,9 Abbé transposition flaps are used for defects medial to the oral commissure and are best suited for philtrum reconstruction, whereas Estlander flaps are for defects that involve the oral commissure.^9,18 Interpolation flaps usually are performed in 2 stages, but some dermatologic surgeons have reported success with single-stage procedures.¹ The second-stage division usually is performed 2 to 3 weeks after flap insetting to allow time for neovascularization, which is crucial for pedicle survival.^8,9,19

Advantages of this type of flap are the preservation of orbicularis oris strength and a functional and aesthetic result with minimal change in appearance for defects sized from one-third to two-thirds the width of the lip.²⁰ This aesthetic effect is particularly notable when the donor flap is taken from the mediolateral upper lip, allowing the scarred area to blend into the nasolabial fold.⁸ Disadvantages of this flap are a risk for microstomia, lip vermilion misalignment, and lip adhesion.²¹ It is important that patients are educated on the need for multiple surgeries when using this type of flap, as patients favor single-step procedures.¹ The Abbé flap requires 2 surgeries, whereas the Estlander flap requires only 1. However, patients commonly require commissuroplasty with the Estlander flap alone.²¹

Gillies Fan Flap, Karapandzic Flap, Bernard-Webster Flap, and Bernard-Burrow-Webster Flap

The Gillies fan flap, Karapandzic flap, Bernard-Webster (BW) flap, and modified Bernard-Burrow-Webster flap are the likely choices for repair of lip defects that encompass more than two-thirds of the lip.^9,10,22 The Karapandzic and BW flaps are the 2 most frequently used for reconstruction of larger lower lip defects and only require 1 surgery.

Upper lip full-thickness defects that are too big for an Abbé-Estlander flap are closed with the Gillies fan flap.¹⁸ These defects involve 70% to 80% of the horizontal lip.⁹ The Gillies fan flap design redistributes the remaining lip to provide similar tissue quality and texture to fill the large defects.^9,23 Compared to Karapandzic and Bernard flaps, Gillies fan incision closures are hidden well in the nasolabial folds, and the degree of microstomy is decreased because of the rotation of the flaps. However, rotation of medial cheek flaps can distort the orbicular muscular fibers and the anatomy of the commissure, which may require repair with commissurotomy. Drawbacks include a risk for denervation that can result in temporary oral sphincter incompetence.²³ The bilateral Gillies fan flap carries a risk for microstomy as well as misalignment of the lip vermilion and round commissures.²¹

The Karapandzic flap is similar to the Gillies fan flap but only involves the skin and mucosa.⁹ This flap can be used for lateral or medial upper lip defects greater than one-third the width of the entire lip. This single-procedure flap allows for labial continuity, preserved sensation, and motor function; however, microstomia and misalignment of the oral commissure are common.^1,18,21 In a retrospective study by Nicholas et al,⁴ the only flap reported to have a poor functional outcome was the Karapandzic flap, with 3 patients reporting altered sensation and 1 patient reporting persistent stiffness while smiling.

The BW flap can be applied for extensive full-thickness defects greater than one-third the lower lip and for defects with limited residual lip. This flap also can be used in cases where only skin is excised, as the flap does not depend on reminiscent lip tissue for reconstruction of the new lower lip. Sensory function is maintained given adequate visualization and preservation of the local vascular, nervous, and muscular systems. Disadvantages of the BW flap include an incision notch in the region of the lower lip; blunting of the alveolobuccal sulcus; and functional deficits, such as lip incontinence to liquids during the postoperative period.²¹

The Bernard-Burrow-Webster flap is used for large lower lip defects and preserves the oral commissures by advancing adjacent cheek tissue and remaining lip tissue medially.¹⁰ It allows for larger site mobilization, but it is possible to see some resulting oral incontinence.^1,10 The Burow wedge flap is a variant of the advancement flap, with the Burow triangle located lateral to the oral commissure. Caution must be taken to avoid intraoperative bleeding from the labial and angular arteries. In addition, there also may be downward displacement of the vermilion border.⁵

How to Choose a Flap

The orbicularis oris is a circular muscle that surrounds both the upper and lower lips. It is pulled into an oval, allowing for sphincter function by radially oriented muscles, all of which are innervated by the facial nerve. Other key anatomical structures of the lips include the tubercle (vermilion prominence), Cupid’s bow and philtrum, nasolabial folds, white roll, hair-bearing area, and vermilion border. The lips are divided into cutaneous, mucosal, and vermilion parts, with the vermilion area divided into dry/external and wet/internal areas. Sensation to the upper lip is provided by the maxillary division of the trigeminal nerve via the infraorbital nerve. The lower lip is innervated by the mandibular division of the trigeminal nerve via the inferior alveolar nerve. The labial artery, a branch of the facial artery, is responsible for blood supply to the lips.^3,9 Because of the complex anatomy of the lips, careful reconstruction is crucial for functional and aesthetic preservation.

There are a variety of lip defect repairs, but all local flaps aim to preserve aesthetics and function. The Table summarizes the key risks and benefits of each flap. Local flap techniques can be used in combination for more complex defects.³ For example, Nadiminti et al¹⁹ described the combination of the Abbé flap and V-Y advancement flap to restore function and create a new symmetric nasolabial fold. Dermatologic surgeons will determine the most suitable technique based on tumor location, tumor stage or depth of invasion (partial or full thickness), and preservation of function and aesthetics.¹

Other factors to consider when choosing a local flap are the patient’s age, tissue laxity, dentition/need for dentures, and any prior treatments.⁷ Scar revision surgery may be needed after reconstruction, especially with longer vertical scars in areas without other rhytides. In addition, paresthesia is common after Mohs micrographic surgery of the face; however, new neural networks are created postoperatively, and most paresthesia resolves within 1 year of the repair.⁴ Dermabrasion and Z-plasty also may be considered, as they have been shown to be successful in improving final outcomes.⁹ Overall, local flaps have risks for infection, flap necrosis, and bleeding, though the incidence is low in reconstructions of the face.

Final Thoughts

There are several mechanisms to repair upper and lower lip defects resulting from surgical removal of cutaneous cancers. This review of specific flaps used in lip reconstruction provides a comprehensive overview of indications, advantages, and disadvantages of available lip flaps.

The lip is commonly affected by skin cancer because of increased sun exposure and actinic damage, with basal cell carcinoma typically occurring on the upper lip and squamous cell carcinoma (SCC) on the lower lip. The risk for metastatic spread of SCC on the lip is higher than cutaneous SCC on other facial locations but lower than SCC of the oral mucosa.^1,2 If the tumor is operable and the patient has no contraindications to surgery, Mohs micrographic surgery is the preferred treatment, as it allows for maximal healthy tissue preservation and has the lowest recurrence rates.^1-3 Once the tumor is removed and margins are confirmed to be negative, one must consider the options for defect closure, including healing by secondary intention, primary/direct closure, full-thickness skin grafts, local flaps, or free flaps.⁴ Secondary intention may lead to wound contracture and suboptimal functional and cosmetic outcomes. Primary wedge closure can be utilized for optimal functional and cosmetic outcomes when the defect involves less than one-third of the horizontal width of the vermilion. For larger defects, the surgeon must consider a flap or graft. Skin grafts are less favorable than local flaps because they may have different skin color, texture, and hair-bearing properties than the recipient area.^3,5 In addition, grafts require a separate donor site, which means more pain, recovery time, and risk for complications for the patient.³ Free flaps similarly utilize tissue and blood supply from a donor site to repair major tissue loss. Radial forearm free flaps commonly are used for large lip defects but are more extensive, risky, and costly compared to local flaps for smaller defects under local anesthesia or nerve blocks.^6,7 With these considerations, a local lip flap often is the most ideal repair method.

When performing a local lip flap, it is important to consider the functional and aesthetic aspects of the lips. The lower face is more susceptible to distortion and wound contraction after defect repair because it lacks a substantial supportive fibrous network. The dynamics of opposing lip elevator and depressor muscles make the lips a visual focal point and a crucial structure for facial expression, mastication, oral continence, speech phonation, and mouth opening and closing.^2,4,8,9 Aesthetics and symmetry of the lips also are a large part of facial recognition and self-image.⁹

Lip defects are classified as partial thickness involving skin and muscle or full thickness involving skin, muscle, and mucosa. Partial-thickness wounds less than one-third the width of the horizontal lip can be repaired with a primary wedge resection or left to heal by secondary intention if the defect only involves the superficial vermilion.² For defects larger than one-third the width of the horizontal lip, local flaps are favored to allow for closely matched skin and lip mucosa to fill in the defect.⁹ Full-thickness defects are further classified based on defect width compared to total lip width (ie, less than one-third, between one-third and two-thirds, and greater than two-thirds) as well as location (ie, medial, lateral, upper lip, lower lip).^2,10

There are several local lip flap reconstruction options available, and choosing one is based on defect size and location. We provide a succinct review of the indications, risks, and benefits of commonly utilized flaps (Table), as well as artist renderings of all of the flaps (Figure).

Courtesy of Brinda Chellappan, MD (Galveston, Texas).

Vermilion Flaps

Vermilion flaps are used to close partial-thickness defects of the vermilion border, an area that poses unique obstacles of repair with blending distant tissues to match the surroundings.⁸ Goldstein¹¹ developed an adjacent ipsilateral vermilion flap utilizing an arterialized myocutaneous flap for reconstruction of vermilion defects.Later, this technique was modified by Sawada et al¹² into a bilateral adjacent advancement flap for closure of central vermilion defects and may be preferred for defects 2 cm in size or larger. Bilateral flaps are smaller and therefore more viable than unilateral or larger flaps, allowing for a more aesthetic alignment of the vermilion border and preservation of muscle activity because muscle fibers are not cut. This technique also allows for more efficient stretching or medial advancement of the tissue while generating less tension on the distal flap portions. Burow triangles can be utilized if necessary for improved aesthetic outcome.¹

Mucosal Advancement and Split Myomucosal Advancement Flap

The mucosal advancement technique can be considered for tumors that do not involve the adjacent cutaneous skin or the orbicularis oris muscle; thus, the reconstruction involves only the superficial vermilion area.^7,13 Mucosal incisions are made at the gingivobuccal sulcus, and the mucosal flap is elevated off the orbicularis oris muscle and advanced into the defect.¹⁰ A plane of dissection is maintained while preserving the labial artery. Undermining effectively advances wet mucosa into the dry mucosal lip to create a neovermilion. However, the reconstructed lip often appears thinner and will possibly be a different shade compared to the adjacent native lip. These discrepancies become more evident with deeper defects.⁷

There is a risk for cosmetic distortion and scar contraction with advancing the entire mucosa. Eirís et al¹³ described a solution—a bilateral mucosal rotation flap in which the primary incision is made along the entire vermilion border and tissue is undermined to allow advancement of the mucosa. Because the wound closure tension lays across the entire lip, there is less risk for scar contraction, even if the flap movement is unequal on either side of the defect.¹³

Although mucosal advancement flaps are a classic choice for reconstruction following a vermilion defect, other techniques, such as primary closure, should be considered in elderly patients and patients taking anticoagulants because of the risks for flap necrosis, swelling, bruising, hematoma, and dysesthesia, as well as a decrease in the anterior-posterior dimension of the lip. These risks can be attributed to trauma of surrounding tissue and stress secondary to longer overall operating times.¹⁴

Split myomucosal advancement flaps are used in similar scenarios as myomucosal advancement flaps but for larger red lip defects that are less than 50% the length of the upper or lower lip. Split myomucosal advancement flaps utilize an axial flap based on the labial artery, which provides robust vascular supply to the reconstructed area. This vascularity, along with lateral motor innervation of the orbicularis oris, allows for split myomucosal advancement flaps to restore the resected volume, preserve lip function, and minimize postoperative microstomia.⁷

V-Y Advancement Flaps

V-Y advancement flaps are based on a subcutaneous tissue pedicle and are optimal for partial- and full-thickness defects larger than 1 cm on the lateral upper lips, whereas bilateral V-Y advancement flaps are recommended for central lip defects.^15-17 Advantages of V-Y advancement flaps are preserved facial symmetry and maintenance of the oral sphincter and facial nerve function. The undermining portions allow for advancement of a skin flap of similar thickness and contour into the upper or lower lip.¹⁵ Disadvantages include facial asymmetry with larger defects involving the melolabial fold as well as paresthesia after closure. However, in one study, no paresthesia was reported more than 12 months postprocedure.⁴ The biggest disadvantage of the V-Y advancement flap is the kite-shaped scar and possible trapdoor deformity.^5,15 When working medially, the addition of the pincer modification helps avoid blunting of the philtrum and recreates a Cupid’s bow by curling the lateral flap edges medially to resemble a teardrop shape.¹⁷ V-Y advancement flaps for defects of skin and adipose tissue less than 5 mm in size have the highest need for revision surgery; thus, defects of this small size should be repaired primarily.⁴

When using a V-Y advancement flap to correct large defects, there are 3 common complications that may arise: fullness medial to the commissure, a depressed vermilion lip, and a standing cutaneous deformity along the trailing edge of the flap where the Y is formed upon closure of the donor site. To decrease the fullness, a skin excision from the inferior border of the flap along the vermiliocutaneous border can be made to debulk the area. A vermilion advancement can be used to optimize the vermiliocutaneous junction. Potential standing cutaneous deformity is addressed by excising a small ellipse of skin oriented along the axis of the relaxed skin tension lines.¹⁵

Abbé-Estlander Flap

The Abbé-Estlander flap (also known as a transoral cross-lip flap) is a full-thickness myocutaneous interpolation flap with blood supply from the labial artery. It is used for lower lip tumors that have deep invasion into muscle and are 30% to 60% of the horizontal lip.^8,9 Abbé transposition flaps are used for defects medial to the oral commissure and are best suited for philtrum reconstruction, whereas Estlander flaps are for defects that involve the oral commissure.^9,18 Interpolation flaps usually are performed in 2 stages, but some dermatologic surgeons have reported success with single-stage procedures.¹ The second-stage division usually is performed 2 to 3 weeks after flap insetting to allow time for neovascularization, which is crucial for pedicle survival.^8,9,19

Advantages of this type of flap are the preservation of orbicularis oris strength and a functional and aesthetic result with minimal change in appearance for defects sized from one-third to two-thirds the width of the lip.²⁰ This aesthetic effect is particularly notable when the donor flap is taken from the mediolateral upper lip, allowing the scarred area to blend into the nasolabial fold.⁸ Disadvantages of this flap are a risk for microstomia, lip vermilion misalignment, and lip adhesion.²¹ It is important that patients are educated on the need for multiple surgeries when using this type of flap, as patients favor single-step procedures.¹ The Abbé flap requires 2 surgeries, whereas the Estlander flap requires only 1. However, patients commonly require commissuroplasty with the Estlander flap alone.²¹

Gillies Fan Flap, Karapandzic Flap, Bernard-Webster Flap, and Bernard-Burrow-Webster Flap

The Gillies fan flap, Karapandzic flap, Bernard-Webster (BW) flap, and modified Bernard-Burrow-Webster flap are the likely choices for repair of lip defects that encompass more than two-thirds of the lip.^9,10,22 The Karapandzic and BW flaps are the 2 most frequently used for reconstruction of larger lower lip defects and only require 1 surgery.

Upper lip full-thickness defects that are too big for an Abbé-Estlander flap are closed with the Gillies fan flap.¹⁸ These defects involve 70% to 80% of the horizontal lip.⁹ The Gillies fan flap design redistributes the remaining lip to provide similar tissue quality and texture to fill the large defects.^9,23 Compared to Karapandzic and Bernard flaps, Gillies fan incision closures are hidden well in the nasolabial folds, and the degree of microstomy is decreased because of the rotation of the flaps. However, rotation of medial cheek flaps can distort the orbicular muscular fibers and the anatomy of the commissure, which may require repair with commissurotomy. Drawbacks include a risk for denervation that can result in temporary oral sphincter incompetence.²³ The bilateral Gillies fan flap carries a risk for microstomy as well as misalignment of the lip vermilion and round commissures.²¹

The Karapandzic flap is similar to the Gillies fan flap but only involves the skin and mucosa.⁹ This flap can be used for lateral or medial upper lip defects greater than one-third the width of the entire lip. This single-procedure flap allows for labial continuity, preserved sensation, and motor function; however, microstomia and misalignment of the oral commissure are common.^1,18,21 In a retrospective study by Nicholas et al,⁴ the only flap reported to have a poor functional outcome was the Karapandzic flap, with 3 patients reporting altered sensation and 1 patient reporting persistent stiffness while smiling.

The BW flap can be applied for extensive full-thickness defects greater than one-third the lower lip and for defects with limited residual lip. This flap also can be used in cases where only skin is excised, as the flap does not depend on reminiscent lip tissue for reconstruction of the new lower lip. Sensory function is maintained given adequate visualization and preservation of the local vascular, nervous, and muscular systems. Disadvantages of the BW flap include an incision notch in the region of the lower lip; blunting of the alveolobuccal sulcus; and functional deficits, such as lip incontinence to liquids during the postoperative period.²¹

The Bernard-Burrow-Webster flap is used for large lower lip defects and preserves the oral commissures by advancing adjacent cheek tissue and remaining lip tissue medially.¹⁰ It allows for larger site mobilization, but it is possible to see some resulting oral incontinence.^1,10 The Burow wedge flap is a variant of the advancement flap, with the Burow triangle located lateral to the oral commissure. Caution must be taken to avoid intraoperative bleeding from the labial and angular arteries. In addition, there also may be downward displacement of the vermilion border.⁵

How to Choose a Flap

The orbicularis oris is a circular muscle that surrounds both the upper and lower lips. It is pulled into an oval, allowing for sphincter function by radially oriented muscles, all of which are innervated by the facial nerve. Other key anatomical structures of the lips include the tubercle (vermilion prominence), Cupid’s bow and philtrum, nasolabial folds, white roll, hair-bearing area, and vermilion border. The lips are divided into cutaneous, mucosal, and vermilion parts, with the vermilion area divided into dry/external and wet/internal areas. Sensation to the upper lip is provided by the maxillary division of the trigeminal nerve via the infraorbital nerve. The lower lip is innervated by the mandibular division of the trigeminal nerve via the inferior alveolar nerve. The labial artery, a branch of the facial artery, is responsible for blood supply to the lips.^3,9 Because of the complex anatomy of the lips, careful reconstruction is crucial for functional and aesthetic preservation.

There are a variety of lip defect repairs, but all local flaps aim to preserve aesthetics and function. The Table summarizes the key risks and benefits of each flap. Local flap techniques can be used in combination for more complex defects.³ For example, Nadiminti et al¹⁹ described the combination of the Abbé flap and V-Y advancement flap to restore function and create a new symmetric nasolabial fold. Dermatologic surgeons will determine the most suitable technique based on tumor location, tumor stage or depth of invasion (partial or full thickness), and preservation of function and aesthetics.¹

Other factors to consider when choosing a local flap are the patient’s age, tissue laxity, dentition/need for dentures, and any prior treatments.⁷ Scar revision surgery may be needed after reconstruction, especially with longer vertical scars in areas without other rhytides. In addition, paresthesia is common after Mohs micrographic surgery of the face; however, new neural networks are created postoperatively, and most paresthesia resolves within 1 year of the repair.⁴ Dermabrasion and Z-plasty also may be considered, as they have been shown to be successful in improving final outcomes.⁹ Overall, local flaps have risks for infection, flap necrosis, and bleeding, though the incidence is low in reconstructions of the face.

Final Thoughts

There are several mechanisms to repair upper and lower lip defects resulting from surgical removal of cutaneous cancers. This review of specific flaps used in lip reconstruction provides a comprehensive overview of indications, advantages, and disadvantages of available lip flaps.

The mpox (monkeypox) virus is a zoonotic orthopox DNA virus that results in a smallpoxlike illness.¹ Vaccination against smallpox protects against other orthopox infections, including mpox; however, unlike smallpox, mpox is notable for a variety of not-yet-confirmed animal reservoirs.² Mpox was first identified in Denmark in 1959 among nonhuman primates imported from Singapore, and the first case of human infection was diagnosed in 1970 in a 9-month-old child in the Democratic Republic of Congo.³ Endemic regions of Africa have had sporadic outbreaks with increasing frequency over time since the cessation of smallpox vaccination in 1980.^2,4 Infections in nonendemic countries have occurred intermittently, including in 2003 in the Midwest United States. This outbreak was traced back to prairie dogs infected by exotic animals imported from the Republic of Ghana.⁵

Two genetic clades of mpox that differ in mortality rates have been identified: clade II (formerly the West African clade) generally is self-limited with an estimated mortality of 1% to 6%, whereas clade I (formerly the Congo Basin clade) is more transmissible, with a mortality of approximately 10%.^2,6,7 Notably, as of May 2, 2022, all polymerase chain reaction–confirmed cases of mpox in nonendemic countries were identified as clade II.⁷ Following the continued international spread of mpox, the Director-General of the World Health Organization (WHO) declared the global outbreak a public health emergency of international concern on July 23, 2022.⁸ As of March 1, 2023, the Centers for Disease Control and Prevention (CDC) reports that there have been more than 86,000 cases of laboratory-confirmed mpox worldwide and 105 deaths, 89 of which occurred in nonendemic regions.⁹

Transmission of Mpox

In endemic countries, cases have been largely reported secondary to zoonotic spillover from contact with an infected animal.⁶ However, in nonendemic countries, mpox often results from human-to-human transmission, primarily via skin-to-skin contact with infected skin, but also may occur indirectly via contaminated fomites such as bedding or clothing, respiratory secretions, or vertical transmission.^6,10 The indirect transmission of mpox via contaminated fomites is controversial, though some studies have shown the virus can survive on surfaces for up to 15 days.¹¹ In the current outbreak, human-to-human transmission has been strongly associated with close contact during sexual activity, particularly among men who have sex with men (MSM), with notable physical concentration of initial lesions in the genital region.¹² Anyone can acquire mpox—infections are not exclusive to MSM populations, and cases have been reported in all demographic groups, including women and children. It is important to avoid stigmatization of MSM to prevent the propagation of homophobia as well as a false sense of complacency in non-MSM populations.¹³

Clinical Presentation of Mpox

The incubation period of mpox has been reported to last up to 21 days and is posited to depend on the mode of transmission, with complex invasive exposures having a shorter duration of approximately 9 days compared to noninvasive exposures, which have a duration of approximately 13 days.¹⁴ In a recent report from the Netherlands, the average incubation time was 8.5 days in 18 men with exposure attributed to sexual encounters with men.¹² Following the incubation period, mpox infection typically presents with nonspecific systemic symptoms such as fever, malaise, sore throat, cough, and headache for approximately 2 days, followed by painful generalized or localized lymphadenopathy 1 to 2 days prior to the onset of skin lesions.^1,15 In a recent report from Portugal of more than 20 confirmed cases of mpox, approximately half of patients denied symptoms or had mild systemic symptoms, suggesting that many patients in the current outbreak do not endorse systemic symptoms.¹⁶

Classic cutaneous lesions are the hallmark feature of mpox.¹⁷ Over a period of 1 to 2 weeks, each lesion progresses through morphologic stages of macule, papule (Figure), vesicle, and pustule, which then crusts over, forming a scab that falls off after another 1 to 2 weeks and can result in dyspigmented or pitted scars.^1,15 Lesions may be deep-seated or umbilicated; previously they were noted to typically start on the face and spread centrifugally, but recent cases have been notable for a predominance of anogenital lesions, often with the anogenital area as the sole or primary area of involvement.¹⁸ Given the high proportion of anogenital lesions in 2022, symptoms such as anogenital pain, tenesmus, and diarrhea are not uncommon.¹⁹ A recent study describing 528 international cases of mpox revealed that 95% of patients presented with a rash; nearly 75% had anogenital lesions; and 41%, 25%, and 10% had involvement of mucosae, the face, and palms/soles, respectively. More than half of patients had fewer than 10 lesions, and 10% presented with a single genital lesion.¹⁹

Given the recent predilection of lesions for the anogenital area, the differential diagnosis of mpox should include other common infections localized to these areas. Unlike herpes simplex and varicella-zoster infections, mpox does not exhibit the classic herpetiform clustering of vesicles, and unlike the painless chancre of syphilis, the lesions of mpox are exquisitely painful. Similar to chancroid, mpox presents with painful genital lesions and lymphadenopathy, and the umbilicated papules of molluscum could easily be confused with mpox lesions. Proctitis caused by many sexually transmitted infections (STIs), including chlamydia and gonorrhea, may be difficult to differentiate from proctitis symptoms of mpox. Co-infection with HIV and other STIs is common among patients developing mpox in 2022, which is not surprising given that the primary mechanism of transmission of mpox at this time is through sexual contact, and cases are more common in patients with multiple recent sexual partners.¹⁹ Considering these shared risk factors and similar presentation of multiple STIs, patients suspected of having an mpox infection should be tested for other STIs, including HIV.

Complications of Mpox

Although mpox generally is characterized by a mild disease course, there is concern for adverse outcomes, particularly in more vulnerable populations, including immunocompromised, pregnant, and pediatric populations. Complications of infection can include sepsis, encephalitis, bronchopneumonia, and ophthalmic complications that can result in loss of vision.^6,17 The most common complications requiring hospitalization in a recent international report of 528 mpox cases were pain management, which was primarily due to severe anogenital pain, followed by soft-tissue superinfection, with other complications including severe pharyngitis limiting oral intake and infection control practices.¹⁹ In addition to severe rectal pain, proctitis and even rectal perforation have been reported.^19,20

Vertical transmission has been described with devastating outcomes in a case series from the Democratic Republic of Congo, where 4 cases of mpox were identified in pregnant women; 3 of these pregnancies resulted in fetal demise.¹⁰ The only fetus to survive was born to a mother with mild infection. In comparison, 2 of 3 mothers with moderate to severe disease experienced spontaneous abortion in the first trimester, and 1 pregnancy ended due to intrauterine demise during the eighteenth week of gestation, likely a complication of mpox. These cases suggest that more severe disease may be linked to worse fetal outcomes.¹⁰ Further epidemiologic studies will be crucial, given the potential implications.

Diagnosis

When considering a diagnosis of mpox, clinicians should inquire about recent travel, living arrangements, sexual history, and recent sick contacts.⁶ A complete skin examination should include the oral and genital areas, given the high prevalence of lesions in these areas. A skin biopsy is not recommended for the diagnosis of mpox, as nonspecific viral changes cannot be differentiated from other viral exanthems, but it often is useful to rule out other differential diagnoses.²¹ Additionally, immunohistochemistry and electron microscopy can be utilized to aid in a histologic diagnosis of mpox.

Polymerase chain reaction detection of orthopox or mpox DNA is the gold standard for diagnosis.⁶ Two swabs should be collected from each lesion by swabbing vigorously using sterile swabs made of a synthetic material such as polyester, nylon, or Dacron and placed into a sterile container or viral transport medium.²² Some laboratories may have different instructions for collection of samples, so clinicians are advised to check for instructions from their local laboratory. Deroofing lesions prior to swabbing is not necessary, and specimens can include lesional material or crust. Collection of specimens from 2 to 3 lesions is recommended, preferably from different body areas or lesions with varying morphologies. Anal or rectal swabs can be considered in patients presenting with anal pain or proctitis with clinical suspicion for mpox based on history.¹⁹

Infection Prevention

Interim guidance from the WHO on November 16, 2022, reiterated the goal of outbreak control primarily via public health measures, which includes targeted use of vaccines for at-risk populations or postexposure prophylactic vaccination within 4 days, but heavily relies on surveillance and containment techniques, such as contact tracing with monitoring of contacts for onset of symptoms and isolation of cases through the complete infectious period.²³ Patients are considered infectious from symptom onset until all cutaneous lesions are re-epithelized and should remain in isolation, including from household contacts and domestic and wildlife animals, for the duration of illness.^24,25 Individuals exposed to humans or animals with confirmed mpox should be monitored for the development of symptoms for 21 days following last known exposure, regardless of vaccination status, and should be instructed to measure their temperature twice daily.²⁶ Pets exposed to mpox should be isolated from other animals and humans for 21 days following last known contact.²⁴ Vaccination strategies for preexposure and postexposure prophylaxis (PEP) are discussed below in further detail. Postinfection, the WHO suggests use of condoms for all oral, vaginal, and anal sexual activity for 12 weeks after recovery.⁷

Patients with suspected or confirmed mpox in a hospital should be in a single private room on special droplet and contact precautions.²⁷ No special air handling or negative pressure isolation is needed unless the patient is undergoing an aerosol-generating procedure (eg, intubation, endoscopy, bronchoscopy). When hospitalized, patients should have a dedicated bathroom, if possible, and at-home patients should be isolated from household members until contagion risk resolves; this includes the use of a separate bathroom, when possible. Health care personnel entering the room of a patient should don appropriate personal protective equipment (PPE), including a disposable gown, gloves, eye protection, and N95 respirator or equivalent. Recommendations include standard practices for cleaning, with wet cleaning methods preferred over dry methods, using a disinfectant that covers emerging viral pathogens, and avoidance of shaking linens to prevent the spread of infectious particles.²⁷ A variety of Environmental Protection Agency–registered wipes with virucidal activity against emerging viruses, including those with active ingredients such as quaternary ammonium, hydrogen peroxide, and hypochlorous acid, should be used for disinfecting surfaces.²⁸

Vaccination

ACAM2000 (Emergent Bio Solutions) and JYNNEOS (Bavarian Nordic)(also known as Imvamune or Imvanex) are available in the United States for the prevention of mpox infection.²⁹ ACAM2000, a second-generation, replication-competent, live smallpox vaccine administered as a single percutaneous injection, is contraindicated in immunocompromised populations, including patients with HIV or on immunosuppressive or biologic therapy, pregnant individuals, people with a history of atopic dermatitis or other exfoliative skin diseases with impaired barrier function, and patients with a history of cardiac disease due to the risk of myocarditis and pericarditis.³⁰

JYNNEOS is a nonreplicating live vaccine approved by the US Food and Drug Administration (FDA) for the prevention of mpox in individuals older than 18 years administered as 2 subcutaneous doses 4 weeks apart. Patients are considered fully vaccinated 2 weeks after the second dose, and JYNNEOS is available to pediatric patients with a single patient expanded access use authorization from the FDA.^29,30 More recently, the FDA issued an emergency use authorization (EUA) for administration of the vaccine to patients younger than 18 years who are at high risk of infection after exposure.³¹ More importantly, the FDA also issued an EUA for the intradermal administration of JYNNEOS at one-fifth of the subcutaneous dose to expand the current vaccine supply. This EUA is based on research by Frey et al,³² which showed that intradermal administration, even at a lower dose, elicited similar immune responses among study participants as the higher dose administered subcutaneously.

JYNNEOS is the preferred vaccine for the prevention of mpox because of its poor ability to replicate in human cells and resultant safety for use in populations that are immunocompromised, pregnant, or have skin barrier defects such as atopic dermatitis, without the risk of myocarditis or pericarditis. However, current supplies are limited. JYNNEOS was specifically studied in patients with atopic dermatitis and has been shown to be safe and effective in patients with a history of atopic dermatitis and active disease with a SCORAD (SCORing Atopic Dermatitis) score of 30 or lower.³³ Of note, JYNNEOS is contraindicated in patients allergic to components of the vaccine, including egg, gentamicin, and ciprofloxacin. Although JYNNEOS is safe to administer to persons with immunocompromising conditions, the CDC reports that such persons might be at increased risk for severe disease if an occupational infection occurs, and in the setting of immunocompromise, such persons may be less likely to mount an effective response to vaccination. Therefore, the risk-benefit ratio should be considered to determine if an immunocompromised person should be vaccinated with JYNNEOS.³⁰

The WHO and the CDC do not recommended mass vaccination of the general public for outbreaks of mpox in nonendemic countries, with immunization reserved for appropriate PEP and pre-exposure prophylaxis in intermediate- to high-risk individuals.^23,26 The CDC recommends PEP vaccination for individuals with a high degree of exposure that includes unprotected contact of the skin or mucous membranes of an individual to the skin, lesions, body fluids, or contaminated fomites from a patient with mpox, as well as being within 6 feet of a patient during an aerosolization procedure without proper PPE. Following an intermediate degree of exposure, which includes being within 6 feet for 3 or more hours wearing at minimum a surgical mask or contact with fomites while wearing incomplete PPE, the CDC recommends monitoring and shared decision-making regarding risks and benefits of PEP vaccination. Monitoring without PEP is indicated for low and uncertain degrees of exposure, including entering a room without full PPE such as eye protection, regardless of the duration of contact.^23,26

Postexposure prophylaxis vaccination should be administered within 4 days of a known high-level exposure to mpox to prevent infection.²⁹ If administered within 4 to 14 days postexposure, vaccination may reduce disease severity but will not prevent infection.³⁴

Pre-exposure prophylaxis is recommended for individuals at high risk for exposure to mpox, including health care workers such as laboratory personnel who handle mpox specimens and health care workers who administer ACAM2000 vaccinations or anticipate providing care for many patients with mpox.³⁴

Management

Most cases of mpox are characterized by mild to moderate disease with a self-limited course. Most commonly, medical management of mpox involves supportive care such as fluid resuscitation, supplemental oxygen, and pain management.⁶ Treatment of superinfected skin lesions may require antibiotics. In the event of ophthalmologic involvement, patients should be referred to an ophthalmologist for further management.

Currently, there are no FDA-approved therapies for mpox; however, tecovirimat, cidofovir, brincidofovir, and vaccinia immune globulin intravenous are available under expanded access Investigational New Drug protocols.^6,35 Human data for cidofovir, brincidofovir, and vaccinia immune globulin intravenous in the treatment of mpox are lacking, while cidofovir and brincidofovir have shown efficacy against orthopoxviruses in in vitro and animal studies, but are available therapeutic options.³⁵

Tecovirimat is an antiviral that is FDA approved for smallpox with efficacy data against mpox in animal studies. It is the first-line treatment for patients with severe disease requiring hospitalization or 1 or more complications, including dehydration or secondary skin infections, as well as for populations at risk for severe disease, which includes immunocompromised patients, pediatric patients younger than 8 years, pregnant or breastfeeding individuals, or patients with a history of atopic dermatitis or active exfoliative skin conditions.³⁶ In this current outbreak, both intravenous and oral tecovirimat are weight based in adult and pediatric patients for 14 days, with the intravenous form dosed every 12 hours by infusion over 6 hours, and the oral doses administered every 8 to 12 hours based on patient weight.³⁷ Tecovirimat generally is well tolerated with mild side effects but is notably contraindicated in patients with severe renal impairment with a creatinine clearance less than 30 mL/min, and renal monitoring is indicated in pediatric patients younger than 2 years and in all patients receiving intravenous treatment.

Conclusion

Given that cutaneous lesions are the most specific presenting sign of mpox infection, dermatologists will play an integral role in identifying future cases and managing future outbreaks. Mpox should be considered in the differential diagnosis for all patients presenting with umbilicated or papulovesicular lesions, particularly in an anogenital distribution. The classic presentation of mpox may be more common among patients who are not considered high risk and have not been exposed via sexual activity. All patients with suspicious lesions should be managed following appropriate infection control precautions and should undergo molecular diagnostic assay of swabbed lesions to confirm the diagnosis. JYNNEOS is the only vaccine that is currently being distributed in the United States and is safe to administer to immunocompromised populations. The risks and benefits of vaccination should be considered on an individual basis between a patient and their provider. Taking into consideration that patients with atopic dermatitis are at risk for severe disease if infected with mpox, vaccination should be strongly encouraged if indicated based on patient risk factors. For atopic dermatitis patients treated with dupilumab, shared decision-making is essential given the FDA label, which recommends avoiding the use of live vaccines.³⁸

The mpox epidemic occurring amidst the ongoing COVID-19 pandemic should serve as a wake-up call to the importance of pandemic preparedness and the global health response strategies in the modern era of globalization. Looking forward, widespread vaccination against mpox may be necessary to control the spread of the disease and to protect vulnerable populations, including pregnant individuals. In the current climate of hesitancy surrounding vaccines and the erosion of trust in public health agencies, it is incumbent upon health care providers to educate patients regarding the role of vaccines and public health measures to control this developing global health crisis.

The mpox (monkeypox) virus is a zoonotic orthopox DNA virus that results in a smallpoxlike illness.¹ Vaccination against smallpox protects against other orthopox infections, including mpox; however, unlike smallpox, mpox is notable for a variety of not-yet-confirmed animal reservoirs.² Mpox was first identified in Denmark in 1959 among nonhuman primates imported from Singapore, and the first case of human infection was diagnosed in 1970 in a 9-month-old child in the Democratic Republic of Congo.³ Endemic regions of Africa have had sporadic outbreaks with increasing frequency over time since the cessation of smallpox vaccination in 1980.^2,4 Infections in nonendemic countries have occurred intermittently, including in 2003 in the Midwest United States. This outbreak was traced back to prairie dogs infected by exotic animals imported from the Republic of Ghana.⁵

Two genetic clades of mpox that differ in mortality rates have been identified: clade II (formerly the West African clade) generally is self-limited with an estimated mortality of 1% to 6%, whereas clade I (formerly the Congo Basin clade) is more transmissible, with a mortality of approximately 10%.^2,6,7 Notably, as of May 2, 2022, all polymerase chain reaction–confirmed cases of mpox in nonendemic countries were identified as clade II.⁷ Following the continued international spread of mpox, the Director-General of the World Health Organization (WHO) declared the global outbreak a public health emergency of international concern on July 23, 2022.⁸ As of March 1, 2023, the Centers for Disease Control and Prevention (CDC) reports that there have been more than 86,000 cases of laboratory-confirmed mpox worldwide and 105 deaths, 89 of which occurred in nonendemic regions.⁹

Transmission of Mpox

In endemic countries, cases have been largely reported secondary to zoonotic spillover from contact with an infected animal.⁶ However, in nonendemic countries, mpox often results from human-to-human transmission, primarily via skin-to-skin contact with infected skin, but also may occur indirectly via contaminated fomites such as bedding or clothing, respiratory secretions, or vertical transmission.^6,10 The indirect transmission of mpox via contaminated fomites is controversial, though some studies have shown the virus can survive on surfaces for up to 15 days.¹¹ In the current outbreak, human-to-human transmission has been strongly associated with close contact during sexual activity, particularly among men who have sex with men (MSM), with notable physical concentration of initial lesions in the genital region.¹² Anyone can acquire mpox—infections are not exclusive to MSM populations, and cases have been reported in all demographic groups, including women and children. It is important to avoid stigmatization of MSM to prevent the propagation of homophobia as well as a false sense of complacency in non-MSM populations.¹³

Clinical Presentation of Mpox

The incubation period of mpox has been reported to last up to 21 days and is posited to depend on the mode of transmission, with complex invasive exposures having a shorter duration of approximately 9 days compared to noninvasive exposures, which have a duration of approximately 13 days.¹⁴ In a recent report from the Netherlands, the average incubation time was 8.5 days in 18 men with exposure attributed to sexual encounters with men.¹² Following the incubation period, mpox infection typically presents with nonspecific systemic symptoms such as fever, malaise, sore throat, cough, and headache for approximately 2 days, followed by painful generalized or localized lymphadenopathy 1 to 2 days prior to the onset of skin lesions.^1,15 In a recent report from Portugal of more than 20 confirmed cases of mpox, approximately half of patients denied symptoms or had mild systemic symptoms, suggesting that many patients in the current outbreak do not endorse systemic symptoms.¹⁶

Classic cutaneous lesions are the hallmark feature of mpox.¹⁷ Over a period of 1 to 2 weeks, each lesion progresses through morphologic stages of macule, papule (Figure), vesicle, and pustule, which then crusts over, forming a scab that falls off after another 1 to 2 weeks and can result in dyspigmented or pitted scars.^1,15 Lesions may be deep-seated or umbilicated; previously they were noted to typically start on the face and spread centrifugally, but recent cases have been notable for a predominance of anogenital lesions, often with the anogenital area as the sole or primary area of involvement.¹⁸ Given the high proportion of anogenital lesions in 2022, symptoms such as anogenital pain, tenesmus, and diarrhea are not uncommon.¹⁹ A recent study describing 528 international cases of mpox revealed that 95% of patients presented with a rash; nearly 75% had anogenital lesions; and 41%, 25%, and 10% had involvement of mucosae, the face, and palms/soles, respectively. More than half of patients had fewer than 10 lesions, and 10% presented with a single genital lesion.¹⁹

Given the recent predilection of lesions for the anogenital area, the differential diagnosis of mpox should include other common infections localized to these areas. Unlike herpes simplex and varicella-zoster infections, mpox does not exhibit the classic herpetiform clustering of vesicles, and unlike the painless chancre of syphilis, the lesions of mpox are exquisitely painful. Similar to chancroid, mpox presents with painful genital lesions and lymphadenopathy, and the umbilicated papules of molluscum could easily be confused with mpox lesions. Proctitis caused by many sexually transmitted infections (STIs), including chlamydia and gonorrhea, may be difficult to differentiate from proctitis symptoms of mpox. Co-infection with HIV and other STIs is common among patients developing mpox in 2022, which is not surprising given that the primary mechanism of transmission of mpox at this time is through sexual contact, and cases are more common in patients with multiple recent sexual partners.¹⁹ Considering these shared risk factors and similar presentation of multiple STIs, patients suspected of having an mpox infection should be tested for other STIs, including HIV.

Complications of Mpox

Although mpox generally is characterized by a mild disease course, there is concern for adverse outcomes, particularly in more vulnerable populations, including immunocompromised, pregnant, and pediatric populations. Complications of infection can include sepsis, encephalitis, bronchopneumonia, and ophthalmic complications that can result in loss of vision.^6,17 The most common complications requiring hospitalization in a recent international report of 528 mpox cases were pain management, which was primarily due to severe anogenital pain, followed by soft-tissue superinfection, with other complications including severe pharyngitis limiting oral intake and infection control practices.¹⁹ In addition to severe rectal pain, proctitis and even rectal perforation have been reported.^19,20

Vertical transmission has been described with devastating outcomes in a case series from the Democratic Republic of Congo, where 4 cases of mpox were identified in pregnant women; 3 of these pregnancies resulted in fetal demise.¹⁰ The only fetus to survive was born to a mother with mild infection. In comparison, 2 of 3 mothers with moderate to severe disease experienced spontaneous abortion in the first trimester, and 1 pregnancy ended due to intrauterine demise during the eighteenth week of gestation, likely a complication of mpox. These cases suggest that more severe disease may be linked to worse fetal outcomes.¹⁰ Further epidemiologic studies will be crucial, given the potential implications.

Diagnosis

When considering a diagnosis of mpox, clinicians should inquire about recent travel, living arrangements, sexual history, and recent sick contacts.⁶ A complete skin examination should include the oral and genital areas, given the high prevalence of lesions in these areas. A skin biopsy is not recommended for the diagnosis of mpox, as nonspecific viral changes cannot be differentiated from other viral exanthems, but it often is useful to rule out other differential diagnoses.²¹ Additionally, immunohistochemistry and electron microscopy can be utilized to aid in a histologic diagnosis of mpox.

Polymerase chain reaction detection of orthopox or mpox DNA is the gold standard for diagnosis.⁶ Two swabs should be collected from each lesion by swabbing vigorously using sterile swabs made of a synthetic material such as polyester, nylon, or Dacron and placed into a sterile container or viral transport medium.²² Some laboratories may have different instructions for collection of samples, so clinicians are advised to check for instructions from their local laboratory. Deroofing lesions prior to swabbing is not necessary, and specimens can include lesional material or crust. Collection of specimens from 2 to 3 lesions is recommended, preferably from different body areas or lesions with varying morphologies. Anal or rectal swabs can be considered in patients presenting with anal pain or proctitis with clinical suspicion for mpox based on history.¹⁹

Infection Prevention

Interim guidance from the WHO on November 16, 2022, reiterated the goal of outbreak control primarily via public health measures, which includes targeted use of vaccines for at-risk populations or postexposure prophylactic vaccination within 4 days, but heavily relies on surveillance and containment techniques, such as contact tracing with monitoring of contacts for onset of symptoms and isolation of cases through the complete infectious period.²³ Patients are considered infectious from symptom onset until all cutaneous lesions are re-epithelized and should remain in isolation, including from household contacts and domestic and wildlife animals, for the duration of illness.^24,25 Individuals exposed to humans or animals with confirmed mpox should be monitored for the development of symptoms for 21 days following last known exposure, regardless of vaccination status, and should be instructed to measure their temperature twice daily.²⁶ Pets exposed to mpox should be isolated from other animals and humans for 21 days following last known contact.²⁴ Vaccination strategies for preexposure and postexposure prophylaxis (PEP) are discussed below in further detail. Postinfection, the WHO suggests use of condoms for all oral, vaginal, and anal sexual activity for 12 weeks after recovery.⁷

Patients with suspected or confirmed mpox in a hospital should be in a single private room on special droplet and contact precautions.²⁷ No special air handling or negative pressure isolation is needed unless the patient is undergoing an aerosol-generating procedure (eg, intubation, endoscopy, bronchoscopy). When hospitalized, patients should have a dedicated bathroom, if possible, and at-home patients should be isolated from household members until contagion risk resolves; this includes the use of a separate bathroom, when possible. Health care personnel entering the room of a patient should don appropriate personal protective equipment (PPE), including a disposable gown, gloves, eye protection, and N95 respirator or equivalent. Recommendations include standard practices for cleaning, with wet cleaning methods preferred over dry methods, using a disinfectant that covers emerging viral pathogens, and avoidance of shaking linens to prevent the spread of infectious particles.²⁷ A variety of Environmental Protection Agency–registered wipes with virucidal activity against emerging viruses, including those with active ingredients such as quaternary ammonium, hydrogen peroxide, and hypochlorous acid, should be used for disinfecting surfaces.²⁸

Vaccination

ACAM2000 (Emergent Bio Solutions) and JYNNEOS (Bavarian Nordic)(also known as Imvamune or Imvanex) are available in the United States for the prevention of mpox infection.²⁹ ACAM2000, a second-generation, replication-competent, live smallpox vaccine administered as a single percutaneous injection, is contraindicated in immunocompromised populations, including patients with HIV or on immunosuppressive or biologic therapy, pregnant individuals, people with a history of atopic dermatitis or other exfoliative skin diseases with impaired barrier function, and patients with a history of cardiac disease due to the risk of myocarditis and pericarditis.³⁰

JYNNEOS is a nonreplicating live vaccine approved by the US Food and Drug Administration (FDA) for the prevention of mpox in individuals older than 18 years administered as 2 subcutaneous doses 4 weeks apart. Patients are considered fully vaccinated 2 weeks after the second dose, and JYNNEOS is available to pediatric patients with a single patient expanded access use authorization from the FDA.^29,30 More recently, the FDA issued an emergency use authorization (EUA) for administration of the vaccine to patients younger than 18 years who are at high risk of infection after exposure.³¹ More importantly, the FDA also issued an EUA for the intradermal administration of JYNNEOS at one-fifth of the subcutaneous dose to expand the current vaccine supply. This EUA is based on research by Frey et al,³² which showed that intradermal administration, even at a lower dose, elicited similar immune responses among study participants as the higher dose administered subcutaneously.

JYNNEOS is the preferred vaccine for the prevention of mpox because of its poor ability to replicate in human cells and resultant safety for use in populations that are immunocompromised, pregnant, or have skin barrier defects such as atopic dermatitis, without the risk of myocarditis or pericarditis. However, current supplies are limited. JYNNEOS was specifically studied in patients with atopic dermatitis and has been shown to be safe and effective in patients with a history of atopic dermatitis and active disease with a SCORAD (SCORing Atopic Dermatitis) score of 30 or lower.³³ Of note, JYNNEOS is contraindicated in patients allergic to components of the vaccine, including egg, gentamicin, and ciprofloxacin. Although JYNNEOS is safe to administer to persons with immunocompromising conditions, the CDC reports that such persons might be at increased risk for severe disease if an occupational infection occurs, and in the setting of immunocompromise, such persons may be less likely to mount an effective response to vaccination. Therefore, the risk-benefit ratio should be considered to determine if an immunocompromised person should be vaccinated with JYNNEOS.³⁰

The WHO and the CDC do not recommended mass vaccination of the general public for outbreaks of mpox in nonendemic countries, with immunization reserved for appropriate PEP and pre-exposure prophylaxis in intermediate- to high-risk individuals.^23,26 The CDC recommends PEP vaccination for individuals with a high degree of exposure that includes unprotected contact of the skin or mucous membranes of an individual to the skin, lesions, body fluids, or contaminated fomites from a patient with mpox, as well as being within 6 feet of a patient during an aerosolization procedure without proper PPE. Following an intermediate degree of exposure, which includes being within 6 feet for 3 or more hours wearing at minimum a surgical mask or contact with fomites while wearing incomplete PPE, the CDC recommends monitoring and shared decision-making regarding risks and benefits of PEP vaccination. Monitoring without PEP is indicated for low and uncertain degrees of exposure, including entering a room without full PPE such as eye protection, regardless of the duration of contact.^23,26

Postexposure prophylaxis vaccination should be administered within 4 days of a known high-level exposure to mpox to prevent infection.²⁹ If administered within 4 to 14 days postexposure, vaccination may reduce disease severity but will not prevent infection.³⁴

Pre-exposure prophylaxis is recommended for individuals at high risk for exposure to mpox, including health care workers such as laboratory personnel who handle mpox specimens and health care workers who administer ACAM2000 vaccinations or anticipate providing care for many patients with mpox.³⁴

Management

Most cases of mpox are characterized by mild to moderate disease with a self-limited course. Most commonly, medical management of mpox involves supportive care such as fluid resuscitation, supplemental oxygen, and pain management.⁶ Treatment of superinfected skin lesions may require antibiotics. In the event of ophthalmologic involvement, patients should be referred to an ophthalmologist for further management.

Currently, there are no FDA-approved therapies for mpox; however, tecovirimat, cidofovir, brincidofovir, and vaccinia immune globulin intravenous are available under expanded access Investigational New Drug protocols.^6,35 Human data for cidofovir, brincidofovir, and vaccinia immune globulin intravenous in the treatment of mpox are lacking, while cidofovir and brincidofovir have shown efficacy against orthopoxviruses in in vitro and animal studies, but are available therapeutic options.³⁵

Tecovirimat is an antiviral that is FDA approved for smallpox with efficacy data against mpox in animal studies. It is the first-line treatment for patients with severe disease requiring hospitalization or 1 or more complications, including dehydration or secondary skin infections, as well as for populations at risk for severe disease, which includes immunocompromised patients, pediatric patients younger than 8 years, pregnant or breastfeeding individuals, or patients with a history of atopic dermatitis or active exfoliative skin conditions.³⁶ In this current outbreak, both intravenous and oral tecovirimat are weight based in adult and pediatric patients for 14 days, with the intravenous form dosed every 12 hours by infusion over 6 hours, and the oral doses administered every 8 to 12 hours based on patient weight.³⁷ Tecovirimat generally is well tolerated with mild side effects but is notably contraindicated in patients with severe renal impairment with a creatinine clearance less than 30 mL/min, and renal monitoring is indicated in pediatric patients younger than 2 years and in all patients receiving intravenous treatment.

Conclusion

Given that cutaneous lesions are the most specific presenting sign of mpox infection, dermatologists will play an integral role in identifying future cases and managing future outbreaks. Mpox should be considered in the differential diagnosis for all patients presenting with umbilicated or papulovesicular lesions, particularly in an anogenital distribution. The classic presentation of mpox may be more common among patients who are not considered high risk and have not been exposed via sexual activity. All patients with suspicious lesions should be managed following appropriate infection control precautions and should undergo molecular diagnostic assay of swabbed lesions to confirm the diagnosis. JYNNEOS is the only vaccine that is currently being distributed in the United States and is safe to administer to immunocompromised populations. The risks and benefits of vaccination should be considered on an individual basis between a patient and their provider. Taking into consideration that patients with atopic dermatitis are at risk for severe disease if infected with mpox, vaccination should be strongly encouraged if indicated based on patient risk factors. For atopic dermatitis patients treated with dupilumab, shared decision-making is essential given the FDA label, which recommends avoiding the use of live vaccines.³⁸

The mpox epidemic occurring amidst the ongoing COVID-19 pandemic should serve as a wake-up call to the importance of pandemic preparedness and the global health response strategies in the modern era of globalization. Looking forward, widespread vaccination against mpox may be necessary to control the spread of the disease and to protect vulnerable populations, including pregnant individuals. In the current climate of hesitancy surrounding vaccines and the erosion of trust in public health agencies, it is incumbent upon health care providers to educate patients regarding the role of vaccines and public health measures to control this developing global health crisis.

The mpox (monkeypox) virus is a zoonotic orthopox DNA virus that results in a smallpoxlike illness.¹ Vaccination against smallpox protects against other orthopox infections, including mpox; however, unlike smallpox, mpox is notable for a variety of not-yet-confirmed animal reservoirs.² Mpox was first identified in Denmark in 1959 among nonhuman primates imported from Singapore, and the first case of human infection was diagnosed in 1970 in a 9-month-old child in the Democratic Republic of Congo.³ Endemic regions of Africa have had sporadic outbreaks with increasing frequency over time since the cessation of smallpox vaccination in 1980.^2,4 Infections in nonendemic countries have occurred intermittently, including in 2003 in the Midwest United States. This outbreak was traced back to prairie dogs infected by exotic animals imported from the Republic of Ghana.⁵

Two genetic clades of mpox that differ in mortality rates have been identified: clade II (formerly the West African clade) generally is self-limited with an estimated mortality of 1% to 6%, whereas clade I (formerly the Congo Basin clade) is more transmissible, with a mortality of approximately 10%.^2,6,7 Notably, as of May 2, 2022, all polymerase chain reaction–confirmed cases of mpox in nonendemic countries were identified as clade II.⁷ Following the continued international spread of mpox, the Director-General of the World Health Organization (WHO) declared the global outbreak a public health emergency of international concern on July 23, 2022.⁸ As of March 1, 2023, the Centers for Disease Control and Prevention (CDC) reports that there have been more than 86,000 cases of laboratory-confirmed mpox worldwide and 105 deaths, 89 of which occurred in nonendemic regions.⁹

Transmission of Mpox

In endemic countries, cases have been largely reported secondary to zoonotic spillover from contact with an infected animal.⁶ However, in nonendemic countries, mpox often results from human-to-human transmission, primarily via skin-to-skin contact with infected skin, but also may occur indirectly via contaminated fomites such as bedding or clothing, respiratory secretions, or vertical transmission.^6,10 The indirect transmission of mpox via contaminated fomites is controversial, though some studies have shown the virus can survive on surfaces for up to 15 days.¹¹ In the current outbreak, human-to-human transmission has been strongly associated with close contact during sexual activity, particularly among men who have sex with men (MSM), with notable physical concentration of initial lesions in the genital region.¹² Anyone can acquire mpox—infections are not exclusive to MSM populations, and cases have been reported in all demographic groups, including women and children. It is important to avoid stigmatization of MSM to prevent the propagation of homophobia as well as a false sense of complacency in non-MSM populations.¹³

Clinical Presentation of Mpox

The incubation period of mpox has been reported to last up to 21 days and is posited to depend on the mode of transmission, with complex invasive exposures having a shorter duration of approximately 9 days compared to noninvasive exposures, which have a duration of approximately 13 days.¹⁴ In a recent report from the Netherlands, the average incubation time was 8.5 days in 18 men with exposure attributed to sexual encounters with men.¹² Following the incubation period, mpox infection typically presents with nonspecific systemic symptoms such as fever, malaise, sore throat, cough, and headache for approximately 2 days, followed by painful generalized or localized lymphadenopathy 1 to 2 days prior to the onset of skin lesions.^1,15 In a recent report from Portugal of more than 20 confirmed cases of mpox, approximately half of patients denied symptoms or had mild systemic symptoms, suggesting that many patients in the current outbreak do not endorse systemic symptoms.¹⁶

Classic cutaneous lesions are the hallmark feature of mpox.¹⁷ Over a period of 1 to 2 weeks, each lesion progresses through morphologic stages of macule, papule (Figure), vesicle, and pustule, which then crusts over, forming a scab that falls off after another 1 to 2 weeks and can result in dyspigmented or pitted scars.^1,15 Lesions may be deep-seated or umbilicated; previously they were noted to typically start on the face and spread centrifugally, but recent cases have been notable for a predominance of anogenital lesions, often with the anogenital area as the sole or primary area of involvement.¹⁸ Given the high proportion of anogenital lesions in 2022, symptoms such as anogenital pain, tenesmus, and diarrhea are not uncommon.¹⁹ A recent study describing 528 international cases of mpox revealed that 95% of patients presented with a rash; nearly 75% had anogenital lesions; and 41%, 25%, and 10% had involvement of mucosae, the face, and palms/soles, respectively. More than half of patients had fewer than 10 lesions, and 10% presented with a single genital lesion.¹⁹

Given the recent predilection of lesions for the anogenital area, the differential diagnosis of mpox should include other common infections localized to these areas. Unlike herpes simplex and varicella-zoster infections, mpox does not exhibit the classic herpetiform clustering of vesicles, and unlike the painless chancre of syphilis, the lesions of mpox are exquisitely painful. Similar to chancroid, mpox presents with painful genital lesions and lymphadenopathy, and the umbilicated papules of molluscum could easily be confused with mpox lesions. Proctitis caused by many sexually transmitted infections (STIs), including chlamydia and gonorrhea, may be difficult to differentiate from proctitis symptoms of mpox. Co-infection with HIV and other STIs is common among patients developing mpox in 2022, which is not surprising given that the primary mechanism of transmission of mpox at this time is through sexual contact, and cases are more common in patients with multiple recent sexual partners.¹⁹ Considering these shared risk factors and similar presentation of multiple STIs, patients suspected of having an mpox infection should be tested for other STIs, including HIV.

Complications of Mpox

Although mpox generally is characterized by a mild disease course, there is concern for adverse outcomes, particularly in more vulnerable populations, including immunocompromised, pregnant, and pediatric populations. Complications of infection can include sepsis, encephalitis, bronchopneumonia, and ophthalmic complications that can result in loss of vision.^6,17 The most common complications requiring hospitalization in a recent international report of 528 mpox cases were pain management, which was primarily due to severe anogenital pain, followed by soft-tissue superinfection, with other complications including severe pharyngitis limiting oral intake and infection control practices.¹⁹ In addition to severe rectal pain, proctitis and even rectal perforation have been reported.^19,20

Vertical transmission has been described with devastating outcomes in a case series from the Democratic Republic of Congo, where 4 cases of mpox were identified in pregnant women; 3 of these pregnancies resulted in fetal demise.¹⁰ The only fetus to survive was born to a mother with mild infection. In comparison, 2 of 3 mothers with moderate to severe disease experienced spontaneous abortion in the first trimester, and 1 pregnancy ended due to intrauterine demise during the eighteenth week of gestation, likely a complication of mpox. These cases suggest that more severe disease may be linked to worse fetal outcomes.¹⁰ Further epidemiologic studies will be crucial, given the potential implications.

Diagnosis

When considering a diagnosis of mpox, clinicians should inquire about recent travel, living arrangements, sexual history, and recent sick contacts.⁶ A complete skin examination should include the oral and genital areas, given the high prevalence of lesions in these areas. A skin biopsy is not recommended for the diagnosis of mpox, as nonspecific viral changes cannot be differentiated from other viral exanthems, but it often is useful to rule out other differential diagnoses.²¹ Additionally, immunohistochemistry and electron microscopy can be utilized to aid in a histologic diagnosis of mpox.

Polymerase chain reaction detection of orthopox or mpox DNA is the gold standard for diagnosis.⁶ Two swabs should be collected from each lesion by swabbing vigorously using sterile swabs made of a synthetic material such as polyester, nylon, or Dacron and placed into a sterile container or viral transport medium.²² Some laboratories may have different instructions for collection of samples, so clinicians are advised to check for instructions from their local laboratory. Deroofing lesions prior to swabbing is not necessary, and specimens can include lesional material or crust. Collection of specimens from 2 to 3 lesions is recommended, preferably from different body areas or lesions with varying morphologies. Anal or rectal swabs can be considered in patients presenting with anal pain or proctitis with clinical suspicion for mpox based on history.¹⁹

Infection Prevention

Interim guidance from the WHO on November 16, 2022, reiterated the goal of outbreak control primarily via public health measures, which includes targeted use of vaccines for at-risk populations or postexposure prophylactic vaccination within 4 days, but heavily relies on surveillance and containment techniques, such as contact tracing with monitoring of contacts for onset of symptoms and isolation of cases through the complete infectious period.²³ Patients are considered infectious from symptom onset until all cutaneous lesions are re-epithelized and should remain in isolation, including from household contacts and domestic and wildlife animals, for the duration of illness.^24,25 Individuals exposed to humans or animals with confirmed mpox should be monitored for the development of symptoms for 21 days following last known exposure, regardless of vaccination status, and should be instructed to measure their temperature twice daily.²⁶ Pets exposed to mpox should be isolated from other animals and humans for 21 days following last known contact.²⁴ Vaccination strategies for preexposure and postexposure prophylaxis (PEP) are discussed below in further detail. Postinfection, the WHO suggests use of condoms for all oral, vaginal, and anal sexual activity for 12 weeks after recovery.⁷

Patients with suspected or confirmed mpox in a hospital should be in a single private room on special droplet and contact precautions.²⁷ No special air handling or negative pressure isolation is needed unless the patient is undergoing an aerosol-generating procedure (eg, intubation, endoscopy, bronchoscopy). When hospitalized, patients should have a dedicated bathroom, if possible, and at-home patients should be isolated from household members until contagion risk resolves; this includes the use of a separate bathroom, when possible. Health care personnel entering the room of a patient should don appropriate personal protective equipment (PPE), including a disposable gown, gloves, eye protection, and N95 respirator or equivalent. Recommendations include standard practices for cleaning, with wet cleaning methods preferred over dry methods, using a disinfectant that covers emerging viral pathogens, and avoidance of shaking linens to prevent the spread of infectious particles.²⁷ A variety of Environmental Protection Agency–registered wipes with virucidal activity against emerging viruses, including those with active ingredients such as quaternary ammonium, hydrogen peroxide, and hypochlorous acid, should be used for disinfecting surfaces.²⁸

Vaccination

ACAM2000 (Emergent Bio Solutions) and JYNNEOS (Bavarian Nordic)(also known as Imvamune or Imvanex) are available in the United States for the prevention of mpox infection.²⁹ ACAM2000, a second-generation, replication-competent, live smallpox vaccine administered as a single percutaneous injection, is contraindicated in immunocompromised populations, including patients with HIV or on immunosuppressive or biologic therapy, pregnant individuals, people with a history of atopic dermatitis or other exfoliative skin diseases with impaired barrier function, and patients with a history of cardiac disease due to the risk of myocarditis and pericarditis.³⁰

JYNNEOS is a nonreplicating live vaccine approved by the US Food and Drug Administration (FDA) for the prevention of mpox in individuals older than 18 years administered as 2 subcutaneous doses 4 weeks apart. Patients are considered fully vaccinated 2 weeks after the second dose, and JYNNEOS is available to pediatric patients with a single patient expanded access use authorization from the FDA.^29,30 More recently, the FDA issued an emergency use authorization (EUA) for administration of the vaccine to patients younger than 18 years who are at high risk of infection after exposure.³¹ More importantly, the FDA also issued an EUA for the intradermal administration of JYNNEOS at one-fifth of the subcutaneous dose to expand the current vaccine supply. This EUA is based on research by Frey et al,³² which showed that intradermal administration, even at a lower dose, elicited similar immune responses among study participants as the higher dose administered subcutaneously.

JYNNEOS is the preferred vaccine for the prevention of mpox because of its poor ability to replicate in human cells and resultant safety for use in populations that are immunocompromised, pregnant, or have skin barrier defects such as atopic dermatitis, without the risk of myocarditis or pericarditis. However, current supplies are limited. JYNNEOS was specifically studied in patients with atopic dermatitis and has been shown to be safe and effective in patients with a history of atopic dermatitis and active disease with a SCORAD (SCORing Atopic Dermatitis) score of 30 or lower.³³ Of note, JYNNEOS is contraindicated in patients allergic to components of the vaccine, including egg, gentamicin, and ciprofloxacin. Although JYNNEOS is safe to administer to persons with immunocompromising conditions, the CDC reports that such persons might be at increased risk for severe disease if an occupational infection occurs, and in the setting of immunocompromise, such persons may be less likely to mount an effective response to vaccination. Therefore, the risk-benefit ratio should be considered to determine if an immunocompromised person should be vaccinated with JYNNEOS.³⁰

The WHO and the CDC do not recommended mass vaccination of the general public for outbreaks of mpox in nonendemic countries, with immunization reserved for appropriate PEP and pre-exposure prophylaxis in intermediate- to high-risk individuals.^23,26 The CDC recommends PEP vaccination for individuals with a high degree of exposure that includes unprotected contact of the skin or mucous membranes of an individual to the skin, lesions, body fluids, or contaminated fomites from a patient with mpox, as well as being within 6 feet of a patient during an aerosolization procedure without proper PPE. Following an intermediate degree of exposure, which includes being within 6 feet for 3 or more hours wearing at minimum a surgical mask or contact with fomites while wearing incomplete PPE, the CDC recommends monitoring and shared decision-making regarding risks and benefits of PEP vaccination. Monitoring without PEP is indicated for low and uncertain degrees of exposure, including entering a room without full PPE such as eye protection, regardless of the duration of contact.^23,26

Postexposure prophylaxis vaccination should be administered within 4 days of a known high-level exposure to mpox to prevent infection.²⁹ If administered within 4 to 14 days postexposure, vaccination may reduce disease severity but will not prevent infection.³⁴

Pre-exposure prophylaxis is recommended for individuals at high risk for exposure to mpox, including health care workers such as laboratory personnel who handle mpox specimens and health care workers who administer ACAM2000 vaccinations or anticipate providing care for many patients with mpox.³⁴

Management

Most cases of mpox are characterized by mild to moderate disease with a self-limited course. Most commonly, medical management of mpox involves supportive care such as fluid resuscitation, supplemental oxygen, and pain management.⁶ Treatment of superinfected skin lesions may require antibiotics. In the event of ophthalmologic involvement, patients should be referred to an ophthalmologist for further management.

Currently, there are no FDA-approved therapies for mpox; however, tecovirimat, cidofovir, brincidofovir, and vaccinia immune globulin intravenous are available under expanded access Investigational New Drug protocols.^6,35 Human data for cidofovir, brincidofovir, and vaccinia immune globulin intravenous in the treatment of mpox are lacking, while cidofovir and brincidofovir have shown efficacy against orthopoxviruses in in vitro and animal studies, but are available therapeutic options.³⁵

Tecovirimat is an antiviral that is FDA approved for smallpox with efficacy data against mpox in animal studies. It is the first-line treatment for patients with severe disease requiring hospitalization or 1 or more complications, including dehydration or secondary skin infections, as well as for populations at risk for severe disease, which includes immunocompromised patients, pediatric patients younger than 8 years, pregnant or breastfeeding individuals, or patients with a history of atopic dermatitis or active exfoliative skin conditions.³⁶ In this current outbreak, both intravenous and oral tecovirimat are weight based in adult and pediatric patients for 14 days, with the intravenous form dosed every 12 hours by infusion over 6 hours, and the oral doses administered every 8 to 12 hours based on patient weight.³⁷ Tecovirimat generally is well tolerated with mild side effects but is notably contraindicated in patients with severe renal impairment with a creatinine clearance less than 30 mL/min, and renal monitoring is indicated in pediatric patients younger than 2 years and in all patients receiving intravenous treatment.

Conclusion

Given that cutaneous lesions are the most specific presenting sign of mpox infection, dermatologists will play an integral role in identifying future cases and managing future outbreaks. Mpox should be considered in the differential diagnosis for all patients presenting with umbilicated or papulovesicular lesions, particularly in an anogenital distribution. The classic presentation of mpox may be more common among patients who are not considered high risk and have not been exposed via sexual activity. All patients with suspicious lesions should be managed following appropriate infection control precautions and should undergo molecular diagnostic assay of swabbed lesions to confirm the diagnosis. JYNNEOS is the only vaccine that is currently being distributed in the United States and is safe to administer to immunocompromised populations. The risks and benefits of vaccination should be considered on an individual basis between a patient and their provider. Taking into consideration that patients with atopic dermatitis are at risk for severe disease if infected with mpox, vaccination should be strongly encouraged if indicated based on patient risk factors. For atopic dermatitis patients treated with dupilumab, shared decision-making is essential given the FDA label, which recommends avoiding the use of live vaccines.³⁸

The mpox epidemic occurring amidst the ongoing COVID-19 pandemic should serve as a wake-up call to the importance of pandemic preparedness and the global health response strategies in the modern era of globalization. Looking forward, widespread vaccination against mpox may be necessary to control the spread of the disease and to protect vulnerable populations, including pregnant individuals. In the current climate of hesitancy surrounding vaccines and the erosion of trust in public health agencies, it is incumbent upon health care providers to educate patients regarding the role of vaccines and public health measures to control this developing global health crisis.

Practice Gap

Skin picking disorder is characterized by repetitive deliberate manipulation of the skin that causes noticeable tissue damage. It affects approximately 1.6% of adults in the United States and is associated with marked distress as well as a psychosocial impact.¹ Complications of skin picking disorder can include ulceration, infection, scarring, and disfigurement.

Cognitive behavioral therapy (CBT) techniques have been established to be effective in treating skin picking disorder.² Although referral to a mental health professional is appropriate for patients with skin picking disorder, many of them may not be interested. Cognitive behavioral therapy for diseases at the intersection of psychiatry and dermatology typically is not included in dermatology curricula. Therefore, dermatologists should be aware of CBT techniques that can mitigate the impact of skin picking disorder for patients who decline referral to a mental health professional.

The Technique

Cognitive behavioral therapy is one of the more effective forms of psychotherapy for the treatment of skin picking disorder. Consistent utilization of CBT techniques can achieve relatively permanent change in brain function and contribute to long-term treatment outcomes. A particularly useful CBT technique for skin picking disorder is habit reversal therapy (HRT)(Table). Studies have shown that HRT techniques have demonstrated efficacy in skin picking disorder with sustained impact.³ Patients treated with HRT have reported a greater decrease in skin picking compared with controls after only 3 sessions (P<.01).⁴ There are 3 elements to HRT:

1. Sensitization and awareness training: This facet of HRT involves helping the patient become attuned to warning signals, or feelings, that precede their skin picking, as skin picking often occurs automatically without the patient noticing. Such feelings can include tingling of the skin, tension, and a feeling of being overwhelmed.⁵ Ideally, the physician works with the patient to identify 2 or 3 warning signals that precede skin picking behavior.

2. Competing response training: The patient is encouraged to substitute skin picking with a preventive behavior—for example, crossing the arms and gently squeezing the fists—that is incompatible with skin picking. The preventive behavior should be performed for at least 1 minute as soon as a warning signal appears or skin picking behavior starts. After 1 minute, if the urge for skin picking recurs, then the patient should repeat the preventive behavior.⁵ It can be helpful to practice the preventive behavior with the patient once in the clinic.

3. Social support: This technique involves identifying a close social contact of the patient (eg, relative, friend, partner) to help the patient increase their awareness of skin picking behavior and encourage them to perform the preventive behavior.⁵ The purpose of identifying a close social contact is to ensure accountability for the patient in their day-to-day life, given the limited scope of the relationship between the patient and the dermatologist.

Other practical solutions to skin picking include advising patients to cut their nails short; using finger cots to cover the nails and thus lessen the potential for skin injury; and using a sensory toy, such as a fidget spinner, to distract or occupy the patient when they feel the urge for skin picking.

Practice Implications

Although skin picking disorder is a challenging condition to manage, there are proven techniques for treatment. Techniques drawn from HRT are quite practical and can be implemented by dermatologists for patients with skin picking disorder to reduce the burden of their disease.

Practice Gap

Skin picking disorder is characterized by repetitive deliberate manipulation of the skin that causes noticeable tissue damage. It affects approximately 1.6% of adults in the United States and is associated with marked distress as well as a psychosocial impact.¹ Complications of skin picking disorder can include ulceration, infection, scarring, and disfigurement.

Cognitive behavioral therapy (CBT) techniques have been established to be effective in treating skin picking disorder.² Although referral to a mental health professional is appropriate for patients with skin picking disorder, many of them may not be interested. Cognitive behavioral therapy for diseases at the intersection of psychiatry and dermatology typically is not included in dermatology curricula. Therefore, dermatologists should be aware of CBT techniques that can mitigate the impact of skin picking disorder for patients who decline referral to a mental health professional.

The Technique

Cognitive behavioral therapy is one of the more effective forms of psychotherapy for the treatment of skin picking disorder. Consistent utilization of CBT techniques can achieve relatively permanent change in brain function and contribute to long-term treatment outcomes. A particularly useful CBT technique for skin picking disorder is habit reversal therapy (HRT)(Table). Studies have shown that HRT techniques have demonstrated efficacy in skin picking disorder with sustained impact.³ Patients treated with HRT have reported a greater decrease in skin picking compared with controls after only 3 sessions (P<.01).⁴ There are 3 elements to HRT:

1. Sensitization and awareness training: This facet of HRT involves helping the patient become attuned to warning signals, or feelings, that precede their skin picking, as skin picking often occurs automatically without the patient noticing. Such feelings can include tingling of the skin, tension, and a feeling of being overwhelmed.⁵ Ideally, the physician works with the patient to identify 2 or 3 warning signals that precede skin picking behavior.

2. Competing response training: The patient is encouraged to substitute skin picking with a preventive behavior—for example, crossing the arms and gently squeezing the fists—that is incompatible with skin picking. The preventive behavior should be performed for at least 1 minute as soon as a warning signal appears or skin picking behavior starts. After 1 minute, if the urge for skin picking recurs, then the patient should repeat the preventive behavior.⁵ It can be helpful to practice the preventive behavior with the patient once in the clinic.

3. Social support: This technique involves identifying a close social contact of the patient (eg, relative, friend, partner) to help the patient increase their awareness of skin picking behavior and encourage them to perform the preventive behavior.⁵ The purpose of identifying a close social contact is to ensure accountability for the patient in their day-to-day life, given the limited scope of the relationship between the patient and the dermatologist.

Other practical solutions to skin picking include advising patients to cut their nails short; using finger cots to cover the nails and thus lessen the potential for skin injury; and using a sensory toy, such as a fidget spinner, to distract or occupy the patient when they feel the urge for skin picking.

Practice Implications

Although skin picking disorder is a challenging condition to manage, there are proven techniques for treatment. Techniques drawn from HRT are quite practical and can be implemented by dermatologists for patients with skin picking disorder to reduce the burden of their disease.

Practice Gap

Skin picking disorder is characterized by repetitive deliberate manipulation of the skin that causes noticeable tissue damage. It affects approximately 1.6% of adults in the United States and is associated with marked distress as well as a psychosocial impact.¹ Complications of skin picking disorder can include ulceration, infection, scarring, and disfigurement.

Cognitive behavioral therapy (CBT) techniques have been established to be effective in treating skin picking disorder.² Although referral to a mental health professional is appropriate for patients with skin picking disorder, many of them may not be interested. Cognitive behavioral therapy for diseases at the intersection of psychiatry and dermatology typically is not included in dermatology curricula. Therefore, dermatologists should be aware of CBT techniques that can mitigate the impact of skin picking disorder for patients who decline referral to a mental health professional.

The Technique

Cognitive behavioral therapy is one of the more effective forms of psychotherapy for the treatment of skin picking disorder. Consistent utilization of CBT techniques can achieve relatively permanent change in brain function and contribute to long-term treatment outcomes. A particularly useful CBT technique for skin picking disorder is habit reversal therapy (HRT)(Table). Studies have shown that HRT techniques have demonstrated efficacy in skin picking disorder with sustained impact.³ Patients treated with HRT have reported a greater decrease in skin picking compared with controls after only 3 sessions (P<.01).⁴ There are 3 elements to HRT:

1. Sensitization and awareness training: This facet of HRT involves helping the patient become attuned to warning signals, or feelings, that precede their skin picking, as skin picking often occurs automatically without the patient noticing. Such feelings can include tingling of the skin, tension, and a feeling of being overwhelmed.⁵ Ideally, the physician works with the patient to identify 2 or 3 warning signals that precede skin picking behavior.

2. Competing response training: The patient is encouraged to substitute skin picking with a preventive behavior—for example, crossing the arms and gently squeezing the fists—that is incompatible with skin picking. The preventive behavior should be performed for at least 1 minute as soon as a warning signal appears or skin picking behavior starts. After 1 minute, if the urge for skin picking recurs, then the patient should repeat the preventive behavior.⁵ It can be helpful to practice the preventive behavior with the patient once in the clinic.

3. Social support: This technique involves identifying a close social contact of the patient (eg, relative, friend, partner) to help the patient increase their awareness of skin picking behavior and encourage them to perform the preventive behavior.⁵ The purpose of identifying a close social contact is to ensure accountability for the patient in their day-to-day life, given the limited scope of the relationship between the patient and the dermatologist.

Other practical solutions to skin picking include advising patients to cut their nails short; using finger cots to cover the nails and thus lessen the potential for skin injury; and using a sensory toy, such as a fidget spinner, to distract or occupy the patient when they feel the urge for skin picking.

Practice Implications

Although skin picking disorder is a challenging condition to manage, there are proven techniques for treatment. Techniques drawn from HRT are quite practical and can be implemented by dermatologists for patients with skin picking disorder to reduce the burden of their disease.

The Diagnosis: Porokeratosis Plantaris Palmaris et Disseminata

A 3-mm punch biopsy of the right upper arm showed incipient cornoid lamellae formation, pigment incontinence, and sparse dermal lymphocytic inflammation (Figure), suggestive of porokeratosis plantaris palmaris et disseminata (PPPD). The dermatopathologist recommended a second biopsy to confirm the diagnosis and to confirm that the lesions on the palms and soles also were suggestive of porokeratosis. A second 4-mm punch biopsy of the left palm was consistent with PPPD.

The risks of PPPD as a precancerous entity along with the benefits and side effects of the various management options were discussed with our patient. We recommended that he start low-dose isotretinoin (20 mg/d) due to the large body surface area affected, making focal and field treatments likely insufficient. However, our patient opted not to treat and did not return for follow-up.

Subtypes of porokeratosis, including disseminated superficial actinic porokeratosis (DSAP) and PPPD, are conditions that disrupt the normal maturation of keratin and present clinically with symmetric, crusted, annular papules.¹ The signature but nonspecific histopathologic feature shared among the subtypes is the presence of a cornoid lamellae.² Several triggers of porokeratosis have been proposed, including trauma and exposure to UV and ionizing radiation.^2,3 The clinical variants of porokeratosis are important conditions to diagnose correctly because they portend a risk for Bowen disease and invasive squamous cell carcinoma and may indicate the presence of an underlying hematologic and/or solid organ malignancy.⁴ Management of porokeratosis is difficult, as treatments have shown limited efficacy and variable recurrence rates. Treatment options include focal, field, and systemic options, such as 5-fluorouracil, topical compound of cholesterol and lovastatin, isotretinoin, and acitretin.^1,2

Porokeratoses may arise from gene mutations in the mevalonate pathway,⁵ which is essential for the production of cholesterol.⁶ Topical cholesterol alone has not been shown to improve porokeratosis, but the combination topical therapy of cholesterol and lovastatin is promising. It is theorized to deliver benefit by both providing the essential end product of the pathway and simultaneously reducing the number of potentially toxic intermediates.⁶

Porokeratosis plantaris palmaris et disseminata (also known as porokeratosis plantaris) is unique among the subtypes of porokeratosis in that its annular, red-pink, papular rash with scaling and a keratotic border tends to start distally, involving the palms and soles, and progresses proximally to the trunk with smaller lesions.^1,7 This centripetal progression can take years, as was seen in our patient.¹ The disease is uncommon, with a dearth of published reports on PPPD.² However, case reports have shown that PPPD is strongly linked to family history and may have an autosomal-dominant inheritance pattern. Penetrance is greater in men than in women, as PPPD is twice as common in men.⁸ Most cases of PPPD have been diagnosed in patients in their 20s and 30s, but Hartman et al9 reported a case wherein a patient was diagnosed with PPPD after 65 years of age, similar to our patient.

Although the lesions in DSAP can appear similar to those in PPPD, DSAP is more common among the family of porokeratotic conditions, affecting women twice as often as men, with a sporadic pattern of inheritance.² These same features are present in some other types of porokeratosis but not PPPD. Furthermore, DSAP progresses proximally to distally but often with truncal sparing.²

Akin to PPPD, pityriasis rubra pilaris (PRP) often presents with palmoplantar keratoderma.¹⁰ There are at least 6 types of PRP with varying degrees of similarity to PPPD. However, in many cases PRP is associated with a background of diffuse erythema on the body with islands of spared skin. In addition, cases of PRP have been linked to extracutaneous findings such as ectropion and joint pain.¹¹

Darier disease, especially the acrokeratosis verruciformis of Hopf variant, is more common in men and involves younger populations, as in PPPD.¹¹ However, the crusted lesions seen in Darier disease frequently involve the skin folds. These intertriginous lesions may coalesce, mimicking warts in appearance, and are at risk for secondary infection. Nail findings in Darier disease also are distinct and include longitudinal white or red stripes running along the nail bed, in addition to V-shaped nicks at the nail tips.

Psoriasis can occur anywhere on the body and is associated with silver scaling atop a salmon-colored dermatitis.¹² It results from aberrant proliferation of keratinocytes. Some distinguishing features of psoriasis include a disease course that waxes and wanes as well as pitting of the nails.

Although PPPD typically affects young adults, we presented a case of PPPD in an older man. Porokeratosis plantaris palmaris et disseminata in older adults may represent a delayed diagnosis, imply a broader range for the age of onset, or suggest its manifestation secondary to radiation treatment or another phenomenon. For example, our patient received 35 radiotherapy cycles for tongue cancer more than 5 years prior to the onset of PPPD.

The Diagnosis: Porokeratosis Plantaris Palmaris et Disseminata

A 3-mm punch biopsy of the right upper arm showed incipient cornoid lamellae formation, pigment incontinence, and sparse dermal lymphocytic inflammation (Figure), suggestive of porokeratosis plantaris palmaris et disseminata (PPPD). The dermatopathologist recommended a second biopsy to confirm the diagnosis and to confirm that the lesions on the palms and soles also were suggestive of porokeratosis. A second 4-mm punch biopsy of the left palm was consistent with PPPD.

The risks of PPPD as a precancerous entity along with the benefits and side effects of the various management options were discussed with our patient. We recommended that he start low-dose isotretinoin (20 mg/d) due to the large body surface area affected, making focal and field treatments likely insufficient. However, our patient opted not to treat and did not return for follow-up.

Subtypes of porokeratosis, including disseminated superficial actinic porokeratosis (DSAP) and PPPD, are conditions that disrupt the normal maturation of keratin and present clinically with symmetric, crusted, annular papules.¹ The signature but nonspecific histopathologic feature shared among the subtypes is the presence of a cornoid lamellae.² Several triggers of porokeratosis have been proposed, including trauma and exposure to UV and ionizing radiation.^2,3 The clinical variants of porokeratosis are important conditions to diagnose correctly because they portend a risk for Bowen disease and invasive squamous cell carcinoma and may indicate the presence of an underlying hematologic and/or solid organ malignancy.⁴ Management of porokeratosis is difficult, as treatments have shown limited efficacy and variable recurrence rates. Treatment options include focal, field, and systemic options, such as 5-fluorouracil, topical compound of cholesterol and lovastatin, isotretinoin, and acitretin.^1,2

Porokeratoses may arise from gene mutations in the mevalonate pathway,⁵ which is essential for the production of cholesterol.⁶ Topical cholesterol alone has not been shown to improve porokeratosis, but the combination topical therapy of cholesterol and lovastatin is promising. It is theorized to deliver benefit by both providing the essential end product of the pathway and simultaneously reducing the number of potentially toxic intermediates.⁶

Porokeratosis plantaris palmaris et disseminata (also known as porokeratosis plantaris) is unique among the subtypes of porokeratosis in that its annular, red-pink, papular rash with scaling and a keratotic border tends to start distally, involving the palms and soles, and progresses proximally to the trunk with smaller lesions.^1,7 This centripetal progression can take years, as was seen in our patient.¹ The disease is uncommon, with a dearth of published reports on PPPD.² However, case reports have shown that PPPD is strongly linked to family history and may have an autosomal-dominant inheritance pattern. Penetrance is greater in men than in women, as PPPD is twice as common in men.⁸ Most cases of PPPD have been diagnosed in patients in their 20s and 30s, but Hartman et al9 reported a case wherein a patient was diagnosed with PPPD after 65 years of age, similar to our patient.

Although the lesions in DSAP can appear similar to those in PPPD, DSAP is more common among the family of porokeratotic conditions, affecting women twice as often as men, with a sporadic pattern of inheritance.² These same features are present in some other types of porokeratosis but not PPPD. Furthermore, DSAP progresses proximally to distally but often with truncal sparing.²

Akin to PPPD, pityriasis rubra pilaris (PRP) often presents with palmoplantar keratoderma.¹⁰ There are at least 6 types of PRP with varying degrees of similarity to PPPD. However, in many cases PRP is associated with a background of diffuse erythema on the body with islands of spared skin. In addition, cases of PRP have been linked to extracutaneous findings such as ectropion and joint pain.¹¹

Darier disease, especially the acrokeratosis verruciformis of Hopf variant, is more common in men and involves younger populations, as in PPPD.¹¹ However, the crusted lesions seen in Darier disease frequently involve the skin folds. These intertriginous lesions may coalesce, mimicking warts in appearance, and are at risk for secondary infection. Nail findings in Darier disease also are distinct and include longitudinal white or red stripes running along the nail bed, in addition to V-shaped nicks at the nail tips.

Psoriasis can occur anywhere on the body and is associated with silver scaling atop a salmon-colored dermatitis.¹² It results from aberrant proliferation of keratinocytes. Some distinguishing features of psoriasis include a disease course that waxes and wanes as well as pitting of the nails.

Although PPPD typically affects young adults, we presented a case of PPPD in an older man. Porokeratosis plantaris palmaris et disseminata in older adults may represent a delayed diagnosis, imply a broader range for the age of onset, or suggest its manifestation secondary to radiation treatment or another phenomenon. For example, our patient received 35 radiotherapy cycles for tongue cancer more than 5 years prior to the onset of PPPD.

The Diagnosis: Porokeratosis Plantaris Palmaris et Disseminata

A 3-mm punch biopsy of the right upper arm showed incipient cornoid lamellae formation, pigment incontinence, and sparse dermal lymphocytic inflammation (Figure), suggestive of porokeratosis plantaris palmaris et disseminata (PPPD). The dermatopathologist recommended a second biopsy to confirm the diagnosis and to confirm that the lesions on the palms and soles also were suggestive of porokeratosis. A second 4-mm punch biopsy of the left palm was consistent with PPPD.

The risks of PPPD as a precancerous entity along with the benefits and side effects of the various management options were discussed with our patient. We recommended that he start low-dose isotretinoin (20 mg/d) due to the large body surface area affected, making focal and field treatments likely insufficient. However, our patient opted not to treat and did not return for follow-up.

Subtypes of porokeratosis, including disseminated superficial actinic porokeratosis (DSAP) and PPPD, are conditions that disrupt the normal maturation of keratin and present clinically with symmetric, crusted, annular papules.¹ The signature but nonspecific histopathologic feature shared among the subtypes is the presence of a cornoid lamellae.² Several triggers of porokeratosis have been proposed, including trauma and exposure to UV and ionizing radiation.^2,3 The clinical variants of porokeratosis are important conditions to diagnose correctly because they portend a risk for Bowen disease and invasive squamous cell carcinoma and may indicate the presence of an underlying hematologic and/or solid organ malignancy.⁴ Management of porokeratosis is difficult, as treatments have shown limited efficacy and variable recurrence rates. Treatment options include focal, field, and systemic options, such as 5-fluorouracil, topical compound of cholesterol and lovastatin, isotretinoin, and acitretin.^1,2

Porokeratoses may arise from gene mutations in the mevalonate pathway,⁵ which is essential for the production of cholesterol.⁶ Topical cholesterol alone has not been shown to improve porokeratosis, but the combination topical therapy of cholesterol and lovastatin is promising. It is theorized to deliver benefit by both providing the essential end product of the pathway and simultaneously reducing the number of potentially toxic intermediates.⁶

Porokeratosis plantaris palmaris et disseminata (also known as porokeratosis plantaris) is unique among the subtypes of porokeratosis in that its annular, red-pink, papular rash with scaling and a keratotic border tends to start distally, involving the palms and soles, and progresses proximally to the trunk with smaller lesions.^1,7 This centripetal progression can take years, as was seen in our patient.¹ The disease is uncommon, with a dearth of published reports on PPPD.² However, case reports have shown that PPPD is strongly linked to family history and may have an autosomal-dominant inheritance pattern. Penetrance is greater in men than in women, as PPPD is twice as common in men.⁸ Most cases of PPPD have been diagnosed in patients in their 20s and 30s, but Hartman et al9 reported a case wherein a patient was diagnosed with PPPD after 65 years of age, similar to our patient.

Although the lesions in DSAP can appear similar to those in PPPD, DSAP is more common among the family of porokeratotic conditions, affecting women twice as often as men, with a sporadic pattern of inheritance.² These same features are present in some other types of porokeratosis but not PPPD. Furthermore, DSAP progresses proximally to distally but often with truncal sparing.²

Akin to PPPD, pityriasis rubra pilaris (PRP) often presents with palmoplantar keratoderma.¹⁰ There are at least 6 types of PRP with varying degrees of similarity to PPPD. However, in many cases PRP is associated with a background of diffuse erythema on the body with islands of spared skin. In addition, cases of PRP have been linked to extracutaneous findings such as ectropion and joint pain.¹¹

Darier disease, especially the acrokeratosis verruciformis of Hopf variant, is more common in men and involves younger populations, as in PPPD.¹¹ However, the crusted lesions seen in Darier disease frequently involve the skin folds. These intertriginous lesions may coalesce, mimicking warts in appearance, and are at risk for secondary infection. Nail findings in Darier disease also are distinct and include longitudinal white or red stripes running along the nail bed, in addition to V-shaped nicks at the nail tips.

Psoriasis can occur anywhere on the body and is associated with silver scaling atop a salmon-colored dermatitis.¹² It results from aberrant proliferation of keratinocytes. Some distinguishing features of psoriasis include a disease course that waxes and wanes as well as pitting of the nails.

Although PPPD typically affects young adults, we presented a case of PPPD in an older man. Porokeratosis plantaris palmaris et disseminata in older adults may represent a delayed diagnosis, imply a broader range for the age of onset, or suggest its manifestation secondary to radiation treatment or another phenomenon. For example, our patient received 35 radiotherapy cycles for tongue cancer more than 5 years prior to the onset of PPPD.

Just 16% of psoriasis-related visits to dermatology providers in the United States involve screening for cardiovascular (CV) risk factors, with screening lowest in the region with the highest CV disease burden, according to an analysis of 10 years of national survey data.

From 2007 to 2016, national screening rates for four CV risk factors at 14.8 million psoriasis-related visits to dermatology providers were 11% (body-mass index), 7.4% (blood pressure), 2.9% (cholesterol), and 1.7% (glucose). Data from the National Ambulatory Medical Care Survey showed that at least one of the four factors was screened at 16% of dermatology visits, said William B. Song, BS, of the department of dermatology, University of Pennsylvania, Philadelphia, and associates.

The main focus of their study, however, was regional differences. “CV risk factor screening by dermatology providers for patients with psoriasis is low across all regions of the United States and lowest in the South, the region that experiences the highest CVD burden in the United States,” they wrote in a letter to the editor.

Compared with the South, the adjusted odds of any CV screening were 0.98 in the West, 1.25 in the Northeast, and 1.92 in the Midwest. Blood pressure screening was significantly higher in all three regions, compared with the South, while BMI screening was actually lower in the West (0.74), the investigators reported. Odds ratios were not available for cholesterol and glucose screening because of sample size limitations.

The regional variation in screening rates “is not explained by patient demographics or disease severity,” they noted, adding that 2.8 million visits with BP screening would have been added over the 10-year study period “if providers in the South screened patients with psoriasis for high blood pressure at the same rate as providers in the Northeast.”

Guidelines published in 2019 by the American Academy of Dermatology and the National Psoriasis Foundation – which were cowritten by Joel M. Gelfand, MD, senior author of the current study – noted that dermatologists “play an important role in evidence-based screening of CV risk factors in patients with psoriasis,” the investigators wrote. But the regional variations suggest “that some regions experience barriers to appropriate screening or challenges in adhering to guidelines for managing psoriasis and CV risk.”

While the lack of data from after 2016 is one of the study limitations, they added, “continued efforts to develop effective interventions to improve CV screening and care for people with psoriasis in all regions of the U.S. are needed to more effectively address the burden of CV disease experienced by people with psoriasis.”

The study was partly funded by the National Psoriasis Foundation. Three of the seven investigators disclosed earnings from private companies in the form of consultant fees, research support, and honoraria. Dr. Gelfand is a deputy editor for the Journal of Investigative Dermatology.

Just 16% of psoriasis-related visits to dermatology providers in the United States involve screening for cardiovascular (CV) risk factors, with screening lowest in the region with the highest CV disease burden, according to an analysis of 10 years of national survey data.

From 2007 to 2016, national screening rates for four CV risk factors at 14.8 million psoriasis-related visits to dermatology providers were 11% (body-mass index), 7.4% (blood pressure), 2.9% (cholesterol), and 1.7% (glucose). Data from the National Ambulatory Medical Care Survey showed that at least one of the four factors was screened at 16% of dermatology visits, said William B. Song, BS, of the department of dermatology, University of Pennsylvania, Philadelphia, and associates.

The main focus of their study, however, was regional differences. “CV risk factor screening by dermatology providers for patients with psoriasis is low across all regions of the United States and lowest in the South, the region that experiences the highest CVD burden in the United States,” they wrote in a letter to the editor.

Compared with the South, the adjusted odds of any CV screening were 0.98 in the West, 1.25 in the Northeast, and 1.92 in the Midwest. Blood pressure screening was significantly higher in all three regions, compared with the South, while BMI screening was actually lower in the West (0.74), the investigators reported. Odds ratios were not available for cholesterol and glucose screening because of sample size limitations.

The regional variation in screening rates “is not explained by patient demographics or disease severity,” they noted, adding that 2.8 million visits with BP screening would have been added over the 10-year study period “if providers in the South screened patients with psoriasis for high blood pressure at the same rate as providers in the Northeast.”

Guidelines published in 2019 by the American Academy of Dermatology and the National Psoriasis Foundation – which were cowritten by Joel M. Gelfand, MD, senior author of the current study – noted that dermatologists “play an important role in evidence-based screening of CV risk factors in patients with psoriasis,” the investigators wrote. But the regional variations suggest “that some regions experience barriers to appropriate screening or challenges in adhering to guidelines for managing psoriasis and CV risk.”

While the lack of data from after 2016 is one of the study limitations, they added, “continued efforts to develop effective interventions to improve CV screening and care for people with psoriasis in all regions of the U.S. are needed to more effectively address the burden of CV disease experienced by people with psoriasis.”

The study was partly funded by the National Psoriasis Foundation. Three of the seven investigators disclosed earnings from private companies in the form of consultant fees, research support, and honoraria. Dr. Gelfand is a deputy editor for the Journal of Investigative Dermatology.

Just 16% of psoriasis-related visits to dermatology providers in the United States involve screening for cardiovascular (CV) risk factors, with screening lowest in the region with the highest CV disease burden, according to an analysis of 10 years of national survey data.

From 2007 to 2016, national screening rates for four CV risk factors at 14.8 million psoriasis-related visits to dermatology providers were 11% (body-mass index), 7.4% (blood pressure), 2.9% (cholesterol), and 1.7% (glucose). Data from the National Ambulatory Medical Care Survey showed that at least one of the four factors was screened at 16% of dermatology visits, said William B. Song, BS, of the department of dermatology, University of Pennsylvania, Philadelphia, and associates.

The main focus of their study, however, was regional differences. “CV risk factor screening by dermatology providers for patients with psoriasis is low across all regions of the United States and lowest in the South, the region that experiences the highest CVD burden in the United States,” they wrote in a letter to the editor.

Compared with the South, the adjusted odds of any CV screening were 0.98 in the West, 1.25 in the Northeast, and 1.92 in the Midwest. Blood pressure screening was significantly higher in all three regions, compared with the South, while BMI screening was actually lower in the West (0.74), the investigators reported. Odds ratios were not available for cholesterol and glucose screening because of sample size limitations.

The regional variation in screening rates “is not explained by patient demographics or disease severity,” they noted, adding that 2.8 million visits with BP screening would have been added over the 10-year study period “if providers in the South screened patients with psoriasis for high blood pressure at the same rate as providers in the Northeast.”

Guidelines published in 2019 by the American Academy of Dermatology and the National Psoriasis Foundation – which were cowritten by Joel M. Gelfand, MD, senior author of the current study – noted that dermatologists “play an important role in evidence-based screening of CV risk factors in patients with psoriasis,” the investigators wrote. But the regional variations suggest “that some regions experience barriers to appropriate screening or challenges in adhering to guidelines for managing psoriasis and CV risk.”

While the lack of data from after 2016 is one of the study limitations, they added, “continued efforts to develop effective interventions to improve CV screening and care for people with psoriasis in all regions of the U.S. are needed to more effectively address the burden of CV disease experienced by people with psoriasis.”

The study was partly funded by the National Psoriasis Foundation. Three of the seven investigators disclosed earnings from private companies in the form of consultant fees, research support, and honoraria. Dr. Gelfand is a deputy editor for the Journal of Investigative Dermatology.

During 2 days of hearings on potential modifications to the isotretinoin iPLEDGE Risk Evaluation and Mitigation Strategy (REMS), there was much agreement among dermatologists, industry representatives, and Food and Drug Administration representatives that provider and patient burdens persist after the chaotic rollout of the new REMS platform at the end of 2021.

On March 29, at the end of the FDA’s joint meeting of two advisory committees that addressed ways to improve the iPLEDGE program, most panelists voted to change the 19-day lockout period for patients who can become pregnant, and the requirement that every month, providers must document counseling of those who cannot get pregnant and are taking the drug for acne.

However, there was no consensus on whether there should be a lockout at all or for how long, and what an appropriate interval for counseling those who cannot get pregnant would be, if not monthly. Those voting on the questions repeatedly cited a lack of data to make well-informed decisions.

The meeting of the two panels, the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, was held March 28-29, to discuss proposed changes to iPLEDGE requirements, to minimize the program’s burden on patients, prescribers, and pharmacies – while maintaining safe use of the highly teratogenic drug.

Lockout based on outdated reasoning

John S. Barbieri, MD, a dermatologist and epidemiologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, speaking as deputy chair of the American Academy of Dermatology Association (AADA) iPLEDGE work group, described the burden of getting the drug to patients. He was not on the panel, but spoke during the open public hearing.

“Compared to other acne medications, the time it takes to successfully go from prescribed (isotretinoin) to when the patient actually has it in their hands is 5- to 10-fold higher,” he said.

Many don’t have a monthly cycle

But Dr. Barbieri said that reasoning is outdated.

“The current program’s focus on the menstrual cycle is really an antiquated approach,” he said. “Many patients do not have a monthly cycle due to medical conditions like polycystic ovarian syndrome, or due to [certain kinds of] contraception.”

He added, “By removing this 19-day lockout and, really, the archaic timing around the menstrual cycle in general in this program, we can simplify the program, improve it, and better align it with the real-world biology of our patients.” He added that patients are often missing the 7-day window for picking up their prescriptions through no fault of their own. Speakers at the hearing also mentioned insurance hassles and ordering delays.


 

Communication with IPMG

Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and outgoing chair of the AADA iPLEDGE work group, cited difficulty in working with IPMG on modifications as another barrier. She also spoke during the open public hearing.

UCSF

“Despite many, many attempts to work with the IPMG, we are not aware of any organizational structure or key leaders to communicate with. Instead we have been given repeatedly a generic email address for trying to establish a working relationship and we believe this may explain the inaction of the IPMG since our proposals 4 years ago in 2019.”

Among those proposals, she said, were allowing telemedicine visits as part of the iPLEDGE REMS program and reducing counseling attestation to every 6 months instead of monthly for those who cannot become pregnant.

She pointed to the chaotic rollout of modifications to the iPLEDGE program on a new website at the end of 2021.

In 2021, she said, “despite 6 months of notification, no prescriber input was solicited before revamping the website. This lack of transparency and accountability has been a major hurdle in improving iPLEDGE.”

Dr. Barbieri called the rollout “a debacle” that could have been mitigated with communication with IPMG. “We warned about every issue that happened and talked about ways to mitigate it and were largely ignored,” he said.

“By including dermatologists and key stakeholders in these discussions, as we move forward with changes to improve this program, we can make sure that it’s patient-centered.”

IPMG did not address the specific complaints about the working relationship with the AADA workgroup at the meeting.
 

Monthly attestation for counseling patients who cannot get pregnant

Dr. Barbieri said the monthly requirement to counsel patients who cannot get pregnant and document that counseling unfairly burdens clinicians and patients. “We’re essentially asking patients to come in monthly just to tell them not to share their drugs [or] donate blood,” he said.

Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among the panel members voting not to continue the 19-day lockout.

“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”

IPMG representative Dr. Wedin, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”

He said that while an extension to 120 days would reduce burden on prescribers, it comes with the risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.

“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Dr. Wedin said.
 

Home pregnancy testing

The advisory groups were also tasked with discussing whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most committee members and those in the public hearing who spoke on the issue agreed that home tests should continue in an effort to increase access and decrease burden.

During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory.

Lindsey Crist, PharmD, a risk management analyst at the FDA, who presented the FDA review committee’s analysis, said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.

“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” Dr. Crist said.

Dr. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
 

Workaround to avoid falsification

Advisory committee member Brian P. Green, DO, associate professor of dermatology at Penn State University, Hershey, Pa., spoke in support of home pregnancy tests.

“What we have people do for telemedicine is take the stick, write their name, write the date on it, and send a picture of that the same day as their visit,” he said. “That way we have the pregnancy test the same day. Allowing this to continue to happen at home is important. Bringing people in is burdensome and costly.”

Emmy Graber, MD, a dermatologist who practices in Boston, and a director of the American Acne and Rosacea Society (AARS), relayed an example of the burden for a patient using isotretinoin who lives 1.5 hours away from the dermatology office. She is able to meet the requirements of iPLEDGE only through telehealth.

Suggestions for improvement

At the end of the hearing, advisory committee members were asked to propose improvements to the iPLEDGE REMS program.

Dr. Green advocated for the addition of an iPLEDGE mobile app.

“Most people go to their phones rather than their computers, particularly teenagers and younger people,” he noted.

Advisory committee member Megha M. Tollefson, MD, professor of dermatology and pediatric and adolescent medicine at Mayo Clinic in Rochester, Minn., echoed the need for an iPLEDGE app.

The young patients getting isotretinoin “don’t respond to email, they don’t necessarily go onto web pages. If we’re going to be as effective as possible, it’s going to have to be through an app-based system.”

Dr. Tollefson said she would like to see patient counseling standardized through the app. “I think there’s a lot of variability in what counseling is given when it’s left to the individual prescriber or practice,” she said.
 

Exceptions for long-acting contraceptives?

Advisory committee member Abbey B. Berenson, MD, PhD, professor of obstetrics and gynecology at University of Texas Medical Branch in Galveston, said that patients taking long-acting reversible contraceptives (LARCs) may need to be considered differently when deciding the intervals for attestation or whether to have a lockout period.

“LARC methods’ rate of failure is extremely low,” she said. “While it is true, as it has been pointed out, that all methods can fail, when they’re over 99% effective, I think that we can treat those methods differently than we treat methods such as birth control pills or abstinence that fail far more often. That is one way we could minimize burden on the providers and the patients.”

She also suggested using members of the health care team other than physicians to complete counseling, such as a nurse or pharmacist.
 

Prescriptions for emergency contraception

Advisory committee member Sascha Dublin, MD, PhD, senior scientific investigator for Kaiser Permanente Washington Health Research Institute in Seattle, said most patients taking the drug who can get pregnant should get a prescription for emergency contraception at the time of the first isotretinoin prescription.

“They don’t have to buy it, but to make it available at the very beginning sets the expectation that it would be good to have in your medicine cabinet, particularly if the [contraception] choice is abstinence or birth control pills.”

Dr. Dublin also called for better transparency surrounding the role of IPMG.

She said IPMG should be expected to collect data in a way that allows examination of health disparities, including by race and ethnicity and insurance status. Dr. Dublin added that she was concerned about the poor communication between dermatological societies and IPMG.

“The FDA should really require that IPMG hold periodic, regularly scheduled stakeholder forums,” she said. “There has to be a mechanism in place for IPMG to listen to those concerns in real time and respond.”

The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.

During 2 days of hearings on potential modifications to the isotretinoin iPLEDGE Risk Evaluation and Mitigation Strategy (REMS), there was much agreement among dermatologists, industry representatives, and Food and Drug Administration representatives that provider and patient burdens persist after the chaotic rollout of the new REMS platform at the end of 2021.

On March 29, at the end of the FDA’s joint meeting of two advisory committees that addressed ways to improve the iPLEDGE program, most panelists voted to change the 19-day lockout period for patients who can become pregnant, and the requirement that every month, providers must document counseling of those who cannot get pregnant and are taking the drug for acne.

However, there was no consensus on whether there should be a lockout at all or for how long, and what an appropriate interval for counseling those who cannot get pregnant would be, if not monthly. Those voting on the questions repeatedly cited a lack of data to make well-informed decisions.

The meeting of the two panels, the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, was held March 28-29, to discuss proposed changes to iPLEDGE requirements, to minimize the program’s burden on patients, prescribers, and pharmacies – while maintaining safe use of the highly teratogenic drug.

Lockout based on outdated reasoning

John S. Barbieri, MD, a dermatologist and epidemiologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, speaking as deputy chair of the American Academy of Dermatology Association (AADA) iPLEDGE work group, described the burden of getting the drug to patients. He was not on the panel, but spoke during the open public hearing.

“Compared to other acne medications, the time it takes to successfully go from prescribed (isotretinoin) to when the patient actually has it in their hands is 5- to 10-fold higher,” he said.

Many don’t have a monthly cycle

But Dr. Barbieri said that reasoning is outdated.

“The current program’s focus on the menstrual cycle is really an antiquated approach,” he said. “Many patients do not have a monthly cycle due to medical conditions like polycystic ovarian syndrome, or due to [certain kinds of] contraception.”

He added, “By removing this 19-day lockout and, really, the archaic timing around the menstrual cycle in general in this program, we can simplify the program, improve it, and better align it with the real-world biology of our patients.” He added that patients are often missing the 7-day window for picking up their prescriptions through no fault of their own. Speakers at the hearing also mentioned insurance hassles and ordering delays.


 

Communication with IPMG

Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and outgoing chair of the AADA iPLEDGE work group, cited difficulty in working with IPMG on modifications as another barrier. She also spoke during the open public hearing.

UCSF

“Despite many, many attempts to work with the IPMG, we are not aware of any organizational structure or key leaders to communicate with. Instead we have been given repeatedly a generic email address for trying to establish a working relationship and we believe this may explain the inaction of the IPMG since our proposals 4 years ago in 2019.”

Among those proposals, she said, were allowing telemedicine visits as part of the iPLEDGE REMS program and reducing counseling attestation to every 6 months instead of monthly for those who cannot become pregnant.

She pointed to the chaotic rollout of modifications to the iPLEDGE program on a new website at the end of 2021.

In 2021, she said, “despite 6 months of notification, no prescriber input was solicited before revamping the website. This lack of transparency and accountability has been a major hurdle in improving iPLEDGE.”

Dr. Barbieri called the rollout “a debacle” that could have been mitigated with communication with IPMG. “We warned about every issue that happened and talked about ways to mitigate it and were largely ignored,” he said.

“By including dermatologists and key stakeholders in these discussions, as we move forward with changes to improve this program, we can make sure that it’s patient-centered.”

IPMG did not address the specific complaints about the working relationship with the AADA workgroup at the meeting.
 

Monthly attestation for counseling patients who cannot get pregnant

Dr. Barbieri said the monthly requirement to counsel patients who cannot get pregnant and document that counseling unfairly burdens clinicians and patients. “We’re essentially asking patients to come in monthly just to tell them not to share their drugs [or] donate blood,” he said.

Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among the panel members voting not to continue the 19-day lockout.

“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”

IPMG representative Dr. Wedin, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”

He said that while an extension to 120 days would reduce burden on prescribers, it comes with the risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.

“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Dr. Wedin said.
 

Home pregnancy testing

The advisory groups were also tasked with discussing whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most committee members and those in the public hearing who spoke on the issue agreed that home tests should continue in an effort to increase access and decrease burden.

During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory.

Lindsey Crist, PharmD, a risk management analyst at the FDA, who presented the FDA review committee’s analysis, said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.

“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” Dr. Crist said.

Dr. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
 

Workaround to avoid falsification

Advisory committee member Brian P. Green, DO, associate professor of dermatology at Penn State University, Hershey, Pa., spoke in support of home pregnancy tests.

“What we have people do for telemedicine is take the stick, write their name, write the date on it, and send a picture of that the same day as their visit,” he said. “That way we have the pregnancy test the same day. Allowing this to continue to happen at home is important. Bringing people in is burdensome and costly.”

Emmy Graber, MD, a dermatologist who practices in Boston, and a director of the American Acne and Rosacea Society (AARS), relayed an example of the burden for a patient using isotretinoin who lives 1.5 hours away from the dermatology office. She is able to meet the requirements of iPLEDGE only through telehealth.

Suggestions for improvement

At the end of the hearing, advisory committee members were asked to propose improvements to the iPLEDGE REMS program.

Dr. Green advocated for the addition of an iPLEDGE mobile app.

“Most people go to their phones rather than their computers, particularly teenagers and younger people,” he noted.

Advisory committee member Megha M. Tollefson, MD, professor of dermatology and pediatric and adolescent medicine at Mayo Clinic in Rochester, Minn., echoed the need for an iPLEDGE app.

The young patients getting isotretinoin “don’t respond to email, they don’t necessarily go onto web pages. If we’re going to be as effective as possible, it’s going to have to be through an app-based system.”

Dr. Tollefson said she would like to see patient counseling standardized through the app. “I think there’s a lot of variability in what counseling is given when it’s left to the individual prescriber or practice,” she said.
 

Exceptions for long-acting contraceptives?

Advisory committee member Abbey B. Berenson, MD, PhD, professor of obstetrics and gynecology at University of Texas Medical Branch in Galveston, said that patients taking long-acting reversible contraceptives (LARCs) may need to be considered differently when deciding the intervals for attestation or whether to have a lockout period.

“LARC methods’ rate of failure is extremely low,” she said. “While it is true, as it has been pointed out, that all methods can fail, when they’re over 99% effective, I think that we can treat those methods differently than we treat methods such as birth control pills or abstinence that fail far more often. That is one way we could minimize burden on the providers and the patients.”

She also suggested using members of the health care team other than physicians to complete counseling, such as a nurse or pharmacist.
 

Prescriptions for emergency contraception

Advisory committee member Sascha Dublin, MD, PhD, senior scientific investigator for Kaiser Permanente Washington Health Research Institute in Seattle, said most patients taking the drug who can get pregnant should get a prescription for emergency contraception at the time of the first isotretinoin prescription.

“They don’t have to buy it, but to make it available at the very beginning sets the expectation that it would be good to have in your medicine cabinet, particularly if the [contraception] choice is abstinence or birth control pills.”

Dr. Dublin also called for better transparency surrounding the role of IPMG.

She said IPMG should be expected to collect data in a way that allows examination of health disparities, including by race and ethnicity and insurance status. Dr. Dublin added that she was concerned about the poor communication between dermatological societies and IPMG.

“The FDA should really require that IPMG hold periodic, regularly scheduled stakeholder forums,” she said. “There has to be a mechanism in place for IPMG to listen to those concerns in real time and respond.”

The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.

During 2 days of hearings on potential modifications to the isotretinoin iPLEDGE Risk Evaluation and Mitigation Strategy (REMS), there was much agreement among dermatologists, industry representatives, and Food and Drug Administration representatives that provider and patient burdens persist after the chaotic rollout of the new REMS platform at the end of 2021.

On March 29, at the end of the FDA’s joint meeting of two advisory committees that addressed ways to improve the iPLEDGE program, most panelists voted to change the 19-day lockout period for patients who can become pregnant, and the requirement that every month, providers must document counseling of those who cannot get pregnant and are taking the drug for acne.

However, there was no consensus on whether there should be a lockout at all or for how long, and what an appropriate interval for counseling those who cannot get pregnant would be, if not monthly. Those voting on the questions repeatedly cited a lack of data to make well-informed decisions.

The meeting of the two panels, the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, was held March 28-29, to discuss proposed changes to iPLEDGE requirements, to minimize the program’s burden on patients, prescribers, and pharmacies – while maintaining safe use of the highly teratogenic drug.

Lockout based on outdated reasoning

John S. Barbieri, MD, a dermatologist and epidemiologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, speaking as deputy chair of the American Academy of Dermatology Association (AADA) iPLEDGE work group, described the burden of getting the drug to patients. He was not on the panel, but spoke during the open public hearing.

“Compared to other acne medications, the time it takes to successfully go from prescribed (isotretinoin) to when the patient actually has it in their hands is 5- to 10-fold higher,” he said.

Many don’t have a monthly cycle

But Dr. Barbieri said that reasoning is outdated.

“The current program’s focus on the menstrual cycle is really an antiquated approach,” he said. “Many patients do not have a monthly cycle due to medical conditions like polycystic ovarian syndrome, or due to [certain kinds of] contraception.”

He added, “By removing this 19-day lockout and, really, the archaic timing around the menstrual cycle in general in this program, we can simplify the program, improve it, and better align it with the real-world biology of our patients.” He added that patients are often missing the 7-day window for picking up their prescriptions through no fault of their own. Speakers at the hearing also mentioned insurance hassles and ordering delays.


 

Communication with IPMG

Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and outgoing chair of the AADA iPLEDGE work group, cited difficulty in working with IPMG on modifications as another barrier. She also spoke during the open public hearing.

UCSF

“Despite many, many attempts to work with the IPMG, we are not aware of any organizational structure or key leaders to communicate with. Instead we have been given repeatedly a generic email address for trying to establish a working relationship and we believe this may explain the inaction of the IPMG since our proposals 4 years ago in 2019.”

Among those proposals, she said, were allowing telemedicine visits as part of the iPLEDGE REMS program and reducing counseling attestation to every 6 months instead of monthly for those who cannot become pregnant.

She pointed to the chaotic rollout of modifications to the iPLEDGE program on a new website at the end of 2021.

In 2021, she said, “despite 6 months of notification, no prescriber input was solicited before revamping the website. This lack of transparency and accountability has been a major hurdle in improving iPLEDGE.”

Dr. Barbieri called the rollout “a debacle” that could have been mitigated with communication with IPMG. “We warned about every issue that happened and talked about ways to mitigate it and were largely ignored,” he said.

“By including dermatologists and key stakeholders in these discussions, as we move forward with changes to improve this program, we can make sure that it’s patient-centered.”

IPMG did not address the specific complaints about the working relationship with the AADA workgroup at the meeting.
 

Monthly attestation for counseling patients who cannot get pregnant

Dr. Barbieri said the monthly requirement to counsel patients who cannot get pregnant and document that counseling unfairly burdens clinicians and patients. “We’re essentially asking patients to come in monthly just to tell them not to share their drugs [or] donate blood,” he said.

Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among the panel members voting not to continue the 19-day lockout.

“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”

IPMG representative Dr. Wedin, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”

He said that while an extension to 120 days would reduce burden on prescribers, it comes with the risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.

“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Dr. Wedin said.
 

Home pregnancy testing

The advisory groups were also tasked with discussing whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most committee members and those in the public hearing who spoke on the issue agreed that home tests should continue in an effort to increase access and decrease burden.

During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory.

Lindsey Crist, PharmD, a risk management analyst at the FDA, who presented the FDA review committee’s analysis, said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.

“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” Dr. Crist said.

Dr. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
 

Workaround to avoid falsification

Advisory committee member Brian P. Green, DO, associate professor of dermatology at Penn State University, Hershey, Pa., spoke in support of home pregnancy tests.

“What we have people do for telemedicine is take the stick, write their name, write the date on it, and send a picture of that the same day as their visit,” he said. “That way we have the pregnancy test the same day. Allowing this to continue to happen at home is important. Bringing people in is burdensome and costly.”

Emmy Graber, MD, a dermatologist who practices in Boston, and a director of the American Acne and Rosacea Society (AARS), relayed an example of the burden for a patient using isotretinoin who lives 1.5 hours away from the dermatology office. She is able to meet the requirements of iPLEDGE only through telehealth.

Suggestions for improvement

At the end of the hearing, advisory committee members were asked to propose improvements to the iPLEDGE REMS program.

Dr. Green advocated for the addition of an iPLEDGE mobile app.

“Most people go to their phones rather than their computers, particularly teenagers and younger people,” he noted.

Advisory committee member Megha M. Tollefson, MD, professor of dermatology and pediatric and adolescent medicine at Mayo Clinic in Rochester, Minn., echoed the need for an iPLEDGE app.

The young patients getting isotretinoin “don’t respond to email, they don’t necessarily go onto web pages. If we’re going to be as effective as possible, it’s going to have to be through an app-based system.”

Dr. Tollefson said she would like to see patient counseling standardized through the app. “I think there’s a lot of variability in what counseling is given when it’s left to the individual prescriber or practice,” she said.
 

Exceptions for long-acting contraceptives?

Advisory committee member Abbey B. Berenson, MD, PhD, professor of obstetrics and gynecology at University of Texas Medical Branch in Galveston, said that patients taking long-acting reversible contraceptives (LARCs) may need to be considered differently when deciding the intervals for attestation or whether to have a lockout period.

“LARC methods’ rate of failure is extremely low,” she said. “While it is true, as it has been pointed out, that all methods can fail, when they’re over 99% effective, I think that we can treat those methods differently than we treat methods such as birth control pills or abstinence that fail far more often. That is one way we could minimize burden on the providers and the patients.”

She also suggested using members of the health care team other than physicians to complete counseling, such as a nurse or pharmacist.
 

Prescriptions for emergency contraception

Advisory committee member Sascha Dublin, MD, PhD, senior scientific investigator for Kaiser Permanente Washington Health Research Institute in Seattle, said most patients taking the drug who can get pregnant should get a prescription for emergency contraception at the time of the first isotretinoin prescription.

“They don’t have to buy it, but to make it available at the very beginning sets the expectation that it would be good to have in your medicine cabinet, particularly if the [contraception] choice is abstinence or birth control pills.”

Dr. Dublin also called for better transparency surrounding the role of IPMG.

She said IPMG should be expected to collect data in a way that allows examination of health disparities, including by race and ethnicity and insurance status. Dr. Dublin added that she was concerned about the poor communication between dermatological societies and IPMG.

“The FDA should really require that IPMG hold periodic, regularly scheduled stakeholder forums,” she said. “There has to be a mechanism in place for IPMG to listen to those concerns in real time and respond.”

The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.

Diversity of health care professionals improves medical outcomes and quality of life in patients. ¹ There is a lack of diversity in dermatology, with only 4.2% of dermatologists identifying as Hispanic and 3% identifying as African American, ² possibly due to a lack of early exposure to dermatology among high school and undergraduate students, a low number of underrepresented students in medical school, a lack of formal mentorship programs geared to underrepresented students, and implicit biases. ^1-4 Furthermore, the field is competitive, with many more applicants than available positions. In 2022, there were 851 applicants competing for 492 residency positions in dermatology. ⁵ Thus, it is important to educate young students about dermatology and understand root causes as to why the number of u nderrepresented in medicine (UiM) dermatologists remains stagnant.

According to Pritchett et al,⁴ it is crucial for dermatologists to interact with high school and college students to foster an early interest in dermatology. Many racial minority students do not progress from high school to college and then from college to medical school, which leaves a substantially reduced number of eligible UiM applicants who can progress into dermatology.⁶ Increasing the amount of UiM students going to medical school requires early mediation. Collaborating with pre-existing premedical school organizations through presentations and workshops is another way to promote an early interest in dermatology.⁴ Special consideration should be given to students who are UiM.

Among the general medical school curriculum, requirements for exposure to dermatology are not high. In one study, the median number of clinical and preclinical hours required was 10. Furthermore, 20% of 33 medical schools did not require preclinical dermatology hours (hours done before medical school rotations begin and in an academic setting), 36% required no clinical hours (rotational hours), 8% required no dermatology hours whatsoever, and only 10% required clinical dermatology rotation.³ Based on these findings, it is clear that dermatology is not well incorporated into medical school curricula. Furthermore, curricula have historically neglected to display adequate representation of skin of color.⁷ As a result, medical students generally have limited exposure to dermatology³ and are exposed even less to presentations of dermatologic issues in historically marginalized populations.⁷

Given the paucity of research on UiM students’ perceptions of dermatology prior to medical school, our cross-sectional survey study sought to evaluate the level of interest in dermatology of UiM premedical undergraduates. This survey specifically evaluated exposure to dermatology, preconceived notions about the field, and mentorship opportunities. By understanding these factors, dermatologists and dermatology residency programs can use this information to create mentorship opportunities and better adjust existing programs to meet students’ needs.

Methods

A 19-question multiple-choice survey was administered electronically (SurveyMonkey) in May 2020 to premedical students at Howard University (Washington, DC). One screening question was used: “What is your major?” Those who considered themselves a science major and/or with premedical interest were allowed to complete the survey. All students surveyed were members of the Health Professions Society at Howard University. Students who were interested in pursuing medical school were invited to respond. Approval for this study was obtained from the Howard University institutional review board (FWA00000891).

The survey was divided into 3 sections: Demographics, Exposure to Medicine and Dermatology, and Perceptions of Dermatology. The Demographics section addressed gender, age, and race/ethnicity. The Exposure to Medicine and Dermatology section addressed interest in attending medical school, shadowing experience, exposure to dermatology, and mentoring. The Perceptions of Dermatology section addressed preconceived notions about the field (eg, “dermatology is interesting and exciting”).

Statistical Analysis—The data represented are percentages based on the number of respondents who answered each question. Answers in response to “Please enter any comments” were organized into themes, and the number of respondents who discussed each theme was quantified into a table.

A total of 271 survey invitations were sent to premedical students at Howard University. Students were informed of the study protocol and asked to consent before proceeding to have their responses anonymously collected. Based on the screening question, 152 participants qualified for the survey, and 152 participants completed it (response rate, 56%; completion rate, 100%). Participants were asked to complete the survey only once.

Demographics—Eighty-four percent of respondents identified as science majors, and the remaining 16% identified as nonscience premedical. Ninety-four percent of participants identified as Black or African American; 3% as Asian or Asian American; and the remaining 3% as Other. Most respondents were female (82%), 16% were male, and 2% were either nonbinary or preferred not to answer. Ninety-nine percent were aged 18 to 24 years, and 1% were aged 25 to 34 years (Table 1).

Exposure to Medicine and Dermatology—Ninety-three percent of participants planned on attending medical school, and most students developed an interest in medicine from an early age. Ninety-six percent cited that they became interested in medicine prior to beginning their undergraduate education, and 4% developed an interest as freshmen or sophomores. When asked what led to their interest in medicine, family influence had the single greatest impact on students’ decision to pursue medicine (33%). Classes/school were the second most influential factor (24%), followed by volunteering (15%), shadowing (13%), other (7%), and peer influence (3%)(Figure 1).

Many (56%) premedical students surveyed had shadowing experience to varying degrees. Approximately 18% had fewer than 8 hours of shadowing experience, 24% had 8 to 40 hours, and 14% had more than 40 hours. However, many (43%) premedical students had no shadowing experience (Figure 2). Similarly, 30% of premedical students responded to having a physician as a mentor.

Regarding exposure to dermatology, 42% of premedical students had none. However, 58% of students had exposure to dermatology by being a patient themselves, 40% through seeing a dermatologist with a family member, 21% through seeing a dermatologist on television or social media, 5% through shadowing or volunteering, 3% through mentorship, and 1% through dermatology research (Figure 3).

Of students who said they were interested in dermatology (32%), 16% developed their interest before undergraduate education, while 9% developed interest in their freshman or sophomore year and 7% in their junior or senior year of undergraduate education. Three percent of respondents indicated that they had a dermatology mentorship.

Perceptions of Dermatology—To further evaluate the level of interest that UiM premedical students have in the field of dermatology, students were asked how much they agree or disagree on whether the field of dermatology is interesting. Sixty-three percent of the students agreed that the field of dermatology is interesting, 34% remained uncertain, and 3% disagreed. Additionally, students were asked whether they would consider dermatology as a career; 54% of respondents would consider dermatology as a career, 30% remained uncertain, and 16% would not consider dermatology as a career choice.

Nearly all (95%) students agreed that dermatologists do valuable work that goes beyond the scope of cosmetic procedures such as neuromodulators, fillers, chemical peels, and lasers. Some students also noted they had personal experiences interacting with a dermatologist. For example, one student described visiting the dermatologist many times to get a treatment regimen for their eczema.

Overall themes from the survey are depicted in Table 2. Major themes found in the comments included the desire for more dermatology-related opportunities, mentorship, exposure, connections, and a discussion of disparities faced by Black patients and students within dermatology. Students also expressed an interest in dermatology and the desire to learn more about the specialty.

Comment

Interest in Dermatology—In this cross-sectional survey study of 152 UiM undergraduate students, it was found that many students were interested in dermatology as a career, and more than 70% would be interested in attending events that increased exposure to the field of dermatology. Of the students who had any exposure to dermatology, less than 5% had shadowed an actual dermatologist. The survey showed that there is great potential interest in exposing UiM undergraduate students to the field of dermatology. We found that UiM students are interested in learning more about dermatology, with 80% indicating that they would be willing to participate in dermatology-focused events if they were available. Overall, students mentioned a lack of opportunities, mentorship, exposure, and connections in dermatology despite their interest in the field.

Racial Disparities in Dermatology—Additionally, students discussed disparities they encountered with dermatology due to a lack of patient-provider race concordance and the perceived difference in care when encountering a race-concordant dermatologist. One student noted that they went to multiple White dermatologists for their eczema, and “it wasn’t until I was evaluated by a Black dermatologist (diagnosed with eczema as well) [that I was] prescribed . . . the perfect medication.” Another student noted how a Black dermatologist sparked their interest in getting to know more about the field and remarked that they “think it is an important field that lacks representation for Black people.” This research stresses the need for more dermatology mentorship among UiM undergraduates.

Family Influence on Career Selection—The majority of UiM students in our study became interested in medicine because of family, which is consistent with other studies. In a cross-sectional survey of 300 Pakistani students (150 medical and 150 nonmedical), 87% of students stated that their family had an influence on their career selection.⁸ In another study of 15 junior doctors in Sierra Leone, the most common reasons for pursuing medicine were the desire to help and familial and peer influence.⁹ This again showcases how family can have a positive impact on career selection for medical professionals and highlights the need for early intervention.

Shadowing—One way in which student exposure to dermatology can be effectively increased is by shadowing. In a study evaluating a 30-week shadowing program at the Pediatric Continuity Clinic in Los Angeles, California, a greater proportion of premedical students believed they had a good understanding of the job of a resident physician after the program’s completion compared to before starting the program (an increase from 78% to 100%).¹⁰ The proportion of students reporting a good understanding of the patient-physician relationship after completing the program also increased from 33% to 78%. Furthermore, 72% of the residents stated that having the undergraduates in the clinic was a positive experience.¹⁰ Thus, increasing shadowing opportunities is one extremely effective way to increase student knowledge and awareness of and exposure to dermatology.

Dermatology Mentors—Although 32% of students were interested in dermatology, 3% of students had mentorship in dermatology. In prior studies, it has been shown that mentorship is of great importance in student success and interest in pursuing a specialty. A report from the Association of American Medical Colleges 2019 Medical School Graduation Questionnaire found that the third most influential factor (52.1%) in specialty selection was role model influence.¹¹ In fact, having a role model is consistently one of the top 3 influences on student specialty choice and interest in the last 5 years of survey research. Some studies also have shown mentorship as a positive influence in specialty interest at the undergraduate and graduate levels. A study on an undergraduate student interest group noted that surgeon mentorship and exposure were positive factors to students’ interests in surgery.¹² In fact, the Association of American Medical Colleges noted that some surgical specialties, such as orthopedic surgery, had 45% of respondents who were interested in the specialty before medical school pursue their initial preference in medical school.¹³ Another survey corroborated these findings; more orthopedic-bound students compared with other specialties indicated they were more likely to pursue their field because of experiences prior to medical school.¹⁴

One of the reasons students might not have been exposed to as many opportunities for mentorship in dermatology is because the specialty is one of the smaller fields in medicine and tends to be concentrated in more well-resourced metropolitan areas.¹⁵ Dermatologists make up only 1.3% of the physician workforce.¹⁶ Because there might not be as much exposure to the field, students might also explore their interests in dermatology through other fields, such as through shadowing and observing primary care physicians who often treat patients with dermatologic issues. Skin diseases are a common reason for primary care visits, and one study suggested dermatologic diseases can make up approximately 8.4% of visits in primary care.¹⁷

Moreover, only 1% of medical schools require an elective in dermatology.¹⁸ With exposure being a crucial component to pursuing the specialty, it also is important to pursue formal mentorship within the specialty itself. One study noted that formal mentorship in dermatology was important for most (67%) respondents when considering the specialty; however, 39% of respondents mentioned receiving mentorship in the past. In fact, dermatology was one of the top 3 specialties for which respondents agreed that formal mentorship was important.¹⁹

Mentorship also has been shown to provide students with a variety of opportunities to develop personally and professionally. Some of these opportunities include increased confidence in their personal and professional success, increased desire to pursue a career in a field of interest, networking opportunities, career coaching, and support and research guidance.²⁰ A research study among medical students at Albert Einstein College of Medicine in New York, New York, found that US Medical Licensing Examination Step 1 scores, clinical grades, and the chance of not matching were important factors preventing them from applying to dermatology.²¹

Factors in Dermatology Residency Selection—A survey was conducted wherein 95 of 114 dermatology program directors expressed that among the top 5 criteria for dermatology resident selection were Step 1 scores and clinical grades, supporting the notion that academic factors were given a great emphasis during residency selection.²² Furthermore, among underrepresented minority medical students, a lack of diversity, the belief that minority students are seen negatively by residencies, socioeconomic factors, and not having mentors were major reasons for being dissuaded from applying to dermatology.²¹ These results showcase the heightened importance of mentors for underrepresented minority medical students in particular.

In graduate medical education, resources such as wikis, social networking sites, and blogs provide media through which trainees can communicate, exchange ideas, and enhance their medical knowledge.^23,24 A survey of 9606 osteopathic medical students showed that 35% of 992 respondents had used social media to learn more about residencies, and 10% believed that social media had influenced their choice of residency.²⁵ Given the impact social media has on recruitment, it also can be employed in a similar manner by dermatologists and dermatology residency programs to attract younger students to the field.

Access to More Opportunities to Learn About Dermatology—Besides shadowing and mentorship, other avenues of exposure to dermatology are possible and should be considered. In our study, 80% of students agreed that they would attend an event that increases exposure to dermatology if held by the premedical group, which suggests that students are eager to learn more about the field and want access to more opportunities, which could include learning procedures such as suturing or how to use a dermatoscope, attending guest speaker events, or participating in Learn2Derm volunteer events.

Learn2Derm was a skin cancer prevention fair first organized by medical students at George Washington University in Washington, DC. Students and residents sought to deliver sunscreens to underserved areas in Washington, DC, as well as teach residents about the importance of skin health. Participating in such events could be an excellent opportunity for all students to gain exposure to important topics in dermatology.²⁶

General Opinions of Dermatology—General opinions about dermatology and medicine were collected from the students through the optional “Additional Comments” section. Major themes found in the comments included the desire for more opportunities, mentorship, exposure, connections, and a discussion of disparities faced by Black patients/students within dermatology. Students also expressed an interest in dermatology and the desire to learn more about the specialty. From these themes, it can be gleaned that students are open to and eager for more opportunities to gain exposure and connections, and increasing the number of minority dermatologists is of importance.

Limitations—An important limitation of this study was the potential for selection bias, as the sample was chosen from a population at one university, which is not representative of the general population. Further, we only sampled students who were premedical and likely from a UiM racial group due to the demographics of the student population at the university, but given that the goal of the survey was to understand exposure to dermatology in underrepresented groups, we believe it was the appropriate population to target. Additionally, results were not compared with other more represented racial groups to see if these findings were unique to UiM undergraduate students.

Conclusion

Among premedical students, dermatology is an area of great interest with minimal opportunities available for exposure and learning because it is a smaller specialty with fewer experiences available for shadowing and mentorship. Although most UiM premedical students who were surveyed were exposed to the field through either the media or being a dermatology patient, fewer were exposed to the field through clinical experiences (such as shadowing) or mentorship. Most respondents found dermatology to be interesting and have considered pursuing it as a career. In particular, race-concordant mentoring in dermatologic care was valued by many students in garnering their interest in the field.

Most UiM students wanted more exposure to dermatology-related opportunities as well as mentorship and connections. Increasing shadowing, research, pipeline programs, and general events geared to dermatology are some modalities that could help improve exposure to dermatology for UiM students, especially for those interested in pursuing the field. This increased exposure can help positively influence more UiM students to pursue dermatology and help close the diversity gap in the field. Additionally, many were interested in attending potential dermatology informational events.

Given the fact that dermatology is a small field and mentorship may be hard to access, increasing informational events may be a more reasonable approach to inspiring and supporting interest. These events could include learning how to use certain tools and techniques, guest speaker events, or participating in educational volunteer efforts such as Learn2Derm.²⁶

Future research should focus on identifying beneficial factors of UiM premedical students who retain an interest in dermatology throughout their careers and actually apply to dermatology programs and become dermatologists. Those who do not apply to the specialty can be identified to understand potential dissuading factors and obstacles. Ultimately, more research and development of exposure opportunities, including mentorship programs and informational events, can be used to close the gap and improve diversity and health outcomes in dermatology.

Diversity of health care professionals improves medical outcomes and quality of life in patients. ¹ There is a lack of diversity in dermatology, with only 4.2% of dermatologists identifying as Hispanic and 3% identifying as African American, ² possibly due to a lack of early exposure to dermatology among high school and undergraduate students, a low number of underrepresented students in medical school, a lack of formal mentorship programs geared to underrepresented students, and implicit biases. ^1-4 Furthermore, the field is competitive, with many more applicants than available positions. In 2022, there were 851 applicants competing for 492 residency positions in dermatology. ⁵ Thus, it is important to educate young students about dermatology and understand root causes as to why the number of u nderrepresented in medicine (UiM) dermatologists remains stagnant.

According to Pritchett et al,⁴ it is crucial for dermatologists to interact with high school and college students to foster an early interest in dermatology. Many racial minority students do not progress from high school to college and then from college to medical school, which leaves a substantially reduced number of eligible UiM applicants who can progress into dermatology.⁶ Increasing the amount of UiM students going to medical school requires early mediation. Collaborating with pre-existing premedical school organizations through presentations and workshops is another way to promote an early interest in dermatology.⁴ Special consideration should be given to students who are UiM.

Among the general medical school curriculum, requirements for exposure to dermatology are not high. In one study, the median number of clinical and preclinical hours required was 10. Furthermore, 20% of 33 medical schools did not require preclinical dermatology hours (hours done before medical school rotations begin and in an academic setting), 36% required no clinical hours (rotational hours), 8% required no dermatology hours whatsoever, and only 10% required clinical dermatology rotation.³ Based on these findings, it is clear that dermatology is not well incorporated into medical school curricula. Furthermore, curricula have historically neglected to display adequate representation of skin of color.⁷ As a result, medical students generally have limited exposure to dermatology³ and are exposed even less to presentations of dermatologic issues in historically marginalized populations.⁷

Given the paucity of research on UiM students’ perceptions of dermatology prior to medical school, our cross-sectional survey study sought to evaluate the level of interest in dermatology of UiM premedical undergraduates. This survey specifically evaluated exposure to dermatology, preconceived notions about the field, and mentorship opportunities. By understanding these factors, dermatologists and dermatology residency programs can use this information to create mentorship opportunities and better adjust existing programs to meet students’ needs.

Methods

A 19-question multiple-choice survey was administered electronically (SurveyMonkey) in May 2020 to premedical students at Howard University (Washington, DC). One screening question was used: “What is your major?” Those who considered themselves a science major and/or with premedical interest were allowed to complete the survey. All students surveyed were members of the Health Professions Society at Howard University. Students who were interested in pursuing medical school were invited to respond. Approval for this study was obtained from the Howard University institutional review board (FWA00000891).

The survey was divided into 3 sections: Demographics, Exposure to Medicine and Dermatology, and Perceptions of Dermatology. The Demographics section addressed gender, age, and race/ethnicity. The Exposure to Medicine and Dermatology section addressed interest in attending medical school, shadowing experience, exposure to dermatology, and mentoring. The Perceptions of Dermatology section addressed preconceived notions about the field (eg, “dermatology is interesting and exciting”).

Statistical Analysis—The data represented are percentages based on the number of respondents who answered each question. Answers in response to “Please enter any comments” were organized into themes, and the number of respondents who discussed each theme was quantified into a table.

A total of 271 survey invitations were sent to premedical students at Howard University. Students were informed of the study protocol and asked to consent before proceeding to have their responses anonymously collected. Based on the screening question, 152 participants qualified for the survey, and 152 participants completed it (response rate, 56%; completion rate, 100%). Participants were asked to complete the survey only once.

Demographics—Eighty-four percent of respondents identified as science majors, and the remaining 16% identified as nonscience premedical. Ninety-four percent of participants identified as Black or African American; 3% as Asian or Asian American; and the remaining 3% as Other. Most respondents were female (82%), 16% were male, and 2% were either nonbinary or preferred not to answer. Ninety-nine percent were aged 18 to 24 years, and 1% were aged 25 to 34 years (Table 1).

Exposure to Medicine and Dermatology—Ninety-three percent of participants planned on attending medical school, and most students developed an interest in medicine from an early age. Ninety-six percent cited that they became interested in medicine prior to beginning their undergraduate education, and 4% developed an interest as freshmen or sophomores. When asked what led to their interest in medicine, family influence had the single greatest impact on students’ decision to pursue medicine (33%). Classes/school were the second most influential factor (24%), followed by volunteering (15%), shadowing (13%), other (7%), and peer influence (3%)(Figure 1).

Many (56%) premedical students surveyed had shadowing experience to varying degrees. Approximately 18% had fewer than 8 hours of shadowing experience, 24% had 8 to 40 hours, and 14% had more than 40 hours. However, many (43%) premedical students had no shadowing experience (Figure 2). Similarly, 30% of premedical students responded to having a physician as a mentor.

Regarding exposure to dermatology, 42% of premedical students had none. However, 58% of students had exposure to dermatology by being a patient themselves, 40% through seeing a dermatologist with a family member, 21% through seeing a dermatologist on television or social media, 5% through shadowing or volunteering, 3% through mentorship, and 1% through dermatology research (Figure 3).

Of students who said they were interested in dermatology (32%), 16% developed their interest before undergraduate education, while 9% developed interest in their freshman or sophomore year and 7% in their junior or senior year of undergraduate education. Three percent of respondents indicated that they had a dermatology mentorship.

Perceptions of Dermatology—To further evaluate the level of interest that UiM premedical students have in the field of dermatology, students were asked how much they agree or disagree on whether the field of dermatology is interesting. Sixty-three percent of the students agreed that the field of dermatology is interesting, 34% remained uncertain, and 3% disagreed. Additionally, students were asked whether they would consider dermatology as a career; 54% of respondents would consider dermatology as a career, 30% remained uncertain, and 16% would not consider dermatology as a career choice.

Nearly all (95%) students agreed that dermatologists do valuable work that goes beyond the scope of cosmetic procedures such as neuromodulators, fillers, chemical peels, and lasers. Some students also noted they had personal experiences interacting with a dermatologist. For example, one student described visiting the dermatologist many times to get a treatment regimen for their eczema.

Overall themes from the survey are depicted in Table 2. Major themes found in the comments included the desire for more dermatology-related opportunities, mentorship, exposure, connections, and a discussion of disparities faced by Black patients and students within dermatology. Students also expressed an interest in dermatology and the desire to learn more about the specialty.

Comment

Interest in Dermatology—In this cross-sectional survey study of 152 UiM undergraduate students, it was found that many students were interested in dermatology as a career, and more than 70% would be interested in attending events that increased exposure to the field of dermatology. Of the students who had any exposure to dermatology, less than 5% had shadowed an actual dermatologist. The survey showed that there is great potential interest in exposing UiM undergraduate students to the field of dermatology. We found that UiM students are interested in learning more about dermatology, with 80% indicating that they would be willing to participate in dermatology-focused events if they were available. Overall, students mentioned a lack of opportunities, mentorship, exposure, and connections in dermatology despite their interest in the field.

Racial Disparities in Dermatology—Additionally, students discussed disparities they encountered with dermatology due to a lack of patient-provider race concordance and the perceived difference in care when encountering a race-concordant dermatologist. One student noted that they went to multiple White dermatologists for their eczema, and “it wasn’t until I was evaluated by a Black dermatologist (diagnosed with eczema as well) [that I was] prescribed . . . the perfect medication.” Another student noted how a Black dermatologist sparked their interest in getting to know more about the field and remarked that they “think it is an important field that lacks representation for Black people.” This research stresses the need for more dermatology mentorship among UiM undergraduates.

Family Influence on Career Selection—The majority of UiM students in our study became interested in medicine because of family, which is consistent with other studies. In a cross-sectional survey of 300 Pakistani students (150 medical and 150 nonmedical), 87% of students stated that their family had an influence on their career selection.⁸ In another study of 15 junior doctors in Sierra Leone, the most common reasons for pursuing medicine were the desire to help and familial and peer influence.⁹ This again showcases how family can have a positive impact on career selection for medical professionals and highlights the need for early intervention.

Shadowing—One way in which student exposure to dermatology can be effectively increased is by shadowing. In a study evaluating a 30-week shadowing program at the Pediatric Continuity Clinic in Los Angeles, California, a greater proportion of premedical students believed they had a good understanding of the job of a resident physician after the program’s completion compared to before starting the program (an increase from 78% to 100%).¹⁰ The proportion of students reporting a good understanding of the patient-physician relationship after completing the program also increased from 33% to 78%. Furthermore, 72% of the residents stated that having the undergraduates in the clinic was a positive experience.¹⁰ Thus, increasing shadowing opportunities is one extremely effective way to increase student knowledge and awareness of and exposure to dermatology.

Dermatology Mentors—Although 32% of students were interested in dermatology, 3% of students had mentorship in dermatology. In prior studies, it has been shown that mentorship is of great importance in student success and interest in pursuing a specialty. A report from the Association of American Medical Colleges 2019 Medical School Graduation Questionnaire found that the third most influential factor (52.1%) in specialty selection was role model influence.¹¹ In fact, having a role model is consistently one of the top 3 influences on student specialty choice and interest in the last 5 years of survey research. Some studies also have shown mentorship as a positive influence in specialty interest at the undergraduate and graduate levels. A study on an undergraduate student interest group noted that surgeon mentorship and exposure were positive factors to students’ interests in surgery.¹² In fact, the Association of American Medical Colleges noted that some surgical specialties, such as orthopedic surgery, had 45% of respondents who were interested in the specialty before medical school pursue their initial preference in medical school.¹³ Another survey corroborated these findings; more orthopedic-bound students compared with other specialties indicated they were more likely to pursue their field because of experiences prior to medical school.¹⁴

One of the reasons students might not have been exposed to as many opportunities for mentorship in dermatology is because the specialty is one of the smaller fields in medicine and tends to be concentrated in more well-resourced metropolitan areas.¹⁵ Dermatologists make up only 1.3% of the physician workforce.¹⁶ Because there might not be as much exposure to the field, students might also explore their interests in dermatology through other fields, such as through shadowing and observing primary care physicians who often treat patients with dermatologic issues. Skin diseases are a common reason for primary care visits, and one study suggested dermatologic diseases can make up approximately 8.4% of visits in primary care.¹⁷

Moreover, only 1% of medical schools require an elective in dermatology.¹⁸ With exposure being a crucial component to pursuing the specialty, it also is important to pursue formal mentorship within the specialty itself. One study noted that formal mentorship in dermatology was important for most (67%) respondents when considering the specialty; however, 39% of respondents mentioned receiving mentorship in the past. In fact, dermatology was one of the top 3 specialties for which respondents agreed that formal mentorship was important.¹⁹

Mentorship also has been shown to provide students with a variety of opportunities to develop personally and professionally. Some of these opportunities include increased confidence in their personal and professional success, increased desire to pursue a career in a field of interest, networking opportunities, career coaching, and support and research guidance.²⁰ A research study among medical students at Albert Einstein College of Medicine in New York, New York, found that US Medical Licensing Examination Step 1 scores, clinical grades, and the chance of not matching were important factors preventing them from applying to dermatology.²¹

Factors in Dermatology Residency Selection—A survey was conducted wherein 95 of 114 dermatology program directors expressed that among the top 5 criteria for dermatology resident selection were Step 1 scores and clinical grades, supporting the notion that academic factors were given a great emphasis during residency selection.²² Furthermore, among underrepresented minority medical students, a lack of diversity, the belief that minority students are seen negatively by residencies, socioeconomic factors, and not having mentors were major reasons for being dissuaded from applying to dermatology.²¹ These results showcase the heightened importance of mentors for underrepresented minority medical students in particular.

In graduate medical education, resources such as wikis, social networking sites, and blogs provide media through which trainees can communicate, exchange ideas, and enhance their medical knowledge.^23,24 A survey of 9606 osteopathic medical students showed that 35% of 992 respondents had used social media to learn more about residencies, and 10% believed that social media had influenced their choice of residency.²⁵ Given the impact social media has on recruitment, it also can be employed in a similar manner by dermatologists and dermatology residency programs to attract younger students to the field.

Access to More Opportunities to Learn About Dermatology—Besides shadowing and mentorship, other avenues of exposure to dermatology are possible and should be considered. In our study, 80% of students agreed that they would attend an event that increases exposure to dermatology if held by the premedical group, which suggests that students are eager to learn more about the field and want access to more opportunities, which could include learning procedures such as suturing or how to use a dermatoscope, attending guest speaker events, or participating in Learn2Derm volunteer events.

Learn2Derm was a skin cancer prevention fair first organized by medical students at George Washington University in Washington, DC. Students and residents sought to deliver sunscreens to underserved areas in Washington, DC, as well as teach residents about the importance of skin health. Participating in such events could be an excellent opportunity for all students to gain exposure to important topics in dermatology.²⁶

General Opinions of Dermatology—General opinions about dermatology and medicine were collected from the students through the optional “Additional Comments” section. Major themes found in the comments included the desire for more opportunities, mentorship, exposure, connections, and a discussion of disparities faced by Black patients/students within dermatology. Students also expressed an interest in dermatology and the desire to learn more about the specialty. From these themes, it can be gleaned that students are open to and eager for more opportunities to gain exposure and connections, and increasing the number of minority dermatologists is of importance.

Limitations—An important limitation of this study was the potential for selection bias, as the sample was chosen from a population at one university, which is not representative of the general population. Further, we only sampled students who were premedical and likely from a UiM racial group due to the demographics of the student population at the university, but given that the goal of the survey was to understand exposure to dermatology in underrepresented groups, we believe it was the appropriate population to target. Additionally, results were not compared with other more represented racial groups to see if these findings were unique to UiM undergraduate students.

Conclusion

Among premedical students, dermatology is an area of great interest with minimal opportunities available for exposure and learning because it is a smaller specialty with fewer experiences available for shadowing and mentorship. Although most UiM premedical students who were surveyed were exposed to the field through either the media or being a dermatology patient, fewer were exposed to the field through clinical experiences (such as shadowing) or mentorship. Most respondents found dermatology to be interesting and have considered pursuing it as a career. In particular, race-concordant mentoring in dermatologic care was valued by many students in garnering their interest in the field.

Most UiM students wanted more exposure to dermatology-related opportunities as well as mentorship and connections. Increasing shadowing, research, pipeline programs, and general events geared to dermatology are some modalities that could help improve exposure to dermatology for UiM students, especially for those interested in pursuing the field. This increased exposure can help positively influence more UiM students to pursue dermatology and help close the diversity gap in the field. Additionally, many were interested in attending potential dermatology informational events.

Given the fact that dermatology is a small field and mentorship may be hard to access, increasing informational events may be a more reasonable approach to inspiring and supporting interest. These events could include learning how to use certain tools and techniques, guest speaker events, or participating in educational volunteer efforts such as Learn2Derm.²⁶

Future research should focus on identifying beneficial factors of UiM premedical students who retain an interest in dermatology throughout their careers and actually apply to dermatology programs and become dermatologists. Those who do not apply to the specialty can be identified to understand potential dissuading factors and obstacles. Ultimately, more research and development of exposure opportunities, including mentorship programs and informational events, can be used to close the gap and improve diversity and health outcomes in dermatology.

Diversity of health care professionals improves medical outcomes and quality of life in patients. ¹ There is a lack of diversity in dermatology, with only 4.2% of dermatologists identifying as Hispanic and 3% identifying as African American, ² possibly due to a lack of early exposure to dermatology among high school and undergraduate students, a low number of underrepresented students in medical school, a lack of formal mentorship programs geared to underrepresented students, and implicit biases. ^1-4 Furthermore, the field is competitive, with many more applicants than available positions. In 2022, there were 851 applicants competing for 492 residency positions in dermatology. ⁵ Thus, it is important to educate young students about dermatology and understand root causes as to why the number of u nderrepresented in medicine (UiM) dermatologists remains stagnant.

According to Pritchett et al,⁴ it is crucial for dermatologists to interact with high school and college students to foster an early interest in dermatology. Many racial minority students do not progress from high school to college and then from college to medical school, which leaves a substantially reduced number of eligible UiM applicants who can progress into dermatology.⁶ Increasing the amount of UiM students going to medical school requires early mediation. Collaborating with pre-existing premedical school organizations through presentations and workshops is another way to promote an early interest in dermatology.⁴ Special consideration should be given to students who are UiM.

Among the general medical school curriculum, requirements for exposure to dermatology are not high. In one study, the median number of clinical and preclinical hours required was 10. Furthermore, 20% of 33 medical schools did not require preclinical dermatology hours (hours done before medical school rotations begin and in an academic setting), 36% required no clinical hours (rotational hours), 8% required no dermatology hours whatsoever, and only 10% required clinical dermatology rotation.³ Based on these findings, it is clear that dermatology is not well incorporated into medical school curricula. Furthermore, curricula have historically neglected to display adequate representation of skin of color.⁷ As a result, medical students generally have limited exposure to dermatology³ and are exposed even less to presentations of dermatologic issues in historically marginalized populations.⁷

Given the paucity of research on UiM students’ perceptions of dermatology prior to medical school, our cross-sectional survey study sought to evaluate the level of interest in dermatology of UiM premedical undergraduates. This survey specifically evaluated exposure to dermatology, preconceived notions about the field, and mentorship opportunities. By understanding these factors, dermatologists and dermatology residency programs can use this information to create mentorship opportunities and better adjust existing programs to meet students’ needs.

Methods

A 19-question multiple-choice survey was administered electronically (SurveyMonkey) in May 2020 to premedical students at Howard University (Washington, DC). One screening question was used: “What is your major?” Those who considered themselves a science major and/or with premedical interest were allowed to complete the survey. All students surveyed were members of the Health Professions Society at Howard University. Students who were interested in pursuing medical school were invited to respond. Approval for this study was obtained from the Howard University institutional review board (FWA00000891).

The survey was divided into 3 sections: Demographics, Exposure to Medicine and Dermatology, and Perceptions of Dermatology. The Demographics section addressed gender, age, and race/ethnicity. The Exposure to Medicine and Dermatology section addressed interest in attending medical school, shadowing experience, exposure to dermatology, and mentoring. The Perceptions of Dermatology section addressed preconceived notions about the field (eg, “dermatology is interesting and exciting”).

Statistical Analysis—The data represented are percentages based on the number of respondents who answered each question. Answers in response to “Please enter any comments” were organized into themes, and the number of respondents who discussed each theme was quantified into a table.

A total of 271 survey invitations were sent to premedical students at Howard University. Students were informed of the study protocol and asked to consent before proceeding to have their responses anonymously collected. Based on the screening question, 152 participants qualified for the survey, and 152 participants completed it (response rate, 56%; completion rate, 100%). Participants were asked to complete the survey only once.

Demographics—Eighty-four percent of respondents identified as science majors, and the remaining 16% identified as nonscience premedical. Ninety-four percent of participants identified as Black or African American; 3% as Asian or Asian American; and the remaining 3% as Other. Most respondents were female (82%), 16% were male, and 2% were either nonbinary or preferred not to answer. Ninety-nine percent were aged 18 to 24 years, and 1% were aged 25 to 34 years (Table 1).

Exposure to Medicine and Dermatology—Ninety-three percent of participants planned on attending medical school, and most students developed an interest in medicine from an early age. Ninety-six percent cited that they became interested in medicine prior to beginning their undergraduate education, and 4% developed an interest as freshmen or sophomores. When asked what led to their interest in medicine, family influence had the single greatest impact on students’ decision to pursue medicine (33%). Classes/school were the second most influential factor (24%), followed by volunteering (15%), shadowing (13%), other (7%), and peer influence (3%)(Figure 1).

Many (56%) premedical students surveyed had shadowing experience to varying degrees. Approximately 18% had fewer than 8 hours of shadowing experience, 24% had 8 to 40 hours, and 14% had more than 40 hours. However, many (43%) premedical students had no shadowing experience (Figure 2). Similarly, 30% of premedical students responded to having a physician as a mentor.

Regarding exposure to dermatology, 42% of premedical students had none. However, 58% of students had exposure to dermatology by being a patient themselves, 40% through seeing a dermatologist with a family member, 21% through seeing a dermatologist on television or social media, 5% through shadowing or volunteering, 3% through mentorship, and 1% through dermatology research (Figure 3).

Of students who said they were interested in dermatology (32%), 16% developed their interest before undergraduate education, while 9% developed interest in their freshman or sophomore year and 7% in their junior or senior year of undergraduate education. Three percent of respondents indicated that they had a dermatology mentorship.

Perceptions of Dermatology—To further evaluate the level of interest that UiM premedical students have in the field of dermatology, students were asked how much they agree or disagree on whether the field of dermatology is interesting. Sixty-three percent of the students agreed that the field of dermatology is interesting, 34% remained uncertain, and 3% disagreed. Additionally, students were asked whether they would consider dermatology as a career; 54% of respondents would consider dermatology as a career, 30% remained uncertain, and 16% would not consider dermatology as a career choice.

Nearly all (95%) students agreed that dermatologists do valuable work that goes beyond the scope of cosmetic procedures such as neuromodulators, fillers, chemical peels, and lasers. Some students also noted they had personal experiences interacting with a dermatologist. For example, one student described visiting the dermatologist many times to get a treatment regimen for their eczema.

Overall themes from the survey are depicted in Table 2. Major themes found in the comments included the desire for more dermatology-related opportunities, mentorship, exposure, connections, and a discussion of disparities faced by Black patients and students within dermatology. Students also expressed an interest in dermatology and the desire to learn more about the specialty.

Comment

Interest in Dermatology—In this cross-sectional survey study of 152 UiM undergraduate students, it was found that many students were interested in dermatology as a career, and more than 70% would be interested in attending events that increased exposure to the field of dermatology. Of the students who had any exposure to dermatology, less than 5% had shadowed an actual dermatologist. The survey showed that there is great potential interest in exposing UiM undergraduate students to the field of dermatology. We found that UiM students are interested in learning more about dermatology, with 80% indicating that they would be willing to participate in dermatology-focused events if they were available. Overall, students mentioned a lack of opportunities, mentorship, exposure, and connections in dermatology despite their interest in the field.

Racial Disparities in Dermatology—Additionally, students discussed disparities they encountered with dermatology due to a lack of patient-provider race concordance and the perceived difference in care when encountering a race-concordant dermatologist. One student noted that they went to multiple White dermatologists for their eczema, and “it wasn’t until I was evaluated by a Black dermatologist (diagnosed with eczema as well) [that I was] prescribed . . . the perfect medication.” Another student noted how a Black dermatologist sparked their interest in getting to know more about the field and remarked that they “think it is an important field that lacks representation for Black people.” This research stresses the need for more dermatology mentorship among UiM undergraduates.

Family Influence on Career Selection—The majority of UiM students in our study became interested in medicine because of family, which is consistent with other studies. In a cross-sectional survey of 300 Pakistani students (150 medical and 150 nonmedical), 87% of students stated that their family had an influence on their career selection.⁸ In another study of 15 junior doctors in Sierra Leone, the most common reasons for pursuing medicine were the desire to help and familial and peer influence.⁹ This again showcases how family can have a positive impact on career selection for medical professionals and highlights the need for early intervention.

Shadowing—One way in which student exposure to dermatology can be effectively increased is by shadowing. In a study evaluating a 30-week shadowing program at the Pediatric Continuity Clinic in Los Angeles, California, a greater proportion of premedical students believed they had a good understanding of the job of a resident physician after the program’s completion compared to before starting the program (an increase from 78% to 100%).¹⁰ The proportion of students reporting a good understanding of the patient-physician relationship after completing the program also increased from 33% to 78%. Furthermore, 72% of the residents stated that having the undergraduates in the clinic was a positive experience.¹⁰ Thus, increasing shadowing opportunities is one extremely effective way to increase student knowledge and awareness of and exposure to dermatology.

Dermatology Mentors—Although 32% of students were interested in dermatology, 3% of students had mentorship in dermatology. In prior studies, it has been shown that mentorship is of great importance in student success and interest in pursuing a specialty. A report from the Association of American Medical Colleges 2019 Medical School Graduation Questionnaire found that the third most influential factor (52.1%) in specialty selection was role model influence.¹¹ In fact, having a role model is consistently one of the top 3 influences on student specialty choice and interest in the last 5 years of survey research. Some studies also have shown mentorship as a positive influence in specialty interest at the undergraduate and graduate levels. A study on an undergraduate student interest group noted that surgeon mentorship and exposure were positive factors to students’ interests in surgery.¹² In fact, the Association of American Medical Colleges noted that some surgical specialties, such as orthopedic surgery, had 45% of respondents who were interested in the specialty before medical school pursue their initial preference in medical school.¹³ Another survey corroborated these findings; more orthopedic-bound students compared with other specialties indicated they were more likely to pursue their field because of experiences prior to medical school.¹⁴

One of the reasons students might not have been exposed to as many opportunities for mentorship in dermatology is because the specialty is one of the smaller fields in medicine and tends to be concentrated in more well-resourced metropolitan areas.¹⁵ Dermatologists make up only 1.3% of the physician workforce.¹⁶ Because there might not be as much exposure to the field, students might also explore their interests in dermatology through other fields, such as through shadowing and observing primary care physicians who often treat patients with dermatologic issues. Skin diseases are a common reason for primary care visits, and one study suggested dermatologic diseases can make up approximately 8.4% of visits in primary care.¹⁷

Moreover, only 1% of medical schools require an elective in dermatology.¹⁸ With exposure being a crucial component to pursuing the specialty, it also is important to pursue formal mentorship within the specialty itself. One study noted that formal mentorship in dermatology was important for most (67%) respondents when considering the specialty; however, 39% of respondents mentioned receiving mentorship in the past. In fact, dermatology was one of the top 3 specialties for which respondents agreed that formal mentorship was important.¹⁹

Mentorship also has been shown to provide students with a variety of opportunities to develop personally and professionally. Some of these opportunities include increased confidence in their personal and professional success, increased desire to pursue a career in a field of interest, networking opportunities, career coaching, and support and research guidance.²⁰ A research study among medical students at Albert Einstein College of Medicine in New York, New York, found that US Medical Licensing Examination Step 1 scores, clinical grades, and the chance of not matching were important factors preventing them from applying to dermatology.²¹

Factors in Dermatology Residency Selection—A survey was conducted wherein 95 of 114 dermatology program directors expressed that among the top 5 criteria for dermatology resident selection were Step 1 scores and clinical grades, supporting the notion that academic factors were given a great emphasis during residency selection.²² Furthermore, among underrepresented minority medical students, a lack of diversity, the belief that minority students are seen negatively by residencies, socioeconomic factors, and not having mentors were major reasons for being dissuaded from applying to dermatology.²¹ These results showcase the heightened importance of mentors for underrepresented minority medical students in particular.

In graduate medical education, resources such as wikis, social networking sites, and blogs provide media through which trainees can communicate, exchange ideas, and enhance their medical knowledge.^23,24 A survey of 9606 osteopathic medical students showed that 35% of 992 respondents had used social media to learn more about residencies, and 10% believed that social media had influenced their choice of residency.²⁵ Given the impact social media has on recruitment, it also can be employed in a similar manner by dermatologists and dermatology residency programs to attract younger students to the field.

Access to More Opportunities to Learn About Dermatology—Besides shadowing and mentorship, other avenues of exposure to dermatology are possible and should be considered. In our study, 80% of students agreed that they would attend an event that increases exposure to dermatology if held by the premedical group, which suggests that students are eager to learn more about the field and want access to more opportunities, which could include learning procedures such as suturing or how to use a dermatoscope, attending guest speaker events, or participating in Learn2Derm volunteer events.

Learn2Derm was a skin cancer prevention fair first organized by medical students at George Washington University in Washington, DC. Students and residents sought to deliver sunscreens to underserved areas in Washington, DC, as well as teach residents about the importance of skin health. Participating in such events could be an excellent opportunity for all students to gain exposure to important topics in dermatology.²⁶

General Opinions of Dermatology—General opinions about dermatology and medicine were collected from the students through the optional “Additional Comments” section. Major themes found in the comments included the desire for more opportunities, mentorship, exposure, connections, and a discussion of disparities faced by Black patients/students within dermatology. Students also expressed an interest in dermatology and the desire to learn more about the specialty. From these themes, it can be gleaned that students are open to and eager for more opportunities to gain exposure and connections, and increasing the number of minority dermatologists is of importance.

Limitations—An important limitation of this study was the potential for selection bias, as the sample was chosen from a population at one university, which is not representative of the general population. Further, we only sampled students who were premedical and likely from a UiM racial group due to the demographics of the student population at the university, but given that the goal of the survey was to understand exposure to dermatology in underrepresented groups, we believe it was the appropriate population to target. Additionally, results were not compared with other more represented racial groups to see if these findings were unique to UiM undergraduate students.

Conclusion

Among premedical students, dermatology is an area of great interest with minimal opportunities available for exposure and learning because it is a smaller specialty with fewer experiences available for shadowing and mentorship. Although most UiM premedical students who were surveyed were exposed to the field through either the media or being a dermatology patient, fewer were exposed to the field through clinical experiences (such as shadowing) or mentorship. Most respondents found dermatology to be interesting and have considered pursuing it as a career. In particular, race-concordant mentoring in dermatologic care was valued by many students in garnering their interest in the field.

Most UiM students wanted more exposure to dermatology-related opportunities as well as mentorship and connections. Increasing shadowing, research, pipeline programs, and general events geared to dermatology are some modalities that could help improve exposure to dermatology for UiM students, especially for those interested in pursuing the field. This increased exposure can help positively influence more UiM students to pursue dermatology and help close the diversity gap in the field. Additionally, many were interested in attending potential dermatology informational events.

Given the fact that dermatology is a small field and mentorship may be hard to access, increasing informational events may be a more reasonable approach to inspiring and supporting interest. These events could include learning how to use certain tools and techniques, guest speaker events, or participating in educational volunteer efforts such as Learn2Derm.²⁶

Future research should focus on identifying beneficial factors of UiM premedical students who retain an interest in dermatology throughout their careers and actually apply to dermatology programs and become dermatologists. Those who do not apply to the specialty can be identified to understand potential dissuading factors and obstacles. Ultimately, more research and development of exposure opportunities, including mentorship programs and informational events, can be used to close the gap and improve diversity and health outcomes in dermatology.

NEW ORLEANS – With the Asian population estimated to increase to 41 million by 2050 in the United States, expect the demand for experienced dermatologic care of patients with Asian skin to increase in the coming years, Hye Jin (Leah) Chung, MD, said at the annual meeting of the American Academy of Dermatology.

“Asians account for about 60% of the global population,” said Dr. Chung, assistant professor of dermatology at Harvard Medical School, and director of the Asian Skin Clinic at Beth Israel Deaconess Medical Center, Boston. Along with the estimate that Asians are expected to make up 25% of Canada’s population by 2036, “we will most likely encounter more Asian skin type patients in North America,” Dr. Chung said, noting that the Asian population “is very diverse, ranging from skin type 3 in Far East Asia to skin type 5 in India.”

Doug Brunk/MDedge News

During her presentation, she provided tips for treating hypertrophic scars and keloids in this patient population when intralesional corticosteroids fail. Typically, her first option is to combine an intralesional corticosteroid with 5-fluorouracil (5-FU), a pyrimidine analogue with antimetabolite activity. 5-FU “can cause cell apoptosis of endothelial cells and fibroblasts (which steroids cannot), cell cycle arrest, and TGF-beta [transforming growth factor beta]-induced COL1A2 transcription,” Dr. Chung said. The recommended ratio between 5-FU and steroids in the literature is variable, from a 9:1 ratio to a 1:1 ratio. “In my practice I do not inject more than 100 mg at a time,” she said. Several studies of this approach led by Asian investigators used weekly injections, “but that’s not practical in the U.S. I usually do monthly injections.”

A large systematic review and meta-analysis confirmed that the combination of intralesional triamcinolone acetonide and 5-FU achieved a better efficacy and fewer complications than triamcinolone alone for treating hypertrophic scars and keloids. Potential side effects from 5-FU injections include pain/pruritus, transient hyperpigmentation (especially in skin types 4-6), ulceration, teratogenicity, and transient alopecia.

A more recent meta-analysis comparing the efficacy of multiple drug injections for hypertrophic scars and keloids confirmed that the combination of triamcinolone and 5-FU was superior to bleomycin, verapamil, 5-FU alone, and triamcinolone alone. “And, there was no difference between 5-FU/steroid combination and botulinum toxin A,” Dr. Chung added. “Some parts of the world are using botulinum toxin with mixed results. Based on the amount of toxin required for keloids, this would be cost prohibitive in the U.S.”

Another approach to treating hypertrophic scars and keloids in Asian skin is laser-assisted drug delivery. “First, you can use a fractional ablative laser to create a hole in the epidermis and dermis,” Dr. Chung said. “Then you can apply the suspension topically to the holes. You can also use a steroid ointment or cream after laser treatment for drug delivery.”

Combining pulsed dye laser with steroid injections is another option. Pulsed dye lasers coagulate microvasculature within keloid tissue, “which can cause tissue hypoxia and can decrease growth factors or cytokines for fibrosis within the tissue,” Dr. Chung said. At the cellular level, pulsed dye laser alone can decrease connective tissue growth factor (CTGF), TGF-beta 1, proliferating cell nuclear antigen, and collagen III, and increases matrix metalloproteinase–13 (MMP-13), P53, ERK and p38 MAPK, apoptosis, blockade of AP-1 transcription, and cell cycle changes.

In 2004, plastic surgeons in Korea described a new approach for removing earlobe keloids, which they termed a “keloid fillet flap”. For the procedure, about 50% of the keloid margin is incised with a #15 scalpel blade. “Then you dissect the keloid from the surrounding tissue with a blade or curved scissors,” Dr. Chung said. “Next, you excise the keloid, so you have some dead space. After hemostasis you place the fillet flap to cover the wound. After you trim the redundant tissue, you can close it with epidermal sutures.”

In her clinical experience, she finds the fillet flap “very helpful for fast recovery” and it is associated with less pain. “Several studies have confirmed an excellent improvement of keloids, low recurrence rate, and rare side effects from a fillet flap and adjuvant intralesional corticosteroids. Occasionally, you may see flap necrosis but usually patients do well with topical antibiotics or petrolatum jelly.”

Dr. Chung also discussed her approach to treating papular scars in Asian patients. She described papular scars as underrecognized, anetoderma-like scars on the central face and trunk. “They comprise about 11% of all acne scars but up to 19% of patients with such scars may not recall a history of acne,” she said. Biopsies of papular scars reveal marked reduction or thinning of elastic fibers around hair follicles.

“Papular scars are difficult to treat,” she said. “If you have a conventional Er:YAG or CO₂ laser, you can create tiny holes within the scars,” she said, referring to studies on these approaches. Another treatment option is needle-guided radiofrequency, she noted.

Dr. Chung reported having no relevant financial disclosures.

NEW ORLEANS – With the Asian population estimated to increase to 41 million by 2050 in the United States, expect the demand for experienced dermatologic care of patients with Asian skin to increase in the coming years, Hye Jin (Leah) Chung, MD, said at the annual meeting of the American Academy of Dermatology.

“Asians account for about 60% of the global population,” said Dr. Chung, assistant professor of dermatology at Harvard Medical School, and director of the Asian Skin Clinic at Beth Israel Deaconess Medical Center, Boston. Along with the estimate that Asians are expected to make up 25% of Canada’s population by 2036, “we will most likely encounter more Asian skin type patients in North America,” Dr. Chung said, noting that the Asian population “is very diverse, ranging from skin type 3 in Far East Asia to skin type 5 in India.”

Doug Brunk/MDedge News

During her presentation, she provided tips for treating hypertrophic scars and keloids in this patient population when intralesional corticosteroids fail. Typically, her first option is to combine an intralesional corticosteroid with 5-fluorouracil (5-FU), a pyrimidine analogue with antimetabolite activity. 5-FU “can cause cell apoptosis of endothelial cells and fibroblasts (which steroids cannot), cell cycle arrest, and TGF-beta [transforming growth factor beta]-induced COL1A2 transcription,” Dr. Chung said. The recommended ratio between 5-FU and steroids in the literature is variable, from a 9:1 ratio to a 1:1 ratio. “In my practice I do not inject more than 100 mg at a time,” she said. Several studies of this approach led by Asian investigators used weekly injections, “but that’s not practical in the U.S. I usually do monthly injections.”

A large systematic review and meta-analysis confirmed that the combination of intralesional triamcinolone acetonide and 5-FU achieved a better efficacy and fewer complications than triamcinolone alone for treating hypertrophic scars and keloids. Potential side effects from 5-FU injections include pain/pruritus, transient hyperpigmentation (especially in skin types 4-6), ulceration, teratogenicity, and transient alopecia.

A more recent meta-analysis comparing the efficacy of multiple drug injections for hypertrophic scars and keloids confirmed that the combination of triamcinolone and 5-FU was superior to bleomycin, verapamil, 5-FU alone, and triamcinolone alone. “And, there was no difference between 5-FU/steroid combination and botulinum toxin A,” Dr. Chung added. “Some parts of the world are using botulinum toxin with mixed results. Based on the amount of toxin required for keloids, this would be cost prohibitive in the U.S.”

Another approach to treating hypertrophic scars and keloids in Asian skin is laser-assisted drug delivery. “First, you can use a fractional ablative laser to create a hole in the epidermis and dermis,” Dr. Chung said. “Then you can apply the suspension topically to the holes. You can also use a steroid ointment or cream after laser treatment for drug delivery.”

Combining pulsed dye laser with steroid injections is another option. Pulsed dye lasers coagulate microvasculature within keloid tissue, “which can cause tissue hypoxia and can decrease growth factors or cytokines for fibrosis within the tissue,” Dr. Chung said. At the cellular level, pulsed dye laser alone can decrease connective tissue growth factor (CTGF), TGF-beta 1, proliferating cell nuclear antigen, and collagen III, and increases matrix metalloproteinase–13 (MMP-13), P53, ERK and p38 MAPK, apoptosis, blockade of AP-1 transcription, and cell cycle changes.

In 2004, plastic surgeons in Korea described a new approach for removing earlobe keloids, which they termed a “keloid fillet flap”. For the procedure, about 50% of the keloid margin is incised with a #15 scalpel blade. “Then you dissect the keloid from the surrounding tissue with a blade or curved scissors,” Dr. Chung said. “Next, you excise the keloid, so you have some dead space. After hemostasis you place the fillet flap to cover the wound. After you trim the redundant tissue, you can close it with epidermal sutures.”

In her clinical experience, she finds the fillet flap “very helpful for fast recovery” and it is associated with less pain. “Several studies have confirmed an excellent improvement of keloids, low recurrence rate, and rare side effects from a fillet flap and adjuvant intralesional corticosteroids. Occasionally, you may see flap necrosis but usually patients do well with topical antibiotics or petrolatum jelly.”

Dr. Chung also discussed her approach to treating papular scars in Asian patients. She described papular scars as underrecognized, anetoderma-like scars on the central face and trunk. “They comprise about 11% of all acne scars but up to 19% of patients with such scars may not recall a history of acne,” she said. Biopsies of papular scars reveal marked reduction or thinning of elastic fibers around hair follicles.

“Papular scars are difficult to treat,” she said. “If you have a conventional Er:YAG or CO₂ laser, you can create tiny holes within the scars,” she said, referring to studies on these approaches. Another treatment option is needle-guided radiofrequency, she noted.

Dr. Chung reported having no relevant financial disclosures.

NEW ORLEANS – With the Asian population estimated to increase to 41 million by 2050 in the United States, expect the demand for experienced dermatologic care of patients with Asian skin to increase in the coming years, Hye Jin (Leah) Chung, MD, said at the annual meeting of the American Academy of Dermatology.

“Asians account for about 60% of the global population,” said Dr. Chung, assistant professor of dermatology at Harvard Medical School, and director of the Asian Skin Clinic at Beth Israel Deaconess Medical Center, Boston. Along with the estimate that Asians are expected to make up 25% of Canada’s population by 2036, “we will most likely encounter more Asian skin type patients in North America,” Dr. Chung said, noting that the Asian population “is very diverse, ranging from skin type 3 in Far East Asia to skin type 5 in India.”

Doug Brunk/MDedge News

During her presentation, she provided tips for treating hypertrophic scars and keloids in this patient population when intralesional corticosteroids fail. Typically, her first option is to combine an intralesional corticosteroid with 5-fluorouracil (5-FU), a pyrimidine analogue with antimetabolite activity. 5-FU “can cause cell apoptosis of endothelial cells and fibroblasts (which steroids cannot), cell cycle arrest, and TGF-beta [transforming growth factor beta]-induced COL1A2 transcription,” Dr. Chung said. The recommended ratio between 5-FU and steroids in the literature is variable, from a 9:1 ratio to a 1:1 ratio. “In my practice I do not inject more than 100 mg at a time,” she said. Several studies of this approach led by Asian investigators used weekly injections, “but that’s not practical in the U.S. I usually do monthly injections.”

A large systematic review and meta-analysis confirmed that the combination of intralesional triamcinolone acetonide and 5-FU achieved a better efficacy and fewer complications than triamcinolone alone for treating hypertrophic scars and keloids. Potential side effects from 5-FU injections include pain/pruritus, transient hyperpigmentation (especially in skin types 4-6), ulceration, teratogenicity, and transient alopecia.

A more recent meta-analysis comparing the efficacy of multiple drug injections for hypertrophic scars and keloids confirmed that the combination of triamcinolone and 5-FU was superior to bleomycin, verapamil, 5-FU alone, and triamcinolone alone. “And, there was no difference between 5-FU/steroid combination and botulinum toxin A,” Dr. Chung added. “Some parts of the world are using botulinum toxin with mixed results. Based on the amount of toxin required for keloids, this would be cost prohibitive in the U.S.”

Another approach to treating hypertrophic scars and keloids in Asian skin is laser-assisted drug delivery. “First, you can use a fractional ablative laser to create a hole in the epidermis and dermis,” Dr. Chung said. “Then you can apply the suspension topically to the holes. You can also use a steroid ointment or cream after laser treatment for drug delivery.”

Combining pulsed dye laser with steroid injections is another option. Pulsed dye lasers coagulate microvasculature within keloid tissue, “which can cause tissue hypoxia and can decrease growth factors or cytokines for fibrosis within the tissue,” Dr. Chung said. At the cellular level, pulsed dye laser alone can decrease connective tissue growth factor (CTGF), TGF-beta 1, proliferating cell nuclear antigen, and collagen III, and increases matrix metalloproteinase–13 (MMP-13), P53, ERK and p38 MAPK, apoptosis, blockade of AP-1 transcription, and cell cycle changes.

In 2004, plastic surgeons in Korea described a new approach for removing earlobe keloids, which they termed a “keloid fillet flap”. For the procedure, about 50% of the keloid margin is incised with a #15 scalpel blade. “Then you dissect the keloid from the surrounding tissue with a blade or curved scissors,” Dr. Chung said. “Next, you excise the keloid, so you have some dead space. After hemostasis you place the fillet flap to cover the wound. After you trim the redundant tissue, you can close it with epidermal sutures.”

In her clinical experience, she finds the fillet flap “very helpful for fast recovery” and it is associated with less pain. “Several studies have confirmed an excellent improvement of keloids, low recurrence rate, and rare side effects from a fillet flap and adjuvant intralesional corticosteroids. Occasionally, you may see flap necrosis but usually patients do well with topical antibiotics or petrolatum jelly.”

Dr. Chung also discussed her approach to treating papular scars in Asian patients. She described papular scars as underrecognized, anetoderma-like scars on the central face and trunk. “They comprise about 11% of all acne scars but up to 19% of patients with such scars may not recall a history of acne,” she said. Biopsies of papular scars reveal marked reduction or thinning of elastic fibers around hair follicles.

“Papular scars are difficult to treat,” she said. “If you have a conventional Er:YAG or CO₂ laser, you can create tiny holes within the scars,” she said, referring to studies on these approaches. Another treatment option is needle-guided radiofrequency, she noted.

Dr. Chung reported having no relevant financial disclosures.

To the Editor:

Subcutaneous panniculitic T-cell lymphoma (SPTCL) is a rare cutaneous T-cell lymphoma that was first described in 1991¹ and comprises less than 1% of all non-Hodgkin lymphomas (NHLs). It most commonly occurs in young adults, with a median patient age of 36 years and a slight female predominance.² Patients typically present with skin nodules or deep-seated plaques involving the legs, arms, and/or trunk. Presentation on the face is less common.^2,3 Paraneoplastic edema has been reported in several cases of SPTCL with facial and periorbital swelling.^4-9

Diagnosis of SPTCL is achieved via analysis of a deep tissue skin biopsy and close clinicopathologic correlation. Histopathology demonstrates lobular panniculitis with an atypical lymphoid infiltrate in the subcutaneous tissue with predominantly CD8⁺ T cells without overlying epidermotropism or interface dermatitis.³ The degree of cellular atypia, fat necrosis, karyorrhexis, cytophagia, and lack of angioinvasion can help to distinguish SPTCL from other panniculitides.^2,3

The prognosis of SPTCL is good, with a 5-year survival rate of 82%, and many patients are able to achieve remission.² However, SPTCL can progress to a fatal hemophagocytic syndrome, which has been reported in 17% of cases, making early diagnosis and treatment of this malignancy imperative.^1,2 Treatment varies depending on the progression and extent of disease and can include the use of steroids, multidrug chemotherapy regimens, radiotherapy, and stem cell transplant in refractory cases.^2-4,10,11

Subcutaneous panniculitic T-cell lymphoma with edema has been reported in a 2-year-old child.¹² We present a case of SPTCL in an adult patient with known stage IV chronic lymphocytic leukemia (CLL) who also had full-body edema.

A 60-year-old woman with a 7-year history of stage IV CLL presented with anasarca of 3 months’ duration. At the time of presentation to dermatology, physical examination revealed erythematous tender nodules on the arms and legs. She had no other medical conditions and was undergoing treatment with ibrutinib for the CLL. The patient reported profound fatigue but no fever, chills, night sweats, cough, or dyspnea. The swelling had begun initially in the legs and progressively worsened to involve the arms, face, and body. She was hospitalized and treated with intravenous steroids and antihistamines, which led to minor improvement in the swelling. The patient’s preliminary diagnosis of erythema nodosum was thought to be related to the CLL or ibrutinib; therefore, treatment subsequently was discontinued and she was discharged from the hospital.

The swelling continued to worsen over the following 3 months, and the patient gained approximately 25 pounds. She presented to our office again with severe periorbital, facial, and lip edema as well as diffuse edema of the torso, arms, and legs (Figure 1). Erythematous tender subcutaneous nodules were noted on the right proximal thigh, left lateral calf, and forearms. She was again hospitalized, and extensive evaluation was performed to exclude other causes of anasarca, including a complete blood cell count; comprehensive metabolic profile; hepatitis panels; HIV test; C3 and C4, complement CH50, C1 esterase inhibitor, IgE, and angiotensin-converting enzyme levels; urine protein to creatinine ratio; computed tomography of the chest, abdomen, and pelvis; and allergy evaluation. The analyses failed to reveal the cause of the anasarca.

During hospitalization, the patient underwent a lymph node biopsy, bone marrow biopsy, and a 6-mm punch biopsy of the right thigh nodule. The lymph node and bone marrow biopsy results were consistent with the known diagnosis of CLL, and the patient was started on intravenous chemotherapy with bendamustine. The skin biopsy demonstrated a predominant T-cell infiltrate consistent with a lobular panniculitis with variable amounts of adipocytes rimmed by lymphocytes, nuclear debris, and karyorrhexis (Figure 2). CD3⁺, CD8⁺, and CD4⁻ T cells were positive for T-cell receptor (TCR) βF1 and negative for TCR-γ with strong expression of cytotoxic markers including granzyme B, perforin, and T-cell intracytoplasmic antigen 1. Rare CD56⁺ cells also were noted. The biopsy did not demonstrate any notable interface dermatitis, epidermotropism, or angioinvasion. T-cell receptor gene rearrangement studies did not show clonality for γ- or β-chain probes. Subcutaneous panniculitic T-cell lymphoma was diagnosed, making this case unique with the presentation of anasarca. This case also is noteworthy due to the rare diagnosis of the secondary malignancy of SPTCL in a patient with known CLL. The patient opted to pursue hospice and comfort measures due to the effects of persistent pancytopenia and the progression of CLL. She died 2 months later.

Clinical courses of SPTCL vary based on the TCR phenotype and immunophenotypic characteristics of the tumor cells. The TCR-αβ phenotype, as described in this case, typically is CD4⁻, CD8⁺, and CD56^– and leads to a more indolent disease course. Lymphomas with the TCR-γδ phenotype typically are CD4⁻, CD8⁻, and CD56⁺; they often are associated with hemophagocytic syndrome and thus a worse prognosis. In 2009, the World Health Organization–European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas restricted the category of SPTCL to the TCR-αβ phenotype due to the stark differences between the 2 types. The TCR-γδ phenotype was given its own diagnostic category—primary cutaneous γδ T-cell lymphoma.³

Patients with SPTCL commonly present with nodular skin lesions or deep-seated plaques on the legs, arms, and/or trunk; presentation on the face is rare.^2,3 Fever, chills, night sweats, and/or weight loss were present in approximately 50% of recorded cases. Underlying autoimmune disease was present in 12 of 63 (19%) patients in a 2008 study.² Facial and periorbital swelling with SPTCL has been reported.^4-9 The presentation of anasarca, as seen in our adult patient, has been reported in a 2-year-old child.¹² Anasarca as a presenting symptom of NHL is a rare phenomenon proposed to be induced by malignant cells secreting a cytokine that causes a vascular leak syndrome.¹³ Specifically, tumor necrosis factor α was found to be elevated in at least 2 patients with NHL presenting with anasarca in a prior study. Tumor necrosis factor α is known to cause increased capillary permeability, vascular leakage, and development of edema.¹³ In retrospect, obtaining cytokine levels in our patient would have been useful to support or refute tumor necrosis factor α as a possible cause of anasarca in the setting of NHL. This case continues to highlight that a diagnosis of SPTCL and analysis of a skin biopsy should be considered in cases of sudden unremitting facial and/or body swelling that cannot be explained by other more common causes.

Subcutaneous panniculitic T-cell lymphoma can be diagnosed and distinguished from other panniculitides via analysis of a deep tissue skin biopsy. Multiple biopsies may be required to ensure an adequate sample is obtained.⁴ Histopathology displays an atypical lymphoid infiltrate with a predominant presence of T cells. Neoplastic cells show CD3⁺, CD8⁺, and CD4⁻ T cells, which strongly express cytotoxic proteins such as granzyme B, T-cell intracellular antigen 1, and perforin.³ The degree of cellular atypia, fat necrosis, karyorrhexis, and cytophagia, as well as the lack of angioinvasion, interface dermatitis, and epidermotropism help to distinguish SPTCL from other panniculitides.^2,3 According to a previous study, clonal TCR gene rearrangement was identified in 50% to 80% of cases, but the absence of this clonal rearrangement does not exclude the diagnosis.¹⁴

This case also highlights the occurrence of secondary malignancies in patients with CLL, an NHL that is classified as a low-grade lymphoproliferative malignancy with clonal expansion of B cells.¹⁵ Secondary CTCLs in patients with CLL are rare, but they have been previously described. In 2017, Chang et al¹⁶ identified 12 patients with CLL who subsequently developed CTCL between 1992 and 2008. Of the 12 patients, 7 developed mycosis fungoides, 3 had CTCL not otherwise specified, 1 had mature T-cell lymphoma not otherwise specified, and 1 had primary cutaneous CD30⁺ T-cell lymphoma.¹⁶ The proliferation of 2 separate lymphocytic lineages is rare, but this study demonstrated an increased risk for CTCL to develop in patients with CLL. One possible explanation is that malignant cells come from a common stem cell progenitor or from genetic events. They occur secondary to carcinogens, viruses, or cytokines from T-cell or B-cell clones; they evolve due to treatment of the preexisting lymphoproliferative disease; or they occur simply by coincidence. The behavior of the CTCL may be more aggressive in patients with CLL due to immunosuppression, which may have contributed to the extreme presentation in our patient.¹⁶ Subcutaneous panniculitic T-cell lymphoma also has been reported in a patient with CLL that was thought to be associated with prior rituximab treatment.¹⁷

Treatment of SPTCL depends on the severity and course of the disease. In patients with more indolent disease, systemic steroids have been the most frequently used initial treatment.^2,3,10 However, the disease often will progress after steroid tapering and require further intervention. Localized lesions may be treated with radiation alone or in combination with other systemic therapies.^3,10 In refractory, aggressive, or relapsing cases, polychemotherapeutic regimens have proven to produce long-term remission in 30% of patients, with an overall response rate of 50%.¹⁰ These regimens most commonly have included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like treatment (EPOCH regimen [etoposide, prednisone, oncovin, cyclophosphamide, and doxorubicin hydrochloride]).^3,10 A stem cell transplant can be considered in patients with recurrent and refractory disease, and it also has been shown to induce remission.^4,17 In patients with a good response to therapy, the disease often can be controlled for long periods of time, with an estimated 5-year survival rate of 80%.¹⁵

This case highlights the diagnostic challenges and variable presentations of SPTCL. Dermatologists, oncologists, and dermatopathologists should be aware of this condition and consider it in the differential diagnosis of a patient with a hematologic malignancy and unremitting facial and/or body swelling without any other cause. The possibility of a secondary hematologic cancer in a patient with CLL also must be taken into consideration. Early diagnosis and treatment can minimize morbidity and induce remission in most patients.

To the Editor:

Subcutaneous panniculitic T-cell lymphoma (SPTCL) is a rare cutaneous T-cell lymphoma that was first described in 1991¹ and comprises less than 1% of all non-Hodgkin lymphomas (NHLs). It most commonly occurs in young adults, with a median patient age of 36 years and a slight female predominance.² Patients typically present with skin nodules or deep-seated plaques involving the legs, arms, and/or trunk. Presentation on the face is less common.^2,3 Paraneoplastic edema has been reported in several cases of SPTCL with facial and periorbital swelling.^4-9

Diagnosis of SPTCL is achieved via analysis of a deep tissue skin biopsy and close clinicopathologic correlation. Histopathology demonstrates lobular panniculitis with an atypical lymphoid infiltrate in the subcutaneous tissue with predominantly CD8⁺ T cells without overlying epidermotropism or interface dermatitis.³ The degree of cellular atypia, fat necrosis, karyorrhexis, cytophagia, and lack of angioinvasion can help to distinguish SPTCL from other panniculitides.^2,3

The prognosis of SPTCL is good, with a 5-year survival rate of 82%, and many patients are able to achieve remission.² However, SPTCL can progress to a fatal hemophagocytic syndrome, which has been reported in 17% of cases, making early diagnosis and treatment of this malignancy imperative.^1,2 Treatment varies depending on the progression and extent of disease and can include the use of steroids, multidrug chemotherapy regimens, radiotherapy, and stem cell transplant in refractory cases.^2-4,10,11

Subcutaneous panniculitic T-cell lymphoma with edema has been reported in a 2-year-old child.¹² We present a case of SPTCL in an adult patient with known stage IV chronic lymphocytic leukemia (CLL) who also had full-body edema.

A 60-year-old woman with a 7-year history of stage IV CLL presented with anasarca of 3 months’ duration. At the time of presentation to dermatology, physical examination revealed erythematous tender nodules on the arms and legs. She had no other medical conditions and was undergoing treatment with ibrutinib for the CLL. The patient reported profound fatigue but no fever, chills, night sweats, cough, or dyspnea. The swelling had begun initially in the legs and progressively worsened to involve the arms, face, and body. She was hospitalized and treated with intravenous steroids and antihistamines, which led to minor improvement in the swelling. The patient’s preliminary diagnosis of erythema nodosum was thought to be related to the CLL or ibrutinib; therefore, treatment subsequently was discontinued and she was discharged from the hospital.

The swelling continued to worsen over the following 3 months, and the patient gained approximately 25 pounds. She presented to our office again with severe periorbital, facial, and lip edema as well as diffuse edema of the torso, arms, and legs (Figure 1). Erythematous tender subcutaneous nodules were noted on the right proximal thigh, left lateral calf, and forearms. She was again hospitalized, and extensive evaluation was performed to exclude other causes of anasarca, including a complete blood cell count; comprehensive metabolic profile; hepatitis panels; HIV test; C3 and C4, complement CH50, C1 esterase inhibitor, IgE, and angiotensin-converting enzyme levels; urine protein to creatinine ratio; computed tomography of the chest, abdomen, and pelvis; and allergy evaluation. The analyses failed to reveal the cause of the anasarca.

During hospitalization, the patient underwent a lymph node biopsy, bone marrow biopsy, and a 6-mm punch biopsy of the right thigh nodule. The lymph node and bone marrow biopsy results were consistent with the known diagnosis of CLL, and the patient was started on intravenous chemotherapy with bendamustine. The skin biopsy demonstrated a predominant T-cell infiltrate consistent with a lobular panniculitis with variable amounts of adipocytes rimmed by lymphocytes, nuclear debris, and karyorrhexis (Figure 2). CD3⁺, CD8⁺, and CD4⁻ T cells were positive for T-cell receptor (TCR) βF1 and negative for TCR-γ with strong expression of cytotoxic markers including granzyme B, perforin, and T-cell intracytoplasmic antigen 1. Rare CD56⁺ cells also were noted. The biopsy did not demonstrate any notable interface dermatitis, epidermotropism, or angioinvasion. T-cell receptor gene rearrangement studies did not show clonality for γ- or β-chain probes. Subcutaneous panniculitic T-cell lymphoma was diagnosed, making this case unique with the presentation of anasarca. This case also is noteworthy due to the rare diagnosis of the secondary malignancy of SPTCL in a patient with known CLL. The patient opted to pursue hospice and comfort measures due to the effects of persistent pancytopenia and the progression of CLL. She died 2 months later.

Clinical courses of SPTCL vary based on the TCR phenotype and immunophenotypic characteristics of the tumor cells. The TCR-αβ phenotype, as described in this case, typically is CD4⁻, CD8⁺, and CD56^– and leads to a more indolent disease course. Lymphomas with the TCR-γδ phenotype typically are CD4⁻, CD8⁻, and CD56⁺; they often are associated with hemophagocytic syndrome and thus a worse prognosis. In 2009, the World Health Organization–European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas restricted the category of SPTCL to the TCR-αβ phenotype due to the stark differences between the 2 types. The TCR-γδ phenotype was given its own diagnostic category—primary cutaneous γδ T-cell lymphoma.³

Patients with SPTCL commonly present with nodular skin lesions or deep-seated plaques on the legs, arms, and/or trunk; presentation on the face is rare.^2,3 Fever, chills, night sweats, and/or weight loss were present in approximately 50% of recorded cases. Underlying autoimmune disease was present in 12 of 63 (19%) patients in a 2008 study.² Facial and periorbital swelling with SPTCL has been reported.^4-9 The presentation of anasarca, as seen in our adult patient, has been reported in a 2-year-old child.¹² Anasarca as a presenting symptom of NHL is a rare phenomenon proposed to be induced by malignant cells secreting a cytokine that causes a vascular leak syndrome.¹³ Specifically, tumor necrosis factor α was found to be elevated in at least 2 patients with NHL presenting with anasarca in a prior study. Tumor necrosis factor α is known to cause increased capillary permeability, vascular leakage, and development of edema.¹³ In retrospect, obtaining cytokine levels in our patient would have been useful to support or refute tumor necrosis factor α as a possible cause of anasarca in the setting of NHL. This case continues to highlight that a diagnosis of SPTCL and analysis of a skin biopsy should be considered in cases of sudden unremitting facial and/or body swelling that cannot be explained by other more common causes.

Subcutaneous panniculitic T-cell lymphoma can be diagnosed and distinguished from other panniculitides via analysis of a deep tissue skin biopsy. Multiple biopsies may be required to ensure an adequate sample is obtained.⁴ Histopathology displays an atypical lymphoid infiltrate with a predominant presence of T cells. Neoplastic cells show CD3⁺, CD8⁺, and CD4⁻ T cells, which strongly express cytotoxic proteins such as granzyme B, T-cell intracellular antigen 1, and perforin.³ The degree of cellular atypia, fat necrosis, karyorrhexis, and cytophagia, as well as the lack of angioinvasion, interface dermatitis, and epidermotropism help to distinguish SPTCL from other panniculitides.^2,3 According to a previous study, clonal TCR gene rearrangement was identified in 50% to 80% of cases, but the absence of this clonal rearrangement does not exclude the diagnosis.¹⁴

This case also highlights the occurrence of secondary malignancies in patients with CLL, an NHL that is classified as a low-grade lymphoproliferative malignancy with clonal expansion of B cells.¹⁵ Secondary CTCLs in patients with CLL are rare, but they have been previously described. In 2017, Chang et al¹⁶ identified 12 patients with CLL who subsequently developed CTCL between 1992 and 2008. Of the 12 patients, 7 developed mycosis fungoides, 3 had CTCL not otherwise specified, 1 had mature T-cell lymphoma not otherwise specified, and 1 had primary cutaneous CD30⁺ T-cell lymphoma.¹⁶ The proliferation of 2 separate lymphocytic lineages is rare, but this study demonstrated an increased risk for CTCL to develop in patients with CLL. One possible explanation is that malignant cells come from a common stem cell progenitor or from genetic events. They occur secondary to carcinogens, viruses, or cytokines from T-cell or B-cell clones; they evolve due to treatment of the preexisting lymphoproliferative disease; or they occur simply by coincidence. The behavior of the CTCL may be more aggressive in patients with CLL due to immunosuppression, which may have contributed to the extreme presentation in our patient.¹⁶ Subcutaneous panniculitic T-cell lymphoma also has been reported in a patient with CLL that was thought to be associated with prior rituximab treatment.¹⁷

Treatment of SPTCL depends on the severity and course of the disease. In patients with more indolent disease, systemic steroids have been the most frequently used initial treatment.^2,3,10 However, the disease often will progress after steroid tapering and require further intervention. Localized lesions may be treated with radiation alone or in combination with other systemic therapies.^3,10 In refractory, aggressive, or relapsing cases, polychemotherapeutic regimens have proven to produce long-term remission in 30% of patients, with an overall response rate of 50%.¹⁰ These regimens most commonly have included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like treatment (EPOCH regimen [etoposide, prednisone, oncovin, cyclophosphamide, and doxorubicin hydrochloride]).^3,10 A stem cell transplant can be considered in patients with recurrent and refractory disease, and it also has been shown to induce remission.^4,17 In patients with a good response to therapy, the disease often can be controlled for long periods of time, with an estimated 5-year survival rate of 80%.¹⁵

This case highlights the diagnostic challenges and variable presentations of SPTCL. Dermatologists, oncologists, and dermatopathologists should be aware of this condition and consider it in the differential diagnosis of a patient with a hematologic malignancy and unremitting facial and/or body swelling without any other cause. The possibility of a secondary hematologic cancer in a patient with CLL also must be taken into consideration. Early diagnosis and treatment can minimize morbidity and induce remission in most patients.

To the Editor:

Subcutaneous panniculitic T-cell lymphoma (SPTCL) is a rare cutaneous T-cell lymphoma that was first described in 1991¹ and comprises less than 1% of all non-Hodgkin lymphomas (NHLs). It most commonly occurs in young adults, with a median patient age of 36 years and a slight female predominance.² Patients typically present with skin nodules or deep-seated plaques involving the legs, arms, and/or trunk. Presentation on the face is less common.^2,3 Paraneoplastic edema has been reported in several cases of SPTCL with facial and periorbital swelling.^4-9

Diagnosis of SPTCL is achieved via analysis of a deep tissue skin biopsy and close clinicopathologic correlation. Histopathology demonstrates lobular panniculitis with an atypical lymphoid infiltrate in the subcutaneous tissue with predominantly CD8⁺ T cells without overlying epidermotropism or interface dermatitis.³ The degree of cellular atypia, fat necrosis, karyorrhexis, cytophagia, and lack of angioinvasion can help to distinguish SPTCL from other panniculitides.^2,3

The prognosis of SPTCL is good, with a 5-year survival rate of 82%, and many patients are able to achieve remission.² However, SPTCL can progress to a fatal hemophagocytic syndrome, which has been reported in 17% of cases, making early diagnosis and treatment of this malignancy imperative.^1,2 Treatment varies depending on the progression and extent of disease and can include the use of steroids, multidrug chemotherapy regimens, radiotherapy, and stem cell transplant in refractory cases.^2-4,10,11

Subcutaneous panniculitic T-cell lymphoma with edema has been reported in a 2-year-old child.¹² We present a case of SPTCL in an adult patient with known stage IV chronic lymphocytic leukemia (CLL) who also had full-body edema.

A 60-year-old woman with a 7-year history of stage IV CLL presented with anasarca of 3 months’ duration. At the time of presentation to dermatology, physical examination revealed erythematous tender nodules on the arms and legs. She had no other medical conditions and was undergoing treatment with ibrutinib for the CLL. The patient reported profound fatigue but no fever, chills, night sweats, cough, or dyspnea. The swelling had begun initially in the legs and progressively worsened to involve the arms, face, and body. She was hospitalized and treated with intravenous steroids and antihistamines, which led to minor improvement in the swelling. The patient’s preliminary diagnosis of erythema nodosum was thought to be related to the CLL or ibrutinib; therefore, treatment subsequently was discontinued and she was discharged from the hospital.

The swelling continued to worsen over the following 3 months, and the patient gained approximately 25 pounds. She presented to our office again with severe periorbital, facial, and lip edema as well as diffuse edema of the torso, arms, and legs (Figure 1). Erythematous tender subcutaneous nodules were noted on the right proximal thigh, left lateral calf, and forearms. She was again hospitalized, and extensive evaluation was performed to exclude other causes of anasarca, including a complete blood cell count; comprehensive metabolic profile; hepatitis panels; HIV test; C3 and C4, complement CH50, C1 esterase inhibitor, IgE, and angiotensin-converting enzyme levels; urine protein to creatinine ratio; computed tomography of the chest, abdomen, and pelvis; and allergy evaluation. The analyses failed to reveal the cause of the anasarca.

During hospitalization, the patient underwent a lymph node biopsy, bone marrow biopsy, and a 6-mm punch biopsy of the right thigh nodule. The lymph node and bone marrow biopsy results were consistent with the known diagnosis of CLL, and the patient was started on intravenous chemotherapy with bendamustine. The skin biopsy demonstrated a predominant T-cell infiltrate consistent with a lobular panniculitis with variable amounts of adipocytes rimmed by lymphocytes, nuclear debris, and karyorrhexis (Figure 2). CD3⁺, CD8⁺, and CD4⁻ T cells were positive for T-cell receptor (TCR) βF1 and negative for TCR-γ with strong expression of cytotoxic markers including granzyme B, perforin, and T-cell intracytoplasmic antigen 1. Rare CD56⁺ cells also were noted. The biopsy did not demonstrate any notable interface dermatitis, epidermotropism, or angioinvasion. T-cell receptor gene rearrangement studies did not show clonality for γ- or β-chain probes. Subcutaneous panniculitic T-cell lymphoma was diagnosed, making this case unique with the presentation of anasarca. This case also is noteworthy due to the rare diagnosis of the secondary malignancy of SPTCL in a patient with known CLL. The patient opted to pursue hospice and comfort measures due to the effects of persistent pancytopenia and the progression of CLL. She died 2 months later.

Clinical courses of SPTCL vary based on the TCR phenotype and immunophenotypic characteristics of the tumor cells. The TCR-αβ phenotype, as described in this case, typically is CD4⁻, CD8⁺, and CD56^– and leads to a more indolent disease course. Lymphomas with the TCR-γδ phenotype typically are CD4⁻, CD8⁻, and CD56⁺; they often are associated with hemophagocytic syndrome and thus a worse prognosis. In 2009, the World Health Organization–European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas restricted the category of SPTCL to the TCR-αβ phenotype due to the stark differences between the 2 types. The TCR-γδ phenotype was given its own diagnostic category—primary cutaneous γδ T-cell lymphoma.³

Patients with SPTCL commonly present with nodular skin lesions or deep-seated plaques on the legs, arms, and/or trunk; presentation on the face is rare.^2,3 Fever, chills, night sweats, and/or weight loss were present in approximately 50% of recorded cases. Underlying autoimmune disease was present in 12 of 63 (19%) patients in a 2008 study.² Facial and periorbital swelling with SPTCL has been reported.^4-9 The presentation of anasarca, as seen in our adult patient, has been reported in a 2-year-old child.¹² Anasarca as a presenting symptom of NHL is a rare phenomenon proposed to be induced by malignant cells secreting a cytokine that causes a vascular leak syndrome.¹³ Specifically, tumor necrosis factor α was found to be elevated in at least 2 patients with NHL presenting with anasarca in a prior study. Tumor necrosis factor α is known to cause increased capillary permeability, vascular leakage, and development of edema.¹³ In retrospect, obtaining cytokine levels in our patient would have been useful to support or refute tumor necrosis factor α as a possible cause of anasarca in the setting of NHL. This case continues to highlight that a diagnosis of SPTCL and analysis of a skin biopsy should be considered in cases of sudden unremitting facial and/or body swelling that cannot be explained by other more common causes.

Subcutaneous panniculitic T-cell lymphoma can be diagnosed and distinguished from other panniculitides via analysis of a deep tissue skin biopsy. Multiple biopsies may be required to ensure an adequate sample is obtained.⁴ Histopathology displays an atypical lymphoid infiltrate with a predominant presence of T cells. Neoplastic cells show CD3⁺, CD8⁺, and CD4⁻ T cells, which strongly express cytotoxic proteins such as granzyme B, T-cell intracellular antigen 1, and perforin.³ The degree of cellular atypia, fat necrosis, karyorrhexis, and cytophagia, as well as the lack of angioinvasion, interface dermatitis, and epidermotropism help to distinguish SPTCL from other panniculitides.^2,3 According to a previous study, clonal TCR gene rearrangement was identified in 50% to 80% of cases, but the absence of this clonal rearrangement does not exclude the diagnosis.¹⁴

This case also highlights the occurrence of secondary malignancies in patients with CLL, an NHL that is classified as a low-grade lymphoproliferative malignancy with clonal expansion of B cells.¹⁵ Secondary CTCLs in patients with CLL are rare, but they have been previously described. In 2017, Chang et al¹⁶ identified 12 patients with CLL who subsequently developed CTCL between 1992 and 2008. Of the 12 patients, 7 developed mycosis fungoides, 3 had CTCL not otherwise specified, 1 had mature T-cell lymphoma not otherwise specified, and 1 had primary cutaneous CD30⁺ T-cell lymphoma.¹⁶ The proliferation of 2 separate lymphocytic lineages is rare, but this study demonstrated an increased risk for CTCL to develop in patients with CLL. One possible explanation is that malignant cells come from a common stem cell progenitor or from genetic events. They occur secondary to carcinogens, viruses, or cytokines from T-cell or B-cell clones; they evolve due to treatment of the preexisting lymphoproliferative disease; or they occur simply by coincidence. The behavior of the CTCL may be more aggressive in patients with CLL due to immunosuppression, which may have contributed to the extreme presentation in our patient.¹⁶ Subcutaneous panniculitic T-cell lymphoma also has been reported in a patient with CLL that was thought to be associated with prior rituximab treatment.¹⁷

Treatment of SPTCL depends on the severity and course of the disease. In patients with more indolent disease, systemic steroids have been the most frequently used initial treatment.^2,3,10 However, the disease often will progress after steroid tapering and require further intervention. Localized lesions may be treated with radiation alone or in combination with other systemic therapies.^3,10 In refractory, aggressive, or relapsing cases, polychemotherapeutic regimens have proven to produce long-term remission in 30% of patients, with an overall response rate of 50%.¹⁰ These regimens most commonly have included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like treatment (EPOCH regimen [etoposide, prednisone, oncovin, cyclophosphamide, and doxorubicin hydrochloride]).^3,10 A stem cell transplant can be considered in patients with recurrent and refractory disease, and it also has been shown to induce remission.^4,17 In patients with a good response to therapy, the disease often can be controlled for long periods of time, with an estimated 5-year survival rate of 80%.¹⁵

This case highlights the diagnostic challenges and variable presentations of SPTCL. Dermatologists, oncologists, and dermatopathologists should be aware of this condition and consider it in the differential diagnosis of a patient with a hematologic malignancy and unremitting facial and/or body swelling without any other cause. The possibility of a secondary hematologic cancer in a patient with CLL also must be taken into consideration. Early diagnosis and treatment can minimize morbidity and induce remission in most patients.

To the Editor:

The organisms of the genus Nocardia are gram-positive, ubiquitous, aerobic actinomycetes found worldwide in soil, decaying organic material, and water.¹ The genus Nocardia includes more than 50 species; some species, such as Nocardia asteroides, Nocardia farcinica, Nocardia nova, and Nocardia brasiliensis, are the cause of nocardiosis in humans and animals.^2,3 Nocardiosis is a rare and opportunistic infection that predominantly affects immunocompromised individuals; however, up to 30% of infections can occur in immunocompetent hosts.⁴ Nocardiosis can manifest in 3 disease forms: cutaneous, pulmonary, or disseminated. Cutaneous nocardiosis commonly develops in immunocompetent individuals who have experienced a predisposing traumatic injury to the skin,⁵ and it can exhibit a diverse variety of clinical manifestations, making diagnosis difficult. We describe a case of serious progressive primary cutaneous nocardiosis with an unusual presentation in an immunocompetent patient.

A 26-year-old immunocompetent man presented with pain, swelling, nodules, abscesses, ulcers, and sinus drainage of the left arm. The left elbow lesion initially developed at the site of a trauma 6 years prior that was painless but was contaminated with mossy soil. The condition slowly progressed over the next 2 years, and the patient experienced increased swelling and eventually developed multiple draining sinus tracts. Over the next 4 years, the lesions multiplied, spreading to the forearm and upper arm; associated severe pain and swelling at the elbow and wrist joint developed. The patient sought medical care at a local hospital and subsequently was diagnosed with suspected cutaneous tuberculosis. The patient was empirically treated with a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol; however, the lesions continued to progress and worsen. The patient had to stop antibiotic treatment because of substantially elevated alanine aminotransferase and aspartate aminotransferase levels.

He subsequently was evaluated at our hospital. He had no notable medical history and was afebrile. Physical examination revealed multiple erythematous nodules, abscesses, and ulcers on the left arm. There were several nodules with open sinus tracts and seropurulent crusts along with numerous atrophic, ovoid, stellate scars. Other nodules and ulcers with purulent drainage were located along the lymphatic nodes extending up the patient’s left forearm (Figure 1A). The yellowish-white pus discharge from several active sinuses contained no apparent granules. The lesions were densely distributed along the elbow, wrist, and shoulder, which resulted in associated skin swelling and restricted joint movement. The left axillary lymph nodes were enlarged.

Laboratory analyses revealed a hemoglobin level of 9.6 g/dL (reference range, 13–17.5 g/dL), platelet count of 621×10⁹/L (reference range, 125–350×10⁹/L), and leukocyte count of 14.3×10⁹/L (reference range, 3.5–9.5 ×10⁹/L). C-reactive protein level was 88.4 mg/L (reference range, 0–10 mg/L). Blood, renal, and liver tests, as well as tumor marker, peripheral blood lymphocyte subset, immunoglobulin, and complement results were within reference ranges. Results for Treponema pallidum and HIV antibody tests were negative. Hepatitis B virus markers were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody, and the serum concentration of hepatitis B virus DNA was 3.12×10⁷ IU/mL (reference range, <5×10² IU/mL). Computed tomography of the chest and cranium were unremarkable. Ultrasonography of the left arm revealed multiple vertical sinus tracts and several horizontal communicating branches that were accompanied by worm-eaten bone destruction (Figure 2).

Additional testing included histopathologic staining of a skin tissue specimen—hematoxylin and eosin, periodic acid–Schiff, and acid-fast staining—showed nonspecific, diffuse, inflammatory cell infiltration suggestive of chronic suppurative granuloma (Figure 3) but failed to reveal any special strains or organisms. Gram stain examination of the purulent fluid collected from the subcutaneous tissue showed no apparent positive bacillus or filamentous granules. The specimen was then inoculated on Sabouraud dextrose agar and Lowenstein-Jensen medium for fungus and mycobacteria culture, respectively. After 5 days, chalky, yellow, adherent colonies were observed on the Löwenstein-Jensen medium, and after 26 days, yellow crinkled colonies were observed on Sabouraud dextrose agar. The colonies were then inoculated on Columbia blood agar and incubated for 1 week to aid in the identification of organisms. Growth of yellow colonies that were adherent to the agar, moist, and smooth with a velvety surface, as well as a characteristic moldy odor resulted. Gram staining revealed gram-positive, thin, and beaded branching filaments (Figure 4). Based on colony characteristics, physiological properties, and biochemical tests, the isolate was identified as Nocardia. Results of further investigations employing polymerase chain reaction analysis of the skin specimen and bacterial colonies using a Nocardia genus 596-bp fragment of 16S ribosomal RNA primer (forward primer NG1: 5’-ACCGACCACAAGGGG-3’, reverse primer NG2: 5’-GGTTGTAACCTCTTCGA-3’)⁶ were completely consistent with the reference for identification of N brasiliensis. Evaluation of these results led to a diagnosis of cutaneous nocardiosis after traumatic inoculation.

Because there was a high suspicion of actinophytosis or nocardiosis at admission, the patient received a combination antibiotic treatment with intravenous aqueous penicillin (4 million U every 4 hours) and oral trimethoprim-sulfamethoxazole (160/800 mg twice daily). Subsequently, treatment was changed to a combination of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily) and moxifloxacin (400 mg once daily) based on pathogen identification and antibiotic sensitivity testing. After 1 month of treatment, the cutaneous lesions and left limb swelling dramatically improved and purulent drainage ceased, though some scarring occurred during the healing process. In addition, the mobility of the affected shoulder, elbow, and wrist joints slightly improved. Notable improvement in the mobility and swelling of the joints was observed at 6-month follow-up (Figure 1B). The patient continues to be monitored on an outpatient basis.

Cutaneous nocardiosis is a disfiguring granulomatous infection involving cutaneous and subcutaneous tissue that can progress to cause injury to viscera and bone.⁷ It has been called one of the great imitators because cutaneous nocardiosis can present in multiple forms,^8,9 including mycetoma, sporotrichoid infection, superficial skin infection, and disseminated infection with cutaneous involvement. The differential diagnoses of cutaneous nocardiosis are broad and include tuberculosis; actinomycosis; deep fungal infections such as sporotrichosis, blastomycosis, phaeohyphomycosis, histoplasmosis, and coccidioidomycosis; other bacterial causes of cellulitis, abscess, or ecthyma; and malignancies.¹⁰ The principle method of diagnosis is the identification of Nocardia from the infection site.

Our patient ultimately was diagnosed with primary cutaneous nocardiosis resulting from a traumatic injury to the skin that was contaminated with soil. The clinical manifestation pattern was a compound type, including both mycetoma and sporotrichoid infections. Initially, Nocardia mycetoma occurred with subcutaneous infection by direct extension^10,11 and appeared as dense, predominantly painless, swollen lesions. After 4 years, the skin lesions continued to spread linearly to the patient’s upper arm and forearm and manifested as the sporotrichoid infection type with painful swollen lesions at the site of inoculation and painful enlargement of the ipsilateral axillary lymph node.

Although nocardiosis is found worldwide, it is endemic to tropical and subtropical regions such as India, Africa, Southeast Asia, and Latin America.¹² Nocardiosis most often is observed in individuals aged 20 to 40 years. It affects men more than women, and it commonly occurs in field laborers and cultivators whose occupations involve direct contact with the soil.¹³ Most lesions are found on the lower extremities, though localized nocardiosis infections can occur in other areas such as the neck, breasts, back, buttocks, and elbows.

Our patient initially was misdiagnosed, and treatment was delayed for several reasons. First, nocardiosis is not common in China, and most clinicians are unfamiliar with the disease. Second, the related lesions do not have specific features, and our patient had a complex clinical presentation that included mycetoma and sporotrichoid infection. Third, the characteristic grain of Nocardia species is small but that of N brasiliensis is even smaller (approximately 0.1–0.2 mm in diameter), which makes visualization difficult in both histopathologic and microbiologic examinations.¹⁴ The histopathologic examination results of our patient in the local hospital were nonspecific. Fourth, our patient did not initially go to the hospital but instead purchased some over-the-counter antibiotic ointments for external application because the lesions were painless. Moreover, microbiologic smear and culture examinations were not conducted in the local hospital before administering antituberculosis treatment to the patient. Instead, a polymerase chain reaction examination of skin lesion tissue for tubercle bacilli and atypical mycobacteria was negative. These findings imply that the traditional microbial smear and culture evaluations cannot be omitted. Furthermore, culture examinations should be conducted on multiple skin tissue and purulent fluid specimens to increase the likelihood of detection. These cultures should be monitored for at least 2 to 4 weeks because Nocardia is a slow-growing organism.¹⁰

The optimal antimicrobial treatment regimens for nocardiosis have not been firmly established.¹⁵ Trimethoprim-sulfamethoxazole is regarded as the first-line antimicrobial agent for treatment of nocardial infections. The optimal duration of antimicrobial therapy for nocardiosis also has not been determined, and the treatment regimen depends on the severity and extent of the infection as well as on the presence of infection-related complications. The main complication is bone involvement. Notable bony changes include periosteal thickening, osteoporosis, and osteolysis.

We considered the severity of skin lesions and bone marrow invasion in our patient and planned to treat him continually with oral trimethoprim-sulfamethoxazole according to the in vitro drug susceptibility test. The patient showed clinical improvement after 1 month of treatment, and he continued to improve after 6 months of treatment. To prevent recurrence, we found it necessary to treat the patient with a long-term antibiotic course over 6 to 12 months.¹⁶

Cutaneous nocardiosis remains a diagnostic challenge because of its nonspecific and diverse clinical and histopathological presentations. Diagnosis is further complicated by the inherent difficulty of cultivating and identifying the clinical isolate in the laboratory. A high degree of clinical suspicion followed by successful identification of the organism by a laboratory technologist will aid in the early diagnosis and treatment of the infection, ultimately reducing the risk for complications and morbidity.

To the Editor:

The organisms of the genus Nocardia are gram-positive, ubiquitous, aerobic actinomycetes found worldwide in soil, decaying organic material, and water.¹ The genus Nocardia includes more than 50 species; some species, such as Nocardia asteroides, Nocardia farcinica, Nocardia nova, and Nocardia brasiliensis, are the cause of nocardiosis in humans and animals.^2,3 Nocardiosis is a rare and opportunistic infection that predominantly affects immunocompromised individuals; however, up to 30% of infections can occur in immunocompetent hosts.⁴ Nocardiosis can manifest in 3 disease forms: cutaneous, pulmonary, or disseminated. Cutaneous nocardiosis commonly develops in immunocompetent individuals who have experienced a predisposing traumatic injury to the skin,⁵ and it can exhibit a diverse variety of clinical manifestations, making diagnosis difficult. We describe a case of serious progressive primary cutaneous nocardiosis with an unusual presentation in an immunocompetent patient.

A 26-year-old immunocompetent man presented with pain, swelling, nodules, abscesses, ulcers, and sinus drainage of the left arm. The left elbow lesion initially developed at the site of a trauma 6 years prior that was painless but was contaminated with mossy soil. The condition slowly progressed over the next 2 years, and the patient experienced increased swelling and eventually developed multiple draining sinus tracts. Over the next 4 years, the lesions multiplied, spreading to the forearm and upper arm; associated severe pain and swelling at the elbow and wrist joint developed. The patient sought medical care at a local hospital and subsequently was diagnosed with suspected cutaneous tuberculosis. The patient was empirically treated with a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol; however, the lesions continued to progress and worsen. The patient had to stop antibiotic treatment because of substantially elevated alanine aminotransferase and aspartate aminotransferase levels.

He subsequently was evaluated at our hospital. He had no notable medical history and was afebrile. Physical examination revealed multiple erythematous nodules, abscesses, and ulcers on the left arm. There were several nodules with open sinus tracts and seropurulent crusts along with numerous atrophic, ovoid, stellate scars. Other nodules and ulcers with purulent drainage were located along the lymphatic nodes extending up the patient’s left forearm (Figure 1A). The yellowish-white pus discharge from several active sinuses contained no apparent granules. The lesions were densely distributed along the elbow, wrist, and shoulder, which resulted in associated skin swelling and restricted joint movement. The left axillary lymph nodes were enlarged.

Laboratory analyses revealed a hemoglobin level of 9.6 g/dL (reference range, 13–17.5 g/dL), platelet count of 621×10⁹/L (reference range, 125–350×10⁹/L), and leukocyte count of 14.3×10⁹/L (reference range, 3.5–9.5 ×10⁹/L). C-reactive protein level was 88.4 mg/L (reference range, 0–10 mg/L). Blood, renal, and liver tests, as well as tumor marker, peripheral blood lymphocyte subset, immunoglobulin, and complement results were within reference ranges. Results for Treponema pallidum and HIV antibody tests were negative. Hepatitis B virus markers were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody, and the serum concentration of hepatitis B virus DNA was 3.12×10⁷ IU/mL (reference range, <5×10² IU/mL). Computed tomography of the chest and cranium were unremarkable. Ultrasonography of the left arm revealed multiple vertical sinus tracts and several horizontal communicating branches that were accompanied by worm-eaten bone destruction (Figure 2).

Additional testing included histopathologic staining of a skin tissue specimen—hematoxylin and eosin, periodic acid–Schiff, and acid-fast staining—showed nonspecific, diffuse, inflammatory cell infiltration suggestive of chronic suppurative granuloma (Figure 3) but failed to reveal any special strains or organisms. Gram stain examination of the purulent fluid collected from the subcutaneous tissue showed no apparent positive bacillus or filamentous granules. The specimen was then inoculated on Sabouraud dextrose agar and Lowenstein-Jensen medium for fungus and mycobacteria culture, respectively. After 5 days, chalky, yellow, adherent colonies were observed on the Löwenstein-Jensen medium, and after 26 days, yellow crinkled colonies were observed on Sabouraud dextrose agar. The colonies were then inoculated on Columbia blood agar and incubated for 1 week to aid in the identification of organisms. Growth of yellow colonies that were adherent to the agar, moist, and smooth with a velvety surface, as well as a characteristic moldy odor resulted. Gram staining revealed gram-positive, thin, and beaded branching filaments (Figure 4). Based on colony characteristics, physiological properties, and biochemical tests, the isolate was identified as Nocardia. Results of further investigations employing polymerase chain reaction analysis of the skin specimen and bacterial colonies using a Nocardia genus 596-bp fragment of 16S ribosomal RNA primer (forward primer NG1: 5’-ACCGACCACAAGGGG-3’, reverse primer NG2: 5’-GGTTGTAACCTCTTCGA-3’)⁶ were completely consistent with the reference for identification of N brasiliensis. Evaluation of these results led to a diagnosis of cutaneous nocardiosis after traumatic inoculation.

Because there was a high suspicion of actinophytosis or nocardiosis at admission, the patient received a combination antibiotic treatment with intravenous aqueous penicillin (4 million U every 4 hours) and oral trimethoprim-sulfamethoxazole (160/800 mg twice daily). Subsequently, treatment was changed to a combination of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily) and moxifloxacin (400 mg once daily) based on pathogen identification and antibiotic sensitivity testing. After 1 month of treatment, the cutaneous lesions and left limb swelling dramatically improved and purulent drainage ceased, though some scarring occurred during the healing process. In addition, the mobility of the affected shoulder, elbow, and wrist joints slightly improved. Notable improvement in the mobility and swelling of the joints was observed at 6-month follow-up (Figure 1B). The patient continues to be monitored on an outpatient basis.

Cutaneous nocardiosis is a disfiguring granulomatous infection involving cutaneous and subcutaneous tissue that can progress to cause injury to viscera and bone.⁷ It has been called one of the great imitators because cutaneous nocardiosis can present in multiple forms,^8,9 including mycetoma, sporotrichoid infection, superficial skin infection, and disseminated infection with cutaneous involvement. The differential diagnoses of cutaneous nocardiosis are broad and include tuberculosis; actinomycosis; deep fungal infections such as sporotrichosis, blastomycosis, phaeohyphomycosis, histoplasmosis, and coccidioidomycosis; other bacterial causes of cellulitis, abscess, or ecthyma; and malignancies.¹⁰ The principle method of diagnosis is the identification of Nocardia from the infection site.

Our patient ultimately was diagnosed with primary cutaneous nocardiosis resulting from a traumatic injury to the skin that was contaminated with soil. The clinical manifestation pattern was a compound type, including both mycetoma and sporotrichoid infections. Initially, Nocardia mycetoma occurred with subcutaneous infection by direct extension^10,11 and appeared as dense, predominantly painless, swollen lesions. After 4 years, the skin lesions continued to spread linearly to the patient’s upper arm and forearm and manifested as the sporotrichoid infection type with painful swollen lesions at the site of inoculation and painful enlargement of the ipsilateral axillary lymph node.

Although nocardiosis is found worldwide, it is endemic to tropical and subtropical regions such as India, Africa, Southeast Asia, and Latin America.¹² Nocardiosis most often is observed in individuals aged 20 to 40 years. It affects men more than women, and it commonly occurs in field laborers and cultivators whose occupations involve direct contact with the soil.¹³ Most lesions are found on the lower extremities, though localized nocardiosis infections can occur in other areas such as the neck, breasts, back, buttocks, and elbows.

Our patient initially was misdiagnosed, and treatment was delayed for several reasons. First, nocardiosis is not common in China, and most clinicians are unfamiliar with the disease. Second, the related lesions do not have specific features, and our patient had a complex clinical presentation that included mycetoma and sporotrichoid infection. Third, the characteristic grain of Nocardia species is small but that of N brasiliensis is even smaller (approximately 0.1–0.2 mm in diameter), which makes visualization difficult in both histopathologic and microbiologic examinations.¹⁴ The histopathologic examination results of our patient in the local hospital were nonspecific. Fourth, our patient did not initially go to the hospital but instead purchased some over-the-counter antibiotic ointments for external application because the lesions were painless. Moreover, microbiologic smear and culture examinations were not conducted in the local hospital before administering antituberculosis treatment to the patient. Instead, a polymerase chain reaction examination of skin lesion tissue for tubercle bacilli and atypical mycobacteria was negative. These findings imply that the traditional microbial smear and culture evaluations cannot be omitted. Furthermore, culture examinations should be conducted on multiple skin tissue and purulent fluid specimens to increase the likelihood of detection. These cultures should be monitored for at least 2 to 4 weeks because Nocardia is a slow-growing organism.¹⁰

The optimal antimicrobial treatment regimens for nocardiosis have not been firmly established.¹⁵ Trimethoprim-sulfamethoxazole is regarded as the first-line antimicrobial agent for treatment of nocardial infections. The optimal duration of antimicrobial therapy for nocardiosis also has not been determined, and the treatment regimen depends on the severity and extent of the infection as well as on the presence of infection-related complications. The main complication is bone involvement. Notable bony changes include periosteal thickening, osteoporosis, and osteolysis.

We considered the severity of skin lesions and bone marrow invasion in our patient and planned to treat him continually with oral trimethoprim-sulfamethoxazole according to the in vitro drug susceptibility test. The patient showed clinical improvement after 1 month of treatment, and he continued to improve after 6 months of treatment. To prevent recurrence, we found it necessary to treat the patient with a long-term antibiotic course over 6 to 12 months.¹⁶

Cutaneous nocardiosis remains a diagnostic challenge because of its nonspecific and diverse clinical and histopathological presentations. Diagnosis is further complicated by the inherent difficulty of cultivating and identifying the clinical isolate in the laboratory. A high degree of clinical suspicion followed by successful identification of the organism by a laboratory technologist will aid in the early diagnosis and treatment of the infection, ultimately reducing the risk for complications and morbidity.

To the Editor:

The organisms of the genus Nocardia are gram-positive, ubiquitous, aerobic actinomycetes found worldwide in soil, decaying organic material, and water.¹ The genus Nocardia includes more than 50 species; some species, such as Nocardia asteroides, Nocardia farcinica, Nocardia nova, and Nocardia brasiliensis, are the cause of nocardiosis in humans and animals.^2,3 Nocardiosis is a rare and opportunistic infection that predominantly affects immunocompromised individuals; however, up to 30% of infections can occur in immunocompetent hosts.⁴ Nocardiosis can manifest in 3 disease forms: cutaneous, pulmonary, or disseminated. Cutaneous nocardiosis commonly develops in immunocompetent individuals who have experienced a predisposing traumatic injury to the skin,⁵ and it can exhibit a diverse variety of clinical manifestations, making diagnosis difficult. We describe a case of serious progressive primary cutaneous nocardiosis with an unusual presentation in an immunocompetent patient.

A 26-year-old immunocompetent man presented with pain, swelling, nodules, abscesses, ulcers, and sinus drainage of the left arm. The left elbow lesion initially developed at the site of a trauma 6 years prior that was painless but was contaminated with mossy soil. The condition slowly progressed over the next 2 years, and the patient experienced increased swelling and eventually developed multiple draining sinus tracts. Over the next 4 years, the lesions multiplied, spreading to the forearm and upper arm; associated severe pain and swelling at the elbow and wrist joint developed. The patient sought medical care at a local hospital and subsequently was diagnosed with suspected cutaneous tuberculosis. The patient was empirically treated with a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol; however, the lesions continued to progress and worsen. The patient had to stop antibiotic treatment because of substantially elevated alanine aminotransferase and aspartate aminotransferase levels.

He subsequently was evaluated at our hospital. He had no notable medical history and was afebrile. Physical examination revealed multiple erythematous nodules, abscesses, and ulcers on the left arm. There were several nodules with open sinus tracts and seropurulent crusts along with numerous atrophic, ovoid, stellate scars. Other nodules and ulcers with purulent drainage were located along the lymphatic nodes extending up the patient’s left forearm (Figure 1A). The yellowish-white pus discharge from several active sinuses contained no apparent granules. The lesions were densely distributed along the elbow, wrist, and shoulder, which resulted in associated skin swelling and restricted joint movement. The left axillary lymph nodes were enlarged.

Laboratory analyses revealed a hemoglobin level of 9.6 g/dL (reference range, 13–17.5 g/dL), platelet count of 621×10⁹/L (reference range, 125–350×10⁹/L), and leukocyte count of 14.3×10⁹/L (reference range, 3.5–9.5 ×10⁹/L). C-reactive protein level was 88.4 mg/L (reference range, 0–10 mg/L). Blood, renal, and liver tests, as well as tumor marker, peripheral blood lymphocyte subset, immunoglobulin, and complement results were within reference ranges. Results for Treponema pallidum and HIV antibody tests were negative. Hepatitis B virus markers were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody, and the serum concentration of hepatitis B virus DNA was 3.12×10⁷ IU/mL (reference range, <5×10² IU/mL). Computed tomography of the chest and cranium were unremarkable. Ultrasonography of the left arm revealed multiple vertical sinus tracts and several horizontal communicating branches that were accompanied by worm-eaten bone destruction (Figure 2).

Additional testing included histopathologic staining of a skin tissue specimen—hematoxylin and eosin, periodic acid–Schiff, and acid-fast staining—showed nonspecific, diffuse, inflammatory cell infiltration suggestive of chronic suppurative granuloma (Figure 3) but failed to reveal any special strains or organisms. Gram stain examination of the purulent fluid collected from the subcutaneous tissue showed no apparent positive bacillus or filamentous granules. The specimen was then inoculated on Sabouraud dextrose agar and Lowenstein-Jensen medium for fungus and mycobacteria culture, respectively. After 5 days, chalky, yellow, adherent colonies were observed on the Löwenstein-Jensen medium, and after 26 days, yellow crinkled colonies were observed on Sabouraud dextrose agar. The colonies were then inoculated on Columbia blood agar and incubated for 1 week to aid in the identification of organisms. Growth of yellow colonies that were adherent to the agar, moist, and smooth with a velvety surface, as well as a characteristic moldy odor resulted. Gram staining revealed gram-positive, thin, and beaded branching filaments (Figure 4). Based on colony characteristics, physiological properties, and biochemical tests, the isolate was identified as Nocardia. Results of further investigations employing polymerase chain reaction analysis of the skin specimen and bacterial colonies using a Nocardia genus 596-bp fragment of 16S ribosomal RNA primer (forward primer NG1: 5’-ACCGACCACAAGGGG-3’, reverse primer NG2: 5’-GGTTGTAACCTCTTCGA-3’)⁶ were completely consistent with the reference for identification of N brasiliensis. Evaluation of these results led to a diagnosis of cutaneous nocardiosis after traumatic inoculation.

Because there was a high suspicion of actinophytosis or nocardiosis at admission, the patient received a combination antibiotic treatment with intravenous aqueous penicillin (4 million U every 4 hours) and oral trimethoprim-sulfamethoxazole (160/800 mg twice daily). Subsequently, treatment was changed to a combination of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily) and moxifloxacin (400 mg once daily) based on pathogen identification and antibiotic sensitivity testing. After 1 month of treatment, the cutaneous lesions and left limb swelling dramatically improved and purulent drainage ceased, though some scarring occurred during the healing process. In addition, the mobility of the affected shoulder, elbow, and wrist joints slightly improved. Notable improvement in the mobility and swelling of the joints was observed at 6-month follow-up (Figure 1B). The patient continues to be monitored on an outpatient basis.

Cutaneous nocardiosis is a disfiguring granulomatous infection involving cutaneous and subcutaneous tissue that can progress to cause injury to viscera and bone.⁷ It has been called one of the great imitators because cutaneous nocardiosis can present in multiple forms,^8,9 including mycetoma, sporotrichoid infection, superficial skin infection, and disseminated infection with cutaneous involvement. The differential diagnoses of cutaneous nocardiosis are broad and include tuberculosis; actinomycosis; deep fungal infections such as sporotrichosis, blastomycosis, phaeohyphomycosis, histoplasmosis, and coccidioidomycosis; other bacterial causes of cellulitis, abscess, or ecthyma; and malignancies.¹⁰ The principle method of diagnosis is the identification of Nocardia from the infection site.

Our patient ultimately was diagnosed with primary cutaneous nocardiosis resulting from a traumatic injury to the skin that was contaminated with soil. The clinical manifestation pattern was a compound type, including both mycetoma and sporotrichoid infections. Initially, Nocardia mycetoma occurred with subcutaneous infection by direct extension^10,11 and appeared as dense, predominantly painless, swollen lesions. After 4 years, the skin lesions continued to spread linearly to the patient’s upper arm and forearm and manifested as the sporotrichoid infection type with painful swollen lesions at the site of inoculation and painful enlargement of the ipsilateral axillary lymph node.

Although nocardiosis is found worldwide, it is endemic to tropical and subtropical regions such as India, Africa, Southeast Asia, and Latin America.¹² Nocardiosis most often is observed in individuals aged 20 to 40 years. It affects men more than women, and it commonly occurs in field laborers and cultivators whose occupations involve direct contact with the soil.¹³ Most lesions are found on the lower extremities, though localized nocardiosis infections can occur in other areas such as the neck, breasts, back, buttocks, and elbows.

Our patient initially was misdiagnosed, and treatment was delayed for several reasons. First, nocardiosis is not common in China, and most clinicians are unfamiliar with the disease. Second, the related lesions do not have specific features, and our patient had a complex clinical presentation that included mycetoma and sporotrichoid infection. Third, the characteristic grain of Nocardia species is small but that of N brasiliensis is even smaller (approximately 0.1–0.2 mm in diameter), which makes visualization difficult in both histopathologic and microbiologic examinations.¹⁴ The histopathologic examination results of our patient in the local hospital were nonspecific. Fourth, our patient did not initially go to the hospital but instead purchased some over-the-counter antibiotic ointments for external application because the lesions were painless. Moreover, microbiologic smear and culture examinations were not conducted in the local hospital before administering antituberculosis treatment to the patient. Instead, a polymerase chain reaction examination of skin lesion tissue for tubercle bacilli and atypical mycobacteria was negative. These findings imply that the traditional microbial smear and culture evaluations cannot be omitted. Furthermore, culture examinations should be conducted on multiple skin tissue and purulent fluid specimens to increase the likelihood of detection. These cultures should be monitored for at least 2 to 4 weeks because Nocardia is a slow-growing organism.¹⁰

The optimal antimicrobial treatment regimens for nocardiosis have not been firmly established.¹⁵ Trimethoprim-sulfamethoxazole is regarded as the first-line antimicrobial agent for treatment of nocardial infections. The optimal duration of antimicrobial therapy for nocardiosis also has not been determined, and the treatment regimen depends on the severity and extent of the infection as well as on the presence of infection-related complications. The main complication is bone involvement. Notable bony changes include periosteal thickening, osteoporosis, and osteolysis.

We considered the severity of skin lesions and bone marrow invasion in our patient and planned to treat him continually with oral trimethoprim-sulfamethoxazole according to the in vitro drug susceptibility test. The patient showed clinical improvement after 1 month of treatment, and he continued to improve after 6 months of treatment. To prevent recurrence, we found it necessary to treat the patient with a long-term antibiotic course over 6 to 12 months.¹⁶

Cutaneous nocardiosis remains a diagnostic challenge because of its nonspecific and diverse clinical and histopathological presentations. Diagnosis is further complicated by the inherent difficulty of cultivating and identifying the clinical isolate in the laboratory. A high degree of clinical suspicion followed by successful identification of the organism by a laboratory technologist will aid in the early diagnosis and treatment of the infection, ultimately reducing the risk for complications and morbidity.