Nonmelanoma Skin Cancer

PHOENIX – During the incidental treatment of melanocytic nevi during laser hair removal, common clinical changes include regression and decreased size, while common histologic changes include mild atypia and thermal damage, according to results from a systematic review of literature on the topic. To date, no severe cases of severe dysplasia or melanoma have been reported.

“That’s reassuring,” study author Ahuva Cices, MD, said in an interview at the annual conference of the American Society for Laser Medicine and Surgery, where she presented the results during an abstract session. “But, with that in mind, we want to avoid treating nevi with laser hair removal to avoid changes that could be concerning. We also recommend baseline skin exams so we know what we’re looking at before we start treating with lasers, and any changes can be recognized from that baseline status. It’s important to keep an eye out for changes and always be evaluating.”

Doug Brunk/MDedge News

In December of 2022, Dr. Cices, chief dermatology resident at Mount Sinai Health System, New York, searched PubMed for articles that evaluated changes in melanocytic nevi after laser hair removal procedures. She used the search terms “nevi laser hair removal,” “nevi diode,” “nevi long pulse alexandrite,” “nevi long pulse neodymium doped yttrium aluminum garnet,” and “melanoma laser hair removal,” and limited the analysis to English language patient-based reports that discussed incidental treatment of melanocytic nevi while undergoing hair removal with a laser.

Reports excluded from the analysis were those that focused on changes following hair removal with nonlaser devices such as intense pulsed light (IPL), those evaluating nonmelanocytic nevi such as Becker’s nevus or nevus of Ota, and those evaluating the intentional ablation or removal of melanocytic lesions.

The search yielded 10 relevant studies for systematic review: seven case reports or series and three observational trials, two of which were prospective and one retrospective.

The results of the review, according to Dr. Cices, revealed that clinical and dermoscopic changes were noted to present as early as 15 days after treatment and persist to the maximum follow up time, at 3 years. Commonly reported changes included regression, decreased size, laser-induced asymmetry, bleaching, darkening, and altered pattern on dermoscopy. Histologic changes included mild atypia, thermal damage, scar formation, and regression.

“Although some of the clinical and dermoscopic alterations may be concerning for malignancy, to our knowledge, there are no documented cases of malignant transformation of nevi following treatment with laser hair removal,” she wrote in the abstract.

Dr. Cices acknowledged certain limitations of the systematic review, including the low number of relevant reports and their generally small sample size, many of which were limited to single cases.

Omar A. Ibrahimi, MD, PhD, medical director of the Connecticut Skin Institute, Stamford, who was asked to comment on the review, characterized the findings as important because laser hair removal is such a commonly performed procedure.

While the study is limited by the small number of studies on the subject matter, “it brings up an important discussion,” Dr. Ibrahimi said in an interview. “Generally speaking, we know that most hair removal lasers do indeed target melanin pigment and can be absorbed by melanocytes. While the wavelengths used for LHR [laser hair removal] will not result in DNA damage or cause mutations that can lead to melanoma, they can sometimes alter the appearance of pigmented lesions and that may change the dermatologist’s ability to monitor them for atypia,” he noted.

“For that reason, I would recommend all patients see a dermatologist for evaluation of their nevi prior to any treatments and they consider very carefully where they get their laser treatments. If they have any atypical pigmented lesions, then that information should be disclosed with the person performing the laser hair removal procedure particularly if there are lesions that are being specifically monitored.”

Dr. Cices reported having no disclosures. Dr. Ibrahimi disclosed that he is a member of the advisory board for Accure Acne, AbbVie, Cutera, Lutronic, Blueberry Therapeutics, Cytrellis, and Quthero. He also holds stock in many device and pharmaceutical companies.

PHOENIX – During the incidental treatment of melanocytic nevi during laser hair removal, common clinical changes include regression and decreased size, while common histologic changes include mild atypia and thermal damage, according to results from a systematic review of literature on the topic. To date, no severe cases of severe dysplasia or melanoma have been reported.

“That’s reassuring,” study author Ahuva Cices, MD, said in an interview at the annual conference of the American Society for Laser Medicine and Surgery, where she presented the results during an abstract session. “But, with that in mind, we want to avoid treating nevi with laser hair removal to avoid changes that could be concerning. We also recommend baseline skin exams so we know what we’re looking at before we start treating with lasers, and any changes can be recognized from that baseline status. It’s important to keep an eye out for changes and always be evaluating.”

Doug Brunk/MDedge News

In December of 2022, Dr. Cices, chief dermatology resident at Mount Sinai Health System, New York, searched PubMed for articles that evaluated changes in melanocytic nevi after laser hair removal procedures. She used the search terms “nevi laser hair removal,” “nevi diode,” “nevi long pulse alexandrite,” “nevi long pulse neodymium doped yttrium aluminum garnet,” and “melanoma laser hair removal,” and limited the analysis to English language patient-based reports that discussed incidental treatment of melanocytic nevi while undergoing hair removal with a laser.

Reports excluded from the analysis were those that focused on changes following hair removal with nonlaser devices such as intense pulsed light (IPL), those evaluating nonmelanocytic nevi such as Becker’s nevus or nevus of Ota, and those evaluating the intentional ablation or removal of melanocytic lesions.

The search yielded 10 relevant studies for systematic review: seven case reports or series and three observational trials, two of which were prospective and one retrospective.

The results of the review, according to Dr. Cices, revealed that clinical and dermoscopic changes were noted to present as early as 15 days after treatment and persist to the maximum follow up time, at 3 years. Commonly reported changes included regression, decreased size, laser-induced asymmetry, bleaching, darkening, and altered pattern on dermoscopy. Histologic changes included mild atypia, thermal damage, scar formation, and regression.

“Although some of the clinical and dermoscopic alterations may be concerning for malignancy, to our knowledge, there are no documented cases of malignant transformation of nevi following treatment with laser hair removal,” she wrote in the abstract.

Dr. Cices acknowledged certain limitations of the systematic review, including the low number of relevant reports and their generally small sample size, many of which were limited to single cases.

Omar A. Ibrahimi, MD, PhD, medical director of the Connecticut Skin Institute, Stamford, who was asked to comment on the review, characterized the findings as important because laser hair removal is such a commonly performed procedure.

While the study is limited by the small number of studies on the subject matter, “it brings up an important discussion,” Dr. Ibrahimi said in an interview. “Generally speaking, we know that most hair removal lasers do indeed target melanin pigment and can be absorbed by melanocytes. While the wavelengths used for LHR [laser hair removal] will not result in DNA damage or cause mutations that can lead to melanoma, they can sometimes alter the appearance of pigmented lesions and that may change the dermatologist’s ability to monitor them for atypia,” he noted.

“For that reason, I would recommend all patients see a dermatologist for evaluation of their nevi prior to any treatments and they consider very carefully where they get their laser treatments. If they have any atypical pigmented lesions, then that information should be disclosed with the person performing the laser hair removal procedure particularly if there are lesions that are being specifically monitored.”

Dr. Cices reported having no disclosures. Dr. Ibrahimi disclosed that he is a member of the advisory board for Accure Acne, AbbVie, Cutera, Lutronic, Blueberry Therapeutics, Cytrellis, and Quthero. He also holds stock in many device and pharmaceutical companies.

PHOENIX – During the incidental treatment of melanocytic nevi during laser hair removal, common clinical changes include regression and decreased size, while common histologic changes include mild atypia and thermal damage, according to results from a systematic review of literature on the topic. To date, no severe cases of severe dysplasia or melanoma have been reported.

“That’s reassuring,” study author Ahuva Cices, MD, said in an interview at the annual conference of the American Society for Laser Medicine and Surgery, where she presented the results during an abstract session. “But, with that in mind, we want to avoid treating nevi with laser hair removal to avoid changes that could be concerning. We also recommend baseline skin exams so we know what we’re looking at before we start treating with lasers, and any changes can be recognized from that baseline status. It’s important to keep an eye out for changes and always be evaluating.”

Doug Brunk/MDedge News

In December of 2022, Dr. Cices, chief dermatology resident at Mount Sinai Health System, New York, searched PubMed for articles that evaluated changes in melanocytic nevi after laser hair removal procedures. She used the search terms “nevi laser hair removal,” “nevi diode,” “nevi long pulse alexandrite,” “nevi long pulse neodymium doped yttrium aluminum garnet,” and “melanoma laser hair removal,” and limited the analysis to English language patient-based reports that discussed incidental treatment of melanocytic nevi while undergoing hair removal with a laser.

Reports excluded from the analysis were those that focused on changes following hair removal with nonlaser devices such as intense pulsed light (IPL), those evaluating nonmelanocytic nevi such as Becker’s nevus or nevus of Ota, and those evaluating the intentional ablation or removal of melanocytic lesions.

The search yielded 10 relevant studies for systematic review: seven case reports or series and three observational trials, two of which were prospective and one retrospective.

The results of the review, according to Dr. Cices, revealed that clinical and dermoscopic changes were noted to present as early as 15 days after treatment and persist to the maximum follow up time, at 3 years. Commonly reported changes included regression, decreased size, laser-induced asymmetry, bleaching, darkening, and altered pattern on dermoscopy. Histologic changes included mild atypia, thermal damage, scar formation, and regression.

“Although some of the clinical and dermoscopic alterations may be concerning for malignancy, to our knowledge, there are no documented cases of malignant transformation of nevi following treatment with laser hair removal,” she wrote in the abstract.

Dr. Cices acknowledged certain limitations of the systematic review, including the low number of relevant reports and their generally small sample size, many of which were limited to single cases.

Omar A. Ibrahimi, MD, PhD, medical director of the Connecticut Skin Institute, Stamford, who was asked to comment on the review, characterized the findings as important because laser hair removal is such a commonly performed procedure.

While the study is limited by the small number of studies on the subject matter, “it brings up an important discussion,” Dr. Ibrahimi said in an interview. “Generally speaking, we know that most hair removal lasers do indeed target melanin pigment and can be absorbed by melanocytes. While the wavelengths used for LHR [laser hair removal] will not result in DNA damage or cause mutations that can lead to melanoma, they can sometimes alter the appearance of pigmented lesions and that may change the dermatologist’s ability to monitor them for atypia,” he noted.

“For that reason, I would recommend all patients see a dermatologist for evaluation of their nevi prior to any treatments and they consider very carefully where they get their laser treatments. If they have any atypical pigmented lesions, then that information should be disclosed with the person performing the laser hair removal procedure particularly if there are lesions that are being specifically monitored.”

Dr. Cices reported having no disclosures. Dr. Ibrahimi disclosed that he is a member of the advisory board for Accure Acne, AbbVie, Cutera, Lutronic, Blueberry Therapeutics, Cytrellis, and Quthero. He also holds stock in many device and pharmaceutical companies.

Results of a study recently published in Nature Communications suggests that radiation from ultraviolet nail polish dryers could induce cell death and trigger molecular changes linked to cancer in human cells. According to two experts, these findings raise concerns regarding the safety of frequent use of these nail dryers.

In the study, human and mouse cells were exposed to radiation from UV nail dryers. Exposing human and mice skin cells to UVA light for 20 minutes resulted in the death of 20%-30% of cells; three consecutive 20-minute sessions resulted in the death of 65%-70% of cells. Additionally, surviving cells suffered oxidative damage to their DNA and mitochondria, with mutational patterns similar to those seen in skin cancer, study investigator Maria Zhivagui, PhD, of the University of California, San Diego, and associates reported.  

“This study showed that irradiation of human and mouse cell lines using UV nail polish dryers resulted in DNA damage and genome mutations,” Shari Lipner, MD, PhD, director of the nail division at New York–Presbyterian Hospital/Weill Cornell Medicine, New York, said in an interview. The study “ties together exposure to UV light from nail polish dryers and genetic mutations that are associated with skin cancers,” added Dr. Lipner, who was not involved with the study.

UV nail lamps are commonly used to dry and harden gel nail polish formulas. Often referred to as “mini tanning beds,” these devices emit UVA radiation, classified as a Group 1 Carcinogen by the International Agency for Research on Cancer.

“Both UVA and UVB are main drivers of both melanoma and keratinocyte carcinomas (basal cell carcinoma and squamous cell carcinoma),” said Anthony Rossi, MD, a dermatologic surgeon at Memorial Sloan Kettering Cancer Center, New York, who was also not a study investigator. UV irradiance “produces DNA mutations that are specific to forming types of skin cancer,” he said in an interview.

UVA wavelengths commonly used in nail dryers can penetrate all layers of the epidermis, the top layer of the skin, potentially affecting stem cells in the skin, according to the study.

Dr. Lipner noted that “there have been several case reports of patients with histories of gel manicures using UV nail polish dryers who later developed squamous cell carcinomas on the dorsal hands, fingers, and nails, and articles describing high UV emissions from nail polish dryers, but the direct connection between UV dryers and skin cancer development was tenuous.” The first of its kind, the new study investigated the impact of UV nail drying devices at a cellular level.

The results of this study, in combination with previous case reports suggesting the development of skin cancers following UVA dryer use, raise concern regarding the safety of these commonly used devices. The study, the authors wrote, “does not provide direct evidence for an increased cancer risk in human beings,” but their findings and “prior evidence strongly suggest that radiation emitted by UV nail polish dryers may cause cancers of the hand and that UV nail polish dryers, similar to tanning beds, may increase the risk of early onset skin cancer.”

Courtesy MSKCC

Dr. Rossi said that, “while this study shows that the UV exposure does affect human cells and causes mutations, the study was not done in vivo in human beings, so further studies are needed to know at what dose and frequency gel manicures would be needed to cause detrimental effects.” However, for people who regularly receive gel manicures involving UV nail dryers, both Dr. Lipner and Dr. Rossi recommend applying a broad-spectrum sunscreen to protect the dorsal hands, fingertips, and skin surrounding the nails, or wearing UV-protective gloves.

The study was supported by an Alfred B. Sloan Research Fellowship to one of the authors and grants from the National Institutes of Health to two authors. One author reported being a compensated consultant and having an equity interest in io9. Dr. Lipner and Dr. Rossi reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Results of a study recently published in Nature Communications suggests that radiation from ultraviolet nail polish dryers could induce cell death and trigger molecular changes linked to cancer in human cells. According to two experts, these findings raise concerns regarding the safety of frequent use of these nail dryers.

In the study, human and mouse cells were exposed to radiation from UV nail dryers. Exposing human and mice skin cells to UVA light for 20 minutes resulted in the death of 20%-30% of cells; three consecutive 20-minute sessions resulted in the death of 65%-70% of cells. Additionally, surviving cells suffered oxidative damage to their DNA and mitochondria, with mutational patterns similar to those seen in skin cancer, study investigator Maria Zhivagui, PhD, of the University of California, San Diego, and associates reported.  

“This study showed that irradiation of human and mouse cell lines using UV nail polish dryers resulted in DNA damage and genome mutations,” Shari Lipner, MD, PhD, director of the nail division at New York–Presbyterian Hospital/Weill Cornell Medicine, New York, said in an interview. The study “ties together exposure to UV light from nail polish dryers and genetic mutations that are associated with skin cancers,” added Dr. Lipner, who was not involved with the study.

UV nail lamps are commonly used to dry and harden gel nail polish formulas. Often referred to as “mini tanning beds,” these devices emit UVA radiation, classified as a Group 1 Carcinogen by the International Agency for Research on Cancer.

“Both UVA and UVB are main drivers of both melanoma and keratinocyte carcinomas (basal cell carcinoma and squamous cell carcinoma),” said Anthony Rossi, MD, a dermatologic surgeon at Memorial Sloan Kettering Cancer Center, New York, who was also not a study investigator. UV irradiance “produces DNA mutations that are specific to forming types of skin cancer,” he said in an interview.

UVA wavelengths commonly used in nail dryers can penetrate all layers of the epidermis, the top layer of the skin, potentially affecting stem cells in the skin, according to the study.

Dr. Lipner noted that “there have been several case reports of patients with histories of gel manicures using UV nail polish dryers who later developed squamous cell carcinomas on the dorsal hands, fingers, and nails, and articles describing high UV emissions from nail polish dryers, but the direct connection between UV dryers and skin cancer development was tenuous.” The first of its kind, the new study investigated the impact of UV nail drying devices at a cellular level.

The results of this study, in combination with previous case reports suggesting the development of skin cancers following UVA dryer use, raise concern regarding the safety of these commonly used devices. The study, the authors wrote, “does not provide direct evidence for an increased cancer risk in human beings,” but their findings and “prior evidence strongly suggest that radiation emitted by UV nail polish dryers may cause cancers of the hand and that UV nail polish dryers, similar to tanning beds, may increase the risk of early onset skin cancer.”

Courtesy MSKCC

Dr. Rossi said that, “while this study shows that the UV exposure does affect human cells and causes mutations, the study was not done in vivo in human beings, so further studies are needed to know at what dose and frequency gel manicures would be needed to cause detrimental effects.” However, for people who regularly receive gel manicures involving UV nail dryers, both Dr. Lipner and Dr. Rossi recommend applying a broad-spectrum sunscreen to protect the dorsal hands, fingertips, and skin surrounding the nails, or wearing UV-protective gloves.

The study was supported by an Alfred B. Sloan Research Fellowship to one of the authors and grants from the National Institutes of Health to two authors. One author reported being a compensated consultant and having an equity interest in io9. Dr. Lipner and Dr. Rossi reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Results of a study recently published in Nature Communications suggests that radiation from ultraviolet nail polish dryers could induce cell death and trigger molecular changes linked to cancer in human cells. According to two experts, these findings raise concerns regarding the safety of frequent use of these nail dryers.

In the study, human and mouse cells were exposed to radiation from UV nail dryers. Exposing human and mice skin cells to UVA light for 20 minutes resulted in the death of 20%-30% of cells; three consecutive 20-minute sessions resulted in the death of 65%-70% of cells. Additionally, surviving cells suffered oxidative damage to their DNA and mitochondria, with mutational patterns similar to those seen in skin cancer, study investigator Maria Zhivagui, PhD, of the University of California, San Diego, and associates reported.  

“This study showed that irradiation of human and mouse cell lines using UV nail polish dryers resulted in DNA damage and genome mutations,” Shari Lipner, MD, PhD, director of the nail division at New York–Presbyterian Hospital/Weill Cornell Medicine, New York, said in an interview. The study “ties together exposure to UV light from nail polish dryers and genetic mutations that are associated with skin cancers,” added Dr. Lipner, who was not involved with the study.

UV nail lamps are commonly used to dry and harden gel nail polish formulas. Often referred to as “mini tanning beds,” these devices emit UVA radiation, classified as a Group 1 Carcinogen by the International Agency for Research on Cancer.

“Both UVA and UVB are main drivers of both melanoma and keratinocyte carcinomas (basal cell carcinoma and squamous cell carcinoma),” said Anthony Rossi, MD, a dermatologic surgeon at Memorial Sloan Kettering Cancer Center, New York, who was also not a study investigator. UV irradiance “produces DNA mutations that are specific to forming types of skin cancer,” he said in an interview.

UVA wavelengths commonly used in nail dryers can penetrate all layers of the epidermis, the top layer of the skin, potentially affecting stem cells in the skin, according to the study.

Dr. Lipner noted that “there have been several case reports of patients with histories of gel manicures using UV nail polish dryers who later developed squamous cell carcinomas on the dorsal hands, fingers, and nails, and articles describing high UV emissions from nail polish dryers, but the direct connection between UV dryers and skin cancer development was tenuous.” The first of its kind, the new study investigated the impact of UV nail drying devices at a cellular level.

The results of this study, in combination with previous case reports suggesting the development of skin cancers following UVA dryer use, raise concern regarding the safety of these commonly used devices. The study, the authors wrote, “does not provide direct evidence for an increased cancer risk in human beings,” but their findings and “prior evidence strongly suggest that radiation emitted by UV nail polish dryers may cause cancers of the hand and that UV nail polish dryers, similar to tanning beds, may increase the risk of early onset skin cancer.”

Courtesy MSKCC

Dr. Rossi said that, “while this study shows that the UV exposure does affect human cells and causes mutations, the study was not done in vivo in human beings, so further studies are needed to know at what dose and frequency gel manicures would be needed to cause detrimental effects.” However, for people who regularly receive gel manicures involving UV nail dryers, both Dr. Lipner and Dr. Rossi recommend applying a broad-spectrum sunscreen to protect the dorsal hands, fingertips, and skin surrounding the nails, or wearing UV-protective gloves.

The study was supported by an Alfred B. Sloan Research Fellowship to one of the authors and grants from the National Institutes of Health to two authors. One author reported being a compensated consultant and having an equity interest in io9. Dr. Lipner and Dr. Rossi reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

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.

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.

The Food and Drug Administration has approved retifanlimab-dlwr (Zynyz), an intravenous programmed death–1 (PD-1) inhibitor, for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC), the agency announced.

This marks the first regulatory approval for the PD-1 inhibitor. The FDA granted accelerated approval for the drug on the basis of tumor response rate and duration of response from the POD1UM-201 trial. Drugmaker Incyte said that “continued approval of Zynyz for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”

MCC is a rare and aggressive skin cancer with a high rate of metastatic disease and an estimated 5-year overall survival of just 14% among those who present with metastatic disease. Incidence is rapidly increasing in the United States, particularly among adults older than 65 years, Incyte noted.

“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” principal author Shailender Bhatia, MD, of the University of Washington and Fred Hutchinson Cancer Center, both in Seattle, said in a news release. “The approval of Zynyz offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease.”

POD1UM-201 was an open-label, single-arm, phase 2 study that evaluated the agent in 65 systemic treatment–naive adults with metastatic or recurrent locally advanced MCC.

Overall, 52% of patients had an objective response rate. A complete response was observed in 12 patients (18%), and a partial response was observed in 22 patients (34%).

Duration of response ranged from 1.1 to 24.9 months; 76% of responders experienced responses of 6 months or longer, and 62% experienced responses of 12 months or longer.

Study participants received a 500-mg dose of retifanlimab every 4 weeks for up to 24 weeks or until disease progression or unacceptable toxicity. Serious adverse events occurred in 22% of patients and most often included fatigue, arrhythmia, and pneumonitis; 11% of patients discontinued treatment because of serious adverse events.

Retifanlimab may cause a severe or life-threatening immune response during treatment or after discontinuation. Patients should be advised to immediately report any new or worsening signs or symptoms to their health care provider. Side effects can also be reported to the FDA.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved retifanlimab-dlwr (Zynyz), an intravenous programmed death–1 (PD-1) inhibitor, for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC), the agency announced.

This marks the first regulatory approval for the PD-1 inhibitor. The FDA granted accelerated approval for the drug on the basis of tumor response rate and duration of response from the POD1UM-201 trial. Drugmaker Incyte said that “continued approval of Zynyz for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”

MCC is a rare and aggressive skin cancer with a high rate of metastatic disease and an estimated 5-year overall survival of just 14% among those who present with metastatic disease. Incidence is rapidly increasing in the United States, particularly among adults older than 65 years, Incyte noted.

“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” principal author Shailender Bhatia, MD, of the University of Washington and Fred Hutchinson Cancer Center, both in Seattle, said in a news release. “The approval of Zynyz offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease.”

POD1UM-201 was an open-label, single-arm, phase 2 study that evaluated the agent in 65 systemic treatment–naive adults with metastatic or recurrent locally advanced MCC.

Overall, 52% of patients had an objective response rate. A complete response was observed in 12 patients (18%), and a partial response was observed in 22 patients (34%).

Duration of response ranged from 1.1 to 24.9 months; 76% of responders experienced responses of 6 months or longer, and 62% experienced responses of 12 months or longer.

Study participants received a 500-mg dose of retifanlimab every 4 weeks for up to 24 weeks or until disease progression or unacceptable toxicity. Serious adverse events occurred in 22% of patients and most often included fatigue, arrhythmia, and pneumonitis; 11% of patients discontinued treatment because of serious adverse events.

Retifanlimab may cause a severe or life-threatening immune response during treatment or after discontinuation. Patients should be advised to immediately report any new or worsening signs or symptoms to their health care provider. Side effects can also be reported to the FDA.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved retifanlimab-dlwr (Zynyz), an intravenous programmed death–1 (PD-1) inhibitor, for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC), the agency announced.

This marks the first regulatory approval for the PD-1 inhibitor. The FDA granted accelerated approval for the drug on the basis of tumor response rate and duration of response from the POD1UM-201 trial. Drugmaker Incyte said that “continued approval of Zynyz for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”

MCC is a rare and aggressive skin cancer with a high rate of metastatic disease and an estimated 5-year overall survival of just 14% among those who present with metastatic disease. Incidence is rapidly increasing in the United States, particularly among adults older than 65 years, Incyte noted.

“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” principal author Shailender Bhatia, MD, of the University of Washington and Fred Hutchinson Cancer Center, both in Seattle, said in a news release. “The approval of Zynyz offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease.”

POD1UM-201 was an open-label, single-arm, phase 2 study that evaluated the agent in 65 systemic treatment–naive adults with metastatic or recurrent locally advanced MCC.

Overall, 52% of patients had an objective response rate. A complete response was observed in 12 patients (18%), and a partial response was observed in 22 patients (34%).

Duration of response ranged from 1.1 to 24.9 months; 76% of responders experienced responses of 6 months or longer, and 62% experienced responses of 12 months or longer.

Study participants received a 500-mg dose of retifanlimab every 4 weeks for up to 24 weeks or until disease progression or unacceptable toxicity. Serious adverse events occurred in 22% of patients and most often included fatigue, arrhythmia, and pneumonitis; 11% of patients discontinued treatment because of serious adverse events.

Retifanlimab may cause a severe or life-threatening immune response during treatment or after discontinuation. Patients should be advised to immediately report any new or worsening signs or symptoms to their health care provider. Side effects can also be reported to the FDA.

A version of this article first appeared on Medscape.com.

Although routinely recommended, nicotinamide does not prevent nonmelanoma skin cancers in solid-organ transplant patients, according to a randomized trial published in the New England Journal of Medicine.

“No signal of efficacy was observed,” said investigators led by Nicholas Allen, MPH, of the University of Sydney department of dermatology.

These results fill an “important gap in our understanding” and “will probably change the practice of many skin-cancer physicians,” two experts on the topic commented in a related editorial.

The editorialists are David Miller, MD, PhD, a dermatologist and medical oncologist at Massachusetts General Hospital, and Kevin Emerick, MD, a head and neck surgeon as Massachusetts Eye and Ear, both in Boston.

Transplant patients have 50 times the risk of nonmelanoma skin cancers – also known as keratinocyte cancers – than the general public, owing to immunosuppression, and their lesions are more aggressive and are more likely to metastasize, they explain.

Nicotinamide (vitamin B3) has been shown to prevent nonmelanoma skin cancers in healthy, immunocompetent people, so physicians routinely prescribe it to transplant patients on the assumption that it will do the same for them, they comment.

The Australian investigators decided to put the assumption to the test.

The team randomly assigned 79 patients who had undergone solid-organ transplant to receive nicotinamide 500 mg twice a day and 79 other patients to receive twice-daily placebo for a year. Participants underwent dermatology exams every 3 months to check for new lesions.

The participants were at high risk for new lesions; some had had more than 40 in the previous 5 years. The two groups were well balanced; kidney transplants were the most common.

At 12 months, there was virtually no difference in the incidence of new nonmelanoma skin cancers: 207 in the nicotinamide group and 210 in the placebo group (P = .96).

There was also no significant difference in squamous cell and basal cell carcinoma counts or actinic keratosis counts.

“The interpretation of the results is straightforward: nicotinamide lacks clinical usefulness in preventing the development of keratinocyte carcinomas in solid-organ transplant recipients,” the team concludes.

As for why nicotinamide didn’t work in the trial, the investigators say it could be because it is not potent enough to overcome the stifling of antitumor immunity and DNA-repair enzymes with immunosuppression.

Fewer than half of participants in the trial reported using sunscreen at any point during the study, which is in line with past reports that transplant patients don’t routinely use sunscreen.

Two other strategies for preventing squamous cell carcinoma after transplant – use of oral retinoids and mTOR inhibitors – are problematic for various reasons, and use was low in both study arms.

Editorialists Dr. Miller and Dr. Emerick suggest a possible new approach: immune checkpoint inhibitors before transplant to reduce the risk of nonmelanoma skin cancer afterward. They say the strategy should be explored and that ongoing efforts to minimize or eliminate the need for immunosuppression after transplant are promising.

The investigators originally planned to enroll 254 persons, but the trial was stopped early because of poor recruitment. Potential participants may already have been taking nicotinamide, which is commonly used, and that may have affected recruitment, the investigators say.

The work was funded by Australia’s National Health and Medical Research Council. Dr. Allen has disclosed no relevant financial relationships. One investigator has received speaker’s fees from BMS. Another is a consultant for many companies, including Amgen, BMS, GlaxoSmithKline, and Merck. Dr. Emerick is an advisor for Regeneron, Sanofi, and Castle Biosciences. Dr. Miller is a researcher or consultant for those companies as well as Pfizer and others and has stock options in Avstera.

A version of this article first appeared on Medscape.com.

Although routinely recommended, nicotinamide does not prevent nonmelanoma skin cancers in solid-organ transplant patients, according to a randomized trial published in the New England Journal of Medicine.

“No signal of efficacy was observed,” said investigators led by Nicholas Allen, MPH, of the University of Sydney department of dermatology.

These results fill an “important gap in our understanding” and “will probably change the practice of many skin-cancer physicians,” two experts on the topic commented in a related editorial.

The editorialists are David Miller, MD, PhD, a dermatologist and medical oncologist at Massachusetts General Hospital, and Kevin Emerick, MD, a head and neck surgeon as Massachusetts Eye and Ear, both in Boston.

Transplant patients have 50 times the risk of nonmelanoma skin cancers – also known as keratinocyte cancers – than the general public, owing to immunosuppression, and their lesions are more aggressive and are more likely to metastasize, they explain.

Nicotinamide (vitamin B3) has been shown to prevent nonmelanoma skin cancers in healthy, immunocompetent people, so physicians routinely prescribe it to transplant patients on the assumption that it will do the same for them, they comment.

The Australian investigators decided to put the assumption to the test.

The team randomly assigned 79 patients who had undergone solid-organ transplant to receive nicotinamide 500 mg twice a day and 79 other patients to receive twice-daily placebo for a year. Participants underwent dermatology exams every 3 months to check for new lesions.

The participants were at high risk for new lesions; some had had more than 40 in the previous 5 years. The two groups were well balanced; kidney transplants were the most common.

At 12 months, there was virtually no difference in the incidence of new nonmelanoma skin cancers: 207 in the nicotinamide group and 210 in the placebo group (P = .96).

There was also no significant difference in squamous cell and basal cell carcinoma counts or actinic keratosis counts.

“The interpretation of the results is straightforward: nicotinamide lacks clinical usefulness in preventing the development of keratinocyte carcinomas in solid-organ transplant recipients,” the team concludes.

As for why nicotinamide didn’t work in the trial, the investigators say it could be because it is not potent enough to overcome the stifling of antitumor immunity and DNA-repair enzymes with immunosuppression.

Fewer than half of participants in the trial reported using sunscreen at any point during the study, which is in line with past reports that transplant patients don’t routinely use sunscreen.

Two other strategies for preventing squamous cell carcinoma after transplant – use of oral retinoids and mTOR inhibitors – are problematic for various reasons, and use was low in both study arms.

Editorialists Dr. Miller and Dr. Emerick suggest a possible new approach: immune checkpoint inhibitors before transplant to reduce the risk of nonmelanoma skin cancer afterward. They say the strategy should be explored and that ongoing efforts to minimize or eliminate the need for immunosuppression after transplant are promising.

The investigators originally planned to enroll 254 persons, but the trial was stopped early because of poor recruitment. Potential participants may already have been taking nicotinamide, which is commonly used, and that may have affected recruitment, the investigators say.

The work was funded by Australia’s National Health and Medical Research Council. Dr. Allen has disclosed no relevant financial relationships. One investigator has received speaker’s fees from BMS. Another is a consultant for many companies, including Amgen, BMS, GlaxoSmithKline, and Merck. Dr. Emerick is an advisor for Regeneron, Sanofi, and Castle Biosciences. Dr. Miller is a researcher or consultant for those companies as well as Pfizer and others and has stock options in Avstera.

A version of this article first appeared on Medscape.com.

Although routinely recommended, nicotinamide does not prevent nonmelanoma skin cancers in solid-organ transplant patients, according to a randomized trial published in the New England Journal of Medicine.

“No signal of efficacy was observed,” said investigators led by Nicholas Allen, MPH, of the University of Sydney department of dermatology.

These results fill an “important gap in our understanding” and “will probably change the practice of many skin-cancer physicians,” two experts on the topic commented in a related editorial.

The editorialists are David Miller, MD, PhD, a dermatologist and medical oncologist at Massachusetts General Hospital, and Kevin Emerick, MD, a head and neck surgeon as Massachusetts Eye and Ear, both in Boston.

Transplant patients have 50 times the risk of nonmelanoma skin cancers – also known as keratinocyte cancers – than the general public, owing to immunosuppression, and their lesions are more aggressive and are more likely to metastasize, they explain.

Nicotinamide (vitamin B3) has been shown to prevent nonmelanoma skin cancers in healthy, immunocompetent people, so physicians routinely prescribe it to transplant patients on the assumption that it will do the same for them, they comment.

The Australian investigators decided to put the assumption to the test.

The team randomly assigned 79 patients who had undergone solid-organ transplant to receive nicotinamide 500 mg twice a day and 79 other patients to receive twice-daily placebo for a year. Participants underwent dermatology exams every 3 months to check for new lesions.

The participants were at high risk for new lesions; some had had more than 40 in the previous 5 years. The two groups were well balanced; kidney transplants were the most common.

At 12 months, there was virtually no difference in the incidence of new nonmelanoma skin cancers: 207 in the nicotinamide group and 210 in the placebo group (P = .96).

There was also no significant difference in squamous cell and basal cell carcinoma counts or actinic keratosis counts.

“The interpretation of the results is straightforward: nicotinamide lacks clinical usefulness in preventing the development of keratinocyte carcinomas in solid-organ transplant recipients,” the team concludes.

As for why nicotinamide didn’t work in the trial, the investigators say it could be because it is not potent enough to overcome the stifling of antitumor immunity and DNA-repair enzymes with immunosuppression.

Fewer than half of participants in the trial reported using sunscreen at any point during the study, which is in line with past reports that transplant patients don’t routinely use sunscreen.

Two other strategies for preventing squamous cell carcinoma after transplant – use of oral retinoids and mTOR inhibitors – are problematic for various reasons, and use was low in both study arms.

Editorialists Dr. Miller and Dr. Emerick suggest a possible new approach: immune checkpoint inhibitors before transplant to reduce the risk of nonmelanoma skin cancer afterward. They say the strategy should be explored and that ongoing efforts to minimize or eliminate the need for immunosuppression after transplant are promising.

The investigators originally planned to enroll 254 persons, but the trial was stopped early because of poor recruitment. Potential participants may already have been taking nicotinamide, which is commonly used, and that may have affected recruitment, the investigators say.

The work was funded by Australia’s National Health and Medical Research Council. Dr. Allen has disclosed no relevant financial relationships. One investigator has received speaker’s fees from BMS. Another is a consultant for many companies, including Amgen, BMS, GlaxoSmithKline, and Merck. Dr. Emerick is an advisor for Regeneron, Sanofi, and Castle Biosciences. Dr. Miller is a researcher or consultant for those companies as well as Pfizer and others and has stock options in Avstera.

A version of this article first appeared on Medscape.com.

Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. ¹ The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. ²  There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). ³ Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. ⁴ Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. ^5-9

The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.^10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.¹⁴ Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.^5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.¹⁵ Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.^16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.^20-22

Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.²³ As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.

METHODS

A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).

A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.

RESULTS

Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.^24-27 One case affecting both feet reported known exposure to lead arsenate pesticides²⁷; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.^28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.^31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.

Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.^36-41 Two cases reported association with human papillomavirus type 2.^7,42

Metastases to dermal and subdermal lymphatics, regional lymph nodes, and the lungs were reported in 3 cases, repectively.^43-45 Of these, one primary tumor had received low-dose irradiation in the form of X-ray therapy.⁴⁵

Treatment Modalities

The cases of EC that we reviewed included treatment with surgical and systemic therapies as well as other modalities such as acitretin, interferon alfa, topical imiquimod, curettage, debridement, electrodesiccation, and radiation. The Table includes a complete summary of the treatments we analyzed.

Surgical Therapy—The majority (91% [105/115]) of cases were treated surgically. The most common treatment modality was WLE (50% [58/115]), followed by amputation (37% [43/115]) and MMS (12% [14/115]).

Wide local excision was the most frequently reported treatment, with excision margins of at least 5 mm to 1 cm.⁴⁸ Incidence of recurrence was reported for 57% (33/58) of cases treated with WLE; of these, the recurrence rate was 33% (11/33). For patients with EC recurrence, the most common secondary treatment was repeat excision with wider margins (1–2 cm) or amputation (5/11).^49-52 Few postoperative complications were reported but included pain, infection, and difficulty walking, which were mostly associated with repair modality (eg, split-thickness skin grafts, rotational flaps).⁵³ 
Amputation was the second most common treatment modality, with a 67% (29/43) incidence of recurrence. Types of amputation included transmetatarsal ray amputation (7/43 [16%]), foot or forefoot amputation (2/43 [5%]), above-the-knee amputation (1/43 [2%]), and below-the-knee amputation (1/43 [2%]). Complications associated with amputation included infection and requirement of prosthetics for ambulation. Split-thickness skin grafts and rotational flaps were the most common surgical repairs performed.^52,53

Mohs micrographic surgery was the least frequently reported surgical treatment modality. Both traditional MMS on fresh tissue and “slow Mohs,” with formalin-fixed paraffin embedded tissue examination over several days, were performed for EC with horizontal en face sectioning.^54-56 Incidence of recurrence was reported for 86% (12/14) of MMS cases. Of these, recurrence was seen in 17% (2/12) that utilized a flat horizontal processing of tissue sections coupled with saucerlike excisions to enable examination of the entire undersurface and margins. In one case, the patient was treated with MMS with recurrence noted 1 month later; thus, repeat MMS was performed, and the tumor was found to be entwined around the flexor tendon.⁵⁷ The tendon was removed, and clear margins were obtained. Follow-up 3 years after the second MMS revealed no signs of recurrence.⁵⁷ In the other case, the patient had a particularly aggressive course with bilateral VC in the setting of diabetic ulcers that was treated with WLE prior to MMS and recurrence still noted after MMS.²⁶ No complications were reported with MMS.

Overall, recurrence was most frequently reported with WLE (11/33 [33%]), followed by MMS (2/12 [17%]) and amputation (3/29 [10%]). When comparing WLE and amputation, the relationship between treatment modality and recurrence was statistically significant using a χ² test of independence (χ²=4.7; P=.03). However, results were not significant with Yates correction for continuity (χ²=3.4; P=.06). The χ² test of independence showed no significant association between treatment method and recurrence when comparing WLE with MMS (χ²=1.2; P=.28). Reported follow-up times varied greatly from a few months to 10 years.

Systemic Therapy—Of the total cases, only 2 cases reported treatment with acitretin and 2 utilized interferon alfa.^58,59 In one case, treatment of EC with interferon alfa alone required more aggressive therapy (ie, amputation).⁵⁸ Neither of the 2 cases using acitretin reported recurrence.^59,60 Complications of acitretin therapy included cheilitis and transaminitis.⁶⁰

Other Treatment Modalities—Three cases utilized imiquimod, with 2 cases of imiquimod monotherapy and 1 case of imiquimod in combination with electrodesiccation and WLE.³⁷ One of the cases of EC treated with imiquimod monotherapy recurred and required WLE.⁶¹

There were reports of other treatments including curettage alone (2% [2/115]),^40,62 debridement alone (1% [1/115]),⁴⁰ electrodesiccation (1% [1/115]),³⁷ and radiation (1% [1/115]).⁴³ Recurrence was found with curettage alone and debridement alone. Electrodesiccation was reported in conjunction with WLE without recurrence. Radiation was used to treat a case of VC that had metastasized to the lymph nodes; no follow-up was described.⁴³

COMMENT

Epithelioma cuniculatum is an indolent malignancy of the plantar foot that likely is frequently underdiagnosed or misdiagnosed because of location, sampling error, and challenges in histopathologic diagnosis. Once diagnosed, surgical removal with margin control is the first-line therapy for EC. Our review found a number of surgical, systemic, and other treatment modalities that have been used to treat EC, but there remains a lack of evidence to provide clear guidelines as to which therapies are most effective. Current data on the treatment of EC largely are limited to case reports and case series. To date, there are no reports of higher-quality studies or randomized controlled trials to assess the efficacy of various treatment modalities.

Our review found that WLE is the most common treatment modality for EC, followed by amputation and MMS. Three cases^43-45 that reported metastasis to lymph nodes also were treated with fine-needle aspiration or biopsy, and it is recommended that sentinel lymph node biopsy be performed when there is a history of radiation exposure or clinically and sonographically unsuspicious lymph nodes, while dissection of regional nodes should be performed if lymph node metastasis is suspected.⁵³ Additional treatments reported included acitretin, interferon alfa, topical imiquimod, curettage, debridement, and electrodesiccation, but because of the limited number of cases and variable efficacy, no conclusions can be made on the utility of these alternative modalities.

The lowest rate of reported recurrence was found with amputation, followed by MMS and WLE. Amputation is the most aggressive treatment option, but its superiority in lower recurrence rates was not statistically significant when compared with either WLE or MMS after Yates correction. Despite treatment with radical surgery, recurrence is still possible and may be associated with factors including greater size (>2 cm) and depth (>4 mm), poor histologic differentiation, perineural involvement, failure of previous treatments, and immunosuppression.⁶³ No statistically significant difference in recurrence rates was found among surgical methods, though data trended toward lower rates of recurrence with MMS compared with WLE, as recurrence with MMS was only reported in 2 cases.^25,56

The efficacy of MMS is well documented for tumors with contiguous growth and enables maximum preservation of normal tissue structure and function with complete margin visualization. Thus, our results are in agreement with those of prior studies,^54-56,64 suggesting that MMS is associated with lower recurrence rates for EC than WLE. Future studies and reporting of MMS for EC are particularly important because of the functional importance of the plantar foot.

It is important to note that there are local and systemic risk factors that increase the likelihood of developing EC and facilitate tumor growth, including antecedent trauma to the lesion site, chronic irritation or infection, and immunosuppression (HIV related or iatrogenic medication induced). These risk factors may play a role in the treatment modality utilized (eg, more aggressive EC may be treated with amputation instead of WLE). Underlying patient comorbidities could potentially affect recurrence rates, which is a variable we could not control for in our analysis.

Our findings are limited by study design, with supporting evidence consisting of case reports and series. The review is limited by interstudy variability and heterogeneity of results. Additionally, recurrence is not reported in all cases and may be a source of sampling bias. Further complicating the generalizability of these results is the lack of follow-up to evaluate morbidity and quality of life after treatment.

CONCLUSION

This review suggests that MMS is associated with lower recurrence rates than WLE for the treatment of EC. Further investigation of MMS for EC with appropriate follow-up is necessary to identify whether MMS is associated with lower recurrence and less functional impairment. Nonsurgical treatments, including topical imiquimod, interferon alfa, and acitretin, may be useful in cases where surgical therapies are contraindicated, but there is little evidence to support these treatment modalities. Treatment guidelines for EC are not established, and appropriate treatment guidelines should be developed in the future.

Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. ¹ The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. ²  There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). ³ Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. ⁴ Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. ^5-9

The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.^10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.¹⁴ Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.^5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.¹⁵ Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.^16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.^20-22

Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.²³ As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.

METHODS

A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).

A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.

RESULTS

Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.^24-27 One case affecting both feet reported known exposure to lead arsenate pesticides²⁷; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.^28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.^31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.

Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.^36-41 Two cases reported association with human papillomavirus type 2.^7,42

Metastases to dermal and subdermal lymphatics, regional lymph nodes, and the lungs were reported in 3 cases, repectively.^43-45 Of these, one primary tumor had received low-dose irradiation in the form of X-ray therapy.⁴⁵

Treatment Modalities

The cases of EC that we reviewed included treatment with surgical and systemic therapies as well as other modalities such as acitretin, interferon alfa, topical imiquimod, curettage, debridement, electrodesiccation, and radiation. The Table includes a complete summary of the treatments we analyzed.

Surgical Therapy—The majority (91% [105/115]) of cases were treated surgically. The most common treatment modality was WLE (50% [58/115]), followed by amputation (37% [43/115]) and MMS (12% [14/115]).

Wide local excision was the most frequently reported treatment, with excision margins of at least 5 mm to 1 cm.⁴⁸ Incidence of recurrence was reported for 57% (33/58) of cases treated with WLE; of these, the recurrence rate was 33% (11/33). For patients with EC recurrence, the most common secondary treatment was repeat excision with wider margins (1–2 cm) or amputation (5/11).^49-52 Few postoperative complications were reported but included pain, infection, and difficulty walking, which were mostly associated with repair modality (eg, split-thickness skin grafts, rotational flaps).⁵³ 
Amputation was the second most common treatment modality, with a 67% (29/43) incidence of recurrence. Types of amputation included transmetatarsal ray amputation (7/43 [16%]), foot or forefoot amputation (2/43 [5%]), above-the-knee amputation (1/43 [2%]), and below-the-knee amputation (1/43 [2%]). Complications associated with amputation included infection and requirement of prosthetics for ambulation. Split-thickness skin grafts and rotational flaps were the most common surgical repairs performed.^52,53

Mohs micrographic surgery was the least frequently reported surgical treatment modality. Both traditional MMS on fresh tissue and “slow Mohs,” with formalin-fixed paraffin embedded tissue examination over several days, were performed for EC with horizontal en face sectioning.^54-56 Incidence of recurrence was reported for 86% (12/14) of MMS cases. Of these, recurrence was seen in 17% (2/12) that utilized a flat horizontal processing of tissue sections coupled with saucerlike excisions to enable examination of the entire undersurface and margins. In one case, the patient was treated with MMS with recurrence noted 1 month later; thus, repeat MMS was performed, and the tumor was found to be entwined around the flexor tendon.⁵⁷ The tendon was removed, and clear margins were obtained. Follow-up 3 years after the second MMS revealed no signs of recurrence.⁵⁷ In the other case, the patient had a particularly aggressive course with bilateral VC in the setting of diabetic ulcers that was treated with WLE prior to MMS and recurrence still noted after MMS.²⁶ No complications were reported with MMS.

Overall, recurrence was most frequently reported with WLE (11/33 [33%]), followed by MMS (2/12 [17%]) and amputation (3/29 [10%]). When comparing WLE and amputation, the relationship between treatment modality and recurrence was statistically significant using a χ² test of independence (χ²=4.7; P=.03). However, results were not significant with Yates correction for continuity (χ²=3.4; P=.06). The χ² test of independence showed no significant association between treatment method and recurrence when comparing WLE with MMS (χ²=1.2; P=.28). Reported follow-up times varied greatly from a few months to 10 years.

Systemic Therapy—Of the total cases, only 2 cases reported treatment with acitretin and 2 utilized interferon alfa.^58,59 In one case, treatment of EC with interferon alfa alone required more aggressive therapy (ie, amputation).⁵⁸ Neither of the 2 cases using acitretin reported recurrence.^59,60 Complications of acitretin therapy included cheilitis and transaminitis.⁶⁰

Other Treatment Modalities—Three cases utilized imiquimod, with 2 cases of imiquimod monotherapy and 1 case of imiquimod in combination with electrodesiccation and WLE.³⁷ One of the cases of EC treated with imiquimod monotherapy recurred and required WLE.⁶¹

There were reports of other treatments including curettage alone (2% [2/115]),^40,62 debridement alone (1% [1/115]),⁴⁰ electrodesiccation (1% [1/115]),³⁷ and radiation (1% [1/115]).⁴³ Recurrence was found with curettage alone and debridement alone. Electrodesiccation was reported in conjunction with WLE without recurrence. Radiation was used to treat a case of VC that had metastasized to the lymph nodes; no follow-up was described.⁴³

COMMENT

Epithelioma cuniculatum is an indolent malignancy of the plantar foot that likely is frequently underdiagnosed or misdiagnosed because of location, sampling error, and challenges in histopathologic diagnosis. Once diagnosed, surgical removal with margin control is the first-line therapy for EC. Our review found a number of surgical, systemic, and other treatment modalities that have been used to treat EC, but there remains a lack of evidence to provide clear guidelines as to which therapies are most effective. Current data on the treatment of EC largely are limited to case reports and case series. To date, there are no reports of higher-quality studies or randomized controlled trials to assess the efficacy of various treatment modalities.

Our review found that WLE is the most common treatment modality for EC, followed by amputation and MMS. Three cases^43-45 that reported metastasis to lymph nodes also were treated with fine-needle aspiration or biopsy, and it is recommended that sentinel lymph node biopsy be performed when there is a history of radiation exposure or clinically and sonographically unsuspicious lymph nodes, while dissection of regional nodes should be performed if lymph node metastasis is suspected.⁵³ Additional treatments reported included acitretin, interferon alfa, topical imiquimod, curettage, debridement, and electrodesiccation, but because of the limited number of cases and variable efficacy, no conclusions can be made on the utility of these alternative modalities.

The lowest rate of reported recurrence was found with amputation, followed by MMS and WLE. Amputation is the most aggressive treatment option, but its superiority in lower recurrence rates was not statistically significant when compared with either WLE or MMS after Yates correction. Despite treatment with radical surgery, recurrence is still possible and may be associated with factors including greater size (>2 cm) and depth (>4 mm), poor histologic differentiation, perineural involvement, failure of previous treatments, and immunosuppression.⁶³ No statistically significant difference in recurrence rates was found among surgical methods, though data trended toward lower rates of recurrence with MMS compared with WLE, as recurrence with MMS was only reported in 2 cases.^25,56

The efficacy of MMS is well documented for tumors with contiguous growth and enables maximum preservation of normal tissue structure and function with complete margin visualization. Thus, our results are in agreement with those of prior studies,^54-56,64 suggesting that MMS is associated with lower recurrence rates for EC than WLE. Future studies and reporting of MMS for EC are particularly important because of the functional importance of the plantar foot.

It is important to note that there are local and systemic risk factors that increase the likelihood of developing EC and facilitate tumor growth, including antecedent trauma to the lesion site, chronic irritation or infection, and immunosuppression (HIV related or iatrogenic medication induced). These risk factors may play a role in the treatment modality utilized (eg, more aggressive EC may be treated with amputation instead of WLE). Underlying patient comorbidities could potentially affect recurrence rates, which is a variable we could not control for in our analysis.

Our findings are limited by study design, with supporting evidence consisting of case reports and series. The review is limited by interstudy variability and heterogeneity of results. Additionally, recurrence is not reported in all cases and may be a source of sampling bias. Further complicating the generalizability of these results is the lack of follow-up to evaluate morbidity and quality of life after treatment.

CONCLUSION

This review suggests that MMS is associated with lower recurrence rates than WLE for the treatment of EC. Further investigation of MMS for EC with appropriate follow-up is necessary to identify whether MMS is associated with lower recurrence and less functional impairment. Nonsurgical treatments, including topical imiquimod, interferon alfa, and acitretin, may be useful in cases where surgical therapies are contraindicated, but there is little evidence to support these treatment modalities. Treatment guidelines for EC are not established, and appropriate treatment guidelines should be developed in the future.

Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. ¹ The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. ²  There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). ³ Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. ⁴ Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. ^5-9

The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.^10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.¹⁴ Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.^5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.¹⁵ Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.^16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.^20-22

Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.²³ As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.

METHODS

A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).

A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.

RESULTS

Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.^24-27 One case affecting both feet reported known exposure to lead arsenate pesticides²⁷; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.^28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.^31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.

Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.^36-41 Two cases reported association with human papillomavirus type 2.^7,42

Metastases to dermal and subdermal lymphatics, regional lymph nodes, and the lungs were reported in 3 cases, repectively.^43-45 Of these, one primary tumor had received low-dose irradiation in the form of X-ray therapy.⁴⁵

Treatment Modalities

The cases of EC that we reviewed included treatment with surgical and systemic therapies as well as other modalities such as acitretin, interferon alfa, topical imiquimod, curettage, debridement, electrodesiccation, and radiation. The Table includes a complete summary of the treatments we analyzed.

Surgical Therapy—The majority (91% [105/115]) of cases were treated surgically. The most common treatment modality was WLE (50% [58/115]), followed by amputation (37% [43/115]) and MMS (12% [14/115]).

Wide local excision was the most frequently reported treatment, with excision margins of at least 5 mm to 1 cm.⁴⁸ Incidence of recurrence was reported for 57% (33/58) of cases treated with WLE; of these, the recurrence rate was 33% (11/33). For patients with EC recurrence, the most common secondary treatment was repeat excision with wider margins (1–2 cm) or amputation (5/11).^49-52 Few postoperative complications were reported but included pain, infection, and difficulty walking, which were mostly associated with repair modality (eg, split-thickness skin grafts, rotational flaps).⁵³ 
Amputation was the second most common treatment modality, with a 67% (29/43) incidence of recurrence. Types of amputation included transmetatarsal ray amputation (7/43 [16%]), foot or forefoot amputation (2/43 [5%]), above-the-knee amputation (1/43 [2%]), and below-the-knee amputation (1/43 [2%]). Complications associated with amputation included infection and requirement of prosthetics for ambulation. Split-thickness skin grafts and rotational flaps were the most common surgical repairs performed.^52,53

Mohs micrographic surgery was the least frequently reported surgical treatment modality. Both traditional MMS on fresh tissue and “slow Mohs,” with formalin-fixed paraffin embedded tissue examination over several days, were performed for EC with horizontal en face sectioning.^54-56 Incidence of recurrence was reported for 86% (12/14) of MMS cases. Of these, recurrence was seen in 17% (2/12) that utilized a flat horizontal processing of tissue sections coupled with saucerlike excisions to enable examination of the entire undersurface and margins. In one case, the patient was treated with MMS with recurrence noted 1 month later; thus, repeat MMS was performed, and the tumor was found to be entwined around the flexor tendon.⁵⁷ The tendon was removed, and clear margins were obtained. Follow-up 3 years after the second MMS revealed no signs of recurrence.⁵⁷ In the other case, the patient had a particularly aggressive course with bilateral VC in the setting of diabetic ulcers that was treated with WLE prior to MMS and recurrence still noted after MMS.²⁶ No complications were reported with MMS.

Overall, recurrence was most frequently reported with WLE (11/33 [33%]), followed by MMS (2/12 [17%]) and amputation (3/29 [10%]). When comparing WLE and amputation, the relationship between treatment modality and recurrence was statistically significant using a χ² test of independence (χ²=4.7; P=.03). However, results were not significant with Yates correction for continuity (χ²=3.4; P=.06). The χ² test of independence showed no significant association between treatment method and recurrence when comparing WLE with MMS (χ²=1.2; P=.28). Reported follow-up times varied greatly from a few months to 10 years.

Systemic Therapy—Of the total cases, only 2 cases reported treatment with acitretin and 2 utilized interferon alfa.^58,59 In one case, treatment of EC with interferon alfa alone required more aggressive therapy (ie, amputation).⁵⁸ Neither of the 2 cases using acitretin reported recurrence.^59,60 Complications of acitretin therapy included cheilitis and transaminitis.⁶⁰

Other Treatment Modalities—Three cases utilized imiquimod, with 2 cases of imiquimod monotherapy and 1 case of imiquimod in combination with electrodesiccation and WLE.³⁷ One of the cases of EC treated with imiquimod monotherapy recurred and required WLE.⁶¹

There were reports of other treatments including curettage alone (2% [2/115]),^40,62 debridement alone (1% [1/115]),⁴⁰ electrodesiccation (1% [1/115]),³⁷ and radiation (1% [1/115]).⁴³ Recurrence was found with curettage alone and debridement alone. Electrodesiccation was reported in conjunction with WLE without recurrence. Radiation was used to treat a case of VC that had metastasized to the lymph nodes; no follow-up was described.⁴³

COMMENT

Epithelioma cuniculatum is an indolent malignancy of the plantar foot that likely is frequently underdiagnosed or misdiagnosed because of location, sampling error, and challenges in histopathologic diagnosis. Once diagnosed, surgical removal with margin control is the first-line therapy for EC. Our review found a number of surgical, systemic, and other treatment modalities that have been used to treat EC, but there remains a lack of evidence to provide clear guidelines as to which therapies are most effective. Current data on the treatment of EC largely are limited to case reports and case series. To date, there are no reports of higher-quality studies or randomized controlled trials to assess the efficacy of various treatment modalities.

Our review found that WLE is the most common treatment modality for EC, followed by amputation and MMS. Three cases^43-45 that reported metastasis to lymph nodes also were treated with fine-needle aspiration or biopsy, and it is recommended that sentinel lymph node biopsy be performed when there is a history of radiation exposure or clinically and sonographically unsuspicious lymph nodes, while dissection of regional nodes should be performed if lymph node metastasis is suspected.⁵³ Additional treatments reported included acitretin, interferon alfa, topical imiquimod, curettage, debridement, and electrodesiccation, but because of the limited number of cases and variable efficacy, no conclusions can be made on the utility of these alternative modalities.

The lowest rate of reported recurrence was found with amputation, followed by MMS and WLE. Amputation is the most aggressive treatment option, but its superiority in lower recurrence rates was not statistically significant when compared with either WLE or MMS after Yates correction. Despite treatment with radical surgery, recurrence is still possible and may be associated with factors including greater size (>2 cm) and depth (>4 mm), poor histologic differentiation, perineural involvement, failure of previous treatments, and immunosuppression.⁶³ No statistically significant difference in recurrence rates was found among surgical methods, though data trended toward lower rates of recurrence with MMS compared with WLE, as recurrence with MMS was only reported in 2 cases.^25,56

The efficacy of MMS is well documented for tumors with contiguous growth and enables maximum preservation of normal tissue structure and function with complete margin visualization. Thus, our results are in agreement with those of prior studies,^54-56,64 suggesting that MMS is associated with lower recurrence rates for EC than WLE. Future studies and reporting of MMS for EC are particularly important because of the functional importance of the plantar foot.

It is important to note that there are local and systemic risk factors that increase the likelihood of developing EC and facilitate tumor growth, including antecedent trauma to the lesion site, chronic irritation or infection, and immunosuppression (HIV related or iatrogenic medication induced). These risk factors may play a role in the treatment modality utilized (eg, more aggressive EC may be treated with amputation instead of WLE). Underlying patient comorbidities could potentially affect recurrence rates, which is a variable we could not control for in our analysis.

Our findings are limited by study design, with supporting evidence consisting of case reports and series. The review is limited by interstudy variability and heterogeneity of results. Additionally, recurrence is not reported in all cases and may be a source of sampling bias. Further complicating the generalizability of these results is the lack of follow-up to evaluate morbidity and quality of life after treatment.

CONCLUSION

This review suggests that MMS is associated with lower recurrence rates than WLE for the treatment of EC. Further investigation of MMS for EC with appropriate follow-up is necessary to identify whether MMS is associated with lower recurrence and less functional impairment. Nonsurgical treatments, including topical imiquimod, interferon alfa, and acitretin, may be useful in cases where surgical therapies are contraindicated, but there is little evidence to support these treatment modalities. Treatment guidelines for EC are not established, and appropriate treatment guidelines should be developed in the future.

The Diagnosis: Plasmablastic Lymphoma

A punch biopsy of one of the leg nodules with hematoxylin and eosin staining revealed sheets of medium to large cells with plasmacytic differentiation (Figure, A and B). Immunohistochemistry showed CD79, epithelial membrane antigen, multiple myeloma 1, and CD138 positivity, as well as CD-19 negativity and positive staining on Epstein-Barr virus (EBV) in situ hybridization (Figure, C). Ki-67 stained greater than 90% of the neoplastic cells. Neoplastic cells were found to be λ restricted on κ and λ immunohistochemistry. Human herpesvirus 8 (HHV-8), CD3, and CD20 stains were negative. Subsequent fluorescent in situ hybridization was positive for MYC/immunoglobulin heavy chain (MYC/IGH) rearrangement t(8;14), confirming a diagnosis of plasmablastic lymphoma (PBL).

A bone marrow biopsy revealed normocellular bone marrow with trilineage hematopoiesis and no morphologic, immunophenotypic, or fluorescent in situ hybridization evidence of plasmablastic lymphoma or other pathology in the bone marrow. Our patient was started on hyper-CVAD (cyclophosphamide, vincristine, doxorubicin hydrochloride, dexamethasone) chemotherapy and was doing well with plans for a fourth course of chemotherapy. There is no standardized treatment course for cutaneous PBL, though excision with adjunctive chemotherapy treatment commonly has been reported in the literature.¹

Plasmablastic lymphoma is a rare and aggressive diffuse large B-cell lymphoma associated with EBV infection that compromises approximately 2% to 3% of all HIV-related lymphomas.^1,2 It frequently is associated with immunosuppression in patients with HIV or in transplant recipients on immunosuppression; however, it has been reported in immunocompetent individuals such as elderly patients.² Plasmablastic lymphoma most commonly presents on the buccal mucosa but also can affect the gastrointestinal tract and occasionally has cutaneous manifestations.^1,2 Cutaneous manifestations of PBL range from erythematous infiltrated plaques to ulcerated nodules presenting in an array of colors from flesh colored to violaceous.² Primary cutaneous lesions can be seen on the legs, as in our patient.

Histopathologic examination reveals sheets of plasmablasts or large cells with eccentric nuclei and abundant basophilic cytoplasm.¹ Plasmablastic lymphoma frequently is positive for mature B-cell markers such as CD38, CD138, multiple myeloma 1, and B lymphocyte–induced maturation protein 1.^2,3 Uncommonly, PBL expresses paired box protein Pax-5 and CD20 markers.³ Although pathogenesis is poorly understood, it has been speculated that EBV infection is a common pathogenic factor. Epstein-Barr virus positivity has been noted in 60% of cases.²

Plasmablastic lymphoma and other malignant plasma cell processes such as plasmablastic myeloma (PBM) are morphologically similar. Proliferation of plasmablasts with rare plasmacytic cells is common in PBL, while plasmacytic cells are predominant in PBM. MYC rearrangement/ immunoglobulin heavy chain rearrangement t(8;14) was used to differentiate PBL from PBM in our patient; however, more cases of PBM with MYC/IGH rearrangement t(8;14) have been reported, making it an unreliable differentiating factor.⁴ A detailed clinical, pathologic, and genetic survey remains necessary for confirmatory diagnosis of PBL. Compared to other malignant plasma cell processes, PBL more commonly is seen in immunocompromised patients or those with HIV, such as our patient. Additionally, EBV testing is more likely to be positive in patients with PBL, further supporting this diagnosis in our patient.⁴

Presentations of bacillary angiomatosis, Kaposi sarcoma, and cutaneous lymphoma may be clinically similar; therefore, careful immunohistopathologic differentiation is necessary. Kaposi sarcoma is an angioproliferative disorder that develops from HHV-8 infection and commonly is associated with HIV. It presents as painless vascular lesions in a range of colors with typical progression from patch to plaque to nodules, frequently on the lower extremities. Histologically, admixtures of bland spindle cells, slitlike small vessel proliferation, and lymphocytic infiltration are typical. Neoplastic vessels lack basement membrane zones, resulting in microhemorrhages and hemosiderin deposition. Neoplastic vessels label with CD31 and CD34 endothelial markers in addition to HHV-8 antibodies, which is highly specific for Kaposi sarcoma and differentiates it from PBL.⁵

Bacillary angiomatosis is an infectious neovascular proliferation characterized by papular lesions that may resemble the lesions of PBL. Mixed cell infiltration in inflammatory cells with clumping of granular material is characteristic. Under Warthin-Starry staining, the granular material is abundant in gram-negative rods representing Bartonella species, which is the implicated infectious agent in bacillary angiomatosis.

Lymphomatoid papulosis (LyP) is the most common CD30+ lymphoproliferative disorder and also may present with exophytic nodules. The etiology of LyP remains unknown, but it is suspected that overexpression of CD30 plays a role. Lymphomatoid papulosis presents as red-violaceous papules and nodules in various stages of healing. Although variable histology among types of LyP exists, CD30+ T-cell lymphocytes remain the hallmark of LyP. Type A LyP, which accounts for 80% of LyP cases, reveals CD4+ and CD30+ cells scattered among neutrophils, eosinophils, and small lymphocytes.5 Lymphomatoid papulosis typically is self-healing, recurrent, and carries an excellent prognosis.

Plasmablastic lymphoma remains a rare and aggressive type of diffuse large B-cell lymphoma that can have primary cutaneous manifestations. It is prudent to consider PBL in the differential diagnosis of nodular lower extremity lesions, especially in immunosuppressed patients.

The Diagnosis: Plasmablastic Lymphoma

A punch biopsy of one of the leg nodules with hematoxylin and eosin staining revealed sheets of medium to large cells with plasmacytic differentiation (Figure, A and B). Immunohistochemistry showed CD79, epithelial membrane antigen, multiple myeloma 1, and CD138 positivity, as well as CD-19 negativity and positive staining on Epstein-Barr virus (EBV) in situ hybridization (Figure, C). Ki-67 stained greater than 90% of the neoplastic cells. Neoplastic cells were found to be λ restricted on κ and λ immunohistochemistry. Human herpesvirus 8 (HHV-8), CD3, and CD20 stains were negative. Subsequent fluorescent in situ hybridization was positive for MYC/immunoglobulin heavy chain (MYC/IGH) rearrangement t(8;14), confirming a diagnosis of plasmablastic lymphoma (PBL).

A bone marrow biopsy revealed normocellular bone marrow with trilineage hematopoiesis and no morphologic, immunophenotypic, or fluorescent in situ hybridization evidence of plasmablastic lymphoma or other pathology in the bone marrow. Our patient was started on hyper-CVAD (cyclophosphamide, vincristine, doxorubicin hydrochloride, dexamethasone) chemotherapy and was doing well with plans for a fourth course of chemotherapy. There is no standardized treatment course for cutaneous PBL, though excision with adjunctive chemotherapy treatment commonly has been reported in the literature.¹

Plasmablastic lymphoma is a rare and aggressive diffuse large B-cell lymphoma associated with EBV infection that compromises approximately 2% to 3% of all HIV-related lymphomas.^1,2 It frequently is associated with immunosuppression in patients with HIV or in transplant recipients on immunosuppression; however, it has been reported in immunocompetent individuals such as elderly patients.² Plasmablastic lymphoma most commonly presents on the buccal mucosa but also can affect the gastrointestinal tract and occasionally has cutaneous manifestations.^1,2 Cutaneous manifestations of PBL range from erythematous infiltrated plaques to ulcerated nodules presenting in an array of colors from flesh colored to violaceous.² Primary cutaneous lesions can be seen on the legs, as in our patient.

Histopathologic examination reveals sheets of plasmablasts or large cells with eccentric nuclei and abundant basophilic cytoplasm.¹ Plasmablastic lymphoma frequently is positive for mature B-cell markers such as CD38, CD138, multiple myeloma 1, and B lymphocyte–induced maturation protein 1.^2,3 Uncommonly, PBL expresses paired box protein Pax-5 and CD20 markers.³ Although pathogenesis is poorly understood, it has been speculated that EBV infection is a common pathogenic factor. Epstein-Barr virus positivity has been noted in 60% of cases.²

Plasmablastic lymphoma and other malignant plasma cell processes such as plasmablastic myeloma (PBM) are morphologically similar. Proliferation of plasmablasts with rare plasmacytic cells is common in PBL, while plasmacytic cells are predominant in PBM. MYC rearrangement/ immunoglobulin heavy chain rearrangement t(8;14) was used to differentiate PBL from PBM in our patient; however, more cases of PBM with MYC/IGH rearrangement t(8;14) have been reported, making it an unreliable differentiating factor.⁴ A detailed clinical, pathologic, and genetic survey remains necessary for confirmatory diagnosis of PBL. Compared to other malignant plasma cell processes, PBL more commonly is seen in immunocompromised patients or those with HIV, such as our patient. Additionally, EBV testing is more likely to be positive in patients with PBL, further supporting this diagnosis in our patient.⁴

Presentations of bacillary angiomatosis, Kaposi sarcoma, and cutaneous lymphoma may be clinically similar; therefore, careful immunohistopathologic differentiation is necessary. Kaposi sarcoma is an angioproliferative disorder that develops from HHV-8 infection and commonly is associated with HIV. It presents as painless vascular lesions in a range of colors with typical progression from patch to plaque to nodules, frequently on the lower extremities. Histologically, admixtures of bland spindle cells, slitlike small vessel proliferation, and lymphocytic infiltration are typical. Neoplastic vessels lack basement membrane zones, resulting in microhemorrhages and hemosiderin deposition. Neoplastic vessels label with CD31 and CD34 endothelial markers in addition to HHV-8 antibodies, which is highly specific for Kaposi sarcoma and differentiates it from PBL.⁵

Bacillary angiomatosis is an infectious neovascular proliferation characterized by papular lesions that may resemble the lesions of PBL. Mixed cell infiltration in inflammatory cells with clumping of granular material is characteristic. Under Warthin-Starry staining, the granular material is abundant in gram-negative rods representing Bartonella species, which is the implicated infectious agent in bacillary angiomatosis.

Lymphomatoid papulosis (LyP) is the most common CD30+ lymphoproliferative disorder and also may present with exophytic nodules. The etiology of LyP remains unknown, but it is suspected that overexpression of CD30 plays a role. Lymphomatoid papulosis presents as red-violaceous papules and nodules in various stages of healing. Although variable histology among types of LyP exists, CD30+ T-cell lymphocytes remain the hallmark of LyP. Type A LyP, which accounts for 80% of LyP cases, reveals CD4+ and CD30+ cells scattered among neutrophils, eosinophils, and small lymphocytes.5 Lymphomatoid papulosis typically is self-healing, recurrent, and carries an excellent prognosis.

Plasmablastic lymphoma remains a rare and aggressive type of diffuse large B-cell lymphoma that can have primary cutaneous manifestations. It is prudent to consider PBL in the differential diagnosis of nodular lower extremity lesions, especially in immunosuppressed patients.

The Diagnosis: Plasmablastic Lymphoma

A punch biopsy of one of the leg nodules with hematoxylin and eosin staining revealed sheets of medium to large cells with plasmacytic differentiation (Figure, A and B). Immunohistochemistry showed CD79, epithelial membrane antigen, multiple myeloma 1, and CD138 positivity, as well as CD-19 negativity and positive staining on Epstein-Barr virus (EBV) in situ hybridization (Figure, C). Ki-67 stained greater than 90% of the neoplastic cells. Neoplastic cells were found to be λ restricted on κ and λ immunohistochemistry. Human herpesvirus 8 (HHV-8), CD3, and CD20 stains were negative. Subsequent fluorescent in situ hybridization was positive for MYC/immunoglobulin heavy chain (MYC/IGH) rearrangement t(8;14), confirming a diagnosis of plasmablastic lymphoma (PBL).

A bone marrow biopsy revealed normocellular bone marrow with trilineage hematopoiesis and no morphologic, immunophenotypic, or fluorescent in situ hybridization evidence of plasmablastic lymphoma or other pathology in the bone marrow. Our patient was started on hyper-CVAD (cyclophosphamide, vincristine, doxorubicin hydrochloride, dexamethasone) chemotherapy and was doing well with plans for a fourth course of chemotherapy. There is no standardized treatment course for cutaneous PBL, though excision with adjunctive chemotherapy treatment commonly has been reported in the literature.¹

Plasmablastic lymphoma is a rare and aggressive diffuse large B-cell lymphoma associated with EBV infection that compromises approximately 2% to 3% of all HIV-related lymphomas.^1,2 It frequently is associated with immunosuppression in patients with HIV or in transplant recipients on immunosuppression; however, it has been reported in immunocompetent individuals such as elderly patients.² Plasmablastic lymphoma most commonly presents on the buccal mucosa but also can affect the gastrointestinal tract and occasionally has cutaneous manifestations.^1,2 Cutaneous manifestations of PBL range from erythematous infiltrated plaques to ulcerated nodules presenting in an array of colors from flesh colored to violaceous.² Primary cutaneous lesions can be seen on the legs, as in our patient.

Histopathologic examination reveals sheets of plasmablasts or large cells with eccentric nuclei and abundant basophilic cytoplasm.¹ Plasmablastic lymphoma frequently is positive for mature B-cell markers such as CD38, CD138, multiple myeloma 1, and B lymphocyte–induced maturation protein 1.^2,3 Uncommonly, PBL expresses paired box protein Pax-5 and CD20 markers.³ Although pathogenesis is poorly understood, it has been speculated that EBV infection is a common pathogenic factor. Epstein-Barr virus positivity has been noted in 60% of cases.²

Plasmablastic lymphoma and other malignant plasma cell processes such as plasmablastic myeloma (PBM) are morphologically similar. Proliferation of plasmablasts with rare plasmacytic cells is common in PBL, while plasmacytic cells are predominant in PBM. MYC rearrangement/ immunoglobulin heavy chain rearrangement t(8;14) was used to differentiate PBL from PBM in our patient; however, more cases of PBM with MYC/IGH rearrangement t(8;14) have been reported, making it an unreliable differentiating factor.⁴ A detailed clinical, pathologic, and genetic survey remains necessary for confirmatory diagnosis of PBL. Compared to other malignant plasma cell processes, PBL more commonly is seen in immunocompromised patients or those with HIV, such as our patient. Additionally, EBV testing is more likely to be positive in patients with PBL, further supporting this diagnosis in our patient.⁴

Presentations of bacillary angiomatosis, Kaposi sarcoma, and cutaneous lymphoma may be clinically similar; therefore, careful immunohistopathologic differentiation is necessary. Kaposi sarcoma is an angioproliferative disorder that develops from HHV-8 infection and commonly is associated with HIV. It presents as painless vascular lesions in a range of colors with typical progression from patch to plaque to nodules, frequently on the lower extremities. Histologically, admixtures of bland spindle cells, slitlike small vessel proliferation, and lymphocytic infiltration are typical. Neoplastic vessels lack basement membrane zones, resulting in microhemorrhages and hemosiderin deposition. Neoplastic vessels label with CD31 and CD34 endothelial markers in addition to HHV-8 antibodies, which is highly specific for Kaposi sarcoma and differentiates it from PBL.⁵

Bacillary angiomatosis is an infectious neovascular proliferation characterized by papular lesions that may resemble the lesions of PBL. Mixed cell infiltration in inflammatory cells with clumping of granular material is characteristic. Under Warthin-Starry staining, the granular material is abundant in gram-negative rods representing Bartonella species, which is the implicated infectious agent in bacillary angiomatosis.

Lymphomatoid papulosis (LyP) is the most common CD30+ lymphoproliferative disorder and also may present with exophytic nodules. The etiology of LyP remains unknown, but it is suspected that overexpression of CD30 plays a role. Lymphomatoid papulosis presents as red-violaceous papules and nodules in various stages of healing. Although variable histology among types of LyP exists, CD30+ T-cell lymphocytes remain the hallmark of LyP. Type A LyP, which accounts for 80% of LyP cases, reveals CD4+ and CD30+ cells scattered among neutrophils, eosinophils, and small lymphocytes.5 Lymphomatoid papulosis typically is self-healing, recurrent, and carries an excellent prognosis.

Plasmablastic lymphoma remains a rare and aggressive type of diffuse large B-cell lymphoma that can have primary cutaneous manifestations. It is prudent to consider PBL in the differential diagnosis of nodular lower extremity lesions, especially in immunosuppressed patients.

San Diego – The way Benjamin Kelley, MD, sees it, the term dysplastic nevi (DN) suffers from an identity crisis, with different clinicians using different terms to describe a subset of melanocytic nevi that are clinically atypical.

Doug Brunk/MDedge News

“There’s a confusion in the terminology, a term the late A. Bernard Ackerman, MD, called ‘patho-babel,’ ” Dr. Kelley, a Mohs micrographic surgeon and dermatopathologist in La Jolla, Calif., said at the annual Cutaneous Malignancy Update. “The idea of DN was originally used to describe a clinical melanoma syndrome. Now we use it for individual lesions, not just clinically but histologically. Some dermatologists refer to DN as ‘pre-melanoma,’ which is a negative framing,” he noted.

“We also refer to common nevi as ‘benign,’ which implies that DN are not benign,” he added. “The good news is that regardless of what they are called, the histologic criteria is generally agreed upon. The names can be used interchangeably.”

The bad news, he continued, is that there is less-than-perfect interobserver variability for grading DN lesions and significant variability in the treatment recommendations that pathologists give to clinicians. In one study, a group of pathology experts was asked to review 48 photomicrographs of melanocytic lesions and provide their diagnosis and treatment recommendations based on the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis scheme. For one, which showed a broad lesion with irregular epidermal thinning and thickening, the diagnoses ranged from solar lentigo to melanoma in situ. Treatment recommendations ranged from no treatment to re-excise with appropriate margins.

“This is an extreme example, but it shows you how difficult [establishing a diagnosis] can be,” Dr. Kelley said.

In a more recent study, researchers analyzed interobserver reproducibility in grading 179 DN cases among three observers who applied the 2018 World Health Organization grading criteria. The observers showed moderate to good agreement for most of the architectural features, except for criteria regarding focal continuous basal proliferation of melanocytes, density of non-nested junctional melanocytes, and presence of dyscohesive nests of intraepidermal melanocytes, whereas fair agreement was achieved for the cytological criteria. “So, it sounds to me like there was not a whole lot of agreement,” Dr. Kelley said.

An earlier single-center study titled “Clinicians Are From Mars and Pathologists Are From Venus” found that surgeons misunderstood the pathologist’s report 30% of the time.

In Dr. Kelly’s opinion, management of DNs will be successful if clinicians have a good working relationship with their dermatopathologists, if they biopsy to ensure an adequate, representative specimen, and if that they know what the terminology on the pathology report means and what actions to take. “The biopsy method matters,” he emphasized.

In a 14-year follow-up survey, investigators assessed DN management trends among 703 U.S. dermatologists. One key finding was that 69% of dermatologists in 2015 performed total removals when biopsying DN to achieve clear margins, compared with 86% in 2001.

A subsequent survey of 213 New England–based dermatologists found that the degree of clinical suspicion for melanoma was important in DN biopsy technique, with more respondents favoring shave biopsies for lesions with low suspicion and full-thickness biopsies for highly suspicious lesions.

“Misdiagnosis is more common for melanomas that have been assessed with punch and shave biopsies than with an excisional biopsy,” Dr. Kelley said. “I’m not too much of a stickler. I don’t require everyone to send me a giant excision, but I do want a representative sample.”

What about re-excision of DN considered to be mild or moderate? In 2015, members of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group published a consensus statement on DN management recommendations for clinically atypical nevi/DN based on a review of published evidence. The subcommittee members concluded that mildly and moderately DN with clear margins do not need to be re-excised, and that mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than re-excised.

For moderately DN with positive histologic margins without clinically apparent residual pigmentation, the subcommittee members concluded that observation may be reasonable.

In his own informal analysis, Dr. Kelley compiled data from published studies he could find on DN management and divided them into two groups: the observation group, in which researchers from eight studies biopsied the DN lesion and watched the patients over time to see what happened, and the re-excision group, in which researchers from seven studies biopsied the DN lesion and subsequently re-excised it. There were about 1,500 patients in both groups. No deaths occurred in either group, he said, but 15 patients in the re-excision group developed a melanoma at the site of the original biopsy (1%), compared with 7 in the observation group (0.5%).

Six of seven melanomas in the observation group came from one article conducted at a VA clinic. In the study, 6 of 304 observed DN subsequently developed melanoma at the site of the lesion. “However, five of six that developed melanoma had an original biopsy that was a partial biopsy with grossly positive margins; I think that’s where the problem lies,” Dr. Kelley said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “All five grew lentigo maligna type melanoma, which we know can extend multiple millimeters beyond the clinically apparent lesion.”

The findings support mounting evidence that re-excising mild and moderate DN, regardless of border involvement, may not be necessary. “Currently, most clinicians still re-excise moderate and severe DN involving margins, especially if there is residual pigment,” Dr. Kelley said. “Most re-excise severe DN regardless of margin involvement, but beware if your biopsy was a partial sample of a larger lesion.”

He acknowledged limitations to pathologic studies of DN, including the potential for diagnostic uncertainty. “That doesn’t necessarily mean that the pathologist got the diagnosis wrong. It could be, what is the risk that the portion of tissue not visualized contains melanoma? If you give me a 5 mm sample of a DN, and I cut it into 4-micrometer sections, I’m only looking at less than 1% of the actual nevus. That’s compounded if the pathologist only receives a partial sample.”

Dr. Kelley reported having no relevant disclosures.

San Diego – The way Benjamin Kelley, MD, sees it, the term dysplastic nevi (DN) suffers from an identity crisis, with different clinicians using different terms to describe a subset of melanocytic nevi that are clinically atypical.

Doug Brunk/MDedge News

“There’s a confusion in the terminology, a term the late A. Bernard Ackerman, MD, called ‘patho-babel,’ ” Dr. Kelley, a Mohs micrographic surgeon and dermatopathologist in La Jolla, Calif., said at the annual Cutaneous Malignancy Update. “The idea of DN was originally used to describe a clinical melanoma syndrome. Now we use it for individual lesions, not just clinically but histologically. Some dermatologists refer to DN as ‘pre-melanoma,’ which is a negative framing,” he noted.

“We also refer to common nevi as ‘benign,’ which implies that DN are not benign,” he added. “The good news is that regardless of what they are called, the histologic criteria is generally agreed upon. The names can be used interchangeably.”

The bad news, he continued, is that there is less-than-perfect interobserver variability for grading DN lesions and significant variability in the treatment recommendations that pathologists give to clinicians. In one study, a group of pathology experts was asked to review 48 photomicrographs of melanocytic lesions and provide their diagnosis and treatment recommendations based on the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis scheme. For one, which showed a broad lesion with irregular epidermal thinning and thickening, the diagnoses ranged from solar lentigo to melanoma in situ. Treatment recommendations ranged from no treatment to re-excise with appropriate margins.

“This is an extreme example, but it shows you how difficult [establishing a diagnosis] can be,” Dr. Kelley said.

In a more recent study, researchers analyzed interobserver reproducibility in grading 179 DN cases among three observers who applied the 2018 World Health Organization grading criteria. The observers showed moderate to good agreement for most of the architectural features, except for criteria regarding focal continuous basal proliferation of melanocytes, density of non-nested junctional melanocytes, and presence of dyscohesive nests of intraepidermal melanocytes, whereas fair agreement was achieved for the cytological criteria. “So, it sounds to me like there was not a whole lot of agreement,” Dr. Kelley said.

An earlier single-center study titled “Clinicians Are From Mars and Pathologists Are From Venus” found that surgeons misunderstood the pathologist’s report 30% of the time.

In Dr. Kelly’s opinion, management of DNs will be successful if clinicians have a good working relationship with their dermatopathologists, if they biopsy to ensure an adequate, representative specimen, and if that they know what the terminology on the pathology report means and what actions to take. “The biopsy method matters,” he emphasized.

In a 14-year follow-up survey, investigators assessed DN management trends among 703 U.S. dermatologists. One key finding was that 69% of dermatologists in 2015 performed total removals when biopsying DN to achieve clear margins, compared with 86% in 2001.

A subsequent survey of 213 New England–based dermatologists found that the degree of clinical suspicion for melanoma was important in DN biopsy technique, with more respondents favoring shave biopsies for lesions with low suspicion and full-thickness biopsies for highly suspicious lesions.

“Misdiagnosis is more common for melanomas that have been assessed with punch and shave biopsies than with an excisional biopsy,” Dr. Kelley said. “I’m not too much of a stickler. I don’t require everyone to send me a giant excision, but I do want a representative sample.”

What about re-excision of DN considered to be mild or moderate? In 2015, members of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group published a consensus statement on DN management recommendations for clinically atypical nevi/DN based on a review of published evidence. The subcommittee members concluded that mildly and moderately DN with clear margins do not need to be re-excised, and that mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than re-excised.

For moderately DN with positive histologic margins without clinically apparent residual pigmentation, the subcommittee members concluded that observation may be reasonable.

In his own informal analysis, Dr. Kelley compiled data from published studies he could find on DN management and divided them into two groups: the observation group, in which researchers from eight studies biopsied the DN lesion and watched the patients over time to see what happened, and the re-excision group, in which researchers from seven studies biopsied the DN lesion and subsequently re-excised it. There were about 1,500 patients in both groups. No deaths occurred in either group, he said, but 15 patients in the re-excision group developed a melanoma at the site of the original biopsy (1%), compared with 7 in the observation group (0.5%).

Six of seven melanomas in the observation group came from one article conducted at a VA clinic. In the study, 6 of 304 observed DN subsequently developed melanoma at the site of the lesion. “However, five of six that developed melanoma had an original biopsy that was a partial biopsy with grossly positive margins; I think that’s where the problem lies,” Dr. Kelley said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “All five grew lentigo maligna type melanoma, which we know can extend multiple millimeters beyond the clinically apparent lesion.”

The findings support mounting evidence that re-excising mild and moderate DN, regardless of border involvement, may not be necessary. “Currently, most clinicians still re-excise moderate and severe DN involving margins, especially if there is residual pigment,” Dr. Kelley said. “Most re-excise severe DN regardless of margin involvement, but beware if your biopsy was a partial sample of a larger lesion.”

He acknowledged limitations to pathologic studies of DN, including the potential for diagnostic uncertainty. “That doesn’t necessarily mean that the pathologist got the diagnosis wrong. It could be, what is the risk that the portion of tissue not visualized contains melanoma? If you give me a 5 mm sample of a DN, and I cut it into 4-micrometer sections, I’m only looking at less than 1% of the actual nevus. That’s compounded if the pathologist only receives a partial sample.”

Dr. Kelley reported having no relevant disclosures.

San Diego – The way Benjamin Kelley, MD, sees it, the term dysplastic nevi (DN) suffers from an identity crisis, with different clinicians using different terms to describe a subset of melanocytic nevi that are clinically atypical.

Doug Brunk/MDedge News

“There’s a confusion in the terminology, a term the late A. Bernard Ackerman, MD, called ‘patho-babel,’ ” Dr. Kelley, a Mohs micrographic surgeon and dermatopathologist in La Jolla, Calif., said at the annual Cutaneous Malignancy Update. “The idea of DN was originally used to describe a clinical melanoma syndrome. Now we use it for individual lesions, not just clinically but histologically. Some dermatologists refer to DN as ‘pre-melanoma,’ which is a negative framing,” he noted.

“We also refer to common nevi as ‘benign,’ which implies that DN are not benign,” he added. “The good news is that regardless of what they are called, the histologic criteria is generally agreed upon. The names can be used interchangeably.”

The bad news, he continued, is that there is less-than-perfect interobserver variability for grading DN lesions and significant variability in the treatment recommendations that pathologists give to clinicians. In one study, a group of pathology experts was asked to review 48 photomicrographs of melanocytic lesions and provide their diagnosis and treatment recommendations based on the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis scheme. For one, which showed a broad lesion with irregular epidermal thinning and thickening, the diagnoses ranged from solar lentigo to melanoma in situ. Treatment recommendations ranged from no treatment to re-excise with appropriate margins.

“This is an extreme example, but it shows you how difficult [establishing a diagnosis] can be,” Dr. Kelley said.

In a more recent study, researchers analyzed interobserver reproducibility in grading 179 DN cases among three observers who applied the 2018 World Health Organization grading criteria. The observers showed moderate to good agreement for most of the architectural features, except for criteria regarding focal continuous basal proliferation of melanocytes, density of non-nested junctional melanocytes, and presence of dyscohesive nests of intraepidermal melanocytes, whereas fair agreement was achieved for the cytological criteria. “So, it sounds to me like there was not a whole lot of agreement,” Dr. Kelley said.

An earlier single-center study titled “Clinicians Are From Mars and Pathologists Are From Venus” found that surgeons misunderstood the pathologist’s report 30% of the time.

In Dr. Kelly’s opinion, management of DNs will be successful if clinicians have a good working relationship with their dermatopathologists, if they biopsy to ensure an adequate, representative specimen, and if that they know what the terminology on the pathology report means and what actions to take. “The biopsy method matters,” he emphasized.

In a 14-year follow-up survey, investigators assessed DN management trends among 703 U.S. dermatologists. One key finding was that 69% of dermatologists in 2015 performed total removals when biopsying DN to achieve clear margins, compared with 86% in 2001.

A subsequent survey of 213 New England–based dermatologists found that the degree of clinical suspicion for melanoma was important in DN biopsy technique, with more respondents favoring shave biopsies for lesions with low suspicion and full-thickness biopsies for highly suspicious lesions.

“Misdiagnosis is more common for melanomas that have been assessed with punch and shave biopsies than with an excisional biopsy,” Dr. Kelley said. “I’m not too much of a stickler. I don’t require everyone to send me a giant excision, but I do want a representative sample.”

What about re-excision of DN considered to be mild or moderate? In 2015, members of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group published a consensus statement on DN management recommendations for clinically atypical nevi/DN based on a review of published evidence. The subcommittee members concluded that mildly and moderately DN with clear margins do not need to be re-excised, and that mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than re-excised.

For moderately DN with positive histologic margins without clinically apparent residual pigmentation, the subcommittee members concluded that observation may be reasonable.

In his own informal analysis, Dr. Kelley compiled data from published studies he could find on DN management and divided them into two groups: the observation group, in which researchers from eight studies biopsied the DN lesion and watched the patients over time to see what happened, and the re-excision group, in which researchers from seven studies biopsied the DN lesion and subsequently re-excised it. There were about 1,500 patients in both groups. No deaths occurred in either group, he said, but 15 patients in the re-excision group developed a melanoma at the site of the original biopsy (1%), compared with 7 in the observation group (0.5%).

Six of seven melanomas in the observation group came from one article conducted at a VA clinic. In the study, 6 of 304 observed DN subsequently developed melanoma at the site of the lesion. “However, five of six that developed melanoma had an original biopsy that was a partial biopsy with grossly positive margins; I think that’s where the problem lies,” Dr. Kelley said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “All five grew lentigo maligna type melanoma, which we know can extend multiple millimeters beyond the clinically apparent lesion.”

The findings support mounting evidence that re-excising mild and moderate DN, regardless of border involvement, may not be necessary. “Currently, most clinicians still re-excise moderate and severe DN involving margins, especially if there is residual pigment,” Dr. Kelley said. “Most re-excise severe DN regardless of margin involvement, but beware if your biopsy was a partial sample of a larger lesion.”

He acknowledged limitations to pathologic studies of DN, including the potential for diagnostic uncertainty. “That doesn’t necessarily mean that the pathologist got the diagnosis wrong. It could be, what is the risk that the portion of tissue not visualized contains melanoma? If you give me a 5 mm sample of a DN, and I cut it into 4-micrometer sections, I’m only looking at less than 1% of the actual nevus. That’s compounded if the pathologist only receives a partial sample.”

Dr. Kelley reported having no relevant disclosures.

San Diego – Despite advances in dermoscopy and other techniques for diagnosing cutaneous melanoma, histology remains the gold standard.

“I don’t think that’s going to change in the short term,” Travis W. Blalock, MD, director of dermatologic surgery, Mohs micrographic surgery, and cutaneous oncology at Emory University, Atlanta, said at the annual Cutaneous Malignancy Update. “But I do think we can supplement that with other modalities that will improve the clinical examination and help dermatopathologists as they assess and evaluate these lesions,” he said, adding: “The reality is, histopathology, while it may be the gold standard, is not necessarily a consistently reproducible evaluation. That raises the question: What can we do better?”

Christoph Burgstedt/Science Photo Library/Getty Images

According to Dr. Blalock, the future may include more routine use of noninvasive genetic molecular assays to assist with the diagnostics challenges linked to the visual image and pattern recognition approach of detecting cutaneous melanoma. For example, a two-gene classification method based on LINC00518 and preferentially expressed antigen in melanoma (PRAME) gene expression was evaluated and validated in 555 pigmented lesions obtained noninvasively via adhesive patch biopsy.

“Today, you can pick up a kit from your local pharmacy that can tell you a bit about broad genetic susceptibilities,” he said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. He predicted that using adhesive patch biopsies to assess suspicious melanocytic lesions “is likely the wave of the future.” This may increase patient understanding “as to the types of risks they have, the different lesions they have, and minimize invasive disease, but it also will pose different challenges for us when it comes to deploying patient-centered health care. For example, in a patient with multiple different lesions, how are you going to keep track of them all?”

Dermoscopy

In Dr. Blalock’s clinical opinion, dermoscopy improves the sensitivity of human visual detection of melanoma and may allow detection before a lesion displays classical features described with the “ABCDE rule.” However, the learning curve for dermoscopy is steep, he added, and whether the technique should be considered a first-line tool or as a supplement to other methods of examining cutaneous lesions remains a matter of debate.

“Dermoscopy is our version of the stethoscope,” he said. “We need to figure out when we’re going to use it. Should we be using it all of the time or only some of the time? Based on the clinical setting, maybe it’s a personal choice, but this can be a helpful skill and art in your practice if you’re willing to take the time to learn.”

In 2007, the International Dermoscopy Society (IDS) established a proposal for the standardization and recommended criteria necessary to effectively convey dermoscopic findings to consulting physicians and colleagues. The document includes 10 points categorized as either recommended or optional for a standardized dermoscopy report.

“The first step is to assess the lesion to determine whether or not it’s melanocytic in the first place,” said Dr. Blalock. “There are many different features – the mile-high [global features] evaluation of the lesions – then more specific local features that may clue you in to specific diagnoses,” he noted. “Once we get past that first step of determining that a lesion is melanocytic, it’s not enough to stop there, because we don’t want to biopsy every single lesion that’s melanocytic,” so there is a need to determine which ones require intervention, which is where dermoscopy “gets trickier and a little more challenging.”

According to the IDS, a standard dermoscopy report should include the patient’s age, relevant history pertaining to the lesion, pertinent personal and family history (recommended); clinical description of the lesion (recommended); the two-step method of dermoscopy differentiating melanocytic from nonmelanocytic tumors (recommended); and the use of standardized terms to describe structures as defined by the Dermoscopy Consensus Report published in 2003.

For new terms, the document states, “it would be helpful” for the physician to provide a working definition (recommended); the dermoscopic algorithm used should be mentioned (optional); information on the imaging equipment and magnification (recommended); clinical and dermoscopic images of the tumor (recommended); a diagnosis or differential diagnosis (recommended); decision concerning management (recommended), and specific comments for the pathologist when excision and histopathologic examination are recommended (optional).

The 2007 IDS document also includes a proposed seven-point checklist to differentiate between benign and melanocytic lesions on dermoscopy. Three major criteria are worth two points each: The presence of an atypical pigment network, gray-blue areas (commonly known as the veil), and an atypical vascular pattern. Four minor criteria are worth one point each: Irregular streaks, irregular dots/globules, irregular pigmentation, and regression structures. A minimum total score of 3 is required to establish a diagnosis of melanoma.

Another diagnostic technique, digital mole mapping, involves the use of photography to detect new or changing lesions. Dr. Blalock described this approach as rife with limitations, including variations in quality, challenges of storing and maintaining records, cost, time required to evaluate them, and determining which patients are appropriate candidates.

Other techniques being evaluated include computer algorithms to help dermatologists determine the diagnosis of melanoma from dermoscopic images, electrical impedance spectroscopy for noninvasive evaluation of atypical pigmented lesions, and ultrasound for staging of cutaneous malignant tumors.

Ultimately, “I think we’ll have multiple tools in our belt,” Dr. Blalock said, adding, “How do we pull them out at the right time to improve the lives of our patients? Are we going to use ultrasound? Dermoscopy? Integrate them with some of the genetic findings?”

Dr. Blalock disclosed that he has served as a principal investigator for Castle Biosciences.

San Diego – Despite advances in dermoscopy and other techniques for diagnosing cutaneous melanoma, histology remains the gold standard.

“I don’t think that’s going to change in the short term,” Travis W. Blalock, MD, director of dermatologic surgery, Mohs micrographic surgery, and cutaneous oncology at Emory University, Atlanta, said at the annual Cutaneous Malignancy Update. “But I do think we can supplement that with other modalities that will improve the clinical examination and help dermatopathologists as they assess and evaluate these lesions,” he said, adding: “The reality is, histopathology, while it may be the gold standard, is not necessarily a consistently reproducible evaluation. That raises the question: What can we do better?”

Christoph Burgstedt/Science Photo Library/Getty Images

According to Dr. Blalock, the future may include more routine use of noninvasive genetic molecular assays to assist with the diagnostics challenges linked to the visual image and pattern recognition approach of detecting cutaneous melanoma. For example, a two-gene classification method based on LINC00518 and preferentially expressed antigen in melanoma (PRAME) gene expression was evaluated and validated in 555 pigmented lesions obtained noninvasively via adhesive patch biopsy.

“Today, you can pick up a kit from your local pharmacy that can tell you a bit about broad genetic susceptibilities,” he said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. He predicted that using adhesive patch biopsies to assess suspicious melanocytic lesions “is likely the wave of the future.” This may increase patient understanding “as to the types of risks they have, the different lesions they have, and minimize invasive disease, but it also will pose different challenges for us when it comes to deploying patient-centered health care. For example, in a patient with multiple different lesions, how are you going to keep track of them all?”

Dermoscopy

In Dr. Blalock’s clinical opinion, dermoscopy improves the sensitivity of human visual detection of melanoma and may allow detection before a lesion displays classical features described with the “ABCDE rule.” However, the learning curve for dermoscopy is steep, he added, and whether the technique should be considered a first-line tool or as a supplement to other methods of examining cutaneous lesions remains a matter of debate.

“Dermoscopy is our version of the stethoscope,” he said. “We need to figure out when we’re going to use it. Should we be using it all of the time or only some of the time? Based on the clinical setting, maybe it’s a personal choice, but this can be a helpful skill and art in your practice if you’re willing to take the time to learn.”

In 2007, the International Dermoscopy Society (IDS) established a proposal for the standardization and recommended criteria necessary to effectively convey dermoscopic findings to consulting physicians and colleagues. The document includes 10 points categorized as either recommended or optional for a standardized dermoscopy report.

“The first step is to assess the lesion to determine whether or not it’s melanocytic in the first place,” said Dr. Blalock. “There are many different features – the mile-high [global features] evaluation of the lesions – then more specific local features that may clue you in to specific diagnoses,” he noted. “Once we get past that first step of determining that a lesion is melanocytic, it’s not enough to stop there, because we don’t want to biopsy every single lesion that’s melanocytic,” so there is a need to determine which ones require intervention, which is where dermoscopy “gets trickier and a little more challenging.”

According to the IDS, a standard dermoscopy report should include the patient’s age, relevant history pertaining to the lesion, pertinent personal and family history (recommended); clinical description of the lesion (recommended); the two-step method of dermoscopy differentiating melanocytic from nonmelanocytic tumors (recommended); and the use of standardized terms to describe structures as defined by the Dermoscopy Consensus Report published in 2003.

For new terms, the document states, “it would be helpful” for the physician to provide a working definition (recommended); the dermoscopic algorithm used should be mentioned (optional); information on the imaging equipment and magnification (recommended); clinical and dermoscopic images of the tumor (recommended); a diagnosis or differential diagnosis (recommended); decision concerning management (recommended), and specific comments for the pathologist when excision and histopathologic examination are recommended (optional).

The 2007 IDS document also includes a proposed seven-point checklist to differentiate between benign and melanocytic lesions on dermoscopy. Three major criteria are worth two points each: The presence of an atypical pigment network, gray-blue areas (commonly known as the veil), and an atypical vascular pattern. Four minor criteria are worth one point each: Irregular streaks, irregular dots/globules, irregular pigmentation, and regression structures. A minimum total score of 3 is required to establish a diagnosis of melanoma.

Another diagnostic technique, digital mole mapping, involves the use of photography to detect new or changing lesions. Dr. Blalock described this approach as rife with limitations, including variations in quality, challenges of storing and maintaining records, cost, time required to evaluate them, and determining which patients are appropriate candidates.

Other techniques being evaluated include computer algorithms to help dermatologists determine the diagnosis of melanoma from dermoscopic images, electrical impedance spectroscopy for noninvasive evaluation of atypical pigmented lesions, and ultrasound for staging of cutaneous malignant tumors.

Ultimately, “I think we’ll have multiple tools in our belt,” Dr. Blalock said, adding, “How do we pull them out at the right time to improve the lives of our patients? Are we going to use ultrasound? Dermoscopy? Integrate them with some of the genetic findings?”

Dr. Blalock disclosed that he has served as a principal investigator for Castle Biosciences.

San Diego – Despite advances in dermoscopy and other techniques for diagnosing cutaneous melanoma, histology remains the gold standard.

“I don’t think that’s going to change in the short term,” Travis W. Blalock, MD, director of dermatologic surgery, Mohs micrographic surgery, and cutaneous oncology at Emory University, Atlanta, said at the annual Cutaneous Malignancy Update. “But I do think we can supplement that with other modalities that will improve the clinical examination and help dermatopathologists as they assess and evaluate these lesions,” he said, adding: “The reality is, histopathology, while it may be the gold standard, is not necessarily a consistently reproducible evaluation. That raises the question: What can we do better?”

Christoph Burgstedt/Science Photo Library/Getty Images

According to Dr. Blalock, the future may include more routine use of noninvasive genetic molecular assays to assist with the diagnostics challenges linked to the visual image and pattern recognition approach of detecting cutaneous melanoma. For example, a two-gene classification method based on LINC00518 and preferentially expressed antigen in melanoma (PRAME) gene expression was evaluated and validated in 555 pigmented lesions obtained noninvasively via adhesive patch biopsy.

“Today, you can pick up a kit from your local pharmacy that can tell you a bit about broad genetic susceptibilities,” he said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. He predicted that using adhesive patch biopsies to assess suspicious melanocytic lesions “is likely the wave of the future.” This may increase patient understanding “as to the types of risks they have, the different lesions they have, and minimize invasive disease, but it also will pose different challenges for us when it comes to deploying patient-centered health care. For example, in a patient with multiple different lesions, how are you going to keep track of them all?”

Dermoscopy

In Dr. Blalock’s clinical opinion, dermoscopy improves the sensitivity of human visual detection of melanoma and may allow detection before a lesion displays classical features described with the “ABCDE rule.” However, the learning curve for dermoscopy is steep, he added, and whether the technique should be considered a first-line tool or as a supplement to other methods of examining cutaneous lesions remains a matter of debate.

“Dermoscopy is our version of the stethoscope,” he said. “We need to figure out when we’re going to use it. Should we be using it all of the time or only some of the time? Based on the clinical setting, maybe it’s a personal choice, but this can be a helpful skill and art in your practice if you’re willing to take the time to learn.”

In 2007, the International Dermoscopy Society (IDS) established a proposal for the standardization and recommended criteria necessary to effectively convey dermoscopic findings to consulting physicians and colleagues. The document includes 10 points categorized as either recommended or optional for a standardized dermoscopy report.

“The first step is to assess the lesion to determine whether or not it’s melanocytic in the first place,” said Dr. Blalock. “There are many different features – the mile-high [global features] evaluation of the lesions – then more specific local features that may clue you in to specific diagnoses,” he noted. “Once we get past that first step of determining that a lesion is melanocytic, it’s not enough to stop there, because we don’t want to biopsy every single lesion that’s melanocytic,” so there is a need to determine which ones require intervention, which is where dermoscopy “gets trickier and a little more challenging.”

According to the IDS, a standard dermoscopy report should include the patient’s age, relevant history pertaining to the lesion, pertinent personal and family history (recommended); clinical description of the lesion (recommended); the two-step method of dermoscopy differentiating melanocytic from nonmelanocytic tumors (recommended); and the use of standardized terms to describe structures as defined by the Dermoscopy Consensus Report published in 2003.

For new terms, the document states, “it would be helpful” for the physician to provide a working definition (recommended); the dermoscopic algorithm used should be mentioned (optional); information on the imaging equipment and magnification (recommended); clinical and dermoscopic images of the tumor (recommended); a diagnosis or differential diagnosis (recommended); decision concerning management (recommended), and specific comments for the pathologist when excision and histopathologic examination are recommended (optional).

The 2007 IDS document also includes a proposed seven-point checklist to differentiate between benign and melanocytic lesions on dermoscopy. Three major criteria are worth two points each: The presence of an atypical pigment network, gray-blue areas (commonly known as the veil), and an atypical vascular pattern. Four minor criteria are worth one point each: Irregular streaks, irregular dots/globules, irregular pigmentation, and regression structures. A minimum total score of 3 is required to establish a diagnosis of melanoma.

Another diagnostic technique, digital mole mapping, involves the use of photography to detect new or changing lesions. Dr. Blalock described this approach as rife with limitations, including variations in quality, challenges of storing and maintaining records, cost, time required to evaluate them, and determining which patients are appropriate candidates.

Other techniques being evaluated include computer algorithms to help dermatologists determine the diagnosis of melanoma from dermoscopic images, electrical impedance spectroscopy for noninvasive evaluation of atypical pigmented lesions, and ultrasound for staging of cutaneous malignant tumors.

Ultimately, “I think we’ll have multiple tools in our belt,” Dr. Blalock said, adding, “How do we pull them out at the right time to improve the lives of our patients? Are we going to use ultrasound? Dermoscopy? Integrate them with some of the genetic findings?”

Dr. Blalock disclosed that he has served as a principal investigator for Castle Biosciences.