Julien Lanoue, MD

To the Editor:

Relapsing polychondritis (RP) is a chronic, progressive, and episodic systemic inflammatory disease that primarily affects the cartilaginous structures of the ears and nose. Involvement of other proteoglycan-rich structures such as the joints, eyes, inner ears, blood vessels, heart, and kidneys also may be seen. Dermatologic manifestations occur in 35% to 50% of patients and may be the presenting sign in up to 12% of cases.¹ The most commonly reported dermatologic findings include oral aphthosis, erythema nodosum, and purpura with vasculitic changes. Less commonly reported associations include Sweet syndrome, pyoderma gangrenosum, panniculitis, erythema elevatum diutinum, erythema annulare centrifugum, and erythema multiforme.¹

A 43-year-old woman who was otherwise healthy developed new-onset tenderness and swelling of the left pinna while on vacation. She was treated with trimethoprim-sulfamethoxazole, clindamycin, and levofloxacin for presumed auricular cellulitis. The patient developed a fever; sore throat; and a progressive, pruritic, blistering rash on the face, torso, bilateral extremities, palms, and soles 1 day after completing the antibiotic course. After 5 days of unremitting symptoms despite oral, intramuscular, and topical steroids, the patient presented to the emergency department. Physical examination revealed diffuse, tender, erythematous to violaceous macules with varying degrees of coalescence on the chest, back, and extremities. Scattered flaccid bullae and erosions of the oral and genital mucosa also were seen. Laboratory analysis was notable only for a urinary tract infection with Klebsiella pneumoniae. A punch biopsy demonstrated full-thickness necrosis of the epidermis with subepidermal bullae and a mild to moderate lymphocytic infiltrate with rare eosinophils, consistent with a diagnosis of Stevens-Johnson syndrome (SJS). Because of the body surface area involved (20%) and the recent history of trimethoprim-sulfamethoxazole use, a diagnosis of SJS/toxic epidermal necrolysis (TEN) overlap syndrome was made. The patient was successfully treated with subcutaneous etanercept (50 mg), supportive care, and cephalexin for the urinary tract infection.

Approximately 5 weeks after discharge from the hospital, the patient was evaluated for new-onset pain and swelling of the right ear (Figure) in conjunction with recent tenderness and depression of the superior septal structure of the nose. A punch biopsy of the ear revealed mild perichondral inflammation without vasculitic changes and a superficial, deep perivascular, and periadnexal lymphoplasmacytic inflammatory infiltrate with scattered eosinophils. A diagnosis of RP was made, as the patient met Damiani and Levine’s² criteria with bilateral auricular inflammation, ocular inflammation, and nasal chondritis.

We report a unique case of SJS/TEN overlap syndrome occurring in a patient with RP.¹ Although the association may be coincidental, it is well known that patients with lupus erythematosus are predisposed to the development of SJS and TEN. Therefore, a shared underlying genetic predisposition or immune system hyperactivity secondary to active RP is a possible explanation for our patient’s unique presentation.

To the Editor:

Relapsing polychondritis (RP) is a chronic, progressive, and episodic systemic inflammatory disease that primarily affects the cartilaginous structures of the ears and nose. Involvement of other proteoglycan-rich structures such as the joints, eyes, inner ears, blood vessels, heart, and kidneys also may be seen. Dermatologic manifestations occur in 35% to 50% of patients and may be the presenting sign in up to 12% of cases.¹ The most commonly reported dermatologic findings include oral aphthosis, erythema nodosum, and purpura with vasculitic changes. Less commonly reported associations include Sweet syndrome, pyoderma gangrenosum, panniculitis, erythema elevatum diutinum, erythema annulare centrifugum, and erythema multiforme.¹

A 43-year-old woman who was otherwise healthy developed new-onset tenderness and swelling of the left pinna while on vacation. She was treated with trimethoprim-sulfamethoxazole, clindamycin, and levofloxacin for presumed auricular cellulitis. The patient developed a fever; sore throat; and a progressive, pruritic, blistering rash on the face, torso, bilateral extremities, palms, and soles 1 day after completing the antibiotic course. After 5 days of unremitting symptoms despite oral, intramuscular, and topical steroids, the patient presented to the emergency department. Physical examination revealed diffuse, tender, erythematous to violaceous macules with varying degrees of coalescence on the chest, back, and extremities. Scattered flaccid bullae and erosions of the oral and genital mucosa also were seen. Laboratory analysis was notable only for a urinary tract infection with Klebsiella pneumoniae. A punch biopsy demonstrated full-thickness necrosis of the epidermis with subepidermal bullae and a mild to moderate lymphocytic infiltrate with rare eosinophils, consistent with a diagnosis of Stevens-Johnson syndrome (SJS). Because of the body surface area involved (20%) and the recent history of trimethoprim-sulfamethoxazole use, a diagnosis of SJS/toxic epidermal necrolysis (TEN) overlap syndrome was made. The patient was successfully treated with subcutaneous etanercept (50 mg), supportive care, and cephalexin for the urinary tract infection.

Approximately 5 weeks after discharge from the hospital, the patient was evaluated for new-onset pain and swelling of the right ear (Figure) in conjunction with recent tenderness and depression of the superior septal structure of the nose. A punch biopsy of the ear revealed mild perichondral inflammation without vasculitic changes and a superficial, deep perivascular, and periadnexal lymphoplasmacytic inflammatory infiltrate with scattered eosinophils. A diagnosis of RP was made, as the patient met Damiani and Levine’s² criteria with bilateral auricular inflammation, ocular inflammation, and nasal chondritis.

We report a unique case of SJS/TEN overlap syndrome occurring in a patient with RP.¹ Although the association may be coincidental, it is well known that patients with lupus erythematosus are predisposed to the development of SJS and TEN. Therefore, a shared underlying genetic predisposition or immune system hyperactivity secondary to active RP is a possible explanation for our patient’s unique presentation.

To the Editor:

Relapsing polychondritis (RP) is a chronic, progressive, and episodic systemic inflammatory disease that primarily affects the cartilaginous structures of the ears and nose. Involvement of other proteoglycan-rich structures such as the joints, eyes, inner ears, blood vessels, heart, and kidneys also may be seen. Dermatologic manifestations occur in 35% to 50% of patients and may be the presenting sign in up to 12% of cases.¹ The most commonly reported dermatologic findings include oral aphthosis, erythema nodosum, and purpura with vasculitic changes. Less commonly reported associations include Sweet syndrome, pyoderma gangrenosum, panniculitis, erythema elevatum diutinum, erythema annulare centrifugum, and erythema multiforme.¹

A 43-year-old woman who was otherwise healthy developed new-onset tenderness and swelling of the left pinna while on vacation. She was treated with trimethoprim-sulfamethoxazole, clindamycin, and levofloxacin for presumed auricular cellulitis. The patient developed a fever; sore throat; and a progressive, pruritic, blistering rash on the face, torso, bilateral extremities, palms, and soles 1 day after completing the antibiotic course. After 5 days of unremitting symptoms despite oral, intramuscular, and topical steroids, the patient presented to the emergency department. Physical examination revealed diffuse, tender, erythematous to violaceous macules with varying degrees of coalescence on the chest, back, and extremities. Scattered flaccid bullae and erosions of the oral and genital mucosa also were seen. Laboratory analysis was notable only for a urinary tract infection with Klebsiella pneumoniae. A punch biopsy demonstrated full-thickness necrosis of the epidermis with subepidermal bullae and a mild to moderate lymphocytic infiltrate with rare eosinophils, consistent with a diagnosis of Stevens-Johnson syndrome (SJS). Because of the body surface area involved (20%) and the recent history of trimethoprim-sulfamethoxazole use, a diagnosis of SJS/toxic epidermal necrolysis (TEN) overlap syndrome was made. The patient was successfully treated with subcutaneous etanercept (50 mg), supportive care, and cephalexin for the urinary tract infection.

Approximately 5 weeks after discharge from the hospital, the patient was evaluated for new-onset pain and swelling of the right ear (Figure) in conjunction with recent tenderness and depression of the superior septal structure of the nose. A punch biopsy of the ear revealed mild perichondral inflammation without vasculitic changes and a superficial, deep perivascular, and periadnexal lymphoplasmacytic inflammatory infiltrate with scattered eosinophils. A diagnosis of RP was made, as the patient met Damiani and Levine’s² criteria with bilateral auricular inflammation, ocular inflammation, and nasal chondritis.

We report a unique case of SJS/TEN overlap syndrome occurring in a patient with RP.¹ Although the association may be coincidental, it is well known that patients with lupus erythematosus are predisposed to the development of SJS and TEN. Therefore, a shared underlying genetic predisposition or immune system hyperactivity secondary to active RP is a possible explanation for our patient’s unique presentation.

The first botulinum neurotoxin (BoNT) approved by the US Food and Drug Administration (FDA) was onabotulinumtoxinA in 1989 for the treatment of strabismus and blepharospasm. It was not until 1992, however, that the aesthetic benefits of BoNT were first reported in the medical literature by Carruthers and Carruthers,¹ and a cosmetic indication was not approved by the FDA until 2002. Since that time, the popularity of BoNT products has grown rapidly with a nearly 6500% increase in popularity from 1997 to 2015 in addition to the introduction of a variety of new BoNT formulations to the market.² It is estimated by the American Society for Aesthetic Plastic Surgery that there were at least 4,000,000 BoNT injections performed in 2015 alone, making it the most popular nonsurgical aesthetic procedure available.² As the demand for minimally invasive cosmetic procedures continues to increase, we will continue to see the introduction of additional formulations of BoNT products as well as novel administration techniques and delivery devices. In this article, we provide an update on current and upcoming BoNT products and also review the literature on novel administration methods based on studies published from January 1, 2014, to December 31, 2015.

Current Products

To date, there are only 4 FDA-approved formulations of BoNT available for clinical use (eg, cervical dystonia, strabismus, blepharospasm, headache, urinary incontinence) in the United States: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB.The FDA-approved dermatologic indications (eg, moderate to severe glabellar or canthal lines, severe axillary hyperhidrosis) for these products are provided in the Table. On a global scale, there are several other commonly utilized formulations of BoNT, including a Korean serotype resembling onabotulinumtoxinA and a Chinese botulinum toxin type A.³ Although there is some evidence to demonstrate comparable efficacy and safety of these latter products, the literature is relatively lacking in comparison to the FDA-approved products.^4,5

Upcoming Products

Currently, there are several new BoNT formulations being studied for clinical use. RT 002 (Revance Therapeutics, Inc) is a novel injectable formulation of onabotulinumtoxinA that consists of the purified neurotoxin in combination with patented TransMTS peptides that have been shown to provide high-binding avidity for the neurotoxin, and thus the product is designed to reduce diffusion to adjacent muscles and diminish unwanted effects. With a reduced level of neurotoxin dissemination, it is theorized that a higher administration of targeted doses can be injected, which may lead to a longer duration of desired effects.⁶ A clinical pilot study done to establish the safety and efficacy of RT 002 for treatment of moderate to severe glabellar lines evaluated 4 equally sized cohorts of 12 participants, each receiving single-dose administration of RT 002 ranging in potency equivalent to 25 U, 50 U, 75 U, and 100 U of abobotulinumtoxinA as determined by the gelatin phosphate method.⁶ It was concluded that RT 002 is both safe and efficacious with an extended duration of action, with a median duration of effect of 7 months observed in the highest dose group (dose equivalent to 100 U of abobotulinumtoxinA). Notably, 80% of all 48 participants maintained a minimum 1-point improvement in investigator-determined glabellar line severity scores at the 6-month time point and 60% achieved wrinkle scores of none or mild at 6 months posttreatment.⁶

DWP 450 (Daewoong Pharmaceutical Co, Ltd) is derived from the wild-type Clostridium botulinum and is reported to be of higher purity than standard onabotulinumtoxinA. An initial 16-week pilot study demonstrated that 20 U of DWP 450 is noninferior and of comparable efficacy and safety to 20 U of onabotulinumtoxinA in the treatment of glabellar lines.⁷

NTC (Botulax [Hugel, Inc]) is the name of the toxin derived from the C botulinum strain CBFC26, which has already been approved in many Asian, European, and Latin American countries for the treatment of blepharospasm. This formulation has demonstrated noninferiority to onabotulinumtoxinA at equivalent 20-U doses for the treatment of moderate to severe glabellar lines in a double-blind, randomized, multicenter, phase 3 trial of 272 participants with a 16-week follow-up.⁸

MT 10109L (Medytox Inc) is a unique product in that it is distributed as a liquid type A botulinum toxin rather than the standard freeze-dried formulation; thus, a major advantage of this product is its convenience, as it does not need reconstitution or dilution prior to administration. In a double-blind, randomized, active drug–controlled, phase 3 study of 168 participants, it was determined that MT 10109L (20 U) is comparable in efficacy to onabotulinumtoxinA (20 U) for the treatment of moderate to severe glabellar lines. No significant difference was seen between the 2 treatment groups when glabellar lines were assessed at rest at 4 and 16 weeks after treatment, but a significantly greater improvement in glabellar lines was seen at maximum frown in the MT 10109L group at the 16-week follow-up (P=.0064).⁹

Administration Techniques

With regard to safe and effective BoNT product administration techniques, a variety of studies have provided insight into optimal practice methods. A 2015 expert consensus statement formed by an American Society for Dermatologic Surgery task force reviewed data from 42 papers and unanimously determined that for all current type A BoNT products available in the United States, a vial of BoNT reconstituted appropriately for the purpose of facial injections can be reconstituted at least 4 weeks prior to administration without contamination risk or decrease in efficacy and that multiple patients can be treated with the same vial.Although the statement was not explicit on whether or not preserved or unpreserved saline is to be used, it is considered routine practice to use preservative-containing saline to reconstitute BoNT, as it has been shown to reduce patient discomfort and is not associated with adverse effects.¹⁰

Pain Minimization
With respect to minimizing the pain associated with BoNT injections, several studies have assessed administration techniques to minimize patient discomfort. A split-face, double-blind study of 20 participants demonstrated that the use of a 32-gauge needle has a significantly greater chance of reducing clinically significant levels of pain as compared to a 30-gauge needle when performing facial injections (P=.04). Overall, however, injections of the face and arms were on average only nominally and not significantly more painful with 30-gauge needles compared to 32-gauge needles.¹¹

Another technique that has been found to reduce patient discomfort is the application of cold packs prior to injection. A study of patients with chronic facial palsy observed a significant reduction in pain with the administration of a cold (3°C–5°C) gel pack for 1 minute compared to a room temperature (20°C) gel pack prior to the administration of onabotulinumtoxinA into the platysma (P<.001).¹² In the matter of injection with rimabotulinumtoxinB, which has been shown to be considerably more painful to receive than its more popularly administered counterpart onabotulinumtoxinA, a split-face pilot study examined the effect of increasing the pH of rimabotulinumtoxinB to 7.5 with sodium bicarbonate from the usual pH of 5.6.^13,14 Pain was reported to be considerably less in the higher pH group and no reduction of efficacy was seen over the 10-week follow-up period.¹⁴

Delivery Methods
Several preliminary studies also have examined novel delivery techniques to identify minimally painful yet effective methods for administering BoNT. It has been reported that standard BoNT formulations are not effective as topical agents in a comparison study in which onabotulinumtoxinA injection was compared to topically applied onabotulinumtoxinA.¹⁵ However, a follow-up prospective study by the same authors has demonstrated efficacy of topical onabotulinumtoxinA following pretreatment with a fractional ablative CO₂ laser for treatment of crow’s-feet. In this randomized, split-face, controlled trial (N=10), participants were first pretreated with topical lidocaine 30% before receiving a single pass of fractional ablative CO₂ laser with no overlap and a pulse energy of 100 mJ. Within 60 seconds of laser treatment, participants then received either 100 U of abobotulinumtoxinA diluted in 0.1 mL of saline or simple normal saline applied topically. A clinically significant improvement in periorbital wrinkles was seen both at 1-week and 1-month posttreatment in the laser and onabotulinumtoxinA–treated group compared to the laser and topical saline–treated group (P<.02).¹⁵

Another unique administration method studied, albeit with less successful results, involves the use of iontophoresis to deliver BoNT painlessly in a transdermal fashion with the assistance of an electrical current.¹⁶ This prospective, randomized, assessor-blinded, split-axilla, controlled trial of 11 participants compared the effectiveness of administering onabotulinumtoxinA via iontophoresis to traditional injection with onabotulinumtoxinA (250 U). Iontophoresis was accomplished with a single electrode pad soaked with 250 U of onabotulinumtoxinA applied directly to the axilla and a second electrode pad soaked in 0.9% saline applied to the hand to complete the circuit. An alternating electrical current was slowly increased for 30 minutes to a maximum current of 15 mA with a voltage of 12 V. Among the 11 participants recruited, the side treated with traditional injection showed a significantly greater percentage reduction in baseline sweating at the 1-week, 1-month, and 6-month posttreatment evaluations compared to iontophoresis (84%, 76%, and 50%, respectively vs 73%, 22%, and 32%, respectively)(P<.05). Despite being less efficacious than standard injection therapy, participants reported that iontophoresis delivery was significantly less painful (P<.05).¹⁶

A high-pressure oxygen delivery device, which utilizes a powerful jet of microdroplets containing water, the drug, air, and oxygen to deliver medication onto the skin surface, also has been studied as a means of delivery of BoNT in a minimally painful manner. In this study, the device was used to assess the efficacy of transdermal delivery of BoNT via jet nebulization in the treatment of primary palmar, plantar, and axillary hyperhidrosis.¹⁷ The 20 participants included in the study were randomized to receive either a combination of lidocaine and onabotulinumtoxinA (50 U) administered through the device or lidocaine delivered through the device followed by multiple transcutaneous injections of onabotulinumtoxinA (100 U). Both treatments significantly reduced sweating compared to baseline as measured by a visual analogue scale at 3-month follow-up (P<.001), but the combination delivery of lidocaine and onabotulinumtoxinA via the device resulted in significantly less procedure-related pain and sweating (P<.001) as well as significantly greater patient satisfaction (P<.001).¹⁷

Optimizing Aesthetic Outcomes
A frequent concern of patients receiving BoNT for cosmetic purposes is a desire to avoid a “frozen” or expressionless look. As such, many clinicians have attempted a variety of techniques to achieve more natural aesthetic results. One such method is known as the multipoint and multilevel injection technique, which consists of utilizing multiple injection sites at varying depths (intramuscular, subcutaneous, or intradermal) and doses (2–6 U) depending on the degree of contractility of the targeted muscle. In a preliminary study of 223 participants using this technique with a total dose of 125 U of abobotulinumtoxinA, good and natural results were reported with perseveration of facial emotion in all participants in addition to a mean overall satisfaction rate of 6.4 of 7 on the Facial Line Treatment Satisfaction Questionnaire with the maximum satisfaction rating possible reported in 66% of cases.¹⁸ It also has been postulated that injection depth of BoNT can affect brow elevation whereupon deeper injection depths can result in inactivation of the brow depressors and allow for increased elevation of the eyebrows. This technique has been applied in attempts to correct brow height asymmetry. However, a prospective, split-face study of 23 women suggested that this method is not effective.¹⁹ Participants received 64 U of onabotulinumtoxinA via 16 injection sites in the glabella, forehead, and lateral canthal area with either all deep or all shallow injections depending on the side treated and whether brow-lift was desired. Results at 4 weeks posttreatment showed no significant difference in brow height, and it was concluded that eyebrow depressor muscles cannot be accurately targeted with deep injection into the muscle belly for correction of eyebrow height discrepancies.¹⁹ Conversely, a 5-year retrospective, nonrandomized study of 227 patients with 563 treatments utilizing a “microdroplet” technique reported success at selectively targeting the eyebrow depressors while leaving the brow elevators unaffected.²⁰ Here, a total dose of 33 U of onabotulinumtoxinA was administered via microdroplets of 10 to 20 μL, each with more than 60 to 100 injections into the brow, glabella, and crow’s-feet area. This method of injection resulted in a statistically significant improvement of forehead lines and brow ptosis and furrowing at follow-up between 10 and 45 days after treatment (P<.0001). Additionally, average brow height was significantly increased from 24.6 mm to 25 mm after treatment (P=.02).²⁰

Conclusion

The use of BoNT products for both on- and off-label cosmetic and medical indications has rapidly grown over the past 2 decades. As demonstrated in this review, a variety of promising new products and delivery techniques are being developed. Given the rise in popularity of BoNT products among both physicians and consumers, clinicians should be aware of the current data and ongoing research.

The first botulinum neurotoxin (BoNT) approved by the US Food and Drug Administration (FDA) was onabotulinumtoxinA in 1989 for the treatment of strabismus and blepharospasm. It was not until 1992, however, that the aesthetic benefits of BoNT were first reported in the medical literature by Carruthers and Carruthers,¹ and a cosmetic indication was not approved by the FDA until 2002. Since that time, the popularity of BoNT products has grown rapidly with a nearly 6500% increase in popularity from 1997 to 2015 in addition to the introduction of a variety of new BoNT formulations to the market.² It is estimated by the American Society for Aesthetic Plastic Surgery that there were at least 4,000,000 BoNT injections performed in 2015 alone, making it the most popular nonsurgical aesthetic procedure available.² As the demand for minimally invasive cosmetic procedures continues to increase, we will continue to see the introduction of additional formulations of BoNT products as well as novel administration techniques and delivery devices. In this article, we provide an update on current and upcoming BoNT products and also review the literature on novel administration methods based on studies published from January 1, 2014, to December 31, 2015.

Current Products

To date, there are only 4 FDA-approved formulations of BoNT available for clinical use (eg, cervical dystonia, strabismus, blepharospasm, headache, urinary incontinence) in the United States: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB.The FDA-approved dermatologic indications (eg, moderate to severe glabellar or canthal lines, severe axillary hyperhidrosis) for these products are provided in the Table. On a global scale, there are several other commonly utilized formulations of BoNT, including a Korean serotype resembling onabotulinumtoxinA and a Chinese botulinum toxin type A.³ Although there is some evidence to demonstrate comparable efficacy and safety of these latter products, the literature is relatively lacking in comparison to the FDA-approved products.^4,5

Upcoming Products

Currently, there are several new BoNT formulations being studied for clinical use. RT 002 (Revance Therapeutics, Inc) is a novel injectable formulation of onabotulinumtoxinA that consists of the purified neurotoxin in combination with patented TransMTS peptides that have been shown to provide high-binding avidity for the neurotoxin, and thus the product is designed to reduce diffusion to adjacent muscles and diminish unwanted effects. With a reduced level of neurotoxin dissemination, it is theorized that a higher administration of targeted doses can be injected, which may lead to a longer duration of desired effects.⁶ A clinical pilot study done to establish the safety and efficacy of RT 002 for treatment of moderate to severe glabellar lines evaluated 4 equally sized cohorts of 12 participants, each receiving single-dose administration of RT 002 ranging in potency equivalent to 25 U, 50 U, 75 U, and 100 U of abobotulinumtoxinA as determined by the gelatin phosphate method.⁶ It was concluded that RT 002 is both safe and efficacious with an extended duration of action, with a median duration of effect of 7 months observed in the highest dose group (dose equivalent to 100 U of abobotulinumtoxinA). Notably, 80% of all 48 participants maintained a minimum 1-point improvement in investigator-determined glabellar line severity scores at the 6-month time point and 60% achieved wrinkle scores of none or mild at 6 months posttreatment.⁶

DWP 450 (Daewoong Pharmaceutical Co, Ltd) is derived from the wild-type Clostridium botulinum and is reported to be of higher purity than standard onabotulinumtoxinA. An initial 16-week pilot study demonstrated that 20 U of DWP 450 is noninferior and of comparable efficacy and safety to 20 U of onabotulinumtoxinA in the treatment of glabellar lines.⁷

NTC (Botulax [Hugel, Inc]) is the name of the toxin derived from the C botulinum strain CBFC26, which has already been approved in many Asian, European, and Latin American countries for the treatment of blepharospasm. This formulation has demonstrated noninferiority to onabotulinumtoxinA at equivalent 20-U doses for the treatment of moderate to severe glabellar lines in a double-blind, randomized, multicenter, phase 3 trial of 272 participants with a 16-week follow-up.⁸

MT 10109L (Medytox Inc) is a unique product in that it is distributed as a liquid type A botulinum toxin rather than the standard freeze-dried formulation; thus, a major advantage of this product is its convenience, as it does not need reconstitution or dilution prior to administration. In a double-blind, randomized, active drug–controlled, phase 3 study of 168 participants, it was determined that MT 10109L (20 U) is comparable in efficacy to onabotulinumtoxinA (20 U) for the treatment of moderate to severe glabellar lines. No significant difference was seen between the 2 treatment groups when glabellar lines were assessed at rest at 4 and 16 weeks after treatment, but a significantly greater improvement in glabellar lines was seen at maximum frown in the MT 10109L group at the 16-week follow-up (P=.0064).⁹

Administration Techniques

With regard to safe and effective BoNT product administration techniques, a variety of studies have provided insight into optimal practice methods. A 2015 expert consensus statement formed by an American Society for Dermatologic Surgery task force reviewed data from 42 papers and unanimously determined that for all current type A BoNT products available in the United States, a vial of BoNT reconstituted appropriately for the purpose of facial injections can be reconstituted at least 4 weeks prior to administration without contamination risk or decrease in efficacy and that multiple patients can be treated with the same vial.Although the statement was not explicit on whether or not preserved or unpreserved saline is to be used, it is considered routine practice to use preservative-containing saline to reconstitute BoNT, as it has been shown to reduce patient discomfort and is not associated with adverse effects.¹⁰

Pain Minimization
With respect to minimizing the pain associated with BoNT injections, several studies have assessed administration techniques to minimize patient discomfort. A split-face, double-blind study of 20 participants demonstrated that the use of a 32-gauge needle has a significantly greater chance of reducing clinically significant levels of pain as compared to a 30-gauge needle when performing facial injections (P=.04). Overall, however, injections of the face and arms were on average only nominally and not significantly more painful with 30-gauge needles compared to 32-gauge needles.¹¹

Another technique that has been found to reduce patient discomfort is the application of cold packs prior to injection. A study of patients with chronic facial palsy observed a significant reduction in pain with the administration of a cold (3°C–5°C) gel pack for 1 minute compared to a room temperature (20°C) gel pack prior to the administration of onabotulinumtoxinA into the platysma (P<.001).¹² In the matter of injection with rimabotulinumtoxinB, which has been shown to be considerably more painful to receive than its more popularly administered counterpart onabotulinumtoxinA, a split-face pilot study examined the effect of increasing the pH of rimabotulinumtoxinB to 7.5 with sodium bicarbonate from the usual pH of 5.6.^13,14 Pain was reported to be considerably less in the higher pH group and no reduction of efficacy was seen over the 10-week follow-up period.¹⁴

Delivery Methods
Several preliminary studies also have examined novel delivery techniques to identify minimally painful yet effective methods for administering BoNT. It has been reported that standard BoNT formulations are not effective as topical agents in a comparison study in which onabotulinumtoxinA injection was compared to topically applied onabotulinumtoxinA.¹⁵ However, a follow-up prospective study by the same authors has demonstrated efficacy of topical onabotulinumtoxinA following pretreatment with a fractional ablative CO₂ laser for treatment of crow’s-feet. In this randomized, split-face, controlled trial (N=10), participants were first pretreated with topical lidocaine 30% before receiving a single pass of fractional ablative CO₂ laser with no overlap and a pulse energy of 100 mJ. Within 60 seconds of laser treatment, participants then received either 100 U of abobotulinumtoxinA diluted in 0.1 mL of saline or simple normal saline applied topically. A clinically significant improvement in periorbital wrinkles was seen both at 1-week and 1-month posttreatment in the laser and onabotulinumtoxinA–treated group compared to the laser and topical saline–treated group (P<.02).¹⁵

Another unique administration method studied, albeit with less successful results, involves the use of iontophoresis to deliver BoNT painlessly in a transdermal fashion with the assistance of an electrical current.¹⁶ This prospective, randomized, assessor-blinded, split-axilla, controlled trial of 11 participants compared the effectiveness of administering onabotulinumtoxinA via iontophoresis to traditional injection with onabotulinumtoxinA (250 U). Iontophoresis was accomplished with a single electrode pad soaked with 250 U of onabotulinumtoxinA applied directly to the axilla and a second electrode pad soaked in 0.9% saline applied to the hand to complete the circuit. An alternating electrical current was slowly increased for 30 minutes to a maximum current of 15 mA with a voltage of 12 V. Among the 11 participants recruited, the side treated with traditional injection showed a significantly greater percentage reduction in baseline sweating at the 1-week, 1-month, and 6-month posttreatment evaluations compared to iontophoresis (84%, 76%, and 50%, respectively vs 73%, 22%, and 32%, respectively)(P<.05). Despite being less efficacious than standard injection therapy, participants reported that iontophoresis delivery was significantly less painful (P<.05).¹⁶

A high-pressure oxygen delivery device, which utilizes a powerful jet of microdroplets containing water, the drug, air, and oxygen to deliver medication onto the skin surface, also has been studied as a means of delivery of BoNT in a minimally painful manner. In this study, the device was used to assess the efficacy of transdermal delivery of BoNT via jet nebulization in the treatment of primary palmar, plantar, and axillary hyperhidrosis.¹⁷ The 20 participants included in the study were randomized to receive either a combination of lidocaine and onabotulinumtoxinA (50 U) administered through the device or lidocaine delivered through the device followed by multiple transcutaneous injections of onabotulinumtoxinA (100 U). Both treatments significantly reduced sweating compared to baseline as measured by a visual analogue scale at 3-month follow-up (P<.001), but the combination delivery of lidocaine and onabotulinumtoxinA via the device resulted in significantly less procedure-related pain and sweating (P<.001) as well as significantly greater patient satisfaction (P<.001).¹⁷

Optimizing Aesthetic Outcomes
A frequent concern of patients receiving BoNT for cosmetic purposes is a desire to avoid a “frozen” or expressionless look. As such, many clinicians have attempted a variety of techniques to achieve more natural aesthetic results. One such method is known as the multipoint and multilevel injection technique, which consists of utilizing multiple injection sites at varying depths (intramuscular, subcutaneous, or intradermal) and doses (2–6 U) depending on the degree of contractility of the targeted muscle. In a preliminary study of 223 participants using this technique with a total dose of 125 U of abobotulinumtoxinA, good and natural results were reported with perseveration of facial emotion in all participants in addition to a mean overall satisfaction rate of 6.4 of 7 on the Facial Line Treatment Satisfaction Questionnaire with the maximum satisfaction rating possible reported in 66% of cases.¹⁸ It also has been postulated that injection depth of BoNT can affect brow elevation whereupon deeper injection depths can result in inactivation of the brow depressors and allow for increased elevation of the eyebrows. This technique has been applied in attempts to correct brow height asymmetry. However, a prospective, split-face study of 23 women suggested that this method is not effective.¹⁹ Participants received 64 U of onabotulinumtoxinA via 16 injection sites in the glabella, forehead, and lateral canthal area with either all deep or all shallow injections depending on the side treated and whether brow-lift was desired. Results at 4 weeks posttreatment showed no significant difference in brow height, and it was concluded that eyebrow depressor muscles cannot be accurately targeted with deep injection into the muscle belly for correction of eyebrow height discrepancies.¹⁹ Conversely, a 5-year retrospective, nonrandomized study of 227 patients with 563 treatments utilizing a “microdroplet” technique reported success at selectively targeting the eyebrow depressors while leaving the brow elevators unaffected.²⁰ Here, a total dose of 33 U of onabotulinumtoxinA was administered via microdroplets of 10 to 20 μL, each with more than 60 to 100 injections into the brow, glabella, and crow’s-feet area. This method of injection resulted in a statistically significant improvement of forehead lines and brow ptosis and furrowing at follow-up between 10 and 45 days after treatment (P<.0001). Additionally, average brow height was significantly increased from 24.6 mm to 25 mm after treatment (P=.02).²⁰

Conclusion

The use of BoNT products for both on- and off-label cosmetic and medical indications has rapidly grown over the past 2 decades. As demonstrated in this review, a variety of promising new products and delivery techniques are being developed. Given the rise in popularity of BoNT products among both physicians and consumers, clinicians should be aware of the current data and ongoing research.

The first botulinum neurotoxin (BoNT) approved by the US Food and Drug Administration (FDA) was onabotulinumtoxinA in 1989 for the treatment of strabismus and blepharospasm. It was not until 1992, however, that the aesthetic benefits of BoNT were first reported in the medical literature by Carruthers and Carruthers,¹ and a cosmetic indication was not approved by the FDA until 2002. Since that time, the popularity of BoNT products has grown rapidly with a nearly 6500% increase in popularity from 1997 to 2015 in addition to the introduction of a variety of new BoNT formulations to the market.² It is estimated by the American Society for Aesthetic Plastic Surgery that there were at least 4,000,000 BoNT injections performed in 2015 alone, making it the most popular nonsurgical aesthetic procedure available.² As the demand for minimally invasive cosmetic procedures continues to increase, we will continue to see the introduction of additional formulations of BoNT products as well as novel administration techniques and delivery devices. In this article, we provide an update on current and upcoming BoNT products and also review the literature on novel administration methods based on studies published from January 1, 2014, to December 31, 2015.

Current Products

To date, there are only 4 FDA-approved formulations of BoNT available for clinical use (eg, cervical dystonia, strabismus, blepharospasm, headache, urinary incontinence) in the United States: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB.The FDA-approved dermatologic indications (eg, moderate to severe glabellar or canthal lines, severe axillary hyperhidrosis) for these products are provided in the Table. On a global scale, there are several other commonly utilized formulations of BoNT, including a Korean serotype resembling onabotulinumtoxinA and a Chinese botulinum toxin type A.³ Although there is some evidence to demonstrate comparable efficacy and safety of these latter products, the literature is relatively lacking in comparison to the FDA-approved products.^4,5

Upcoming Products

Currently, there are several new BoNT formulations being studied for clinical use. RT 002 (Revance Therapeutics, Inc) is a novel injectable formulation of onabotulinumtoxinA that consists of the purified neurotoxin in combination with patented TransMTS peptides that have been shown to provide high-binding avidity for the neurotoxin, and thus the product is designed to reduce diffusion to adjacent muscles and diminish unwanted effects. With a reduced level of neurotoxin dissemination, it is theorized that a higher administration of targeted doses can be injected, which may lead to a longer duration of desired effects.⁶ A clinical pilot study done to establish the safety and efficacy of RT 002 for treatment of moderate to severe glabellar lines evaluated 4 equally sized cohorts of 12 participants, each receiving single-dose administration of RT 002 ranging in potency equivalent to 25 U, 50 U, 75 U, and 100 U of abobotulinumtoxinA as determined by the gelatin phosphate method.⁶ It was concluded that RT 002 is both safe and efficacious with an extended duration of action, with a median duration of effect of 7 months observed in the highest dose group (dose equivalent to 100 U of abobotulinumtoxinA). Notably, 80% of all 48 participants maintained a minimum 1-point improvement in investigator-determined glabellar line severity scores at the 6-month time point and 60% achieved wrinkle scores of none or mild at 6 months posttreatment.⁶

DWP 450 (Daewoong Pharmaceutical Co, Ltd) is derived from the wild-type Clostridium botulinum and is reported to be of higher purity than standard onabotulinumtoxinA. An initial 16-week pilot study demonstrated that 20 U of DWP 450 is noninferior and of comparable efficacy and safety to 20 U of onabotulinumtoxinA in the treatment of glabellar lines.⁷

NTC (Botulax [Hugel, Inc]) is the name of the toxin derived from the C botulinum strain CBFC26, which has already been approved in many Asian, European, and Latin American countries for the treatment of blepharospasm. This formulation has demonstrated noninferiority to onabotulinumtoxinA at equivalent 20-U doses for the treatment of moderate to severe glabellar lines in a double-blind, randomized, multicenter, phase 3 trial of 272 participants with a 16-week follow-up.⁸

MT 10109L (Medytox Inc) is a unique product in that it is distributed as a liquid type A botulinum toxin rather than the standard freeze-dried formulation; thus, a major advantage of this product is its convenience, as it does not need reconstitution or dilution prior to administration. In a double-blind, randomized, active drug–controlled, phase 3 study of 168 participants, it was determined that MT 10109L (20 U) is comparable in efficacy to onabotulinumtoxinA (20 U) for the treatment of moderate to severe glabellar lines. No significant difference was seen between the 2 treatment groups when glabellar lines were assessed at rest at 4 and 16 weeks after treatment, but a significantly greater improvement in glabellar lines was seen at maximum frown in the MT 10109L group at the 16-week follow-up (P=.0064).⁹

Administration Techniques

With regard to safe and effective BoNT product administration techniques, a variety of studies have provided insight into optimal practice methods. A 2015 expert consensus statement formed by an American Society for Dermatologic Surgery task force reviewed data from 42 papers and unanimously determined that for all current type A BoNT products available in the United States, a vial of BoNT reconstituted appropriately for the purpose of facial injections can be reconstituted at least 4 weeks prior to administration without contamination risk or decrease in efficacy and that multiple patients can be treated with the same vial.Although the statement was not explicit on whether or not preserved or unpreserved saline is to be used, it is considered routine practice to use preservative-containing saline to reconstitute BoNT, as it has been shown to reduce patient discomfort and is not associated with adverse effects.¹⁰

Pain Minimization
With respect to minimizing the pain associated with BoNT injections, several studies have assessed administration techniques to minimize patient discomfort. A split-face, double-blind study of 20 participants demonstrated that the use of a 32-gauge needle has a significantly greater chance of reducing clinically significant levels of pain as compared to a 30-gauge needle when performing facial injections (P=.04). Overall, however, injections of the face and arms were on average only nominally and not significantly more painful with 30-gauge needles compared to 32-gauge needles.¹¹

Another technique that has been found to reduce patient discomfort is the application of cold packs prior to injection. A study of patients with chronic facial palsy observed a significant reduction in pain with the administration of a cold (3°C–5°C) gel pack for 1 minute compared to a room temperature (20°C) gel pack prior to the administration of onabotulinumtoxinA into the platysma (P<.001).¹² In the matter of injection with rimabotulinumtoxinB, which has been shown to be considerably more painful to receive than its more popularly administered counterpart onabotulinumtoxinA, a split-face pilot study examined the effect of increasing the pH of rimabotulinumtoxinB to 7.5 with sodium bicarbonate from the usual pH of 5.6.^13,14 Pain was reported to be considerably less in the higher pH group and no reduction of efficacy was seen over the 10-week follow-up period.¹⁴

Delivery Methods
Several preliminary studies also have examined novel delivery techniques to identify minimally painful yet effective methods for administering BoNT. It has been reported that standard BoNT formulations are not effective as topical agents in a comparison study in which onabotulinumtoxinA injection was compared to topically applied onabotulinumtoxinA.¹⁵ However, a follow-up prospective study by the same authors has demonstrated efficacy of topical onabotulinumtoxinA following pretreatment with a fractional ablative CO₂ laser for treatment of crow’s-feet. In this randomized, split-face, controlled trial (N=10), participants were first pretreated with topical lidocaine 30% before receiving a single pass of fractional ablative CO₂ laser with no overlap and a pulse energy of 100 mJ. Within 60 seconds of laser treatment, participants then received either 100 U of abobotulinumtoxinA diluted in 0.1 mL of saline or simple normal saline applied topically. A clinically significant improvement in periorbital wrinkles was seen both at 1-week and 1-month posttreatment in the laser and onabotulinumtoxinA–treated group compared to the laser and topical saline–treated group (P<.02).¹⁵

Another unique administration method studied, albeit with less successful results, involves the use of iontophoresis to deliver BoNT painlessly in a transdermal fashion with the assistance of an electrical current.¹⁶ This prospective, randomized, assessor-blinded, split-axilla, controlled trial of 11 participants compared the effectiveness of administering onabotulinumtoxinA via iontophoresis to traditional injection with onabotulinumtoxinA (250 U). Iontophoresis was accomplished with a single electrode pad soaked with 250 U of onabotulinumtoxinA applied directly to the axilla and a second electrode pad soaked in 0.9% saline applied to the hand to complete the circuit. An alternating electrical current was slowly increased for 30 minutes to a maximum current of 15 mA with a voltage of 12 V. Among the 11 participants recruited, the side treated with traditional injection showed a significantly greater percentage reduction in baseline sweating at the 1-week, 1-month, and 6-month posttreatment evaluations compared to iontophoresis (84%, 76%, and 50%, respectively vs 73%, 22%, and 32%, respectively)(P<.05). Despite being less efficacious than standard injection therapy, participants reported that iontophoresis delivery was significantly less painful (P<.05).¹⁶

A high-pressure oxygen delivery device, which utilizes a powerful jet of microdroplets containing water, the drug, air, and oxygen to deliver medication onto the skin surface, also has been studied as a means of delivery of BoNT in a minimally painful manner. In this study, the device was used to assess the efficacy of transdermal delivery of BoNT via jet nebulization in the treatment of primary palmar, plantar, and axillary hyperhidrosis.¹⁷ The 20 participants included in the study were randomized to receive either a combination of lidocaine and onabotulinumtoxinA (50 U) administered through the device or lidocaine delivered through the device followed by multiple transcutaneous injections of onabotulinumtoxinA (100 U). Both treatments significantly reduced sweating compared to baseline as measured by a visual analogue scale at 3-month follow-up (P<.001), but the combination delivery of lidocaine and onabotulinumtoxinA via the device resulted in significantly less procedure-related pain and sweating (P<.001) as well as significantly greater patient satisfaction (P<.001).¹⁷

Optimizing Aesthetic Outcomes
A frequent concern of patients receiving BoNT for cosmetic purposes is a desire to avoid a “frozen” or expressionless look. As such, many clinicians have attempted a variety of techniques to achieve more natural aesthetic results. One such method is known as the multipoint and multilevel injection technique, which consists of utilizing multiple injection sites at varying depths (intramuscular, subcutaneous, or intradermal) and doses (2–6 U) depending on the degree of contractility of the targeted muscle. In a preliminary study of 223 participants using this technique with a total dose of 125 U of abobotulinumtoxinA, good and natural results were reported with perseveration of facial emotion in all participants in addition to a mean overall satisfaction rate of 6.4 of 7 on the Facial Line Treatment Satisfaction Questionnaire with the maximum satisfaction rating possible reported in 66% of cases.¹⁸ It also has been postulated that injection depth of BoNT can affect brow elevation whereupon deeper injection depths can result in inactivation of the brow depressors and allow for increased elevation of the eyebrows. This technique has been applied in attempts to correct brow height asymmetry. However, a prospective, split-face study of 23 women suggested that this method is not effective.¹⁹ Participants received 64 U of onabotulinumtoxinA via 16 injection sites in the glabella, forehead, and lateral canthal area with either all deep or all shallow injections depending on the side treated and whether brow-lift was desired. Results at 4 weeks posttreatment showed no significant difference in brow height, and it was concluded that eyebrow depressor muscles cannot be accurately targeted with deep injection into the muscle belly for correction of eyebrow height discrepancies.¹⁹ Conversely, a 5-year retrospective, nonrandomized study of 227 patients with 563 treatments utilizing a “microdroplet” technique reported success at selectively targeting the eyebrow depressors while leaving the brow elevators unaffected.²⁰ Here, a total dose of 33 U of onabotulinumtoxinA was administered via microdroplets of 10 to 20 μL, each with more than 60 to 100 injections into the brow, glabella, and crow’s-feet area. This method of injection resulted in a statistically significant improvement of forehead lines and brow ptosis and furrowing at follow-up between 10 and 45 days after treatment (P<.0001). Additionally, average brow height was significantly increased from 24.6 mm to 25 mm after treatment (P=.02).²⁰

Conclusion

The use of BoNT products for both on- and off-label cosmetic and medical indications has rapidly grown over the past 2 decades. As demonstrated in this review, a variety of promising new products and delivery techniques are being developed. Given the rise in popularity of BoNT products among both physicians and consumers, clinicians should be aware of the current data and ongoing research.

Enlarged facial pores are superficial skin structures that are visualized as small openings on the skin corresponding to the openings of the pilosebaceous apparatus. These openings may be impacted with horny follicular plugs consisting of sebaceous debris that appear as open comedones.¹ Skin pores is a lay term that is poorly defined in the medical literature and often is categorized in terms of arbitrary circular diameters determined through cosmetic skin analyzers.² The term refers to pilosebaceous follicular enlargements (with or without open comedonal horny impactions) that can be visualized by the naked eye, most commonly occurring on the face and scalp. These enlarged pores remain a pervasive cosmetic concern that impacts patient quality of life. Enlarged pores are difficult to treat, in part due to lack of knowledge of the pathophysiology; thus, we review the currently proposed causes of enlarged pilosebaceous openings and the treatments in the scope of this pathogenesis with a focus on therapeutic efficacy.

Pathogenesis of Enlarged Facial Pores

It is now thought that seborrhea, loss of skin elasticity and tension, and hair follicle size are most clinically relevant to the pathogenesis of enlarged pores.² Other potential associated and causative factors include genetic predisposition, acne, comedogenic xenobiotics, chronic photodamage, chronic radiodermatitis, and vitamin A deficiency.^1,3

The direct relationship between sebum output and pore size has been well established, particularly in men who generally have higher sebum output levels than women, which likely is testosterone driven.^4,5 However, there are contradictory data on whether sex affects pore size, as females also exhibit contributory hormonal factors. Sebum output and pore size increase substantially during the ovulation phase of the female menstrual cycle, likely secondary to increased progesterone affecting sebaceous gland activity.^2,4 The presence of acne also is associated with enlarged facial pores, though the extent of seborrhea as a confounding factor is unclear. Furthermore, acne severity does not correlate with increased pore size.⁵ However, the processes of acne and facial pores are interlinked, given the frequent occurrence of open comedones within the pores.

Skin elasticity and tensile strength when defined visually and mechanically has shown a negative correlation with facial pore size and density.⁵ It is well known that cutaneous aging and chronic photodamage cause perturbation in the collagen and elastin framework that allows for the skin to maintain its resilient properties.⁶ Aged and photodamaged skin also demonstrates decreased expression of microfibril-associated glycoprotein-1 (MAGP-1), a crucial component in elastic fiber assembly and skin elasticity in the dermis and perifollicular/pore areas.⁷

Pore density and size appears to range diversely across ethnicities, though Chinese women exhibit notably lower pore size and density across all ages as compared to other ethnicities.⁸ Black individuals have aberrant epidermal architecture, defined as the presence of stalagmitelike structures at the dermoepidermal junction, correlating with enlarged pore size compared to other ethnicities.^2,8

Treating Enlarged Facial Pores

Treatments for enlarged facial pores primarily aim to decrease sebum production, rejuvenate skin, remove hair, and/or decrease follicular size. Evidence-based studies are limited, and many currently used therapies have not been studied with enlarged facial pores as a primary investigative outcome. Here, we include studies that report efficacy in decreasing pore size specifically. It is important to note the lack of a uniform and objective modality with which to report skin pore size. Studies use a wide range of techniques including patient self-reporting, physician observation, and software image analyzers.

Topical Therapies

Topical retinoids are vitamin A derivatives, and they are first-line therapies in reversing the aberrant collagen and elastin-associated epidermal and dermal changes that occur with chronological aging and photoaging. Tretinoin, isotretinoin, and tazarotene have shown efficacy in multiple parameters of skin rejuvenation, including facial pores, skin wrinkling, hyperpigmentation, skin laxity, and sebum production.⁹ However, it is important to note that retinoids treat keratinocyte atypia in acne, and efficacy in facial pores is confounded by improvement in follicular keratinization. Because studies have not distinctly uncoupled this association, it is erroneous to conclude that retinoids reduce facial pore size and density irrespective of concomitant acne vulgaris.

Tazarotene has been evaluated for use in reducing facial pore size. In one investigation, 568 patients with moderate wrinkling or hyperpigmentation were randomized to receive tazarotene cream 0.1% or placebo once daily for 24 weeks and were evaluated for enlarged facial pores as a secondary outcome using a double-blinded physician 5-point scale.¹⁰ At week 24, 42% of tazarotene-treated patients achieved improvement of at least 1 point compared to 20% of placebo-treated patients (P<.001). Adverse events were dermatitic, as can be expected of retinoids, leading to a 4% discontinuation rate in the tazarotene group compared to 1% in the placebo group.¹⁰

Tretinoin has long been used off label for antiaging treatments but has only recently shown efficacy for facial pores. In one study, 60 women who had previously sought antiaging procedures were treated with tretinoin cream 0.025% once daily and no other antiaging products or procedures for 90 days.¹¹ Facial pore evaluations were determined by a modified dermatoscope with a polarized analyzer for clinical scoring using a photonumeric scale. Patients improved from a baseline average score of 3.2 in facial pores to a posttreatment average score of 2.0 (P<.05) at day 84. This improvement was sustained from day 28 of treatment and corresponded to patient self-perception. Adverse events included xerosis, desquamation, burning, and erythema, which led to 3 premature discontinuations.¹¹

Various chemical peel formulations are used in skin rejuvenation and have shown application in enlarged facial pores. Chemical peels act at the epidermal or dermal level to induce temporary breakdown and regeneration of healthier cells and improved skin matrix.¹² Twenty-two Japanese women applied glycolic acid (30% solution) every 2 weeks for a total of 5 treatments and exhibited reduced appearance of conspicuous, open, and dark pores, defined by surface area and shading as determined through dermatoscopic and software analysis, with mean improvement rates of 34.6%, 11%, and 34.3%, respectively. More than 70% of participants exhibited improvement in enlarged facial pores.¹³ A study involving a 40% glycolic acid and vitamin C formulation demonstrated significant improvement in facial pores (28.3%; P<.001).¹⁴

The newest topical therapies studied for use in minimizing facial pilosebaceous openings are natural plant-derived copper chlorophyllin complex sodium salt (CHLcu) and tetra-hydro-jasmonic acid (LR2412). Clinical trials of these botanicals are limited with small sample sizes but are included here as novel treatments requiring further investigation.

Chlorophyllin copper complex sodium salt is derived from chlorophyll, a green pigment found in plants, and has been investigated as a topical gel in liposomal dispersions for application in photodamaged and aged skin. Chlorophyllin copper complex sodium salt exerts in vitro hyaluronidase inhibitory activity to maintain hyaluronic acid in the extracellular matrix and counteract the structural breakdown of cutaneous aging.¹⁵ Two small single-center pilot trials enrolled 10 participants each in a 3-week study of CHLcu 0.1% twice daily and an 8-week study of CHLcu 0.066% twice daily.^16,17 After 3 weeks, patients treated with CHLcu 0.1% exhibited a 22.2% improvement in facial pores by clinical assessment grading, though this improvement was not significant on software imaging analysis. Patients improved the most on parameters of facial seborrhea by clinical assessment.¹⁶ After 8 weeks, patients treated with CHLcu 0.066% exhibited 25.3% improvement in facial pores by clinical assessment grading.¹⁷ Treatments were reported to be well tolerated without noted adverse events in both studies.

Tetra-hydro-jasmonic acid is an analogue of jasmonic acid, a plant hormone derived from linoleic acid. Due to its favorable safety profile and bioavailability, penetration into epidermal and dermal layers, and potential effects in rejuvenating desquamation, LR2412 is currently being assessed for treatment of skin wrinkles, texture, and pores.¹⁸ Its effect is thought to relate to stimulation of laminin-5, collagen IV, and fibrillin deposition at the dermoepidermal junction.¹⁹ In an open-label trial of a topical preparation of LR2412, 15 participants were treated twice daily for 6 weeks and assessed through investigator clinical assessment scoring.²⁰ Investigator scoring of pores improved by 25.2% from baseline (P<.05) after 6 weeks of treatment. Improvement in pores was seen as early as days 1 and 3. No serious adverse events were reported, though 2 participants developed acne on follow-up.²⁰

Tetra-hydro-jasmonic acid also is formulated with retinol (retinol 0.2%/LR2412 2.0%) and demonstrated cosmetic efficacy in a noninferiority trial with tretinoin cream 0.025%.¹¹ Sixty patients each were randomized to retinol/LR2412 or tretinoin at bedtime and treated for 90 days. At day 84, participants in the retinol/LR2412 group exhibited an improvement in investigator clinical assessment scoring from a baseline of 3.6 to 2.5 (P<.05). There were no significant differences in investigator-assessed efficacy between the treatment arms. Participants reported similar or better results and fewer side effects with retinol/LR2412 on self-questionnaires. Eight participants treated with retinol/LR2412 and 15 participants treated with tretinoin reported various incidences of skin irritation, burning, and desquamation.¹¹

Oral Therapies

The most commonly used oral therapies for enlarged pores are antiandrogens, such as combined oral contraceptives, spironolactone, and cyproterone acetate, which modulate sebum production due to the presence of androgen receptors within sebaceous glands.²¹ Forty-four white women in an open-label, phase 4 study were treated with combined oral contraceptives containing chlormadinone acetate–ethinyl estradiol for 6 menstrual cycles, with standardized photography taken before and after the treatment period for software analysis. After 6 treatment cycles, 9.1% (4/44) of participants had visibly enlarged pores of the forehead and cheeks compared to 43.2% (19/44) of participants at baseline (P<.0001).²² The effects of other antiandrogens on facial pores have not been studied in this capacity.

Lasers, Radiofrequency, and Ultrasound Devices

The development of various devices that can deliver targeted thermal or ultrasound energy to the skin offers the newest and most robust modality in cosmetic therapy. The mechanism of their efficacy may be due to a combination of induced remodeling of collagen fibers near pilosebaceous openings to increase skin elasticity and decrease sebum production.^2,23

Devices with established antiaging effects have been extensively reviewed and include the gold particle 800-nm diode laser, 1450-nm diode laser, microneedle apparatuses, fractional radiofrequency devices, 2790-nm erbium:YAG laser, nonablative 1410-nm fractionated erbium-doped fiber laser, and nonablative 1440-nm fractional laser.²

Literature on the use of these devices for minimizing facial pore size is limited. One treatment of intense focused ultrasound using a 3-mm transducer successfully improved overall pore appearance in 91% of sites at 6-week follow-up on a clinical grading scale.²⁴ Three sessions of nonablative 1410-nm fractionated erbium-doped fiber laser treatments yielded facial skin pore minimization of greater than 51% in 14 of 15 participants.²⁵

The nonablative 1440-nm diode fractional laser received 510(k) clearance by the US Food and Drug Administration in 2011 for aesthetic use in chronologically aged and photoaged skin. Twenty participants treated for 2 weeks and a total of 6 facial treatments with this laser system showed a 17% average improvement in facial pore score on software analysis (P≤.002). Adverse events were mild and included erythema and xerosis.²⁶

Conclusion

The reliability of available literature on efficacy of various treatments in diminishing facial skin pores has been challenging given that most studies are low in power, lack control groups, use nonuniform methods of reporting outcomes, and do not report complete adverse events. Thus, all results should be interpreted with caution.

Overall, it is clear that the pathogenesis of enlarged facial pores is multifactorial and complex, necessitating a similar approach to therapeutics. Topical treatments offer a range of diverse therapies with proven benefit in facial pore reduction. The advent of lasers and devices offers constantly evolving therapeutic options with diffuse antiaging effects. Despite the numerous topical, oral, and device-oriented options, enlarged facial pores remain a challenging cosmetic concern. More robust efficacy studies on new treatments are necessary.

Enlarged facial pores are superficial skin structures that are visualized as small openings on the skin corresponding to the openings of the pilosebaceous apparatus. These openings may be impacted with horny follicular plugs consisting of sebaceous debris that appear as open comedones.¹ Skin pores is a lay term that is poorly defined in the medical literature and often is categorized in terms of arbitrary circular diameters determined through cosmetic skin analyzers.² The term refers to pilosebaceous follicular enlargements (with or without open comedonal horny impactions) that can be visualized by the naked eye, most commonly occurring on the face and scalp. These enlarged pores remain a pervasive cosmetic concern that impacts patient quality of life. Enlarged pores are difficult to treat, in part due to lack of knowledge of the pathophysiology; thus, we review the currently proposed causes of enlarged pilosebaceous openings and the treatments in the scope of this pathogenesis with a focus on therapeutic efficacy.

Pathogenesis of Enlarged Facial Pores

It is now thought that seborrhea, loss of skin elasticity and tension, and hair follicle size are most clinically relevant to the pathogenesis of enlarged pores.² Other potential associated and causative factors include genetic predisposition, acne, comedogenic xenobiotics, chronic photodamage, chronic radiodermatitis, and vitamin A deficiency.^1,3

The direct relationship between sebum output and pore size has been well established, particularly in men who generally have higher sebum output levels than women, which likely is testosterone driven.^4,5 However, there are contradictory data on whether sex affects pore size, as females also exhibit contributory hormonal factors. Sebum output and pore size increase substantially during the ovulation phase of the female menstrual cycle, likely secondary to increased progesterone affecting sebaceous gland activity.^2,4 The presence of acne also is associated with enlarged facial pores, though the extent of seborrhea as a confounding factor is unclear. Furthermore, acne severity does not correlate with increased pore size.⁵ However, the processes of acne and facial pores are interlinked, given the frequent occurrence of open comedones within the pores.

Skin elasticity and tensile strength when defined visually and mechanically has shown a negative correlation with facial pore size and density.⁵ It is well known that cutaneous aging and chronic photodamage cause perturbation in the collagen and elastin framework that allows for the skin to maintain its resilient properties.⁶ Aged and photodamaged skin also demonstrates decreased expression of microfibril-associated glycoprotein-1 (MAGP-1), a crucial component in elastic fiber assembly and skin elasticity in the dermis and perifollicular/pore areas.⁷

Pore density and size appears to range diversely across ethnicities, though Chinese women exhibit notably lower pore size and density across all ages as compared to other ethnicities.⁸ Black individuals have aberrant epidermal architecture, defined as the presence of stalagmitelike structures at the dermoepidermal junction, correlating with enlarged pore size compared to other ethnicities.^2,8

Treating Enlarged Facial Pores

Treatments for enlarged facial pores primarily aim to decrease sebum production, rejuvenate skin, remove hair, and/or decrease follicular size. Evidence-based studies are limited, and many currently used therapies have not been studied with enlarged facial pores as a primary investigative outcome. Here, we include studies that report efficacy in decreasing pore size specifically. It is important to note the lack of a uniform and objective modality with which to report skin pore size. Studies use a wide range of techniques including patient self-reporting, physician observation, and software image analyzers.

Topical Therapies

Topical retinoids are vitamin A derivatives, and they are first-line therapies in reversing the aberrant collagen and elastin-associated epidermal and dermal changes that occur with chronological aging and photoaging. Tretinoin, isotretinoin, and tazarotene have shown efficacy in multiple parameters of skin rejuvenation, including facial pores, skin wrinkling, hyperpigmentation, skin laxity, and sebum production.⁹ However, it is important to note that retinoids treat keratinocyte atypia in acne, and efficacy in facial pores is confounded by improvement in follicular keratinization. Because studies have not distinctly uncoupled this association, it is erroneous to conclude that retinoids reduce facial pore size and density irrespective of concomitant acne vulgaris.

Tazarotene has been evaluated for use in reducing facial pore size. In one investigation, 568 patients with moderate wrinkling or hyperpigmentation were randomized to receive tazarotene cream 0.1% or placebo once daily for 24 weeks and were evaluated for enlarged facial pores as a secondary outcome using a double-blinded physician 5-point scale.¹⁰ At week 24, 42% of tazarotene-treated patients achieved improvement of at least 1 point compared to 20% of placebo-treated patients (P<.001). Adverse events were dermatitic, as can be expected of retinoids, leading to a 4% discontinuation rate in the tazarotene group compared to 1% in the placebo group.¹⁰

Tretinoin has long been used off label for antiaging treatments but has only recently shown efficacy for facial pores. In one study, 60 women who had previously sought antiaging procedures were treated with tretinoin cream 0.025% once daily and no other antiaging products or procedures for 90 days.¹¹ Facial pore evaluations were determined by a modified dermatoscope with a polarized analyzer for clinical scoring using a photonumeric scale. Patients improved from a baseline average score of 3.2 in facial pores to a posttreatment average score of 2.0 (P<.05) at day 84. This improvement was sustained from day 28 of treatment and corresponded to patient self-perception. Adverse events included xerosis, desquamation, burning, and erythema, which led to 3 premature discontinuations.¹¹

Various chemical peel formulations are used in skin rejuvenation and have shown application in enlarged facial pores. Chemical peels act at the epidermal or dermal level to induce temporary breakdown and regeneration of healthier cells and improved skin matrix.¹² Twenty-two Japanese women applied glycolic acid (30% solution) every 2 weeks for a total of 5 treatments and exhibited reduced appearance of conspicuous, open, and dark pores, defined by surface area and shading as determined through dermatoscopic and software analysis, with mean improvement rates of 34.6%, 11%, and 34.3%, respectively. More than 70% of participants exhibited improvement in enlarged facial pores.¹³ A study involving a 40% glycolic acid and vitamin C formulation demonstrated significant improvement in facial pores (28.3%; P<.001).¹⁴

The newest topical therapies studied for use in minimizing facial pilosebaceous openings are natural plant-derived copper chlorophyllin complex sodium salt (CHLcu) and tetra-hydro-jasmonic acid (LR2412). Clinical trials of these botanicals are limited with small sample sizes but are included here as novel treatments requiring further investigation.

Chlorophyllin copper complex sodium salt is derived from chlorophyll, a green pigment found in plants, and has been investigated as a topical gel in liposomal dispersions for application in photodamaged and aged skin. Chlorophyllin copper complex sodium salt exerts in vitro hyaluronidase inhibitory activity to maintain hyaluronic acid in the extracellular matrix and counteract the structural breakdown of cutaneous aging.¹⁵ Two small single-center pilot trials enrolled 10 participants each in a 3-week study of CHLcu 0.1% twice daily and an 8-week study of CHLcu 0.066% twice daily.^16,17 After 3 weeks, patients treated with CHLcu 0.1% exhibited a 22.2% improvement in facial pores by clinical assessment grading, though this improvement was not significant on software imaging analysis. Patients improved the most on parameters of facial seborrhea by clinical assessment.¹⁶ After 8 weeks, patients treated with CHLcu 0.066% exhibited 25.3% improvement in facial pores by clinical assessment grading.¹⁷ Treatments were reported to be well tolerated without noted adverse events in both studies.

Tetra-hydro-jasmonic acid is an analogue of jasmonic acid, a plant hormone derived from linoleic acid. Due to its favorable safety profile and bioavailability, penetration into epidermal and dermal layers, and potential effects in rejuvenating desquamation, LR2412 is currently being assessed for treatment of skin wrinkles, texture, and pores.¹⁸ Its effect is thought to relate to stimulation of laminin-5, collagen IV, and fibrillin deposition at the dermoepidermal junction.¹⁹ In an open-label trial of a topical preparation of LR2412, 15 participants were treated twice daily for 6 weeks and assessed through investigator clinical assessment scoring.²⁰ Investigator scoring of pores improved by 25.2% from baseline (P<.05) after 6 weeks of treatment. Improvement in pores was seen as early as days 1 and 3. No serious adverse events were reported, though 2 participants developed acne on follow-up.²⁰

Tetra-hydro-jasmonic acid also is formulated with retinol (retinol 0.2%/LR2412 2.0%) and demonstrated cosmetic efficacy in a noninferiority trial with tretinoin cream 0.025%.¹¹ Sixty patients each were randomized to retinol/LR2412 or tretinoin at bedtime and treated for 90 days. At day 84, participants in the retinol/LR2412 group exhibited an improvement in investigator clinical assessment scoring from a baseline of 3.6 to 2.5 (P<.05). There were no significant differences in investigator-assessed efficacy between the treatment arms. Participants reported similar or better results and fewer side effects with retinol/LR2412 on self-questionnaires. Eight participants treated with retinol/LR2412 and 15 participants treated with tretinoin reported various incidences of skin irritation, burning, and desquamation.¹¹

Oral Therapies

The most commonly used oral therapies for enlarged pores are antiandrogens, such as combined oral contraceptives, spironolactone, and cyproterone acetate, which modulate sebum production due to the presence of androgen receptors within sebaceous glands.²¹ Forty-four white women in an open-label, phase 4 study were treated with combined oral contraceptives containing chlormadinone acetate–ethinyl estradiol for 6 menstrual cycles, with standardized photography taken before and after the treatment period for software analysis. After 6 treatment cycles, 9.1% (4/44) of participants had visibly enlarged pores of the forehead and cheeks compared to 43.2% (19/44) of participants at baseline (P<.0001).²² The effects of other antiandrogens on facial pores have not been studied in this capacity.

Lasers, Radiofrequency, and Ultrasound Devices

The development of various devices that can deliver targeted thermal or ultrasound energy to the skin offers the newest and most robust modality in cosmetic therapy. The mechanism of their efficacy may be due to a combination of induced remodeling of collagen fibers near pilosebaceous openings to increase skin elasticity and decrease sebum production.^2,23

Devices with established antiaging effects have been extensively reviewed and include the gold particle 800-nm diode laser, 1450-nm diode laser, microneedle apparatuses, fractional radiofrequency devices, 2790-nm erbium:YAG laser, nonablative 1410-nm fractionated erbium-doped fiber laser, and nonablative 1440-nm fractional laser.²

Literature on the use of these devices for minimizing facial pore size is limited. One treatment of intense focused ultrasound using a 3-mm transducer successfully improved overall pore appearance in 91% of sites at 6-week follow-up on a clinical grading scale.²⁴ Three sessions of nonablative 1410-nm fractionated erbium-doped fiber laser treatments yielded facial skin pore minimization of greater than 51% in 14 of 15 participants.²⁵

The nonablative 1440-nm diode fractional laser received 510(k) clearance by the US Food and Drug Administration in 2011 for aesthetic use in chronologically aged and photoaged skin. Twenty participants treated for 2 weeks and a total of 6 facial treatments with this laser system showed a 17% average improvement in facial pore score on software analysis (P≤.002). Adverse events were mild and included erythema and xerosis.²⁶

Conclusion

The reliability of available literature on efficacy of various treatments in diminishing facial skin pores has been challenging given that most studies are low in power, lack control groups, use nonuniform methods of reporting outcomes, and do not report complete adverse events. Thus, all results should be interpreted with caution.

Overall, it is clear that the pathogenesis of enlarged facial pores is multifactorial and complex, necessitating a similar approach to therapeutics. Topical treatments offer a range of diverse therapies with proven benefit in facial pore reduction. The advent of lasers and devices offers constantly evolving therapeutic options with diffuse antiaging effects. Despite the numerous topical, oral, and device-oriented options, enlarged facial pores remain a challenging cosmetic concern. More robust efficacy studies on new treatments are necessary.

Enlarged facial pores are superficial skin structures that are visualized as small openings on the skin corresponding to the openings of the pilosebaceous apparatus. These openings may be impacted with horny follicular plugs consisting of sebaceous debris that appear as open comedones.¹ Skin pores is a lay term that is poorly defined in the medical literature and often is categorized in terms of arbitrary circular diameters determined through cosmetic skin analyzers.² The term refers to pilosebaceous follicular enlargements (with or without open comedonal horny impactions) that can be visualized by the naked eye, most commonly occurring on the face and scalp. These enlarged pores remain a pervasive cosmetic concern that impacts patient quality of life. Enlarged pores are difficult to treat, in part due to lack of knowledge of the pathophysiology; thus, we review the currently proposed causes of enlarged pilosebaceous openings and the treatments in the scope of this pathogenesis with a focus on therapeutic efficacy.

Pathogenesis of Enlarged Facial Pores

It is now thought that seborrhea, loss of skin elasticity and tension, and hair follicle size are most clinically relevant to the pathogenesis of enlarged pores.² Other potential associated and causative factors include genetic predisposition, acne, comedogenic xenobiotics, chronic photodamage, chronic radiodermatitis, and vitamin A deficiency.^1,3

The direct relationship between sebum output and pore size has been well established, particularly in men who generally have higher sebum output levels than women, which likely is testosterone driven.^4,5 However, there are contradictory data on whether sex affects pore size, as females also exhibit contributory hormonal factors. Sebum output and pore size increase substantially during the ovulation phase of the female menstrual cycle, likely secondary to increased progesterone affecting sebaceous gland activity.^2,4 The presence of acne also is associated with enlarged facial pores, though the extent of seborrhea as a confounding factor is unclear. Furthermore, acne severity does not correlate with increased pore size.⁵ However, the processes of acne and facial pores are interlinked, given the frequent occurrence of open comedones within the pores.

Skin elasticity and tensile strength when defined visually and mechanically has shown a negative correlation with facial pore size and density.⁵ It is well known that cutaneous aging and chronic photodamage cause perturbation in the collagen and elastin framework that allows for the skin to maintain its resilient properties.⁶ Aged and photodamaged skin also demonstrates decreased expression of microfibril-associated glycoprotein-1 (MAGP-1), a crucial component in elastic fiber assembly and skin elasticity in the dermis and perifollicular/pore areas.⁷

Pore density and size appears to range diversely across ethnicities, though Chinese women exhibit notably lower pore size and density across all ages as compared to other ethnicities.⁸ Black individuals have aberrant epidermal architecture, defined as the presence of stalagmitelike structures at the dermoepidermal junction, correlating with enlarged pore size compared to other ethnicities.^2,8

Treating Enlarged Facial Pores

Treatments for enlarged facial pores primarily aim to decrease sebum production, rejuvenate skin, remove hair, and/or decrease follicular size. Evidence-based studies are limited, and many currently used therapies have not been studied with enlarged facial pores as a primary investigative outcome. Here, we include studies that report efficacy in decreasing pore size specifically. It is important to note the lack of a uniform and objective modality with which to report skin pore size. Studies use a wide range of techniques including patient self-reporting, physician observation, and software image analyzers.

Topical Therapies

Topical retinoids are vitamin A derivatives, and they are first-line therapies in reversing the aberrant collagen and elastin-associated epidermal and dermal changes that occur with chronological aging and photoaging. Tretinoin, isotretinoin, and tazarotene have shown efficacy in multiple parameters of skin rejuvenation, including facial pores, skin wrinkling, hyperpigmentation, skin laxity, and sebum production.⁹ However, it is important to note that retinoids treat keratinocyte atypia in acne, and efficacy in facial pores is confounded by improvement in follicular keratinization. Because studies have not distinctly uncoupled this association, it is erroneous to conclude that retinoids reduce facial pore size and density irrespective of concomitant acne vulgaris.

Tazarotene has been evaluated for use in reducing facial pore size. In one investigation, 568 patients with moderate wrinkling or hyperpigmentation were randomized to receive tazarotene cream 0.1% or placebo once daily for 24 weeks and were evaluated for enlarged facial pores as a secondary outcome using a double-blinded physician 5-point scale.¹⁰ At week 24, 42% of tazarotene-treated patients achieved improvement of at least 1 point compared to 20% of placebo-treated patients (P<.001). Adverse events were dermatitic, as can be expected of retinoids, leading to a 4% discontinuation rate in the tazarotene group compared to 1% in the placebo group.¹⁰

Tretinoin has long been used off label for antiaging treatments but has only recently shown efficacy for facial pores. In one study, 60 women who had previously sought antiaging procedures were treated with tretinoin cream 0.025% once daily and no other antiaging products or procedures for 90 days.¹¹ Facial pore evaluations were determined by a modified dermatoscope with a polarized analyzer for clinical scoring using a photonumeric scale. Patients improved from a baseline average score of 3.2 in facial pores to a posttreatment average score of 2.0 (P<.05) at day 84. This improvement was sustained from day 28 of treatment and corresponded to patient self-perception. Adverse events included xerosis, desquamation, burning, and erythema, which led to 3 premature discontinuations.¹¹

Various chemical peel formulations are used in skin rejuvenation and have shown application in enlarged facial pores. Chemical peels act at the epidermal or dermal level to induce temporary breakdown and regeneration of healthier cells and improved skin matrix.¹² Twenty-two Japanese women applied glycolic acid (30% solution) every 2 weeks for a total of 5 treatments and exhibited reduced appearance of conspicuous, open, and dark pores, defined by surface area and shading as determined through dermatoscopic and software analysis, with mean improvement rates of 34.6%, 11%, and 34.3%, respectively. More than 70% of participants exhibited improvement in enlarged facial pores.¹³ A study involving a 40% glycolic acid and vitamin C formulation demonstrated significant improvement in facial pores (28.3%; P<.001).¹⁴

The newest topical therapies studied for use in minimizing facial pilosebaceous openings are natural plant-derived copper chlorophyllin complex sodium salt (CHLcu) and tetra-hydro-jasmonic acid (LR2412). Clinical trials of these botanicals are limited with small sample sizes but are included here as novel treatments requiring further investigation.

Chlorophyllin copper complex sodium salt is derived from chlorophyll, a green pigment found in plants, and has been investigated as a topical gel in liposomal dispersions for application in photodamaged and aged skin. Chlorophyllin copper complex sodium salt exerts in vitro hyaluronidase inhibitory activity to maintain hyaluronic acid in the extracellular matrix and counteract the structural breakdown of cutaneous aging.¹⁵ Two small single-center pilot trials enrolled 10 participants each in a 3-week study of CHLcu 0.1% twice daily and an 8-week study of CHLcu 0.066% twice daily.^16,17 After 3 weeks, patients treated with CHLcu 0.1% exhibited a 22.2% improvement in facial pores by clinical assessment grading, though this improvement was not significant on software imaging analysis. Patients improved the most on parameters of facial seborrhea by clinical assessment.¹⁶ After 8 weeks, patients treated with CHLcu 0.066% exhibited 25.3% improvement in facial pores by clinical assessment grading.¹⁷ Treatments were reported to be well tolerated without noted adverse events in both studies.

Tetra-hydro-jasmonic acid is an analogue of jasmonic acid, a plant hormone derived from linoleic acid. Due to its favorable safety profile and bioavailability, penetration into epidermal and dermal layers, and potential effects in rejuvenating desquamation, LR2412 is currently being assessed for treatment of skin wrinkles, texture, and pores.¹⁸ Its effect is thought to relate to stimulation of laminin-5, collagen IV, and fibrillin deposition at the dermoepidermal junction.¹⁹ In an open-label trial of a topical preparation of LR2412, 15 participants were treated twice daily for 6 weeks and assessed through investigator clinical assessment scoring.²⁰ Investigator scoring of pores improved by 25.2% from baseline (P<.05) after 6 weeks of treatment. Improvement in pores was seen as early as days 1 and 3. No serious adverse events were reported, though 2 participants developed acne on follow-up.²⁰

Tetra-hydro-jasmonic acid also is formulated with retinol (retinol 0.2%/LR2412 2.0%) and demonstrated cosmetic efficacy in a noninferiority trial with tretinoin cream 0.025%.¹¹ Sixty patients each were randomized to retinol/LR2412 or tretinoin at bedtime and treated for 90 days. At day 84, participants in the retinol/LR2412 group exhibited an improvement in investigator clinical assessment scoring from a baseline of 3.6 to 2.5 (P<.05). There were no significant differences in investigator-assessed efficacy between the treatment arms. Participants reported similar or better results and fewer side effects with retinol/LR2412 on self-questionnaires. Eight participants treated with retinol/LR2412 and 15 participants treated with tretinoin reported various incidences of skin irritation, burning, and desquamation.¹¹

Oral Therapies

The most commonly used oral therapies for enlarged pores are antiandrogens, such as combined oral contraceptives, spironolactone, and cyproterone acetate, which modulate sebum production due to the presence of androgen receptors within sebaceous glands.²¹ Forty-four white women in an open-label, phase 4 study were treated with combined oral contraceptives containing chlormadinone acetate–ethinyl estradiol for 6 menstrual cycles, with standardized photography taken before and after the treatment period for software analysis. After 6 treatment cycles, 9.1% (4/44) of participants had visibly enlarged pores of the forehead and cheeks compared to 43.2% (19/44) of participants at baseline (P<.0001).²² The effects of other antiandrogens on facial pores have not been studied in this capacity.

Lasers, Radiofrequency, and Ultrasound Devices

The development of various devices that can deliver targeted thermal or ultrasound energy to the skin offers the newest and most robust modality in cosmetic therapy. The mechanism of their efficacy may be due to a combination of induced remodeling of collagen fibers near pilosebaceous openings to increase skin elasticity and decrease sebum production.^2,23

Devices with established antiaging effects have been extensively reviewed and include the gold particle 800-nm diode laser, 1450-nm diode laser, microneedle apparatuses, fractional radiofrequency devices, 2790-nm erbium:YAG laser, nonablative 1410-nm fractionated erbium-doped fiber laser, and nonablative 1440-nm fractional laser.²

Literature on the use of these devices for minimizing facial pore size is limited. One treatment of intense focused ultrasound using a 3-mm transducer successfully improved overall pore appearance in 91% of sites at 6-week follow-up on a clinical grading scale.²⁴ Three sessions of nonablative 1410-nm fractionated erbium-doped fiber laser treatments yielded facial skin pore minimization of greater than 51% in 14 of 15 participants.²⁵

The nonablative 1440-nm diode fractional laser received 510(k) clearance by the US Food and Drug Administration in 2011 for aesthetic use in chronologically aged and photoaged skin. Twenty participants treated for 2 weeks and a total of 6 facial treatments with this laser system showed a 17% average improvement in facial pore score on software analysis (P≤.002). Adverse events were mild and included erythema and xerosis.²⁶

Conclusion

The reliability of available literature on efficacy of various treatments in diminishing facial skin pores has been challenging given that most studies are low in power, lack control groups, use nonuniform methods of reporting outcomes, and do not report complete adverse events. Thus, all results should be interpreted with caution.

Overall, it is clear that the pathogenesis of enlarged facial pores is multifactorial and complex, necessitating a similar approach to therapeutics. Topical treatments offer a range of diverse therapies with proven benefit in facial pore reduction. The advent of lasers and devices offers constantly evolving therapeutic options with diffuse antiaging effects. Despite the numerous topical, oral, and device-oriented options, enlarged facial pores remain a challenging cosmetic concern. More robust efficacy studies on new treatments are necessary.

The concept of field cancerization was first proposed in 1953 by Slaughter et al¹ in their study of oral squamous carcinomas. Their findings of multifocal patches of premalignant disease, abnormal tissue surrounding tumors, multiple localized primary tumors, and tumor recurrence following surgical resection was suggestive of a field of dysplastic cells with malignant potential.¹ Since then, modern molecular techniques have been used to establish a genetic basis for this model in many different types of cancer, including cutaneous malignancies.^2-4 The field begins from a singular stem cell, which undergoes one or more genetic changes that allow for a growth advantage compared to surrounding cells. The stem cell then divides, forming a patch of clonal daughter cells that displace the surrounding normal epithelium. Growth of this patch eventually leads to a dysplastic field of monoclonal cells, which notably does not yet show invasive growth or metastatic behavior. Over time, continued carcinogenic exposure results in additional genetic alterations among different cells in the field, which leads to new subclonal proliferations that share common clonal origin but exhibit unique genetic changes. Eventually, transformative events may occur, resulting in cells with invasive and metastatic properties, thus forming a carcinoma.⁵

In the case of cutaneous malignancies, UV radiation in the form of UVA and UVB rays is the most common source of carcinogenesis. It is well established that UV radiation has numerous effects on the body, including but not limited to local and systemic immunosuppression, alteration of signal transduction pathways, and the development of mutations in DNA via direct damage by UVB or indirect damage by free radical formation with UVA.^6,7 Normally, DNA is protected from UV radiation–induced genetic alteration by the p53 gene, TP53. As such, damage to this gene is highly associated with cancer induction. One study found that more than 90% of squamous cell carcinomas (SCCs) and more than 50% of basal cell carcinomas (BCCs) contain UV-like mutations in TP53.⁸ The concept of field cancerization suggests that because the skin surrounding cutaneous malignancies has been exposed to the same chronic UV light as the initial lesion, it is at an increased risk for genetic abnormalities and thus possible malignant transformation.

Actinic keratoses (AKs) are common neoplasms of the skin that generally are regarded as precancerous lesions or may be considered to be the earliest stage of SCC in situ.⁹ Actinic keratoses usually develop as a consequence of chronic exposure to UV radiation and often are clinically apparent as erythematous scaly papules in sun-exposed areas (Figure 1).¹⁰ They also are identified histologically as atypical keratinocytes along the basal layer of the epidermis with possible enlargement, hyperchromatic nuclei, lack of maturation, mitotic figures, inflammatory infiltrate, and/or hyperkeratosis.¹⁰ Furthermore, the genetic changes associated with AKs are well documented and are strongly associated with changes to p53.¹¹ Given these characteristics, AKs serve as good markers of genetic damage with potential for malignancy. In this study, we used histologically identified AKs to assess the presence of field damage in the tissue immediately surrounding excision specimens of SCCs, BCCs, and malignant melanomas (MMs).

Methods

This study was approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai (New York, New York) prior to initiation. All cutaneous specimens submitted to the dermatopathology service for consultation between April 2013 and June 2013 were reviewed for inclusion in this study. Data collection was extended for MMs to include all specimens from January 2013 to June 2013 given the limited number of cases in the original data collection period.

Initial screening for this study was done electronically and assessed for a diagnosis of SCC (Figure 2), BCC (Figure 3), or MM (Figure 4) as determined by a board-certified dermatopathologist (G.G.). The resulting pool of specimens was then screened to include only excision specimens and to exclude curettage specimens and superficial specimens that lacked dermis. In this study, we chose to look at reexcisions rather than initial biopsies so that there was a greater likelihood of having an intact epidermis surrounding a malignancy that could be assessed for the presence of AKs as markers for field cancerization. Specimens were examined in full via serial transverse cross-sections at 3-mm intervals. Additional step sections were obtained at smaller intervals when margins were close or unclear.

Selected cases were reassessed by a board-certified dermatopathologist (G.G.) to confirm the diagnosis and to assess for the presence of at least 1 AK within the specimen sample that was separated from the original malignancy by histologically normal-appearing cells. Samples were also assessed for the presence of an AK within 0.1 mm of the distal lateral margins of the tissue sample. Information regarding patient age, gender, lesion location, lesion type, and specimen size was collected for each sample. In accordance with institutional review board protocol, research data were collected without any protected health information. All analyses and results were deidentified and stored on a password-protected computer database. Statistical analysis was performed using SPSS software. When applicable, P<.05 was considered to indicate statistical significance.

Results

There were 205 cases that passed the initial screening filters, of which 56 were excluded due to the presence of curettage or lack of a sufficient tissue sample. Of the remaining 149 cases, the distribution by malignancy type was tabulated along with the percentage of observed AKs. If an AK was observed, the percentage that had an AK at the lateral margins (marginal AK) was determined (Table 1). A χ² analysis determined that AKs were observed significantly more often in SCC specimens (57% [35/61]) than BCC (33% [21/64]) or malignant melanoma (25% [6/24]) specimens (P=.0125).

Statistics regarding patient age and gender as well as specimen size were stratified by malignancy type (Table 2). Using a receiver operating characteristic curve and the Youden index, an optimal cutoff of older than 67 years was determined to increase probability of observing an AK (P=.077) with sensitivity of 0.531 and specificity of 0.529. The distribution of specimen excision location for each malignancy type is shown in Table 3.

A multivariate analysis was performed to determine if the variables of patient age, gender, biopsy size, malignancy type (SCC, BCC, or MM), or cancer location (head, neck, trunk, arms, or legs) were independently useful in predicting whether an AK would be observed in the excision specimen. The significance of variables in the logistic regression model was assessed using a backward stepwise regression selection procedure entering variables if P<.15 and excluding variables if P>.25. Significant variables in predicting the occurrence of AK were SCC malignancy type (P=.007; odds ratio [OR], 2.61) and location on the head (P=.044; OR, 2.39) and arms (P=.042; OR, 2.55).

Comment

The χ² analysis of our data showed that SCC specimens were significantly more likely to have an associated AK than either BCCs or MMs (P=.0125), which is not surprising given that AKs are considered by many to be early-stage SCCs.¹² It is important to note, however, that BCCs and MMs both had nonnegligible rates of associated AKs. Although BCC and MM do not arise from the same background of genetic changes as SCC, this finding is noteworthy because it demonstrates definitive field damage with malignant potential in the area surrounding these cutaneous malignancies.

Our data also showed that there was a significantly greater association of AKs in malignancies located on the head (P=.044) and arms (P=.042), possibly because these 2 areas tend to be the most sun exposed and thus are more likely to have sustained field damage as evidenced by the higher percentage of AKs. A study by Jonason et al¹³ described a similar finding in which sun-exposed skin exhibited significantly more frequent (P=.04) and larger (P=.02) clonal patches of mutated p53 keratinocytes than sun-protected skin.

It is likely that the field damage surrounding the cutaneous lesions in our study is actually greater than what we reported because the AK was present at the margin of the excision specimens the majority of the time (56%), which suggests that there likely may have been more AKs found if a wider area surrounding the malignancy had been studied given that AKs often are at the periphery of the lesion and may be missed by a small excision. Fewer marginal AKs were observed with MM cases, possibly because the excision specimens were more than double the size of SCC or BCC excisions. Furthermore, there likely is to be more damage than what can be appreciated by visual changes alone.

Kanjilal et al¹⁴ used polymerase chain reaction and DNA sequencing to demonstrate numerous p53 mutations in nonmalignant-appearing skin surrounding BCCs and SCCs. Brennan et al¹⁵ found p53 mutations in surgical margins of excised SCCs considered to be tumor free by histopathologic analysis in more than half of the specimens studied. Notably, tumor recurrence was significantly more likely in areas where mutations were found and no tumor recurrence was seen in areas free of p53 mutations (P=.02).¹⁵ Tabor et al⁴ similarly found genetically altered fields in histologically clear surgical margins of SCCs but also showed that local tumor recurrence following excision had more molecular markers in common with the nonresected premalignant field than it did with the primary tumor. Thus, these studies provide a genetic basis for field damage that can exist even in histologically benign-appearing cells.

We believe our findings are clinically relevant, as they provide additional evidence for the theory of field cancerization as demonstrated by the nonnegligible rates of AKs and thus field damage with malignant potential in the skin immediately surrounding cutaneous malignancies. The limitations of our study, however, include a small sample size; no consideration of the effects of prior topical, field, or systemic treatments; and lack of a control group. Nevertheless, our findings emphasize the importance of assessing the extent of field damage when determining treatment strategies. Clinicians treating cutaneous malignancies should consider the need for field therapy, especially in sun-exposed regions, to avoid additional primary tumors.¹⁶ Further research is needed, however, to identify optimal methods for quantifying field damage clinically and determining the most effective treatment strategies.

The concept of field cancerization was first proposed in 1953 by Slaughter et al¹ in their study of oral squamous carcinomas. Their findings of multifocal patches of premalignant disease, abnormal tissue surrounding tumors, multiple localized primary tumors, and tumor recurrence following surgical resection was suggestive of a field of dysplastic cells with malignant potential.¹ Since then, modern molecular techniques have been used to establish a genetic basis for this model in many different types of cancer, including cutaneous malignancies.^2-4 The field begins from a singular stem cell, which undergoes one or more genetic changes that allow for a growth advantage compared to surrounding cells. The stem cell then divides, forming a patch of clonal daughter cells that displace the surrounding normal epithelium. Growth of this patch eventually leads to a dysplastic field of monoclonal cells, which notably does not yet show invasive growth or metastatic behavior. Over time, continued carcinogenic exposure results in additional genetic alterations among different cells in the field, which leads to new subclonal proliferations that share common clonal origin but exhibit unique genetic changes. Eventually, transformative events may occur, resulting in cells with invasive and metastatic properties, thus forming a carcinoma.⁵

In the case of cutaneous malignancies, UV radiation in the form of UVA and UVB rays is the most common source of carcinogenesis. It is well established that UV radiation has numerous effects on the body, including but not limited to local and systemic immunosuppression, alteration of signal transduction pathways, and the development of mutations in DNA via direct damage by UVB or indirect damage by free radical formation with UVA.^6,7 Normally, DNA is protected from UV radiation–induced genetic alteration by the p53 gene, TP53. As such, damage to this gene is highly associated with cancer induction. One study found that more than 90% of squamous cell carcinomas (SCCs) and more than 50% of basal cell carcinomas (BCCs) contain UV-like mutations in TP53.⁸ The concept of field cancerization suggests that because the skin surrounding cutaneous malignancies has been exposed to the same chronic UV light as the initial lesion, it is at an increased risk for genetic abnormalities and thus possible malignant transformation.

Actinic keratoses (AKs) are common neoplasms of the skin that generally are regarded as precancerous lesions or may be considered to be the earliest stage of SCC in situ.⁹ Actinic keratoses usually develop as a consequence of chronic exposure to UV radiation and often are clinically apparent as erythematous scaly papules in sun-exposed areas (Figure 1).¹⁰ They also are identified histologically as atypical keratinocytes along the basal layer of the epidermis with possible enlargement, hyperchromatic nuclei, lack of maturation, mitotic figures, inflammatory infiltrate, and/or hyperkeratosis.¹⁰ Furthermore, the genetic changes associated with AKs are well documented and are strongly associated with changes to p53.¹¹ Given these characteristics, AKs serve as good markers of genetic damage with potential for malignancy. In this study, we used histologically identified AKs to assess the presence of field damage in the tissue immediately surrounding excision specimens of SCCs, BCCs, and malignant melanomas (MMs).

Methods

This study was approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai (New York, New York) prior to initiation. All cutaneous specimens submitted to the dermatopathology service for consultation between April 2013 and June 2013 were reviewed for inclusion in this study. Data collection was extended for MMs to include all specimens from January 2013 to June 2013 given the limited number of cases in the original data collection period.

Initial screening for this study was done electronically and assessed for a diagnosis of SCC (Figure 2), BCC (Figure 3), or MM (Figure 4) as determined by a board-certified dermatopathologist (G.G.). The resulting pool of specimens was then screened to include only excision specimens and to exclude curettage specimens and superficial specimens that lacked dermis. In this study, we chose to look at reexcisions rather than initial biopsies so that there was a greater likelihood of having an intact epidermis surrounding a malignancy that could be assessed for the presence of AKs as markers for field cancerization. Specimens were examined in full via serial transverse cross-sections at 3-mm intervals. Additional step sections were obtained at smaller intervals when margins were close or unclear.

Selected cases were reassessed by a board-certified dermatopathologist (G.G.) to confirm the diagnosis and to assess for the presence of at least 1 AK within the specimen sample that was separated from the original malignancy by histologically normal-appearing cells. Samples were also assessed for the presence of an AK within 0.1 mm of the distal lateral margins of the tissue sample. Information regarding patient age, gender, lesion location, lesion type, and specimen size was collected for each sample. In accordance with institutional review board protocol, research data were collected without any protected health information. All analyses and results were deidentified and stored on a password-protected computer database. Statistical analysis was performed using SPSS software. When applicable, P<.05 was considered to indicate statistical significance.

Results

There were 205 cases that passed the initial screening filters, of which 56 were excluded due to the presence of curettage or lack of a sufficient tissue sample. Of the remaining 149 cases, the distribution by malignancy type was tabulated along with the percentage of observed AKs. If an AK was observed, the percentage that had an AK at the lateral margins (marginal AK) was determined (Table 1). A χ² analysis determined that AKs were observed significantly more often in SCC specimens (57% [35/61]) than BCC (33% [21/64]) or malignant melanoma (25% [6/24]) specimens (P=.0125).

Statistics regarding patient age and gender as well as specimen size were stratified by malignancy type (Table 2). Using a receiver operating characteristic curve and the Youden index, an optimal cutoff of older than 67 years was determined to increase probability of observing an AK (P=.077) with sensitivity of 0.531 and specificity of 0.529. The distribution of specimen excision location for each malignancy type is shown in Table 3.

A multivariate analysis was performed to determine if the variables of patient age, gender, biopsy size, malignancy type (SCC, BCC, or MM), or cancer location (head, neck, trunk, arms, or legs) were independently useful in predicting whether an AK would be observed in the excision specimen. The significance of variables in the logistic regression model was assessed using a backward stepwise regression selection procedure entering variables if P<.15 and excluding variables if P>.25. Significant variables in predicting the occurrence of AK were SCC malignancy type (P=.007; odds ratio [OR], 2.61) and location on the head (P=.044; OR, 2.39) and arms (P=.042; OR, 2.55).

Comment

The χ² analysis of our data showed that SCC specimens were significantly more likely to have an associated AK than either BCCs or MMs (P=.0125), which is not surprising given that AKs are considered by many to be early-stage SCCs.¹² It is important to note, however, that BCCs and MMs both had nonnegligible rates of associated AKs. Although BCC and MM do not arise from the same background of genetic changes as SCC, this finding is noteworthy because it demonstrates definitive field damage with malignant potential in the area surrounding these cutaneous malignancies.

Our data also showed that there was a significantly greater association of AKs in malignancies located on the head (P=.044) and arms (P=.042), possibly because these 2 areas tend to be the most sun exposed and thus are more likely to have sustained field damage as evidenced by the higher percentage of AKs. A study by Jonason et al¹³ described a similar finding in which sun-exposed skin exhibited significantly more frequent (P=.04) and larger (P=.02) clonal patches of mutated p53 keratinocytes than sun-protected skin.

It is likely that the field damage surrounding the cutaneous lesions in our study is actually greater than what we reported because the AK was present at the margin of the excision specimens the majority of the time (56%), which suggests that there likely may have been more AKs found if a wider area surrounding the malignancy had been studied given that AKs often are at the periphery of the lesion and may be missed by a small excision. Fewer marginal AKs were observed with MM cases, possibly because the excision specimens were more than double the size of SCC or BCC excisions. Furthermore, there likely is to be more damage than what can be appreciated by visual changes alone.

Kanjilal et al¹⁴ used polymerase chain reaction and DNA sequencing to demonstrate numerous p53 mutations in nonmalignant-appearing skin surrounding BCCs and SCCs. Brennan et al¹⁵ found p53 mutations in surgical margins of excised SCCs considered to be tumor free by histopathologic analysis in more than half of the specimens studied. Notably, tumor recurrence was significantly more likely in areas where mutations were found and no tumor recurrence was seen in areas free of p53 mutations (P=.02).¹⁵ Tabor et al⁴ similarly found genetically altered fields in histologically clear surgical margins of SCCs but also showed that local tumor recurrence following excision had more molecular markers in common with the nonresected premalignant field than it did with the primary tumor. Thus, these studies provide a genetic basis for field damage that can exist even in histologically benign-appearing cells.

We believe our findings are clinically relevant, as they provide additional evidence for the theory of field cancerization as demonstrated by the nonnegligible rates of AKs and thus field damage with malignant potential in the skin immediately surrounding cutaneous malignancies. The limitations of our study, however, include a small sample size; no consideration of the effects of prior topical, field, or systemic treatments; and lack of a control group. Nevertheless, our findings emphasize the importance of assessing the extent of field damage when determining treatment strategies. Clinicians treating cutaneous malignancies should consider the need for field therapy, especially in sun-exposed regions, to avoid additional primary tumors.¹⁶ Further research is needed, however, to identify optimal methods for quantifying field damage clinically and determining the most effective treatment strategies.

The concept of field cancerization was first proposed in 1953 by Slaughter et al¹ in their study of oral squamous carcinomas. Their findings of multifocal patches of premalignant disease, abnormal tissue surrounding tumors, multiple localized primary tumors, and tumor recurrence following surgical resection was suggestive of a field of dysplastic cells with malignant potential.¹ Since then, modern molecular techniques have been used to establish a genetic basis for this model in many different types of cancer, including cutaneous malignancies.^2-4 The field begins from a singular stem cell, which undergoes one or more genetic changes that allow for a growth advantage compared to surrounding cells. The stem cell then divides, forming a patch of clonal daughter cells that displace the surrounding normal epithelium. Growth of this patch eventually leads to a dysplastic field of monoclonal cells, which notably does not yet show invasive growth or metastatic behavior. Over time, continued carcinogenic exposure results in additional genetic alterations among different cells in the field, which leads to new subclonal proliferations that share common clonal origin but exhibit unique genetic changes. Eventually, transformative events may occur, resulting in cells with invasive and metastatic properties, thus forming a carcinoma.⁵

In the case of cutaneous malignancies, UV radiation in the form of UVA and UVB rays is the most common source of carcinogenesis. It is well established that UV radiation has numerous effects on the body, including but not limited to local and systemic immunosuppression, alteration of signal transduction pathways, and the development of mutations in DNA via direct damage by UVB or indirect damage by free radical formation with UVA.^6,7 Normally, DNA is protected from UV radiation–induced genetic alteration by the p53 gene, TP53. As such, damage to this gene is highly associated with cancer induction. One study found that more than 90% of squamous cell carcinomas (SCCs) and more than 50% of basal cell carcinomas (BCCs) contain UV-like mutations in TP53.⁸ The concept of field cancerization suggests that because the skin surrounding cutaneous malignancies has been exposed to the same chronic UV light as the initial lesion, it is at an increased risk for genetic abnormalities and thus possible malignant transformation.

Actinic keratoses (AKs) are common neoplasms of the skin that generally are regarded as precancerous lesions or may be considered to be the earliest stage of SCC in situ.⁹ Actinic keratoses usually develop as a consequence of chronic exposure to UV radiation and often are clinically apparent as erythematous scaly papules in sun-exposed areas (Figure 1).¹⁰ They also are identified histologically as atypical keratinocytes along the basal layer of the epidermis with possible enlargement, hyperchromatic nuclei, lack of maturation, mitotic figures, inflammatory infiltrate, and/or hyperkeratosis.¹⁰ Furthermore, the genetic changes associated with AKs are well documented and are strongly associated with changes to p53.¹¹ Given these characteristics, AKs serve as good markers of genetic damage with potential for malignancy. In this study, we used histologically identified AKs to assess the presence of field damage in the tissue immediately surrounding excision specimens of SCCs, BCCs, and malignant melanomas (MMs).

Methods

This study was approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai (New York, New York) prior to initiation. All cutaneous specimens submitted to the dermatopathology service for consultation between April 2013 and June 2013 were reviewed for inclusion in this study. Data collection was extended for MMs to include all specimens from January 2013 to June 2013 given the limited number of cases in the original data collection period.

Initial screening for this study was done electronically and assessed for a diagnosis of SCC (Figure 2), BCC (Figure 3), or MM (Figure 4) as determined by a board-certified dermatopathologist (G.G.). The resulting pool of specimens was then screened to include only excision specimens and to exclude curettage specimens and superficial specimens that lacked dermis. In this study, we chose to look at reexcisions rather than initial biopsies so that there was a greater likelihood of having an intact epidermis surrounding a malignancy that could be assessed for the presence of AKs as markers for field cancerization. Specimens were examined in full via serial transverse cross-sections at 3-mm intervals. Additional step sections were obtained at smaller intervals when margins were close or unclear.

Selected cases were reassessed by a board-certified dermatopathologist (G.G.) to confirm the diagnosis and to assess for the presence of at least 1 AK within the specimen sample that was separated from the original malignancy by histologically normal-appearing cells. Samples were also assessed for the presence of an AK within 0.1 mm of the distal lateral margins of the tissue sample. Information regarding patient age, gender, lesion location, lesion type, and specimen size was collected for each sample. In accordance with institutional review board protocol, research data were collected without any protected health information. All analyses and results were deidentified and stored on a password-protected computer database. Statistical analysis was performed using SPSS software. When applicable, P<.05 was considered to indicate statistical significance.

Results

There were 205 cases that passed the initial screening filters, of which 56 were excluded due to the presence of curettage or lack of a sufficient tissue sample. Of the remaining 149 cases, the distribution by malignancy type was tabulated along with the percentage of observed AKs. If an AK was observed, the percentage that had an AK at the lateral margins (marginal AK) was determined (Table 1). A χ² analysis determined that AKs were observed significantly more often in SCC specimens (57% [35/61]) than BCC (33% [21/64]) or malignant melanoma (25% [6/24]) specimens (P=.0125).

Statistics regarding patient age and gender as well as specimen size were stratified by malignancy type (Table 2). Using a receiver operating characteristic curve and the Youden index, an optimal cutoff of older than 67 years was determined to increase probability of observing an AK (P=.077) with sensitivity of 0.531 and specificity of 0.529. The distribution of specimen excision location for each malignancy type is shown in Table 3.

A multivariate analysis was performed to determine if the variables of patient age, gender, biopsy size, malignancy type (SCC, BCC, or MM), or cancer location (head, neck, trunk, arms, or legs) were independently useful in predicting whether an AK would be observed in the excision specimen. The significance of variables in the logistic regression model was assessed using a backward stepwise regression selection procedure entering variables if P<.15 and excluding variables if P>.25. Significant variables in predicting the occurrence of AK were SCC malignancy type (P=.007; odds ratio [OR], 2.61) and location on the head (P=.044; OR, 2.39) and arms (P=.042; OR, 2.55).

Comment

The χ² analysis of our data showed that SCC specimens were significantly more likely to have an associated AK than either BCCs or MMs (P=.0125), which is not surprising given that AKs are considered by many to be early-stage SCCs.¹² It is important to note, however, that BCCs and MMs both had nonnegligible rates of associated AKs. Although BCC and MM do not arise from the same background of genetic changes as SCC, this finding is noteworthy because it demonstrates definitive field damage with malignant potential in the area surrounding these cutaneous malignancies.

Our data also showed that there was a significantly greater association of AKs in malignancies located on the head (P=.044) and arms (P=.042), possibly because these 2 areas tend to be the most sun exposed and thus are more likely to have sustained field damage as evidenced by the higher percentage of AKs. A study by Jonason et al¹³ described a similar finding in which sun-exposed skin exhibited significantly more frequent (P=.04) and larger (P=.02) clonal patches of mutated p53 keratinocytes than sun-protected skin.

It is likely that the field damage surrounding the cutaneous lesions in our study is actually greater than what we reported because the AK was present at the margin of the excision specimens the majority of the time (56%), which suggests that there likely may have been more AKs found if a wider area surrounding the malignancy had been studied given that AKs often are at the periphery of the lesion and may be missed by a small excision. Fewer marginal AKs were observed with MM cases, possibly because the excision specimens were more than double the size of SCC or BCC excisions. Furthermore, there likely is to be more damage than what can be appreciated by visual changes alone.

Kanjilal et al¹⁴ used polymerase chain reaction and DNA sequencing to demonstrate numerous p53 mutations in nonmalignant-appearing skin surrounding BCCs and SCCs. Brennan et al¹⁵ found p53 mutations in surgical margins of excised SCCs considered to be tumor free by histopathologic analysis in more than half of the specimens studied. Notably, tumor recurrence was significantly more likely in areas where mutations were found and no tumor recurrence was seen in areas free of p53 mutations (P=.02).¹⁵ Tabor et al⁴ similarly found genetically altered fields in histologically clear surgical margins of SCCs but also showed that local tumor recurrence following excision had more molecular markers in common with the nonresected premalignant field than it did with the primary tumor. Thus, these studies provide a genetic basis for field damage that can exist even in histologically benign-appearing cells.

We believe our findings are clinically relevant, as they provide additional evidence for the theory of field cancerization as demonstrated by the nonnegligible rates of AKs and thus field damage with malignant potential in the skin immediately surrounding cutaneous malignancies. The limitations of our study, however, include a small sample size; no consideration of the effects of prior topical, field, or systemic treatments; and lack of a control group. Nevertheless, our findings emphasize the importance of assessing the extent of field damage when determining treatment strategies. Clinicians treating cutaneous malignancies should consider the need for field therapy, especially in sun-exposed regions, to avoid additional primary tumors.¹⁶ Further research is needed, however, to identify optimal methods for quantifying field damage clinically and determining the most effective treatment strategies.