Division of Dermatology, Department of Medicine, University of Alberta, AB, Canada

Introduction

For decades, skin care has primarily been considered to be the domain of women, but recently, an increasing number of men are also endeavouring to maintain optimal skin health and prevent unwanted changes that can occur with intrinsic and extrinsic aging. Caring for the skin requires a basic understanding of its functions and the differences between genders, as well as variations among individuals. Although some skin care products can be effectively used by both men and women, awareness of gender-specific attributes are helpful for guiding aspects of skin care regimens and the choice of products, in order to improve outcomes. This article will focus on the unique facets of men’s skin physiology with particular emphasis on shaving and the treatment of pseudofolliculitis barbae.

Overview of Differences in Men

The skin provides the interface between the body’s internal and external environments. As the largest organ in the body, its complex functions include temperature regulation, biochemical and immune defence against microorganisms, buffering and protection of internal organs, as well as sensation (in relation to physical and social interactions). Among other factors, the skin of men and women differs as a consequence of hormonal influences. Herein, some male-specific physiologic features (Table 1) related to skin are described.

Hair:

Although hair does not perform a vital function, its importance in self-perception and social interactions is considerable. All hair follicles form before birth and later respond to hormonal influences.

• Hair distribution and characteristics differ between genders and are largely determined by a combination of genetic, cultural, interpersonal, and behavioural factors.
• During adolescence, under the influence of sex hormones (e.g., testosterone), vellus hairs of androgen-sensitive areas (facial, pubic, and axillary regions) mature to terminal hair follicles.
• In addition to stimulating hair growth, the rise in testosterone levels in males increases the size, growth rate, and pigmentation of hair. As such, men have more facial hair than women, making this attribute one of the most defining features of males.¹

Sebaceous glands:

Sebaceous glands (SGs) are associated with hair follicles throughout the body, with the face and scalp having the highest density. Oily secretions (sebum) from SGs are thought to influence stratum corneum hydration and lubrication, as well as provide protection from microorganisms.

• SGs are regulated by androgens, resulting in increased size and secretory activity.
• Typically, men produce more sebum than women, therefore, severe acne and subsequent potential sequela of acne scarring are more prevalent in men than in women.^1,2

Skin thickness:

Skin thickness reflects the composition of epidermis and dermis; collagen, ground substance, water, and elastic fibers contribute to skin thickness.

• At all ages, male skin is thicker than that of females in all anatomic areas, but onset of skin thinning can occur as early as 20 years of age.^1-3
• In contrast, women’s skin, although thinner, maintains its thickness until about the fourth or fifth decades
• of life.

Sweating:

Sweat, an odourless liquid, is produced by eccrine and apocrine glands. Eccrine glands are distributed throughout the body except at the mucous membranes. Apocrine glands are localized in the axillae, areolae, and in the perineal regions.

• Men have a higher sweat rate than women.¹
• In comparison with men, sweating is triggered at higher body temperatures before perspiration occurs in women.
• Consistently warm conditions, especially in the underarm regions, encourage bacterial growth that causes body odours. Particularly in males, increased hair density in these areas helps to control moisture. The regimented use of antiperspirants or deodorants can also assist in reducing and managing perspiration and/or odours.

Immunity:

Based on intricate processes, testosterone generally inhibits the immune system, whereas estrogen stimulates it.

• Men have a greater predisposition to bacterial and viral infections, and therefore, recovery from internal infections may present more challenges.^1,3

Wound healing:

Animal studies indicate that male rat fetuses experience slower rates of epidermal barrier formation in comparison with females. Improved cutaneous wound healing was observed when male mice were castrated, decreasing the influence of androgens.

• At all ages, men appear to have slower wound healing rates than women^1,3 and are at greater risk for dysregulated wound healing, which is particularly evident in the elderly population.

Skin cancer:

Men may have greater susceptibility to skin cancer. More specifically, squamous cell carcinoma and basal cell carcinoma are more commonly diagnosed in males.^1,3 In addition, men have higher mortality rates from melanoma, when compared with women.

• Behavioural aspects of men’s lives, as well as gender distinctions in immunity, may explain these differences.
• Consequently, the need for adequate sun protective strategies and annual skin check-ups should be reinforced across all at-risk patient populations.

Top

Shaving

Facial hair removal practices adopted by men and women can differ significantly. Women prefer manual razors, waxing, threading, electrolysis, or the use of depilatories; whereas men favour the use of manual or electric razors to manage facial hair growth.⁴ The shaving ritual is individualistic and focused on easing the associated discomfort. As such, the goal of shaving products should be to improve the process by increasing the closeness of the shave and avoid causing redness, dryness, and ingrown hairs. The optimal shave should be fast, comfortable (minimizing irritation, nick/cuts, and razor burns), effective (e.g., achieving desired results and restoring smoother skin post-shave with moisturizers), and safe (e.g., without aggravating or causing more skin problems, such as redness, infection, and ingrown hairs).

The key components of successful shaving include:

1. Pre-shave:

In this phase, the hair and skin need to be prepared for shaving. It is important to cleanse the face of pollutants, dirt, and contaminants by using lukewarm water and mild soap. This is followed by application of shaving lubricant (e.g., creams or gels). This step serves to moisten the skin and hairs, making them softer and easier to cut; a dry razor shave is difficult to achieve without aggravating the skin and causing razor burn. Although adequate hydration time allows for easy hair cutting, excess hydration can weaken the skin, making it more vulnerable to damage (i.e., insufficient hydration will leave hair too rigid and excessive hydration will leave skin too soft to withstand contact with the blade). Furthermore, shaving lubricants assist in reducing friction between the skin and the shaving blade, allowing for an easier glide of strokes. The shaving preparation should not aggravate the skin or cause undesirable effects, such as worsening of acne or induce an allergic reaction. Other properties, such as a mild anesthetic effect (minimizing pain and razor burn), scent, as well as texture, may enhance product appeal.

2. Shave:

The many different blade-shaving technologies include single- and multiple-blade systems, which are further diversified by manual or electric operation. The basic design premise of multi-blade systems is that it produces a smoother shave in fewer strokes. Less passes improves shaving efficiency and causes less trauma to softened skin. These devices should also allow for full facial as well as neck shaving, while maintaining flexibility in order to access hard-to-reach areas, such as the cleft chin, corners of the mouth, and the region under the nose. The blades should meet quality standards, as imperfections in the free edge can damage skin and even cause scarring. Disposable razors or blade cartridges should be frequently inspected and replaced regularly depending on frequency of use to minimize the chance for cuts, irritation, and infection.

3. Post-shave:

Once the actual shaving is completed, it is essential to restore hydration to just-shaved areas. During the shaving process, the outermost layer of the skin can be removed with the razor blade, resulting in decreased barrier function as well as micro-trauma to the skin, causing dryness and irritation. Moisturization and protection may be restored through the use of non-irritating, emollient enriched aftershave products that do not leave a greasy feel.

Pseudofolliculitis Barbae

Pseudofolliculitis barbae (PFB) (razor bumps) is a common chronic inflammatory, non-infectious condition affecting both men and women; a male preponderance is seen in individuals with coarse or curly hair who shave. PFB frequently results from the habitual removal of unwanted hair, which promotes hairs to enter the dermis or epidermis prior to exiting the follicular opening (trans-follicular penetration) or re-entering skin that is adjacent to the follicular opening (extra-follicular penetration).^5,6 The use of inappropriate shaving techniques or devices that tug and pull at the skin), such as a dry and/or close shave (e.g., when pulling the skin taut) can promote trans-follicular penetration. Dry shaves create sharper hair tips and when a close shave is achieved, hair retracts into the follicle, creating conditions for penetration of the follicular wall by the regrown hair. Adequate pre-shave preparation and post-shave use of hydrating emollients can contribute to skin barrier maintenance and reduce the incidence of PFB.

The treatment of PFB should be centered on several key aspects:

Education:

Patients need to be well informed as to the causes of PFB with respect to unwanted hair removal and shaving practices.

Treatment:

It is essential to minimize trans-follicular penetration and extra-follicular penetration. As such, the hair should be left extended slightly (0.5mm to 1mm) above the follicular opening. Initially, growing a full beard is advisable to decrease the acute inflammation that is present during the active phase of PFB. Subsequently, shave hairs with the aid of a spacer (protects up to 1mm of hair from being cut), then the use of chemical depilatories or laser hair removal may be advisable.^4,7

Goal:

Reinforce the message to patients that the benefits from following a balanced, healthy lifestyle outweigh the pursuit of managing physical imperfections.

Prognosis:

The desired improvement can only be achieved with persistence and focus on avoiding aggravating factors. Over time, repetitive skin trauma can cause papules and pustules to form, further progressing to keloid scars that appear as hard hyperpigmented bumps. The persistent pattern of hair removal practices, as well as patient dissatisfaction with their appearance, can lead to substantial psychosocial distress.

Conclusion

As more manufactures are responding to the growing demand for men’s skin care products and services, it is helpful for clinicians to be aware of the unique properties of male skin physiology, especially when patients seek advice prior to the implementation of therapeutic and cosmetic approaches. In particular, facial skin differs greatly between genders. In contemporary culture, shaving has evolved into a common, often necessary, ritual. With that in mind, acquiring a basic understanding of the complexities of men’s skin better positions physicians to encourage patients to adopt optimal grooming strategies for shaving and skin care in order to avoid inflicting skin damage that can cause other complications, such as pseudofolliculitis barbae, allergenicity, hyperpigmentation, or even permanent scarring.

References

1. Giacomoni PU, et al. Gender-linked differences in human skin. J Dermatol Sci 55(3):144-9 (2009 Sep).
2. Tur E. Physiology of the skin – differences between women and men. Dermatol Clin 15(1):5-16 (1997 Jan-Feb).
3. Dao H Jr, et al. Gender differences in skin: a review of the literature. Gend Med 4(4):308-28 (2007 Dec).
4. Klein AW, et al. Depilatory and shaving products. Clin Dermatol 6(3):68-70 (1988 Jul-Sep).
5. Halder RM. Pseudofolliculitis barbae and related disorders. Dermatol Clin 6(3):407-12 (1988 Jul).
6. Crutchfield III CE. The causes and treatment of pseudofolliculitis barbae. Cutis 61(6):351-6 (1998 Jun).
7. Bridgeman-Shah S. The medical and surgical therapy of pseudofolliculitis barbae. Dermatol Ther 17(2):158-63 (2004).

Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB
Western Canada Dermatology Institute, Surgical Unit, Edmonton, AB

Background

Cutaneous concerns continue to be a significant part of family and specialty practices, as increasingly, patients are seeking medical consultation for the management of photodamage, actinic keratoses, and nonmelanoma skin cancer (NMSC), which is now a global epidemic. The 2 most prevalent forms of NMSC are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).

• The earliest clinically recognizable manifestation of SCC is actinic keratosis (AK).
• The impact of skin malignancies is substantial. They commonly result in considerable deformities, either from the disease itself or from the results of selected therapies.
• The incidence of both AKs and SCC continues to rise.

Actinic Keratoses

• All AKs deserve our attention and treatment.
• They represent clinical evidence that patients have sustained sufficient UV damage to the epidermis to cause visually abnormal skin changes and alteration in the DNA structure.
• The risk of progression of AK to invasive SCC has been estimated to range from 0.025% to 16% per year.¹

Diagnosis

Actinic keratoses are skin neoplasms that reflect cumulative UV damage to the epidermis.

• Present as skin-colored, lightly pigmented, or erythematous scaly papules localized on chronically sun-exposed areas.
• Are generally
• Frequently, confirmation of diagnosis is achieved by palpation rather than visual examination alone.
• Predominantly found on skin areas receiving the highest levels of sun-exposure, such as the face, scalp, ears, neck, arms, and hands.
• Any lesion with induration or epidermal thickening should be biopsied.
• Risk factors for their development include blonde hair, blue eyes, fair complexion, an inability to tan, a history of long-term sun exposure, and immunosuppression, such as that seen in organ-transplant recipients.

Treatment

Successful treatment of AK rests on the:

• choice of appropriate modality
• medical status of the patient
• patient’s lesion count
• lesion characteristics (e.g., size, duration, and growth pattern)
• anatomic location.

Several treatment options are available for AKs, including local destruction and topical drug therapy.

Locally Destructive Measures

Locally destructive measures are specialized, office-based, physician-administered, and are well suited to treat:

• individual lesions (i.e., cryosurgery, curettage, electrosurgery, or excision).
• extensive diffuse disease (i.e., chemical peels, dermabrasion, or laser ablation).

Cryosurgery

• Considered the “gold standard” of locally destructive measures.
• Can be associated with patient discomfort.
• Can result in scar formation or dyschromia (abnormal skin color).
• Success rate is highly technique-dependent.

Topical Drug Therapy

Imiquimod

• The only topical immune response modifier approved by Health Canada and the US FDA for the topical treatment of AKs and superficial BCCs (sBCCs).
• Enhances both the innate and acquired immune responses by increasing regional antiviral, antitumor and immunoregulatory activities.
  • Stimulates cytokine production, especially interferon, which explains imiquimod’s success in the treatment of AKs and sBCCs.

5-fluorouracil (5-FU)

• 5-FU is one of the most commonly used topical treatments.
• It is a structural analog of the DNA precursor thymine.
• The majority of people being treated with 5-FU will have moderate-to-severe erythema.
• Works by inhibiting the enzyme thymidylate synthetase, and:
  • interferes with the DNA synthesis.
  • creates unbalanced growth and cell death.
  • has its greatest effect in more rapidly dividing cells.

Photodynamic Therapy

• Based on the activation of a photosensitizer by visible light.
• Creates cytotoxic oxygen species and free radicals, which selectively destroy rapidly proliferating cells.
• 5-aminolevulinic acid (5-ALA) is:
  • a topical form of a photosensitizer.
  • absorbed to a greater extent by rapidly proliferating cells than by normal cells.
  • converted to protoporphyrin IX (PpIX), which is a potent photosensitizer within the cell. Activation of PpIX by physician-administered visible light produces singlet oxygen and free radicals, which leads to cell destruction.

Combination Therapy

In clinical practice, physicians frequently combine physical/destructive modalities, such as liquid nitrogen cryotherapy, to deal with visible AKs and imiquimod to treat the underlying field cancerization. This combination of cryotherapy and topical immunomodifier brings together a targeted approach through the precise immune system destruction of subclinical AK lesions that likely offers enhanced AK clearance. A recent study reported²:

• • imiquimod or vehicle used twice weekly was applied for 8 weeks following 3- to 5-second cryotherapy of target AKs within 50cm2 fields on the face or scalp.
• • at 12 weeks, more subjects treated with imiquimod achieved clearance of subclinical and total AKs.

Head-to-Head European Study

A recent comparative study evaluated 5% imiquimod with cryotherapy and 5-FU for the treatment of patients with AKs.³ This pivotal study by Stockfleth and colleagues addressed several critical components in the therapeutic management of AKs:

• clinical observation
• histologic assessment
• cosmetic outcome
• sustained clearance.

Histologically confirmed AKs were treated as follows:

The assessment was performed after the treatments (Test of Cure [TOC] 6 weeks after cryotherapy, 4 weeks after 5-FU and 8 weeks after imiquimod therapies), and at 12 months following the end of treatment. Treatment dosages are based on levels approved by the European Medicines Agency.

• TOC clearance rate is similar between 5-FU and imiquimod.
• In terms of extended efficacy, imiquimod demonstrates significantly greater sustained clearance rates at 12 months.
• The cosmetic outcome at 12 months also favors the use of imiquimod.

The differences in the results may be explained by their mode of action.

• Cryotherapy indiscriminately destroys good and bad cells.
• 5-FU interferes with DNA synthesis (again, good and bad cells are affected).
• Imiquimod selectively stimulates the immune system to act against both subclinical and clinically visible abnormal cells.
• Targeted lesion treatment using cryotherapy in combination with field therapy with imiquimod may yield optimal rates of clearance.

Previous research initiatives lacked the thorough comparative approach taken by this evidence-based study in exploring these common AK treatments. The data presented confirms that treatment with a topical immunomodifier provided superior sustained clearance and cosmetic outcomes in comparison to other commonly used therapies. Furthermore, these new study findings suggest that imiquimod can be considered by physicians as one of the first therapeutic options in the treatment of actinic keratoses.

References

1. Glogau RG. J Am Acad Dermatol 42(1 Pt 2):23-4 (2000 Jan).
2. Tan JK, et al. J Cutan Med Surg 11(6):195-201 (2007 Nov-Dec).
3. Krawtchenko N, et al. Br J Dermatol 157(Suppl 2):34-40 (2007 Dec).

Department of Medicine, Division of Dermatology, University of Alberta, Edmonton, AB, Canada

ABSTRACT

Aesthetic volume rejuvenation with dermal fillers continues to be a very popular procedure that is sought by a growing number of patients who seek the rounder softer contours attributable to a more youthful appearance, including fuller curves of the cheeks, lips, and temples. Not only are fillers easier to use, but the outcomes that equal or exceed more invasive surgical options make volume restoration an increasingly popular procedure. Continued patient demand has fueled the introduction of a wider variety of injectable fillers, which include dermal and subdermal fillers with varying degrees of viscosity and duration of benefit. There are also several dermal implants that have stood the test of time or offer innovative technologies and approaches. This article will focus on the most popular, time tested, and innovative fillers available today.

Key Words:
Dermal fillers, facial rejuvenation, lip augmentation

The advances in medical care and improvements in patients’ quality of life have resulted in an increasing movement from practicing medicine for disease detection and treatment, to the prevention and alleviation of the inevitable signs of ageing. The youthful fullness and curves of the face are altered and reduced as we age. One of the features of the ageing face is the loss and redistribution of facial fat and collagen. These changes, in combination with static and dynamic facial rhytids, are largely responsible for the emergence and expansion of corrective surgery. There is a trend toward less invasive approaches. Different modalities are used to address each aspect of facial ageing. In most cases, these techniques work synergistically to deliver the desired results, and in that regard, facial volume augmentation can be considered as one of the most important components of a comprehensive facial rejuvenation program.

Recent advances in soft tissue augmentation materials, techniques, and approaches have greatly increased the therapeutic options available to our patients. With proper techniques and skills, these products can restore the facial youthfulness with relative ease and little or no downtime for patient recovery. The following discussion will focus on the most popular dermal and subdermal fillers that have stood the test of time, as well as those that offer innovative advances and approaches.

Autologous Fat

Autologous fat continues to be one of the more popular dermal fillers because it is fully biocompatible, allowing for transferability from one area of the body to another in the same patient. It is also biodegradable and plentiful. The degree of permanency of autologous fat in the recipient site varies depending on the technique used by the physician, as well as patient factors. Influencing factors such as smoking habits and anticoagulation (both exert a negative effect on fat graft survival), as well as physician care, and meticulous attention to detail (both can enhance the effect on fat graft survival) are important predictors of procedural and outcome success. With the abundance of supply, larger volumes can be injected/ transferred without significantly adding cost to the patient. The objective of the procedure is to produce a high rate of fat graft uptake by optimizing conditions for survivability of cells at recipient sites, such as the cheeks, lips, temples, as well as the back of the hands.

Recently, the technique for harvesting, processing/ preparation, and delivery of fat has been refined, and longterm corrective results have been documented.1 Having said that, it is important to note that the predictability of this procedure depends on many factors, making it challenging for novice practitioners to successfully achieve desired outcomes.

Collagen

Collagen is one of the most important components of the dermis, and so, quite naturally, was developed for cosmetic applications. Injectable bovine collagen was the first dermal filler to be granted US FDA clearance more than 25 years ago. There are several sources of injectable collagen available. (See Table 1)

Although skin testing is required for some of the earlier established bovine-derived products, the newer injectable collagens do not require skin allergy testing. The recently introduced porcine-derived Evolence™, with an innovative cross-linking technology, has been
shown to produce longer lasting results than Zyplast^® for the correction of nasolabial folds.2 Collagen-based products enjoy an impressive long-term safety profile and, as such, will remain one of the more popular choices for dermal augmentation.

Hyaluronic Acid

Hyaluronic acid (HA) is a naturally occurring linear polysaccharide that is a component of all connective tissues. Because of its uniform structure throughout all living species, adverse immune reactions are rare. HA has hydrophilic properties, allowing it to attract and attach to water molecules. There are several families of popular HA injectables. (See Table 2)

The duration of benefit following therapy with different HA fillers has not been rigorously studied. Although all products contain essentially the same HA molecule, the differences between the formulations relate to the quantity/ concentration of HA, the degree of crosslinking, and the amount of proteins incorporated, which affect flow characteristics and the target placement within the dermal-subcutaneous continuum.3,4 Recently, a new HA product has been approved by the US FDA for soft tissue augmentation, Elevess™ (Anika Therapeutics). This novel formulation includes a high concentration of HA combined with lidocaine, which can provide patients with a more comfortable procedural experience.

The versatility of HA products expands the physician’s options when selecting an implant for each unique application (dermal, subdermal, subcutaneous or supraperiosteal injections). This versatility, combined with the low risk of immune reactions, makes HA products the cornerstone of injectable fillers.

Calcium Hydroxylapatite

Calcium hydroxylapatite (CaHA), the major mineral constituent of bone, has been used for more than a decade in dentistry and reconstructive surgery. Its safety record in these disciplines is well established. Recently, a product containing microscopic CaHA particles suspended in a polysaccharide gel (Radiesse^®, BioForm Medical) has been successfully used for aesthetic soft tissue augmentation.5 When injected, the small particles of CaHA act as a scaffold for collagen to grow. Because there are no animal-based ingredients contained in the product, skin testing is not required. Over time, CaHA particles are slowly dissolved into calcium and phosphate ions through normal metabolic processes. Current studies indicate that some degree of correction persists for up to 18 months.6 It is important to note that CaHA is radio opaque and can be visible on regular X-Rays.

Poly-L-Lactic Acid

Poly-L-lactic acid (PLLA) (Sculptra™, Sanofi-Aventis) is not a classic filler, but rather, a stimulator. PLLA has been safely used for over 4 decades as suture material. It is a nontoxic, immunologically inactive, synthetic biodegradable lactic acid polymer. Unlike other products discussed in this review, Sculptra™ is reconstituted with sterile water prior to injection. The mixture is injected into the deep dermis or subcutaneous space with the tunneling or threading technique. It is important to distribute the product evenly to minimize the possibility of granuloma formations. Patients usually require three monthly treatments to achieve the desired results. With each treatment, there is stimulation of neocollagenesis secondary to small PLLA particles. It is important to note that the initial studies demonstrate an increase in skin thickness as early as 6 weeks after injection.7 The duration of the desired effects can last up to 96 weeks, making Sculptra™ a unique option to consider, as well as providing extended results for the patient.

Silicone

Silicone oil, derived from silica and composed of purified polydimethylsiloxane, has been used for facial augmentation and scar revision for decades. The recent introduction of Silikon^® 1000 (Alcon Laboratories) has revived the use of this controversial filler. A microdroplet technique is used to inject silicone into the dermalsubcutaneous junction. Overcorrection is avoided and repeat treatments at intervals of 4–6 weeks are advisable. Complications in the past, such as granulomas, were primarily due to large volume injections or adulteration of the silicone used. Because injected silicone provides permanency, it does not require skin testing and will not support bacterial growth. Its cost, relative to other available dermal fillers on the market, make it an attractive option, however, more research is needed to fully establish its place in the aesthetic arena.

Polymethylmethacrylate

Polymethylmethacrylate (PMMA) microspheres (Artecoll^®, Artefill^®, Artesense™, Artes Medical) is a permanent filler and stimulator of neo collagenesis, where the PMMA particles are suspended in a collagen vehicle. Following the injection, the collagen is quickly degraded, leaving the PMMA beads indefinitely; the subsequent collagen reaction around the particles creates volume. Unlike temporary fillers, the immediate filling effect disappears rather quickly and, over time, gradual, but long-lasting correction is established. Although granulomas have been reported, with the use of proper technique (injection at the dermal subcutaneous junction using threading or tunneling methods) and applying a series of injections at appropriate sites, PMMA fillers can provide excellent long-term correction.8

Adverse Effects

Complications arising from soft tissue augmentation can be attributed to several factors: the patient, the physician, and product characteristics.9 Patient suitability and appropriate product selection are paramount in obtaining the desired results. However, even if these criteria are satisfied, complications can arise.

The most common early side-effects include bleeding (bruising and hematomas), pain, swelling, and erythema. To reduce the incidence and the severity of these complications, any substance that can impede blood clotting (e.g., acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, and excessive alcohol consumption) should be discontinued for an appropriate length of time prior to receiving treatment unless otherwise recommended by a physician. In addition, appropriate topical, as well as local/ regional anesthesia, and cold compresses can be used to relieve mild symptoms. Rare complications, such as skin necrosis and blindness, require rapid diagnosis and immediate intervention. Delayed complications include chronic inflammation, late allergic reactions, nodules, granulomas, discoloration, migration, and hypertrophic scarring. Although some of these adverse reactions cannot be predicted, early detection and initiation of appropriate therapy can help to minimize patient discomfort, severity of side-effects, and prevent the onset of sequelae.

Conclusion

The ever-expanding array of products for soft tissue augmentation is of real benefit for patients and physicians. From the patients’ perspective, expectation of results, safety, and product durability are of primary concern. Physicians, on the other hand, can combine their knowledge of the anatomy and the ageing process to assess patient suitability, and determine the choice of product that will ultimately provide the results that each individual patient expects and deserves. As always, safety is of paramount importance, especially when physicians are dealing with the vulnerabilities of their patients.

References

1. Butterwick KJ, Nootheti PK, Hsu JW, et al. Autologous fat transfer: an in-depth look at varying concepts and techniques. Facial Plast Surg Clin North Am 15(1):99-111 (2007 Feb).
2. Monstrey SJ, Pitaru S, Hamdi M, et al. A two-stage phase I trial of Evolence30 collagen for soft-tissue contour correction. Plast Reconstr Surg 120(1):303-11 (2007 Jul).
3. Lupo MP. Hyaluronic acid fillers in facial rejuvenation. Semin Cutan Med Surg 25(3):122-6 (2006 Sep).
4. Lowe NJ, Grover R. Injectable hyaluronic acid implant for malar and mental enhancement. Dermatol Surg 32(7):881-5 (2006 Jul).
5. Alam M, Yoo SS. Technique for calcium hydroxylapatite injection for correction of nasolabial fold depressions. J Am Acad Dermatol 56(2):285-9 (2007 Feb).
6. Silvers SL, Eviatar JA, Echavez MI, et al. Prospective, open-label, 18-month trial of calcium hydroxylapatite (Radiesse^®) for facial soft-tissue augmentation in patients with human immunodeficiency virus-associated lipoatrophy: one-year durability. Plast Reconstr Surg 118(3 Suppl):34S-45S (2006 Sep).

Department of Medicine, Division of Dermatology, University of Alberta, Edmonton, Alberta, Canada

ABSTRACT

Skin cancer, the most common human cancer, is now a global epidemic. The most prevalent form of nonmelanoma skin cancer is basal cell carcinoma (BCC), the incidence of which continues to increase prompting development of new treatment modalities designed to add or complement current therapies. Although destructive modalities continue to be an important treatment options for BCC, nondestructive measures are a welcome addition to our therapeutic choices. Imiquimod, a topical immune response modifier, belongs to the family of immunostimulators. It enhances both the innate and acquired immune response, and has successfully treated both superficial and nodular basal cell carcinomas through the localized activation of elaborate immune response. Imiquimod can either be used alone or in combination with other treatment modalities. The most common adverse effects of topical use of imiquimod are localized to the site of application and easily managed.

Key Words: imiquimod, basal cell carcinoma, therapy, skin

Skin cancer is the most common human cancer, and nonmelanoma skin cancer (NMSC) is now a global epidemic. BCC accounts for approximately 80% of new cases with superficial (sBCC) and nodular (nBCC) BCCs representing the majority of cases reported. The impact of cutaneous malignancies is significant, since they frequently lead to considerable deformities, either from the disease itself or from the resulting therapy. BCCs can destroy tissue through their relentless local growth. New, less invasive, nonsurgical therapies are welcomed as they may offer treatment without the use of destructive modalities.

The immune system plays an important role in the pathogenesis of NMSC. Immunosuppressed patients, such as organ-transplant recipients, have a greater incidence of BCCs. Regressing BCCs are frequently infiltrated with activated T lymphocytes and cytokines including interferon (IFN)-g, interleukin (IL)-2, and tumor necrosis factor (TNF)-b. Intralesional IFN has been demonstrated to successfully treat BCCs.1

Imiquimod (Aldara™, 3M), a topical immune response modifier, enhances both the innate and acquired immune responses, in particular, the cell-mediated immune pathways,2 and has therefore been studied for the treatment of BCCs.

Mechanism of Action

Imiquimod is a toll-like receptor-7 agonist enhancing both the innate and acquired immune response.3 It activates the production of numerous compounds, including IFN-a, IL-1, -6, -8, -10, -12, and TNF-a, stimulates natural killer cells and the proliferation of B-cells. It also activates Langerhans cells, the key antigen-presenting cell in the skin, and promotes their migration to the regional lymph nodes. Imiquimod stimulates TH-1 cells to produce IFN-g, which in turn can activate cytotoxic T lymphocytes. These cells provide long-term immune memory, which can offer future protection against the previously encountered virus or tumor. In animal models, imiquimod use can establish long-term immunity against viruses and certain tumors.4

Recently, imiquimod has been shown to promote the expression of cellular receptors that are associated with apoptosis.5,6 There is mounting evidence that imiquimod antitumor activity in vivo stems from the effect it has on the innate and cell-mediated immune response, including cell surface markers.

Pharmacokinetics

Imiquimod is applied topically to the affected areas and its clinical effects are primarily localized to the skin. It has minimal percutaneous absorption in healthy skin, the skin of genital warts, and in sun damaged skin. When imiquimod was applied 3 times per week for 16 weeks in 58 patients with actinic keratoses (AKs), the mean peak serum levels at the end of week-16 were very low, measuring approximately 0.1-3.5ng/ml depending whether one packet (12.5mg) was used or up to six packets (75mg) were used. The half-life of topically applied imiquimod is approximately 26 hours with urinary recovery of less then 0.6%.

Clinical Trials

The most common indications for the topical use of imiquimod are the treatment of external anogenital warts, AKs, and sBCCs. In this review, we will concentrate on the evidence for BCC therapy.

In one of the first studies, Beutner and colleagues evaluated the response of BCCs (87% of treated sites were sBCCs) to the topical application of imiquimod.7 The best response (100% histologic clearance) was seen in the b.i.d., q.d. and 3x/week groups. In the first multicenter, randomized, open-label, dose-response trial, 99 patients were randomized to apply imiquimod b.i.d. every day, q.d., b.i.d. 3 times per week, or just once per day, 3x/week for 6 weeks. In an intent-to-treat analysis, the histologic clearance rates were highest in the b.i.d. every day regimen (100%) and lower in the 3x/week regimen (69.7%).8 In a second multicenter, prospective, randomized double-blind, vehicle-controlled study, 128 patients with sBCC were randomized to 12 weeks of imiquimod b.i.d., q.d., 5x/week and 3x/week. Once again, the complete clearance rates varied based on the frequency of drug application from 100% in the b.i.d. group to 51.7 % in the 3x/week group.9

The treatment of nBCC using imiquimod was also assessed with or without occlusion using 6- and 12-week protocols.10,11 Once daily dosing produced the highest clearance rates with 71% and 76% of cancers showing clearance in the 6- and 12-week studies, respectively. Occlusion did not have a clinically significant effect on the treatment of either sBCC or nBCC. The data suggested that a 6-week treatment protocol would be as effective as a 12-week long regimen.

Table 1: Summary of the key published studies assessing efficacy of topical imiquimod in the treatment of basal cell carcinomas.
Abbreviation: Rand – randomized, DB – double-blind, VC – vehicle controlled, OL – open-label, b.i.d. – twice per day, q.d. – once per day, occl – under occlusion

In the two recent double-blind, vehicle-controlled clinical studies, 364 patients with primary sBCCs were treated with imiquimod or vehicle 5 or 7x/week for 6 weeks.12 Twelve weeks following the treatment, histologic clearance rates were 82% and 79% for the 5 and 7x/week groups, respectively. Since the response rates were similar in both groups and the frequency of adverse effects was lower in the 5x/week protocol, the authors recommended that patients with sBCC be treated 5x/week for 6 weeks.
Imiquimod can also be used in combination with other treatment modalities. In particular, it has been studied as an adjunct modality with Mohs surgery,13 electrodesiccation & curettage as well as curettage alone.14

Treating BCC with imiquimod prior to Mohs surgery reduces the size of the tumor and results in a smaller surgical defect. The use of curettage, one of the most common physical treatment modalities, and imiquimod (an immunological agent) allows for the ability to manually debulk the cancer and to ascertain its extent in addition to allowing subsequent application of the topical immune response modifier.

Dosage

The recommended dosing frequency for the treatment of sBCC is 5x/week for 6 weeks prior to normal sleeping hours. In addition to the tumor itself, a 1cm area of normal skin around the tumor needs to be treated. This allows for application to the site of subclinical tumor extensions. When imiquimod is used in combination with curettage, it can be started 1-week postcurettage up to 5x/week and continued for up to 6 weeks. Rest periods can be used as required to manage local skin reactions.

Adverse Effects

Application site reactions, which were the most common adverse effects, were seen in up to 87% of patients treated for sBCCs with imiquimod applied 5x/week for 6 weeks. The most common application site reactions were erythema, edema, induration, erosion, scaling, crusting, pruritus and burning sensations.
Only 2% of patients discontinued the treatment due to the local skin reactions. Some patients may require a rest period if the local reaction severity warrants temporary cessation of treatment. From the clinical point of view, it appears that a patient’s local reaction correlates with the treatment success rate. The incidence of distant reactions, i.e., at sites other than the site of application, is low. Distant reactions include erythema, fatigue, myalgia, arthralgia as well as lymphadenopathy.

Conclusion

Topical, non-invasive, patient-administered modalities continue to expand our options for treating a variety of skin conditions including skin cancers. Less patient discomfort, favorable cosmetic outcome and documented efficacy against BCCs make imiquimod an attractive treatment choice. In addition, patients who are poor surgical candidates (i.e., patients who are elderly, anticoagulated or who have implanted cardiac pacemakers) would benefit from this non-invasive, self-administered topical therapy.
Its usefulness as an adjunct to surgical modalities, such as curettage or surgical excision, allows us to combine immunological- based treatment with surgical intervention.

Imiquimod stimulates innate and cell-mediated immune pathways, which are critical components of the body’s defence mechanisms against both viruses and tumors. The clinical potential of this new family of compounds is growing. What started as a treatment for external anogenital warts has already evolved into an excellent treatment choice for selected skin malignancies.

References

1. Greenway HT, Cornell RC, Tanner DJ, Peets E, Bordin GM, Nagi C. Treatment of basal cell carcinoma with intralesional interferon. J Am Acad Dermatol 15(3):437-43 (1986 Sep).
2. Miller RL, Gerster JF, Owens ML, Slade HB, Tomai MA. Imiquimod applied topically: a novel immune response modifier and new class of drug. Int J Immunopharmacol 21(1):1-14 (1999 Jan).
3. Gibson S, Lind J, Riter T, et al. Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. Cellular Immunol 218(1-2):74-86 (2002 Jul-Aug).
4. Harison CJ, Miller RL, Bernstein DI. Post therapy suppression of genital simplex virus (HSV) recurrences and enhancement of HSV-specific T-cell memory by imiquimod in guinea pigs. Antimicrob Agents Chemo 38(9):2059-64 (1994 Sep).
5. Meyer T, Nindl I, Schmook T, Ulrich C, Sterry W, Stockfleth E. Induction of apoptosis by toll-like receptor-7 agonist in tissue cultures. Br J Dermatol 149(Suppl 66):9-14 (2003 Nov).
6. Sullivan TP, Dearaujo T, Vincek V, Berman B. Evaluation of superficial basal cell carcinomas after treatment with imiquimod 5% cream or vehicle for apoptosis and lymphocyte phenotyping. Dermatol Surg 29(12):1181-6 (2003 Dec).
7. Beutner KR, Geisse JK, Helman D, Fox TL, Ginkel A, Owens ML. Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 41(6):1002-7 (1999 Dec).
8. Marks R, Gebauer K, Shumack S, et al. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol 44(5):807-13 (2001 May).
9. Geisse JK, Rich P, Pandya A, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol 47(3):390-8 (2002 Sep).
10. Shumack S, Robinson J, Kossard S, et al. Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma. Arch Dermatol 138(9):1165-71 (2002 Sep).
11. Sterry W, Ruzicka T, Herrera E, et al. Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. Br J Dermatol 147(6):1227-36 (2002 Dec).
12. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 50(5):722-33 (2004 May).
13. Torres A, Niemeyer A, Berkes B, et al. 5% imiquimod cream and reflectance-mode confocal microscopy as adjunct modalities to Mohs micrographic surgery for treatment of basal cell carcinoma. Dermatol Surg 30(12 Pt 1):1462-9 (2004 Dec).
14. Sapijaszko MJA. Curettage and topical imiquimod 5% cream for the treatment of nodular basal cell carcinomas – A new approach combining physical and immunological modalities. At: 13th Congress of the European Academy of Dermatology and Venereology (2004), Florence, Italy.