A joint project of the American Academy of Dermatology Association (AAD) and the Society for Investigative Dermatology (SID) reported that in 2004 the prevalence of AKs in the United States was 39.5 million, the estimated annual costs were $1.04 million, and that AKs accounted for more than 10% of all dermatology visits.12 AKs are second only to acne vulgaris as the most common reason for patients to visit a dermatologist and it is estimated that almost all persons over the age of 80 have AKs.13
Various risk factors have been identified for the expression of AKs. The two major ones are individual susceptibility and cumulative UV radiation exposure (Table 113-2). One of the most important susceptibility risk factors is age, because all the epidemiologic studies indicate that AKs increase in prevalence with increasing age, with rates ranging from less than 10% in white adults aged 20–29 years to 80% in white adults aged 60–69 years. Males appear to have more AKs than females in most epidemiologic studies, which presumably reflects greater cumulative sun exposure in males than in females.14 This gender differential is more pronounced at younger ages. Other individual susceptibility risk factors include a phenotype of fair skin that easily burns and freckles, and rarely tans; blue or light-colored eyes; and red or blond hair.14 Another individual risk factor is immunosuppression, because it is known that organ transplant recipients and patients receiving certain chemotherapy agents and possibly even biologic therapies are at increased risk of developing AKs and SCCs.15–18 In addition, persons with certain genetic syndromes, namely, albinism and xeroderma pigmentosum, and possibly Rothmund–Thomson and Bloom syndromes, are at greater risk of developing AKs.
Table 113-2 Risk Factors for Development of Actinic Keratoses ||Download (.pdf)
Table 113-2 Risk Factors for Development of Actinic Keratoses
• Individual susceptibility
• Older age
• Male gender
• Fair skin that easily burns and freckles
• Blond or red hair
• Light-colored eyes
• Cumulative ultraviolet radiation exposure
• Prior history of actinic keratoses or other skin cancers
• Genetic syndromes
• Xeroderma pigmentosum
• Bloom syndrome
• Rothmund–Thomson syndrome
Cumulative exposure to UV radiation, including tanning beds, is the other major risk factor for developing AKs. Evidence that sun exposure plays a role in the development of AKs is the fact that over 80% of all AKs are distributed on habitually sun-exposed areas of the body, such as the scalp, head, neck, forearms, and dorsal hands.14 Variables that affect a person's cumulative UV radiation exposure include age, gender, occupation, recreational activities, and place of residence. As previously stated, the older the individual, the greater the prevalence of AKs and, intuitively, the greater the cumulative exposure to UV radiation. The age at which a person received the greatest amount and intensity of exposure to UV radiation appears to be significant, with such exposure in childhood apparently posing the greatest risk. In migration studies in Australia, British immigrants who moved to Australia before the age of 20 had fewer AKs than the native white Australians early in life, but they had the same rate of AKs as the native Australians in later years. British immigrants who moved to Australia after the age of 20 years never showed the same rate of AKs as the native Australians or the British immigrants who arrived at a young age.19
The typical patient with AKs is an older, fair-skinned, light-eyed individual who has a history of significant sun exposure, who burns and freckles rather than tans, and who has significant solar elastosis on examination (Fig. 113-2). AKs can be seen in younger individuals if these individuals have sustained sufficient sun exposure over their lives. Eighty percent of AKs are found on habitually sun-exposed sites of the body, such as the head, neck, forearms, and dorsal hands. Common signs and symptoms include pruritus, burning or stinging pain, bleeding, and crusting. The typical AK lesion, sometimes called the erythematous AK, presents most commonly as a 2–6-mm erythematous, flat, rough, gritty or scaly papule. It is usually more easily felt than seen. AKs can vary in size and sometimes reach to several centimeters in diameter. They are most often found against a background of photodamaged skin or dermatoheliosis, with solar elastosis, dyspigmentation, yellow discoloration, ephelides and lentigos, telangiectases, and sagging skin notably prominent. At times, the number and confluence of AKs are so great that the patient appears to have a rash.
Severe solar damage of the face revealing telangiectases as well as actinic keratoses at different stages of development, including the flat, pink macules and hyperkeratotic papules.
In addition to the typical erythematous AK, there are several other clinical subtypes (Table 113-3). The hypertrophic AK (HAK) presents as a thicker, scaly, rough papule or plaque that is skin-colored, gray–white, or erythematous (Fig. 113-3A). It can be found on any habitually sun-exposed site on the body but has a propensity for the dorsal hands, arms, and scalp. A typical erythematous AK can progress into an HAK. It can be difficult to distinguish an HAK from an SCC, clinically necessitating a biopsy. Biopsies must be taken to a level deep enough to ensure that the dermal extent of the keratinocytic proliferation can be evaluated in order to obtain an unequivocal histopathologic diagnosis. Induration or thickness, pain, and ulceration are the main clues to the transition of AK to SCC.
Table 113-3 Clinical and Histopathologic Variants of Actinic Keratoses ||Download (.pdf)
Table 113-3 Clinical and Histopathologic Variants of Actinic Keratoses
Clinical Variants of Actinic Keratoses
• Erythematous actinic keratosis
• Inflamed actinic keratosis
• Hypertrophic actinic keratosis
• Cutaneous horn
• Actinic cheilitis
• Pigmented actinic keratosis
• Spreading pigmented actinic keratosis
• Proliferative actinic keratosis
• Conjunctival actinic keratosis
Histopathologic Variants of Actinic Keratoses
• Inflamed actinic keratosis
• Hypertrophic actinic keratosis
• Cutaneous horn
• Atrophic actinic keratosis
• Bowenoid actinic keratosis
• Pigmented actinic keratosis
• Proliferative actinic keratosis
• Lichenoid actinic keratosis
• Acantholytic actinic keratosis
• Clear cell actinic keratosis
A. Severe solar damage of the dorsal arm demonstrating hypertrophic actinic keratoses (AKs) and AKs. B. Histopathologic preparation of actinic keratosis demonstrates atypical cells along the basal layer with sparing of adnexal epithelium.
Cutaneous horn, also known as cornu cutaneum, refers to a reaction pattern and not a particular lesion (Fig. 113-4). In reference to AKs, a cutaneous horn is a type of HAK that presents with a conical hypertrophic protuberance emanating from a skin-colored to erythematous papular base. Classical definitions of a cutaneous horn maintain that the height is at least one-half of the largest diameter. Thirty-eight percent to 40% of all cutaneous horns represent AKs.21 The pathology underlying a cutaneous horn can be a number of different lesions, such as AK, SCC, seborrheic keratosis, filiform verruca vulgaris, trichilemmoma, or keratoacanthoma. The most common underlying lesion in elderly, fair-skinned persons is an HAK.
A. Cutaneous horn of the ear. Only biopsy will confirm whether this is an actinic keratosis or a squamous cell carcinoma. B. Cutaneous horn of the cheek.
Actinic cheilitis represents confluent AKs on the lips, most often the lower lip (Fig. 113-5). Persons with this condition have red, scaly, chapped lips, and at times erosions or fissures may be present. The vermillion border of the lip is often indistinct, and focal hyperkeratosis and leukoplakia may also be seen. Individuals with this condition often complain of persistent dryness and cracking of the lips, and the diagnosis of actinic cheilitis should always be suspected in photodamaged patients with such complaints. Persistent ulcerations or indurated areas on the lip require biopsy to ensure that SCC is not present.
Actinic cheilitis of the lower lip in a young man with a marine occupation. The patient is at risk for developing squamous cell carcinoma of the lip. Preventative treatment of the actinic cheilitis can include laser, cryosurgery, and topical treatment.
The typical erythematous AK has characteristic architectural and cytologic histopathologic features. All of the abnormalities are confined to the epidermis, although dermal solar elastosis is usually present and an inflammatory dermal infiltrate may also be seen. The classic histopathologic findings include foci of atypical, pleomorphic keratinocytes along the basal cell layer and protruding as buds into the papillary dermis. The basal cell layer appears more basophilic because of crowding of the atypical keratinocytes. Overlying these foci of abnormal cells, one often sees irregular acanthosis, hyperkeratosis, and parakeratosis. There is notable sparing of the adnexal epithelium, with orthokeratosis overlying these structures, which gives rise to the characteristic pattern of alternating orthokeratosis and parakeratosis (see Fig. 113-3B
). Cytologically, there is an increased nuclear–cytoplasmic ratio in the atypical keratinocytes in addition to nuclear pleomorphism and mitoses.
Just as there are clinical variants of AKs, there are histopathologic variants. These histopathologic variants all share the classic features of the AK as described earlier, but with some additional findings. In HAK, the hypertrophic areas consist of marked hyperkeratosis and parakeratosis. A cutaneous horn that represents AK demonstrates changes similar to but more exaggerated than those in HAKs with massive tiers of hyperkeratosis and parakeratosis. The base of such a cutaneous horn shows the typical histopathologic changes of an AK. An atrophic AK has very mild hyperkeratosis and a thinned epidermis that is devoid of rete ridges. Bowenoid AK is a histopathologic variant that demonstrates near full-thickness epidermal dysplasia, but unlike true Bowen disease (BD) or SCC in situ, there is no or very little involvement of the adnexal epithelium. In proliferative AK there are exaggerated bud-like downgrowth of atypical keratinocytes into the papillary dermis. Although difficult to distinguish from SCC at times, these proliferative bud-like downgrowth are contiguous with the epidermis in the proliferative AK, unlike in true SCC.
In the pigmented AK one sees excessive amounts of melanin, especially in the basal cell layer. In the spreading pigmented AK variant, in addition to the typical AK histopathologic findings, one may see increased melanin in melanocytes and in the atypical keratinocytes. Lichenoid AKs are characterized by a dense, band-like lymphohistiocytic infiltrate at the dermal–epidermal junction with basal cell liquefactive degeneration and occasional Civatte bodies. In the acantholytic AK variant there are clefts of lacunae directly above the atypical keratinocytes with discohesive individual atypical keratinocytes within the clefts, reminiscent of the changes seen in Darier's disease. The acantholysis in an acantholytic AK is a result of the anaplastic changes occurring in the lower epidermis and loss of normal keratinocytic attachments. The clear cell variant of AK arises from an excess of cytoplasmic glycogen, which results histopathologically in marked vacuolation of the epidermis.
Two different histopathologic reaction patterns may be seen in AKs: namely, epidermolytic hyperkeratosis (EHK) and the pattern known as intraepidermal epithelioma of Borst-Jadassohn
. In an otherwise histopathologically classic AK, one may find incidental changes consistent with EHK. The findings of EHK in these AKs most commonly are focal and isolated and have no clinical importance. Some authors consider intraepidermal epithelioma of Borst-Jadassohn to be a specific lesion,23
but other authors24
believe that this entity actually represents a type of reaction pattern found in a variety of lesions, such as AK, pagetoid BD, clonal seborrheic keratosis, intraepidermal malignant eccrine poroma, mammary and extramammary Paget's disease, intraepidermal junctional nevus, and melanoma in situ. The pattern so named is that of an intraepidermal neoplasm characterized by nests and individual cells proliferating or scattered within normal epidermis. In so-called pagetoid AK
, there are adjacent typical changes of AK, although differentiating this entity from pagetoid BD is often quite difficult.
An important point to remember in making the diagnosis of AK histopathologically is that if the physician has a strong clinical suspicion of SCC or basal cell carcinoma (BCC) and the initial cuts reveal AK, it is prudent to section more deeply into the block of tissue to ensure that an SCC or BCC is not missed. In one study additional diagnostic findings were present on step sections in 23 of 69 specimens (33%) initially diagnosed histopathologically as AK. Of these additional findings, 13% were indicative of BD, 4% of BCC, and 3% of invasive SCC. Three variables that correlated with the discovery of malignancy on step sections were ulceration on the first level, a clinical diagnosis of skin cancer, and a history of skin cancer confirmed previously by biopsy examination.25
Because of the intimate association between AK and SCC, a number of dermatopathologists have proposed a more descriptive diagnosis that would more accurately reflect the nature of this disease. Cockerell has argued that because this entity is closely akin to cervical intraepithelial neoplasia (CIN), terms such as solar keratotic intraepidermal SCC
or keratinocytic intraepidermal neoplasia
would better define AK.1,8
has argued that solar keratosis is in fact SCC and should not be distinguished histopathologically. At this time, actinic keratosis
and solar keratosis
are the most recognized terms for this diagnosis, and most authors consider these lesions precursors of SCC rather than the malignant entity itself.
Diagnosis and Differential Diagnosis
The diagnosis of AK is accurately made by clinical examination in most instances when the examiner is familiar with AK and skilled in making such diagnoses. However, some investigators have commented on the difficulty of accurate and consistent counting of AK lesions by experts involved in AK research studies.27
In practice, very few AKs are histopathologically confirmed, and thus few data exist on the accuracy of clinical diagnosis. The accuracy of clinical diagnosis is higher in a clinical referral setting than in the general community setting. One study involving a referral setting revealed a diagnostic accuracy of 94%, based upon the correct histopathologic diagnosis of 34 of 36 clinically suspect, typical AKs.28
Another study in a community-based setting reported a diagnostic accuracy of approximately 80% when random clinically diagnosed AKs were subject to histopathologic confirmation.29
In the more recent multicenter Veterans Affairs Topical Tretinoin
Chemoprevention Trial (VATTC), researchers found that the greatest disagreements in the histopathologic diagnosis of BCC and SCC (keratinocytic carcinomas) between two referral dermatopathologists were in making the diagnoses of AK and invasive SCC.30
The clinical features of typical erythematous AKs are not unique to these lesions. The differential diagnosis includes other common lesions as noted in eBox 113-0.1
. Of the clinical AK variants, pigmented AK is difficult to distinguish from solar lentigo and sometimes lentigo maligna; spreading pigmented AK, from lentigo maligna or a large seborrheic keratosis; HAK, from SCC; and cutaneous horn, from the many entities it may represent.
eBox 113-0.1 Clinical Differential Diagnosis of Actinic Keratosis ||Download (.pdf)
eBox 113-0.1 Clinical Differential Diagnosis of Actinic Keratosis
- Erythematous actinic keratosis
- Benign lichenoid keratosis
- Irritated seborrheic keratosis
- Seborrheic dermatitis
- Hypertrophic actinic keratosis
- Verruca vulgaris
- Squamous cell carcinoma
- Discoid lupus erythematosus
- Cutaneous horn
- Seborrheic keratosis
- Verruca vulgaris
- Squamous cell carcinoma
- Pigmented actinic keratosis
- Solar lentigo
- Flat seborrheic keratosis
- Lentigo maligna
- Spreading pigmented actinic keratosis
- Large seborrheic keratosis
- Lentigo maligna
- Actinic cheilitis
- Dry, chapped lips
- Lichen planus
- Other variants of cheilitis
Always Rule Out
- Inflamed actinic keratosis
- Bowen disease
- Squamous cell carcinoma
- Basal cell carcinoma
- Hypertrophic actinic keratosis or cutaneous horn
- Squamous cell carcinoma
- Pigmented or spreading pigmented actinic keratosis
Clinically, the greatest challenge is to distinguish an AK from an SCC, because the latter portends a more serious prognosis and requires different treatment. There are no reliable clinical criteria for distinguishing between these two entities, but findings of induration, pain, larger size, marked hyperkeratosis, ulceration, bleeding, rapid growth, and recurrence or persistence after treatment make the diagnosis of SCC more likely.
Histopathologically, AK can be confused with benign lichenoid keratosis (BLK) or lichen planus-like keratosis (LPLK), because both can show vacuolar alteration of the basal cell layer and lichenoid infiltrates. However, closer inspection reveals that in BLK/LPLK there is no cellular atypia of the keratinocytes as is seen in AK, and often the remnants of solar lentigo are seen at the periphery of the lichenoid infiltrate. An atrophic AK can be mistaken for cutaneous lupus erythematosus, because both can demonstrate epidermal thinning and basal cell liquefaction. In cutaneous lupus, however, other classic features of the disease should also be present, such as follicular plugging and a patchy periappendageal infiltrate. Finally, pigmented AK may be confused histopathologically with lentigo maligna, but the latter usually has more flattening of the epidermis, an increased number of single and nested melanocytes, atypical melanocytes, and normal keratinocytes.
Prognosis and Clinical Course
The prognosis of AK includes persistence, regression, or malignant transformation into invasive SCC. The relative risk of progression to SCC depends on factors related to the AK itself, such as the length of time an AK has been present and the number of baseline AKs that are on the skin. In addition, the risk for SCC increases with increased UV radiation exposure and with certain individual patient characteristics, such as suppressed immune status. Berhane et al observed that before an AK progresses to SCC it may become clinically tender and inflamed. Histopathologic examination of such clinically inflamed AKs revealed the actual presence of overt SCC in 50%.31 Thus, pain and inflammation in an AK may be a marker of progression to SCC.
Several studies have attempted to determine the risk for the progression of AK to SCC, but most of them are inadequate in one respect or another. The risk for progression of AK to SCC reported in the literature varies from less than 1%32 to 20%.33 In a review of five clinical research studies carried out between 1988 and 1998, Glogau found that the published risk of progression of AK to SCC for individual lesions ranged from 0.025% to 16% per year.34 Extrapolation from these clinical studies suggests a rate of risk of progression of AK to SCC of approximately 8%, computed as an average of the cited statistical rates.34 A more recent study by Criscione et al found that the risk of progression of AK to primary SCC (invasive or in situ) was 0.60% at 1 year and 2.57% at 4 years.35 The risk of malignant transformation can also be assessed by evaluating the percentage of SCCs that arise from preexisting AKs. Several older studies have approached this issue by histopathologically examining invasive SCC specimens and determining the percentage of cases in which an associated or contiguous AK could be identified. An associated AK was identified at the periphery or within the SCC in 60%,32 82.4%,36 97%,37 97.2%,38 and 100%39 of reviewed cases in various studies. There has been one prospective study in which all SCCs treated by the authors in one calendar year were evaluated histopathologically to see if an AK was present in the specimen. They found a contiguous AK within a histopathologically confirmed SCC in 72% of cases.40 The most recent 2009 VATTC trial by Criscione et al showed that the majority of primary SCCs (65%) and, interestingly, 36% of all primary BCCs arose within a previously clinically diagnosed AK.35 Their findings that a sizeable number of initially clinically identified AKs were later determined to be BCCs at follow-up translated into a risk of progression of 0.48% at 1 year and 1.56% at 4 years. The authors commented that it was not clear if the initially identified AKs developed into BCCs, a phenomenon that has never before been reported, or if the BCCs were previously misidentified as AKs. We have to assume the latter, as BCCs originate from the follicular germ cells and are distinct from AK/SCC.41
Their conclusion, however, was that there was an almost linear increased risk of clinically diagnosed AKs progressing to either SCC or BCC at 4 years, demonstrating that AKs have a significant role in the overall burden of keratinocyte carcinomas and are an important marker for the development of NMSC.35
Spontaneous regression of AKs has been reported, but it is impossible to predict for any particular AK lesion.35,42,43 One study reported that up to 25% of AKs remitted over a 1-year period, especially if sun exposure was limited during that time.44 Another study found that more AKs regressed in individuals who routinely wore sunscreen.29 The 2009 VATTC study reported that 55% and 70% of AKs followed clinically were not present at 1-year and 5-year follow-up points, respectively.35 However, the authors noted that most importantly the vast majority (87%) of AK lesions identified at the 1- and 5-year visits were not clinically identified during at least one of the 6-month intervals, suggesting that AKs come and go.35
The presence of AKs indicates long-term sun damage and identifies a group of people who are at high risk for developing SCC, BCC, and, to a lesser extent, melanoma.9–11
The estimated rates of metastases arising from actinically derived SCC have ranged from 1% to 2% to over 20% depending primarily on depth of invasion, location (with the lip, ear, and scalp representing the sites of highest risk), differentiation, and the presence of perineural invasion.45
The inability to predict which AKs will persist, regress, or become SCCs makes treatment of these lesions equally confusing. Although some clinicians have argued that because of the low malignant transformation risk, treatment of AKs is unnecessary, most dermatologists advocate the treatment of AKs to avoid any chance of progression to invasive SCC.46,47 The 2009 VATTC trial researchers concluded from their findings that despite the possibility of AK regression, new AKs and keratinocyte carcinomas can develop and that active treatment of AK lesions is warranted, especially given the overall contribution of AKs to SCC and BCC burden.35 Treatment of this disease is also warranted to minimize symptoms, such as pain and pruritus, in affected patients.
In selection of the proper treatment, there are no absolute guidelines or algorithms because published studies vary considerably in their design, measured outcomes, and follow-up time (Fig. 113-6). The clinical diagnosis of AK even by expert dermatologists can be inconsistent.27
Approach to the management of actinic keratoses. 5-FU = 5-fluorouracil; PDT = photodynamic therapy; UVR = ultraviolet radiation.
Treatment modalities for AKs can be broadly divided into lesion-targeted therapies and field therapies (Box 113-1).
Box 113-1 Treatment of Actinic Keratoses ||Download (.pdf)
Box 113-1 Treatment of Actinic Keratoses
- Liquid nitrogen cryotherapy
- Curettage with or without electrosurgery
- Shave excision
- Medium-depth chemical peel
- Deep chemical peel
- Laser resurfacing
- Photodynamic therapy
Lesion-Targeted Treatments for Actinic Keratosis
The majority of the lesion-targeted therapies for the treatment of AKs are destructive, i.e., they work by physically removing the AK. Such destructive treatments are currently the most common methods used to treat AKs.48
Liquid Nitrogen Cryosurgery
Liquid nitrogen cryosurgery is the most common destructive procedure and is typically administered with a spray device or a cotton-tipped applicator (see Chapter 246). The first prospective study looking at efficacy rates of cryosurgery was performed in 2004.49 The overall complete clearance rate when the patients were checked 3 months after treatment was 67.2%. A subgroup analysis of these data based on actual freeze times indicated that a complete response occurred in 39% of cases with freeze times of 5 seconds or less, in 69% with freeze times between 6 seconds and 20 seconds, and in 83% with freeze times longer than 20 seconds. Hypopigmentation was seen in 29% of sites from which AK was eradicated most probably those with longer freeze times as the melanocyte is particularly susceptible to cold injury. The investigators concluded that the ideal freeze time was somewhere between 10 seconds and 15 seconds.
The benefits of cryosurgery are its ease of administration in trained hands, the lack of need for anesthetic, and the lack of reliance on patient compliance other than in posttreatment care of treated lesions. Potential disadvantages of cryosurgery include pain and discomfort, the presence of unsightly blisters and crusted wounds for a week or longer, hypopigmentation, scarring, and possible alopecia in treated areas.50 In rare cases, serious injury to underlying tendons and nerves may occur with deep or prolonged liquid nitrogen application to the hands. Most important, cryosurgery is best used to treat a limited number of clinically perceptible or symptomatic lesions.
Curettage, with or without electrosurgery (see Chapter 246), is another destructive lesion-targeted treatment for AKs. This procedure and cryosurgery together constitute approximately 80% of all treatments for AKs in the United States.48 A curette is used to mechanically scrape away the atypical keratinocytes comprising the AK. Electrosurgery may or may not be used to further destroy atypical cells and to provide hemostasis. If electrosurgery is employed, minimal use is advised to enhance the final cosmetic result. A local anesthetic is needed for this procedure, and hemostatic agents such as aluminum chloride can be used to stop the bleeding if electrosurgery is not utilized. There are no controlled studies addressing cure rates with the use of this technique for the treatment of AKs, but experience says it is quite effective, at the expense of potential scarring. Patients can expect some discomfort with injection of the local anesthetic, and the treated area will take a few weeks to heal completely. This technique is most appropriate for patients with relatively few AKs. It is also beneficial for treatment of lesions after biopsy and for the treatment of HAKs. Potential side effects include infection, scarring, and dyspigmentation. If a biopsy is to be performed, procurement of a shaved specimen before curettage provides a much more acceptable histopathologic portrait and avoids overinterpretation or underinterpretation. Obtaining biopsy samples through curettage produces crushed and fragmented specimens that are difficult to interpret, which can lead to erroneous diagnoses.
The third lesion-targeted destructive therapy for AKs is shave excision. This technique involves injection of a local anesthetic followed by tangential excision of the lesion with a surgical blade (see Chapter 243). Hemostatic agents must also be used to stop the bleeding. No data exist on the cure rate of this technique, but as with curettage, anecdotal experience says it is effective. Healing time may be 1–2 weeks, and potential complications include infection, scarring, and dyspigmentation. Use of this technique is most often indicated when a clinically apparent AK is suspicious for SCC or BCC and histopathologic examination is needed. Shave excision offers the patient an attempt at curative therapy simultaneous with a diagnostic procedure. Signs and symptoms that should arouse suspicion of SCC include marked erythema, pain, ulceration, bleeding, induration, or failure to respond to prior destructive therapies. Care must be taken to shave deeply enough to avoid transecting the AK at the deep margin, because this precludes unequivocal interpretation due to the proclivity for invasive SCC to develop at the deepest extensions of the atypical keratinocytes in AKs.
Field Therapies for Actinic Keratosis
Field therapies treat larger areas of photodamaged skin that contain both clinical and subclinical AK lesions. Field therapies can be further categorized into topical/medical and procedural field therapies. Such treatments are best used in patients with moderate to severely photodamaged skin and numerous AKs that would be too burdensome and painful to treat with the lesion-targeted therapies. Many patients with AKs, upon close inspection, are found to be extensively affected with early disease in sun-exposed areas, which may make field therapy a more rational approach to this difficult problem.
Several topical agents are available and approved by the US Food and Drug Administration (FDA) for the generalized treatment of AKs, including 5-fluorouracil (5-FU), 5% imiquimod cream, and 3% diclofenac gel (Box 113-2).
Box 113-2 Topical Field Therapies of Actinic Keratoses* ||Download (.pdf)
Box 113-2 Topical Field Therapies of Actinic Keratoses*
0.5% micronized cream
Twice daily for up to 4 weeks
Once daily for 4 weeks
Twice per week for 16 wks
daily for 2 wks, then no treatment for 2 wks, then daily for 2 weeks
Twice daily for 90 days
5-FU therapy has been a mainstay of topical treatment for AKs since the 1960s (see Chapter 220
). 5-FU is a pyrimidine analog that inhibits the enzyme, thymidylate synthase, thus, interfering in DNA synthesis and ultimately resulting in apoptosis and tumor cell death. 5-FU acts selectively to cause cellular destruction in actinically damaged cells but not in normal skin. 5-FU treatment of sun-damaged skin usually causes a brisk inflammatory reaction, which is felt to contribute to its overall efficacy.
Although many different treatment regimens have been proposed and used with topical 5-FU, the historical standard FDA-approved method consists of twice-daily application of 5-FU cream or solution to the entire affected region, typically for 2–4 weeks. Spot treatment of specific AK lesions is not recommended but is a common practice. There is also some evidence that concurrent treatment or pretreatment with topical tretinoin
is more effective than 5-FU alone for AKs on the extremities.51
Therapy should be continued until the treated area demonstrates erythema, erosion, crusting, and necrosis, at which time treatment should be discontinued. Different strengths (1%, 2%, 5%) and vehicles (cream or solution) of topical 5-FU are available. More recently, a 0.5% micronized 5-FU cream has become available and FDA approved for treating AKs. It can be applied once daily for 4 weeks. The choice of which topical 5-FU formulation to use depends on physician preference, individual patient characteristics, and the number and location of AKs being treated.
Anecdotally, topical 5-FU has been thought to be 75% effective, that is, seven or eight out of ten treated AKs will resolve with appropriate therapy.52
The long-term remission rates after 5-FU treatment vary, but the condition frequently recrudesces in a few years and severely affected patients sometimes return to baseline.
The once-daily, 0.5% micronized 5-FU cream was developed in an attempt to make the topical 5-FU therapy more tolerable. It is FDA approved for the treatment of multiple AKs on the face and anterior scalp. Premarketing studies of this medication showed that more than 75% of treated lesions clinically resolved in 60%–80% of patients treated for 4 weeks. One study found an overall 89% reduction of AKs and a complete clearance rate of 48% in patients treated for 4 weeks with a once-daily application of 0.5% micronized 5-FU cream.53
In a split-face comparison study of 5% 5-FU and 0.5% 5-FU cream, similar complete clearance rates of approximately 50% were observed for both therapies.54
The investigators noted a similar reaction rate with erythema, crusting, and scabbing, but overall the patients preferred the 0.5% micronized 5-FU cream because of its once-daily application regimen and a perception of less irritation.
Effective treatment relies greatly on the patient's understanding and compliance with the prescribed 5-FU regimen. The clinician should spend time with the patient educating the patient about the proper application of the medication, the duration of therapy, and the expected outcome. Written handouts reiterating this information and photographs of the expected reaction are helpful for patients to view and take home.
Patients should expect discomfort, pruritus, and burning at the sites of application, as well as erythema, erosion, crusting, and possibly ulceration beginning at around 1 week into treatment (eFig. 113-6.1
). These and other adverse reactions to 5-FU are further discussed in Chapter 220
. Other photodamaged areas of the skin that seemingly have no visible evidence of AKs may also become quite inflamed during treatment, leading not only to the treatment of unmasked AKs, but also to the histopathologically proven rejuvenation of the skin.55
Much lower cure rates are seen when patient compliance is poor and the expected end points are not reached.
A. Erythema and crusting secondary to treatment with 5-fluorouracil (5-FU). B. Superficial hemorrhage in a patient taking warfarin (Coumadin) who was treated with 5-FU.
The second agent available for topical field treatment of multiple AKs is imiquimod
cream (see Chapter 220
). It works by inducing both the innate and adaptive arms of the immune system to recognize and destroy AKs. It is available in 5%, 3.75% and 2.5% formulations. First approved in 1997 by the FDA for the treatment of genital and perianal warts, it was approved in 2004 for the treatment of nonhypertrophic AKs on the face and scalp in immunocompetent adults. It is also approved for treatment of superficial BCC (see Chapter 115
The FDA-approved regimens for the three different strengths of imiquimod
are outlined in Box 113-2
. Treatment with imiquimod
cream is associated with adverse reactions, most notably local skin reactions such as erythema, scabbing, flaking, erosion, weeping, and vesicle formation. Such reactions are actually predictive of better ultimate clearance of the AKs, as the greatest resolution of AKs has been seen in patients with the most severe reactions.56–58
Systemic absorption is minimal, and overall excellent safety margins have been demonstrated with the topical administration of imiquimod
Systemic adverse effects, including interferon-like side effects such as flu-like symptoms, headaches, and myalgia, have been infrequently reported particularly when large surface areas are treated.
The short-term efficacy of imiquimod
cream for eradicating AKs has been well studied in the last several years. The first systematic review and meta-analysis of short-term randomized controlled trials evaluating its efficacy and safety has been published.60
For this meta-analysis, five trials57,58,61–63
involving a total of 1,293 patients were selected for inclusion based on their high-quality scores, minimal risk of bias, validity, adequate treatment duration, inclusion of patients with multiple AK lesions, and use of at-home application. Complete clearance occurred in 50% of patients treated with imiquimod
versus 5% treated with vehicle alone. Partial clearance (more than 75% of lesions) was seen in 65% of imiquimod-treated patients versus 11% of vehicle-treated patients.60
Evidence also supports the use of imiquimod
in the treatment of AKs to promote long-term immune surveillance and lower recurrence rates. Stockfleth et al56
followed 25 imiquimod-treated patients from a previous short-term study61
for up to 2 more years. Of these 25 patients (one was lost to follow-up), 8% (n
= 2), 16% (n
= 4), and 20% (n
= 5) developed new AKs or were lost to follow-up at 12, 18, and 24 months, respectively, after completion of the initial regimen of imiquimod
application three times a week for 12 weeks. No patients had developed SCC in the imiquimod-treated areas at 2 years after treatment. Ten of the vehicle-treated patients from the original study61
were also observed for 1 year after their initial treatment. In this group, 90% (n
= 9) developed new AKs in the vehicle-treated area, 10% (n
= 1) had spontaneous remission of their AKs, and 10% (n
= 1) developed an SCC in the vehicle-treated area.
In a second study of long-term efficacy, Lee et al64
looked at patients from four previous phase III randomized, vehicle-controlled studies who showed complete clearance of all of the AKs in the treated areas at 8-weeks posttreatment. After a median follow-up of 16 months they found that 25% (n
= 19/77) and 43% (n
= 23/54) of patients treated with imiquimod
three times per week and two times per week, respectively, for a duration of 16 weeks experienced a recurrence of one or more AKs in original treated area.
has been shown to be safe and effective in treating AKs in the organ transplant population, with no evidence of graft rejection and no trends toward diminished graft functioning.65
Rare flares of underlying autoimmune disease were observed during preapproval research studies and have been documented in the literature.66
The third FDA-approved topical field therapy for treating AKs is 3% diclofenac
is a nonsteroidal anti-inflammatory drug whose mechanism of action is not completely understood but is thought to involve inhibition of cyclooxygenase (COX), a rate-limiting enzyme in the synthesis of prostaglandins. Diclofenac
appears to have greater affinity for the COX-2 enzyme than for the COX-1 isoform. One theory regarding its role in eradicating AKs relates to the finding that the production of prostaglandins from arachidonic acid may contribute to UV radiation-induced NMSC. Thus, inhibition of this cascade by diclofenac
may also explain its efficacy in treating AKs.67
The FDA-approved regimen for diclofenac
in the treatment of AKs is twice-daily application for 90 days. Compared with imiquimod
and 5-FU, diclofenac
does not cause as much inflammation, irritation, or downtime for the patient. Adverse effects include mild local site reactions, such as erythema, pruritus, flaking, and possible contact dermatitis. In a blinded, controlled study involving 96 patients complete clearance of AKs was observed in 50% of the diclofenac-treated group and in 20% of the vehicle-treated group 30 days after the conclusion of therapy.68
At 1-year follow-up, 91% of patients had at least 75% clearance of the targeted lesions, and of these patients, 79% showed 100% clearance.68
The second category of field therapies for treating diffuse AKs is the procedural field therapies. These include cryopeeling (see Chapter 246), dermabrasion, medium and deep chemical peels (see Chapter 251), laser resurfacing (see Chapter 251), and photodynamic therapy (PDT) (see Chapter 238).
Cryopeeling consists of extensive liquid nitrogen cryosurgery to the areas of discrete AKs as well as to the surrounding actinically damaged skin.
Dermabrasion is an older technique that is quite effective in the treatment and prophylaxis of AKs but is now rarely used for this purpose. It causes physical destruction of the AKs with abrasion using either drywall sanding sheets or dermabrasion diamond fraises, which are powered or handheld (see Chapter 251).
Medium-depth chemical peels using Jessner's solution and 35% trichloroacetic acid (TCA) are moderately effective in treating diffuse AKs, especially when a series of such peels are administered over time69,70 (see Chapter 251). A combined peel, in which 35% TCA is used, after applied to obtain uniform frosting after Jessner's solution degreasing and deepithelialization, has been shown to be equivalent in efficacy to 5-FU therapy.71
Deep chemical peeling using phenol or high concentrations of TCA is more effective in treating thick AKs or those with appendageal epithelial atypia but are rarely used because of the potential cardiac and renal toxicity of phenol, the greater risk of scarring and infection, and the dramatic hypopigmentation that may occur postoperatively.
Laser resurfacing for the treatment and prophylaxis of AKs is another procedural field therapy that has been utilized. The carbon dioxide (CO2) laser and the erbium:yttrium-aluminum-garnet (er:YAG) laser are the two laser systems that have primarily been investigated for these purposes (see Chapter 252). Both of these devices ablate the epidermis at varying depths allowing reepithelialization with adnexal keratinocytes that are less actinically damaged.
In preliminary small series, both laser resurfacing systems have been reported to be effective in short-term clearing of multiple facial and scalp AKs72–74 and in the long-term prevention of recurrences75 and possibly the development of NSMC.72 Laser resurfacing is probably best reserved for use by specially trained and experienced physicians and for patients with more cosmetic concerns or with diffuse AKs for which topical field therapies and/or chemical peeling have failed. They are also excellent modalities for patients with severe actinic cheilitis and for those patients with multiple, thicker AKs.
PDT is another procedural therapy available for the treatment of multiple and diffuse AKs. The FDA has approved two PDT systems for the treatment of non-HAK lesions on the face and scalp (see Chapter 238). The first to receive approval was the combination of 5-aminolevulinic acid (ALA) with a blue light source in 1998. More recently, the FDA approved a system that has been widely available in Europe, combining a methyl ester of aminolevulinic acid (MAL) with a red light source. The topically applied ALA or MAL accumulates preferentially in the more rapidly dividing atypical cells and is converted sequentially to protoporphyrin IX, a heme precursor and photosensitizer. When the ALA or MAL-treated skin is then exposed to a light source of the appropriate wavelength several hours later, the accumulated protoporphyrin IX generates a phototoxic reaction that destroys the treated cells.76–79
Randomized, placebo-controlled studies have demonstrated the efficacy of both ALA and MAL PDT for the treatment of AKs.79–82 A more recent, randomized, double-blind, prospective study comparing the safety and efficacy of ALA-PDT with MAL-PDT found both forms to have no significant difference in efficacy of decreasing AK lesion burden, but that ALA-PDT was associated with more painful and adverse effects and a longer duration of discomfort compared with MAL-PDT.82 Patients can expect some discomfort with PDT, including erythema, edema, and burning or stinging during exposure to the light source. In a subgroup of patients with severe sun damage, PDT can create intolerable pain that sometimes results in premature discontinuation of treatment. Allergic reactions to ALA and MAL have also been reported. Severe phototoxic reactions can occur if patients do not follow the protocol and practice strict sun avoidance for the recommended period after ALA and MAL application. Cosmetic outcomes have been good to excellent in those who complete adequate treatment.
There is a paucity of comparative effectiveness research amongst these various field therapies for AKs. In general, topical 5-FU, 5% imiquimod cream, diclofenac gel, and PDT are all effective in decreasing the AK lesion burden. From the mostly small comparative studies that have been published, a few additional points can be made. Topical 5-FU and topical 5% imiquimod cream seem to create more inflammation, irritation, and patient discomfort compared with topical diclofenac gel. There is some data to suggest that topical 5% imiquimod cream may have lower, long-term recurrence rates of AKs, in part by creating longer term immune memory and antitumor response.56,83 A pharmacoeconomic study of AK field treatment modalities (5% imiquimod vs. diclofenac gel vs. 5-FU vs. ALA-PDT) in combination with liquid nitrogen cryosurgery found that ALA-PDT was the least costly and that imiquimod was the most expensive.84
In summary, evidence supports the treatment of AKs to prevent the progression to malignancy. There are a number of effective lesion targeted and field treatments available to choose from to decrease the burden of AKs. Consideration of the individual's needs, the physician's skills, the mechanisms of action of the various treatments and their side effect profiles, plus the cost of treatment should all be considered when choosing a treatment strategy. To help physicians in choosing a treatment strategy for their patients, the American Academy of Dermatology and the European Dermatology Forum has proposed guidelines for the management of AKs, based upon available evidence at the time of their writings.85,86 In addition, the authors of this chapter have proposed a treatment algorithm (Fig. 113-6).
Given the potential of AKs to progress to malignant lesions, it is important to focus on the prevention of these precancerous lesions. Educational and preventive efforts should be directed toward children, targeted high-risk populations, and all patients. Avoidance of UV radiation is the single most effective means of decreasing the risk of AKs. A strategy designed to limit the amount and intensity of sun exposure, starting in childhood and continuing throughout the person's life, will likely decrease the number of AKs an individual will develop. Because complete avoidance of the sun is impractical, the next best preventive measures are to avoid exposure to intense midday sun; consistently apply and reapply broad-spectrum sunscreens; wear UV-protective clothing, hats, and sunglasses; install UV-protective windows where indicated; and make sure to take an oral vitamin D supplement if necessary to avoid vitamin D insufficiency or deficiency.90
Numerous randomized studies have shown that the use of sunscreen can decrease the incidence and prevalence of AKs, reduce the number of AK lesions, and increase their rate of regression.29,91–94 There is also evidence that sunscreen use can prevent certain types of skin cancer, mostly SCC.93,94 There is limited evidence that adhering to a diet low in fat may decrease the incidence of AKs95,96 and NMSC.97,98 In older studies, topical retinoids were shown to reduce the number of AKs after long-term consistent use,99,100 and in another study, long-term treatment with topical retinoic acid was shown to reduce keratinocyte and melanocyte atypia in photoaged skin.101 However, the more recent multicenter VATTC trial found that up to twice-daily application of 0.1% tretinoin cream over 1.5–5.5 years in mostly elderly (n = 1,131, mean age = 70 years) males (95%) at very high risk for NMSC was ineffective for preventing BCC and SCC.102 This study was stopped 6 months prematurely because of excess mortality in the treatment group. However, the authors could not establish a cause and effect relationship.103 They also concluded that retinoids may have very different clinical effects when administered topically as opposed to orally.102
Unlike the controversy with topical retinoids, there is strong evidence for the use of systemic retinoids in preventing NMSC and AKs, especially in high-risk populations, such as organ transplant recipients, patients with xeroderma pigmentosum, and other chronically immunosuppressed patients.104–107 Unfortunately, the systemic retinoids are only effective while the patient is taking them and their use is also limited by the frequent occurrence of systemic toxicities, including hypercholesterolemia, hypertriglyceridemia, mucocutaneous xerosis, musculoskeletal abnormalities, and alteration in liver function. Thus, when considering the use of systemic retinoids in such high-risk patients, one must weigh these risks and benefits.
Topical imiquimod has also been safely used in the organ transplant population to prevent the development of cutaneous SCC.65,108