As with any other disease, the initial assessment of a patient with AK should include a general medical history supplemented by a series of additional questions to gather information that may prove important in the design of the treatment and follow-up strategy. In the case of AK, the following additional information is of interest10:

• 1.

  Prior treatments to determine the effectiveness and tolerance profile in the patient.

• 2.

  Past history of nonmelanoma skin cancer.

• 3.

  Exposure to sunlight at work and/or in the course of outdoor leisure activities, and UV-A sun lamp use.

• 4.

  Past or current immunosuppressant therapy for any reason.

• 5.

  Symptoms (itching, pain, burning, etc).

• 6.

  The motive for the consultation (symptoms, concern about skin cancer, cosmetic issues).

• 7.

  It is also essential to include questions in the medical history aimed at identifying any signs or symptoms indicative of progress to invasive squamous cell carcinoma (Table 1).10

  Table 1.

  Signs Associated with Suspicion of Progression From Actinic Keratosis to Invasive Squamous Cell Carcinoma.

  Inflammation or induration of the lesion

  Longest diameter of 1-2cm

  Bleeding

  Rapid enlargement

  Ulceration

  Lack of response to treatment (no response to treatment or rapid recurrence following an initial response)

The procedure for the physical examination of a patient with AK is as follows:

• 1.

  Complete dermatological examination, paying particular attention to areas of the skin usually exposed to sunlight (face, balding scalp, ears, upper chest or neckline, and the dorsum of hands and forearms). Patients usually have multiple AKs rather than a single lesion. Patients with AKs are also more likely to have other skin tumors associated with exposure to sunlight, including basal cell carcinoma, squamous cell carcinoma, and melanoma.6

• 2.

  A detailed description of the type, site, and extent of lesions is required because these factors will determine the appropriate treatment. Not all treatments are indicated in all cases or sites.

• 3.

  The clinician should make a note of all signs of chronic actinic damage (telangiectasias, pigmentary changes, elastosis, and wrinkles), scars, and patches of hypopigmentation caused by previous treatments (cryotherapy, surgery, etc.), and note the visible presence, if any, of field cancerization.

AKs typically present as a macule, papule, or plaque that is rough to the touch and skin color or slightly erythematous, measuring between a few mm and 2 to 3cm. The number of AKs observed varies (single or multiple lesions) and lesions are usually located in areas of the skin characterized by signs of chronic sun damage caused by exposure to UV radiation, such as the face, the balding scalp, the upper chest, the ears, the dorsum of the hands and forearms, and the lower lip (actinic cheilitis). Since AKs generally cause no pain or discomfort or produce only mild symptoms, patients often delay consulting a dermatologist.

In addition to the classic presentation, other types of AK have been classified according to their clinical and histologic features.10

• –

  Pigmented AK. Hyperkeratotic macules or flat papules that may be hyperpigmented or reticulated, but lack any erythematous component.

• –

  Lichenoid AK. Clinically similar to the classic form of AK but present pronounced erythema around the base of the lesion secondary to an underlying lichenoid infiltrate.

• –

  Hypertrophic or hyperkeratotic AK. These easily identifiable lesions take the form of a highly keratotic papule or plaque on an inflammatory substrate. A cutaneous horn may develop over time.

• –

  Atrophic AK. In this form of AK, the lesion is a somewhat scaly erythematous macule. Histology reveals an atrophic epidermis.

Since the presence or absence of a cancerization field is an important consideration in the design of a treatment strategy, this factor must always be evaluated in patients with AK.

The cancerization field is the area of actinically damaged skin that may surround each AK and display similar genetic alterations. The field may contain clinically visible AKs, subclinical AKs (only visible under a microscope), groups of keratinocytes with genetic mutations only detectable using molecular biology methods, and normal skin.22,23

The problem associated with the evaluation of field cancerization is that it is impossible to clearly delimit the area clinically, making the delimitation of the size of the field somewhat arbitrary. Reflectance confocal microscopy could be very useful in delimiting the cancerization field, but the equipment required is not usually available in clinical practice, at least in Spain.

The presence of field cancerization has important implications for treatment. If we only treat clinically visible lesions, the targeted lesions will be eliminated but the field will continue to pose a problem, giving rise to new AKs over time. However, by treating the cancerization field, we can eliminate not only the visible AKs but also the subclinical lesions, and possibly the clones of cells that would eventually become AKs.

In any case, the treatment of field cancerization is still a more theoretical than practical concept given the impossibility of reliably establishing the clinical boundaries of the field and the lack of any evidence that treating field cancerization decreases the risk of invasive squamous cell carcinoma.

The therapeutic armamentarium is extensive and includes ablative, non-ablative, and mixed modalities.

Destructive methods are generally used to treat solitary lesions or small numbers of lesions, but not to treat field cancerization.10 They include curettage with or without electrocoagulation, cryotherapy, CO2 laser, Erbium-doped yttrium aluminum garnet (Er:YAG) laser, and surgery. Most of the nondestructive and mixed methods are indicated for the treatment of lesions and cancerization fields.6,10 Commercial preparations available in Spain include 0.5% 5-fluorouracil+10% salicylic acid; 3.75% and 5% imiquimod; 3% diclofenac in 2.5% hyaluronic acid gel; 0.05% and 0.015% ingenol mebutate; 5% 5-fluorouracil can be obtained as a customized compound.10 Mixed modality approaches include photodynamic therapy, which often requires pretreatment curettage of the AK to facilitate penetration of the photosensitizer (ALA or MAL).

Details of the application of the different therapeutic modalities are shown in Table 4.

It is important to note that destructive and nondestructive therapies are not incompatible. In fact, the combination of a lesion-directed therapy and a field-directed therapy is common, often well tolerated, and achieves greater efficacy in terms of total clearance and prevention of recurrence than the use of either method alone.25–27

Treating field cancerization as well as clinically visible lesions is to a certain extent a preventive strategy because it stops subclinical lesions from progressing to clinically visible lesions which could eventually become squamous cell carcinoma.28 Moreover, by preventing new lesions or delaying their onset, field-directed therapy can serve to increase the interval between follow-up visits.

The decision on whether to use a lesion-directed or field-directed therapy and which modality to use will depend on many factors that must be evaluated on a case-by-case basis. The factors that affect the choice of treatment are shown in Table 5.

Given the large number of factors, it would be very difficult to design a treatment algorithm covering all clinical situations. In fact, the different strategies that have been proposed in the clinical practice guidelines of different countries vary somewhat.6,10,24,29,30 However, a useful starting point is to establish a strategy based on the number of lesions to be treated,6 their distribution (whether they are isolated or grouped), and the presence or absence of field cancerization. The different options can then be modeled on the basis of other factors.

In patients with between 1 and 5 ungrouped lesions located in different anatomical areas, therapies that target individual lesions or topical pharmacological treatments can be used (Table 4). In Spain, and many other countries, cryotherapy is undoubtedly the most widely used treatment in this setting. However, this does not mean that it has been shown to be the most effective or the most efficient option, and the recurrence rate after cryotherapy is high.10,31 It is interesting to note that cryotherapy was strongly recommended in recent European evidence-based guidelines despite the paucity of evidence and scant number of comparative clinical trials.6 In patients with a few isolated lesions, the use of other lesion-directed, ablative treatments (photodynamic therapy and CO2 or Er:YAG laser therapy) is limited in Spain due to the high cost and lack of equipment. Finally, the risk of scarring limits the use of curettage, electrocoagulation therapy, and surgery. These destructive modalities are, nonetheless, necessary in some cases, for example in highly hyperkeratotic lesions or when histopathologic study is required to resolve diagnostic doubt.10

In other situations, topical therapies can be used. If the lesion is moderately or very hyperkeratotic, 0.5% 5-fluorouracil in 10% salicylic acid should be used, as indicated in the Summary of Product Characteristics and because it has been shown to obtain good results, as assessed by both patient and clinician.32 Other topical treatments can be used to treat lesions without hyperkeratosis.10 When there is little or no hyperkeratosis, 3% diclofenac in 2.5% hyaluronic acid gel is less effective than other topical treatments33 but is the best tolerated therapy34,35 The other topical drug therapies can provoke intense local inflammatory reactions. These local reactions include erythema, scaling, scabbing, edema, vesicles, pustules, erosions, ulceration, and scarring with hyperpigmentation or hypopigmentation of greater or lesser severity. In general, adverse reactions appear a few days after start of treatment and persist throughout treatment and for a few days or weeks after completion.33 They often reduce adherence to treatment. In the case of ingenol mebutate, the duration of treatment is shorter and it is the only therapy in which the local reaction develops after the patient has completed the treatment regimen; as a result, adverse reactions rarely influence adherence.36 Moreover, some of these therapies, including sodium diclofenac and photodynamic therapy, can cause photosensitivity, and others, such as imiquimod, can produce systemic symptoms, including general malaise and flu-like syndrome associated with the local skin reaction.6 In light of the immune-mediated mechanism of action of several of these drug therapies, the application of topical corticosteroids is not recommended for the treatment of these localized skin reactions.

If the lesions are numerous (6 or more) and affect different anatomical areas, the principles are the same as those detailed above except that in this case topical drug therapies are the recommended option because of the pain associated with destructive modalities and the risk of superinfection, pigmentation disorders, and scar formation.6

Another clinical situation is that of a patient with fewer than 6 AKs, which are grouped in a single anatomical area or are associated with hyperkeratosis and marked changes due to chronic actinic damage in the surrounding area (field cancerization). In this situation, destructive approaches are not appropriate, and the choice of photodynamic therapy or topical drug therapy will depend on what is agreed between the physician and the patient after analysis of the advantages and disadvantages of each modality, seeking the best balance between efficacy and tolerance and the best cost-benefit profile.37 In these situations, ablative treatments should only be used to treat an isolated lesion that does not respond to topical treatment or photodynamic therapy or is highly hyperkeratotic; they should never used to treat field cancerization.

Another anomalous clinical situation is that of immunocompromized patients with AK, who often present multiple lesions. In this group of patients—given the possibility of more rapid progression to invasive squamous cell carcinoma and, in some cases, the difficulty of diagnosis—the most usual approach is to use a combination of lesion-directed and field-directed therapies. The most common approach in such cases is a destructive lesion-directed therapy in combination with topical drug treatment or photodynamic therapy.32 The appropriateness of using immune boosting drugs on large areas in iatrogenically immunosuppressed patients should be considered with particular attention because of the potentially negative impact of such treatment on the patient's underlying condition. Nevertheless, 5% imiquimod, 5% 5-fluorouracil, 3% sodium diclofenac, and photodynamic therapy have all been shown to be safe in this group of patients.32

A definitive diagnosis of BD usually requires a skin biopsy. The clinical presentation, which is described above, is very indicative. Dermoscopy can aid diagnosis by revealing glomeruloid vessels and scales,50 but a biopsy is generally required to exclude other possible diagnoses. The main differential diagnoses are infiltrating squamous cell carcinoma, superficial basal cell carcinoma, nummular eczema, condylomata acuminata, porokeratosis, chronic discoid cutaneous lupus erythematosus, and seborrheic keratosis.

BD is characterized microscopically by full-thickness intraepidermal proliferation of atypical keratinocytes that may include the intraepidermal portion of skin appendages. Typically, the atypical keratinocytes are pleomorphic and hyperchromatic. They can also be vacuolated and have a clear and prominent cytoplasm reminiscent of Paget cells. Other common findings are cellular dyspolarity, loss of maturation, and the presence of numerous mitotic figures. Other typical features include hyperkeratosis, to a greater or lesser degree, and parakeratosis, as well as acanthosis and complete architectural disorder. A chronic inflammatory infiltrate composed of lymphocytes, plasma cells, and histiocytes is usually found in the superficial dermis. Several histologic variants have been described: psoriasiform, atrophic, and acantholytic BD.