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PREMALIGNANT LESIONS

Actinic keratosis

Actinic (solar) keratoses (AKs) are an extremely common disorder, with a small malignant potential. A more diffuse form on the lower lip, termed actinic cheilitis, is also discussed.

Etiology and pathogenesis

Actinic keratoses are related to long-term cumulative sunlight exposure, which eventually leads to disordered epidermal maturation. In a study of AKs in bald men, the hair loss preceded keratoses by about 30 years. They are very common by the age of 70 years, and may be extensive.

Clinical features

Typical AKs (Figs 32.1 – 32.5) are characterized by their hard, spiky scale, which typically arises from a rather banal base. They are often easier to feel than to see. They may vary from an apparently solitary lesion in some patients, to extensive sheets of apparently confluent keratoses. There are inevitably other signs of solar damage in affected individuals, such as elastosis, telangiectasia, and atrophy; squamous cell carcinoma or other epidermal neoplasia may coexist.

    The most frequently misdiagnosed variant is an almost flat, erythematous or telangiectatic type, which may be mildly scaly and rather diffuse (Fig.32.6). This is most frequently found on the forehead or temple skin, and is often incorrectly diagnosed as eczema.

    Hypertrophic AKs, which have a thickened, fleshy base, cause concern, as they resemble a slowly growing squamous cell carcinoma. These often have a large and firmly adherent horn arising from the fleshy base (Fig.32.7). The risk of squamous cell carcinoma arising from an AK (Fig.32.8) is uncertain, as it is impossible in retrospect to know whether a precursor keratosis was actually a small squamous cell carcinoma or an AK, but the risk of transformation is probably in the order of 1:500 to 1:1000 per year.

    Pigmented AKs (Fig.32.9) are uncommon, and may resemble seborrheic keratoses or even malignant melanoma. Extensive diffuse AKs may occur, often with a history of extensive use of tanning sunbeds, and are often very itchy and confused with eczema (Fig. 32.10).

Fig. 32.1 Actinic keratosis. A typical lesion with hard, spiky, white keratosis on the dorsum of the hand.

Fig. 32.2 Actinic keratosis. A typical lesion with hard, spiky, white keratosis on the dorsum of the hand.

Fig. 32.3 Actinic keratoses on the hand, a common site for this disorder; note the associated photodamage generally.

Fig. 32.4 Actinic keratoses on the scalp and neck. A large number of lesions scattered across the bald scalp vertex is a common pattern. Recent research demonstrates a period of about 30 years between development of baldness and of actinic keratoses, supporting the relationship to long-term cumulative sunlight damage.

Fig. 32.5 Close-up of (a) scalp and (b) temple actinic keratosis, showing the typical hard scale and stuck-on appearance.

Fig. 32.6 Actinic keratoses showing the diffuse pattern, which is often erroneously treated as eczema.

Fig. 32.7 Cutaneous horns caused by an actinic keratosis on the face (a) and an early invasive squamous carcinoma on the arm (b). This term is a description, not a diagnosis. Cutaneous horns may arise on the basis of actinic keratoses, viral warts, seborrheic keratoses, and other benign squamous papillomas; squamous cell carcinoma; keratoacanthoma; and even non-epidermal tumors such as Kaposi sarcoma or benign dermatofibromas. Note the surrounding dysplastic actinic damage in (a). A lesion with a fleshy base is more suspicious than one that is purely a column of keratin.

Fig. 32.8 Squamous cell carcinoma (SCC) on the dorsum of the hand in a man with multiple actinic keratoses in the same distribution. It is impossible to know whether the SCC has arisen from a preexisting actinic keratosis, or whether it is in the same body site distribution due to the fact that both disorders have chronic solar exposure as their etiology.

Fig. 32.9 Pigmented actinic keratosis (AK). This is a relatively uncommon pattern, and may be confused with melanoma or pigmented basal cell carcinoma (see Fig.32.34). At this site on the rim of the ear, AK is much the most likely diagnosis and was confirmed histologically.

Fig. 32.10 Diffuse and essentially confluent actinic keratoses on the leg, referred as a case of eczema. This patient had a long history of frequent sunbed use and solar exposure, and also had a squamous cell carcinoma on the knee. Long-term treatment has included systemic retinoids with intermittent topical 5-fluorouracil and occasional cryotherapy.

Actinic cheilitis

This is a variant of AK that usually affects the sun-exposed lower lip (Figs 32.11 and 32.12).

Differential diagnosis

This depends on the clinical pattern (Table 32.1).

Treatment

Treatment options include emollients alone, topical 5-fluorouracil or diclofenac, imiquimod, cryotherapy, curettage, excision, lasers, photodynamic therapy (PDT), and occasionally radiotherapy. Topical 5-fluorouracil is useful for patients with multiple thin lesions, in whom cryotherapy or other destructive treatments would cause significant morbidity. Topical diclofenac is used in similar situations, and usually causes less inflammation but may be less effective. Imiquimod is a topical immunomodulatory agent that can also be effective, although it is relatively expensive compared with the other topical agents. Cryotherapy is the most widely used technique for treating AK; however, a surgical technique that allows histologic examination is prudent for any hypertrophic or cryotherapy-resistant lesions. PDT may be used for individual or groups of lesions. Use of a prophylactic sunscreen slows the rate of development of further keratoses, and some may apparently regress.

Fig. 32.11 (a,b) Actinic cheilitis. This affects mainly the lower lip, and is related to chronic solar damage.

Fig. 32.12 Erosion of the lip following topical 5-fluorouracil treatment for actinic cheilitis. Other options include cryotherapy, laser ablation, and vermilionectomy with a mucosal advancement flap (‘lip shave’).

Fig. 32.13 Bowen disease: a typical, rather psoriasiform lesion on the leg. Solitary lesions with this morphology in older patients are unlikely to be psoriasis, but the diagnosis can be difficult if a few lesions are present.

Bowen disease

This is a type of in situ carcinoma, which has histologically striking features of atypical keratinocytes and giant ‘starburst' mitoses scattered throughout the epidermis and follicles. A male genital variant termed erythroplasia of Queyrat is also discussed.

Etiology and pathogenesis

Bowen disease is probably due mainly to solar exposure. The peak age at diagnosis is in the seventh decade, and the main sites affected are the head and neck in countries with intense sunlight, and the female lower leg in temperate climates. Other etiologic agents include arsenic exposure (the interval before development of Bowen disease is usually over 20 years), immunosuppression, and viral infection. Human papillomavirus (HPV) has been variably demonstrated in Bowen disease, but particularly HPV-16 in genital and perianal lesions.

Clinical features and variants

Lesions are usually solitary, but may be multiple in 20% and are occasionally very numerous. Individually, they are sharply marginated erythematous plaques with surface scaling and crusting (Figs 32.13 – 32.16). The border, particularly as lesions enlarge, is often rather geographic in outline.

    There are several morphologic and body site variants of Bowen disease, including hypertrophic lesions, pigmented Bowen disease, subungual Bowen disease, penile Bowen disease (erythroplasia of Queyrat, see later), and perianal Bowen disease (Figs 32.16 – 32.18). Pigmented Bowen disease is an uncommon variant that has a predilection for flexural or genital areas; lesions around fingernails and toenails may also be pigmented.

Fig. 32.14 Bowen disease: a large lesion with lobulated border.

Fig. 32.15 Bowen disease showing multiple lesions. This was treated with 5-fluorouracil under occlusion initially, then with topical 5-fluorouracil for 2 weeks about every 2 months, giving excellent long-term control. Other options would include sequential cryotherapy or photodynamic therapy. It is easy to see why eczema or psoriasis may be considered as diagnostic possibilities, but neither of these tends to affect the lower leg essentially in isolation.

Fig. 32.16 An example of verrucous Bowen disease. This is uncommon, and requires biopsy to exclude invasive squamous cell carcinoma.

Fig. 32.17 Perianal Bowen disease is an uncommon variant that requires biopsy for diagnosis. Recurrences after treatment are common with all modalities. Wide surgical excision is probably the preferred option, although radiotherapy can achieve good results.

    Moist areas, or nodules within Bowen disease, are suggestive of progression to invasive squamous cell carcinoma, which occurs in about 3% of lesions (Fig. 32.19).

Fig. 32.18 Bowen disease of the finger. Involvement of the dorsum of the finger (a) is not uncommon. However, Bowen disease affecting the subungual and periungual skin (b) is less common and poses greater diagnostic and management problems. This is probably best treated with excision (with micrographic control if available), although laser ablation has also been used with success.

Fig. 32.19 A thickened and eroded moist area within Bowen disease is suspicious of development of squamous cell carcinoma, although it can occur due to secondary infection. Note the large arsenical keratosis on the thumb in this case.

Fig. 32.20 Erythroplasia of Queyrat is a variant of Bowen disease that occurs under the prepuce of uncircumcised men. Typically for eruptions at this site, it is relatively non-crusted compared with the corresponding disorder at exposed sites. The risk of squamous cell carcinoma and subsequent metastasis is higher than for Bowen disease at more typical body sites. (Courtesy of Michael O. Murphy, M.D.)

Fig. 32.21 Erythroplasia of Queyrat with more scattered, thin lesions on the distal penis, which could be amenable to 5-fluorouracil therapy.

Erythroplasia of Queyrat

This disorder is histologically identical to Bowen disease but occurs specifically on the glans penis, usually in uncircumcised men (Figs 32.20 and 32.21). It tends to be less crusted at this site, due to the occlusion by the foreskin. Frank neoplasia (squamous cell carcinoma) needs to be excluded by biopsy. The risk of invasive malignancy and subsequent metastasis is higher than for Bowen disease at more typical sites.

Differential diagnosis

The differential diagnosis of Bowen disease may potentially include disorders such as AK or basal cell carcinoma at any site, but the most likely differential (or the most likely referral diagnosis) varies according to affected site and also whether lesions are solitary or multiple.

Treatment

This may be a very slowly progressive disorder, and small lesions (particularly if situated on edematous lower legs) may be best left untreated. Topical 5-fluorouracil is useful, especially in patients with multiple small lesions. Topical imiquimod also appears to be useful. A variety of destructive treatments have also been used, including cryotherapy, curettage, excision, lasers, PDT, and radiotherapy. All can give good results, and the decision of which to use if often based on practical issues such as the number, site, and size of lesions, especially in the case of lesions on the lower leg, where healing may be poor. Overall, PDT probably has the best combination of cure rate and healing, but it is more expensive and time-consuming than the other options. All treatments have a small failure rate, which may relate to the involvement of the full depth of the follicles by the neoplastic process. Biopsy for histology should be performed for larger or thicker lesions, in which development of squamous cell carcinoma may have occurred.

    Genital and perianal Bowen disease pose particular problems due to their higher recurrence and metastatic rates, and the technical aspects of surgery at these sites.

Porokeratosis

Etiology and pathogenesis

This group of disorders may be congenital or acquired. The congenital lesions may be extensive and have a rather reticulate pattern. Acquired lesions may be solitary, broad lesions, or multiple, scattered, individual lesions (disseminated superficial actinic porokeratosis), for which sunlight is felt to have a causative role. However, causation by sunlight in patients with disseminated superficial actinic porokeratosis is often not convincing in either the distribution pattern or the previous sun exposure history. There are links between immunosuppression and development of porokeratosis, and squamous cell carcinoma may arise within lesions.

    A rare disorder known as porokeratotic eccrine and ostial dermal duct nevus is a type of birthmark and is not considered here.

Clinical

The clinical patterns vary somewhat, as shown in Figs 32.22 – 32.25, but all types share a characteristic pathologic feature known as a cornoid lamella. This is a thin plume of parakeratosis corresponding to the fine scaling edge of the lesion. This is associated with mild central atrophy. Biopsies to confirm the diagnosis should therefore include the edge of the lesion, and should be oriented in a manner that enables sections to be cut through the edge of the lesion.

Disseminated superficial actinic porokeratosis

Disseminated superficial actinic porokeratosis (DSAP) is the most common clinical pattern of porokeratosis. Multiple lesions occur, usually about 0.5–1cm in diameter, and usually most prominent on the legs and to a lesser extent on the dorsal forearms. They are usually asymptomatic or mildly irritable due to surface scaling. Development of squamous cell carcinoma is infrequent in DSAP but does occur, and any individually more crusted lesion should be biopsied.

Differential diagnosis

Small lesions of DSAP pattern may go unnoticed for years, may be viewed as ‘age spots', or may be treated as dry skin or as mild eczema. The main differential, however, is from AK or, if crusted, from squamous cell carcinoma.

Treatment

Treatment is along the same lines as for AKs (i.e. cryotherapy or other destructive modalities for selected localized lesions, and 5-fluorouracil for multiple scattered lesions). Variable results have been reported with PDT. Many patients with DSAP require no specific intervention, or only to selected lesions, and some may just use emollients, mild keratolytics, or topical retinoids. In some severe cases of porokeratosis, there is a role for systemic retinoids.

Fig. 32.22 Porokeratosis of Mibelli on the finger. This shows the fine, scaly border well, which corresponds with the histologic feature known as a cornoid lamella.

Fig. 32.23 Porokeratosis of Mibelli, a congenital variant with reticulate patterning on the thigh. The central atrophy is apparent.

Fig. 32.24 Disseminated superficial actinic porokeratosis on the dorsum of the foot, showing multiple circular discrete lesions.

Arsenical keratoses

Etiology and pathogenesis

These are due to ingestion of arsenic, either given therapeutically (arsenic used to be a popular constituent of tonics), or in some endemic areas due to natural contamination of water supplies from arsenic in rock (known as hydroarsenicism). Exposure to arsenic has been linked with epidermal neoplasia, especially multiple Bowen disease and multiple basal cell carcinomas, usually with an interval of two or more decades since exposure.

Clinical

Examples of arsenical keratoses and related conditions are shown in Figures 32.19 and 32.26 – 32.28.

Fig. 32.25 Disseminated superficial actinic porokeratosis on the leg, showing multiple discrete crusted lesions, which are more pigmented than in many cases. The larger lesion created concern about squamous cell carcinoma but did not have histologic evidence of invasive malignancy.

Differential diagnosis

This is as for AK. However, the palmar lesions that occur would not be consistent with AK; the differential diagnosis at this site includes warts, punctuate palmoplantar keratoderma, palmar porokeratosis, and sporadic palmar crease keratosis (usually few in number).

Treatment

These lesions are not usually treated aggressively, due to their multiplicity, but cryotherapy may be useful (as with AKs). The relevance of these lesions is their cancer associations rather than the keratoses themselves, although it is possible for them to become neoplastic. Various internal tumors are associated with previous arsenic ingestion, such as carcinoma of lung; it also appears to be relevant in some patients with Bowen disease, as documented earlier. However, there is no statistically significant link between Bowen disease and internal malignancy, so routine internal tumor screening is not required.

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.