Section 21. Epidermal and Appendageal Tumors

A precancerous or premalignant lesion is one that has a strong likelihood of transforming into a malignancy. There is much debate about the validity of the concept of precancerous lesions, and the terminology has been confusing.1–4 Lesions discussed in this chapter are those that have a clinically demonstrated potential to become invasive carcinomas and are characterized by histologic atypia confined to the epidermis. The focus is only on the precancerous keratinocyte lesions and not on those of other epithelial cells such as the melanocyte, Merkel, and appendageal cells. Discussion of malignancies and premalignancies associated with these cells can be found in (Chapters 119, 120, and 123) respectively.

A common feature of all premalignant keratinocyte tumors (Table 113-1) is that they have the potential to become invasive squamous cell carcinoma (SCC). These precancerous lesions and SCC are considered by many to represent a continuum of disease with dysplasia at one end of the spectrum and invasive carcinoma at the other.

Actinic keratoses (AKs) or solar keratoses are cutaneous neoplasms consisting of proliferations of cytologically abnormal epidermal keratinocytes that develop in response to prolonged exposure to ultraviolet (UV) radiation. The concept of a precancerous keratosis was first presented by Dubreuilh in the late 1800s.5 AKs were first identified and named keratoma senilis by Freudenthal in 1926.6 In 1958, Pinkus further characterized these lesions and coined the term actinic keratosis.7 These lesions have also been called solar keratoses and senile keratoses. Actinic keratosis literally means a condition (-osis) of excessive horny (kerat-) tissue induced by a ray of light (aktis), presumably UV light. AKs have historically been considered precancerous or premalignant lesions with a potential for developing into SCCs. However, in recent years there has been an effort to redefine AKs as malignant neoplasms, because these lesions are essentially intraepithelial SCCs in evolution. Although not all AKs become SCCs, AKs are the initial lesion in a disease continuum that may progress to SCC. This concept of a progression along a spectrum is analogous to that of cervical carcinoma, for which cervical intraepithelial neoplasia (CIN) is the initial, “precancerous” lesion.8

AKs are clinically important lesions, not only because of their potential to develop into SCC, but because they are one of the strongest predictors that an individual may subsequently develop melanoma or nonmelanoma skin cancer (NMSC).9–11 With the increasing incidence and prevalence of melanomas and NMSCs (discussed in Chapters 114, 115, 123, and 124), persons with AKs are the perfect candidates for careful longitudinal observation for prevention of cutaneous malignancy and early intervention.

Epidemiology

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.

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

Etiology and Pathogenesis

Although genetic and environmental factors may play a role in the development of AKs and SCC, it has long been recognized that the most important contributing factor is habitual exposure to UV radiation, namely, sunlight exposure. UV radiation is responsible for the development of AKs, and eventually SCC, in two ways: first, it causes mutations in cellular DNA that, when not repaired, lead to unrestrained growth and tumor formation; and second, it acts as an immunosuppressant preventing tumor rejection20 (see Chapters 109, 110, and 112).

UV radiation-induced mutations in the tumor suppressor gene p53 play a pivotal role in the initiation of AKs and their development into SCC (Fig. 113-1; see Chapter 112). Multiple UV radiation-induced cellular insults to the skin result in a pathway to SCC that begins with photodamaged skin, progresses to the development of AKs, and eventually leads to some SCCs. AKs on photodamaged skin clinically represent expanded clones of genetically mutated cells that have escaped apoptosis and immune surveillance and have gone on to proliferate into clinically evident premalignant lesions.

Clinical Findings

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.

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.

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.

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.

Unusual Actinic Keratoses Variants

Histopathology

Diagnosis and Differential Diagnosis

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

Treatment

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

Treatment modalities for AKs can be broadly divided into lesion-targeted therapies and field therapies (Box 113-1).

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

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.

Shave Excision

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.

Topical Field Therapy

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).

5-Fluorouvacil

Imiquimod

Diclofenac

Procedural Field Therapy

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).

Future Treatments

Prevention

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

Arsenical keratoses (ArKs) are precancerous lesions found in association with chronic arsenicism. These lesions have the potential to develop into invasive SCC. Arsenic is a ubiquitous element that has no color, taste, or odor. It has the potential to cause characteristic acute and chronic syndromes in persons exposed to it, and such exposures are typically obscure because medicinal, occupational, and environmental sources still exist. Detection of acute and chronic arsenicism is important, because the acute form can be fatal and the chronic form is associated with a variety of cutaneous and internal malignancies. ArKs are associated with chronic arsenicism.

Epidemiology

History

Etiology and Pathogenesis

Clinical Findings

Histopathology

Diagnosis and Differential Diagnosis

Prognosis and Clinical Course

ArKs and arsenical-induced BD tend to persist for many years, and progression to invasive SCC is believed to be relatively rare. However, invasive SCCs that arise in ArKs are more locally aggressive and have a greater chance of metastasis than SCCs arising in AKs.110 In lesions of arsenical-induced BD, locally invasive SCC has been seen histopathologically in up to 20% of cases. Once invasive SCC has occurred in BD, it is said that at least one-third will demonstrate evidence of metastasis unless adequate treatment is provided.122

Treatment

Management of patients with chronic arsenicism and ArKs should include regularly scheduled total-body skin examinations and general physical examinations, possibly every 6 months.121 The exact incidence of internal malignancies associated with chronic arsenicism is unknown, so there is no standard protocol for the evaluation of potential internal malignancies. Exhaustive evaluations to detect such malignancies have not been recommended. Biannual detailed history taking and physical examination, yearly chest radiography, and selective testing when clinically indicated are probably reasonable recommendations.

Treatment of ArKs likewise is not standard and not mandatory, although treatment of these lesions is sometimes initiated to relieve the associated discomfort that some patients experience. Available treatment options include surgical excision, cryosurgery, curettage with or without electrosurgery, CO2 laser treatment, and topical chemotherapy with 5-FU, although 5-FU therapy is less successful in treating ArKs than in treating AKs.110 PDT has also been used to treat these lesions. Limited studies suggest that oral retinoids and keratolytics may be useful in treating ArKs.123,124 One case report of effective treatment of ArKs, BD, and BCC lesions in one patient with chronic arsenicism with topical 5% imiquimod cream has been reported.125

Etiology and Pathogenesis

Clinical Findings

Histopathology

Diagnosis and Differential Diagnosis

Prognosis and Treatment

Etiology and Pathogenesis

Clinical Findings

Histopathology

Diagnosis and Differential Diagnosis

Prognosis and Treatment

Clinical Findings

Histopathology

Prognosis and Treatment

History

Etiology and Pathogenesis

Clinical Findings

Histopathology

Diagnosis and Differential Diagnosis

Prognosis and Clinical Course

Treatment and Prevention

Several types of precancerous epithelial lesions have a viral association (Box 113-3), including bowenoid papulosis (BP), epidermodysplasia verruciformis (EV), vulvar intraepithelial neoplasia (VIN), anal and perianal intraepithelial neoplasia (AIN and PaIN), and penile intraepithelial neoplasia (PIN). Extensive research has shown that certain oncogenic or high-risk HPV (hrHPV) types play a significant role in the p s of these precancerous lesions.144 Over 100 types of HPV have been discovered, and the hrHPV subtypes that have been associated with these precancerous epithelial lesions are shown in Box 113-3. The role of the human papillomavirus (HPV) in the etiology and development of these precancerous lesions, as well as other malignant neoplasms, is further discussed in Chapter 196. The premalignant lesions of the lower anogenital tract (VIN, AIN, PaIN, PIN) are discussed later in this chapter.

Bowenoid Papulosis

BP is characterized clinically by the presence of pigmented verrucous papules and plaques primarily on the genitalia of predisposed, usually younger, individuals, and histopathologically by the presence of SCC in situ-like changes (Fig. 113-7) (see also Chapters 77 and 78). Genital lesions that histopathologically resembled SCC in situ were first described by Lloyd in 1970 as multicentric pigmented BD of the groin.145 In 1977, Kopf and Bart described multiple bowenoid papules of the penis.146 In 1979, Wade et al coined the term bowenoid papulosis of the genitalia.147 Other terms used for this condition include pigmented penile papules with carcinoma in situ changes, genital keratinocytic dysplasia, and penile carcinoma in situ associated with HPV infection.

BP is caused by infection with HPV, and numerous HPV types have been linked to BP, particularly hrHPV subtypes 16 and 18, but also including 31–35, 39, 42, 48, and 51–54 (see Chapter 196). Lesions are pink, reddish brown, or violaceous (see Fig. 113-7). Differential diagnosis includes early condylomata acuminata (see Chapters 77 and 78).

Histopathologically, the epidermis is usually hyperplastic with atypia, disordered maturation, scattered mitotic figures, and dyskeratotic keratinocytes.

The course of BP is variable, but mostly benign, ranging from spontaneous regression to persistence of lesions to rarely transformation into BD and invasive SCC. It has been estimated that the risk of malignant transformation is quite low, ranging from less than 1%–2.6 %.144,148 BP is highly contagious and patients with BP and their sexual partners should be followed and examined periodically, because of the increased risk of developing SCC, cervical, and vulvar neoplasia.149 Patients with persistent disease should probably undergo testing for altered immune status. Treatment of BP is recommended, and it typically responds well to local therapy, although recurrences are common. Therapeutic options include local destructive measures such as curettage with or without electrosurgery, CO2 laser, neodymium:YAG laser, cryosurgery, and excision. Topical tretinoin, topical 5-FU, and topical cidofovir have been used in anecdotally reported cases with mixed results.150 More recently, topical 5% imiquimod cream has shown promising results in a few case reports and would be the logical choice given its efficacy against HPV.151–156

Epidermodysplasia Verruciformis

(See Chapter 196)

EV is a rare inherited skin condition that arises when genetically susceptible individuals are infected with certain HPV subtypes, most notably HPV 5 and HPV 8, but also including HPV types 9, 12, 14, 15, 17, 19, 25, 36, 38, 47, and 50. EV individuals present in childhood with numerous thin, pink, flat papules and plaques that resemble verruca plana. They also have widespread scaly, erythematous, or hypopigmented macules and flat papules that appear similar to tinea versicolor. Approximately 30%–60% of persons with EV will develop cutaneous malignancies in these wart-like lesions, most often in the fourth to fifth decades of life and usually on sun-exposed areas of the skin. About 90% of these EV-related SCCs have been associated with HPV subtypes 5 and 8. A susceptibility for EV was localized to chromosome 17q25 in 1999,157 and mutations in two novel genes from this same region (EVER1 and EVER2) were identified and associated with EV more recently.158 In addition to the host genetic background, these EV-HPVs are activated by UV exposure and immunosuppression.

EV histopathologically may mimic other skin conditions and therefore a combination of patient history, clinical and histopathologic findings, plus viral and genetic testing is crucial to making the diagnosis of EV. Lastly, as EV-like lesions have been observed in the setting of immunosuppression (acquired EV), patients suspected of having EV should also be tested for HIV and other etiologies for impaired cell-mediated immunity should be considered.159 No specific or successful treatments exist for EV lesions. Mixed results have been seen with topical 5% imiquimod cream.159

Bowen disease (BD) is SCC in situ, originally described in 1912 by John T. Bowen, a Boston dermatologist.160 It affects both skin and mucous membranes and has the potential to progress to invasive SCC.

Epidemiology

BD may occur at any age in adults, but it is rarely seen in individuals younger than 30 years. The typical patient with BD is older than 60 years. The disease is said to occur with an equal incidence in men and women, although most studies report a slight preponderance in women.161 BD can be found on any body site, including both sun-exposed and nonsun-exposed regions of the body, although it appears to have a predilection for sun-exposed surfaces such as the head and neck and for the lower legs of women, in particular. The exact incidence of BD in the United States is unknown, but in one population study in Hawaii, the incidence was estimated at 142 per 100,000 persons.162 Lesions of BD are usually solitary but are multiple in up to 10%–20% of individuals.

Etiology and Pathogenesis

A number of different factors have been implicated in the development of BD, including a history of significant sun exposure, arsenic exposure, ionizing radiation, immunosuppression, and certain types of HPV infection. Up to 30% of extragenital BD lesions have been found to harbor HPV DNA.163,164 The age group and sites of predilection of BD suggest a strong association with sun exposure. BD is also rare in more heavily pigmented individuals, and it has been described with increased frequency in patients undergoing psoralen plus ultraviolet A (PUVA) therapy. The association with arsenic exposure has already been discussed. SCC in situ is seen commonly in organ transplant recipients after years of immunosuppressive drug therapy. Infection with HPV has been implicated in causing certain subtypes of BD. In particular, HPV-16 has been detected in many cases of anogenital BD and in some cases of finger and periungual BD.165

Clinical Findings

BD typically presents as a discrete, slowly enlarging, pink to erythematous thin plaque with well-demarcated, irregular borders and overlying scale or crust (Fig. 113-8A) resembling a psoriatic plaque. Hyperkeratotic and verrucous surface changes may be seen, and a pigmented variant of BD has been reported in fewer than 2% of cases.166 Individual lesions may measure up to several centimeters in diameter, and multiple lesions are not uncommon. As previously mentioned, sites of predilection include sun-exposed areas such as the head and neck and lower legs, although any body site may be affected.

A few clinical variants of BD deserve special mention. Intertriginous BD can present as an oozing, erythematous, dermatitic plaque or as a pigmented patch or plaque. BD involving the periungual region may appear as an erythematous, scaly, thin plaque around the cuticular margin, a crusted erosion, nail discoloration, erythronychia, onycholysis, a verrucous plaque, or destruction of the nail plate (Fig. 113-8B). BD of the mucosal surfaces can present as verrucous or polypoid papules and plaques, erythroplakia, or a velvety erythematous plaque. These last two entities are discussed below in the sections on precancerous lesions of the oral cavity and the lower anogenital tract, respectively.

Histopathology

The epidermis displays full-thickness atypia, including in the intraepidermal portions of the adnexal structures (see Fig. 113-8C). Involvement reaches from the stratum corneum down through the basal cell layer, although the basement membrane remains intact. Characteristically, parakeratosis and hyperkeratosis are present, as is acanthosis, with complete disorganization of the epidermal architecture. At times, the hyperkeratosis and parakeratosis are so pronounced that a cutaneous horn is present. Throughout the epidermis are numerous atypical, pleomorphic, hyperchromatic keratinocytes. These cells are sometimes vacuolated and have a prominent pale-staining cytoplasm, reminiscent of the cells in Paget disease. These cells show loss of maturation and polarity, in addition to numerous mitotic figures. Individually, keratinized cells with large, rounded, eosinophilic cytoplasm, and hyperchromatic nuclei can be found in the epidermis, as can multinucleated cells. These atypical cells also are seen throughout the pilosebaceous units, within the acrotrichia, follicular infundibula, and sebaceous glands. The upper dermis is typically infiltrated by numerous chronic inflammatory cells, including lymphocytes, plasma cells, and histiocytes.

Several histopathologic subtypes of BD can be seen. Psoriasiform BD displays parakeratosis and marked acanthosis with broad, sometimes fused, epidermal rete ridges. Atrophic BD, like atrophic AK, demonstrates a thinned epidermis, but in addition there is full-thickness atypia and lack of maturation, as well as adnexal involvement. Acantholytic BD shows marked acantholysis in the epidermis. Epidermolytic BD has changes of incidental epidermolytic hyperkeratosis (EHK) present. The phenomenon of intraepidermal epithelioma of Borst-Jadassohn—namely, nesting of the atypical cells within the epidermis, or so-called pagetoid BD—can also be seen.

Diagnosis and Differential Diagnosis

Clinically, BD is most often mistaken for superficial BCC; patches of dermatitis, psoriasis, or lichen planus; AK; benign lichenoid keratosis (BLK) or lichen planus-like keratosis; irritated seborrheic keratosis; or amelanotic melanoma (Box 113-4). More hyperkeratotic or verrucous lesions of BD may be difficult to distinguish clinically from viral warts, seborrheic keratoses, and SCC, and pigmented BD lesions can be mistaken for melanoma. Superficial BCC can sometimes be distinguished by its raised, subtle, and translucent border. Histopathologically, BD must be differentiated from Paget's disease; pagetoid melanoma in situ; eccrine, Merkel, and sebaceous carcinomas; BP; and podophyllin-induced changes in a wart (see Box 113-4). Both Paget's disease and BD may have the findings of vacuolated cells, but in contrast with BD, Paget's disease shows no dyskeratosis. Also, the material present in Paget's cells is periodic acid-Schiff (PAS) positive and diastase-resistant, whereas the PAS-positive material sometimes present in BD cells (i.e., clear cell BD) is glycogen and therefore PAS labile. Finally, staining for carcinoembryonic antigen yields positive results in Paget's disease but negative results in BD. Pagetoid melanoma in situ can be difficult at times to distinguish histopathologically from BD. In BD, the intercellular desmosomal bridges should be identifiable between the atypical keratinocytes, and melanocyte specific immunoperoxidase staining gives positive results in melanoma cells but negative results in BD and Paget's disease cells. The other rare pagetoid neoplasms are usually recognizable, but erroneous diagnoses can be made by the unwary. BP may lack the full-thickness epidermal atypia present in BD, but the clinical setting is paramount. Podophyllin applied topically to skin lesions causes metaphase arrest with resultant bizarre keratinocyte formation and sometimes a pattern of pseudoepitheliomatous hyperplasia that can be mistaken for BD. These changes typically resolve after a few days to a week.167

Prognosis and Clinical Course

The risk that untreated BD will progress to invasive carcinoma has been estimated in one older study at approximately 3%–5%.163 Estimates are that once invasive carcinoma occurs in BD, approximately 13% of these carcinomas will metastasize, and of these cases, 10% will end in death from widespread dissemination.168

The presence of BD in any given individual is a marker for a high risk of developing a subsequent NMSC.169 In studies addressing the association between the presence of BD and the risk of other NMSCs, approximately 30%–50% of BD patients had either previous or subsequent NMSC. Another study estimated the incidence ratio for subsequent NMSC to be 4.3.169 Previous studies also claimed that the presence of BD is a marker for internal malignancy, although a significant number of other investigations have been unable to substantiate this association. Critical analysis and meta-analysis of these past studies do not support the need for routine investigation for internal malignancy in persons with BD. The one exception to this position is in cases of BD related to previous arsenic exposure, in which the possibility of internal malignancy is real, as previously discussed. Also, BD involving the vulvar region in females and the perianal region in males has been associated with an increased risk of uterine, cervical, vaginal, and anal cancer, possibly due to HPV infection, as discussed.122,170

Treatment

A number of different modalities are available for the treatment of BD. Such treatments can be divided into three main categories: surgical and destructive therapies, topical therapies, and nonsurgical ablative therapies (Box 113-5). Surgical and destructive therapies include excision, Mohs micrographic surgery, curettage with or without electrosurgery, chemoablation with TCA, and cryosurgery. Topical therapies include 5-FU and 5% imiquimod cream (see Chapter 221). Nonsurgical ablative therapies are laser ablation, radiotherapy, and PDT (see Chapter 238). Although some of these modalities have reported cure rates that are better than others, no one treatment is right for all forms of BD. Therapy must be guided by the size and location of the BD, in addition to individual patient characteristics, such as age and healing capability. BD warrants definitive surgical therapy if it has previously failed topical chemotherapy or ablative surgery, due to its propensity to eventually affect large surface areas and to become invasive.

Vulvar Intraepithelial Neoplasia (VIN)

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Differential Diagnosis

Prognosis and Clinical Course

Treatment

Prevention

Anal (AIN) and Perianal (PAIN) Intraepithelial Neoplasia

Epidemiology, Etiology, and Pathogenesis

Clinical Findings

Histopathology

Prognosis and Clinical Course

Treatment

Prevention

Penile Intraepithelial Neoplasia (PIN)

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Histopathology

Prognosis and Clinical Course

Treatment

Prevention

In a World Health Organization (WHO) workshop held in 2005, the terminology, definitions, and classification of oral lesions with a predisposition to malignant transformation were discussed.193 The term potentially malignant was preferred over premalignant or precancerous. In addition, it was recommended that the traditional distinction between potentially malignant lesions and potentially malignant conditions be abandoned and that the term potentially malignant disorders be used instead. In this chapter the focus will be on oral leukoplakia (OL) and erythroplakia.

Leukoplakia is a clinical term that refers to a predominantly white lesion of the oral mucosa that cannot be rubbed off or characterized by any other definable lesion or known disease.194 Leukoplakia is the most common precancerous lesion of the oral mucosa, with the potential to become oral SCC (OSCC).195 OL is in the same clinical spectrum of disease as oral erythroplakia (OE), but unlike OE it is a much more frequently diagnosed lesion with a much lower rate of malignant transformation.

Epidemiology

The reported prevalence of OL varies from 0.2% to 5%, although such rates vary significantly among different geographical areas and demographic groups.196 In a worldwide systematic review of OL that included multiple studies involving more than 1,000 subjects, prevalence rates varied between 0.50% and 3.46%.197 The pooled prevalence estimate of OL in this study was between 1.49% and 4.27%.197 Leukoplakia is six times more common among smokers than among nonsmokers.198 Alcohol is an independent risk factor, regardless of beverage type or drinking pattern.199 There are conflicting results as to the possible role of HPV infection.200–202

In addition to potentially becoming a malignant growth, OL, and for that matter OE, have come to be viewed as risk factors or markers for other epithelial cancers of the oral cavity and upper aerodigestive tract. The concept of field cancerization applied to the oral mucosa implies that its entire surface can be affected by carcinogens. Indeed, approximately 20% of patients with SCC of the head and neck will develop another malignancy or precancerous lesion within 5 years of the first diagnosis.203

Etiology and Pathogenesis

Given the current definition of leukoplakia, identification of an etiologic factor for a given white lesion would exclude this diagnosis. Two factors in this setting are tobacco use and candidiasis. Tobacco use is believed to be a strong risk factor for the development of OL. Tobacco-related white lesions of the oral mucosa have been identified and then subsequently found to disappear once the habit of tobacco use has been discontinued. By current definitions and standards, such tobacco-related white lesions are thought to be different entities than true OL, which would not disappear with cessation of tobacco use.

Likewise, there has been much debate as to whether or not Candida infection is a cause of leukoplakia or a superimposed infection within a preexisting OL lesion. If one adheres to the strict and accepted definition of leukoplakia, a white lesion that disappears upon treatment of Candida infection is not leukoplakia. Thus, it is probably best to make a preliminary diagnosis of leukoplakia and then treat any underlying candidal infection and have the patient discontinue use of any tobacco products to see if the white lesion resolves. If such a lesion then resolves, it is not true leukoplakia.

The development of OL has been associated most strongly with the use of tobacco products, including smoked tobacco (cigarettes, cigars, pipe tobacco), smokeless tobacco (snuff, chewing tobacco), pan masala, and betel nut quid, as well as alternative tobacco products like bidis and kreteks. Also, combined tobacco use and alcohol consumption are thought to be synergistic in the development of OL and OSCC. Persons with a previous malignancy or premalignancy of the upper aerodigestive tract are at increased risk for further such lesions and malignancies, as previously mentioned. Preliminary studies suggest that HPV infection is two to three times more prevalent in oral precancerous mucosa and four to five times more prevalent in OSCC than in normal epithelium.204 In the same meta-analysis, hrHPV (16 and 18) were more frequently associated with OSCC than were low-risk HPV types.204

One study addressed the clinical risk factors for OL in a representative sample of the US population drawn from among the 15,811 participants in the US National Health and Nutrition Examination Survey III.205 In this study, females were less likely than males to have OL. The strongest independent risk factor was tobacco smoking. Three other independent predictors of OL were diabetes, increasing age, and lower socioeconomic status. Alcohol consumption, race and ethnicity, years of education, and body mass index all showed no independent association with OL.205 Investigators strongly urged further studies to confirm these findings (see Chapter 76).

Clinical Findings

OL is clinically divided into two subtypes: homogeneous OL and nonhomogeneous OL. Homogeneous OL has been defined as a mostly white, flat, uniform lesion that may have shallow cracks and a smooth, wrinkled, or corrugated surface that is consistent throughout.206 Nonhomogeneous OL has been defined as a mostly white or white and red lesion (erythroleukoplakia) that may be irregular and flat, nodular (speckled), ulcerative, or verrucous. Nonhomogeneous OL purportedly has a risk of malignant transformation that is four to five times higher than that of homogeneous OL. Another clinical subtype of OL is proliferative verrucous leukoplakia, which is most often found in patients who do not use tobacco products. This subtype has a high rate of transformation to malignancy.207

Physical Examination

Additional Diagnostic Tools

Histopathology

If the provisional diagnosis of OL is at all in doubt and/or a waiting period to assess for possible regression or disappearance of a white lesion after eliminating possible causative factors has not resulted in resolution of the lesion, the next advisable step in evaluating the oral white lesion is to obtain a biopsy specimen for histopathologic diagnosis. This is where the concepts of epithelial dysplasia and carcinoma in situ enter the picture.

In relation to the oral mucosa, epithelial dysplasia has been defined as a “precancerous lesion of stratified squamous epithelium characterized by cellular atypia and loss of normal maturation and stratification short of carcinoma in situ.”212 Carcinoma in situ of the oral cavity has been described as “a lesion in which the full thickness, or almost the full thickness, of squamous epithelium shows the cellular features of carcinoma without stromal invasion.”212 Criteria have been put forth for diagnosing these changes, and the more prominent and numerous the designated features are, the more severe the grade of dysplasia.195,206

On the basis of these subjective criteria, lesions are usually graded into mild-, moderate-, and severe epithelial dysplasia. A number of studies have shown significant intra- and interexaminer inconsistencies in assessing the presence or absence of oral epithelial dysplasia as well as its grade on histopathologic examination.195 Other studies have shown great variability in the number of lesions that go on to develop into malignancies based on their degrees of dysplasia. Some studies have shown a positive correlation between the degree of dysplasia and the development of malignancy, and others have demonstrated no correlation whatsoever.195

On the basis of these inconsistencies, three major problems have been identified in attaching significance to the degree of epithelial dysplasia in OL lesions as predictors of their malignant potential. First, the diagnosis of epithelial dysplasia is largely subjective. Second, although a definite correlation between degree of dysplasia and malignant potential has been shown, not all dysplastic lesions will progress to malignancy, and some may even regress. Third, OSCC has been shown to develop from nondysplastic oral epithelial lesions.195

As imperfect as this histopathologic grading system is, epithelial dysplasia in its varying degrees is still one of the few indicators available of an increased risk for OSCC.

Diagnosis and Differential Diagnosis

A diagnosis of leukoplakia is made when a fixed white lesion of the oral mucosa is detected and cannot be identified as any other definable lesion or condition. Some suggest distinguishing between a provisional clinical diagnosis of OL and a definitive diagnosis of OL.194 A provisional diagnosis of OL is made at the time of the initial examination when no other diagnosis for the white lesion is obvious. At this point, other possibilities to consider in the differential diagnosis are tobacco-associated lesions, Candida-associated lesions, lichen planus, leukoedema, lupus erythematosus, Epstein–Barr virus-associated oral hairy leukoplakia, oral white sponge nevus, mechanical or frictional irritation, contact lesions, cheek/lip/tongue biting, linea alba, aspirin burn, OSCC, and verrucous carcinoma (Box 113-6). If causative factors for the white lesion are suspected, it is recommended that these factors be eliminated for a period of 2–6 weeks to observe for regression of the white lesion. If upon reevaluation the white lesion persists, biopsy should be performed. If the lesion is clinically at high-risk for OSCC, biopsy should be performed before such a waiting period.

Prognosis and Clinical Course

Once a definitive diagnosis of OL has been made, the risk of transformation to OSCC needs to be evaluated. The rate of malignant transformation of OL into OSCC has been found to vary from almost 0% to 20% in 1–30 years.213 A study based on European epidemiologic data investigated the natural limit of malignant transformation of OL to OSCC. This study concluded that the upper limit of the annual malignant transformation rate of OL is unlikely to exceed 1%.196

The commonly recognized variables that statistically carry an increased risk for malignant transformation into an SCC are listed in Box 113-7. Of these variables, the presence of dysplasia is the most important indicator. However, it should be recognized that not all dysplastic lesions progress to malignancy. Some remain clinically unchanged and others may spontaneously regress. Furthermore, malignant transformation may occur in nondysplastic leukoplakia.

In spite of great progress in the field of molecular biology, there is not yet one single marker or set of markers that reliably enables prediction of malignant transformation of leukoplakia in an individual with OL.193

Treatment and Prevention

The goal of treatment is to prevent the malignant transformation of OL to OSCC and to relieve patient symptoms, although there is no evidence that treatment of OL can prevent the future development of OSCC. There is no consensus on the most appropriate treatment for OL. Some recommend the following approach: if no or mild epithelial dysplasia exists histopathologically, pursue treatment if the OL is in a high-risk location or is large; if moderate or severe dysplasia exists histopathologically, then active treatment to remove the entire lesion is recommended.206 A systematic review of all the randomized, controlled trials of all therapies for OL (n = 7) concluded that there is no known nonsurgical therapy to prevent OL from developing in the first place or to prevent OL from transforming into OSCC.213 The reviewers did find some evidence that treatment with vitamin A, retinoids, and β-carotene may completely resolve the oral lesions and that treatment with retinoic acid may prevent histopathologic worsening, but these findings were based on only a small number of patients.213

Postexcision recurrences are common and occur in 10%–20% of cases, and OSCC develops within excised areas in 3%–9% of instances.210 In addition, surgical excision with histopathologically clear margins did not prevent OSCC or improve survival outcomes in the group of patients with aneuploid dysplastic OL, the most likely form of OL to progress to OSCC, in one study.214

CO2 laser vaporization is another commonly employed treatment modality—again without substantial data to support its use. In one review of 200 patients with 282 OL lesions treated with CO2 laser vaporization between 1976 and 2001, 89% (n = 251) had no recurrence during a mean follow-up time of 52 months; 9.9% (n = 28) had local recurrence between 5 months and 168 months after treatment; and 1.1% (n = 3) developed OSCC within the treated area at 7, 17, and 19 months after the CO2 laser treatment.215

Because the recurrence of OL after treatment is common and the risk of OSCC is present with or without treatment, and because patients with OL are at increased risk for additional head and neck malignancies, these patients need to be followed at regular intervals with thorough examinations and potentially with additional biopsies. Follow-up intervals may vary from every 3 months in high-risk individuals to every 6 months in those at lower risk, for the rest of the patients’ lives.

Despite all the controversies and inconsistencies surrounding OL, standard historical, clinical, and histopathologic findings are still the most important factors for predicting the possibility of malignant transformation of precancerous oral lesions. Treatment plans are guided mostly by findings from careful clinical and oral examinations, especially in individuals at high risk, and by histopathologic evaluation for the presence and degree of epithelial dysplasia (Fig. 113-9).

Erythroplakia, or erythroplasia, is a clinical term used to describe a red macule or patch on a mucosal surface that cannot be categorized as any other known disease entity caused by inflammatory, vascular, or traumatic factors. Histopathologically, it almost always displays either findings of SCC in situ or focal areas of invasive SCC, and thus is considered a precancerous lesion at best and always warrants treatment. Erythroplakia can involve any mucosal surface but most commonly occurs on the oral mucosa in more than half of all cases. Of all oral precancerous lesions, it is considered to be the most dangerous and carries the greatest risk of progressing to or harboring invasive carcinoma.

Epidemiology

Erythroplakia is an uncommon lesion in the oral cavity, and it is said to be one of the least commonly diagnosed lesions among the group of oral lesions that may or may not become malignant.216 The prevalence, based on a small number of worldwide studies, is between 0.02% and 0.83%.217 Both tobacco and alcohol are considered etiologic factors, and it mainly occurs in middle-aged individuals without a gender preference. It has been well described in the chutta smokers (reverse cigar smokers) of India.217

Etiology and Pathogenesis

Clinical Findings

OE is usually found either intraorally or on the vermillion surface of the lower lip. The most common areas in the oral cavity are the soft palate, the floor of the mouth, and the buccal mucosa. OE usually presents as a solitary, subtle, asymptomatic, erythematous macule or patch. Most often it is less than 1.5 cm in its widest diameter, but lesions up to 4 cm in diameter have been described.217 Characteristically, it is sharply demarcated from the surrounding pink mucosa, and its surface is most often smooth and homogeneous in color. On occasion lesions of erythroplakia demonstrate a pebbled or stippled surface change and on palpation may have a soft and velvety feel. Induration indicates the presence of invasive carcinoma in many instances. Erythroplakia is commonly seen in association with leukoplakia, a condition termed erythroleukoplakia. It is the red patches of erythroleukoplakia that are most likely to contain or develop into a malignancy.

Histopathology

Diagnosis and Differential Diagnosis

Prognosis and Clinical Course

Treatment and Prevention

Cutaneous squamous cell carcinomas (SCCs) are malignant neoplasms derived from suprabasal epidermal keratinocytes. These and basal cell cancers are the nonmelanoma skin cancers that represent the most common malignancies in humans. Whereas basal cell carcinoma (BCC) (see Chapter 115) is thought to arise de novo, SCC probably evolves in most cases from precursor lesions of actinic keratosis (AK) and Bowen disease (SCC in situ) (see Chapter 113). This chapter focuses on clinical aspects of invasive SCC. Cutaneous SCC represents a broad spectrum of disease ranging from easily managed, superficially invasive cancers to highly infiltrative, metastasizing tumors that can result in death. The clinical presentation can be variable despite the existence of easily identified typical lesions. The cellular and molecular aspects of SCC carcinogenesis are discussed elsewhere (see Chapter 113).

Epidemiology

Incidence

The precise incidence of BCC and SCC is unknown, because these cutaneous malignancies are not generally documented by the National Cancer Institute or most state cancer registries. However, it is generally accepted that well over 1 million cases are diagnosed in the United States each year, with approximately 200,000 representing SCC.10 Although less common than BCC, SCC carries a risk of metastasis and thus accounts for the majority of the several thousand deaths attributable to nonmelanoma skin cancer each year. By comparison, cutaneous melanoma accounts for only 60,000 cases, but approximately 9,000 deaths, annually.11 Similar trends for SCC have been noted in Australia12 and the Caribbean.13

SCC is strongly associated with advanced age, and a sharp increase in incidence is seen after age 40 years.14 Today, the lifetime risk of SCC among whites is approximately 15%, almost double that of two decades ago. Increased exposures to ultraviolet (UV) radiation (through greater use of tanning salons, increased time spent outdoors, changes in clothing styles, and ozone depletion) and greater longevity have been suggested as possible causes for the increase in disease. It is likely that this trend will continue as a result of further depletion of the ozone layer and the aging of the US population. The rising incidence of SCC over the past several decades has been paralleled by a 20% decrease in mortality, attributed largely to increased public awareness and aggressive treatment of high-risk lesions.15 After a diagnosis of SCC, patients have a 44%–50% cumulative risk of developing another nonmelanoma skin cancer (18%–30% risk of SCC) in the subsequent 3–5 years.16 In addition, these patients are at increased risk for extracutaneous–cancers.17

Demographics

Squamous cell cancer is twice as common in men as in women, probably as a result of greater lifetime UV exposure in men. Similarly, longer hairstyles and use of lipstick may account for the lower frequency of SCC on the ears and lips of women. There is an inverse relationship between skin pigmentation and SCC incidence, largely because of the protective effect of eumelanin. Thus, persons with white skin, blue eyes, fair complexion, red hair, and Celtic ancestry who tan poorly are at greatest risk. Increased pigmentation is associated not only with a lower incidence of SCC, but also with an inversion in the BCC/SCC ratio. In comparison with whites, the incidence of SCC is decreased by 30-fold in American blacks and the BCC/SCC ratio falls to 0.8:1.14 Tanzanian albinos all develop SCC by young adulthood, and the ratio of BCC to SCC is only 0.2:1. Asians and Polynesians, with intermediate skin pigmentation, have correspondingly intermediate levels of SCC. A gene (MC1R) involved in melanogenesis that encodes the melanocortin 1 receptor is a major determinant of skin pigmentation and hair color. The MC1R gene is highly polymorphic, with more than 20 variants described.18 Several variant MC1R alleles are associated with increased risk of SCC that is independent of skin type and hair color.

Predisposing Factors

There are a number of factors, including both acquired and genetic skin conditions that may predispose to SCC (Table 114-1). Patients often demonstrate a multiplicity of factors that together are sufficient to induce SCC development. For example, a given skin site may be exposed to both UV radiation and another environmental carcinogen.

Precursor Lesions

Most SCCs develop from precursor lesions such as AKs or Bowen disease (see Chapter 113).

Ultraviolet Radiation Exposure

UV radiation is considered the predominant risk factor for SCC. Importantly, there is a linear correlation between the incidence of SCC and exposure to UV radiation. The incidence of SCC has been reported to double with each 8°–10° decline in geographic latitude and is highest at the equator.19 World War II veterans stationed in the Pacific developed much higher rates of SCC than did their colleagues who served in Europe.20 Similarly, SCC is more prevalent in Japanese people who emigrated to Hawaii than in those who remained in Japan.21 Excessive UV radiation appears to be related more to the development of SCC than to the development of BCC. Rates of SCC rise more rapidly than those of BCC with increasing UV exposure,22 and UV radiation-induced skin cancers in mice are almost exclusively SCCs rather than BCCs.23 Moreover, in patients receiving long-term therapy with psoralen plus ultraviolet A (UVA) radiation for treatment of psoriasis there is an associated 30-fold increase in nonmelanoma skin cancers, most of which are SCCs.24

Ionizing Radiation

There is a strong association between SCC and exposure to ionizing radiation. In one survey of SCC patients, an association with radiation therapy was observed only in those whose skin was likely to sunburn (see Chapter 113).

Environmental Carcinogens

Numerous occupational and environmental carcinogens, such as arsenic and aromatic hydrocarbons, predispose to the development of SCCs. With the exception of 3-methylcholanthrene and anthramine, chemical carcinogens generally produce SCCs rather than BCCs.25 Exposures to insecticides and herbicides have also been associated with SCCs. In addition, smoking and alcohol use are strongly associated with SCCs of the oral cavity.

Immunosuppression

Chronic immunosuppression may lead to an increase in SCCs, primarily on sun-exposed sites.26 An 18-fold increase in SCC has been reported in renal transplant patients27; these tend to appear 3–7 years after the onset of long-term immunosuppressive therapy, with corticosteroids, azathioprine, and cyclosporine most frequently implicated. With the increase in the total number of organ transplant patients, management of SCCs in this population is becoming more important. In patients with leukemia and lymphoma, SCCs are both increased and more aggressive.28 Although multiple SCCs have been described in patients infected with human immunodeficiency virus, advanced human immunodeficiency virus infection has generally not been associated with an increased incidence of SCC, possibly because many patients do not live long enough to develop them.

Scars and Underlying Diseases

Historically, SCC was associated with both burn scars and chronic ulcers as noted earlier, but such associations are seldom seen today. Also rare but reported is the development of SCCs in the context of chronic infections, particularly those associated with draining sinuses and scarring, such as perianal pyoderma, osteomyelitis, chromomycosis, hyalohyphomycosis, granuloma inguinale, lupus vulgaris, and leprosy. Chronic inflammatory processes, particularly those associated with scarring, such as venous ulcer, snakebite ulcer, discoid lupus erythematosus, oral lichen planus, morphea, lichen sclerosus, pilonidal cyst, acne conglobata, hidradenitis suppurativa, Hailey–Hailey disease, dissecting folliculitis of the scalp, and necrobiosis lipoidica, all can give rise to SCCs. An exception is vaccination scars, which are associated with BCCs rather than SCCs. SCCs have also been observed in transplanted skin, epidermal cyst, dental cyst, and dermoid cyst.

Thermal Factors

Long-term heat exposure can lead to SCCs. The role of thermal radiation in the development of skin cancer has long been recognized in many cultures, where common practices include placing hot ashes under the clothes to keep warm in winter or smoking opium while lying on heated beds. The incidence of SCCs is increased in persons who habitually sit in front of heating stoves and at sites of erythema ab igne (see Chapter 113).

Viral Infection

A role for human papillomavirus (HPV) infection has been well established in some types of SCCs. Verrucous carcinoma appears to be associated with several HPV types, as noted later. Head and neck and periungual SCCs are frequently associated with HPV-16. Patients with epidermodysplasia verruciformis are chronically infected with HPV, most commonly type 5, and one-third of these patients ultimately develop SCCs (see Chapters 113 and 196). Recently, the MCPyV polyoma virus, originally discovered in Merkel cell carcinoma, was identified in approximately 15% of cutaneous SCCs from immunocompetent patients.A An etiological role for MCPyV in SCC remains to be demonstrated.

Genodermatoses

A variety of heritable diseases predispose to SCC development. Patients with oculocutaneous albinism develop predominantly SCCs (rather than BCCs) at an early age (see Chapter 73). Xeroderma pigmentosum (see Chapters 110 and 139), a disorder of DNA repair, is also characterized by early development of SCCs. SCCs have been reported to develop in the Mibelli, disseminated superficial actinic, and palmaris et plantaris disseminata forms of porokeratosis (see Chapter 52), and in oral lesions of dyskeratosis congenita. As noted in Section “Viral Infection,” lesions of epidermodysplasia verruciformis can degenerate into SCCs (see Chapter 196). Finally, patients with the dystrophic form of epidermolysis bullosa are at increased risk for SCC (see Chapter 62).

Molecular Aspects

As in most cancers, the development of SCC from normal keratinocytes begins with mutations in the cellular DNA and genomic instability. Alterations in gene expression lead to loss of growth controls, penetration of the basement membrane, and ultimately invasion into surrounding tissue. Along the pathway to SCC, keratinocytes become resistant to apoptosis (programed cell death) and immune attack.

Genetic Alterations

Most analyses of genetic alterations in SCCs have been performed in cases of oral or head and neck SCCs. Chromosomal deletions (loss of heterozygosity) commonly involve chromosomes 3, 9, 11, and 17; the regions most commonly identified include 9p21 and 17p13 where the INK4A (p16/Arf) and p53 tumor suppressors, respectively, are located.29 Similar genetic lesions were found in a study of young patients (younger than 40 years of age).30 It is unclear whether these genetic markers will serve as useful prognostic indicators.

p53 in the Defense Against Skin Cancer

A role for p53, cyclin D1, human telomerase reverse transcriptase, p16, and thrombospondin 1 has been identified in the multistep process of human skin carcinogenesis.31

Apoptosis of keratinocytes that have sustained UV radiation-induced DNA damage, termed sunburn cells, requires the p53 tumor suppressor and represents a key protective mechanism against skin cancer by removing premalignant cells that have acquired mutations. In keratinocytes, UV radiation upregulates p53,32 which delays cell cycle progression until DNA damage can be repaired or facilitates cell elimination by apoptosis.33 Compromise of p53 function could undermine this apoptosis-based defense mechanism, giving UV-damaged cells a selective advantage to survive additional cycles of UV exposure.34 Further impairment of p53 and other genes through additional UV radiation-induced mutations may then lead to even greater resistance to apoptosis, increased proliferation, and ultimately development of SCC. The increased susceptibility of p53-deficient mice to UV radiation-induced SCC35 highlights this protective role of p53.

p53 Mutations in Squamous Cell Carcinoma

Consistent with the scenario described in Section “p53 in the Defense Against Skin Cancer,” mutations in the p53 gene are a common finding in SCC.36 In most cases, these are C→T single base and CC→TT tandem transition mutations at dipyrimidine sequences, i.e., “UVB-signature” mutations.37 Most SCCs exhibit loss of heterozygosity with respect to p53 and isolated mutations on the remaining allele. In one study, the p53-apoptosis pathway was disrupted in 50% of oral SCCs. With respect to SCC precursors, p53 mutations were found in up to 75% of AK and SCC in situ lesions.38 Interestingly, although different p53 mutations were found in separate AKs, all cells within a single precursor lesion had the same mutation.31 Mutations in p53 can also be detected in keratinocytes from clinically normal sun-exposed skin.39 Keratinocytes with p53 mutations occur in clonal patches that are larger and more frequently in sun-exposed skin.40 These findings substantiate a clonal basis for UV radiation-induced SCC and suggest that p53 mutation is an early event in the development of SCC.

In addition to undergoing mutation, p53 can be compromised in keratinocytes infected with HPV. The E6 protein encoded by oncogenic HPV types binds p53 and targets it for rapid degradation, which disables the p53-apoptosis pathway. This is a primary mechanism by which HPV infection predisposes to SCC (see Chapter 196).