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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
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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.
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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
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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.
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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
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Etiology and Pathogenesis
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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).
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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.
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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.
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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.
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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.
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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.
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Unusual Actinic Keratoses Variants
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Unusual variants of actinic keratoses (AK) include pigmented AK, spreading pigmented AK, proliferative AK, and conjunctival AK. The pigmented AK presents as a flat, tan to brown, scaly papule or plaque. Clinically, and many times dermatoscopically, it can be difficult to distinguish from a solar lentigo or lentigo maligna.
22 Spreading pigmented AK is a particular lesion that is often found on the face or scalp. It is typically a large lesion, often reaching more than 1 cm in diameter, and presents as a scaly, verrucous, or smooth plaque with variable colors. Proliferative AK is seen as an expanding, red, oval, scaly plaque that reaches up to 4 cm in diameter. It has poorly defined borders. Conjunctival AK is classified as a type of pinguecula or pterygium. It appears as a wedge-shaped, opaque thickening near the limbus, and it may extend onto the cornea from the scleral conjunctiva.
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The typical erythematous AK has characteristic architectural and cytologic histopathologic features. All of the abnormalities are confined to the epidermis, although dermal solar elastosis is usually present and an inflammatory dermal infiltrate may also be seen. The classic histopathologic findings include foci of atypical, pleomorphic keratinocytes along the basal cell layer and protruding as buds into the papillary dermis. The basal cell layer appears more basophilic because of crowding of the atypical keratinocytes. Overlying these foci of abnormal cells, one often sees irregular acanthosis, hyperkeratosis, and parakeratosis. There is notable sparing of the adnexal epithelium, with orthokeratosis overlying these structures, which gives rise to the characteristic pattern of alternating orthokeratosis and parakeratosis (see
Fig. 113-3B). Cytologically, there is an increased nuclear–cytoplasmic ratio in the atypical keratinocytes in addition to nuclear pleomorphism and mitoses.
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Just as there are clinical variants of AKs, there are histopathologic variants. These histopathologic variants all share the classic features of the AK as described earlier, but with some additional findings. In HAK, the hypertrophic areas consist of marked hyperkeratosis and parakeratosis. A cutaneous horn that represents AK demonstrates changes similar to but more exaggerated than those in HAKs with massive tiers of hyperkeratosis and parakeratosis. The base of such a cutaneous horn shows the typical histopathologic changes of an AK. An atrophic AK has very mild hyperkeratosis and a thinned epidermis that is devoid of rete ridges. Bowenoid AK is a histopathologic variant that demonstrates near full-thickness epidermal dysplasia, but unlike true Bowen disease (BD) or SCC in situ, there is no or very little involvement of the adnexal epithelium. In proliferative AK there are exaggerated bud-like downgrowth of atypical keratinocytes into the papillary dermis. Although difficult to distinguish from SCC at times, these proliferative bud-like downgrowth are contiguous with the epidermis in the proliferative AK, unlike in true SCC.
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In the pigmented AK one sees excessive amounts of melanin, especially in the basal cell layer. In the spreading pigmented AK variant, in addition to the typical AK histopathologic findings, one may see increased melanin in melanocytes and in the atypical keratinocytes. Lichenoid AKs are characterized by a dense, band-like lymphohistiocytic infiltrate at the dermal–epidermal junction with basal cell liquefactive degeneration and occasional Civatte bodies. In the acantholytic AK variant there are clefts of lacunae directly above the atypical keratinocytes with discohesive individual atypical keratinocytes within the clefts, reminiscent of the changes seen in Darier's disease. The acantholysis in an acantholytic AK is a result of the anaplastic changes occurring in the lower epidermis and loss of normal keratinocytic attachments. The clear cell variant of AK arises from an excess of cytoplasmic glycogen, which results histopathologically in marked vacuolation of the epidermis.
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Two different histopathologic reaction patterns may be seen in AKs: namely, epidermolytic hyperkeratosis (EHK) and the pattern known as
intraepidermal epithelioma of Borst-Jadassohn. In an otherwise histopathologically classic AK, one may find incidental changes consistent with EHK. The findings of EHK in these AKs most commonly are focal and isolated and have no clinical importance. Some authors consider intraepidermal epithelioma of Borst-Jadassohn to be a specific lesion,
23 but other authors
24 believe that this entity actually represents a type of reaction pattern found in a variety of lesions, such as AK, pagetoid BD, clonal seborrheic keratosis, intraepidermal malignant eccrine poroma, mammary and extramammary Paget's disease, intraepidermal junctional nevus, and melanoma in situ. The pattern so named is that of an intraepidermal neoplasm characterized by nests and individual cells proliferating or scattered within normal epidermis. In so-called
pagetoid AK, there are adjacent typical changes of AK, although differentiating this entity from pagetoid BD is often quite difficult.
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An important point to remember in making the diagnosis of AK histopathologically is that if the physician has a strong clinical suspicion of SCC or basal cell carcinoma (BCC) and the initial cuts reveal AK, it is prudent to section more deeply into the block of tissue to ensure that an SCC or BCC is not missed. In one study additional diagnostic findings were present on step sections in 23 of 69 specimens (33%) initially diagnosed histopathologically as AK. Of these additional findings, 13% were indicative of BD, 4% of BCC, and 3% of invasive SCC. Three variables that correlated with the discovery of malignancy on step sections were ulceration on the first level, a clinical diagnosis of skin cancer, and a history of skin cancer confirmed previously by biopsy examination.
25
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Because of the intimate association between AK and SCC, a number of dermatopathologists have proposed a more descriptive diagnosis that would more accurately reflect the nature of this disease. Cockerell has argued that because this entity is closely akin to cervical intraepithelial neoplasia (CIN), terms such as
solar keratotic intraepidermal SCC or
keratinocytic intraepidermal neoplasia would better define AK.
1,8 Ackerman
26 has argued that solar keratosis is in fact SCC and should not be distinguished histopathologically. At this time,
actinic keratosis and
solar keratosis are the most recognized terms for this diagnosis, and most authors consider these lesions precursors of SCC rather than the malignant entity itself.
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Diagnosis and Differential Diagnosis
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The diagnosis of AK is accurately made by clinical examination in most instances when the examiner is familiar with AK and skilled in making such diagnoses. However, some investigators have commented on the difficulty of accurate and consistent counting of AK lesions by experts involved in AK research studies.
27 In practice, very few AKs are histopathologically confirmed, and thus few data exist on the accuracy of clinical diagnosis. The accuracy of clinical diagnosis is higher in a clinical referral setting than in the general community setting. One study involving a referral setting revealed a diagnostic accuracy of 94%, based upon the correct histopathologic diagnosis of 34 of 36 clinically suspect, typical AKs.
28 Another study in a community-based setting reported a diagnostic accuracy of approximately 80% when random clinically diagnosed AKs were subject to histopathologic confirmation.
29 In the more recent multicenter Veterans Affairs Topical
Tretinoin Chemoprevention Trial (VATTC), researchers found that the greatest disagreements in the histopathologic diagnosis of BCC and SCC (keratinocytic carcinomas) between two referral dermatopathologists were in making the diagnoses of AK and invasive SCC.
30
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The clinical features of typical erythematous AKs are not unique to these lesions. The differential diagnosis includes other common lesions as noted in
eBox 113-0.1. Of the clinical AK variants, pigmented AK is difficult to distinguish from solar lentigo and sometimes lentigo maligna; spreading pigmented AK, from lentigo maligna or a large seborrheic keratosis; HAK, from SCC; and cutaneous horn, from the many entities it may represent.
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Clinically, the greatest challenge is to distinguish an AK from an SCC, because the latter portends a more serious prognosis and requires different treatment. There are no reliable clinical criteria for distinguishing between these two entities, but findings of induration, pain, larger size, marked hyperkeratosis, ulceration, bleeding, rapid growth, and recurrence or persistence after treatment make the diagnosis of SCC more likely.
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Histopathologically, AK can be confused with benign lichenoid keratosis (BLK) or lichen planus-like keratosis (LPLK), because both can show vacuolar alteration of the basal cell layer and lichenoid infiltrates. However, closer inspection reveals that in BLK/LPLK there is no cellular atypia of the keratinocytes as is seen in AK, and often the remnants of solar lentigo are seen at the periphery of the lichenoid infiltrate. An atrophic AK can be mistaken for cutaneous lupus erythematosus, because both can demonstrate epidermal thinning and basal cell liquefaction. In cutaneous lupus, however, other classic features of the disease should also be present, such as follicular plugging and a patchy periappendageal infiltrate. Finally, pigmented AK may be confused histopathologically with lentigo maligna, but the latter usually has more flattening of the epidermis, an increased number of single and nested melanocytes, atypical melanocytes, and normal keratinocytes.
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Prognosis and Clinical Course
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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.
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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
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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
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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
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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
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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
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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.
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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
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Treatment modalities for AKs can be broadly divided into lesion-targeted therapies and field therapies (Box 113-1).
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Lesion-Targeted Treatments for Actinic Keratosis
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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
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Liquid Nitrogen Cryosurgery
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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.
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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.
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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.
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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.
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Field Therapies for Actinic Keratosis
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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.
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Topical Field Therapy
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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).
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5-FU therapy has been a mainstay of topical treatment for AKs since the 1960s (see
Chapter 220). 5-FU is a pyrimidine analog that inhibits the enzyme, thymidylate synthase, thus, interfering in DNA synthesis and ultimately resulting in apoptosis and tumor cell death. 5-FU acts selectively to cause cellular destruction in actinically damaged cells but not in normal skin. 5-FU treatment of sun-damaged skin usually causes a brisk inflammatory reaction, which is felt to contribute to its overall efficacy.
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Although many different treatment regimens have been proposed and used with topical 5-FU, the historical standard FDA-approved method consists of twice-daily application of 5-FU cream or solution to the entire affected region, typically for 2–4 weeks. Spot treatment of specific AK lesions is not recommended but is a common practice. There is also some evidence that concurrent treatment or pretreatment with topical
tretinoin is more effective than 5-FU alone for AKs on the extremities.
51 Therapy should be continued until the treated area demonstrates erythema, erosion, crusting, and necrosis, at which time treatment should be discontinued. Different strengths (1%, 2%, 5%) and vehicles (cream or solution) of topical 5-FU are available. More recently, a 0.5% micronized 5-FU cream has become available and FDA approved for treating AKs. It can be applied once daily for 4 weeks. The choice of which topical 5-FU formulation to use depends on physician preference, individual patient characteristics, and the number and location of AKs being treated.
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Anecdotally, topical 5-FU has been thought to be 75% effective, that is, seven or eight out of ten treated AKs will resolve with appropriate therapy.
52 The long-term remission rates after 5-FU treatment vary, but the condition frequently recrudesces in a few years and severely affected patients sometimes return to baseline.
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The once-daily, 0.5% micronized 5-FU cream was developed in an attempt to make the topical 5-FU therapy more tolerable. It is FDA approved for the treatment of multiple AKs on the face and anterior scalp. Premarketing studies of this medication showed that more than 75% of treated lesions clinically resolved in 60%–80% of patients treated for 4 weeks. One study found an overall 89% reduction of AKs and a complete clearance rate of 48% in patients treated for 4 weeks with a once-daily application of 0.5% micronized 5-FU cream.
53 In a split-face comparison study of 5% 5-FU and 0.5% 5-FU cream, similar complete clearance rates of approximately 50% were observed for both therapies.
54 The investigators noted a similar reaction rate with erythema, crusting, and scabbing, but overall the patients preferred the 0.5% micronized 5-FU cream because of its once-daily application regimen and a perception of less irritation.
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Effective treatment relies greatly on the patient's understanding and compliance with the prescribed 5-FU regimen. The clinician should spend time with the patient educating the patient about the proper application of the medication, the duration of therapy, and the expected outcome. Written handouts reiterating this information and photographs of the expected reaction are helpful for patients to view and take home.
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Patients should expect discomfort, pruritus, and burning at the sites of application, as well as erythema, erosion, crusting, and possibly ulceration beginning at around 1 week into treatment (
eFig. 113-6.1). These and other adverse reactions to 5-FU are further discussed in
Chapter 220. Other photodamaged areas of the skin that seemingly have no visible evidence of AKs may also become quite inflamed during treatment, leading not only to the treatment of unmasked AKs, but also to the histopathologically proven rejuvenation of the skin.
55 Much lower cure rates are seen when patient compliance is poor and the expected end points are not reached.
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The second agent available for topical field treatment of multiple AKs is
imiquimod cream (see
Chapter 220). It works by inducing both the innate and adaptive arms of the immune system to recognize and destroy AKs. It is available in 5%, 3.75% and 2.5% formulations. First approved in 1997 by the FDA for the treatment of genital and perianal warts, it was approved in 2004 for the treatment of nonhypertrophic AKs on the face and scalp in immunocompetent adults. It is also approved for treatment of superficial BCC (see
Chapter 115).
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The FDA-approved regimens for the three different strengths of
imiquimod are outlined in
Box 113-2. Treatment with
imiquimod cream is associated with adverse reactions, most notably local skin reactions such as erythema, scabbing, flaking, erosion, weeping, and vesicle formation. Such reactions are actually predictive of better ultimate clearance of the AKs, as the greatest resolution of AKs has been seen in patients with the most severe reactions.
56–58 Systemic absorption is minimal, and overall excellent safety margins have been demonstrated with the topical administration of
imiquimod cream.
59 Systemic adverse effects, including interferon-like side effects such as flu-like symptoms, headaches, and myalgia, have been infrequently reported particularly when large surface areas are treated.
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The short-term efficacy of
imiquimod cream for eradicating AKs has been well studied in the last several years. The first systematic review and meta-analysis of short-term randomized controlled trials evaluating its efficacy and safety has been published.
60 For this meta-analysis, five trials
57,58,61–63 involving a total of 1,293 patients were selected for inclusion based on their high-quality scores, minimal risk of bias, validity, adequate treatment duration, inclusion of patients with multiple AK lesions, and use of at-home application. Complete clearance occurred in 50% of patients treated with
imiquimod versus 5% treated with vehicle alone. Partial clearance (more than 75% of lesions) was seen in 65% of imiquimod-treated patients versus 11% of vehicle-treated patients.
60
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Evidence also supports the use of
imiquimod in the treatment of AKs to promote long-term immune surveillance and lower recurrence rates. Stockfleth et al
56 followed 25 imiquimod-treated patients from a previous short-term study
61 for up to 2 more years. Of these 25 patients (one was lost to follow-up), 8% (
n = 2), 16% (
n = 4), and 20% (
n = 5) developed new AKs or were lost to follow-up at 12, 18, and 24 months, respectively, after completion of the initial regimen of
imiquimod application three times a week for 12 weeks. No patients had developed SCC in the imiquimod-treated areas at 2 years after treatment. Ten of the vehicle-treated patients from the original study
61 were also observed for 1 year after their initial treatment. In this group, 90% (
n = 9) developed new AKs in the vehicle-treated area, 10% (
n = 1) had spontaneous remission of their AKs, and 10% (
n = 1) developed an SCC in the vehicle-treated area.
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In a second study of long-term efficacy, Lee et al
64 looked at patients from four previous phase III randomized, vehicle-controlled studies who showed complete clearance of all of the AKs in the treated areas at 8-weeks posttreatment. After a median follow-up of 16 months they found that 25% (
n = 19/77) and 43% (
n = 23/54) of patients treated with
imiquimod three times per week and two times per week, respectively, for a duration of 16 weeks experienced a recurrence of one or more AKs in original treated area.
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Imiquimod has been shown to be safe and effective in treating AKs in the organ transplant population, with no evidence of graft rejection and no trends toward diminished graft functioning.
65 Rare flares of underlying autoimmune disease were observed during preapproval research studies and have been documented in the literature.
66
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The third FDA-approved topical field therapy for treating AKs is 3%
diclofenac gel.
Diclofenac is a nonsteroidal anti-inflammatory drug whose mechanism of action is not completely understood but is thought to involve inhibition of cyclooxygenase (COX), a rate-limiting enzyme in the synthesis of prostaglandins.
Diclofenac appears to have greater affinity for the COX-2 enzyme than for the COX-1 isoform. One theory regarding its role in eradicating AKs relates to the finding that the production of prostaglandins from arachidonic acid may contribute to UV radiation-induced NMSC. Thus, inhibition of this cascade by
diclofenac may also explain its efficacy in treating AKs.
67
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The FDA-approved regimen for
diclofenac in the treatment of AKs is twice-daily application for 90 days. Compared with
imiquimod and 5-FU,
diclofenac does not cause as much inflammation, irritation, or downtime for the patient. Adverse effects include mild local site reactions, such as erythema, pruritus, flaking, and possible contact dermatitis. In a blinded, controlled study involving 96 patients complete clearance of AKs was observed in 50% of the diclofenac-treated group and in 20% of the vehicle-treated group 30 days after the conclusion of therapy.
68 At 1-year follow-up, 91% of patients had at least 75% clearance of the targeted lesions, and of these patients, 79% showed 100% clearance.
68
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Procedural Field Therapy
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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).
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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).
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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
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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.
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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.
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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.
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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
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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).
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The future of treatment for AKs is an area of great interest and research. Investigators are looking at reformulating existing topical agents to improve upon efficacy and to decrease adverse side effects. Older methods are being challenged in clinical studies with newer regimens that involve sequential or concurrent therapy with existing AK treatments. Another interesting area of research is looking at the various combinations of lesion-directed therapies with field treatments, and lastly, new emerging agents are undergoing rigorous clinical research to establish their efficacy and safety.
87–89
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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
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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.
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Topical imiquimod has also been safely used in the organ transplant population to prevent the development of cutaneous SCC.65,108
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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.
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Knowledge of the medicinal benefits and poisoning potential of arsenic dates back to ancient times. Arsenic was introduced into the
United States Pharmacopoeia in 1850, and before its use was discontinued around 1965, it was employed medicinally in the United States and Europe in the form of Fowler's solution, Donovan's solution, and Asiatic pills for treatment of various illnesses such as psoriasis, asthma, and syphilis. Medicinal exposure is now basically limited to treatment of tropical diseases, such as African trypanosomiasis, and more recently to treat various hematologic malignancies.
109 Arsenic in opium has been and is still used for medicinal and recreational purposes in India, and inorganic arsenic is still found in some traditional Chinese herbal preparations.
110 Unfortunately, these substances can be easily purchased and are increasingly being used again as homeopathic remedies, resulting in modern day cases of what once was primarily a disease of historical interest.
111,112
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Arsenic exposure can occur in a variety of occupations, either by direct exposure to arsenic or through indirect exposure from contaminated water and landfills. In 1973, it was estimated that more than 1.5 million workers in the United States were potentially exposed to arsenic in the workplace.
113 Occupations that carry risk of exposure include jobs in the mining, smelting, agricultural, computer microchip, forestry, electroplating, semiconductor, and glassmaking industries. Environmental exposure is often obscure and insidious, because there may be latent periods of up to 50 years before manifestations of chronic arsenicism appear. Arsenic is routinely found in soil, and it can accumulate in ground water and well water from these natural sources. It is becoming a public health concern in many areas, including Bangladesh, India, Taiwan, Japan, Mexico, Chile, Argentina, Canada, Pakistan, and the United States.
114 Other routes of environmental exposure include some illegally produced alcoholic beverages and the burning of pressure-treated lumber that has been pretreated with chromated
copper arsenate. In all forms of medicinal, occupational, and environmental exposures, longer duration of exposure and higher cumulative dose are associated with a higher risk for the development of ArKs.
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The association between arsenic exposure and skin cancer was first noted by Paris in 1822.
115 ArKs were first described on the palms and soles of individuals in the late 1800s. In 1898, Dubreuilh categorized ArKs as precancerous lesions.
5 The relationship of arsenic ingestion to palmar and plantar ArKs and to skin cancer has been documented in several studies that examined wide-scale exposure to known sources of arsenic.
116 In particular, chronic arsenicism and an increased risk of skin cancer have been attributed to drinking water that contains more than 0.6 mg of arsenic per liter.
114 The US Environmental Protection Agency has set a maximum arsenic contaminant level at 50 μg/L.
116 Ingestion of as little as 400 mL of Fowler's solution can be associated with signs of chronic arsenicism.
113 A compilation of the results of 12 reports that linked malignancy with the ingestion of inorganic arsenic found that skin cancer occurred in 70% and an internal malignancy in 6.3% of ingesters.
117
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Etiology and Pathogenesis
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Arsenic is present as either organic or inorganic compounds as well as in three potential oxidative states: metalloid, trivalent, and tetravalent. Trivalent arsenicals are the most common and hazardous to humans. The toxicity of these compounds depends on the accumulation of arsenic in target tissues and its metabolism and elimination. Organic arsenicals are excreted rapidly. Trivalent inorganic arsenicals are the most acutely and chemically toxic compounds. Because arsenic is metabolized and detoxified in the liver via methylation, patients with preexisting liver disease may be at greater risk for arsenic-related toxicity.
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The mechanisms of arsenic-induced keratoses and malignancy are not fully understood. Arsenic reacts with the sulfhydryl groups in certain tissue proteins and subsequently affects many different enzymes that are essential to cellular metabolism. Arsenic has been found to cause chromosomal mutations, chromosomal breaks, sister chromatid exchanges, and mutations in
p53.
118,119 A recent study demonstrated that polymorphisms in a nucleotide excision repair pathway gene,
ERCC2, are associated with an increased susceptibility to arsenic-induced genotoxic effects and the formation of ArKs.
120
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ArKs typically begin as pinpoint papules that are more easily felt than seen. They develop into small, 2–0-mm, punctate, yellow, keratotic papules most commonly seen on the palms and soles in areas of constant pressure or repeated trauma (
eFig. 113-6.2A). They preferentially arise on the thenar and lateral borders of the hands, the sides of the fingers, and sometimes on the dorsal aspects of the fingers, overlying the joints. Although it is unusual, ArKs can be found on more widespread body areas such as the trunk, extremities, eyelids, and genitalia. ArKs may also present as slightly elevated, erythematous, scaly, or pigmented plaques. ArKs on the palms and soles are more likely to be seen in individuals with chronic arsenicism caused by medicinal exposure than in those with arsenicism due to occupational exposure. Also, individuals with arsenical-related cancer are more likely to have palmar and plantar ArKs. The mean latency period for the development of ArKs varies considerably from 9 to 30 years.
121
++
++

Other cutaneous neoplasms associated with chronic arsenicism include BD or SCC in situ, SCC (see
Chapter 114), and BCC (see
Chapter 115). Mean latency periods for the development of BD and SCC can also be as long as 40 years.
121 With arsenic as the carcinogen rather than UV radiation, these neoplasms, like ArKs, are distributed in more widespread, random, and nonphotodamaged areas. Arsenical BD often begins as a small flesh-colored to pink papule with a thick horny layer or crust. When this crust is removed, the underlying skin appears erythematous and oozing. Over time, unlike the relatively stable ArKs, these lesions increase in size, forming nodular and plaque-like lesions (see
eFig. 113-6.2B) that often group together. Approximately one-third of patients have multiple lesions of BD.
110
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Arsenic-induced BCCs are also usually multiple, and the majority are of the superficial type, although small nodular BCCs are sometimes seen. These BCCs are found in a random, scattered distribution, primarily on the trunk and in hair-bearing regions. Clinically, the superficial BCCs are often indistinguishable from BD.
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Arsenic-related SCC can arise de novo or from malignant transformation of ArKs and BD lesions. In one study, 55% of SCCs arose from preexisting ArKs or BD lesions.
121 Patients with SCC are more likely to have been exposed to arsenic earlier in life than are those without SCC.
121 They also are more likely to have multiple lesions of BD and more numerous palmar and plantar ArKs. The majority of SCCs have been found on the distal extremities of the hands and feet, and it has been hypothesized that irritation and trauma in these areas may increase the risk of malignant transformation. Clinically, ArKs that show progression to SCC often present with pain, bleeding, fissuring, and later ulceration. They tend to gradually expand in diameter, forming a large erosion or ulceration, and they can, if neglected, reach sizes of up to 20 cm.
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Other signs of chronic arsenicism include hyperpigmentation primarily affecting the nipples, axillae, groin, and other pressure points. Within these hyperpigmented patches are often small areas of guttate hypopigmentation, resembling “raindrops in the dust.” Diffuse alopecia of the scalp may be present. Longer term, patients may develop “blackfoot disease,” which is a peripheral vascular disorder affecting the lower extremities that eventually results in gangrene. Other systemic findings of chronic arsenicism include hematologic disorders, liver disease, sensorimotor neuropathy, hypertension, diabetes, and other gastrointestinal disturbances. A variety of internal malignancies have been associated with chronic arsenicism, with long latency periods of 20–50 years. The internal malignancies linked with chronic arsenicism include lung, urinary tract, and hepatic tumors, hepatic angiosarcoma, leukemia, and lymphoma.
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The histopathologic features of ArKs are essentially the same as those of AKs. No reliable histopathologic criteria can distinguish between the two. Some cases of ArKs are characterized by marked vacuolation of the epithelial cells and keratin horn formation. Also, solar elastosis is usually absent, and a chronic dermal lymphocytic infiltrate is commonly seen. Likewise, arsenic-related BD, BCC, and SCC are histopathologically indistinguishable from their nonarsenic-induced counterparts.
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Diagnosis and Differential Diagnosis
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ArKs may be mistaken for other types of punctate keratoses, such as disseminated punctate keratoderma, Darier disease, corns, and verruca vulgaris. Disseminated punctate keratoderma usually appears earlier in life. It has also been reported that upon removal of the keratinous plugs in punctate keratoderma, small crater-like pits are left behind, whereas no pits are seen on removal of the keratin plugs in ArKs. Darier disease presents with characteristic lesions elsewhere. Corns are usually not so numerous and not so common on the hands. Warts often demonstrate evidence of thrombosed capillaries upon removal of the surface keratin.
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A diagnosis of ArKs and chronic arsenicism should be considered when numerous characteristic keratoses are seen on the palms and soles or when multiple lesions of BD, SCC, or BCC are found on an individual, especially when these lesions are in nonsun-exposed regions of the body. In most patients with such neoplasms, palmar and plantar keratoses will also be present. Such patients should be questioned about previous occupations, living conditions, and environmental and medicinal exposures to elicit a history of potential arsenic exposure anywhere from 10 years to 40 years previously. Biopsy of any changing ArK, erythematous nodule, plaque, or ulcer on the body should be performed to ensure that BD, BCC, or progression to SCC is not present. In addition, laboratory tests to order include a complete blood count, renal and liver function tests, hair and nail analysis to measure arsenic concentration, and nerve conduction studies if a sensorimotor neuropathy is suspected.
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Prognosis and Clinical Course
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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
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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.
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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
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Etiology and Pathogenesis
++

Hydrocarbon keratoses (HKs), also known as
tar keratoses,
pitch keratoses, and
tar warts, are precancerous keratotic skin lesions that occur primarily in persons who are exposed occupationally to polycyclic aromatic hydrocarbons (PAHs). SCC and keratoacanthoma have also been linked to such exposures. PAHs are produced by the incomplete combustion and distillation of coal, natural gas, and oil shale. They are found in tar, fuel oils, lubricating oils, oil shale, and bitumen.
115 Patients at risk for exposure to such compounds include workers in tar distillation and shale extraction, and workers exposed to creosotes, which are one of the main distillate fractions of coal tars and coal tar pitches.
131 Creosotes are used extensively as wood preservatives. Roofers, asphalt workers, road pavers, and highway maintenance workers are exposed to PAHs from fumes formed during the heating of bitumen.
131 Other groups of workers at risk for exposure to coal tar products include railway workers, brick masons, and diesel engineers.
115 Finally, persons exposed to mineral oils, cutting oils, and coolants also are at risk for the development of HKs and SCC.
131
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The most infamous occupational exposure to PAHs was that of chimney sweeps, who developed scrotal SCC or Pott's tumor (named after Dr. Percivall Pott, a London surgeon who described the condition in 1775).
132 Mule spinners (a “mule spinner” is a yarn-producing machine invented in 1779 by Samuel Crompton) have also been reported to develop SCC of the scrotal skin.
115 Mule spinners frequently have their thighs and scrotum in contact with an oil-covered bar on the mule or yarn producing machine.
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HKs, SCCs, and keratoacanthomas develop in persons whose skin is exposed to PAHs over long periods of time. The risk of developing these precancerous and cancerous lesions is associated with dermal exposure to PAHs. Inhalation of PAHs is not associated with skin cancers, although lung cancers have been reported with such exposures. PAHs are known carcinogens that damage DNA and potentially cause mutations in the
p53 gene, at least in lung cancers.
132 UV radiation exposure has been considered a cofactor in the development of HKs and related skin cancers, but one study found that the majority of HKs and SCCs in a large group of tar refinery workers developed in nonsun-exposed regions of the body, which puts this belief into question.
133 The duration of exposure before the development of HKs ranges from 2.5 to 45 years.
134
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HKs present as small, oval-to-round, gray, flat papules that are easily removed without bleeding. These papules can then become larger and more verrucous in appearance, and eventually may develop into invasive SCC. Sites of predilection include the face, nostril rims, upper lip, forearms, volar wrists, dorsal feet, lower legs, vulva, and scrotum.
133 Of note, the lesions on the nostril rims, upper lip, genitalia, and forearms are not in the typical sun-exposed sites of the body. Thus, keratoses or malignancies in these regions should prompt the physician to inquire about potential occupational hazardous exposures. Other cutaneous findings related to PAH skin exposure include patchy hyperpigmentation, acne, and telangiectases at sites of exposure. The presence of acneiform lesions on the forearms and thighs should alert one to the possibility of PAH exposure. Facial features associated with long-term tar exposure include periocular fibromas, brownish or slate-gray discoloration, comedones, and follicular plugs.
133 PAHs have also been reported to cause internal malignancies, such as lung and bladder cancers.
131
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Histopathologically, HKs appear similar to AKs and ArKs, as previously described. Often, HKs show more of a progression to full-thickness atypia or a bowenoid appearance. In early HKs, it has been said that distinction between benign and malignant epidermal changes can be difficult.
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Diagnosis and Differential Diagnosis
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HKs, with their grayish keratotic appearance, may be mistaken for verruca vulgaris, stucco keratoses, or even ArKs. A high index of suspicion is needed to make the diagnosis of HKs, because histopathologically they are difficult to distinguish from AKs and ArKs. The distribution of the lesions and other cutaneous findings of tar-exposed skin can aid in the diagnosis and lead to targeted questioning of the patient.
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Prognosis and Treatment
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The exact risk that an HK will progress to SCC is unknown. Most recommendations in the literature call for biopsy and surgical removal of HKs, especially in the vulvar and scrotal regions and on mucosal surfaces, where the risk of early metastasis from SCC is greater. Cryosurgery and curettage with or without electrosurgery are probably reasonable treatment options for HKs at other cutaneous sites. Prevention is the key for workers exposed to PAHs in their occupations. Long-term follow-up of individuals with previous known PAH exposures is essential for early diagnosis and treatment of lesions and for early detection of internal malignancy in those at risk.
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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.
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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.
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Etiology and Pathogenesis
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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
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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.
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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.
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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.
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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.
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Diagnosis and Differential Diagnosis
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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
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Prognosis and Clinical Course
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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
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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
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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.
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The term
intraepithelial neoplasia (IN) is defined as a precancerous squamous epithelial lesion of the lower anogenital tract. The terminology of these precancerous lesions has been confusing, with various names such as squamous intraepithelial lesion (SIL), erythroplasia of Queyrat (EQ), genital Bowen disease (GBD), bowenoid papulosis (BP), and SCC in situ being used in the past. It is now recommended that the following terms be used, as outlined in
eBox 113-5.1. All of these INs have a disease spectrum ranging from mild-dysplasia to severe- dysplasia, but with no evidence of invasion into the dermis. For the purposes of this chapter, only vulvar intraepithelial neoplasia (VIN), anal intraepithelial neoplasia (AIN) and perianal intraepithelial neoplasia (PaIN), and penile intraepithelial neoplasia (PIN) will be discussed. Because most dermatologists consider BP to be a distinct clinical entity, with a classic presentation in mostly younger individuals, a better prognosis, and a greater chance for spontaneous regression, this entity has been discussed separately under Section “
Viral-Associated Precancerous Lesions.”
++
+++
Vulvar Intraepithelial Neoplasia (VIN)
++
++

VIN is a precursor lesion of vulvar SCC. The original classification of VIN, dating back to 1986, identified three grades of VIN (VIN1, VIN2, VIN3), based upon the degree of atypical cells within the vulvar squamous epithelium. This was analogous to the CIN spectrum. In 2004, the vulvar oncology subcommittee of the International Society for the Study of Vulvar Diseases (ISSVD) proposed a new classification system for VIN, designating the term VIN be used only for high-grade lesions (formerly VIN2 and VIN3) that have the potential to progress to vulvar SCC. Thus, the older designation of VIN1 has been eliminated, primarily because such VIN1 lesions are thought to represent benign, reactive or HPV-related effects, and not precancerous lesions.
171
++

The incidence of VIN is increasing globally. It is primarily a disease of younger women, who comprise about 75% of all cases.
172 The incidence of vulvar cancer is also increasing, but at a slower rate.
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Etiology and Pathogenesis
++

VIN is classified into three main groups: (1) VIN, usual type (warty, basaloid, or mixed), (2) VIN, differentiated type and (3) VIN, unclassified type (
eBox 113-5.2). The VIN, usual type incorporates what was previously called VIN2, VIN3, or SCC in situ. These lesions are associated with hrHPV
16,18,31 infection and are further histopathologically subcategorized into warty, basaloid, or mixed subtypes. VIN, usual type primarily occurs in younger, premenopausal females, and additional risk factors are tobacco use, other sexually transmitted diseases (STDs) and immunosuppression. These lesions are both multifocal and multicentric in their presentation, with more extensive disease displaying confluence of lesions.
++
++

VIN, differentiated type is much less common and accounts for only 2%–10% of all previously designated VIN3 cases.
173 This lesion primarily affects postmenopausal women, is usually unifocal and unicentric, and is often associated with lichen sclerosus. Infection with HPV is uncommon and it is not thought to play a role in its pathogenesis.
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On examination, VIN, usual type can present with a variety of clinical appearances, such as an erythematous, well-defined plaque; a verrucous white plaque; grouped pigmented papules or plaques; erosions or ulcers. These lesions are most often multifocal and may demonstrate extensive involvement of the perineum and the adjacent skin. Over 50% of patients with VIN, usual type, have associated CIN. Individual lesions of VIN, differentiated type may present as an erythematous or hyperkeratotic plaque; a verrucous papule or plaque; or as a nodule or ulcer.
++

Approximately half of all patients with VIN are asymptomatic and the abnormal lesion is discovered on a routine gynecological examination. Symptomatic patients typically present with pruritus as their main complaint. Other symptoms may include pain, burning, dysuria, bleeding, discharge, a palpable lesion, or a persistent ulcer. Any suspicious lesion should be biopsied. A punch or excisional biopsy is preferred, in order to determine the depth of the lesion and to not miss invasive SCC. A patient who has multiple or multifocal lesions will require multiple biopsies. Histopathologically, VIN is characterized by disorderly maturation of keratinocytes within the epithelial layer, nuclear atypia, coarse nuclear chromatin, and multiple mitotic figures above the basal layer.
+++
Differential Diagnosis
++

The clinical differential diagnosis includes other inflammatory disorders, such as lichen sclerosus, lichen planus, candidiasis, condyloma acuminata, and perhaps melanoma in those cases of pigmented lesion presentation.
+++
Prognosis and Clinical Course
++

If left untreated, VIN may persist, regress or progress to vulvar SCC. In a literature review of ten studies that involved 61 untreated VIN patients and 27 with macroscopic residual disease, 9% were found to have progressed to invasive vulvar SCC over the course of 1–8 years.
174 Spontaneous regression has been described primarily in young women (mean age of 20 years). Despite treatment of VIN it may recur in one-third of women and 4%–8% may go on to develop locally invasive SCC. Long-term surveillance of these women is crucial.
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The main goals of treatment are to prevent the progression to invasive SCC; to relieve patient symptoms; and to retain as much of the vulvar anatomy and function as possible. Unfortunately, there are few, sufficiently powered, long-term, randomized trials looking at the management of VIN. Available treatment options include surgical excision, partial or total vulvectomy, laser ablation, and field treatments such as topical 5%
imiquimod and 5-FU creams. Treatment with 5%
imiquimod has been shown to be effective in treating VIN and is preferred by many experts over topical 5-FU, if topical therapy is chosen.
175–179 Obviously, any treatment discussions would be handled in conjunction with the patient's gynecologist. Lastly, any patient in whom VIN is diagnosed will require a complete gynecologic exam because of the high risk of associated CIN.
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The treatment of VIN with currently available HPV vaccines is an exciting, ongoing area of research.
180 A recent study, using an HPV 16 vaccine in females with the usual type of VIN, showed that at 1 year 15/19 patients had a partial (
n = 6) or complete (
n = 9) clearance of their VIN lesions, and that at 2 years these 9 complete responders had a sustained complete response.
181 This study is the first of its kind to show that effective immune responses can be generated against precursor lesions, and in conjunction with the
imiquimod treatment data,
175–177 it also suggests a stronger role for such immunotherapy in the treatment of VIN.
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Prevention of VIN and progression to vulvar SCC is now a reality. It is believed that approximately two-thirds of VIN could be prevented in younger women with the prophylactic use of the currently available HPV vaccines
180,182,183 (see
Chapter 196).
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Anal (AIN) and Perianal (PAIN) Intraepithelial Neoplasia
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AIN is an HPV-associated precursor lesion of anal SCC. PaIN is an SCC in situ cutaneous lesion of the perianal skin. AIN has also been referred to as
anal squamous intraepithelial lesion (ASIL), anal dysplasia, and in precancerous lesions of the perianal skin (PaIN) the terms
GBD,
SCC in situ, and
BP have all been used interchangeably. AIN is classified in the same nomenclature as that used to describe CIN. AIN1, AIN2, and AIN3 correspond to histopathologic mild, moderate, and severe dysplasia, respectively. AIN1 is not considered a direct precancerous lesion of anal SCC, but it can progress to AIN 2 and AIN 3, both of which are considered precancerous lesions.
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Epidemiology, Etiology, and Pathogenesis
++

AIN and anal SCC are increasing in the general population and are most prevalent in HIV-positive men who have sex with men (MSM), and also in HIV-positive females. The greatest risk factors for developing AIN, in both males and females, are infection with HPV, receptive anal intercourse, HIV infection, and decreased CD4 counts, although restoration of CD4 counts to normal with highly active antiretroviral treatment (HAART) does not seem to cause regression of AIN in HIV-positive persons. Other risk factors include immunosuppression, tobacco use, and abnormal cervical cytology in females. The high-risk subtypes of HPV that are associated with AIN and anal cancer are HPV 16, 18, 31, and, less so, 33.
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Patients with AIN may be asymptomatic or may present with localized symptoms, such as pruritus, pain, bleeding, tenesmus, and discharge. On physical exam, AIN can present in a variety of ways. The dermatologist's role is to inspect the perianal skin for suspicious lesions, such as well-demarcated erythematous pink plaques, grouped hyperpigmented papules or plaques, verrucous papules or plaques, and persistent erosions or ulcers. Findings of such suspicious lesions should prompt an excisional or punch biopsy, as well as referral to a specialist in this field of medicine for complete anal exam with high-resolution anoscopy and cytologic exam. Females should also undergo a complete gynecologic exam to rule out CIN.
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No formal AIN screening guidelines have been formulated or accepted, but regular screening for AIN is recommended for all HIV-positive individuals; all MSM; females with a history of high-grade cervical, vulvar, or vaginal IN; and perhaps immunosuppressed patients, such as transplant recipients. Such patients should be screened by physicians who are experienced in the diagnosis and management of AIN. Dermatologists should identify such high-risk patients and perform perianal examinations periodically.
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The histopathology of PaIN is basically that of SCC in situ. AIN and CIN share similar histopathologic features, as described using the 2001 Bethesda classification.
184 High-grade AIN2 and -3 are evident when the abnormal epithelial basaloid cells replace more than half of the entire epithelium.
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Prognosis and Clinical Course
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Relatively little is known about the natural history of high-grade AIN, other than it rarely spontaneously regresses, regardless of HIV status. Low-grade AIN1 may spontaneously regress or progress to high-grade AIN2 or AIN3. Risk factors for progression in MSM include HIV infection, low CD4 counts, anal HPV infection, and high levels of oncogenic HPV subtypes. Also, despite treatment, high rates of recurrence are the norm and thus ongoing surveillance is mandatory.
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The treatment goal in AIN is to prevent progression to anal SCC, but there is a lack of good evidence that screening for and treating high-grade AIN can prevent this progression. There is also limited data on the efficacy of treatments for AIN. Many experts recommend that individuals with high-grade AIN receive treatment, but again, no definitive algorithms exist. True, high-grade AIN is best managed by an expert in this field of medicine. Treatment options for PaIN include similar treatments as described for other cutaneous SCC in situ lesions.
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A recent literature review to assess the efficacy of 5%
imiquimod in treating AIN found that five cohort and case reports have been published to date, all limited to HIV-positive MSM.
184 A pooled analysis of these studies demonstrated a complete response of 48%, with about a 36% recurrence rate.
185
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Prevention of AIN is an exciting possibility with the advent of HPV vaccines, but this is still undergoing investigation. Clinical studies are also underway to see if HPV vaccines can induce regression of high-grade AIN.
186
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PIN is a precancerous lesion that may progress to invasive SCC of the penis. Older, synonymous terms for this in situ carcinoma of the penis are
BD,
GBD,
EQ, and
BP, but many experts in this area now recommend that PIN be the preferred name for this condition.
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Penile Intraepithelial Neoplasia (PIN)
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++

The exact incidence and prevalence of PIN are not known. It is thought to be uncommon in the Western world, but it has been increasing significantly in some developing countries. Of all the penile cancers, in situ SCC and invasive SCC are the most common entities, with SCC representing the majority of invasive penile cancers (∼95%).
148,187
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Etiology and Pathogenesis
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PIN is primarily a disease of older, uncircumcised males, peaking in the sixth and seventh decades of life. Penile SCC is rare in males circumcised at or around the time of birth. In a recent study of 213 adult males with penile SCC, only two (2.3%) with invasive SCC and sixteen (15.7%) with PIN were circumcised as newborns.
148 Risk factors for developing PIN and penile SCC in uncircumcised males include poor hygiene, smegma retention, phimosis, and other chronic inflammatory and infectious conditions affecting the penis. Other risk factors are coinfection with certain oncogenic HPV subtypes, primarily HPV-16, but also HPV-18, 31, and 33; penile lichen sclerosus (LS), also known as balanitis xerotica obliterans (BXO); HIV infection; immunosuppression; tobacco use; and ultraviolet (UV) radiation exposure (PUVA and recreational).
187
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It has been hypothesized that there are two different and independent pathways in the development of PIN and penile SCC: an HPV-positive pathway and an HPV-negative pathway. Approximately 40%–45% of all penile cancers are thought to have an HPV association. The HPV-positive pathway is thought to result from probable sexual transmission of and acquired infection with oncogenic HPV subtypes in young adults. This pathway morphologically is believed to result in a basaloid/warty subtype of penile SCC that histopathologically displays small basaloid cells with poorly defined borders or koilocytosis. These warty/basaloid types of penile SCC display the strongest association with oncogenic HPV infection (70%–100%), and HPV-16 is the predominant subtype.
148
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The HPV-negative pathway is mostly unrelated to HPV infection and primarily affects older males. Morphologically, this pathway results in the usual type or differentiated squamous/keratinized penile SCC that histopathologically shows a keratinizing epithelium with variable degrees of cellular atypia. This usual type of penile SCC comprises the majority (49%) of all penile SCCs. Approximately 30% of such non-HPV-associated penile SCC cases are preceded by LS, but in some cases there is coexistence of LS and hrHPV infection.
148
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PIN and penile SCCs most often originate on the mucosal surfaces of the penis, such as the glans, coronal sulcus, prepuce, urethral meatus, and the mucosal surface of the foreskin. Less than 5% of PIN and such cancers arise on the shaft of the penis. The clinical presentation of PIN is variable and depends upon the anatomic site of involvement. The mucosal presentation has historically been called EQ and the shaft presentation has been called GBD. PIN presenting on the mucosal sites often presents as a well-demarcated, glistening, erythematous, velvety plaque or plaques, as originally described by Queyrat in 1911 (
eFig. 113-8.1).
188 Patients with this EQ variant of PIN may present with symptoms of pain, pruritus, bleeding, crusting and difficulty in foreskin retraction. The EQ PIN variant is associated with HPV 8 in almost all cases and concomitant HPV 16 in most.
189 This EQ variant of PIN more often (up to 30%) progresses to invasive SCC compared with the GBD variant (3%–6%),
189 but it usually progresses slowly and the presence of ulceration may herald the progression to invasive SCC.
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The GBD variant of PIN typically presents on the shaft of the penis as a single, erythematous or variably pigmented, well-demarcated plaque. It may also display secondary scaling, oozing, crusting, or erosion. The development of an ulcer, verrucous or nodular growth, may herald its progression to invasive SCC. Any suspicious or persistent lesion of the penis should be biopsied for definitive histopathologic diagnosis. Other clinical entities to consider in the differential diagnosis of PIN are listed in
eBox 113-5.3.
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Histopathologic examination of both the EQ and GBD variants of PIN are mostly similar and that of SCC in situ. However, in the EQ variant there is often epithelial hypoplasia, fewer multinucleated and dyskeratotic cells, and many more plasma cells in the dermal infiltrate. Histopathologic studies of penile SCC cases have observed a sequence from low-grade PIN to high-grade PIN in many (62%) cases.
190
+++
Prognosis and Clinical Course
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GBD and EQ are histopathologically identified as high-grade PIN and may progress to penile SCC. Progression of PIN to invasive SCC is likely in untreated lesions and more common in the EQ variant versus the GBD variant, although this is not always the case. Treatment of PIN is warranted to prevent progression to invasive penile SCC. Once invasive SCC has occurred, approximately 20% of patients will display evidence of regional lymph node involvement or more distant metastases.
191 Dermatologists can play a role in the early diagnosis and management of disease.
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Therapeutic measures for treatment include wide local excision, Mohs micrographic surgery, laser ablation, and topical 5-FU and 5%
imiquimod cream though evidence for use of the two latter topical therapies is limited to small series and case studies. Each case must be individualized and based upon patient characteristics and preferences, PIN type and size, physician's skills set, and optimal treatment with the most preservation of anatomy and function. Life-long surveillance of patients with all forms of PIN is essential to ensure early detection of recurrence. Patients should also be advised to initiate partner screening for CIN, VIN, and AIN.
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Several preventive strategies for penile SCC have been proposed. Neonatal circumcision has been well established as an effective prophylactic measure for penile cancer, but societal, cultural, and religious beliefs have often hampered the widespread implementation of this procedure. More studies are needed to determine if circumcision in older males can play a role in primary or secondary prevention. In addition to neonatal circumcision, four studies, from four different countries, have shown a significant decrease in penile cancer without implementing circumcision, mainly by advocating better education and by improving sanitation.
192 Other preventive measures that are advocated include good hygiene, stopping smoking, preventing phimosis, treating chronic inflammatory and infectious conditions, and avoiding genital exposure to PUVA or UVR. Lastly, HPV vaccination in young males is being investigated as a prophylactic measure, but to date no efficacy studies have been published.
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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.
++
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
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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
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Etiology and Pathogenesis
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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).
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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
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OL can occur as an isolated single lesion, as multiple separate lesions, or as diffusely outlined lesions. It is recommended that OL lesions be described and documented by the size in centimeters of single lesions and the cumulative sizes of multiple lesions.
206 The exact location should also be documented. OL lesions found on the floor of the mouth, on the lateral or ventral tongue, and possibly on the soft palate have been thought to have a greater malignant potential,
208 but conflicting findings have more recently been published regarding this correlation.
195,209,210
++

Examination of the oral mucosal surface should ideally be part of a patient's total body skin examination. Such an examination is more important in patients with a history of tobacco use or combined tobacco and
alcohol use, or a prior history of documented OL, OE, or OSCC. In patients with definitive OL or possible OL, an examination of the lymph nodes should also be performed. In addition, patients with definitive OL should be followed closely, at regular intervals, for the rest of their lives, because they are at risk for malignant transformation of the lesion and for new lesions.
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Additional Diagnostic Tools
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Vital tissue staining has been identified as an adjunct to the early recognition of malignant or premalignant oral lesions.
211 The stain of choice is toluidine blue (tolonium chloride). The toluidine blue stain is a metachromatic dye that stains mitochondrial DNA, cells with an abnormally high DNA content, and altered DNA in atypical and malignant cells. This staining technique, although very effective, is best used in the hands of experienced persons and at institutions where a large number of patients with head and neck cancer are seen. When used in these settings, this staining assists in identifying sites of malignant change and possible high-grade dysplasia. It can also be helpful in selecting biopsy sites and in outlining lesion margins.
211
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Exfoliative cell collection is another, newer technique in which exfoliated oral mucosal cells are obtained for cytologic and molecular analysis. The newer types of exfoliative cell collection allow one to collect more full-thickness epithelial samples, which aids in diagnostic accuracy. Nonetheless, it is not a highly accurate adjunctive technique at this point.
211
++
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.
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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
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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
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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
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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.
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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).
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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.
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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
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Etiology and Pathogenesis
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The etiology and pathogenesis of OE are not well understood. It is still unclear whether or not OE develops de novo or from a preexisting lesion of OL. The greatest risk factors for its development are thought to be tobacco and
alcohol use. It is not known precisely how
alcohol and tobacco use together induce carcinoma, but the synergistic effect of the two substances in causing intraoral carcinoma is well accepted.
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The largest OE series in the literature was in a study conducted in Kerala, India.
218 This study demonstrated a dramatically increased risk of OE in adults that was associated with chewing tobacco—in particular, tobacco in the form of betel quid and pan masala. This randomized, population-based screening trial confirmed 100 cases of OE among 49,174 persons screened (0.2%). The greatest risk factor for development of OE was the use of chewing tobacco, with a strong dose response associated with increasing number of years of usage and with daily usage. The independent effects of smoking and
alcohol use were smaller, but the use of chewing tobacco combined with either smoking or
alcohol consumption conferred a greater risk than the use of chewing tobacco alone.
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This study is also of importance in the United States, because in the last three decades there has been an increase in the use of smokeless tobacco products in the form of moist snuff, most notably among adolescent and young adult males.
219 A survey of 17,000 school-aged children 12–17 years old found oral premalignant lesions in 2.9% of males and 0.1% of females.
220 In this study, the risk of development of such lesions among white male students was strongly associated with chewing tobacco and using snuff. Another trend of concern among US youth is the rise in the use of other tobacco products, such as sweet-flavored cigarettes, bidis (hand-rolled filterless flavored cigarettes), and kreteks (clove cigarettes).
219
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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.
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Histopathologic examination of a lesion of erythroplakia usually reveals findings of SCC in situ, areas of dermal invasion, or various degrees of dysplasia. Partial or sampling biopsies of erythroplakia may unfortunately miss focal areas of invasive SCC. In one study of clinically homogeneous OE, histopathologic examination revealed that 51% of cases demonstrated invasive carcinoma, 40% showed severe dysplasia or SCC in situ, and 9% demonstrated mild-to-moderate dysplasia.
221
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Diagnosis and Differential Diagnosis
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OE is a diagnosis of exclusion. The onus is upon the clinician to rule out all other erythematous oral lesions before the term
oral erythroplakia (OE) can be applied. Other entities that should be considered in the differential diagnosis include acute and chronic mechanical trauma, thermal or chemical injury, erythematous candidiasis, atrophic lichen planus, lupus erythematosus, pemphigus, cicatricial pemphigoid, Kaposi sarcoma, amelanotic melanoma, chronic contact or allergic dermatitis, submucosal hemorrhage, and various forms of glossitis (see
Box 113-5). As OE is usually solitary, this helps to distinguish it from other inflammatory conditions, which are often bilateral or multiple. Of all of these possibilities, erythematous candidiasis and atrophic lichen planus are the most important considerations. In general, biopsy of any OE lesion should be performed if the cause is not obvious, if the lesion is in a high-risk location in the oral cavity, or if the lesion does not resolve over a period of several weeks.
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Prognosis and Clinical Course
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OE has the greatest risk for malignant transformation of all premalignant oral lesions. This elevated risk for malignant transformation is mostly based on the fact that histopathologic evaluation of OE usually reveals invasive SCC, SCC in situ, or severe dysplasia, as previously discussed. The rate at which in situ carcinoma of the oral cavity progresses to invasive SCC is not known exactly. The transformation rate for OSCC in situ or lesions with severe dysplasia has ranged from 14% to 50%, with an average of 26%.
216 In individuals at high risk, such as heavy smokers or drinkers, up to 80% of OE lesions on biopsy may contain focal areas of invasive carcinoma.
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Treatment and Prevention
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Because OE has been shown to have the highest risk for malignant transformation, early and effective treatment of these lesions is imperative. The definitive treatment is controversial, and studies of the treatment of OE lesions by themselves are lacking. Recurrence rates after treatment of OE lesions are even less clear.
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For severely dysplastic or in situ carcinoma lesions of erythroplakia, surgical excision or Mohs micrographic surgery is generally recommended, because the entire lesion can be removed with the most thorough histopathologic confirmation of adequate margins. The proper management of mildly or moderately dysplastic OE lesions is less clear, with some advocating excision and others promoting a more conservative, observational approach. Other treatment modalities, such as laser ablation, cryosurgery, and electrodesiccation, have also been used, but their roles in treating OE are even less clearly defined. Given the high malignant transformation rate of these lesions, it is difficult to advocate any nonexcisional ablative therapy. Regardless of the treatment method used to remove the lesion, all patients should be followed at regular intervals to be evaluated for recurrence or for the development of a not uncommon second primary lesion in the oral cavity or aerodigestive tract. Exposure to carcinogenic stimuli, such as tobacco and
alcohol, should be discontinued.