Definition

Actinic keratosis, also known as solar keratosis or senile keratosis, is a very common lesion occurring in susceptible persons as a result of prolonged and repeated solar exposures. The action of ultraviolet radiant energy, principally UVB, results in damage to the keratinocytes and produces single or multiple, discrete, dry, rough, adherent scaly lesions. These premalignant lesions may, in time, progress to squamous cell carcinomas.

Epidemiology

Actinic keratosis affects predominantly the sun-exposed areas of fair-skinned people. The incidence in elderly whites may approach 100% in some populations.^1,20 The appearance of actinic keratosis may be at a much younger age (under 30 years) if the susceptible individuals have an outdoor occupation, such as farmers, ranchers, and sailors, or have an outdoor lifestyle in sports or recreation. Skin phototype²¹ (SPT) I and SPT II individuals are affected mainly. It is also more common in transplant recipients^22,23 and albinos.²⁴ It is rare in darker-skinned individuals, and almost never affects blacks, East Indians, or other Asians.

Clinical Features

The onset of actinic keratosis is insidious as a rule and therefore often passes unnoticed for some time. The characteristic lesion is rough and gritty to palpation, similar to the feel of coarse sandpaper. On close examination, they appear as round-to-oval lesions, often less than 1.0 cm in diameter. They may be flat to nodular, as in the hypertrophic variety of actinic keratosis (Figure 123-1). The lesions are usually skin-colored or yellow-brown, often with a reddish tinge. There may be single or multiple scattered discrete lesions, typically limited to sun-exposed areas. A pigmented variant of actinic keratosis, named spreading pigmented actinic keratosis, is a brown, slowly growing, slightly scaly lesion that tends to appear on the face and may be larger than 1.5 cm in diameter, making it difficult to distinguish from lentigo maligna.²⁵

Figure 123-1

Actinic keratosis. Multiple discrete lesions on the scalp. These lesions are “gritty” to palpation. The largest lesion in the center of the picture represents the hypertrophic variant. This must be differentiated from a squamous cell carcinoma (more...)

Histopathology

Histologically, actinic keratosis affects the interfollicular epidermis. On routine stained sections, there is atrophy of the epidermis with maturation disarray of the epidermal keratinocytes. There are varying degrees of keratinocytic atypia and parakeratosis, which typically spares the follicular epithelium and the intraepidermal portion of the eccrine duct.²⁶ The boundary between affected and unaffected epidermis is sharp, thereby producing alternating columns of ortho- and parakeratotic scales. The underlying dermis often shows evidence of extensive elastic fiber damage (solar elastosis).

Diagnosis

The diagnosis of flat actinic keratosis is usually based on clinical examination alone. In contrast, the hypertrophic variant may sometimes be confused with an early squamous cell carcinoma. Suchniak and colleagues²⁷ demonstrated histologically the presence of in situ or invasive squamous cell carcinomas in 50% of lesions diagnosed clinically as hypertrophic actinic keratoses.

Treatment

The flat actinic keratosis lesions are most easily treated with cryotherapy.²⁸ Application of liquid nitrogen with either a Q-tip or a spray gun for 10 to 15 s will suffice in the majority of cases. Retreatment may be necessary for the more stubborn lesions. It is not necessary to freeze to the point of blistering. Curettage and electrodesiccation of the lesions is equally effective, but carries a slightly greater risk of scarring and dyspigmentation. The hypertrophic lesions are best evaluated by biopsy to rule out invasive SCC.

Where large areas of skin are involved, applications of 5-fluorouracil preparations twice a day to the affected areas may be used for up to 3 weeks.²⁹ This will result in a brisk reaction in the treated areas, ranging from redness, soreness, and weeping, to shallow ulceration and crusting (Figure 123-2). The reaction will gradually subside after discontinuation of the cytotoxic cream. Newer formulations with 0.5% 5-fluorouracil may be equally efficacious and may cause less irritation to the skin.³⁰

Figure 123-2

Actinic keratosis. Extensive actinic keratosis on the face. Note that the right half has been used as control and the left half of the forehead and the nose were treated with 5% 5-fluorouracil cream for 14 days. (Four-color version of figure on CD-ROM) (more...)

The use of sunscreens,³¹ as well as avoidance of the mid-day sun, are recommended as preventive measures in order to avoid excessive sun damage.

Course and Prognosis

The lesions of actinic keratosis may rarely disappear spontaneously, but, in general, they persist if not treated. There is an estimated 5% to 20% lifetime risk of transformation into squamous cell carcinomas.³² Marks and colleagues^33,34 reported that 60% of squamous cell carcinomas arise from preexisting solar keratoses diagnosed within the previous year.

Definition

Arsenical keratosis is a premalignant condition that presents with multiple corn-like papules on the palms and soles or other sites of friction and trauma.

Epidemiology

Arsenic exposure may result from environmental sources such as well water, from industrial sources such as pesticides, fabric dyes, or copper and other ores, or from medicinal sources.³² Inorganic arsenic, such as Fowler solution, Donovan solution, and Asiatic pills, was used for a variety of diseases, including psoriasis. The most common form of inorganic trivalent arsenic was Fowler solution, which contains 1% potassium arsenite. There is a direct correlation between the degree of exposure and the development of skin cancer. The minimal latent period for the development of arsenic keratoses is 2.5 years.³⁵ An exposed Japanese population was observed to develop Bowen disease within 10 years, invasive squamous cell carcinoma after 20 years, and pulmonary cancers after 30 years.³⁶ Thus, arsenical keratoses are also markers of possible internal neoplasms.

Clinical Features

These are hard, yellowish, punctate papules, usually 2 to 10 mm in diameter. They are usually multiple and symmetrically distributed. The typical sites of involvement are the palms and soles. They may resemble common warts or punctate hyperkeratosis of the palms and soles, which is an autosomal dominant condition. On other parts of the cutaneous surface, particularly non-sun-exposed areas, erythematous, scaly, slightly elevated lesions are more common (Figure 123-3). Most lesions remain unchanged for many years. However, evolution into basal cell carcinoma, Bowen disease, or squamous cell carcinoma may occur. These arsenic-induced tumors are usually multiple and more common on the trunk and extremities,³⁷ and present as hyperkeratotic crusty plaques that enlarge slowly. Patients exposed to significant amounts may also develop internal cancers.³² The most common sites for the internal malignant neoplasms are the bronchi and the genitourinary tract.³⁸

Figure 123-3

Arsenical keratosis. Erythematous, scaly lesions in a patient who had ingested Fowler solution. (Four-color version of figure on CD-ROM)

Histopathology

Biopsy of the corn-like lesion shows thick, compact hyperkeratosis with a prominent granular layer and acanthosis. Nuclear atypia may be observed. Atrophy and solar elastosis are not seen in arsenic keratosis. Evidence of Bowen disease or squamous cell carcinoma may be present in adjacent areas.

Treatment

The keratoses may be treated with cryotherapy or excisional surgery. Oral retinoids may also be effective and may have the additional systemic benefit of possibly reducing the risk of internal malignancies. However, the long-term side effects of retinoids should be weighed against the potential benefits.

Course and Prognosis

Regular skin and physical examinations are recommended for early detection of malignant lesions.

Definition

Epidermodysplasia verruciformis is a rare, multifactorial disorder consisting of genetic, immunologic, and extrinsic (UVB) components in addition to infection with specific HPV types. Beginning in the third or fourth decade of life, patients may develop multiple in situ and/or invasive squamous cell carcinomas.^46,47

Epidemiology

The disease appears to be determined by an autosomal recessive gene, with increased incidence in consanguineous marriages.⁴⁰ It has no racial or geographic predilection. The age of onset may vary from early infancy to the third decade of life, but the average age is 6 years. The transformation from benign to malignant lesions is proportional to the amount of sun exposure.⁴⁸ Thus, persons with an outdoor lifestyle are at greater risk. HPV 5 is the most commonly encountered HPV in the lesions, although a variety of other HPVs have also been found. More than one HPV type may occur in the same individual.⁴⁹

Ninety percent of the patients have impaired cell-mediated immunity.⁴⁸ Whether this impairment is primary or secondary to chronic papillomavirus infection is still being debated. The humoral immunity remains unaffected.

Clinical Features

The disease most commonly presents in childhood. The lesions are typically 2- to 6-mm wart-like papules, most numerous on the face, neck, and the backs of the hands and feet. On the trunk and upper extremities, the lesions tend be macular and scaly. The color may vary from tan to red, to darkly pigmented or depigmented. Thus, the lesions on the trunk may sometimes resemble tinea versicolor, whereas those on the elbows and knees may mimic psoriasis. The palms, scalp, and mucosal surfaces are spared. The skin lesions are typically resistant to treatment and do not resolve spontaneously.

Histopathology

The histologic changes in the wart-like lesions are similar to verruca plana but differ by being more pronounced and extensive. Koilocytosis may be observed in the upper epidermis, suggesting the presence of a viral infection.⁴⁷ Squamous cell carcinoma in situ or invasive carcinoma may be observed within the lesions of epidermodysplasia verruciformis. On electron microscopic examination, viral particles have been demonstrated within the nuclei of the cells in the granular layer.⁵⁰ HPV-type-specific DNA have been demonstrated in squamous cell carcinomas arising in the lesions of epidermodysplasia verruciformis.

Treatment

There is no effective treatment for epidermodysplasia verruciformis. Protection from exposure to sunlight or x-rays may decrease the risk of malignant transformation. Carcinomas that develop should be excised surgically. Oral retinoids have been tried with some benefit. However, the serious long-term side effects preclude the prolonged use of these medications.⁴⁶

Course and Prognosis

In approximately one-third of patients, epidermodysplasia verruciformis undergoes malignant transformation. The risks for an individual patient may depend on the interplay of the various cofactors. However, the cancers that develop tend to be slow to metastasize.

Definition

Bowenoid papulosis is a relatively new entity that presents with multiple fleshy papules in the genital and perigenital areas of both sexes.^51–56 Although the histology of these lesions mimics that of Bowen disease, the biologic behavior of these lesions is uncertain as progression to true Bowen disease has been reported only rarely.^57,58 There is increasing evidence that HPV plays a part in the etiology of this disease.⁵⁹

Epidemiology

The incidence of bowenoid papulosis is unknown. This entity affects mainly young adults, with a median age of 31 years. It is slightly more common in females. HPV types 16, 18, 31, 32, 34, 35, 39, 42, 48, and 51 through 54 have been reported in association with this disease.^40–42,54 Bowenoid papulosis in women is frequently associated with HPV 16.⁵⁴

Clinical Features

This disease typically presents with solitary to multiple 2- to 10-mm diameter, flesh-colored to dark-brown papules in the genital and perigenital areas. The lesions may have a verrucous or smooth surface. In the female, it typically affects the vulva and labia. In the male, it is most commonly found on the shaft of the penis. The patient is often circumcised, in contrast to true Bowen disease. The lesions may spontaneously regress, but new lesions may appear. Only rare cases of progression to true Bowen disease have been reported.^57,58,60 Approximately 35% of patients have a solitary lesion.

Histopathology

The histology of the lesions is similar to that observed in Bowen disease. Contrasting features include a lack of full-thickness atypia in the epidermis and sparing of the acrotrichia in bowenoid papulosis.⁶¹ Instead, dysplastic keratinocytes are scattered singly throughout the affected epidermis. Bizarre mitotic figures may be present as a result of treatments with topically applied podophyllin. Virus-like particles have been reported.⁶²

Treatment

The lesions may be treated with the application of liquid nitrogen or 5- fluorouracil cream, or by electrosurgery.^57,61 In appropriate cases, surgical excision may be considered. Recurrences are common. Spontaneous regression also occurs.

Course and Prognosis

In view of the uncertain malignant nature of the lesions, careful follow-up is essential. In persistent cases or cases of carcinomatous transformation, evidence of altered immune status should be sought.

Definition

Keratoacanthoma is a common, rapidly growing but benign tumor that will involute spontaneously, even if untreated. It is believed to originate from the hair follicles.^63–65

Epidemiology

Few studies have been done on the incidence of keratoacanthoma.^66–68 Chuang and colleagues⁶⁹ recently reported an incidence rate of 103.6 per 100,000, based on the small population in Kauai, Hawaii. It is most common between the ages of 60 and 65 years⁶⁴ and is rare in persons younger than the age of 20 years. In contrast to squamous cell carcinoma and basal cell carcinoma, there is no increase in frequency in old age. It is uncommon in blacks⁷⁰ or Japanese,⁷¹ and is approximately two to three times more common in males. The majority of patients have a solitary lesion.⁷²

Sun exposure,⁶⁷ and exposure to chemical carcinogens such as tar,⁶⁴ are thought to be etiologic factors. The possibility of a viral etiology is still being debated.^73–76 The presence of HPV has been demonstrated by DNA hybridization and polymerase chain reaction (PCR) studies.^77,78 The possibility of a genetic defect has also been proposed because these tumors are more common in patients with the Muir-Torre syndrome than in the general population.

Clinical Features

Keratoacanthomas characteristically arise on hairy skin. The most common areas are the central parts of the face: the cheeks, nose, ears, lips, eyelids, and forehead. The dorsa of the hands, wrists, and forearms are also common sites.⁷² The trunk and scalp are uncommon sites. Typically, the lesion presents as a solitary, rapidly growing, firm, dome-shaped, flesh-colored to slightly pink lesion with a plug of keratin in the central crater (Figure 123-4). The evolving lesion typically grows rapidly for 2 to 4 weeks to a size of up to 2 cm in diameter. The mature lesion involutes spontaneously after a few months, leaving a scar. The complete cycle of growth to spontaneous resolution takes approximately 4 to 6 months.⁷⁹ Multiple or recurrent lesions may occur, particularly in cases associated with tar exposure. Multiple lesions associated with defects in cell-mediated immunity and with multiple internal malignant neoplasms and sebaceous adenomas, as part of Muir-Torre syndrome,⁸⁰ have been noted. There is no evidence that the solitary type is associated with internal malignancy.⁷²

Figure 123-4

Keratoacanthoma. A pink, dome-shaped lesion with a central core of keratin. This rapidly growing lesion is located on the mid-forehead. Courtesy of P.L. McCarthy, MD. (Four-color version of figure on CD-ROM)

Histopathology

The histologic appearance depends on the stage of evolution of the lesion. In the well-developed tumor, the lesion is cup shaped. The epidermis consists of islands and cords of pale pink, “ground-glass” keratinocytes extending into the upper dermis. The center of the “cup” is filled with keratin. Hyperchromatic nuclei as well as atypical mitoses are often seen but are not indicators of malignancy.

Diagnosis

The main differential diagnosis is to distinguish keratoacanthoma from squamous cell carcinoma. The rapid evolution and spontaneous involution, the characteristic dome shape with a central plug of keratin, and the relatively young age of the patient are all clues to the diagnosis. In most cases, a wedge biopsy is essential in order to exclude an invasive squamous cell carcinoma.

Treatment

Keratoacanthomas resolve spontaneously as a rule, leaving behind a scar. Surgical excision of the lesion will produce better end results cosmetically as well as provide tissue for histopathologic diagnosis. Radiotherapy^67,81–83 has been used successfully in lesions that cannot be distinguished from squamous cell carcinomas, as well as the so-called giant aggressive keratoacanthomas.^84,85 The dosage used, 4,000 to 6,000 cGy, is the same as the tumoricidal dosage used for squamous cell carcinomas. Topical or intralesional 5- fluorouracil^86,87 and intralesional injections of methotrexate⁸⁸ may be effective alternative treatment modalities. Methotrexate, given systemically, is found to be useful in treating multiple, as well as the larger keratoacanthomas.^89,90 Both the solitary⁹¹ and multiple keratoacanthomas⁹² have been successfully treated with oral isotretinoin. Intralesional interferon alpha-2a has also been tried with some success.⁹³ The lack of histologic confirmation with nonsurgical modalities is a major drawback. A biopsy of the lesion to rule out a squamous cell carcinoma prior to treatment may be prudent.

Course and Prognosis

Keratoacanthoma is a benign tumor that carries a very good prognosis. Reports of malignant transformation as well as metastasizing lesions are probably misdiagnosed squamous cell carcinomas.

Definition

Squamous cell carcinoma is a malignant tumor arising from epidermal or appendageal keratinocytes or from the squamous mucosal epithelium. There is often a history of damage by exogenous agents acting as carcinogens, such as sunlight, ionizing radiation, local irritants, or arsenic ingestion. The tumor cells have a tendency toward keratin formation. Bowen disease is an in situ squamous cell carcinoma. Verrucous carcinoma is a variant of low grade squamous cell carcinoma with a clinicopathologically distinct warty appearance. The Buschke-Loewenstein tumor is the subset of verrucous carcinoma found on the genitals.

Epidemiology

The incidence of squamous cell carcinoma of the skin varies greatly for different parts of the world and for different races and different people with different life habits and occupations. In 1963, the age-adjusted incidence of squamous cell carcinoma per 100,000 white residents in 8 American cities was 12.1 for males and 6.7 for females.⁹⁴ This is in contrast to the rate of 62 per 100,000 among whites in Honolulu County, Hawaii, reported by Quisenbery.⁹⁵ In 1983, Scotto and colleagues¹ reported an incidence of 41.4 cases per 100,000, and the incidence of cutaneous squamous cell carcinoma appears to be on the increase. The incidence of all skin cancer in various groups of blacks, including African Americans is only 1 to 2 per 100,000, excluding melanoma,⁹⁶ whereas the rate of skin cancer in India is only 1.4% of all carcinomas.⁹⁷ The incidence of squamous cell carcinoma in Japanese Kauaiians is four times lower than in white Kauaiians.¹⁵ These studies illustrate the marked difference in incidence between light-skinned people and the darker races. Dorn studied the incidence of skin cancer in 10 different areas in the United States and found a much higher frequency in the southern parts of the country than in the north.⁹⁸ Eastcott likewise found a much higher incidence of skin cancer in Australia and New Zealand than in England.⁹⁹ The latitude gradient is steeper for squamous cell carcinoma than for basal cell carcinoma, suggesting a closer correlation between squamous cell carcinomas and chronic cumulative sun exposure than basal cell carcinoma.¹⁰⁰ Lookingbill and colleagues²⁴ reported a higher incidence of nonmelanoma skin cancer, particularly that of squamous cell carcinoma, in an albino population in Tanzania, where the prevalence of skin cancer is low among the normally dark-skinned population.

As previously mentioned, mutations in the p53 tumor-suppressor gene have been found in a number of squamous cell carcinomas.¹⁰¹

Phototherapy patients who had received UVB or psoralen plus ultraviolet A (PUVA) for the treatment of skin diseases, such as psoriasis or mycosis fungoides, are also at increased risk.^102–105 In a study of 368 patients who developed carcinoma of the skin after radiation therapy, one-third of the tumors were squamous cell carcinomas.¹⁰⁶ The incidence of squamous cell carcinoma is reported to be much higher in immunosuppressed patients.^107,108 Gupta found an 18-fold increase in incidence in immunosuppressed renal transplant patients.¹⁰⁹ España and colleagues¹¹⁰ also reported an increase in incidence of both squamous cell carcinomas and basal cell carcinomas in heart transplant recipients. The squamous cell carcinoma to basal cell carcinoma ratio also reverses from 0.25 to 1 in the general population to 1.5 to 3 to 1 in immunosuppressed patients.^{22,107,108,111} McGregor and colleagues¹¹² suggested that mutation of the genes for tumor-suppressor proteins may be important in the biology of these tumors. Tumors in such patients tend to behave in a more aggressive manner.^104,113

Verrucous carcinoma of the skin (epithelioma cuniculatum) is a rare tumor, with more than 100 reported cases.¹¹⁴ Approximately 80% to 90% of patients are male, with a mean age of 52 to 60 years.¹¹⁵ The Buschke-Loewenstein tumor is best considered a verrucous carcinoma of the anogenital mucosa. Penile Buschke-Loewenstein tumor is the most common, with an incidence between 5% and 24% of all penile cancers. Vaginal, cervical, perianal, and perirectal Buschke-Loewenstein tumors are less common than penile ones. The etiology of these tumors is linked to HPV, particularly to HPV 6 and 11.¹¹⁴

The incidence of Bowen disease has not been extensively investigated. Chute and colleagues¹¹⁶ reported an incidence of 14 per 100,000 population for Bowen disease in a Rochester, Minnesota, population. In a 5-year prospective study based on the residents of Kauai, Hawaii, Reizner and colleagues¹¹⁷ reported an incidence of 142 per 100,000 population.

The incidence of squamous cell carcinoma of the oral mucosa also varies significantly for different parts of the world.^118,119 It is high in India, southeast Asia, and Puerto Rico, and is low in Japan, Israel, Norway, and England. The use of betel nut and other spices may be partly responsible for the higher incidence in India and southeast Asia.¹²⁰ In the United States, there are approximately 30,000 new cases per year.¹²¹ It is about nine times more common in males.¹²² Oral cancer is rare in persons younger than age 35 years. The incidence increases with age until the age of 60 to 64 years, and then declines.¹²²

Recently, some squamous cell carcinomas, particularly those in the anogenital and periungual areas, have been linked etiologically to infection with certain types of HPV (HPV 16, 18, and, less commonly, 31, 33, 35, and 45).^{43,44,123–125} These were discussed in more detail under “Human Papillomavirus Induced Premalignant Papules” above.

Clinical Features

Squamous cell carcinoma often arises in damaged skin or skin which has been subjected to chronic irritation. Thus, the skin adjacent to the carcinoma may show evidence of solar damage, such as actinic keratosis, wrinkling and dryness, telangiectasia, and irregular pigmentation. Alternatively, there may be features of radiodermatitis from previous radiation therapy,^106,126,127 a sinus tract associated with an underlying osteomyelitis,¹²⁸ or scarring from a burn (Marjolin ulcer).^125,129,130 Chronic venous ulcers of the lower extremities are also associated with increased risks of developing squamous cell carcinomas.¹³¹ A chronic ulcer that shows features of proliferation beyond the expected granulation process should raise the suspicion of malignant transformation.

Squamous cell carcinoma usually evolves faster than basal cell carcinoma, but not as rapidly as keratoacanthoma. The earliest lesion, the so-called intraepidermal squamous cell carcinoma or carcinoma in situ, typically appears as a scaly, erythematous plaque on sun-exposed areas. The lesion often has a sharply demarcated but irregular outline (Figure 123-5). Bowen disease is clinically identical to squamous cell carcinoma in situ. Bowen disease on the glans penis is also known as erythroplasia of Queyrat.

Figure 123-5

Dermatofibrosarcoma protuberans on the back of the neck. Firm papule resembling a dermatofibroma. Courtesy of R.A. Johnson, MD. (Four-color version of figure on CD-ROM)

Invasive squamous cell carcinoma (Figure 123-6) almost always arises from a preexisting premalignant lesion or from an in situ carcinoma, although de novo squamous cell carcinoma has been reported.¹³² The lesion is typically an erythematous, indurated papule, plaque, or nodule. The shape of the lesion may be polygonal, oval, round, or verrucous (Figures 123-7 and 123-8). The tumor tends to increase both in elevation and diameter with time. A hallmark of squamous cell carcinoma is its firmness on palpation. The late lesion is often eroded, crusted, and ulcerated with an indurated margin. The ulcer is often covered with a purulent exudate and bleeds easily (Figure 123-9). Early ulceration is often a marker for anaplastic lesions. Regional lymphadenopathy may be present either as a response to infection of the ulcer or from metastases. In the latter case, they tend to be rubbery and more irregular and may be fixed to adjacent tissues.

Figure 123-6

Squamous cell carcinoma (SCC) arising in SCC in situ. A nodule of invasive SCC on the lower leg arising within the well-demarcated, erythematous scaly plaque of SCC in situ. (Four-color version of figure on CD-ROM)

Figure 123-7

Invasive squamous cell carcinoma. Erythematous, hyperkeratotic nodule on the forehead resembling a keratoacanthoma (see Figure 123-4). An incisional or excisional biopsy is necessary to distinguish the two lesions. (Four-color version of figure on CD-ROM) (more...)

Figure 123-8

Invasive squamous cell carcinoma. A hyperkeratotic, crusty plaque on the forearm. Note the evidence of sun damage in the surrounding skin: wrinkling, bruising, and a lackluster appearance. (Four-color version of figure on CD-ROM)

Figure 123-9

Invasive squamous cell carcinoma. An ulcerated lesion on the glans penis with an indurated margin. The ulcer typically bleeds easily. (Four-color version of figure on CD-ROM)

Verrucous carcinoma of the skin is most commonly found on the soles of men.¹¹⁴ Typically, it presents as a slowly enlarging cauliflower-like mass. It is locally aggressive and may grow to a significant size. The ball of the foot is involved in more than 50% of cases. Other locations include the face, buttocks, oral cavity, trunk, and extremities. The bulk of the tumor is soft and “squashy,” and may be foul smelling. If left untreated, the tumor will eventually penetrate the underlying soft tissue and bone. However, metastasis is rare.

The Buschke-Loewenstein tumor most commonly affects the penile glans and prepuce of uncircumcised males, presenting as a cauliflower-like, fungating, foul-smelling tumor on the coronal sulcus. In women, it may present on the vagina, cervix, or vulva. The Buschke-Loewenstein tumor has a tendency to infiltrate deeply, causing destruction of underlying tissues.

Squamous cell carcinoma of the oral mucosa may present as an exophytic papillary mass, a discrete ulcer with a raised indurated border, or a firm, slightly raised plaque. The last is characteristic of a deeply infiltrative lesion. There may be hemorrhage, particularly when there is ulceration. An area of leukoplakia may be observed in association with the carcinoma.

Squamous cell carcinoma of the lip may arise from an area of leukoplakia, leukokeratosis, or actinic cheilitis. Approximately 90% of SCCs occur on the lower lip. This tumor is typically much more aggressive than those on glabrous skin and has a high rate of metastasis.

Carcinoma arising in late radiation dermatitis or x-ray keratoses tends to be very anaplastic and extremely aggressive. The rate of metastasis is high in such tumors.¹³³

Histopathology

Because squamous cell carcinoma in situ is an intraepidermal carcinoma, the border between epidermis and dermis remains sharp throughout the lesion. The epidermal keratinocytes are arranged haphazardly with a “windblown” appearance. There is no tendency for the keratinocytes to flatten out and mature as they migrate from the basal layer upward, as is seen in normal epidermis. Abnormal keratinization, in the form of keratin pearls or individual dyskeratotic cells, is characteristic. Many cells are large and atypical, with large and hyperchromatic nuclei. Multinucleated keratinocytes and atypical mitotic figures are observed. These changes tend to extend down the follicular epithelium, in contrast to the sparing of follicular epithelium in actinic keratosis. Staining with the PAS (periodic acid-Schiff) reaction confirms an intact basement membrane zone. There is usually a moderate amount of chronic inflammatory infiltrate in the upper dermis.

In squamous cell carcinoma, the tumor cells are seen to proliferate downward in cords and single cells into the dermis. The degree of atypia of the cells is determined by the variation in size and shape of the cells, hyperchromasia of the nuclei, presence or absence of keratinization of the individual cells, presence or absence of intercellular bridges, and the presence or absence of atypical mitoses. The degree of differentiation is determined by extent of the tumor trying to recapitulate normal keratinizing epithelium, with the spindle-cell squamous cells representing the least differentiated form. The tumor may be graded according to the proportion of undifferentiated cells within the tumor. The more malignant the tumor, the greater is the proportion of atypical cells. Other factors of prognostic importance include the depth of invasion, the presence of perineural invasion and the architectural pattern of invasion. In the last, three patterns are recognized: (1) invasion of the tumor by broad, pushing borders; (2) presence of nests and islands of tumor cells at the advancing border; and (3) single-cell invasion. There is often a brisk chronic inflammatory infiltrate in the dermis.

In cutaneous or mucosal verrucous carcinoma, well-differentiated squamous epithelium is seen projecting deep into stroma. Histologic sinuses and cystic formations in a cuniculate (rabbit burrow-like) pattern may be observed, particularly in the plantar lesions.¹¹⁴ Koilocytosis may be seen in the tumor cells in the granular cell layer, suggesting an infection by human papillomavirus.

In the case of a poorly differentiated spindle-cell tumor, staining with a panel of monoclonal antibodies may help to identify a spindle-cell squamous cell carcinoma, which characteristically stains positive for keratin and negative for vimentin and S-100 protein.¹³⁴ Electron microscopy of such a lesion may demonstrate the presence of intracytoplasmic tonofilaments and the presence of desmosomes.¹³⁵ Electron microscopic study of verrucous carcinoma demonstrates features of a well-differentiated squamous cell carcinoma.¹¹⁵

Treatment

The choice of treatment modality depends on the degree of differentiation of the tumor and the presence or absence of metastasis. The size, shape, location of the tumor, and the predisposing factors should also be considered. In the case of a localized, well-differentiated tumor with no evidence of metastasis, the goal should be complete eradication of the lesion. In the case of a poorly differentiated, recurrent tumor or the presence of lymph node metastases, palliative treatment may be considered, if complete eradication is deemed impossible. The variety of modalities available for consideration include excision surgery, Mohs surgery, cryosurgery, electrosurgery, and radiation therapy.^{7,12,82,136–138} The final result often depends as much on the experience of the surgeon as on the choice of treatment selected. Thus cooperation among dermatologists, surgeons, and radiotherapists is important.

Excision Surgery

Surgical excision with primary closure or repair with skin graft or flap is the treatment of choice for relatively small lesions with distinct borders. There should be an adequate margin of clearance of 3 to 5 mm to minimize the risk of recurrence. Brodland and Zitelli¹³⁹ reported that margins of 4 mm were required to achieve a 95% tumor clearance rate. For invasive or large tumors (> 2 cm), or tumors on high-risk areas such as the scalp, ears, nose, eyelids, or lips, a minimum margin of 6 mm is recommended.

Tumor arising in late radiation dermatitis or x-ray keratosis should also be surgically excised rather than treated with more radiation. Likewise, tumor previously treated with radiation should be excised with the entire radiation scar, if possible, because tumor may exist in multiple foci within the irradiated field.

Large tumors situated near the lip, eyelid, and the anogenital area should be excised in order to preserve the function of the structures and avoid retraction caused by excessive scarring.

Surgery is also preferred for lesions invading bone or cartilage. Treating such lesions with radiation therapy may result in radiation necrosis of the bone or cartilage. Recurrent carcinomas, tumors with indistinct borders, and those arising in scars, ulcers, or sinuses may be treated with surgery to allow histologic examination of the excision margins. Tumors that have metastasized to regional lymph nodes are also best treated with excision surgery and lymph node dissection. Prophylactic lymph node dissection is not recommended because of the relatively low rate of metastasis.

Mohs Surgery

Surgery with microscopic control of the excision margins (Mohs micrographic surgery¹⁴⁰) has become the treatment of choice for extensively invasive and infiltrative tumors or those that are recurrent.⁷ This technique allows maximum conservation of “good tissue” while the surgeon can still be reassured of clear margins. This modality of treatment is also associated with a lower local recurrence rate.¹⁰⁸

Cryosurgery

Treatment of squamous cell carcinoma by freezing with liquid nitrogen is best restricted to the most superficial tumors and carcinoma in situ. This modality has the advantage of simplicity with an excellent cure rate when employed in the proper situation.^137,141 Because collagen, cartilage, and bone are less sensitive to injury by freezing than the tumor cells, scarring and damage to underlying bony or cartilaginous structures can be minimized.

Electrosurgery

The choice of lesions suitable for treatment by curettage and electrodesiccation is similar to those suitable for cryosurgery. In addition, large superficial tumors on the head and neck, trunk and upper extremities have been treated with this modality with excellent results.

Radiation Therapy

Radiation therapy is often employed for poorly differentiated tumors and for patients who may not be able to tolerate other more invasive treatment modalities. The site of the lesion has to be taken into consideration to minimize the late complications of ionizing radiation. Thus, lesions on the dorsum of the hand and those over bony and cartilaginous structures should not be treated with radiation. Tumors that have a tendency to invade along the planes of embryonic closure, such as those in the nasolabial fold and pre- and postauricular areas, are good candidates for this modality of treatment.¹⁴² Excellent results can also be obtained for small lesions of the nose, lip, eyelid, and canthus. A fractionated dose is usually preferred to a single massive dose for the best cure rate and to minimize the local as well as systemic side effects of radiation.^7,82 The treatment schedule is determined by the size, depth, and location of the tumor and the particular time-dose-fractionation schedule used. The total dose is typically between 4,000 and 6,000 cGy.

Rapid anaplastic transformation with widespread metastases has been reported in verrucous carcinoma following radiation therapy.^114,115

Chemotherapy

Although still experimental, intralesional recombinant interferon alfa-2b has also been used for actinically induced squamous cell carcinomas less than 2 cm in largest dimensions with encouraging results.¹⁴³

The use of oral isotretinoin in patients with large, recurrent or metastatic squamous cell carcinomas resulted in partial to complete regression of the tumors.¹⁴⁴ Isotretinoin also decreased the incidence of a second primary squamous cell carcinoma, when given as a chemopreventive agent.¹⁴⁵ However, the benefit from such long-term use has to be weighed against the toxicity. In organ transplant recipients, where the risk of developing skin cancer is increased, the use of retinoids may be justified.^146–148 A new immune-response modifier, imiquimod, stimulates the local production of interferon alpha, and was effective for Bowen disease in a small group of patients.¹⁴⁹

Course and Prognosis

The risk factors correlated with local recurrence and metastatic rates include treatment modality, prior treatment, location, size, depth, histologic differentiation, histologic evidence of perineural involvement, precipitating factors other than ultraviolet light, and host immunosuppression. Squamous cell carcinoma in skin carries an overall metastatic rate of 3% to 6%.^108,150,151 Those arising from sun-damaged skin typically have a low risk for metastasis,^108,151 whereas those arising from chronic osteomyelitic sinus tracts, irradiated areas, and burn scars have a much higher metastatic rate (31%, 20%, and 18%, respectively). Carcinoma on the lower lip, although mostly sun induced, has a metastatic incidence of about 15%. Tumor arising in areas such as the glans penis (see Figure 123-9), the vulva, and the oral mucosa also have a high rate of metastasis.

Histologically, the best prognostic indicators are level of dermal invasion and vertical tumor thickness.¹⁵² In the study by Immerman and colleagues,¹⁵³ all the tumors that recurred were at least 4 mm or more in thickness and involved the deep dermis, whereas all the fatal cases involved tumors more than 1 cm thick, with invasion into the subcutaneous fat or beyond.

With proper treatment, the overall 5-year remission rate is 90%, including squamous cell carcinoma of the lip. Frankel and colleagues ¹⁵⁴ recommended follow-ups at least every 3 months for a year after treatment of squamous cell carcinoma, and semiannually thereafter for up to 4 years.

Verrucous carcinoma and the Buschke- Loewenstein tumor rarely metastasizes to regional lymph nodes if left untreated for many years.¹¹⁴

Definition

Basal cell carcinoma is a malignant tumor that rarely metastasizes.¹⁵⁵ It is composed of cells that arise from the epidermis and the appendages which resemble the basal layer of the epidermis and is associated with a characteristic stroma.¹⁵⁶ It tends to grow slowly and invade locally over many years, which eventually leads to ulceration, hence the name “rodent ulcer.”

Epidemiology

Basal cell carcinomas account for more than 75% of keratinocytic skin cancers diagnosed in the United States each year.^109,157,158 The incidence of basal cell carcinoma varies from 422 per 100,000 general population in Kauai, Hawaii,¹⁵⁹ to 146 per 100,000 in Rochester, Minnesota.¹⁶⁰ The average annual incidence in the United States is 191 per 100,000 white persons.¹⁶¹ It is the most common form of skin cancer in whites.^1,12 It is very rare in darkly pigmented people.^162,163 It most frequently occurs in persons older than 40 years of age. The frequency is slightly higher in males. Other risk factors include geographic locations with high solar intensity, exposures to inorganic trivalent arsenic,^32,37 ionizing radiation,^126,164 and immunosuppression.^22,165 In a review of 368 patients who developed cancer of the skin after radiotherapy, two-thirds were basal cell carcinomas.^2,38,106 Phototherapy patients receiving UVB or PUVA for treatment of certain dermatoses, such as psoriasis or mycosis fungoides, are also at increased risk.¹⁰² Grenz-ray irradiation used in the treatment of benign skin disorders, such as psoriasis, acne, or seborrheic dermatitis, is also associated with the development of multiple basal cell carcinomas within the irradiated areas.¹⁶⁶ Several recent studies suggest a correlation between basal cell carcinomas and exposures to sunlight in early life and intense intermittent (recreational) sun exposures.^16,167,168 This is contrary to the previous belief that basal cell carcinomas result from cumulative lifetime sunlight exposures. Genetic studies show that loss-of-function mutations in the tumor-suppressor gene patched, or gain-of-function mutations in the smoothened gene, lead to the formation of sporadic basal cell tumors.^169,170 A genetically inherited form is described in basal cell nevus syndrome.^171,172

Clinical Features

The basal cell carcinoma is characteristically slow growing over months to years. It is usually asymptomatic unless ulceration occurs, and then there is bleeding. It most frequently occurs on sun-exposed areas such as the face and upper trunk,^173,174 and is rare on the palms and soles.

The early lesions are round-to-oval papules or nodules, often with an umbilicated center which may be ulcerated. The color is pink to red and often has a translucent or pearly quality (Figure 123-10). Basal cell carcinomas (BCCs) are firm to palpation. If left untreated, the lesion enlarges slowly and is destructive to neighboring structures by direct invasion. Longstanding lesions are ulcerated as a rule (Figure 123-11). There are often telangiectasias in the surrounding skin, which also shows other evidence of solar damage, such as actinic keratosis, atrophy, wrinkling, dryness, and irregular pigmentation. Some basal cell carcinomas are pigmented and may exhibit a bluish hue.¹⁷⁵ These may be confused with malignant melanoma (Figure 123-12). The so-called superficial-type basal cell carcinoma usually presents on the trunk as an irregular, atrophic plaque with a slightly raised border (Figure 123-13). Flat basal cell carcinomas can be difficult to detect. They are often ivory-white in color and may resemble morphea and are therefore called morphea-like basal cell carcinomas.^176,177 This type of lesion usually occurs on the face and has a more aggressive behavior.¹⁷⁸

Figure 123-10

Basal cell carcinoma. A pearly nodule with an umbilicated, ulcerated center and telangiectasia. (Four-color version of figure on CD-ROM)

Figure 123-11

Basal cell carcinoma. Note the erosive nature of such a long-standing lesion. (Four-color version of figure on CD-ROM)

Figure 123-12

Pigmented basal cell carcinoma. A pink, irregular plaque with dark-blue to black pigmentation at the center that mimics a superficial spreading melanoma. The shiny quality is one clue to the diagnosis. Examination with the aid of a dermatoscope may also (more...)

Figure 123-13

Superficial basal cell carcinoma. A large, 5-cm lesion on the abdomen. The pearly, string-like border is the clue to the clinical diagnosis. (Four-color version of figure on CD-ROM)

Histopathology

On routine stained sections, the tumor appears as proliferating basaloid cells forming cords and islands, invading into the dermis. The peripheral cells have a characteristic “palisading” arrangement. A connection between the tumor islands and the epidermis can be demonstrated in most cases. There is a characteristic mucinous stroma around the invading tumor. A retraction of the tumor islands away from the adjacent stroma is often observed and is characteristic of basal cell carcinomas. This formation of clefts is an artifact resulting from tissue processing. The tumor may have focal areas of ulceration, with an accompanying chronic inflammatory infiltrate. In the so-called morphea-like basal cell carcinoma, the stroma is sclerotic with an increased deposition of fibrous tissues in the dermis surrounding the thin, strand-like basaloid proliferation. Cystic degeneration may be observed within some islands of tumor cells. There is always evidence of solar elastosis in the underlying dermis.

Treatment

The choice of therapy depends on the type and size of the lesion, the location, the general condition of the patient, the cosmetic considerations, and, not least, the experience and skill of the operator.^7,179 Morphea-like basal cell carcinomas usually have indistinct borders clinically and may result in underestimation of the extent of the tumor and, consequently, in undertreatment. Lesions situated in the nasolabial crease, around the eye, and behind the ear also tend to undermine deeply and extend far beyond the clinical border (Figure 123-14). Lesions that ulcerate early tend to be more aggressive. A knowledge of the behavior of the different clinical and pathologic types of basal cell carcinoma is essential in determining the choice of therapy. Treatment of basal cell carcinomas should be aimed at a cure in the first instance. Undertreatment will result in recurrence and deep invasion, and there is a 50% second recurrence rate for the cases that were treated inadequately in the first instance.

Figure 123-14

A, Basal cell carcinoma. The lesion is quite limited clinically. B, Same patient after treatment with Mohs surgery, illustrating the cryptic extension far beyond the clinically evident border. (Four-color version of figure on CD-ROM)

Surgical Excision

Surgical excision of the tumor with either primary closure, a skin graft or local flap produces good cosmetic results and allows the surgical margins to be examined by the pathologist to confirm adequate margins. Tumor present at the lateral excision margins will result in marginal recurrences, which tend to present early and may be reexcised with relative ease. Inadequate deep margins result in deep recurrences, which tend to present late, together with invasion of deep structures. Surgery is the therapy of choice for lesions with indistinct clinical borders and for the morphea-like lesions.

Mohs Surgery

Surgery with microscopic control of the excision margins (Mohs micrographic surgery¹⁴⁰) is the treatment of choice for the morphea-like lesions and for all extensively invasive or recurrent tumors.^7,136,180 This technique allows maximum conservation of “good tissue,” while the surgeon can still be reassured of clear margins (see Figure 123-14B).

Radiation Therapy

Treatment with ionizing radiation may produce excellent therapeutic and cosmetic results, provided care is taken in patient selection.^82,142,181 Radiation therapy is preferred for elderly and fragile patients, particularly those with medium-sized lesions between 1 and 5 cm in diameter. Lesions larger than 5 cm have higher recurrence rates as compared with smaller tumors.¹⁸² Atrophy, necrosis, and scarring may be kept to a minimum when the total dose, typically in the range of 4,000 to 6,000 cGy, is divided into several smaller fractions over several weeks. The choice of a treatment schedule is chosen according to the type, location, size, and depth of the tumor, the total dose of radiation, and the number of fractions that will be given. The appropriate dose schedule may be determined according to the time-dose-fractionation tables.^183,184

Chemotherapy

Topical applications of 5% 5-fluorouracil cream to the tumor twice a day for several weeks is best suited only for small, superficial tumors in the elderly who will not be able to tolerate other more aggressive forms of treatment.²⁹ The rate of recurrence, however, is considerably higher. Intralesional 5-fluorouracil has also been tried in nodular lesions.^185,186 Imiquimod, a topical immune-response modifier which induces interferon, shows promise in the treatment of superficial basal cell carcinomas, but long-term studies looking at recurrence rates are lacking.¹⁸⁷ Cyclopamine, which specifically blocks the sonic-hedgehog pathway, may be shown to have therapeutic value in the future.¹⁸⁸

Course and Prognosis

Basal cell carcinomas are slow growing as a rule. However, if left untreated, they may reach a large size, with consequent extensive tissue destruction. In a comprehensive review of recurrence rates for primary basal cell carcinomas, the results are highly comparable for the various treatment modalities.¹⁸⁰ Most studies reported a 95% or higher cure rate.^7,12,189,190 A lower 5-year recurrence rate has been reported with Mohs surgery than with other commonly used modalities.^136,180 Metastasis, although rare, may occur, particularly in large and late lesions.^191–193 In such cases, the prognosis is usually poor, with a 1-year survival rate of less than 20%, and a 5-year survival rate of approximately 10%. The 5-year occurrence rate of new basal cell carcinomas developing in patients with a previous basal cell carcinoma may be as high as 45%.¹⁹⁴ No significant benefit was observed in the use of low-dose isotretinoin for the prevention of new basal cell carcinomas.^195,196

Definition

Basal cell nevus syndrome is an inherited multisystem disorder in which multiple basal cell carcinomas are associated with palmoplantar pits, characteristic facies, and a variety of skeletal, soft-tissue, ocular, neurologic, and endocrine abnormalities.^{171,172,197,198} The inheritance is autosomal dominant, with variable penetrance.

Epidemiology

This disorder is uncommon. The majority of patients are white, although cases have been reported in blacks and Asians. Both sexes are affected equally. The age of onset is early, and some patients may be born with hydrocephalus or blind. A few patients have been found to have chromosome abnormalities. Recently, patched gene mutations were found to be associated with Gorlin syndrome.^199,200

Clinical Features

Although the skin manifestations of basal cell nevus syndrome are characteristic and easily recognizable, the early features are usually extracutaneous. Congenital abnormalities may include absent or undescended testes, hydrocephalus, and blindness from coloboma, cataracts, or glaucoma. The patients have characteristic facies with frontal bossing, broad nasal root, and hypertelorism (ie, excessive interorbital distance) (Figure 123-15).

Figure 123-15

Basal cell nevus syndrome. Note the multiple basal cell carcinomas on the face and neck, frontal bossing, broad nasal root, and hypertelorism. Courtesy of R.A. Johnson, MD. (Four-color version of figure on CD-ROM)

The most characteristic cutaneous finding is the early onset of multiple basal cell carcinomas on sun-exposed as well as unexposed areas.²⁰¹ The number of tumors may vary from a few to hundreds. The distribution is usually bilateral and symmetrical. Areas commonly involved include the face, neck, trunk, and axillae. The scalp is often spared, unless patients have received radiation for medulloblastoma in childhood. Their color varies from flesh-colored to pigmented. The size may vary from 1 mm to more than 1 cm in diameter. The tumors on the eyelids, axillae, and neck tend to be pedunculated and may be confused with skin tags or neurofibromas. The pigmented lesions may be mistaken for melanocytic nevi. Ulceration of the tumors is often a sign for invasion.

Approximately 50% of the patients have pinpoint to several millimeter-sized pits on their palms and soles^202,203 (Figure 123-16). These pits are approximately 1 mm in depth and may number from a few to hundreds. They may concentrate on the lateral surfaces of the palms, soles, and fingers. They are formed as a result of the premature shedding of the horny layer within the epidermis.²⁰² Other cutaneous lesions include milia, multiple lipomas, fibromas, desmoids, and cysts.

Figure 123-16

Multiple palmar pits in basal cell nevus syndrome.

The most common stigma of the syndrome is jaw cysts,²⁰⁴ which are usually multiple and may be unilateral or bilateral and are odontogenic keratocysts (Figure 123-17). Other osseous abnormalities include defective dentition, bifid or splayed ribs, pectus excavatum, short fourth metacarpals (Albright sign), scoliosis, and kyphosis. Lamellar calcification of the falx is also a useful diagnostic sign.

Figure 123-17

Radiograph of a jaw cyst in a patient with basal cell nevus syndrome.

Ocular abnormalities may include strabismus as well as hypertelorism, dystopia canthorum, and congenital blindness. Mental retardation is uncommon. Other neurologic abnormalities include congenital agenesis of the corpus callosum and medulloblastoma. Treatment of the medulloblastoma with radiotherapy results in marked increase in the number of basal cell carcinomas within the field of irradiation.²⁰⁵

Soft-tissue abnormalities can include ovarian fibromas, lymphatic mesenteric cysts, ameloblastomas of the oral cavity, teratomas, cystadenomas, and fibrosarcoma of the jaw.

Treatment

The therapeutic choices are similar to those for basal cell carcinomas. However, because of the multiple nature of the tumors, maximum preservation of tissue with Mohs surgery may be preferred. The use of oral retinoids as chemopreventive agents is being debated.^{165,201,202,206}

Definition

The Merkel cell was first described by Merkel in 1875. It is a nondendritic, nonkeratinocytic epithelial clear cell normally found in the epidermis and dermis of mammals and humans. It is believed to be of neuroendocrine origin and functions as a specific slowly adapting sensory touch receptor.

The Merkel cell tumor was first described by Toker in 1972.²⁰⁷ It is thought to arise from the cutaneous Merkel cell. It is a high-grade malignant tumor, with a high rate of local recurrence and metastasis.

Epidemiology

Merkel cell carcinoma is a rare neoplasm, with fewer than 1,000 reported cases to date.^208–212 The tumor is most common in the 60- to 80-year-old age group. The reported age range is 7 to 95 years. It is most common in whites. There is no gender predilection.

Clinical Features

The most common sites of involvement are head and neck (49%), extremities (38%), with the lower extremities more frequently involved than the upper extremities, and trunk (13%), mainly lower back and buttocks.²¹³ The lesions present as papules or nodules, pink to red to violet in color, often with overlying telangiectasia. Typically, the tumors are less than 2 cm in size.

Histopathology

The tumor characteristically involves the dermis with sparing of the epidermis. The tumor cells form irregular trabeculae extending down into the subcutaneous tissue. The tumor may resemble lymphoma, carcinoid, oat cell carcinoma, sweat gland carcinoma, or neuroblastoma.²¹³ The histologic appearance of the tumor has no predictive value on its clinical aggressiveness.

Merkel cell tumors express both neuroendocrine and epithelial markers. They show positive labeling with epithelial membrane antigen, neuron-specific enolase, BER-EP4, chromogranin, and epithelial membrane antigen.^212,214,215 The tumor cells also stain positive for monoclonal antibodies to cytokeratins 8, 18, and 19, which are characteristic of simple and glandular epithelia.^{212,214,216,217} In contrast to normal Merkel cells, the cells of Merkel cell tumor also express cytokeratins (CK20) in a paranuclear location.²¹⁸

Ultrastructurally, the tumor cells contain membrane-bound, dense-core neurosecretory granules in the peripheral cytoplasm.²¹⁹ These granules vary from 80 to 180 nm in diameter, and their presence is an important diagnostic feature. The cells also show characteristic perinuclear filament whorls.

Treatment

Wide local excision with 2.5- to 3.0-cm margins is the standard treatment modality.^220,221 Alternatively, local excision with margin control by frozen-section histology (Mohs surgery) may be the treatment of choice, if the service is available.^222,223 Lymph node dissection should be done if the nodes are clinically involved, or if there is a single drainage area.²²⁴ Two studies show that selective biopsy of the sentinel lymph nodes is predictive of nodal involvement.^225,226 Radiation may be beneficial for either local recurrences or for local control after node dissection.²²⁷ The dosage used is similar to those used for squamous cell carcinoma (5,000 to 6,000 cGy).

Course and Prognosis

The rate of local recurrence is approximately 35% to 43%, with the average time to recurrence being 4.3 months. Lymph node metastasis is present in 41% and visceral metastasis in approximately 18% of patients at diagnosis. Sixty percent of patients without local recurrence develop nodal metastasis, whereas 86% of patients with local recurrence also develop nodal metastasis. One-third of patients with positive nodes develop visceral or central nervous system (CNS) metastasis and die of their disease. The overall survival rates are 88% at 1 year, 72% at 2 years, approximately 55% at 3 years, and between 30% and 64% at 5 years.²²⁸ The average time from diagnosis to death is 2.4 years. The factors associated with a poor prognosis are early age at presentation, male sex, lesion location on the head and neck or trunk, and generalized disease.²²⁹ A recent retrospective study of 132 cases showed that cell size, tumor size, and mitotic rate were the most significant clinical and histologic prognosticators.²¹²

In view of the high recurrence rate, close follow-up is recommended. Ratner and colleagues²¹³ recommended monthly visits for the first 6 months, then every 2 to 3 months for the next 2 years, followed by semiannual to annual visits thereafter.