Table of Contents   This Chapter   All Chapters

MALIGNANT EPIDERMAL TUMORS

Basal cell carcinoma

Basal cell carcinoma (BCC) is the most common skin malignancy (Figs 32.29 – 32.43), accounting for about 80% of epidermal malignancies. It is very rarely metastatic (about 1:10000 cases) but is locally destructive and progressive.

Etiology and pathogenesis

Chronic solar damage is important in the etiology of BCC, although the relationship is not quite so clear as for AK or squamous cell carcinoma. Lesions are most common on the face and neck, and a higher frequency of BCC is found in white-skinned individuals living in countries with high sun exposure. BCC is rare in black skin, and in such patients it tends to occur at non-exposed sites. However, by contrast with AK and squamous cell carcinoma, BCC is very uncommon on the dorsum of the hand, while is not infrequent at relatively shielded areas such as behind the ears, in the concha of the ear, or at the medial canthus of the eyes. Although it has been shown that such sites may be missed when applying sunscreen, this does not explain the specific predisposition for BCC at these sites. Sunlight is undoubtedly the important avoidable factor involved in the pathogenesis of BCC, but other factors must also be important in its anatomic localization.

Fig. 32.26 Arsenical keratoses on the palm in a man treated with ‘blood tonics’ in childhood.

Fig. 32.27 Extensive large arsenical keratoses on the hands.

Fig. 32.28 Arsenical depigmentation: numerous depigmented areas on the leg in a patient with multiple basal cell carcinomas.

    Previous exposure to carcinogens such as ionizing radiation (Fig.32.38) or arsenic explains some cases of BCC. Genetic factors may also be important. The most clear example is Gorlin syndrome (discussed separately later), but less severe cases of multiple familial BCC also occur without other features of this syndrome.

    Precursor lesions are uncommon, but organoid nevi (nevus sebaceus of Jadassohn) are a particularly important precursor of BCC on the scalp (Ch.23), and BCC may arise in other areas of chronic skin damage, including wounds, skin grafts, and discoid lupus erythematosus.

Fig. 32.29 Nodular basal cell carcinomas (a) on the sidewall of the nose and (b) on the forehead. Both have typical morphology and telangiectasia.

Fig. 32.30 Cystic basal cell carcinoma on the nose.

Fig. 32.31 Superficial variant of basal cell carcinoma. Multiple lesions are common with this variant, often on the trunk (a). Closer examination shows the typical raised pearly edge (b).

Fig. 32.32 Fibroepithelioma of Pinkus: a thin pink solitary plaque is typical.

Fig. 32.33 Large basal cell carcinomas. Huge lesions like this one on the forehead (a) are now rare, but even in less dramatic cases, large lesions may be ignored until they ulcerate (b,c).

Fig. 32.34 Pigmented basal cell carcinoma (BCC). Typically the pigment is gray-black and rather coarsely speckled, as seen in (a). Occasionally, much deeper pigmentation occurs, as in (b), a nodular BCC that has the differential diagnosis of melanoma. The central face and forehead seem to be common sites for pigmented BCC. (Panel b courtesy of the Department of Dermatology, University of California, San Diego.)

Fig. 32.35 Basal cell carcinoma may arise within precursor hamartomas, notably nevus sebaceous, as shown here on the ear. These tend to be on the head and neck, usually the scalp (see also Ch. 23).

Fig. 32.36 Basal cell carcinoma (BCC). On the lower leg, BCCs often have less characteristic morphology, appearing as smooth-surfaced, purplish-colored plaques (a) or as moist, red, eroded areas (b); they may be mistaken for ‘ordinary’ leg ulcers, a particularly likely scenario in (b), where exudates have caused adjacent eczematous changes. Treatment at this site can be difficult due to the potential for poor healing and difficult surgical wound closure.

Fig. 32.37 Basal cell carcinoma (BCC) on the nose. These lesions occur in a younger age group than average for BCC, and may be extremely subtle in appearance.

Fig. 32.38 Basal cell carcinomas (BCCs) in a patient treated with radiotherapy for ankylosing spondylitis about 40 years previously. The BCCs are multiple but confined to the paraspinal irradiation field. A similar pattern may occur on the abdomen due to treatment of menorrhagia by ‘radiation menopause’.

Fig. 32.38 Morpheic basal cell carcinoma (BCC). These lesions are scar-like and often slightly yellowish or white compared with the adjacent skin. The borders may be quite indistinct, and this pattern of BCC may reach a large size before becoming noticeable, even when the patient sees the lesion every day in the mirror. This tumor (a) was described as being of 0.5 cm in diameter by the primary care physician, but the true margin (inked) is several centimeters larger (b).

Fig. 32.40 Basal cell carcinomas (BCCs) of different types in the same patient. There is a large and obvious cystic BCC on the cheek, but also an unnoticed larger and more subtle morpheic BCC laterally (arrow).

Fig. 32.41 Basal cell carcinoma of the scalp; clinically, it would be impossible to exclude this being a squamous cell carcinoma, although the latter are usually faster-growing. Note the numerous actinic keratoses. (Courtesy of Dr. L. Barco.)

Fig. 32.42 The relationship between basal cell carcinoma and sunlight is less clear than for some skin cancers; lesions of the vulva (a), scrotum (b), or perianal skin (c) are unusual but are seen occasionally.

Clinical variants

Nodular basal cell carcinoma

This is the most common pattern. It has a domed or plaque shape with a grayish-colored, pearly appearance and surface telangiectasia. As the lesion enlarges, the center becomes umbilicated and may ulcerate. Pigmentation may occur in any BCC, but most lesions with clinically significant pigmentation have a nodular morphology. Most BCCs grow slowly, and have often been present for 12 months or more before the patient seeks advice.

Cystic basal cell carcinoma

This pattern of BCC (about 5% of all BCCs) is typically dome-shaped and resembles some nodular BCCs, but contains mucin. Sometimes it may vary in size, or turn blue due to intralesional bleeding. There is no particular prognostic significance compared with nodular BCC.

Morpheic basal cell carcinoma

This is a less common pattern, accounting for about 2% of BCCs, although focal morpheic patterning within BCC is not uncommon. The name relates to a scar-like fibrous stroma, the basaloid cells of the tumor being relatively sparse. This pattern of BCC is important, as it is usually virtually flat, is not usually ulcerated, and usually has poorly defined margins on both a clinical and a histologic basis. Therefore it tends to present late, with a large diameter, and is difficult to excise reliably due to the large dimensions and poorly defined margin. Local recurrences are therefore common with this type of BCC, and may be difficult to distinguish from scar tissue or postradiotherapy skin changes.

Superficial basal cell carcinoma

This type accounts for about 10% of BCCs, and is most frequent on the trunk. Lesions are broad, and essentially flat apart from a thin, raised border that has the typical pearly appearance when inspected closely.

Fibroepithelioma of Pinkus

This is a variant of BCC that has a reticular, lace-like histologic appearance; clinically, most are a thin pink solitary plaque that may resemble superficial BCC.

Fig. 32.43 Basal cell carcinoma in a dark-skinned patient, an uncommon occurrence.

Nevoid basal cell carcinoma (Gorlin) syndrome

Nevoid basal cell carcinoma syndrome is an autosomal dominantly inherited syndrome in which patients have numerous (often hundreds) of BCCs. These occur at a young age (onset is typically in the second decade) and are usually very small. They may resemble benign skin tags or nevi.

    The condition is due to a chromosomal defect on 9q31 such that all cells of affected individuals carry one defective copy of the gene. Damage (solar, ionizing radiation, and spontaneous mutation) to the other chromosome of the pair leads to development of BCC. Affected patients may have numerous other defects (Figs 32.44 – 32.49, Table 32.2), of which seborrhea, palmar pits, dental cysts, rib abnormalities, and hypertelorism are the most frequent and most easily detected.

Differential diagnosis

Basal cell carcinomas have a wide differential diagnosis, in which the other neoplastic and premalignant lesions in this chapter, appendage neoplasms (Ch.23), and inflammatory lesions such as spectacle granulomas (Fig.32.50), may all be included. The morphologic type, as well as the site, influence the likely differential (Table 32.3).

Treatment

Treatment is usually by cryotherapy, curettage, excision (with or without micrographic margin control), or radiotherapy. With appropriate patient selection, all these will give high success rates of over 95% cure. The best cure rates (over 99% cure) are with Mohs micrographic surgery, which is performed in stages with histologic control of tumor margins (see Ch.5); however, this is more time-consuming and expensive than the other techniques, and is not necessary for many small and well-defined lesions or for most cases of superficial BCC. Laser destruction is used in some centers. Morpheic BCC is best treated with surgery, ideally with margin control, but simple excision or radiotherapy are reasonable for smaller morpheic lesions. Topical or intralesional cytotoxics have been used, and topical imiquimod is a new option (usually for thinner lesions, Fig. 32.51). PDT has a lower cure rate than the standard therapies for thick BCCs but has an increasing role for multiple tiny lesions, or may be useful for tumors at surgically difficult sites.

    Recurrent BCC is most likely with large lesions, in those with infiltrative or morpheic histologic changes, and at some sites: lesions on the nose (a common site) or the ear (less common) have a higher risk. On the nasal tip and ala nasi, the deep sebaceous follicles and fibrous stroma make adequate curettage difficult, but closure of excised wounds may also be limited by lack of loose skin, and there may be a tendency for suboptimal surgery. Locally recurrent tumors can be treated with surgery or radiotherapy, but are usually not treated with cryotherapy, except in expert hands.

    Basal cell carcinoma in Gorlin syndrome should not be treated with radiotherapy, as the risk of further BCC in the radiation field is high.

Fig. 32.44 Gorlin syndrome in a young patient. In this age group, small basal cell carcinomas tend to occur on the face and upper trunk, and may resemble junctional nevi. In this rare patient, however, the basal cell carcinomas were pigmented BCCs.

Fig. 32.45 Gorlin syndrome. Hundreds of small basal cell carcinomas may be present, but often do not look the same as the common sporadic type.

Fig. 32.46 Palmar pits are a characteristic feature of Gorlin syndrome. As it is a familial condition, many patients are aware that these are present.

PRACTICE POINTS

Fig. 32.47 Skull radiograph in Gorlin syndrome, demonstrating calcification of the falx cerebri.

Fig. 32.48 Dental cysts seen on a radiograph of a patient with Gorlin syndrome.

Fig. 32.49 Bifid ribs seen on a chest radiograph of a patient with Gorlin syndrome.

Fig. 32.50 Spectacle granulomas may occur on the side of the nose, as shown here, or behind the ears. They can be very difficult to distinguish from basal cell carcinoma at times, and may require surgery due to the inconvenience they cause.

Squamous cell carcinoma

Squamous cell carcinoma (SCC) is the second most frequent malignant skin tumor after BCC, and has significant metastatic potential (Figs 32.52 – 32.62).

Fig. 32.51 Topical imiquimod is a new option for treating thinner lesions of basal cell carcinoma, in this case an 11-cm trunk lesion of 30 years’ duration in a patient who presented due to discomfort from superficial ulceration (a). Although not eradicated at the stage of illustration (b), imiquimod had given good symptomatic control, with much less morbidity than with other possible options.

Fig. 32.52 An early lesion of squamous cell carcinoma. It may be difficult to distinguish from hypertrophic actinic keratosis.

Fig. 32.53 Squamous cell carcinoma on the cheek, forming a large, horn-like growth.

Fig. 32.54 Squamous cell carcinoma (SCC) on the ear. SCC at this site often presents as a cutaneous horn (see also Fig. 32.7). Wedge excision with the underlying cartilage is the appropriate treatment.

Fig. 32.55 Squamous cell carcinoma. A large, moist nodule such as this is relatively uncommon. This type of lesion grows rapidly and may be confused with keratoacanthoma, but as it is clinically poorly differentiated, it is unable to keratinize and create the typical horn of keratoacanthoma (compare Figs 32.64 – 32.66).

Fig. 32.56 Squamous cell carcinoma of the lip. The lower lip (a) is a relatively commonly affected site. Smoking is a risk factor for this site, and the prognosis is poorer compared with for similar-sized lesions at other sun-exposed sites. Treatment is usually by wedge excision or with radiotherapy. By contrast, the upper lip margin (b) is a relatively uncommon site. The chronic trauma from the patient’s only three teeth may have been relevant.

Fig. 32.57 Squamous cell carcinoma of the vulva. This may occur as a complication of lichen sclerosus or other chronic vulval dermatoses.

Fig. 32.58 Squamous cell carcinoma of perianal skin. These lesions require aggressive therapy.

Fig. 32.59 Squamous cell carcinoma of the scrotum. This condition used to be common due to carcinogens in soot, originally described by Percivall Pott in chimney sweeps in 1775.

Fig. 32.60 Squamous cell carcinoma arising in chronic leg ulcers is a major therapeutic problem; it is often not suspected until it is extensive, may be difficult to diagnose histologically, and may require extensive surgery or amputation. It typically fails to heal after radiotherapy, as it often occurs in elderly patients with impaired lower limb vascularity, and it has a poor prognosis.

Fig. 32.61 Carcinoma cuniculatum is a slowly growing, locally invasive squamous cell carcinoma that usually occurs on the sole of the foot. It may have a viral etiology, and may be confused with a verruca but usually occurs in elderly patients. It has a high local recurrence risk due to indistinct deep margins and infiltration into functionally important tissues of the foot.

Fig. 32.62 Subungual squamous cell carcinoma is a destructive tumor that may mimic a viral wart in the early stages, but in an older age group. Bowen disease (often the pigmented variant) and keratoacanthoma may also rarely occur at subungual sites.

Etiology and pathogenesis

The most important etiologic factor is cumulative solar exposure. SCC may arise de novo or from precursor lesions such as actinic keratoses (low risk), Bowen disease, or erythroplasia of Queyrat. Patients with an SCC usually have some actinic keratoses also; the mean age of development of SCC is about 10 years older than the mean age for first developing actinic keratoses.

    As for Bowen disease, HPV has been implicated in the etiology, and is particularly important at some sites (e.g. genital or perianal SCC). SCC may also arise in skin damaged by previous radiation exposure, or in chronic scars and sinuses (a situation that is associated with high metastatic potential), leg ulcers (Fig.32.60), burn scars (Marjolin ulcer), or other chronic dermatoses such as scars of lupus erythematosus. It may occur in oral leukoplakia or in chronic erosive oral lichen planus (Ch.8); however, management of oral SCC is not in the province of dermatologists, and this is not discussed further.

    Immunosuppression is also a risk factor, whether therapeutic (immunosuppressive drugs) or acquired (AIDS). PUVA photochemotherapy is also associated with a dose-related increase in SCC, and previous arsenic exposure is documented in some individuals.

Clinical features

Squamous cell carcinoma typically presents as a crusted, eroded, or hyperkeratotic nodule, usually at chronically sun-exposed sites and on a background of solar damage. SCC arising in actinic keratoses may be slow and subtle in its development, and should be suspected if there is significant basal thickening of a keratosis.

    Squamous cell carcinoma arising in leg ulcers (Fig.32.60) poses particular diagnostic and therapeutic problems. It may form a poorly demarcated area of macerated hyperkeratosis rather than an obvious tumor nodule, and is often extensive at presentation. Histologically, it may be difficult to distinguish from benign ‘pseudoepitheliomatous hyperplasia' at the edge of a chronic ulcer, and multiple biopsies may be required for a firm diagnosis.

    Carcinoma cuniculatum is also a particular diagnostic problem. This is a type of locally invasive SCC that grows slowly, usually at acral sites, with the morphology suggestive of a large viral wart, but with increasing local tissue destruction (Fig. 32.61). Subungual SCC (Fig. 32.62) may behave in a similar fashion locally.

Differential diagnosis

This is discussed in Table 32.4.

Treatment

The usual options are excision (with micrographic margin control, if available, for larger tumors or complicated sites) or radiotherapy. A minimum 4-mm margin of clinically normal skin is recommended for most SCCs, and a wider margin for high-risk lesions. Curettage with thorough cautery to the wound base appears to have good results, but is probably best avoided for larger lesions or high-risk SCC; the good results with this approach may represent the fact that all therapeutic results depend on case selection. Cryotherapy may also give good results in some cases but should be performed by an experienced operator. Laser therapy and PDT are used in some centers.

    The risk of metastasis (Fig.32.63) varies from less than 1% up to almost 50%, depending on site, degree of differentiation, size of SCC, and other risk factors such as immunosuppression. Large and poorly differentiated tumors have high risk. High-risk sites are any chronic wound (leg ulcers, sinuses, etc.), lip, ear, palm or sole, and perineum. Lesions on chronically sun-exposed skin have lower risk. For high-risk tumors, elective lymph node dissection has been performed, although this is being superseded by sentinel lymph node biopsy (as described for melanoma), and regular follow-up for at least 2 years is recommended.

Keratoacanthoma

Keratoacanthoma (KA) is a rapidly growing tumor that eventually involutes, and may be a self-healing variant of SCC. The etiology is as for SCC.

Clinical features

Keratoacanthoma is a dramatic tumor, as it typically grows rapidly and may reach a large size (Figs 32.64 – 32.68). The face, ears, and dorsa of hands are typically affected; patients are usually aged over 50 years. Three times more men than women are affected. The importance of the lesion is that it can be difficult to distinguish from SCC, both clinically and histologically. Hence, even on excised specimens, laboratory reports may not clearly confirm this diagnosis. The incidence of SCC is two to three times that
of KA.

    The typical history of KA is a period of rapid growth, then a static phase, then involution; each phase lasts 2–3 months. Clinically, symmetry, a yellowish ‘bolstered' base, and a well-formed central horn all favor KA. Conversely, increasing size after 3 months is highly suggestive of SCC. Some clinical and histologic features that help to differentiate SCC from KA are listed in Table 32.5. Biopsies taken in the involuting phase may be very bland, and may have a plasma cell infiltrate rather than the neutrophilic infiltrate of a growing lesion.

    Some uncommon morphologic variants of KA may cause confusion, such as the centrifugum type, which is annular with central clearing, or the giant type (Fig. 32.69). Subungual KA is rare, and can be very difficult to distinguish from SCC, as it is locally destructive. Syndromes of multiple KAs are discussed here.

Differential diagnosis

The most important differential diagnosis is from SCC, as discussed earlier and in Table 32.5. If in doubt, treatment and follow-up should be as for SCC. Otherwise, the differential is largely that of SCC, although sites such as the foot would not be expected to be affected.

Fig. 32.63 Nodules (one subcutaneous, one ulcerated) due to metastatic squamous cell carcinoma on the arm from a primary tumor on the hand. The patient was immunosuppressed following renal transplantation.

Fig. 32.64 Keratoacanthoma on the nose, with typical morphology. (Courtesy of Dr. L. Barco.)

Fig. 32.65 Keratoacanthoma on the eyelid, a technically difficult area for excision. Note that basal cell carcinoma and squamous cell carcinoma are rare on the upper eyelid, although sebaceous epithelioma and carcinoma have a predilection for this anatomic site.

Fig. 32.66 Keratoacanthoma on the arm, with typical symmetry. Loss of the horn is often the first sign of spontaneous resolution.

Fig. 32.67 (a) A keratoacanthoma on the arm that was static when the patient presented and, due to her preference to avoid surgery, was therefore observed rather than actively treated. (b) Appearance 1 month later confirms ongoing regression.

Fig. 32.68 Multiple eruptive keratoacanthomas at the rather unusual site of the lower legs. Treatment was low-dose acitretin.

Fig. 32.69 Giant keratoacanthoma, a rare condition and a potentially difficult diagnostic and therapeutic problem.

Treatment

In general, treatments for SCC are all appropriate but, in view of the benign behavior, the techniques used are generally less aggressive than for SCC. If a lesion is seen at the stage of being static, or is involuting, then a period of observation with serial measurements is appropriate, provided that:

    Curettage is a reasonable option for larger lesions than would normally be treated with this technique if SCC is suspected, and radiotherapy achieves excellent results. Large lesions, in particular, may leave crateriform scars (the original description in 1889 was as ‘the crateriform ulcer of the face'). For this reason, and because of the difficulty of predicting final size, it is usual to treat actively rather than by observation any lesions that are still enlarging when the patient presents.

Multiple keratoacanthomas

Keratoacanthoma is usually a solitary lesion, but sometimes more than one is present. Multiple KAs may occur in patients with photosensitive DNA defects such as xeroderma pigmentosum, or in association with sebaceous tumors in the Muir–Torre syndrome (discussed in Ch.19). Occasionally, immunosuppressed patients may give a reliable history of lesions that have involuted, but in general it is prudent to treat any apparent KA as an SCC in this group.

    There are also two specific disorders in which large numbers of KAs may occur.

Multiple keratoacanthomas (self-healing epitheliomas) of Ferguson–Smith

This is a rare autosomal dominant disorder characterized by eruptive crops of small lesions that behave as KAs, but which have histologic features more suggestive of SCC. Lesions self-heal, as the name suggests, but leave prominent crateriform scars. Surgery may therefore be appropriate for the actively growing lesions, or to subsequent scars; any lesions that continue to grow must be excised. Most lesions appear to develop in the young adult age group, and the typical pattern is for relatively small numbers of KAs to be present at any one time, but occurring over many years.

Generalized eruptive keratoacanthomas of Grzybowski

    This is a rare sporadic disorder in which hundreds or thousands of tiny KAs develop in an eruptive pattern, typically in middle age. Palms, soles, and mucosae are also affected.

Treatment

Multiple KAs may be treated as solitary lesions, for example with curettage. However, the number of lesions may make this less practical compared with solitary KA. Cryotherapy may be appropriate for small lesions, and systemic retinoids have been used for patients with numerous small KAs.

Tumors associated with photochemotherapy and immunosuppression

These two factors are important etiologic factors for SCC and Bowen disease. In both cases, the predominant tumor type is SCC (see Fig. 32.63), which is increased in frequency, with a lesser change in the risk of BCC. Thus the usual excess of BCC over SCC that occurs in the general population is reversed. In phototherapy, there is also an alteration in anticipated sites of SCC, the normally covered skin (such as genitalia) having a particularly increased risk. The mechanism is a decreased immune surveillance combined (in the case of photochemotherapy) with UV exposure, which exerts a dose-related effect. The risk of metastasis is also increased over that for sporadic SCC. The role of therapeutic immunosuppression in skin cancer, and other risks that it poses of relevance to dermatolgists, are discussed further in the section on renal disease in Ch.12.

    Immunosuppression also predisposes to Merkel cell carcinoma (see Ch.33) and photochemotherapy to melanoma (Ch.31).

    In patients with SCC arising in either of these situations, and where the implicated immunosuppressive agent is unable to be withdrawn, systemic retinoid therapy with isotretinoin or acitretin can be useful; they decrease the number of associated warts and benign or actinic keratosis, and most studies have documented a decrease in frequency of new SCCs (in about three-quarters of patients).

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