Pathophysiology and Natural History
The most common causative factor in the induction of BCC is ultraviolet (UV) light, specifically ultraviolet B (UVB, 290-320 nm). It has been shown that UVB induces characteristic DNA mutations in the skin called pyrimidine dimers. The p53 tumor suppressor gene is responsible for arresting the cell cycle so that any induced mutations can be repaired by the cell. In BCC, the same UV light–induced pyrimidine dimer mutations have also been found in the p53 tumor suppressor gene. This mutated p53 gene is nonfunctional and leads to dysregulation of the cell cycle, with resultant unlimited cell proliferation (cancer).
Although the exact mechanism of BCC propagation is unknown, it is believed that basal cell carcinomas arise when mutations that control cell growth via the hedgehog pathway activate immature pluripotential cells in the epidermis. This most often occurs through inactivation of the tumor suppressor gene PTC (patched), located on chromosome 9. Other mutations in SMO (smoothened) and Hh (hedgehog) have also been seen. RAS and p53 mutations may also play a role in oncogenesis. Additionally, the distinctive biologic behavior of BCC, characterized by local invasiveness but rare metastatic spread, may be related to alterations in certain basement membrane components.4
The natural progression of untreated BCC is slow growth with progressive invasion and destruction of adjacent tissues. Metastasis is very rare in BCC, with a relative rate of 0.0028% to 0.1%. When metastasis has occurred, the site of the primary lesion has most often been on the head and neck. The sites of BCC metastasis in order of frequency are the regional lymph nodes, lung, bone, skin, liver, and pleura. The average interval for metastasis is 9 years. Metastatic BCC has a poor prognosis, with a median survival of 8 months. BCC metastasis has usually been observed in men with large neglected ulcerated tumors.
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Signs and symptoms
A, Noduloulcerative basal cell carcinoma, nasal bridge and medial canthus. B, Nodular basal cell carcinoma, left nasofacial sulcus. C, Nodular basal cell carcinoma.
Figure 1: Click to Enlarge
Superficial basal cell carcinoma.
Figure 2: Click to Enlarge
Pigmented basal cell carcinoma, back.
Figure 3: Click to Enlarge
Morpheaform basal cell carcinoma (arrows), left cheek.
Figure 4: Click to Enlarge
BCCs are most often found on the head and neck; the nose is the most common site. The typical lesion is a small pearly (waxy) nodule with a central depression and rolled border containing dilated blood vessels. It might have a history of ulceration, crusting, or bleeding. BCC has five clinicopathologic subtypes: nodular-ulcerative, superficial, pigmented, morpheaform (sclerosing), and basosquamous.
Subtypes
Nodular-Ulcerative.
The nodular-ulcerative variant (Fig. 1) is the most common type of BCC. It manifests as a small, pearly dome-shaped papule with surface telangiectasias and a typical rolled border. Over time, central ulceration with bleeding or crusting is often seen. Differential diagnosis of this lesion includes sebaceous hyperplasia, squamous cell carcinoma, verruca vulgaris virus, molluscum contagiosum, intradermal nevus, appendageal tumors, amelanotic melanoma, and stasis ulcers (when located on the shins).
Superficial.
Superficial BCCs (Fig. 2) are the least aggressive form. They often manifest as several scaly, dry, round-to-oval erythematous plaques with a threadlike raised border on the trunk and extremities. If untreated, superficial BCCs can enlarge to 10 to 15 cm in diameter without ulceration. Differential diagnosis of superficial BCC includes eczema, psoriasis, and Bowen’s disease.
Pigmented.
Pigmented BCCs (Fig. 3) are seen more often in darker-skinned persons such as Latin Americans and Asians. This subtype has all the characteristics of the nodular-ulcerative variety plus brown or black pigmentation from melanin. A history of arsenic ingestion has been seen with pigmented and superficial BCCs.
Morpheaform (Sclerosing)
An indurated yellow to white plaque with an indistinct border and an atrophic surface characterizes morpheaform or sclerosing BCC (Fig. 4). Ulceration and crusting are usually absent. This variety has an aggressive growth pattern, and invasion of muscle, nerve, and bone may be seen. Morpheaform BCC is particularly insidious because of its benign scarlike appearance. Differential diagnosis of morpheaform BCC includes scarring and localized superficial scleroderma (morphea).
Basosquamous
The basosquamous or metatypical variant of BCC is diagnosed on a histologic basis. This tumor possesses features of both BCC and SCC. It is mentioned because it is associated with a higher rate of metastasis.
Related Syndromes
Two syndromes that have multiple BCCs as a feature include nevoid basal cell carcinoma syndrome (Gorlin’s syndrome) and Basex’s syndrome. Gorlin’s syndrome is characterized by BCCs; odontogenic jaw cysts; pitted depression of the hands and feet; osseous anomalies of the ribs, spine, and skull; and characteristic facies (frontal bossing, hypoplastic maxilla, a broad nasal root, and true ocular hypertelorism). 5 This genetic disorder occurs in an autosomal dominant pattern. There is a mutation of the PTC tumor suppressor gene located on chromosome 9. 5 Basex’s syndrome is another autosomally dominant inherited disorder. It is characterized by multiple BCCs of the face, follicular atrophoderma of the extremities, localized or generalized hypohidrosis, and hypotrichosis.
Diagnosis
Clinical diagnosis of BCC is confirmed by performing a biopsy of the suspected lesion for histopathologic interpretation. For the majority of BCC subtypes, a shave biopsy suffices. However, when the lesion is believed to be a morpheaform BCC, a deep shave, punch biopsy, or incisional biopsy is recommended to obtain a sufficient tissue sample for correct interpretation.
Treatment
BCC may be effectively treated by a variety of therapeutic modalities. Among the clinical subtypes of BCC, small nodular or superficial BCCs respond to most treatment options; large nodular ulcerative or morpheaform lesions can require more aggressive therapy. No single treatment method is ideal for all lesions. The treating physician should carefully evaluate each BCC on an individual basis and choose the modality that is most appropriate for the lesion’s size, site, and histologic type, as well as the patient’s age and functional status.1
Electrodesiccation and Curettage
According to the American Academy of Dermatology (AAD) Guidelines of Care, electrodesiccation and curettage (ED&C) is best suited for primary lesions, but it may be useful in some recurrent lesions. It is less effective in the cure of recurrent lesions that are in scar tissue.1 Superficial and nodular BCCs respond especially well to ED&C. It is less effective in the cure of recurrent lesions or in the morpheaform subtype because of indistinct margins. Select low-risk lesions (small, well-defined primary lesions with nonaggressive histology usually in noncritical sites) can achieve 5-year cure rates of up to 97% when treated with ED&C.6
Primary nonmorpheaform basal cell carcinomas are more friable than surrounding normal skin and are initially debulked with a curette. The stroma and surrounding dermis are then electrodesiccated. This process is usually repeated two more times. The resulting wound heals with a hypopigmented scar over 2 to 6 weeks. The main disadvantage of this treatment is the absence of histologic margin control. Treatment of facial lesions with this modality is not advocated because of the risk of deep invasion in embryonal fusion planes, the difficulty of adequate curettage in the sebaceous skin of the nose, and poor cosmetic appearance.
Cryosurgery
According to the AAD Guidelines of Care, cryosurgery is useful in treating primary lesions and some recurrent lesions. It is especially useful in certain areas of the body and in patients with multiple lesions.1 Superficial and small nodular BCCs respond well to liquid nitrogen cryosurgery. Liquid nitrogen (temperature −196°C) produces tissue destruction by reducing the temperature of the skin cancer to tumoricidal levels. It is not indicated for tumors deeper than 3 mm or those with indistinct margins. The main disadvantages include a hypopigmented scar, prolonged healing, pain during the procedure, and risk of recurrence.
Surgical Excision
According to the AAD guidelines, excision is useful in both primary and recurrent tumors. The main goal of any excisional surgery is to remove the tumor entirely. Postoperatively, the surgical margins of the specimen are examined histologically for assessment of adequate tumor removal. The wound defect can be closed primarily with side-to-side closures, flaps, or grafts, or it may be allowed to heal by secondary intention. 1 For small (<20 mm) primary, well-defined BCCs, 3-mm peripheral surgical margins will clear the tumor in 85% of cases, and a 4 to 5 mm margin increases the peripheral clearance rate to approximately 95%. 6 Larger and morpheaform lesions require wider and potentially deeper surgical margins for complete histologic resection. The main disadvantage of surgical excision is incomplete margin control, 6 because the routine vertical sectioning technique (breadloafing and quartering methods of margin checking) only assess 1% of the margin.