Basal Cell Carcinoma
Key Points
Basal cell carcinoma (BCC) is the most common malignant neoplasm of the skin, and in the eyelids it accounts for about 80% to 85% of all malignant cutaneous tumors
It occurs more commonly in fair-skinned adults, with a peak incidence between the 5th to the 8th decades of life
Ultraviolet sunlight exposure-driven mutagenesis is believed to be the major risk factor for BCC causing inappropriate activation of the hedgehog signaling pathway
Nodular BCC presents as an indolent, firm, indurated, elevated lesion with smooth rolled, pearly, shiny borders, and fine telangiectasias are seen around the borders
The morpheaform or sclerosing subtype is more aggressive and presents as an infiltrative, locally destructive lesion with ill-defined margins
Treatment is primarily with wide surgical excision with clear margins
Targeted inhibition of the sonic hedgehog pathway now offers a promising treatment option in selected patients
The prognosis depends upon the histologic type, anatomic location, and the size of the lesion
Metastatic potential is reported but is very low
Basal cell carcinoma (BCC) was first mentioned in the literature by Arthur Jacob in 1827 and referred to as “ulcus rodens.”1 The tumor was clinically described later as a malignant, locally invasive, destructive cancer by Krompecher in 1900.2
BCC is the most common malignant neoplasm of the skin, and in the eyelids, it accounts for about 80% to 85% of all malignant cutaneous tumors. It arises from keratinocyte precursor cells of the interfollicular epithelium where it undergoes mutagenesis.3,4 Basal cell carcinoma occurs more commonly in fair-skinned adults, with a peak incidence between the 5th to the 8th decades of life. The incidence has been increasing in the United States, Europe, and Australia.5,6,7,8 In 1996, it was estimated that more than two million individuals were affected annually in the United States, with a lifetime risk of at least 20% to 30%.9 In 2012, the age-adjusted rate of treatment procedures for BCC in the United States was 3280 per 100,000 Medicare beneficiaries.5 BCC can be seen in younger individuals, particularly those who have predisposing genetic syndromes. However, tumors have been described in healthy young individuals with no predisposing factors. While this is a true malignant tumor, it only rarely metastasizes to distant sites. When neglected, periorbital BCC can be very destructive locally and can invade adjacent structures such as the orbit and paranasal sinuses.
Etiology and Pathogenesis
Ultraviolet sunlight exposure-driven mutagenesis is believed to be the major risk factor for BCC. Sporadic BCCs arise from long-term resident keratinocyte progenitor cells of the interfollicular epidermis and upper infundibulum that undergo mutagenesis, mostly ultraviolet (UV) induced.3,10 Most cases of BCC are UV exposure-induced and 76% have UV signature mutations.11 Daylight UV induces a characteristic UV-specific DNA mutation occurring preferentially at methyl-CpG sites, seen after exposure to both UVA and UVB, but not UVC.12
Focal trauma, scars, previous ionizing irradiation, and systemic immunosuppression are other factors that can predispose to the development of eyelid BCC. Age is an independent risk factor, and the incidence doubles between the ages of 40 and 70 years.13 Cigarette smoking is not believed to be a factor in men but has been implicated as a predisposing factor in women.14 The most important risk factors for the development of BCC include light skin pigmentation, freckling in childhood, and a history of severe sunburn.15 Other factors include occupational UV exposure and the presence of actinic cheilitis, actinic keratosis, and solar lentigo.16 Chronic infection of the pilosebaceous follicle by the mite Demodex folliculorum has also been suggested as a causative factor.17
Most BCCs show inappropriate activation of the hedgehog signaling pathway. The sonic hedgehog protein is necessary for the embryonic development of neural, musculoskeletal, hematopoietic, and skin tissue, and for adult tissue homeostasis. A mutation in the hedgehog pathway may lead to sonic hedgehog protein binding to the transmembrane receptor Patched (Ptc), encoded by a tumor suppressor gene (PTCH-1) that normally inhibits the downstream transmembrane receptor, smoothened (Smo).18 Reversal of this inhibition leads to the release of cytoplasmic sequestration of the transcription factor glioma-associated oncogene homolog 1 (Gli1), allowing it to enter the nucleus to induce gene transcription.19 This results in cellular proliferation and tumorigenesis.
Clinical Presentation
Most cases of BCC occur in individuals between 40 and 80 years of age, with a mean of about 60 years. There may be a slight predilection for males. Solitary lesions most commonly appear on the sun-exposed skin of the face. The lower eyelid is involved in about two-thirds of cases, and the upper eyelid is rarely involved, likely due to protection from sun exposure by the brows. Tumors are typically painless, associated with hair loss, and grow slowly over many months to years before diagnosis.
There are several different clinical variations seen on the eyelids. These include nodular, noduloulcerative, pigmented, cystic, superficial, and morpheaform or sclerotic forms.20,21,22 The nodular form is the most common, accounting for 50% to 80% of all BCCs,15, and has a predilection for sun-exposed areas in the head and neck. Clinical appearance varies greatly but usually presents as an indolent, firm, indurated, elevated lesion with smooth rolled, pearly, shiny borders (Figure 128.1). Fine telangiectasias are seen around the borders. When located near the eyelid margin, distortion or loss of cilia may be seen. Central ulceration is a common finding, often filled with crusty exudate. The ulcerated lesion may bleed easily. Pigmentation is a rare variant seen in up to 5% to 6% of cases and may be difficult to distinguish clinically from malignant melanoma (Figure 128.2).
 FIGURE 128.1 Nodular basal cell carcinoma. |
The superficial subtype accounts for approximately 10% to 30% of BCCs and is the second most common type. Some studies have shown a younger average age of onset for this subtype and a relatively higher incidence in females.23 Superficial BCCs present as a thin, well-circumscribed, erythematous plaque or patch with scales (Figure 128.3) and may have central clearing and narrow rolled borders. They occur most commonly on sun-unexposed or intermittently
exposed areas of the trunk10 but can be seen less commonly on the head and neck. Like the nodular subtype, they rarely can be pigmented.
exposed areas of the trunk10 but can be seen less commonly on the head and neck. Like the nodular subtype, they rarely can be pigmented.
 FIGURE 128.2 Pigmented basal cell carcinoma. |
 FIGURE 128.3 Flat superficial basal cell carcinoma with erythema, fine scales, and a small area of ulceration. |
The morpheaform or sclerosing subtype is less common, comprising less than 10% of BCCs. Among 13,457 BCCs diagnosed at a single center, Scrivener et al found the morpheaform subtype in 6.2% of cases, of which 94.8% occurred on the head.24 This form of BCC is more aggressive, with a greater potential for recurrence and for metastatic spread. Clinically, it appears as a pale, infiltrative, and locally destructive lesion with ill-defined margins (Figure 128.4). Neglected or recurrent tumors can be locally invasive where they may extend into the lacrimal drainage system, orbit, paranasal sinuses, and even the cranial cavity (Figure 128.4). Orbital invasion generally produces displacement of the globe, and motility restriction, and less commonly proptosis (Figure 128.5).
The basosquamous subtype is more aggressive in clinical behavior and has histologic features of both basal cell and
squamous cell carcinomas. It is a rare subtype representing less than 2% of all BCCs. It has nonspecific clinical features differentiating it from other subtypes, and the diagnosis is made primarily on biopsy. Because of its higher recurrence rate and metastatic potential, early diagnosis and treatment are essential.
squamous cell carcinomas. It is a rare subtype representing less than 2% of all BCCs. It has nonspecific clinical features differentiating it from other subtypes, and the diagnosis is made primarily on biopsy. Because of its higher recurrence rate and metastatic potential, early diagnosis and treatment are essential.
Differential Diagnosis
The clinical differential diagnosis for BCC is very broad and includes numerous malignant and benign lesions. Confusing lesions include dermatofibroma, trichoblastoma, trichofolliculoma, sebaceous carcinoma, squamous cell carcinoma, keratoacanthoma, Merkel cell carcinoma, microcystic adnexal carcinoma, and metastatic carcinoma. Immunohistochemistry can help differentiate BCC from its mimics.25 Pigmented BCC may be confused clinically with a melanocytic nevus, melanoma, and seborrheic keratosis. Cystic BCC can mimic an eccrine or apocrine hidrocystoma.
 FIGURE 128.4 Infiltrative morpheaform basal cell carcinoma. |
 FIGURE 128.5 Medial canthal basal cell carcinoma with orbital invasion. |
Treatment
For eyelid BCC lesions where the diagnosis is uncertain, an incisional biopsy is indicated. This will allow a firm histologic diagnosis and allow for preoperative planning of resection and subsequent reconstruction. For smaller, low-risk tumors, surgical excision with a 4-mm margin is the treatment of choice. The goal should be to achieve complete tumor eradication to prevent a recurrence, local destruction, and possible metastatic spread. Resection should include frozen-section control of margins, preferably by Mohs microsurgery. Small, nonmarginal defects can heal by spontaneous granulation with acceptable aesthetic results. Larger defects are repaired by primary layered closure or with more complex reconstructions using myocutaneous flaps and grafts. A wide variety of reconstructive techniques are available depending upon the size and location of the defect and the specific tissues involved.26
Radiotherapy can be used as adjunctive therapy to surgical excision or in combination with orbital exenteration in cases of high-risk aggressive BCC with perineural invasion. It can also be used for patients who are not suitable surgical candidates. The use of radiotherapy remains controversial for smaller low-risk tumors, but some studies have shown good tumor control in many cases.27 Radiotherapy has some potential side effects including dry eye; cataract; punctal, and lacrimal duct stenosis; neovascular glaucoma; and radiation retinopathy.
Electrodissection and curettage use mechanical debridement and electrocoagulation to remove the visible tumor. This technique does not allow for histologic assessment of margins so that it is more prone to leaving some tumors untreated. Complications include loss of eyelashes and some visible scarring following spontaneous granulation of the wound.
Cryosurgery is an alternative option, and some studies have reported high 5-year cure rates. Cosmetic outcomes tend to be inferior to surgery, and the technique generally is contraindicated in hair-bearing areas.
Photodynamic therapy (PDT) is an alternative treatment for BCC. Methyl aminolevulinate or aminolevulinic acid is used as the photosensitizing agent. Activation of the photosensitizer by visible light creates cytotoxic oxygen species and free radicals, which selectively destroy rapidly proliferating cells. A recent meta-analysis concluded that PDT is a useful method for the treatment of BCC that is similar in efficiency to cryosurgery and pharmacologic treatment such as with imiquimod. While it is less effective than surgical excision, PDT results in better cosmetic outcomes.28
For patients in whom surgery is not possible or is declined, topical immunotherapy has emerged as an alternative treatment for periocular BCC. Imiquimod is an immune modulator that stimulates innate immunity and induces apoptosis in tumor cells. For nodular BCC a topical 5% cream once a day for 8 to 16 weeks is applied. Clinical remission and histological clearance of the tumor have been reported in 80% to 100% of patients at follow-up periods of up to 2 years.29,30,31
Given the role of hedgehog signaling in the pathogenesis of BCC, targeted inhibition of the sonic hedgehog pathway now offers a promising treatment option for patients with advanced or recurrent disease not amenable to local resection. Vismodegib is a small-molecule compound that selectively inhibits the transmembrane receptor SMO. Early studies have shown this to be an effective treatment option for locally recurrent cases that have failed surgery, for metastatic BCC, and for advanced cases not amenable to surgery or radiotherapy. Vismodegib has been shown to have manageable side effects in most patients.32,33,34,35,36,37 Neoadjuvant vismodegib therapy has been used followed by eye preserving surgery.33 Sonidegib, another SMO antagonist, also has been approved for similar indications and carries a toxicity profile comparable with that of vismodegib.38
Prognosis
The prognosis for BCC depends upon the histologic type, anatomic location, and the size of the lesion. For nodular lesions, the prognosis is very good following complete surgical excision. With incomplete removal, the tumor can invade adjacent tissues along paths of least resistance. Destruction of muscle, cartilage, and bone can be associated with aggressive recurrences, leading to a poor prognosis. Orbital invasion is rare but is more common with lesions in the medial canthus. With local infiltrative growth patterns, the prognosis is significantly reduced and is associated with multiple recurrences. Recurrence rates average from 4% to 9% for lesions followed less than 5 years or more than 5 years, respectively.39 However, the overall mortality rate is low, less than 1%. Spontaneous regression was reported in 25 of 400 (6%) BCCs, and another 56 (14%) showed foci of regression within the tumor.
BCCs rarely metastasize. The reported rate has been 0.0028% to 0.55%,40 but a more recent study reported a rate of 1%.41 Dissemination to regional or distant sites may occur via lymphatic spread (100%), hematologic spread (25%), or local subcutaneous routes. About 75% of tumors that metastasize are of the morpheaform type and usually involve the regional lymph nodes, lungs, bone, skin, liver, and spleen.42 In one literature review of 100 cases of BCC with regional metastasis (N = 50) or distant metastasis (N = 50), the median survival for patients with regional metastases was 87 months and for distant metastasis it was 24 months.43
Predisposing Genetic Syndromes
Nevoid Basal Cell Carcinoma Syndrome
The basal cell nevus syndrome is also known as Gorlin-Goltz syndrome or Goltz syndrome. It is a rare, autosomal-dominant syndrome, more common in males, and involves both ectoderm and mesoderm tissues.44,45 The clinical manifestations were originally reported simultaneously by Jarisch46 and by White, both in 1894.47 It was later classified as a syndrome with multiple manifestations.20 The condition is characterized by multiple basal
cell carcinomas, odontogenic keratocysts, palmar and/or plantar pits, ectopic calcifications of the falx cerebri, and skeletal abnormalities such as bifid ribs and sometimes other tumors such as medulloblastoma and meningioma (Figure 128.6).48 Other less common ocular abnormalities include congenital cataracts, uveal and optic nerve coloboma, strabismus, nystagmus, and microphthalmos. It is estimated that the prevalence is approximately 1 in 60,000 to 1 in 250,000, depending upon geographic locality and ethnicity. About 0.7% of patients with BCC may have this syndrome. The incidence is greater in regions with higher ultraviolet sunlight exposure, and tumors are more commonly seen in sun-exposed areas such as the face, chest, and back. The syndrome may be more common in young adults presenting with periocular BCCs.49
cell carcinomas, odontogenic keratocysts, palmar and/or plantar pits, ectopic calcifications of the falx cerebri, and skeletal abnormalities such as bifid ribs and sometimes other tumors such as medulloblastoma and meningioma (Figure 128.6).48 Other less common ocular abnormalities include congenital cataracts, uveal and optic nerve coloboma, strabismus, nystagmus, and microphthalmos. It is estimated that the prevalence is approximately 1 in 60,000 to 1 in 250,000, depending upon geographic locality and ethnicity. About 0.7% of patients with BCC may have this syndrome. The incidence is greater in regions with higher ultraviolet sunlight exposure, and tumors are more commonly seen in sun-exposed areas such as the face, chest, and back. The syndrome may be more common in young adults presenting with periocular BCCs.49
 FIGURE 128.6 Nevoid basal cell carcinoma (Gorlin-Goltz) syndrome. |
A gene believed to be responsible for this disorder has been mapped to chromosome 9q23.3-q31 that encodes the patched gene (PTCH-1) which translates into the transmembrane receptor protein for the secreted molecule Sonic Hedgehog in the Hedgehog signaling pathway responsible for the regulation of development and tumor suppression.50,51 Patients may have a few to 1000 or more BCCs that vary in size from 1 to 10 mm in diameter. They may be skin colored and pedunculated or nodular, or even ulcerated. The mainstay of management of the BCCs associated with basal cell nevoid syndrome is surgical excision, preferably by Mohs microsurgery. Adjunctive therapies often include cryosurgery or electrodesiccation. PDT for diffuse BCCs has been used, but this is limited to smaller thin tumors less than 2 mm in thickness. Vismodegib has shown some promise in achieving tumor regression.52
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