Chapter 115. Basal Cell Carcinoma

BCC is the most common cancer in humans. It is estimated that over 1 million new cases occur each year in the United States. The malignancy accounts for approximately 75% of all nonmelanoma skin cancers (NMSC) and almost 25% of all cancers diagnosed in the United States.1 Epidemiological data indicate that the overall incidence is increasing worldwide significantly by 3%–10% per year.2

BCC is more common in elderly individuals but is becoming increasingly frequent in people younger than 50 years of age. Christenson et al noted a disproportionate increase in BCC in women under age 40.3 Men are affected slightly more often than are women. Levi et al reported that the incidence of BCC rose steadily in the Swiss Canton of Vaud between 1976 and 1998 to levels of 75.1 in 100,000 in males and 66.1 in 100,000 in females.4,5 Stang et al in Westphalia, Germany found that the incidence rate of BCC during a 5-year period (1998–2003) was 63.6 in men and 54.0 in women.6 A study of NMSC in Aruba supported these findings.7 In that study, BCC was the most common type of skin cancer diagnosed between 1980 and 1995. Tumors were more frequent in patients older than 60 years of age, and 57% were in men. The highest percentage of lesions occurred on the nose (20.9%), followed by other sites on the face (17.7%).7 Incidence in Europe was examined by the recent study in Croatia. From 2003 to 2005, the crude incidence rate for the Croatian population of 100,000 was 54.9 for men and 53.9 for women. The vast majority of BCCs were located on the head and neck.8

BCC character develops on sun-exposed skin of lighter skinned individuals. Incidence rates of BCC in Asians living in Singapore increased from 1968 to 2006, especially among the older, more fairly complected Chinese patents. Skin cancer trends in Asians from 1968–2006 showed BCC rates increased the most among persons older than 60 years.9

BCC is rare in dark skin because of the inherent photoprotection of melanin and melanosomal dispersion. An estimated 1.8% of BCCs occur in blacks, and BCC is approximately 19 times more common in whites than blacks.10

Risk factors for BCC have been well characterized and include ultraviolet light (UVL) exposure, light hair and eye color, northern European ancestry, and inability to tan.1 An Italian study indicated the important role of sunburns, and therefore intense sun exposure, rather than that of prolonged sun exposure to increase the risk of BCC.11

The pathogenesis of BCC involves exposure to UVL, particularly the ultraviolet B spectrum (290–320 nm) that induces mutations in tumor suppressor genes.12,13 UVB radiation damages DNA and affects the immune system resulting in a progressive genetic alterations and neoplasms. UV-induced mutations in the p53 tumor suppressor gene have been found in about 50% of BCC cases.14

Currently, it is thought that the upregulation of the mammalian development signaling pathway, Hedgehog (HH), is the pivotal abnormality in all BCCs, and there is evidence that little more than this upregulation is required for BCC carcinogenesis.15,16 The mutations that activate the aberrant HH signaling pathway are found in PTCH1 and Smoothened (SMO). Approximately 90% of sporadic BCCs have identifiable mutations in at least one allele of PTCH1, and an additional 10% have activating mutations in the downstream SMO protein.17 The most frequently identified mutations in PTCH1 and SMO are of a type consistent with UV-induced damage.18–20

The contribution of high-intensity sunlight exposure to BCC development in the general population is well established.11 A latency period of 20–50 years is typical between the time of UV damage and the clinical onset of BCC. Therefore, in most cases, BCC develops on sun-exposed skin in elderly people, most commonly in the area of head and neck.21

Some studies indicate that intermittent brief holiday exposures may place patients at higher risk than occupational exposure.9,22 An Italian study confirmed the role of intermittent sun exposure as a strong risk factor for BCC.11 Ramani and Bennett reported a significantly higher incidence of BCCs in World War II servicemen stationed in the Pacific theater than in those stationed in Europe. This suggests that several months or years of intense exposure to UVL may have deleterious long-term effects.23 Truncal BCCs can result from acute intense exposures sufficient to cause sunburn on the skin of the trunk among people whose ability to tan makes the skin of their face generally less susceptible to the carcinogenic effects of UV radiation.24

Other factors that appear to be involved in the pathogenesis include mutations in regulatory genes,17,25 exposure to ionizing radiation,26,27 and alterations in immunosurveillance.28–30

The propensity to develop multiple BCCs may be inherited. Included among heritable conditions predisposing to the development of this epithelial cancer are nevoid basal call carcinoma syndrome or basal cell nevus syndrome (BCNS),31 Bazex syndrome,32 and Rombo syndrome.33 Patients with BCNS may develop hundreds of BCCs and may exhibit a broad nasal root, borderline intelligence, jaw cysts, palmar pits, and multiple skeletal abnormalities. BCNS occurs due to mutations in the tumor suppressor PTCH gene.34,35

Bazex syndrome is transmitted in an X-linked dominant fashion.32 Patients have multiple BCCs, follicular atrophoderma, dilated follicular ostia with ice pick scars, hypotrichosis, and hypohidrosis. In contrast, Rombo syndrome is transmitted in an autosomal dominant fashion.33 Patients have vermiculate atrophoderma, milia, hypertrichosis, trichoepitheliomas, BCCs, and peripheral vasodilation. Hypohidrosis is not a feature of Rombo syndrome.

The role of the immune system in the pathogenesis of skin cancer is not completely understood. Immunosuppressed patients with lymphoma or leukemia36,37 and patients who have received an organ transplant have a marked increase in the incidence of squamous cell carcinoma but only a slight increase in the incidence of BCC.28–30,38 Bastiaens et al found that transplant recipients developed more BCCs on the trunk and arms than did nonimmunosuppressed patients.39 Harwood et al found that fewer BCCs occurred on the head and neck of renal transplant recipients, while more BCCs were found on the trunk and arms compared to the immune competent patients.38 Patients with human immunodeficiency virus infection develop BCCs at the same rate as immunocompetent individuals, based on similar risk factors.19,40,41 Immunosuppressed long-term alcoholics tend to develop infiltrative BCCs with increased frequency.20,42 A potential link between UVL and decreased immunity has been suggested by Gutierrez-Steil et al, who demonstrated that UVL-induced BCCs express Fas ligand (CD95L).43 They further showed that these cells were associated with CD95-bearing T cells undergoing apoptosis.43,44 This represents a potential mechanism by which UVL might help tumor cells avoid being killed by cytotoxic T lymphocytes. Kaporis et al showed that immune suppressive regulatory T cells are surround BCC tumor nests thus providing another potential mechanism for BCC to evade host antitumor immunity.45

Presentation

The presence of any friable, nonhealing lesion should raise the suspicion of skin cancer. Frequently, BCC is diagnosed in patients who state that the lesion bled briefly then healed completely, only to recur. BCC usually develops on sun-exposed areas of the head and neck but can occur anywhere on the body. Features include translucency, ulceration, telangiectasias, and the presence of a rolled border. Characteristics may vary for different clinical subtypes, which include nodular, superficial, morphea-form, and pigmented BCCs and fibroepithelioma of Pinkus (FEP). The anatomic location of BCC may favor the development of a particular subtype.46

Basal Cell Carcinoma Subtypes

Nodular Basal Cell Carcinoma

Nodular BCC is the most common clinical subtype of BCC (Fig. 115-1).47,48 It occurs most commonly on the sun-exposed areas of the head and neck and appears as a translucent papule or nodule depending on duration. There are usually telangiectasias and often a rolled border. Larger lesions with central necrosis are referred to by the historical term rodent ulcer (Fig. 115-2). The differential diagnosis of nodular BCC includes traumatized dermal nevus and amelanotic melanoma.

Pigmented Basal Cell Carcinoma

Pigmented BCC is a subtype of nodular BCC that exhibits increased melanization. Pigmented BCC appears as a hyperpigmented, translucent papule, which may also be eroded (eFig. 115-2.1). The differential diagnosis includes nodular melanoma.

Superficial Basal Cell Carcinoma

Superficial BCC occurs most commonly on the trunk and appears as an erythematous patch (often well demarcated) that resembles eczema (Fig. 115-3).47 An isolated patch of “eczema” that does not respond to treatment should raise suspicion for superficial BCC.

Morpheaform (Sclerosing) Basal Cell Carcinoma

Morpheaform BCC is an aggressive growth variant of BCC with a distinct clinical and histologic appearance. Lesions of morpheaform BCC may have an ivory-white appearance and may resemble a scar or a small lesion of morphea (eFig. 115-3.1). Thus, the appearance of scar tissue in the absence of trauma or previous surgical procedure or the appearance of atypical-appearing scar tissue at the site of a previously treated skin lesion should alert the clinician to the possibility of morpheaform BCC and the need for biopsy.

Fibroepithelioma of Pinkus

FEP classically presents as a pink papule, usually on the lower back.25,50 It may be difficult to distinguish from an acrochordon or skin tag. Similar to basal cell carcinomas, fibroepitheliomas of Pinkus express androgen receptors, supporting its classification as a basal cell carcinoma.51 The differential diagnoses of FEP includes acrochordon.52

Local Invasion

The greatest danger of BCC results from local invasion (Fig. 115-4). In general, BCC is a slow-growing tumor that invades locally rather than metastasizes.26,27,53,54 The doubling time is estimated to be between 6 months and 1 year. If left untreated, the tumor will progress to invade subcutaneous tissue, muscle, and even bone. Anatomic fusion planes appear to provide a low-resistance path for tumor progression. Tumors along the nasofacial or retroauricular sulcus may be extensive. Metastases are rare and most are said to more closely correlate to the size and depth of tumor invasion and less so to the histologic subtype of the original tumor.1

Although metastases are rare, significant patient morbidity, such as local tissue destruction and disfigurement can occur. In one informative case, a patient documented the progression of his own tumor with photographs over a 27-year period.28,55 The lesion, which encompassed an entire side of the face, including the maxillary sinus, apparently doubled over a 10-year period and grew rapidly in the 2 years before hospital admission. This scenario occurs in the context of physical or psychiatric disability that interferes with judgment or access to health care. In one of the first reports of giant BCC in India, a patient presented with a nonhealing ulcer of the face, which had been present and increasing in size for over 20 years. On examination, the ulcer covered the entire left side of the face involving the preauricular, infraorbital, and bucco mandibular units of the cheek and the orbit and resulted in loss of vision.56 In another case, a 35-cm BCC on the back of a 65-year-old man recurred after wide local excision and X-ray therapy (XRT), resulting in spinal cord compression.57 Lethal extension to the central nervous system from aggressive scalp BCC has been reported.58,59

Perineural Invasion

Perineural invasion (PNI) is uncommon in BCC and occurs most often in histologically aggressive or recurrent lesions.54 The presence of PNI has been correlated with recurrent lesions, increased duration and size of lesions, and orbital invasion.60 In one series, Niazi and Lamberty identified PNI in less than 0.2% of cases. In that series, perineural BCC was seen most often with recurrent tumors located in the preauricular and malar areas.61 Brown and Perry found the incidence of PNI to be 3% in aggressive BCC cases. This incidence approaches that reported for cutaneous squamous cell carcinomas.62 Leibovitch et al found an incidence rate of 2.74%.63 Ratner et al found a higher incidence in their study (3.8%); however, this was a smaller study.64 Leibovitch et al reported perineural spread in more than 50% of periocular BCCs eventuating in orbital invasion. These tumors required extensive surgery and in some cases exenteration (Fig. 115-5).65 Perineural spread may manifest as pain, paresthesias, weakness, or paralysis. The presence of focal neurologic symptoms at the site of a previously treated skin cancer should raise concern about nerve involvement.

Metastasis

Metastasis of BCC occurs only rarely, with rates varying from 0.0028% to 0.55%.34–36,66–68 Involvement of regional lymph nodes and lungs is most common. Cases of pulmonary metastasis continue to be reported.69 Metastasis to the bone and bone marrow has been reported.70 Aggressive histologic characteristics, including morpheaform features, squamous metaplasia, and PNI, have been identified as risk factors for metastasis.68 Von Domarus et al reported five cases of metastatic BCC in which perineural or intravascular invasion had been noted in three.71 Squamous differentiation was not observed in the primary tumors in the cases they presented but was noted in two of five cases of metastatic cancer. Overall, squamous differentiation was present in 15% of the primary or metastatic tumors from the 170 cases reviewed in that series.

Diagnosis of BCC is accomplished by accurate interpretation of the skin biopsy results. The preferred biopsy methods are shave biopsy, which is often sufficient, and punch biopsy. A sterilized razor blade, which can be precisely manipulated by the operator to adjust the depth of the biopsy specimen, is often superior to a No. 15 scalpel for shave biopsies. A punch biopsy may be useful for flat lesions of morpheaform BCC or for recurrent BCC occurring in a scar. When biopsying a lesion, adequate tissue should be taken. Small, fragmented tissue samples may make diagnosis difficult; potentially compromising the ability to accurately assess BCC subtype and thickness, which can affect treatment choice.72

Histopathologic features vary somewhat with subtype, but most BCCs share some common histologic characteristics. The malignant basal cells have large nuclei and relatively little cytoplasm. Although the nuclei are large, they may not appear atypical. Usually, mitotic figures are absent. Frequently, slit-like retraction of stroma from tumor islands is present, creating peritumoral lacunae that are helpful in histopathologic diagnosis.73 The most common form of BCC is nodular, followed by superficial, then morpheaform. Also, nodular and morpheaform are most commonly found on the head and neck, while superficial is most often found on the trunk region.74

Nodular Basal Cell Carcinoma

Nodular BCCs account for half of all BCCs and are characterized by nodules of large basophilic cells and stromal retraction (Fig. 115-6A). The term micronodular BCC is used to describe tumors with multiple microscopic nodules smaller than 15 μm (see Fig. 115-6B).73 Clinically, this is the type of BCC that most commonly shows a translucent pearly papule or nodule with a rolled border and telangiectasia. The nodular form of BCC is characterized by discrete nests of basaloid cells in either the papillary or reticular dermis accompanied.1

Pigmented Basal Cell Carcinoma

Pigmented BCC shows histologic features similar to those of nodular BCC but with the addition of melanin.38 Approximately 75% of BCCs contain melanocytes, but only 25% contain large amounts of melanin. The melanocytes are interspersed between tumor cells and contain numerous melanin granules in their cytoplasm and dendrites. Although the tumor cells contain little melanin, numerous melanophages populate the stroma surrounding the tumor.73

Superficial Basal Cell Carcinoma

Superficial BCC is characterized microscopically by buds of malignant cells extending into the dermis from the basal layer of the epidermis.38 The peripheral layer shows palisading cells. There may be epidermal atrophy, and dermal invasion is usually minimal. There may be a chronic inflammatory infiltrate in the upper dermis. This histologic subtype is encountered most often on the trunk and extremities, but may also appear on the head and neck.73

Morpheaform Basal Cell Carcinoma

Morpheaform BCC, also called infiltrative or sclerosing BCC, consists of strands of tumor cells embedded within a dense fibrous stroma (see Fig. 115-6C).73 Tumor cells are closely packed columns and, in some cases, only one to two cells thick enmeshed in a densely collagenized fibrous stroma. Strands of tumor extend deeply into the dermis. The cancer is often larger than the clinical appearance indicates. Recurrent BCC may also demonstrate infiltrating bands and nests of cancer cells embedded within the dense fibrous stroma of scar.

Fibroepithelioma of Pinkus

In FEP, long strands of interwoven basiloma cells are embedded in fibrous stroma with abundant collagen.38 Histologically, FEP shows features of reticulated seborrheic keratoses and superficial BCC.73

Basosquamous Carcinoma

Basosquamous carcinoma is a form of aggressive growth BCC. It can be confused with squamous cell carcinoma and promotes controversy considering its precise histomorphologic classification as it shows both basal cell and squamous cell carcinoma differentiation in a continuous fashion.1 Histologically, basosquamous carcinoma shows infiltrating jagged tongues of tumor cells admixed with other areas that show squamous intercellular bridge formation and cytoplasmic keratinization.

The differential diagnosis for BCC is summarized in Box 115-1.

Management of BCC is guided by anatomic location and histological features. Approaches include standard surgical excision, destruction by various modalities, Mohs micrographic surgery (MMS), and topical chemotherapy.73 The best chance to achieve cure is through adequate treatment of primary BCC, because recurrent tumors are more likely to recur and cause further local destruction. An algorithmic approach to management is summarized in Fig. 115-7. While most trials have only evaluated BCCs in low-risk locations, surgery and radiotherapy appear to be the most effective treatments with surgery showing the lowest failure rates. Although cosmetic outcomes appear good with PDT, long-term follow-up data are needed. Other treatments might have some use but few have been compared to surgery. An ongoing study comparing imiquimod to surgery should clarify whether imiquimod is a useful option.75 Overall, removal of the tumor with clear margins remains the gold standard for treating basal cell carcinoma.

Mohs Micrographic Surgery

MMS offers superior histologic analysis of tumor margins while permitting maximal conservation of tissue compared with standard excisional surgery.76,77 Rowe, Carroll, and Day report a recurrence rate of 1% for primary BCCs treated by MMS. This was superior to the rate for other modalities, including standard excision (10%), curettage and desiccation (C&D) (7.7%), XRT (8.7%), and cryotherapy (7.5%).78 Recurrent BCCs treated by MMS reappeared at a rate of 5.6%, which was again superior to the rate for other modalities, including excision (17.6%), XRT (9.8%), and C&D (40%).79 Leibovitch et al found that after 5 years BCC recurrence was diagnosed in 1.4% of primary and in 4% of recurrent tumors. This low 5-year recurrence rate of BCC with MMS emphasizes the importance of margin-controlled excision over other modalities.80 MMS is the treatment of choice for morpheaform, poorly delineated, incompletely removed, and otherwise high-risk primary BCCs. It is the preferred treatment for recurrent BCC and for any BCC that occurs at a site where tissue conservation is desired. MMS is particularly useful in treating BCCs at high-risk anatomic sites, including the embryonic fusion planes represented by the nasofacial junction and retroauricular sulcus. Based on the fact that MMS provides the lowest recurrence rates, it is the treatment of first choice for primary facial BCCs with an aggressive histopathological subtype and for recurrent facial BCCs.81 MMS has shown greater efficacy than surgical excision for the treatment of recurrent facial BCCs.80 Mosterd et al also found that treatment with MMS leads to a significantly lower number of recurrences than treatment with surgical excision in recurrent facial BCCs.77 From a patient perspective, one large prospective cohort study found that MMS was an independent factor for higher long-term patient satisfaction, when compared to standard excision or C&D.82

Standard Excision

Compared with nonexcisional techniques, standard surgical excision offers the advantage of histologic evaluation of the removed specimen; however, depending on the sectioning method used (e.g., breadloafing), areas of margin involvement can be missed during routine histologic evaluation.83 The authors of a recent Cochrane review concluded that, based on the available published work, surgery is the standard treatment of choice for BCC.75 Although standard excision is appropriate for many BCCs, cure rates for standard excisional surgery are inferior to those for MMS in cases of primary morpheaform BCCs, recurrent BCCs, and tumors located in high-risk anatomic sites.78,79 One disadvantage of standard surgical excision is the potential for incomplete margin control. The incidence of incomplete excision has varied, with reports ranging from 4.7% to 13.2% of treated patients.84–88 Farhi et al found the pathologically reported incomplete excision rate was over 10% and was significantly associated with the location on the face, particularly on the nose and inner canthus, and with infiltrative and multifocal histologic types.89 Wolf and Zitelli demonstrated that margins of 4 mm were adequate for 95% of nonmorpheaform BCCs smaller than 2 cm in diameter when treated by standard excision.90 Huang and Boyce found that, for a 95% cure rate, BCCs <1 cm in diameter required a 0.5-cm margin, those between 1 cm and 2 cm in diameter required a 0.8-cm margin, and a 1.2-cm margin was required for those >2 cm in diameter.91 Johnson, Tromovitch, and Swanson reported a 96.7% cure rate when the excision included a 2-mm margin beyond the area defined by curettage. Tumor was present in 64 of 403 curette margins and in 12 of 403 excision margins. The histologic subtype was aggressive in 11 of 12 cases with positive excision margins. Margins of 5 mm are necessary for primary morpheaform BCC or recurrent BCC.92 Preoperative curettage decreases the frequency of positive margins in the management of BCC. Chiller et al found that curettage before excision decreased the surgical failure rate for BCC by 24% (P = .03).93

Curettage and Desiccation

C&D is one of the most frequently used treatment modalities for BCC.94 That C&D is operator-dependent was shown by Kopf et al, who identified a significant difference in cure rate between patients treated by private practitioners (94.3%) and those treated by residents (81.2%).95 High 5-year cure rates of up to 98.8% have been obtained after C&D of primary, nonfibrosing BCCs of medium- and high-risk areas of the face when performed by a skilled operator.96

Spiller and Spiller reported a cure rate of 97% in 233 patients. Cure rate decreased as a function of primary lesion size: for lesions smaller than 1.0 cm, the cure rate was 98.8%; for lesions between 1.0 cm and 2.0 cm, 95.5%; and for lesions larger than 2.0 cm, 84%. Recurrences were noted most often on the forehead, temple, ears, nose, and shoulders. C&D is not recommended for large primary BCC, morpheaform BCC, or recurrent BCC.97 For appropriately selected lesions and locations, C&D remains an efficacious and cost-effective treatment modality.83

Cryosurgery

Cryosurgery is another destructive modality that has been used in the treatment of BCC. Two freeze-thaw cycles with a tissue temperature of −50°C (−58°F) are required to destroy BCC. In addition, a margin of clinically normal tissue must be destroyed to eradicate subclinical extension.83 A systematic review of recurrence rates published between 1970 and 1997 indicated that cryotherapy in the treatment of primary BCC resulted in a 5-year recurrence rate from 4% to 17%.98 Cryosurgery lacks the benefit of histologic confirmation of tumor removal. Kuflik and Gage reported 99% cure rates in 628 patients followed for 5 years. Possible complications of cryosurgery include hypertrophic scarring and postinflammatory pigmentary changes.99 In regards to cosmesis, patient satisfaction was found to be higher with surgical excision than with cryosurgery and should be taken into consideration when choosing a treatment option.100 Another potential serious adverse outcome is the obscuring of tumor recurrence by fibrous scar tissue. Any recent change in a cryosurgery scar after normal healing is completed should raise the suspicion of recurrent BCC.

Topical Treatment

Imiquimod

Imiquimod (5% cream) has been used in the treatment of skin cancers.101 Approved in 2004 by the FDA for the topical treatment of biopsy-confirmed, small (less than 2 cm), primary superficial BCC, imiquimod is a Toll-like receptor 7 agonist believed to induce interferon-α, tumor necrosis factor-α, and other cytokines to boost T helper 1 type immunity. In two double-blind, randomized, vehicle-controlled trials, clinical and histological clearance rates for dosing five and seven times per week were 75% and 73%, respectively, for superficial BCC.102,103 In another study, 10 of 19 nodular BCCs (approximately 53%) cleared after treatment with imiquimod.104 In general, adverse side effects are limited to local skin reactions; however, researchers have noted the significant correlation between the severity of the local skin reaction (erythema, erosion, and crusting) and the histological clearance rate.102

The safety and effectiveness of imiquimod for other types of BCC have not been established, and with up to 25% of treated patients failing therapy (or with a one in four failure rate), this possible clinical consequence should be discussed and strongly considered when choosing the appropriate treatment. The cost of imiquimod can easily exceed the costs of destructive or surgical modalities as well.105 A case series of 24 patients105 highlights the clinical consequences of imiquimod failure rescued with MMS. The cost of imiquimod can easily exceed the costs of destructive or surgical modalities as well.

Imiquimod can be consideration as a monotherapy only for superficial BCCs limited to small tumors in low-risk locations in patients who will not or cannot undergo treatment with other better-established therapies.106

5-Fluorouracil

5-Fluorouracil (5-FU), a topically applied chemotherapeutic agent used in the treatment of actinic keratoses, has also been used to treat BCCs. In one series, Epstein showed a 5-year recurrence rate of 21% after 5-FU treatment, which was reduced to 6% when curettage was performed initially.107 Gross et al observed a 90% histologic clearance rate 3 weeks after 5-FU treatment, but with no follow-up. 5-FU was also found to be generally well tolerated with a good cosmetic outcome, with the majority of patients having no pain or scarring and only mild erythema.108 5-FU is metabolized by dihydropyrimidine dehydrogenase (DPD), and its use is contraindicated in patients deficient in that enzyme. A 2-(13)C-uracil breath test can identify DPD-deficient individuals.109–111 The use of 5-FU to treat BCC should be considered carefully and should include an evaluation of the risk of recurrence and treatment failure. Topical therapies may be associated with adverse effects, produces lower clearance rates, may be more difficult to administer, and, in some instances, costs more than other well-established therapies for BCC.106

Hedgehog Inhibitors

With strong evidence of HH activation in BCC, there has been significant recent development of HH inhibitors (HHI) for the treatment of metastatic or locally aggressive BCCs. The well-known HHI compound is the plant alkaloid, cyclopamine, which competitively inhibits SMO protein signaling and therefore the growth of malignant cells driven by HH activation.112,113

In a phase 1 trial, GDC-0449, an orally active small molecule derivative that targets the HH pathway via SMO, appears to have antitumor activity in locally advanced or metastatic BCC (ClinicalTrials.gov number, NCT00607724).114 Further studies are needed to ascertain the full efficacy and adverse-effect profiles. Topical HH pathway inhibitors are also being developed for the treatment of BCC.

Photodynamic Therapy

Photodynamic therapy (PDT) involves the activation of a photosensitizing drug by visible light to produce activated oxygen species that destroy the constituent cancer cells. Exogenous δ-aminolevulinic acid increases intracellular production of the endogenous photosensitizer protoporphyrin type IX, which preferentially accumulates in tumor cells.115 Morrison et al reported an 88% initial clearance of 40 large (>2 cm) BCCs after one to three treatments. The time of follow-up was between 12 months and 60 months.116 Basset-Seguin et al reported complete response rates for superficial BCCs from 85% to 93% at 3 months and a response rate on par with cryosurgery at 60 months (75% vs. 74%).117 Marmur et al reviewed PDT for nonmelanoma skin cancer and reported recurrence rates ranging from 0% to 31% for BCC.118 A clinical study comparing methyl-aminolevulinate PDT (MAL-PDT) and surgery in small superficial BCC found that MAL-PDT offers similar high efficacy and a much better cosmetic outcome than standard excision surgery in the treatment of superficial BCC; however, at 12 months, 9.3% lesions recurred with MAL-PDT and none with surgery.119 The long-term cure rates for superficial BCC with PDT remains around 75% and because of the appreciable nonresponse and recurrence rates, patients should be monitored closely during the first 2–3 years after PDT, which is when most lesion recurrences are seen.120 The Cochrane collaboration found that cosmetic outcome for PDT was significantly better than surgery. However, there were also comparatively high failure rates associated with PDT when compared to surgery, radiotherapy and cryotherapy. PDT requires a number of hospital visits and this may not suit all people with BCC.75 Reports of high recurrence rates suggest that this method may be best reserved for select situations in which better established methods are not feasible, particularly in situations where surgery may be problematic or where patients have multiple lesions.

Radiation Therapy

Radiation therapy (XRT) may be useful in cases of primary BCC or in cases in which postsurgical margins are positive for cancer. Advantages include minimal patient discomfort and avoidance of an invasive procedure for a patient unwilling or unable to undergo surgery. XRT may be a very useful modality as adjunct treatment for BCC when margins are positive after excision or for extensive perineural or large nerve involvement.83 Potential disadvantages include lack of histologic verification of tumor removal, prolonged treatment course, cosmetic result that may worsen over time (cutaneous atrophy and telangiectasia), and predisposition to aggressive and extensive recurrences. Local control rates of 93%–97% have been reported; however, cosmesis has been rated inferior to results achieved surgically.116,121

The Cochrane Collaboration found surgery and radiotherapy to appear the most effective treatments for BCC, while the best overall results being obtained with surgery.75

Special Management Issues

Incompletely Excised Basal Cell Carcinoma

On the basis of data from the 1960s suggesting that 50%–70% of incompletely excised BCCs do not recur, some physicians adopted a “wait and see” approach.122 In some cases, flap and graft repair may have been performed before confirmation of negative margins, so that the anatomy was distorted. This confounds identification of positive margins for definitive treatment. Incomplete resection was addressed by Robinson and Fisher,61,123 who reported on 994 patients consecutively referred for treatment of incompletely excised BCCs with subsequent clinical recurrence. Of these, only 32 were referred for MMS for complete tumor removal at the time the original operating surgeon received the pathologic confirmation of positive excision margins. For the remaining 962 recurrent BCCs, the nose was the most common anatomic site (43%), and flap repair was the most common form of reconstruction (52%). The authors recommend MMS for the treatment of incompletely excised BCC. Ideally, patients should receive treatment at the time of diagnosis, because delay will likely result in increased local tissue damage (eFigs. 115-7.1A and 115-7.1B). Patients unable to undergo re-excision to achieve clear margins should be evaluated for XRT.

Neurotropic Basal Cell Carcinoma

PNI by BCC is a rare event (<0.2% of cases). Defined as the observation of malignant cells in the perineural space of nerves,124 when PNI is detected, every effort should be made to clear the tumor, preferably by MMS. Patients with gross PNI manifested by neurologic symptoms would benefit from preoperative magnetic resonance imaging to assess extent of tumor spread. Classic examples include brow paralysis due to involvement of the temporal branch of the facial nerve and midface paresthesias secondary to involvement of the trigeminal nerve.64,65

Metastatic Basal Cell Carcinoma

Although it is exceedingly rare, the possibility of metastatic disease exists and may need to be addressed. If nodal disease is suspected on surgical examination, lymph node biopsy and imaging studies, as well as evaluation by medical and surgical oncologists, are indicated.68 Platinum-based chemotherapy has been used with modest results in treatment of metastatic BCC; however, rapid clinical response was reported using a combination of cisplatin and paclitaxel.125 Complete response to carboplatin and paclitaxel has been reported as well.126

Course and Prognosis

With appropriate treatment, the prognosis for most patients with BCC is excellent. Control rates as high as 99% have been achieved by MMS. Although tumor control rates for primary tumors are high, patients must be monitored for recurrence and development of new primary BCCs. The risk for development of a second primary BCC ranges from 36% to 50%.127 Periodic full-body skin examinations and counseling about sun protection are recommended for any patient with a history of BCC. This is especially important because patients with a history of BCC are at increased risk for melanoma. The prognosis for patients with recurrent BCC is favorable, although recurrent tumors are more likely to appear again and to behave aggressively. Patients with a history of recurrent disease must be monitored more frequently for the development of further recurrences and new primary tumors. An estimated 40%–50% of patients with primary carcinoma will develop at least one or more further BCCs within 5 years.128 For the rare patient with metastatic disease, prognosis is poor, with a mean survival of 8–10 months from the time of diagnosis.