INTRODUCTION Basal cell carcinoma (BCC) is a common skin cancer arising from the basal layer of epidermis and its appendages. These tumors are referred to as "epitheliomas" because of their low metastatic potential; metastases are thought to occur in less than 0.1 percent of cases. However, the term carcinoma is appropriate, since they are locally invasive, aggressive, and destructive of skin and the surrounding structures including bone. Because of their potential for local tissue destruction and disfigurement, early curative treatment is the standard of care. Achieving this goal requires a thorough understanding of the patient's medical history, the histopathologic and clinical features of the tumor, and the available treatment options. The best treatment maximizes the chance of cure while at the same time minimizing the risk and cost to the patient. Most BCCs pose little serious risk to the patient, and can be adequately treated with any of several techniques including cryosurgery, electrodessication and curettage, radiation therapy (RT), topical 5-fluorouracil (5-FU), surgical excision, or Mohs micrographic surgery. Although all of these techniques are associated with a high likelihood of cure in properly selected cases, cure rates and the incidence of treatment-related complications vary widely. In addition, certain BCCs pose more risk to the patient than others, and are poor candidates for certain forms of treatment. An important part of the initial evaluation is to identify "higher risk" tumors that require more aggressive therapy to minimize recurrence risk. INITIAL EVALUATION The preoperative evaluation should be directed toward identifying patient-related factors that may impact the choice of treatment. The patient's medical history, medications, drug allergies, prior operations, treatment preferences, and social (or living) arrangements should be reviewed. Patients with poor general health or functional status are unlikely to manage the wound care required following cryosurgery of a BCC on the leg or back without assistance. Likewise, a twice daily application of 5-FU cream to these areas is probably not feasible. These treatment options would be poor choices compared to simple excision or electrosurgery, particularly if the patient lives alone and has a poor social support system. Likewise, such patients frequently do not tolerate a prolonged surgical procedure, especially if it requires conscious sedation or general anesthesia. Other patient-related factors that could modify the choice of treatment include:
Another important but often underappreciated issue in selecting appropriate treatment is patient expectations. As an example, patients who do not expect or accept the residual pigmentary changes that typically follow cryosurgery and electrocautery may be better served by a different procedure. Identification of high-risk tumors � Fortunately, most patients do not have complicating medical conditions, and treatment choice is based upon tumor characteristics and/or physician-related factors. Some BCCs are of relatively more aggressive histologic types, with a higher risk of incomplete clearance with subsequent local recurrence, or their location may pose a risk to cosmetic or critical structures. Improper treatment of these "high-risk" BCCs may lead to inadequate resection, and the risk of subsequent recurrence with its potentially devastating consequences. Inappropriate treatment selection may also lead to unacceptable but potentially avoidable disfigurement or damage to critical structures such as the eyelid, lips, nose, or face. Several clinical and histologic features have been identified that portend a more aggressive and problematic course. Tumor location Tumors that present on or near critical structures or cosmetically-sensitive areas pose special concern for several reasons:
Size In determining size, both visual inspection and palpation are necessary to determine the extent of dermal and subcutaneous lateral and deep growth. Tumor size directly correlates with the risk of inadequate tumor clearance and subsequent recurrence; larger tumors tend to have more extensive subclinical growth, and require wider margins for adequate clearance. Destructive techniques are less likely to clear such tumors, but even surgical excision, with or without intraoperative margin control, is more likely to fail in achieving negative margins. Large tumors are better served by margin-controlled methods, such as excision with intraoperative frozen section analysis, or Mohs surgery. Electrosurgery, cryosurgery, topical chemotherapy, and RT are unlikely to achieve cure, and may give way to a later recurrence with more widespread disease. Although there are no precisely defined limits, most clinicians consider the following to represent "high-risk" tumors:
Other tumor features BCCs with indistinct clinical margins, recurrent BCCs, and those arising within prior RT fields typically have deeper subclinical extensions, are potentially more destructive, and pose greater difficulty in obtaining tumor-free margins and minimizing disfigurement. Treatment of these high-risk BCCs should include a margin-controlled modality such as excision with intraoperative frozen-sections, or ideally Mohs micrographic surgery (see below). Several histologic features may indicate a more aggressive, difficult to cure lesion. Since this information is critically important in the management of BCCs, all pathology reports should include a description of the growth pattern (or histologic subtype), and indicate the presence of perineural spread or basosquamous differentiation. BCCs with a morpheaform (sclerosing), infiltrative, micronodular or mixed growth pattern, perineural invasion, or basosquamous differentiation tend to have wider subclinical extension and, therefore, are more difficult to eradicate. In addition, BCCs with basosquamous features are thought by many to behave in a pattern intermediate between BCCs and squamous cell carcinomas, with a greater risk of metastatic spread. Once these features are known, a treatment plan can be formulated. The presence of high-risk features warrants consideration of a margin-controlled technique to optimize the opportunity for cure, unless the patient is unable to tolerate such a procedure. Non-margin-controlled destructive techniques (eg, electrosurgery, cryosurgery, RT, or topical chemotherapy) should be discouraged in the treatment of such lesions. The lack of any high-risk features permits greater flexibility in designing the treatment plan. TREATMENT A variety of treatment options are available for the treatment of BCCs. Choosing the "right" treatment for an individual patient depends not only on tumor and patient characteristics, but also features unique to the treatment modalities. Each differs in terms of cost, cure and recurrence rates, and morbidity, which includes wound care, and cosmetic and functional disfigurement. Different modalities may also be utilized to varying degrees depending upon the treating physician. As an example, generalists and surgeons are more likely than dermatologists to utilize surgical excision (with or without frozen section margin control) for BCCs rather than electrosurgery, cryosurgery, RT, or topical 5-FU. In general, recurrence rates are based upon literature reviews. However, many of these studies are retrospective and suffer from selection bias, poor patient follow-up and reporting, and incomplete descriptions of the treatment protocol. This compromises both the quality and generalizability of this information. Most of the available randomized trials have looked predominantly at BCCs in low-risk areas . However, at least one large prospective trial comparing standard surgical excision versus Moh's micrographic surgery for BCCs involving the face has been reported; follow-up of this trial is limited, and five-year recurrence rates are not yet available. Despite these shortcomings, some general conclusions can be drawn from the available data. Primary BCCs are more easily cured than are recurrent tumors . Expected cure rates for primary BCCs with all techniques are 90 percent or better, while the five-year cure rates for recurrent BCCs vary considerably. In one series of 5755 BCCs managed by several different modalities, the five year recurrence rates for recurrent lesions were significantly higher than primary lesions,15.4 versus 10.6 percent, respectively. These data underscore the classification of recurrent BCCs as high-risk tumors, and the necessity of more aggressive therapy, particularly a margin-controlled technique such as Mohs surgery for optimal treatment. Cryosurgery The fundamental principle of cryosurgery is to bulk freeze the tumor, thereby causing death of the malignant cells. Cytotoxicity results from several effects, including the formation of extracellular and intracellular ice crystals, hypertonic damage, disruption of the cellular phospholipid membrane, and vascular damage through vascular stasis . Cryosurgery is a widely accepted therapeutic modality for BCC that is rapid, cost effective, requires minimal anesthesia, and has few disadvantages or contraindications. Cure rates for primary BCCs as high as 97 to 99 percent are reported, and cosmetic results are generally excellent Many of the studies reporting such high cure rates and beneficial cosmetic results suffer from selection bias, and/or poor follow-up. The reported results actually vary widely. As an example, in a trial of 88 patients who were randomly assigned to photodynamic therapy (PDT) or cryosurgery, the cryosurgery group had a 15 percent recurrence rate. In a second report, the cosmetic results following excision of BCC involving the head and neck were considered better than the cosmetic results after cryotherapy. Successful cryosurgical treatment is dependent upon physician skill and proper tumor selection. Mastering cryosurgical techniques can be difficult given the number of variables including the method of application (spray versus cryoprobe), freeze time, thaw time, lateral extent of freezing (halo), halo thaw time, the number of freeze-thaw cycles, and the temperature at the tumor base (as measured by thermocouples) that is necessary to effect cure. For these reasons, five-year recurrence rates are believed to be approximately 8 and 13 percent for primary and recurrent BCCs, respectively. Technique Of the several techniques for performing cryosurgery, the open spray method is the most widely used . Liquid nitrogen under pressure in a closed container is released as a spray from a small opening in the spray tip. Held at a distance of 5 to 10 mm, the tumor is sprayed until it and a rim of normal tissue (the size of which is determined by tumor size, type, and location) is frozen (freeze time). The tissues are then allowed to thaw unaided (thaw time), and in most cases the tissues are refrozen to complete two freeze-thaw cycles. Thaw times between two and four minutes are generally desired. Although two freeze-thaw cycles are thought to be required to cure most tumors, high cure rates (and a better cosmetic outcome) have been reported with a single freeze-thaw cycle for selected superficial BCCs. Some clinicians anesthetize the area to be treated with lidocaine with or without epinephrine. The use of epinephrine is a matter of controversy since it may increase further the extent of cryosurgical damage, resulting in a larger wound with more extensive destruction. If epinephrine is used, alterations in the freeze time, thaw time, and number of freeze-thaw cycles may be warranted. Curettage and electrodessication Curettage and electrodessication (C&D), sometimes referred to as electrosurgery, is practiced nearly exclusively by dermatologists. C&D has an important but limited role in the treatment of BCCs, primarily for low-risk lesions such as superficial and nodular BCCs on the trunk and extremities. In such selected cases, C&D can achieve cure rates as high as 99 percent . In a large review of 2980 BCCs treated with C&D between 1955 and 1982, the overall five-year recurrence rate was 13.2 percent for primary BCCs, and 18.1 percent for recurrent BCCs . Stratified by anatomic site, the five-year recurrence rates for C&D of 2314 primary BCCs were as follows:
Further subgroup analysis showed statistically significantly lower five-year recurrence rates for C&D of 521 primary BCCs treated between 1973 and 1982:
Such high cure rates resulted from a combination of factors including selection bias, the greater use of Mohs micrographic surgery (and less C&D) for treating tumors located in high-risk sites, and by the development of "greater skill" in the C&D procedure by the treating provider. Therefore, with proper lesion selection and operator skill, C&D is capable of superior cure rates. In some other series, recurrence rates for BCCs that have high-risk histologic or clinical features can be as high as 43 percent, depending upon the tumor location . Five-year recurrence rates are considerably higher for recurrent BCCs, particularly those in high-risk areas . There are few contraindications to electrosurgery. BCCs located in the mid-face, including the midnose, nasal alae and sulci, medial canthi, and nasolabial folds should not be treated by C&D unless they are small, well demarcated, and the cosmetic result is of no consequence to the patient. These areas are formed through the union of several embryologic fusion planes, and offer little resistance to the invasion of cancerous islands . Many of these tumor buds are beyond the reach of the curette. Following inadequate treatment, the skin heals (usually by secondary intent) burying the residual tumor inconspicuously beneath the scar. By the time the tumor becomes clinically obvious it can grow to massive size and present an extremely problematic treatment dilemma. Instead, BCCs located in these areas are best treated by excision or Mohs surgery. The major advantage of C&D is its ease, rapidity, lesser cost, and tolerance compared to other treatment modalities. The major disadvantages are the considerable experience required to achieve consistently low recurrence rates, its limited scope of applicability (primarily truncal and extremity tumors), and the resulting hypopigmented scar that is cosmetically undesirable in visibly noticeable areas. An unpleasant smell of smoke is produced during the procedure. Otherwise, it is reasonably well tolerated. Minor, harmless electrical shocks are common, and most often occur in improperly grounded patients who inadvertently touch metal on the treatment table. Rarely, untoward events can occur during electrosurgery; these include unintentional burns, inadvertent fires usually caused by the careless use of alcohol during the procedure, interference with cardiac pacemakers, and life-threatening (very rare) electrical shocks. There is the potential for explosions in the presence of flammable anesthetic agents, oxygen, or colonic gas. In addition, infectious diseases can be transmitted if unclean electrode tips are used. Technique Several techniques are available, a fact that undoubtedly has contributed to the widely varying cure rates of C&D. C&D is a relatively easy technique to learn and cure rates improve as supervised experience is gained. The most common method employs three repetitions of "heavy-handed" curetting followed by electrodessication. First the area is cleaned with alcohol, chlorhexidine, iodine, or normal saline, and local anesthesia is applied. Importantly, care must be exercised in using alcohol at all times during electrosurgery as the two together are combustible. Using a small- to medium-sized curette, the lesion is curetted vigorously in four directions, 90 degrees apart. The use of using progressively smaller curettes is advocated by some to remove smaller tumor extensions. Subsequently, the area is electrodessicated, and the cycle repeated two more times. During treatment, extension of the curette 3 to 4 mm beyond the clinically obvious tumor margins is advised to remove subclinical outgrowths. If at any time during the procedure the curette drops through the dermis into the underlying fat, the procedure should be abandoned in favor of an excision as the important "feel" of both the tumor and dermis that guides electrosurgery has been lost. Wound care generally includes cleansing the area daily with soap and water, hydrogen peroxide, or other cleanser, applying topical antibiotics, and covering the area with a bandage. Pain is usually minimal and easily controlled with acetaminophen or other over-the-counter analgesics. In the lower extremities, swelling may accompany the wound, and can usually be adequately managed using an compression bandage or support hose. Surgical excision Surgical excision is an effective, time-tested treatment method for BCCs. Although useful for treating most tumors, it is best utilized for small BCCs that are located on lower risk areas of the head and neck, trunk, and extremities, and lacking aggressive histologic features. Under these circumstances, 4 to 5 mm margins are generally recommended, and five-year cure rates exceeding 95 percent can be expected. These rates are lower for higher risk BCCs. Five-year cure rates for recurrent tumors are 83 percent, and for primary lesions >15, >20 or over 30 mm in diameter, they are 88, 83, and 77 percent, respectively. Reported cure rates for tumors located on the lips, nose, paranasal or periocular region, ears, and scalp range from 57 to 82 percent. These data are derived predominantly from retrospective series. Lower recurrence rates were reported in a prospective trial in which 612 facial BCCs (408 primary, 204 recurrent) were randomly assigned to standard surgical excision or Moh's micrographic surgery . Although follow-up was short (median 30 months), the recurrence rates with surgical excision for primary (n = 102) and recurrent (n = 102) tumors were 3 and 8 percent, respectively. This trial is discussed in more detail below BCCs with aggressive histologic features have a greater propensity for asymmetric, subclinical extension. For this reason, recurrence rates are higher unless wider margins of normal tissue are taken. Cure rates for these higher risk BCCs can be improved substantially through the use of intraoperative margin evaluation (frozen sections) or Mohs micrographic surgery. There are several advantage of excision over other therapies: it can be performed faster than Mohs surgery, it is relatively inexpensive if frozen section are not required, healing is complete within one to two weeks depending upon the site, and the adequacy of the resection margin can be assessed. Excision is typically performed in an outpatient setting under local anesthesia and is therefore usually well tolerated. Excision is generally suitable for BCCs involving all sites, and the long-term (beyond ten years) cosmetic and functional results are usually superior, particularly when compared to radiation therapy. As a result, it is particularly well suited to elderly patients. On occasion, regional or general anesthesia will be required, especially if the tumor is large or high-risk, or if excision is complicated; this will increase the time, risk, and cost of the procedure. Another advantage to excision is that repair of the surgical defect is usually accomplished immediately by suturing the wound edges together in a side-to-side fashion. This allows the majority of wound healing to be completed within one to two weeks. If primary closure is not possible, adjacent tissue flaps, skin grafts, or distant tissue flaps can be used, or healing can take place by secondary intention. Defects involving cartilaginous structures such as the nose or ear frequently require composite grafts harvested from the opposite ear or ribs. The type of closure depends upon several factors including the size, depth, and location of the defect, the availability and laxity of nearby tissue, and patient and physician preference. Disadvantages of surgical excision include:
Nevertheless, simple excision is a widely practiced and useful treatment modality for BCCs. It is usually reserved for smaller (<2 cm), well-defined, primary BCCs that lack aggressive, high-risk features. On the other hand, treatment of larger, higher risk tumors is better accomplished using either excision with intraoperative frozen section margin evaluation or Mohs micrographic surgery [7] . In addition, simple excision remains a valuable tool for patients with high-risk BCCs who refuse or are unable to tolerate the prolonged nature of Mohs surgery, or are unable/unwilling to undergo the risk and prolonged nature of intraoperative frozen section-controlled excision (typically done under general anesthesia). However, in this situation appropriately larger margins are warranted. Mohs micrographic surgery Mohs micrographic surgery (MMS) is the preferred treatment for many high-risk skin cancers, including basal cell cancers (BCCs). MMS results in five-year cure rates of about 98 to 99 percent for primary BCCs and 95 percent for more difficult recurrent BCCs. It can be used for treating BCCs located on any site including the ears, nose and paranasal structures, lips, eyelids, fingers and nail beds, and genitalia. Technique MMS is performed by the dermatologist in the outpatient setting under local anesthesia and is generally well-tolerated. The tumor, together with a small rim of clinically normal-appearing tissue, is excised at an oblique angle in a series of stages, and microscopically evaluated by the surgeon. Histologic findings are then precisely correlated with the lesion through the use of a diagram (Mohs map) drawn by the surgeon following the stepwise excision of the tumor. If microscopic margins are positive, their precise locations are noted on the Mohs map and another specimen is taken only from areas involved with tumor. This tissue is evaluated in a similar fashion, and the process is repeated until all margins are negative. By excising the specimen at an oblique angle, MMS allows histologic evaluation of 100 percent of the peripheral margin. In contrast, routine histologic processing of a standard surgical excision specimen permits evaluation of less than 1 percent of the tumor margins. This clinicopathologic correlation during surgery is responsible for the improved cure rates with Mohs surgery. Following complete resection of the tumor, the defect is either closed immediately (using either a primary side-to-side closure, local flap, graft, or more rarely a distant flap) or allowed to heal secondarily, depending upon the details of the individual case. Closure can be performed either by the Mohs surgeon or coordinated with another surgeon (eg, plastic or oculoplastic surgeon) if necessary. Advantages and disadvantages The primary benefit of MMS is the precision with which tumors can be excised, resulting in excellent long-term cure rates, even for high-risk tumors. A second advantage is the sparing of normal tissue, often allowing preservation of vital structures and simplifying repair of the surgical wound, thereby improving the cosmetic results. Because most surgical defects are repaired immediately, wound care is generally complete within two weeks. In addition, potential complications associated with sedation and general anesthesia are avoided since MMS is performed under local anesthesia. MMS was compared to standard surgical excision in a prospective, randomized trial that included 612 facial BCCs (408 primary, 204 recurrent) . With an average follow-up of 30 months for primary tumors and 24 months for recurrent BCCs, the difference in the rate of local recurrence was not statistically significant different for primary (2 versus 3 percent, with standard surgical excision) or recurrent BCCs (2 versus 8 percent). However, 18 percent of the primary tumors, and 32 percent of recurrent tumors were incompletely excised with standard surgical excision, and the subsequent larger defects in this group were associated with worse cosmetic outcomes. Risk factors for incomplete excision included aggressive histology, all high-risk locations except lips and preauricular area, and recurrent tumor. The disadvantages of MMS are the duration of the procedure and the cost. A typical procedure lasts two to four hours and more complicated cases can take longer. Reconstruction following MMS can add another hour to the procedure. A significant amount of the total time is spent with histologic preparation and analysis. During this time, patients are temporarily bandaged and may await the final results in a waiting room. Despite this, some patients find it difficult to tolerate a procedure of this length. MMS is significantly more expensive than standard surgical excision and whether MMS is cost-effective is controversial. One study concluded that MMS was cost-effective because of the much lower rates of local recurrence. In contrast, a subsequent analysis concluded that MMS was not cost effective , based upon the low rates of recurrence seen in the randomized trial. Rates of local recurrence may rise with additional follow-up, which could affect these conclusions. Indications MMS provides the highest cure rate of any technique for both primary and recurrent BCCs. However, MMS is indicated only for primary BCCs with high-risk features because of the comparable efficacy of other less invasive, less time-consuming, and less costly procedures for small primary BCCs located in low risk sites. MMS is also useful in cosmetically sensitive or functionally critical areas (eg, periocular, periauricular, or perioral areas, nose and perinasal areas, lips, or ears) . All recurrent BCCs, especially those located in high-risk sites, are potential candidates for MMS. Each patient requires individual assessment, since some cases that might have a strong indication for MMS may be better served by other modalities. Radiation therapy RT is an important option for the treatment of both primary and recurrent BCCs. Most large series report overall five-year cure rates of 91 to 93 percent for primary (untreated) BCCs, with rates as high as 96 percent for smaller, lower risk primary BCCs . In contrast, cure rates are between 86 and 91 percent for recurrent BCCs . Contrary to early reports suggesting a poor outcome for larger or more deeply invasive tumors (ie, those invading cartilage, bone, and/or muscle) with RT alone, series using modern radiation techniques suggest excellent control rates with good cosmesis and functional outcomes. In several reports, three to five-year locoregional control rates are 86 to 91 percent for large and/or locally advanced BCCs with RT. RT is particularly useful for patients who are unable to tolerate outpatient surgery and very elderly patients (life expectancy <15 years) with large tumors, in whom long-term adverse effects are of lesser concern. Technique and indications � RT is usually administered in a fractionated schedule, requiring multiple (four or more) treatments. Although fractionation limits treatment-related side effects in normal tissues, the frequent visits are problematic for many patients. Other major drawbacks include the lack of histologic margin control, the relatively high cost compared to other modalities, and the short- and long-term side effects associated with RT (see below). In addition, BCCs that recur following RT may behave more aggressively than those recurring after surgical procedures, with higher rates of second recurrence and distant metastasis. RT is generally avoided for tumors located on the trunk and extremities because of their greater tendency to develop later pigmentary changes and telangiectasias. Furthermore, because these areas are subjected to greater trauma and tension than skin on the head and neck, they are more prone to break down and ulcerate as a result of the atrophy and poor vascularity of irradiated tissue. RT of cartilaginous and bony structures such as the ear and nose may result in chondroradionecrosis or osteoradionecrosis, although this is uncommon using modern techniques. The major advantages of RT are the relative sparing of cosmetically and functionally important structures, its noninvasive and painless nature, and its utility for many patients who are not candidates for surgical intervention, or who have incompletely excised tumors. The sparing of normal healthy tissue can offer superior cosmetic results for tumors located on or around the lips, nose, and eyelids. However, these beneficial cosmetic results may deteriorate with time. For this reason, and because of the potential for treatment-related cancers, RT is generally avoided in patients younger than 40 to 50 years of age (see below). RT should be considered a treatment of last resort for previously irradiated recurrent BCCs , and should never be used in patients with basal cell nevus syndrome (BCNS) where hundreds of difficult to manage skin cancers may be induced by such therapy. Complications RT is associated with both short- and long-term complications. Short-term cutaneous side effects include erythema and edema, scaling, vesicles, bullae, erosions, ulceration, pain, and occasionally infection. Healing generally occurs within three to four weeks following the final treatment, but symptoms may persist for months in severe cases. Other less common short-term side effects include a "comedo reaction", which is a benign condition characterized by the appearance of large, open comedones at the periphery of the treated area in certain sites (nose, cheeks, ears), the appearance of pseudorecidives (keratosis-like nodules that develop within the irradiated field immediately following treatment), the shedding of nails, and even more rarely, gangrene. Pseudorecidives generally develop several weeks following treatment and resolve spontaneously several months later without long-term sequelae. Because of their appearance and location, they are often difficult to distinguish from local recurrence; diagnostic biopsy may be indicated . Long-term sequelae from RT include cataracts, chronic radiation dermatitis, delayed radiation necrosis, permanent alopecia within the radiation field, secondary cutaneous malignancies, thyroid cancer, and infertility. While some of these complications are common, predictable, and generally unavoidable (eg, chronic radiodermatitis and alopecia), others (eg, cataracts, infertility, and thyroid cancer) are uncommon but predictable, and can be avoided with proper shielding. At doses used to treat cutaneous malignancies, permanent alopecia usually occurs within the treatment field; pretreatment counseling is essential. Chronic radiodermatitis generally appears months to years following therapy and is characterized by permanently mottled areas of hypo- and hyperpigmentation, dry, hyperkeratotic, atrophic, shiny epidermis, telangiectasias, and dermal fibrosis. Although severe dermal and subcutaneous fibrosis is an uncommon consequence of RT for cutaneous malignancies, some data suggests possible therapeutic benefit for pentoxifylline with or without vitamin E Delayed radiation necrosis may develop months to years following RT, and is marked by spontaneous breakdown of the skin within the irradiated field, with erythema, erosions or ulcerations, crusting, and discomfort. It is usually precipitated by trauma, infection, or exposure to cold or sunshine and is secondary to poor vascularity and atrophy of the previously irradiated area. Radiation-induced cutaneous malignancies (both BCCs and squamous cell cancers) most often develop within irradiated sites that are also exposed to solar radiation (eg, the head, neck, and upper extremities). These secondary cancers may occur from 5 to 65 years following RT, and are thought to behave aggressively. They have a higher likelihood of subclinical extension, and in the case of radiation-induced SCCs, a greater risk of metastases and death. Other more rarely associated secondary malignancies include fibrosarcomas and melanomas. Risk factors for secondary cancers after RT include higher radiation doses, larger radiation fields, sun-exposed sites, fair-skin, and early age of radiation exposure. On the other hand, increased fractionation and smaller dose per fraction can reduce this risk. In fact, some investigators feel that the true risk of radiation-induced cutaneous malignancy is much smaller using modern treatment protocols. Nevertheless, RT continues to be avoided in young people, and in those with any genetic susceptibility to radiation-induced malignancies . Topical chemotherapy � Although several topical therapies are available for the treatment of BCC, only 5-FU is approved by the United States Food and Drug Administration (FDA). The long-term efficacy of other topical treatments, including imiquimod (Aldara®), photodynamic therapy, and tazarotene gel (Tazorac® ) has not been proven, and their use should be restricted to investigational study. 5-Fluorouracil 5-FU interferes with DNA synthesis through inhibition of thymidylate synthetase; rapidly proliferating cells are most sensitive to its cytotoxic effect. Topical 5-FU is available as a 1 percent cream or solution, as a 2 or 5 percent cream, and in a 5 percent solution. Although more concentrated topical formulations and sustained-release intralesional preparations have been tested, they are neither standardized nor FDA-approved. Extensive experience with topical 5-FU over the past 40 years indicates that its role is largely confined to superficial BCCs(SBCC) in noncritical locations . For properly selected SBCCs, topical application of 5 percent FU cream can achieve cure rates of up to 95 percent, although lower rates are reported by others. 5-FU is particularly useful in the management of patients with basal cell nevus syndrome (Gorlin's syndrome) who develop numerous BCCs at a young age. (See "Nevoid basal cell carcinoma syndrome"). Treatment of non-superficial, recurrent, and other high-risk BCCs with 5-FU results in low cure rates. Furthermore, topical treatment can give the false impression of a cure despite persistent dermal disease. For this reason, nodular and high-risk BCCs are generally considered contraindications to topical 5-FU. One small pilot study suggests that application of 5-FU using a phosphatidyl choline-based rather than a petrolatum-based cream may increase transepidermal absorption, leading to improved cure rates. Such a preparation is not yet commercially available. Topical 5-FU should be applied as a 5 percent formulation twice daily for at least three to six weeks, and often for 10 or more weeks depending upon the clinical response. An adequate therapeutic response to topical 5-FU depends upon the 5-FU concentration and vehicle, the frequency of application, the use of an occlusive dressing, clinical and histologic tumor features, the patient's complexion, and the degree of sun exposure before and during treatment. The major disadvantage to using topical 5-FU is the brisk inflammatory reaction that develops in treated sites during therapy. Prior to treatment, patients should be thoroughly educated on anticipated side effects, including stinging, burning, pain, erythema, edema, erosions and ulceration with serous oozing, and possibly secondary infections. At times, the discomfort can be significant enough to prompt a temporary or permanent discontinuation of therapy, and it is not uncommon for patients to become virtual social recluses during treatment because of the undesirable cosmetic effects. Special care should be taken when applying 5-FU to areas near the eyes, lips, and nose because of increased sensitivity of these areas. In addition, patients should avoid intense sun exposure during treatment. Following discontinuation of 5-FU, healing generally takes place over the ensuing two or more weeks, leaving residual erythema and occasional hyperpigmentation, which usually fades with time. In general, long-term favorable cosmetic results are one of the advantages of topical 5-FU over other treatment modalities. If intense inflammatory reactions occur, these can be ameliorated by temporary discontinuation of therapy, reduction of drug concentration, application of an emollient (chilled vaseline or hydrated petrolatum), and/or application of an intermediate potency topical steroid. The inflammatory reaction is an indication of the efficacy of topical 5-FU; its absence should prompt a change in the treatment regimen. This can include either increasing the concentration of the medication, increasing the frequency of application, applying it under occlusion, applying it in conjunction with a topical keratolytic agent (salicylic acid, lactic acid, ammonium lactate) or retinoic acid, or changing to a different treatment modality altogether. Other disadvantages to topical 5-FU include its limitation to treatment of low-risk superficial BCCs, occasionally significant post-treatment pigmentary changes, rare cases of allergic contact dermatitis to 5-FU or its vehicle, treatment-associated photosensitivity, and the unfortunate tendency for topical 5-FU to conceal deeper residual tumor nests in improperly selected or incompletely treated cases. This latter point underscores the need to closely monitor these patients for signs or symptoms of recurrence, and to have a low threshold for biopsy of such areas. Other unusual side-effects include temporary reversible onycholysis and onychodystrophy, persistent telangiectasias, hypertrophic scarring in high-risk areas, bullous pemphigoid, cardiac ischemia, and life-threatening systemic toxicity in the rare patient with an inherited deficiency in the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD) Imiquimod Imiquimod is a novel immune response modifier that is FDA-approved for the treatment of external anogenital warts. (See "Condylomata acuminata (anogenital warts)"). It is thought to promote apoptosis in skin cancer cells by circumventing the anti-apoptotic mechanisms that are developed by tumor cells, and/or by stimulating monocytes/macrophages and dendritic cells to produce cytokines that stimulate cell-mediated immunity. Experience over the past several years with topical imiquimod for treatment of low-risk primary superficial BCC is encouraging. In early trials, histologically-confirmed cure rates approaching 90 percent or better were seen with once daily application for 6 to 12 weeks. Higher cure rates are possible for primary BCCs with twice daily treatment, but localized reactions can be severe and are limiting. Cure rates fall off dramatically with less frequent dosing. The efficacy of topical imiquimod was shown in two identical multicenter placebo-controlled trials in which a total of 724 subjects with superficial BCC were randomly assigned to imiquimod once daily five or seven times weekly for six weeks, or topical application of vehicle alone. The lesion site was clinically examined 12 weeks posttreatment, and then excised for histologic evaluation. When data from both studies were pooled, the histologic clearance rates for the five and seven day treatment groups were 82 and 79 percent, respectively, compared to 3 percent in the vehicle-treated group. The severity of erythema, erosion and scabbing/crusting was associated with higher clearance rates. Long-term follow-up was not reported. Treatment of nodular BCCs, however, is less successful, with cure rates closer to 70 to 75 percent following 6 to 12 weeks of once daily dosing, and 65 percent with less frequent dosing. The application of an occlusive dressing seems to offer minimal improvement in cure rates. Sporadic case reports are also emerging that suggest a possible role for imiquimod cream as adjunctive therapy in the management of patients with basal cell nevus syndrome and xeroderma pigmentosum. These patients are predisposed to developing numerous skin cancers � BCCs among them � and can be quite difficult to manage. In this setting, topical treatment of primary early, small, or superficial BCCs can be a valuable asset. Imiquimod was approved for treatment of superficial BCCs in low-risk sites in July, 2004. Topical treatment can be associated with systemic effects, including fatigue and an influenza-like illness. Exfoliative dermatitis and angioedema have also been reported. Summary Until more experience is accumulated, particularly with regard to long-term recurrence rates, imiquimod use should be reserved for the treatment of primary superficial BCCs in low-risk sites, where recurrence is unlikely to be accompanied by substantial morbidity, or in patients who are poor surgical candidates and/or have a limited life expectancy. In these settings, twice daily regimens are clearly favored, but poorly tolerated. Once daily regimens provide acceptably high cure rates with fewer side-effect. Patients should be informed that this use is a non-FDA approved indication for imiquimod and that there is limited knowledge concerning long term effects and recurrence rates. Photodynamic therapy Photodynamic therapy (PDT) combines three otherwise innocuous elements (oxygen, light, and a porphyrin) to activate reactive oxygen species within targeted tissues, resulting in selective tumor destruction. The photosensitizing porphyrin is applied either topically to the lesion (Levulan kerastick®, 5-aminolevulinic acid hydrochloride; methyl aminolevulinate, Metvix® [94] ), or administered systemically (Photofrin®, porfimer sodium), where it is taken up by both normal and abnormal tissue. The topical formulation is generally preferred for basal cell cancers (BCCs), given the prolonged photosensitivity associated with systemic therapy. Several hours following application of the porphyrin, the area is exposed to visible light, usually in the 630 to 635 nanometer range. This light, which penetrates the first 5 to 6 mm of skin, is selectively absorbed by the photosensitizer where it is activated to a highly unstable and reactive singlet state. These reactive oxygen species cause lipid peroxidation, protein crosslinking, increased membrane permeability, and ultimately cell death. In addition, there are direct effects on blood vessels resulting in impaired blood flow, and stimulation of a vigorous local inflammatory reaction that also promote tumor destruction . The tumor selectivity of PDT is based upon both a higher concentration and half-life of porphyrins within the cancerous cells. PDT is only approved by the United States Food and Drug Administration for the treatment of actinic keratoses and for treatment of high grade dysplasia in the setting of Barrett's esophagus. Nevertheless, multiple studies have evaluated its use for the treatment of BCC. Initial response rates have been encouraging for primary superficial BCCs, but follow-up is short in many of these studies. Response rates range from 50 to 100 percent for systemic PDT, and from 82 to 100 percent for topical application . Much lower response rates (10 to 50 percent) have been noted with pigmented BCCs, and for larger, thicker, or sclerotic lesions, such as nodular and morpheaform BCCs. This is probably because topical ALA penetrates poorly and inhomogeneously into such tissues, and for pigmented lesions, melanin absorbs the photoactivating light The comparative efficacy of PDT and surgery was evaluated in a controlled trial of 101 adults with previously untreated nodular BCCs without high-risk features who were randomly assigned to PDT with topical ALA (photoactivating light applied twice, seven days apart) or surgical excision . Thirteen patients with an incomplete response to PDT at three months were retreated. At 12 months, 50 of 52 surgically treated lesions were recurrence-free, compared to 44 of 53 PDT-treated lesions (96 versus 83 percent). By 24 months, five more lesions that initially cleared with PDT had recurred, compared to only one excised lesion. Although the risk of local recurrence was higher with PDT than surgery, the cosmetic result was significantly superior at both 12 and 24 months. Several maneuvers have been evaluated to enhance penetration and ultimately improve efficacy of PDT. These include multiple treatment sessions, combining ALA with dimethylsulfoxide (DMSO), hyperthermia, or deferoxamine, extending the ALA application time, occlusive treatment, combining ALA with curettage of the lesion, and administering ALA by intralesional rather than topical application. Such maneuvers have resulted in higher response rates of between 77 and 100 percent for thinner (<2 mm), nonsclerotic lesions. Although most researchers document short-term recurrence rates between 2 and 9 percent, long-term recurrence rates are unclear. At least one trial suggests that complete responses are durable . A combination of curettage and PDT with ALA and DMSO was used for 119 nodular BCCs 2 mm in thickness, and 113 (95 percent) remained in complete remission from 12 to 26 months following treatment (mean 17 months). Side-effects from PDT include prolonged photosensitivity (up to six weeks with systemic treatment), local pain and burning, erythema, edema, ulceration, and temporary pigmentary change at the treated site. Healing is usually complete within two weeks, and scarring is unusual. The generalized photosensitivity from systemic PDT is not ameliorated through the use of sunscreens. Other complications of systemic therapy include hyperthermia, muscle stiffness, nausea, vomiting, diarrhea, heartburn, headache, dizziness, and occasionally, hepatotoxicity. Rarely, allergic reactions to the vehicle or the porphyrin component may occur. Caution must be exercised in patients with known photosensitivity disorders (eg, SLE, porphyria), since exacerbations may occur. The greatest therapeutic promise for PDT appears to lie in its use for superficial BCCs, especially those that are either large, numerous, or not amenable to other forms of surgical therapy. However, until studies are completed that address not only the long-term recurrence rate, but also the potential long-term carcinogenic effects, PDT should be considered investigational for the treatment of BCCs. Interferon � Both interferon alpha 2b (IFN-a) and IFN gamma (IFN-g), have been injected intralesionally into superficial and nodular BCCs. While IFN-g seems to lack efficacy, IFN-a has been associated with complete clinical and histologic response rates of 80 to 100 percent Thrice weekly injections of high dose (1.5 million IU per injection) IFN for at least three weeks are necessary to achieve response rates 80 percent. In the only placebo-controlled trial, the one year local recurrence rate was 19 percent, prompting some to dismiss the therapy in favor of other more effective modalities . The failure rate for aggressive BCCs treated with intralesional IFN-a may be as high as 73 percent. Side-effects of intralesional IFN-a include local edema, discomfort, and erythema, as well as systemic flu-like symptoms, which can be severe, and necessitate treatment discontinuation. Particular caution is warranted in elderly patients due to potential electrolyte, cardiovascular, and neurologic side-effects. Furthermore, compared to other more treatments for BCC, intralesional IFN is costly. As a result of all of these issues, intralesional IFN-a is not very promising, and should be viewed as an investigational agent only. POSTTREATMENT FOLLOWUP Close follow-up should be maintained following treatment to detect local recurrences and new skin cancers, and to assess post-treatment effects. Most dermatologists recommend reevaluation every 6 months for the first year following surgery, and then yearly for two or three years. In the absence of recurrent tumor or new acinic keratoses, further follow-up should be "as needed." Detection of local recurrence Approximately 50 percent of recurrences will become apparent within the first two years, two-thirds within three years, 80 percent within five years, and roughly 20 percent between five and ten years following treatment of an initial BCC. Periodic evaluation for local recurrence should include not only visual inspection but also palpation of the skin and adjacent structures to determine the presence of deeper recurrences. Patients should be asked about any visible, textural, or sensory changes of the treated area, and any suspicious or questionable areas confirmed histologically with a biopsy. For suspected deeper recurrences, it is important that a deeper punch biopsy (or multiple punch biopsies) be attained. New primary skin cancers Patients who develop a BCC are at greater risk of developing other skin cancers, including more aggressive and potentially life-threatening squamous cell carcinomas (SCCs) and melanomas. The risk of subsequently developing a SCC is believed to be between 5 and 10 percent while the risk of developing melanoma is two to fourfold greater than the general population. Approximately 20 percent of patients with one BCC subsequently develop a separate primary BCC within one year, and roughly 40 percent develop a new BCC within the first five years of their original tumor . This risk increases further for patients with more than one previous BCC, and is especially high in fair-skinned individuals. Although the greatest risk is within the first two years, at least one study suggests that annual risk remains high throughout five years, at ten to twelve times the rate expected in the general population (ie, 10 to 12 percent versus 1 percent per year). Furthermore, only roughly one-fourth of these patients will self-detect their new BCCs, underscoring the importance of periodic full skin examinations by a medical practitioner. Earlier detection may discover tumors that are smaller, less aggressive, and at a lower risk of recurrence; as a result, a wider variety of treatment options may be available. Cosmetic and functional outcome of treatment � With time, the treated site will mature and change. An "ugly" scar may become less obvious with time. In contrast, other scars and repair-related defects are permanent, and may require more than reassurance and time to correct. Other treatment-related complications are more serious and may warrant early intervention. These include an ectropion, stenosis of the ear canal, transection of Stenson's or the lacrimal duct, and radiation-induced secondary cancers. In each of these cases, the treating physician should recognize, address, and treat these problems as they arise. Education regarding preventive measures for skin cancer � An important feature of follow-up in a patients with a skin cancer is education concerning modification of risk factors. Although the exact role of sun avoidance for BCC risk modification in adults is unclear, it seems prudent given our current knowledge to advocate moderate sun avoidance in patients with a history of skin cancer, especially in higher-risk, fairer-skinned patients. These recommendations generally include sun avoidance during peak hours (10 AM and 4 PM), applying a broad spectrum (both UVA and UVB) sunscreen of SPF 15 or greater thirty minutes prior to going out in the morning with frequently reapplication throughout the day depending upon their lifestyle, the use of sun protective clothing and sunglasses including a broad-brimmed hat, avoiding sun bathing and tanning salons, and practicing routine self-skin examinations at least every three months. (See "Primary prevention of melanoma"). SUMMARY BCCs are indolent tumors with a low metastatic potential. However, because of their potential for local tissue destruction and disfigurement, early curative treatment is the standard of care.
The long-term efficacy of other topical treatments, including imiquimod, photodynamic therapy, and tazarotene gel has not been proven, and their use should be restricted to investigational study.
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