1322 Practice of Oncology / Cancers of the Skin dome-shaped, or pedunculated papule, plaque, or nodule.77 It may the surface in a network of anastomoses of cords of cells in loose be difficult to distinguish clinically from amelanotic melanoma. connective tissue. The biologic behavior of the micronodular, infiltrating, and morpheaform (sclerosing) subtypes of BCC is more aggressive HISTOLOGY than that of the nodular and superficial forms. Infiltrative histology is seen in 15% to 20% of BCCs. Individual tumor islands manifest Histologic features defining BCC are aggregates of neoplastic small, irregular outlines with a spiky appearance that invade into basaloid cells stemming from the epidermis or the epithelium of and throughout the dermis. Palisading is characteristically absent. adnexal structures.75 Aggregates are organized as lobules, islands, The stroma is less myxoid than in the nodular form. In the mor- nests, or cords of cells that display an orderly arrangement of the ba- pheaform variant, small groups or cords of tumor cells often only saloid cell nuclei at the periphery, a palisading array. Occasionally, one to two cells in thickness infiltrate and dissect a dense, collag- central necrosis or cystic changes are seen within the tumor lob- enous stroma often parallel to the skin surface. Mixed histology is ules. Individual tumor cells have uniform, hyperchromatic, round frequently apparent in BCCs. Areas of follicular, sebaceous, ec- to oval nuclei. Mitotic figures are uncommon, but the presence of crine, or apocrine differentiation may also be seen in some BCCs. apoptotic cells and necrosis is frequently observed. Pleomorphic BCCs may contain focal areas of squamous differentiation, rang- variant of BCC shows tremendous variability of nuclear size and ing from individual dyskeratotic cells to keratin pearls. The term chromatism, as well as multiple mitoses and multinucleated giant basosquamous (metatypical) carcinoma denotes BCC with a pre- cells. A stromal retraction or clefting around the neoplastic aggre- dominance of mature, atypical keratinizing squamous component. gates is commonly seen in the dermis. An accumulation of mucin Biologic characteristics of a basosquamous carcinoma are more within and around the tumor lobules may be evident. similar to those of SCC with a possibility for metastasis. Histologic subtypes of BCC include nodular and micronod- The significance of histologic subtype lies in the correlation with ular, superficial, and infiltrative BCC (Fig. 92.6A,B). Nodular a tumor’s biologic aggressiveness. The infiltrative and micronodu- BCC accounts for approximately 50% of all histologic variants of lar types are the most likely to be incompletely removed by conven- BCCs and exhibits characteristic features as previously described. tional wide local excision (WLE). Rates of incomplete excision vary Superficial multifocal BCC accounts for approximately 15% from 5% to 17%.78 Incompletely excised infiltrative and micronod- of BCCs and is a broad lesion characterized by basophilic buds ular BCCs recur at rates of 33% to 39%. Recurrences after RT show extending from an atrophic epidermis into the papillary dermis. In a tendency toward infiltrative histology and squamous transforma- a two-dimensional view, tumor buds appear to be multifocal, but tion, and even recurrent BCC after excision or C&D may become upon three- dimensional imaging analysis they form a netlike pat- metatypical. Although historical reports in the literature suggested tern. Retraction artifact is present, as is peripheral palisading within that 60% of incompletely excised BCCs will not recur, none of the buds. FEP, which accounts for 1% of BCCs, is characterized these studies provided an appraisal of recurrence rates as a function by a polypoid lesion in which basaloid cells grow downward from of histologic subtype.68,69 In general, incompletely excised BCCs A B Figure 92.6 (A) Histology of nodular basal cell carcinoma (BCC). Nodular BCC is characterized by the presence of rounded tumor islands extending from the epidermis into the dermis. Peripheral palisading of nuclei is prominent, and surrounding retraction artifact may be present. (B) Histology of multifocal superficial BCC. Superficial BCC is characterized by basophilic buds extending from an atrophic epidermis into the papillary dermis. Retraction artifact is present, as is peripheral palisading within the buds. tahir99 - UnitedVRG Chapter 92 Cancer of the Skin 1323 should be removed completely, preferably by MMS, especially if were excluded. Imiquimod has been used off-label for the treat- they occur in anatomically critical areas such as the central zone of ment of nodular and infiltrative BCC.88,89 Although some studies the face, retroauricular sulcus, or periocular area. have shown favorable cure rates, imiquimod treatment of these tumors is generally not recommended as subclinical disease may persist and lead to late recurrence. TREATMENT The FDA-approved protocol for treating superficial BCC with topical 5-FU is twice-daily application for 3 to 6 weeks irrespective of Excisional surgery, MMS, and C&D have all been used to treat cir- tumor size or location. Longer treatment protocols with an average cumscribed, noninfiltrative BCCs. MMS is the treatment method 11 weeks are reported in the peer-reviewed literature. In a study of of choice for all recurrent and infiltrative BCCs, particularly if a 31 tumors treated twice daily for an average of 11 weeks, a 90% clear- tumor is located on the face.6,79 RT is best suited for poor surgical ance rate was observed histologically 3 weeks posttreatment.90 Topi- candidates and patients with extensive lesions not amenable to sur- cal PDT has also demonstrated efficacy in the treatment of BCC. gery.80,81 RT is not indicated for recurrent or morpheaform lesions Clearance rates for BCC using ALA or MAL PDT range from 76% and in patients with NBCCS. to 97% for superficial to 64% to 92% for nodular BCC after one C&D is frequently used by dermatologists in the treatment of to three treatments.26,28,91 Many studies of PDT for nodular BCC primary BCC. Knox82 noted cure rates as high as 98.3%. Kopf et involve curettage of the lesion prior to treatment, however, and it al.,83 in an earlier study, cited a significant difference in the cure is unclear if the response rate would be as successful without initial rates obtained between patients treated by private practitioners curettage. In a well-designed comparative trial, 601 patients with su- (94.3%) and those treated by trainees in the New York University perficial BCC were randomized to treatment with MAL PDT (two Skin and Cancer Unit (81.2%). This supports the premise that treatments given 1 week apart), imiquimod, or 5-FU according to C&D, although simple and cost-effective, is highly dependent FDA-approved protocols. Complete clinical remission at 1 year was on operator skill. Traditionally, it was recommended that the pro- found to be 72.8% for PDT, 83.4% for imiquimod (superior to PDT), cedure be repeated for three cycles, but histology, location, and and 80.1% for 5-FU (not statistically different from the other treat- behavior of the tumor should dictate the number of cycles. C&D ments). Patients treated with imiquimod or 5-FU were more likely should be reserved for small or superficial BCCs, not located on the to report bothersome local side effects of the treatment, however.92 midface, in patients who may not tolerate more extensive surgery. Historically, systemic therapy for BCC was limited to cytotoxic Surgical excision offers a unique advantage of histologic evalu- chemotherapy that was marginally effective as salvage therapy for ation of the excised specimen. It has been demonstrated that metastatic disease. Elucidation of the critical role of abnormal 4-mm margins are adequate for removal of BCC in 98% of cases hedgehog signaling in BCC, however, has led to development of of nonmorpheaform BCC of <2 cm in diameter.78 Extending the a novel class of molecularly targeted small molecule inhibitors of excision into subcutaneous fat generally is adequate for a small Smoothened, most notably vismodegib.74 Based on a seminal trial primary BCC. of 33 patients with metastatic BCC and 63 patients with locally OF ONCOLOGY PRACTICE MMS permits superior histologic verification of complete advanced BCC not amenable to surgical therapy, vismodegib was removal, allows maximum conservation of tissue, and remains approved (2012) for treatment of advanced BCC (either metastatic cost- effective as compared with traditional excisional surgery for or not amenable to surgery or radiation).73 With once daily oral NMSCs including BCCs.4,6 In a large study of treatment of primary dosing of 150 mg vismodegib, 30% of patients with metastatic BCC by Rowe et al.,84 MMS demonstrated a recurrence rate (RR) BCC and 43% of patients with locally advanced BCC had an of 1% over 5 years. This was superior to all other modalities, includ- objective response (at least 30% decrease in size of tumors), and ing excision (RR = 10%), C&D (RR = 7.7%), RT (RR = 8.7%), 21% of patients with locally advanced BCC had complete clinical and cryotherapy (RR = 7.5%). In a similar study of recurrent BCC, resolution of tumors. None of the patients with metastatic BCC treatment with MMS demonstrated a long-term RR of 5.6%.85 In had a complete response. Adverse events in the trial were com- that treatment group, MMS was superior to all other modalities, mon, including serious adverse events in 25% of patients and fatal including excision (RR = 17.4%), RT (RR = 9.8%), and C&D (RR adverse events in 7% of patients. Most common adverse events = 40%). MMS is the preferred treatment for morpheaform, recur- in this and other trials were muscle spasms, alopecia, dysgeusia rent, poorly delineated, high-risk, and incompletely removed BCC, leading to weight loss, fatigue, diarrhea, and hyponatremia, and and for those sites in which tissue conservation for function and cos- between 12% and 54% of patients discontinued therapy because mesis is imperative.