Summary: Basosquamous Differentiation

•Basosquamous cell carcinoma demonstrates histologic features of both BCC and squamous cell carcinoma (SCC).

•Histologically, basosquamous carcinoma is comprised of basaloid cells with peripheral palisading and stromal retraction along with the keratin pearls and the more eosinophilic cytoplasm that is associated with SCC.

•These tumors tend to metastasize more often than BCC, and several authors suggest that the metastatic potential is similar to squamous cell carcinoma.

16.7Basosquamous Differentiation

Basosquamous cell carcinoma demonstrates histologic features of both BCC and squamous cell carcinoma (SCC) (Fig. 16.8). There is some controversy regarding the exact definition of basosquamous carcinoma; how-

c

Fig. 16.8 (a) BCC with squamous differentiation (b) Basaloid neoplasm that is continuous with an eosinophilic neoplasm. (c) Note the keratinizing features and small cysts. Courtesy of Dr. Evangelos Badiavas

ever, most dermatologists now consider it a BCC subtype [25]. Approximately 1.2–2.7% of BCCs are actually considered basosquamous carcinomas. [25] Histologically, basosquamous carcinoma is comprised

of basaloid cells with peripheral palisading and stromal retraction along with the keratin pearls. They generally have more eosinophilic cytoplasm that is more similar to that observed in SCC. These tumors tend to metastasize more often than BCC, and several authors suggest that the metastatic potential is similar to squamous cell carcinoma with an overall metastatic rate of approximately 9.7% [25–33]. One Australian prospective trial examined 98 cases of basosquamous carcinoma with 4 (4%) recurrences and 2 (2%) lymph node metastases over 5 years [25, 34]. A review of 17 cases of metastatic BCC, of which 10 lesions were available for analysis, demonstrated that 8 of them were either basosquamous or metatypical [35]. Another study found that from 170 metastatic BCC cases, 15% of the cases had areas resembling squamous differentiation [36]. Since basosquamous carcinoma is considered an aggressive BCC subtype, it is considered a strong indication for Mohs micrographic surgery similar to other aggressive BCC subtypes [25].

Summary: Therapeutic Options

•BCC has a very low rate of metastasis ranging from 0.003% to 0.55% of cases.

•Nonsurgical therapies include imiquimod, 5-fluorouracil, and radiotherapy.

•Surgical therapies include curettage and electrodessication, conventional surgical excision, and MMS.

16.8Therapeutic Options

BCC has a very low metastatic rate with rates ranging from 0.003% to 0.55% of cases [12, 37, 38]. The primary goal of treatment is to prevent recurrence with full removal of the tumor while preserving function and if possible, cosmesis [12]. The treatment modality chosen relies on a number of clinical parameters, notably anatomical location, age, overall health of the patient, and biological behavior characteristics of histological subtypes [9].

Nonsurgical options include imiquimod, 5-fluorou- racil, and radiotherapy. Imiquimod can be used for primary BCCs that are less than 2.0 cm in diameter and located on the neck, arms, legs, or trunk. It should not

be used for nodular, infiltrative, or morpheaform BCCs. Side effects include erythema, edema, vesiculation, erosion/ulceration, flaking, headache, nausea, and vomiting [39]. It binds to Toll-like receptors 7 and 8 on macrophages and stimulates release of interferon gamma and tumor necrosis factor, likely upregulating the TH1 response against the tumor [39].

5-Fluorouracil (5-FU) interferes with the production of thymine with the end result being to cause cell death to the tumor cells [1]. It can be used for superficial BCCs for 4–6 weeks, usually causing superficial erosions and erythema at the site of application [1]. Patients applying this medication should be closely followed during this time because substantial pruritus and irritation can develop [39–41]. 5-FU is broken down in the liver by dihydropyrimidine dehydrogenase (DHPDH). Patients who lack DHPDH constitute 1–3% of the population, and 0.1% of the population have a total deficiency of the enzyme [42]. In these patients, care should be taken not to use the topical cream over a large surface area of the body as the unmetabolized 5-FU could potentially lead to a toxic dose, albeit this is more of a concern in IV 5-FU [43] than with topical application.

Radiotherapy uses ionizing energy to destroy tumor cells usually in the form of fractionated doses of superficial X-rays, orthovoltage, or electron beam therapy [1]. The treatment is usually painless, and 63% of patients have good long-term cosmetic results [44]. This is lower than curettage and electrodessication and conventional surgical excision as 91% and 84%, respectively, of patients treated with these modalities have a good long-term cosmetic outcome [44]. Radiation therapy should also not be used in certain situations such as poorly defined BCCs, anatomical locations of the hands, feet, legs, and genitalia, and in patients with genodermatoses that generate a large number of BCCs [1]. It may be useful in cases where the patient cannot undergo surgical procedures [1].

Surgical therapy options include curettage and electrodessication (C&E), cryosurgery, conventional surgical excision, and Mohs micrographic surgery (MMS) [1]. C&E works well due to BCC’s propensity to form fewer connections to the basement membrane. It can be used for small, well-defined, and superficial BCCs with nonaggressive subtypes and not in high-risk anatomical locations; however, the technique is limited by its lack of histological analysis and requirement for 4–6 weeks of wound healing [1]. It may be particularly advantageous for

patients whose BCC meets the above criteria because the patient would not have to limit physical activity postoperatively; which is required when using conventional surgical excision or MMS [1].

Conventional surgical excision uses margins of 3–6 mm and can be used for BCCs less than 2 cm in low-risk anatomical areas with low-risk histological subtypes [1]. Nearly 95% of BCCs with low-risk histological subtypes are completely removed using a surgical margin of 4 mm [1]. At least one study directly compared conventional surgical excision versus cryotherapy and found a 5-year recurrence rate of 17.6% for cryotherapy versus 8.2% for conventional surgical excision, albeit the authors reported that this result was not statistically significant [45]. Similar recurrence rates were noted for other studies involving cryotherapy with recurrence rates ranging from 4.2% to 39% with 2 years of follow-up for cryotherapy [46–50]. Conventional surgical excision is associated with recurrence rates of 1.1–2.9% [51–54]. It should be noted that BCCs within the H zone of the face as well as the nose and ears are associated with a higher recurrence rate when using surgical excision at 8.4% [54, 55]. Conventional surgical excision is a good option when the patient does not have access to a Mohs surgeon or has a low-risk histological subtype of BCC.

Summary: Mohs Micrographic Surgery

•Mohs micrographic surgery (MMS) is considered the treatment of choice for micronodular, morpheaform/sclerosing, and infiltrative subtypes of BCC.

•For primary BCCs less than 3 cm in diameter, MMS cures the tumor 99% of the cases; however, primary BCCs greater than 3 cm only have a cure rate of 93%.

•There are a number of factors including size, location, and histologic subtype that can affect the tumor’s cure rate.

•BCCs located on the face have higher recurrence rates.

16.9Mohs Micrographic Surgery

Mohs micrographic surgery (MMS) is considered the treatment of choice for micronodular, morpheaform/sclerosing, and infiltrative subtypes of BCC

because these subtypes are associated with unpredictable clinical spread with margins that are best observed using horizontal sections [1, 7]. In addition, these subtypes may also leave behind small strands of tumor cells when excised by conventional surgical excision and analyzed by vertical sectioning [56]. MMS offers the advantages of removing the tumor with the smallest necessary surgical margins. For primary BCCs less than 3 cm in diameter, MMS cures the tumor 99% of the cases; however, primary BCCs greater than 3 cm only have a cure rate of 93% [7, 9].

The largest series of patients for which the results of using MMS have been reported was by Dr. Frederic Mohs involving 7,575 patients with a 5-year followup. It was noted that 11% of the tumors were primary and had diameters greater than 2 cm, while 18.3% of the tumors were recurrent. The overall reported 5-year recurrence rate was only 0.7%! [57]. Another study, the second largest, involved 6,982 BCCs with 49% of those tumors being recurrent and 67% being greater than 1.9 cm with 2,960 tumors having 5 years of follow-up. From those 2,960 tumors, a 1.8% recurrence rate for primary BCCs and a 3.4% recurrence rate for recurrent tumors were reported [58]. Drs. Mohs and Robins later reported 5-year cure rates using MMS for periocular BCC of 98% out of 1,414 cases and 98.1% for primary and 93.6% out of 631 recurrent BCCs [59, 60].

Further evidence behind using MMS for BCC can be gained from the perspective of tissue conservation. At least two studies have examined the predicted defect size using conventional surgical excision and actual MMS. One study involved 71 auricular tumors in which 40 were BCC and 29 were SCC [61]. The predicted conventional surgical margins were determined to be 8 mm for primary BCCs less than 3 cm, 1 cm for primary SCC less than 3 cm, and 1.5 cm for recurrent tumors and those greater than 3 cm [61]. If conventional surgical excision had been used, 180% of tissue beyond the MMS defect in primary BCCs and 27% beyond the Mohs defect in recurrent BCCs would have been removed [61]. Additionally, more than one stage of conventional surgical excision would have been required in nine primary tumors as well as eight recurrent tumors [61]. Downes et al. also compared post-surgical wound defects in periorbital BCC between MMS and conventional surgical excision and demonstrated that a local repair, direct

closure, or graft could be used in 15 out of 22 patients undergoing Mohs while those methods could only be used in 6 of 22 patients if conventional surgical excision was used [62]. In fact, the extent of surgery was much less complicated in 41% of the Mohs cases compared to if conventional surgical excision had been carried out [62].

MMS is the primary treatment for aggressive BCCs (those with aggressive histological subtypes) as well as those in precarious anatomical locations such as the face or the genitalia due to its tissue-conserving property [7, 63–65]. Strictly speaking, there are a number of factors including size, location, and histologic subtype that can affect the tumor’s cure rate [7]. If the BCC is greater than 3 cm, then the cure rate is 93% versus 99% if the tumor is less than 3 cm [7]. Primary periocular and perioral BCCs have a 98% cure rate [7]. BCCs located on the face have higher recurrence rates following MMS as one study reported a 5-year recurrence rate of 6.5% for primary BCCs and 10% for recurrent BCCs, with the temple having the highest number of recurrences [66]. Another study demonstrated that 2.5% of primary facial BCCs and 2.4% of recurrent facial BCCs recurred over a 5-year period [67]. Smeets et al. reported that primary facial BCCs recurred 2% of the time with 5 years of follow-up, while none of the recurrent facial BCCs recurred over 5 years [68].

Remarkably, morpheaform BCC has been demonstrated to subclinically spread 7.2 mm on average from the clinically visible tumor [19]. Infiltrative BCCs are known to invade the perineural tissues at higher rates than other BCC subtypes [69, 70]. Additionally, a number of reports have demonstrated that approximately 65% of infiltrative BCCs have a micronodular or infiltrating component [22, 70–75]. Following conventional surgical excision, micronodular BCC has been found to have a positive margin in 18.6% of cases versus only 6.4% of nodular BCC cases with farther tumor extensions being noted in the micronodular BCC cases [7, 76]. This demonstrates the importance of intraoperative histological analysis in micronodular BCC cases. Although superficial BCC is considered a nonaggressive subtype (noninfiltrative) of BCC, it is actually associated with the highest rate of recurrence out of the BCC subtypes [71].

Summary: Conclusions

•BCC is the most common neoplasm diagnosed in humans.

•BCC is the most common indication for MMS with nearly 30% of all BCC cases in the USA treated by MMS.

•The evidence behind using MMS as a surgical therapy for BCC is strong, with studies backed by a high number of patients along with very low recurrence rates reported.

16.10 Conclusion

In conclusion, BCC is the most common neoplasm diagnosed in humans. Interactions between UVB and DNA lead to dipyrimidine formation, which causes constitutive activation of the Sonic hedgehog pathway. BCC is the most common indication for MMS with nearly 30% of all BCC cases in the USA treated by MMS. Infiltrating, micronodular, and morpheaform are considered more aggressive subtypes of BCC. Inflammatory cells, hair follicles, and folliculocentric basaloid proliferations are benign conditions that can resemble BCC when using horizontal frozen sections. More malignant processes such as metastatic breast cancer, ameloblastoma, cloacogenic carcinoma, eccrine spiradenoma, pilomatricomas, and trichoepitheliomas can also mimic BCC. Additionally, BCC may differentiate to simulate many structures such as hair follicles, sweat glands, and sebaceous glands. The evidence behind MMS as a surgical therapy for BCC is strong with studies backed by a high number of patients along with very low recurrence rates reported. It is especially well suited for aggressive histological subtypes of BCC and for BCCs in anatomical regions where tissue conservation is paramount due to intraoperative histological analysis that allows the Mohs surgeon to observe nearly 100% of the surgical borders.

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