because there have been no controlled studies in cutaneous SCC, its impact remains unknown. Review of the English literature [99] consisting of case reports and small case series in which SLN biopsy was used in high-risk SCC showed 21% of cases to have a positive SLN in non-anogenital SCC and 24% in anogenital cases. False negatives were rare and mostly from studies prior to the use of combination lymphoscintigraphy with methylene blue dye. Rates of morbidity from SLN in the literature are low and generally mild. It is not known whether early detection of LN metastasis will improve outcomes for patients with SCC. This awaits further study. Considering that only 5–10% of cases are SLN positive in most melanoma series, it may be that SLN biopsy is underutilized in high-risk SCC. Unlike melanoma, SCC with nodal involvement is highly curable (73% 5-year survival), so early detection via SLN biopsy may more readily impact outcomes than it does in melanoma. However, the right target group for SLN staging in high-risk SCC has yet to be defined.

17.5.4 Surgical Management

As described above, Mohs is an excellent choice for management of SCC and, in particular, of high-risk disease. However, in cases with advanced local extension, surgical clearance may require a multidisciplinary team, particularly if there is bone invasion or intracranial involvement of major nerve branches. A multidisciplinary team approach (Fig. 17.5) using preoperative radiologic imaging and/or SLN biopsy is ideal. Mohs surgeons may establish the peripheral margin while craniofacial or head and neck surgeons manage PNI of major nerves, parotid involvement, and bone extirpation to complete the tumor clearance. Using Mohs under local anesthesia to establish the peripheral margin minimizes general anesthesia time and allows the head and neck or craniofacial surgeon to focus on clearing the deep margin and the reconstruction.

Because high-risk tumors have features that may make it difficult to interpret margins or to track subtle PNI, the addition of cytokeratin immunohistochemical (IHC) stains [100, 101] may help to improve the sensitivity of Mohs in selected cases. IHC helps make individual tumor cells, which are otherwise difficult to identify, more visible than on hematoxylinand eosinstained sections. However, the costs of staining large marginal surfaces can be prohibitive.

17.5.5 Radiation as Primary Therapy

For high-risk SCC, the cure rate with radiation as monotherapy is generally inferior to surgery with local recurrence rates of 15–20% [62]. However, maintenance of oral function and cure rates similar to surgery have been reported with the use of radiation in treating cutaneous SCC of the lower lip [102]. Radiation as primary therapy is generally reserved for select cases of locally advanced SCC in which the prognosis is poor (in which case it may be delivered with palliative rather than curative intent), and/or attempting surgical clearance would introduce risk or morbidity unacceptable to the patient such as blindness or an inability to eat or speak.

17.5.6 Adjuvant Therapy

Radiation: It is accepted that adjuvant radiation therapy (ART) should be considered with certain tumors, particularly those with significant PNI (named nerves or larger-caliber nerves), although no controlled studies have evaluated outcomes; the utility of adjuvant radiation is therefore unknown [54]. There is no clear data regarding which patients should receive ART. However, it is known that patients with surgically clear margins prior to ART have better outcomes [103]. This is seen even when there is invasion of major nerves [81]. Although PNI is the most commonly cited reason for considering ART, data on its impact in this patient group is limited [54]. However, these tumors have high recurrence rates even with clear surgical margins [54, 81, 83]. Therefore, in cases of PNI involving larger nerves, ART should be considered, despite the lack of proof of its utility. Additionally, when surgical clearance of PNI is not possible, salvage radiotherapy may be helpful, but mortality rates as high as 30% have been reported in this setting [60]. In the case of nodal disease, this should be first managed by aggressive surgical resection of all local and regional disease, including LN dissection of multiple nodal basins if indicated. Addition of adjuvant radiation to lymphadenectomy can result in high cure rates, which have been reported as 73% 5-year disease-free survival (DFS) [104].

In summary, it is reasonable to consider ART in the highest-risk patients, particularly those with involvement of nerves >0.1 mm in diameter, and those in whom the surgical margin is uncertain such as in

Fig. 17.5 (a) A very large SCC of the scalp with bone invasion confirmed on MRI. Multiple surrounding areas of shallow erosion were also SCC on biopsy. Mohs was used to establish a clear peripheral margin including periosteum. An 8-cm zone of tissue was left intact anteriorly to prevent tissue necrosis in the event of a delay of the planned complete resection. The wound was closed with a single running suture. (b) The next day, the entire region defined by Mohs was removed by a head and neck

surgeon, including bone immediately below the tumor Photo courtesy of Dr. Don Annino, Brigham and Women’s Head and Neck Surgery. (c) A latissimus dorsi free flap reconstruction was performed by the head and neck surgeon. The patient remained disease-free for over 2 years before death from an unrelated cause. Photo courtesy of Dr. Don Annino, Brigham and Women’s Head and Neck Surgery

poorly differentiated tumors with single-cell spread, multiply recurrent tumors, or tumors with in-transit local metastasis.

Chemotherapy: The use of chemotherapy in the treatment of high-risk cutaneous SCC remains is a

relatively new concept. Retinoids have been the most well studied and reported in these patients. This class of medications is known to slow the development of new tumors but do not alter the course of an existing tumor. They act to promote differentiation, downregulate

proto-oncogenes, and regulate growth in the hyperproliferative epidermis [105, 106]. They are used as prophylactic agents, particularly in OTRs, when there is diffuse actinic damage [106–110]. Doses ranging from 10 to 30 mg/day have proven efficacious, and low-dose therapy is usually sufficient and must be continued indefinitely, as patients usually return to baseline on discontinuation of treatment. Dose escalation, beginning with 10 mg every other day and increasing to an effective tolerated dose, is an acceptable reported method [111]. Once efficacy is achieved, tapering to the lowest effective maintenance dose is reasonable, given the need for indefinite therapy. In the treatment of existing tumors, randomized trials of 13-cis retinoic acid (isotretinoin), either used alone for adjuvant treatment of established mucosal SCC of the head and neck [112] or in combination with interferon [113] for established cutaneous SCC, have shown no benefit. There have been no controlled trials evaluating the use of acitretin in treating existing disease, although in patients with metastatic or inoperable disease, the use of full-dose retinoids can be considered for a possible chemotherapeutic or suppressive effect [111].

In cases of advanced cutaneous SCC, cisplatinbased combination regimens have been tried. These have included combination regimens with 5-fluoroura- cil (5-FU), methotrexate, bleomycin, and doxorubicin. Outcomes have varied, and patients have reported the onset of 5-FU-related adverse effects. Capecitabine (Xeloda, Roche Laboratories, Inc), the oral 5-FU prodrug, is metabolized selectively to 5-FU within tumor cells, with the goal of less resulting systemic toxicity. There have been some reports of improved outcomes when capecitabine is used alone [114] or with subcutaneous interferon [115] to treat locally advanced cutaneous SCC. Capecitabine, when used with cisplatin or paclitaxel [116, 117] or in combination with radiation [118], has shown favorable outcomes in phase II trials of patients with mucosal SCC of the head and neck.

Epidermal growth factor receptor (EGRF) is expressed in normal basal layer and appendageal epidermal keratinocytes [119] and may be over-expressed in deposits of cutaneous SCC [120]. Therefore, the (EGFR) inhibitors have been used off-label in a handful of case reports in the treatment of cutaneous SCC to control proliferation, cell cycle progression, survival, angiogenesis, and metastasis. Cetuximab has had reported success in cases of inoperable tumors, intransit metastases, in metastatic SCC with and without

epidermolysis bullosa, and as combination therapy with celecoxib [121–125]. Gefitinib has been reported to result in palliative tumor shrinkage in a single case report [126]; however, phase II [127] and III [128] trials in metastatic mucosal head and neck SCC failed to show a survival benefit.

While there is a persistent lack of evidence, adjuvant chemotherapy may still be considered in cases of cutaneous SCC that is locally advanced or metastatic. Consultation with medical oncology should be considered in these cases. The available treatments are well tolerated with low risk of serious adverse effects. Further evaluation is needed to determine which patients are most likely to benefit from which adjuvant chemotherapeutics and to determine whether there is a subgroup of high-risk patients who would benefit from adjuvant chemotherapy after surgery to prevent recurrence.

17.5.7 Assessment of Immune Status

All patients with cutaneous SCC require a thorough history and exam to evaluate for the presence of any underlying process that might impair their immune status, placing them at higher risk of a poor outcome. Particularly in OTRs and CLL patients, immunosuppression is the primary cause of an elevated risk of recurrent and metastatic cutaneous SCCs. Accelerated skin cancer formation with multiple invasive cutaneous SCCs may be a marker of worsening immunity. In the case of OTRs, immunosuppression can result in the rapid development of new tumors. When immunosuppression is reduced, the number of new SCCs declines, and outcomes in patients with known aggressive disease improve [111]. Therapy with a single agent is less problematic than multi-agent immunosuppression. Specific newer immunosuppressive agents, particularly sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), are associated with a lower incidence of cutaneous SCC when compared to older calcineurin inhibitors (CNIs) [129, 130]. Further, when switched from traditional CNIs to sirolimus, patients’ tumors were thinner with reduced vascularization [131]; this is in line with the known anti-angiogenic properties of mTOR inhibitors. However, sirolimus has other side effects which limit its use. Changes in dose or class of immunosuppression in OTRs should be carried out with the transplant physician to avoid impairment in graft function and rejection. The risks