Keywords

Introduction

Non-melanoma skin cancers (NMSCs) are the most commonly diagnosed cancers in Canadians, accounting for 28% of all new cancer cases in Canada. In 2014, the Canadian Cancer Society estimated that there will be approximately 76,100 new cases and 440 deaths from squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) combined [1]. The incidence of both tumor types continues to rise despite growing awareness of the risk factors (see Table 19.1) [2, 3]. The American Joint Committee on Cancer (AJCC) eighth edition is the current recommended cutaneous squamous cell carcinoma and other cutaneous carcinoma staging system [4].

Table 19.1 Risk factors [3, 5,6,7,8,9,10]
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Skin lesions in high-risk populations may be challenging to clinically assess. A low threshold for performing skin biopsies is prudent.

Clinical Presentation [3, 5]

Both BCC and SCC characteristically develop on body areas previously exposed to sun.

Early BCCs are small, translucent or pearly, with raised telangiectatic edges; 80% of BCCs occur on the head and neck, followed by trunk (15%) and extremities. Clinical subtypes of BCCs include the following: (1) classic rodent ulcer (indurated edge and ulcerated center), (2) nodular or cystic, (3) superficial, (4) morphoeic (ill-defined borders), and (5) pigmented. Up to 40% of BCCs contain a mixed pattern of two or more histologic subtypes. Nodulocystic BCC is the most common subtype, usually on the head and neck, while superficial BCCs mainly present on the trunk and limbs. BCC is characterized by local and sometimes disfiguring invasiveness if left untreated; however, metastasis is rare, occurring in less than 0.05% of cases [11]. BCC most commonly metastasizes to regional lymph nodes, followed by bone, lung, and liver [7].

SCCs can arise de novo or from premalignant lesions such as actinic keratoses, SCC in situ (Bowen’s disease), keratoacanthoma, and cutaneous horns. Individual actinic keratoses are estimated to progress to invasive SCC at 1–10% over 10 years, but the risk is increased with greater than 5 actinic keratoses. Bowen’s disease presents as slow-developing erythematous scaly or crusted plaques, with a 3–5% risk of progression to SCC. Keratoacanthomas have a rapid onset, progression, and regression within months, with similar clinicopathologic features to well-differentiated SCC. Cutaneous horns are growths that present as a dense cone of epithelium; up to 15% demonstrate invasive SCC at the base. Given the associated risk of progressing to invasive SCC, these precursor lesions are generally excised or consider cryotherapy, topical 5-fluorouracil, topical imiquimod, photodynamic therapy, or curettage and electrodessication.

All SCCs demonstrate induration, which is usually the first sign of malignancy, and typically have an adherent crust with ill-defined margins. In contrast to BCCs, SCCs are responsible for the majority of deaths from NMSCs as they have a higher metastatic potential (~5% at 5 years) [12]. The most common metastatic site for SCC are regional lymph nodes; distant sites include bone, brain, and lung (parotid gland for head and neck SCCs).

Tables 19.2 and 19.3 describe the low- and high-risk factors for local recurrence or metastasis for BCC and SCC.

Table 19.2 Definition: low- and high-risk factors for local recurrence of BCC and metastasis [7, 13,14,15,16,17,18,19,20,21,22,23,24]
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Table 19.3 Definition: low- and high-risk factors for local recurrence or metastases for SCC [3, 14,15,16,17,18,19,20,21,22,23,24]
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Management: Primary Localized Basal and Squamous Cell Carcinoma (No Evidence of Regional or Metastatic Disease) [13, 14, 25, 26]

Management of Low-Risk Basal Cell Carcinoma and Squamous Cell Carcinoma (See Table 19.4)

For patients unable or unwilling to undergo surgical treatment of primary lesions or when clear margins cannot be obtained by Mohs or more extensive surgery, radiation therapy should be pursued. Radiation should also be considered for primary treatment (instead of surgery) to sites that cause significant morbidity or require extensive reconstruction. Radiation is not recommended for patients younger than 60 years of age due to inferior long-term cosmesis and potential for carcinogenesis.

Table 19.4 Management of low-risk BCC and SCC
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Management of High-Risk Basal Cell Carcinoma and Squamous Cell Carcinoma (See Table 19.5)

For patients unable or unwilling to undergo surgical treatment of primary lesions or when clear margins cannot be obtained, radiation therapy should be pursued if over the age of 60 years old. Consider multidisciplinary tumor board consultation to discuss chemoradiation or enrolment into a clinical trial. Radiation should also be considered as primary treatment (instead of surgery) to sites where surgery may be disfiguring, cause significant morbidity, or require extensive reconstruction (i.e., nose, ears, eyelids, lips). Radiotherapy should also be considered in the adjuvant setting if there is extensive perineural or large nerve involvement (≥ 0.1 mm for cutaneous SCC of the head and neck).

Table 19.5 Management of high-risk BCC and SCC
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Mohs Micrographic Surgery

  • Removes malignant skin tumors with rapid, in-office analysis of horizontal frozen-section specimens processed to include 100% of the peripheral and deep surgical margins. If any part of the specimen demonstrates tumor infiltration of a margin, serial margins can be limited to the affected areas, allowing the narrowest possible margin excised.

  • Lowest 5-year recurrence rate of any treatment (1% for primary tumors, 5.6% for recurrent tumors), followed by surgical excision, cryosurgery, and curettage and electrodesiccation.

  • For most NMSCs, Cancer Care Ontario recommends surgery (with postoperative and intraoperative margin assessment), or radiation for those ineligible for surgery, as standard of care. Their indications for Mohs micrographic surgery are limited to histologically confirmed recurrent BCC of the face, and primary BCCs of the face that are >1 cm in size, have aggressive histology, or are located in the H zone [32]. The consideration of Mohs micrographic surgery for high-risk SCC should be made by a multidisciplinary team.

Role for Sentinel Lymph Node Biopsy

  • Although sentinel lymph node biopsy has been used in the management of select patients with high-risk SCC, data remain insufficient to determine whether early detection of microscopic metastatic disease has a beneficial effect on patient outcome. Nevertheless, consider sentinel lymph node biopsy in certain high-risk lesions such as locally advanced SCC and discuss at a multidisciplinary skin cancer tumor board [33,34,35,36].

Regional Metastatic Non-melanoma Skin Cancer

Management of Regional and Metastatic BCC [13]

For nodal or distant metastases, consider surgery and/or radiation therapy, and multidisciplinary tumor board consultation for consideration for a hedgehog pathway inhibitor (i.e., vismodegib, sonidegib) or clinical trial.

Management of Regionally Metastatic SCC [9] (See Table 19.6)

Table 19.6 Management of regionally metastatic SCC
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Referring to Radiation Oncology

  • Patients should be referred to radiation oncology for consideration of radiation as primary therapy if:

    • They have histologically confirmed NMSCs and are unable or unwilling to undergo surgical treatment of their primary lesion.

    • Clear margins cannot be obtained by Mohs or more extensive surgery.

    • Surgery may be disfiguring, cause significant morbidity, or require extensive reconstruction (i.e., nose, ears, eyelids, lips).

  • All patients with positive margins, regional or metastatic disease should also be referred to radiation oncology for consideration of adjuvant radiation therapy.

  • Data on the value of adjuvant radiation after surgical excision with negative margins (particularly after Mohs micrography surgery) remain conflicting [13, 14].

Referring to Medical Oncology

  • All patients with distant metastases or locally advanced disease should be referred to medical oncology for consideration of systemic therapy or clinical trial enrollment.

  • Systemic therapy is usually indicated once surgical and radiation options have been exhausted.

Options

  • Targeted therapy.

    • Hedgehog pathway inhibitors (i.e., vismodegib, sonidegib) (BCC).

  • Immunotherapy.

    • PD-1 inhibitor (i.e., pembrolizumab, cemiplimab).

  • Systemic chemotherapy.

    • Cisplatin alone or with paclitaxel (BCC) [25].

    • Cetuximab, cisplatin/5-fluorouracil or α-interferon, retinoic acid, and cisplatin (SCC) [26].

    • There is no standard chemotherapy treatment plan for NMSCs.

BCC: Vismodegib is now standard of care (and paid for by the Provinces) for BCC not amenable to surgery or radiation. Patients with borderline resectable BCC may also be considered for neoadjuvant vismodegib. Pembrolizumab has shown some efficacity in case reports for patients who are refractory to targeted therapy but regulatory approvals have not yet occurred [37, 38].

SCC: Phase I and II studies demonstrated a 50% response to cemiplimab in locally advanced or metastatic SCC, with adverse effects in at least 15% of patients limited to diarrhea, fatigue, nausea, and rash [39]. Cemiplimab has since received both FDA and Health Canada approval and is now standard of care for metastatic or locally advanced cutaneous SCCs that are not curable with surgery or radiation.

Referring to Multidisciplinary Cancer Conference

  • Patients with positive deep margins following resection with graft/flap reconstruction.

  • All patients with regionally metastatic NMSCs.

  • All patients with distant metastatic NMSCs.

Toronto Pearls

  • Patients with high-risk BCCs or SCCs on the face should be prepared for graft or local flap reconstruction given the cosmetically sensitive nature of this region; high-risk SCCs in other locations may also require graft/flap reconstruction given the potential size of resection.

  • If deep margins are positive following resection and reconstruction, consideration should be given to re-resection.

  • Level 3 axillary dissection for SCC should be considered for palpable disease in the axilla.