Angela Hu BSc, and Ron Vender MD, FRCPC
McMaster University, Hamilton, ON, Canada

Introduction

Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma, represents the most common malignancy.  The aim of this document is to summarize current Canadian guidelines on NMSC management to provide guidance for primary care physicians. Based on a literature review conducted by the NMSC Guidelines Committee, the 2015 recommendations (five chapters) for prevention, management, and treatment of basal cell carcinomas, squamous cell carcinomas and actinic keratoses were condensed for a family physician audience. This practical summary includes a brief review on epidemiology and pathophysiology of NMSCs, recommendations on primary prevention of NMSCs, and management of actinic keratoses, basal cell carcinomas, and squamous cell carcinomas. The importance of education in primary prevention is highlighted, and an overview of treatment options including topical, cryotherapy, photodynamic, surgical, and radiation therapies are discussed.

NMSC Chapter 1: Introduction to the Guidelines

Introduction

  • Non-melanoma skin cancer (NMSC) is the most commonly diagnosed cancer among Canadians,1 with basal cell carcinomas (BCC) and squamous cell carcinoma (SCC) accounting for approximately 95% of these cancers.2
  • Actinic keratoses (AKs) are precancerous lesions that have the potential to develop into SCCs3 and are therefore regarded as a marker of chronic skin photodamage.4

Epidemiology

  • 1 in 6 Canadians will develop some form of skin cancer in their lifetime. In 2013, 81,700 Canadians were diagnosed with NMSCs.5

Risk Factors

  • UV radiation
    • The major environmental risk factor6-8
    • Proximity to equator and increase in altitude are associated with greater UV exposure and accordingly higher rates of NMSCs.9,10
  • Age
    • 70-80% of cases occur in people aged ≥602,11
  • Male sex
    • Male to female ratio of 1.7:1 for SCC and 1.2:1 for BCC5
  • Personal history
    • Personal history of NMSC increases risk12
  • Ethnicity
    • Caucasians are at greatest risk, followed by Asians and Hispanics; risk is lower in African Canadians.13
  • Special patient populations
    • Organ transplant recipients, patients with albinism, xeroderma pigmentosum, HIV/AIDS.14-17

Pathophysiology

  • UV radiation (including short wavelength UVB and long wavelength UVA) is the primary causative agent in NMSCs, via three main mechanisms:
    1. Direct mutagenic effects in the tumour suppressor genes P5318,19 and CDKN2A20-22, as well as the Hedgehog signalling pathway, specifically in the PTCH1 and SMO genes. The first molecularly targeted therapy in NMSC, vismodegib, is an inhibitor of SMO.23
    2. Proliferation of malignant and premalignant cells by stimulating production of cytokines.19
    3. Alteration of cutaneous immune responses. The immunomodulator imiquimod helps target this.24

Diagnosis

  • Basal cell carcinomas (BCC)
    • BCCs are found predominantly on the head and neck (80%), followed by the trunk (15%), arms, and legs.8
    • Histologic subtypes (figure 1)
      • Nodular (most common) – translucent or waxy nodule with raised telangiectatic edges, with or without central ulceration/crusting.
      • Superficial – frequently occur on the trunk, presenting as scaly erythematous patches. Can be difficult to distinguish from psoriasis, eczema or SCC in situ (Bowen’s disease).6
      • Morpheaform – sclerosing or fibrosing
      • Pigmented
      • Infiltrative
    • 40% of patients present with mixed patterns of 2 or more of these subtypes.25
Clinical appearance of BCC subtypes. (A) nodular, (B) superficial, (C) morpheaform, (D) pigmented
Figure 1. Clinical appearance of BCC subtypes.26
(A) nodular, (B) superficial, (C) morpheaform, (D) pigmented
  • Squamous cell carcinoma (SCC) (figure 2)
    • Unlike BCCs, which are thought to develop de novo, invasive SCCs have known precursor lesions e.g. AKs and SCC in situ.4
    • AKs – 80% occur on face, bald scalp, ears, neck and dorsal arms/hands.4
      • Typically red, scaly macules and patches.
    • SCC in situ – slowly growing scaly erythematous macule or patch, similar to superficial BCC.
      • 3-5% risk for progressing to invasive SCC.27
    • SCC – typically thicker than AK, with an erythematous, raised base and irregular borders prone to bleeding. Indurated with or without central ulceration. The edges have a fleshy, rather than clear, appearance.28
    • Keratoacanthomas (KAs) – develop primarily on face, neck, hands.
      • Etiology unclear but lesions believed to originate from hair follicles. Rapid onset, growth and spontaneous regression (usually lasting 4-6 months in total).29-31
      • Difficult to distinguish from SCC on clinical and histological basis, thus management is essentially similar.6
Figure 2. Clinical appearance of SCC variants.26
(A) AK, (B) SCC in situ, (C) SCC, (D) KA

Prognosis and Staging

  • Prognosis depends strongly on the lesion’s histologic grade, tumour location, size, thickness and perineural or perivascular invasion, as well as host immune function and prior treatment history.
  • SCC metastasis occurs in 2-6% of cases,32 with a much lower rate for BCC (0.0028-0.55%).8 Metastatic NMSC has about 44% survival within 5 years.33

Prevention and Management

  • Photoprotection should be started in childhood.
  • Biopsies should always be considered for lesions suspicious for skin cancer.28
    • Suspicion of melanoma – complete excision.
    • Raised lesions – superficial shave biopsy.
    • Small lesions with distinct borders can be completely excised with a 2-10mm punch biopsy
    • Small lesions in areas where tissue loss is acceptable can be excised with 3-4mm margin.
    • Large lesions can be sampled by 1 to 2 small-punch biopsies (2-3mm) of the most suspicious areas; incision or shave biopsies are also appropriate.
  • Modalities of treatment (Chapters 3, 4, 5) include:
    • Nonsurgical (topical, photodynamic therapy, radiation).
    • Surgical (excision, electrodessication with curettage, cryosurgery, laser ablation).
  • Frequent re-evaluation is paramount as the risk for subsequent SCCs or BCCs among patients with previous diagnosis is increased 10-fold.34

Chapter 2: Primary Prevention of Non-Melanoma Skin Cancer

Introduction

  • UV radiation, as described previously, is the major modifiable risk factor for NMSC.
  • In Canada and elsewhere, much effort has gone into educating the public on the hazards of unprotected exposure. However, various myths and misunderstandings about skin cancer risk continue to impede public education efforts.

Some Misguided Notions

  • “I rarely bother with sunscreen”
    • Skin damage from UV exposure accumulates in a roughly linear fashion over time, underscoring the importance of early and lifelong sun protection.35
    • Only 56% of Caucasian North Americans report moderate or frequent use of sunscreen when outside on a sunny day.36
    • In organ transplant recipients, who experience long term immunosuppression and are particularly susceptible to NMSCs, regular sunscreen use was associated with significant reductions in new SCC and AK occurrences.37
  • “A tan will protect me from skin cancer”
    • The protective effect tanning (facultative pigmentation) yields only modest protection, the equivalent of using a sunscreen with a sun protection factor (SPF) of 2-3.38
    • UVB (but not UVA) does induce a small amount of melanin biosynthesis, but the dose of UV radiation required to achieve this is mutagenic in itself39 (as previously described in Chapter 1 – Pathophysiology).
  • “Indoor tanning is safer than the sun”
    • UVA emissions from tanning beds can exceed that from the sun by as much as 10-fold.40
    • Tanning devices increase the risk of BCC and SCC by 1.5 and 2.5-fold, respectively.41
  • “With sunscreen, I can stay out all day”
    • In one study, use of sunscreen was associated with sun exposure that was 13-39% longer than if no sunscreen was applied.42
    • Over-reliance on sunscreen can offset or eliminate the benefits of this protective measure.
    • The most basic photoprotective tools are avoidance of midday sun (when UV index, based on intensity of UVB radiation, is highest) and wearing UV-blocking clothing.
  • “I choose a sunscreen by its SPF”
    • SPF is a measure of how much longer it takes sunscreen-protected skin (applied at 2 mg/cm2) to produce a minimal erythema (redness) response to UVB exposure, compared with unprotected skin.
    • The relationship with UVB deflection is not linear. A product with an SPF of 15, under laboratory-controlled conditions, blocks 93% of UVB rays, while another with an SPF of 30 will block 97% of UVB rays.
    • SPF provides only a crude estimate of how much protection a sunscreen product can provide against UVB-induced damage, since the strength of UV rays can alter with environmental changes.
    • SPF does not indicate efficacy in blocking UVA, which can also be damaging and carcinogenic to the skin.

    Figure 3. An explanation of Sun Protection Factor (SPF)43

    • SPF value has traditionally been synonymous with the efficacy of a sunscreen product; however, SPF measures only UVB protection.
    • Newer UV absorbers cover the entire UV spectrum and can be divided into two groups: organic filters and inorganic blockers.
    • Organic filters are chromophores that absorb UV radiation.44
    • Inorganic blockers (zinc oxide and titanium dioxide) can both absorb and reflect or scatter UV radiation.45
    • The implication of reactive oxygen species in UV-induced lesions has also inspired the inclusion of antioxidants such as vitamin C and E.46
    • Sunscreen products are labelled “broad spectrum” if they protect against both UVA and UVB.
    • Only broad-spectrum products with an SPF of ≥15 can claim to retard/reduce the incidence of skin aging and skin cancer.47
  • “Everyone knows how to use sunscreen”
    • Manufacturers recommend that sunscreens be applied at an even thickness of 2mg/cm2, because SPF values are determined under those laboratory conditions.
    • However, the amount of sunscreen used is typically less than half that recommended,48 decreasing UV protection by 2-4 fold.49
    • Sunscreen application is also not homogenous, with some commonly neglected areas (e.g. ears, neck, back of hands, temples).50,51 With normal bathing, physical activity and towelling, the SPF of a single application of sunscreen is also reduced by 40% and 55% after 4 and 8 hours, respectively.52

Recommendations43

  • Physicians should regularly counsel patients that:
    • They should protect their skin from the sun by wearing appropriate clothing, avoiding exposure to midday sun, and using sunscreen.
    • They should use broad-spectrum sunscreen products with a SPF ≥30 or equivalent.
    • They should apply sunscreen liberally and evenly (2mg/cm2; about 35mL or 2 tablespoons for an average-sized adult), ideally at least 15 minutes before going outside.
    • They should reapply sunscreen, ideally, at least once during the day and more frequently if swimming or sweating and after towelling.
    • Use of sunscreen should not be a reason for extending the duration of sun exposure.
    • Indoor tanning should be avoided at all times.

Chapter 3: Management of Actinic Keratoses

Introduction

  • These lesions are keratinocyte intra-epidermal neoplasias,53 and are by definition confined to the epidermal layer of the skin.
  • They are typically small (3-6mm), flat, pink or nonpigmented, and painless.54
  • However, hyperkeratotic/thickened and pigmented AKs can also occur.
  • Sometimes better detected by palpation as a result of their sandpaper-like texture.
  • Precursors in the evolution of SCC.55

Occurrence and Natural History

  • AKs are common in older, fair-skinned individuals.56
  • AKs often present in clusters on sun-exposed areas of the arms, head and neck.57,58
  • In one study, 0.6% of lesions progressed to in situ or invasive SCC over 1 year, whereas 55% spontaneously regressed clinically.59 However, unless the areas has been surgically excised, there are high rates of recurrence.60,61

Treatment Options

  • Surgical Removal
    • AKs are not routinely surgically excised, and a biopsy is generally unnecessary unless lesions are recurrent or diagnosis is unclear.
    • Shave excision is commonly used for removal of hypertrophic AKs.
    • Curettage may be used alone or in conjunction with shave excision, electrodessication, or cryosurgery.
  • Cryosurgery
    • Local treatment with liquid nitrogen (LN2/cryosurgery) is the most common approach to AK management.
    • Outcomes are operator-dependent and vary depending on freeze time, number of LN2 applications, and other parameters.62
    • Because of these variables, as well as the fact that cryosurgery only targets clinically evident lesions, only 4% of patients remained free of AKs in the treated area.63
  • 5% 5-FU (Fluorouracil) Cream
    • 5% 5-FU cream was first used as treatment for discrete AKs, but may be also used as field therapy.63-65
    • Generally applied twice daily for up to 4 weeks.
    • Leads to local inflammation, erosion and pain, which may be tolerated poorly and reduce compliance.66
    • About half of patients achieve complete clearance, and >90% experience some reduction in lesion number.65
  • 5% Imiquimod Cream
    • Used primarily as field therapy
    • The most commonly used regimen is three-times-weekly dosing, applied in 4-week treatment cycles
    • Transient increase in the number of visible AKs in the treated field, thought to arise from subclinical lesions. These eventually regress and should be regarded as evidence of efficacy67,68
    • With the above regimen, 73% of patients maintained clearance in the treated field for at least a year, which is significantly greater than that of patients using 5% 5-FU (33%) or receiving 2 sessions of cryosurgery (4%)63
  • 75% Imiquimod Cream
    • Used as field therapy, applied daily to face or scalp for two 2-week cycles, separated by a 2-week rest period.
    • Trials reported fewer withdrawals due to adverse effects, compared to 5% imiquimod.54
    • Eight weeks after treatment, complete clearance occurred in about 36% of patients;69 however, within one year further AKs developed in half of these patients.70
  • Ingenol Mebutate Gel
    • Available in two concentrations – one (0.015%) for the face and scalp, and the other (0.05%) for the trunk and extremities.
    • Dosing is once daily for 3 days for the facial and scalp areas, and 2 days for the trunk and extremities – shorter than the other topical agents and potentially advantageous in terms of compliance.71
    • After 12 months about half of the patients remained clear and overall lesion count was reduced >85% in the treated area.72
  • 5% 5-Fluorouracil +10.0% Salicylic Acid Solution
    • A dual-action topical indicated to treat hyperkeratotic AKs.
    • Salicylic Acid (SA) is a keratolytic, and the theory behind its use is to improve penetration in hyperkeratotic AKs.73
    • Dosing is once daily to affected lesions, until lesions have cleared or for a maximum of 12 weeks.
    • At 8 weeks post-treatment, complete histological clearance of a single pre-defined AK lesion was achieved in 70% of patients. 50% of lesions were cleared at end of treatment.73
  • PDT and Daylight PDT
    • Two PDT systems available for AK treatment.
      • Blue light + photosensitizer 5-aminolevulinic acid (ALA)
      • Red light + methyl aminolevulinate (MAL)
    • Reasonable option for AKs disseminated over large areas.
    • In hyperkeratotic AKs, curettage is generally required before PDT.
    • PDT causes a burning sensation while the treated area is being illuminated.74
    • Daylight PDT is currently being explored, in which MAL cream is applied to the photodamaged skin and patients sit in bright sunlight for 2 hours, wearing sunscreen as usual for UV protection. Pain is reported to be significantly reduced.75,76
  • Combined Treatment Modalities
    • One option is the combination of cryosurgery followed with an adjunctive field-directed therapy (e.g. imiquimod, 5-FU) 1-2 weeks after.77,78
  • Treatment Options for Actinic Cheilits (AC)
    • An AK occurring on photodamaged lips, or AC, presents as a white lesion with interspersed red areas.
    • Histologic analysis of the vermillion surrounding ACs commonly identifies foci of SCC;79 because SCCs in this area have an elevated rate of metastasis,80 field-directed therapy may be preferred over cryosurgery.
    • Surgical vermilionectomy allows for long-term clearance but poses risk of cosmetic damage or functional impairment.81
    • Less invasive approaches include field therapy with 5% FU, ALA-PDT, and MAL-PDT. Imiquimod is also commonly used, although Canadian labelling restricts use on the lips.82
Therapy Dosing Efficacy Side Effects
5% 5-FU Cream Twice daily for up to 4 weeks. Complete clearance in 50%, and >90% experience some reduction in lesion number. 33% clear at 1 year. Local inflammation, erosion and pain
5% Imiquimod Cream Three-times-weekly dosing, applied in 4-week treatment cycles. 73% of patients maintained clearance in the treated field at 1 year. Transient increase in number of visible AKs. Irritation, erythema.
3.75% Imiquimod Cream Nightly to face or scalp for 2 weeks; leave on for ~8hours, then remove with mild soap and water. After a 2-week period of no treatment, repeat with a second 2-week treatment. Complete clearance in ~36% of patients at 8 weeks; however, within 1 year further AKs developed in half of these patients. Same as 5% imiquimod but trials report fewer side effects
Ingenol Mebutate Gel 0.015% for the face and scalp. 0.05% for the trunk and extremities.
Dosing is once daily for 3 days for the facial and scalp areas, and 2 days for the trunk and extremities
After 12 months, about half of the patients remained clear and overall lesion count was reduced >85% in the treated area. Local irritation and pain (but shorter treatment length than other topical agents)
0.5% 5-Fluorouracil +10.0% Salicylic Acid Solution Once daily to hyperkeratotic lesions, until lesions have cleared or for a maximum of 12 weeks. At 8 weeks post-treatment, complete histological clearance of a single pre-defined AK lesion was achieved in 70% of patients. 50% of lesions were cleared at end of treatment. Local inflammation, irritation, pruritis
Table 1: Topical treatment table

 

AKs in Organ Transplant Recipients

  • Rate of SCC development increased by ~100-fold.83,84
  • AKs may be morphologically different from typical AKs, appearing more prominent (wartlike) and hyperkeratotic, and their SCCs are at elevated risk of local recurrence and metastasis.82
  • Field treatment with topical therapy or PDT is recommended.85

Treatment Recommendations Summary86

  1. AKs with atypical morphology or presentation or resistant to treatment should be biopsied/excised.
  2. Isolated AKs should generally be treated with cryosurgery or a surgical procedure. Curettage or direct surgical excision are preferred options, if the lesions are hyperkeratotic.
  3. Areas with clustered AKs and those with histologic evidence of field cancerization should be treated with field-directed therapies.
  4. If cryosurgery or surgery is used in patients with solar elastosis or other evidence of extensive photodamage, field-directed therapy may be applied once healing is complete.
  5. Patients with evidence of photodamage or history of AKs should be regularly monitored for new lesions, with increased monitoring with any of the following – history of NMSC, history of nonresponsive AKs, ongoing systemic immunosuppression.
  6. Actinic cheilitis may be treated with any of the following modalities: cryosurgery, field-directed therapy, PDT, complete or partial vermillionectomy, laser resurfacing, ED&C.
  7. Organ transplant recipients and others with long-term systemic immunosuppression and clinical evidence of AKs may receive field-directed therapies to prevent the emergence of AKs and NMSC in areas of photodamage.
  8. In organ transplant recipients, a high level of suspicion for malignant transformation should be noted. Lesions that do not respond to treatment should be biopsied/excised.
Figure 4. Algorithm for management of actinic keratoses.86

Chapter 4: Management of Basal Cell Carcinoma (BCC)

Introduction

  • BCC is the most commonly diagnosed skin cancer in Canada.2
  • It is a slow-growing malignant tumour originating in the basal layer of the epidermis.
  • It rarely metastasizes, but growth leads to local destruction of neighbouring skin and underlying tissue.8,87
  • It most commonly affects sun-exposed surfaces – head and neck predominantly, followed by trunk and extremities.
  • Subtypes:
    • Nodular (60%) – most common on face. Nodular/popular appearance, with pearly quality, and often surface telangiectasias and ulceration.
    • Superficial (30%) – most common on trunk. Red, scaly macule or patch.
    • Morpheaform/scleorsing (5%) – atrophic plaques or papules with ill-defined margins. Aggressive growth pattern
    • Less common, aggressive
      • Infiltrative
      • Micronodular
      • Mixed
  • Risk associated with age (incidences increase ≥60 years of age) and sex (male).88
  • UV radiation is the most significant risk factor. Additional risk factors – fair skin, immunosuppression, environmental exposure to ionizing radiation, arsenic, UV radiation, psoralen plus UVA (PUVA), and a past history of BCC.89-99
  • Basal cell nevus syndrome (BCNS) is an autosomal dominant condition characterized by a mutation in the PTCH gene (important in the Hedgehog signalling pathway), leading to development of multiple BCCs.100
  • With timely detection and treatment, prognosis of BCC is usually excellent.
  • Features used to stratify risk include site, size, histologic subtype, tumour margins, perineural or perivascular invasion, prior treatments, and immune status (table 2).
  • Metastasis is rare (0.028% to 0.5%), usually to regional lymph nodes, lung, bone.8
Feature Low-risk BCC High-risk BCC
Anatomical site Trunk and extremities
Cheeks/forehead/ temples/scalp/neck/chin
Eyelids/nose/lips/ears
Periorbital/periauricular skin
Fingers and toes
Size <2 cm on trunk and extremities
<1 cm on cheeks/forehead/temples/
scalp/neck/chin
≥2 cm all sites
≥1 cm on cheeks/forehead/temples/
scalp/neck/chin
Histologic subtypea Nodular
Superficial
Morpheaform/sclerosing
Infiltrative
Micronodular
Basosquamous
Mixedb
Recurrence Negative history Positive history
Tumour margins Well difined Poorly defined
Perineural involvement No Yes
aA small fraction of nonaggressive, low-risk histologic subtypes includes keratotic, infundibulocystic, and fibroepithelioma of Pinkus. These generally go unmentioned in BCC studies.
bMixed subtype BCCs should be treated as the highest-risk form.
Table 2: Risk stratification of basal cell carcinoma.101

 

Treatment Overview

  • Goal of treatment – complete removal with optimal preservation of function and cosmesis.
  • Surgical
    • Surgical excision with postoperative margin assessment, Mohs micrographic surgery (MMS), cryosurgery, and electrodessication and curettage (ED&C).
  • Nonsurgical
    • Photodynamic therapy (PDT), radiotherapy (RT), and topical therapy.

Surgical Treatment

  • Surgical Excision with Predetermined Margins
    • For well-defined, low-risk BCC <2cm, excising a 3-4mm peripheral margin results in a 95% tumour clearance rate.102,103
    • For high-risk subtypes and large BCCs, 6-10mm margin recommended.102
  • Mohs Micrographic Surgery
    • MMS is a technique used on high-risk skin cancers to maximize tissue sparing and maximize cure rates.
    • MMS begins with narrow margin (0.5-1mm) excision, then the tissue is immediately processed using horizontal frozen sections. The physician examines the sections, and accordingly removes more tissue where any residual tumour is located. This process is continued until the tissue section(s) show no histologic evidence of residual tumour.104
    • Cure rates as high as 99% and 96% for primary and recurrent tumours, respectively.105-107
  • Electrodessication and Curettage (ED&C)
    • Higher cure rates for smaller lesions.108,109
    • Advantages – inexpensive, tissue-sparing, generally well tolerated.
    • Disadvantaged – potential hypopigmented scars, need for specialized training, lack of histologic confirmation of clearance.
  • Cryosurgery
    • Most effective for treating low-risk BCC on trunk and limbs.110,111
    • Not generally indicated for head and neck lesions or high-risk BCC due to poorer outcomes.112,113
    • Curettage often combined with cryosurgery, which may improve cure rates.114

Nonsurgical Treatment

  • Photodynamic therapy (PDT)
    • A topical photosensitizing agent (generally methyl aminolevulinate [MAL]) is applied to the lesion and irradiated with light, causing tumour cell death.
    • Adverse reactions – local pain, pruritus, erythema, edema.115
    • A systematic review reported a 1 year clearance rate of 84%.116
    • Good evidence for use of PDT in treatment of small lesions for patients contraindicated for surgery who can tolerate higher risk of recurrence and for whom cosmetic outcome is important, or possibly for patients with multiple small, low-risk BCCs.
  • Radiation therapy (RT)
    • Primary surgical alternative for high-risk BCC, with long-term cure rates ≥90% for both primary and recurrent high-risk lesions.8
    • RCTs have compared RT with surgically alternatives; for primary facial BCC <4cm, 4-year tumour clearance rates were 99.3% and 92.5% for surgical excision and RT, respectively.117
    • Main advantages – tissue-sparing, non-invasive.118
    • Risks – local erythema, edema, ulceration, infection.
    • Potential long-term sequelae – chronic dermatitis, radio-necrosis, radiation-induced malignancies.119
  • Topical therapy
    • Imiquimod, an immune response modifier, is the main topical therapy used in treating superficial BCCs.120,121
    • Approved for treatment of superficial BCCs on trunk, extremities, neck
    • Clearance rates over 80%.122,123
    • Nodular BCC does not appear to respond as well to topical imiquimod.124

Locally Advanced or Metastatic BCC

  • No standard therapy exists, in large part due to the rarity of such progression.
  • Combination of surgery, radiation, chemotherapy.
  • Newer research examines genetic targets of BCC.
  • The oral agent vismodegib (inhibitor of Smoothened gene) is approved in Canada for treatment of metastatic BCC or locally advanced BCC that is inappropriate for surgery or radiotherapy.124,125
  • Disadvantages – high cost and toxicity (hair loss, muscle cramps, taste disturbance).126

Follow-up

  • A meta-analysis assessing the risk of developing a second BCC reported a 3-year risk ranging from 33-70%, with a mean of around 44%.34
  • Patients who received surgical treatment of low-risk tumours and confirmed histological clearance of high-risk tumours are at very low risk of recurrence and could safely be followed annually.119
  • For patients at higher risk of recurrence (no histological confirmation of clearance, or nonsurgical treatment), biannual skin checks are recommended for the first 3 years, then yearly thereafter.
Figure 5. Algorithm for treatment of BCCs.101

Recommendations

Table 3. Summary of recommendations for treatment of BCCs.101

Chapter 5: Management of Squamous Cell Carcinoma

Introduction

  • Second to BCC, squamous cell carcinoma (SCC) is the most common form of non-melanoma skin cancer, accounting for ~20% of all cases in Canada.2
  • Although less common than BCC, SCC has a great potential for metastasis and is associated with a higher risk of mortality.32,33
  • Chronic exposure to UV radiation is the most important risk factor.6-8
  • SCCs arise from the superficial layers of keratinocytes and commonly appear on sun-exposed surfaces, such as the head and neck.
  • SCC has varied presentations – it can be scaly, centrally ulcerated, or erythematous, and may have irregular borders prone to bleeding. It may arise from actinic keratosis.
  • It is sometimes confined to epidermis (SCC in situ or Bowen disease), but can also invade nearby tissues and metastasize to regional lymph nodes and more distant sites.136

Staging And Prognosis

Clinical Risk Factor SCC Risk
Low: All of the Following High: Any of the Following
Location Non-high-risk sites External ears, lips, scalp.
Size, diameter <2 cm ≥2 cm
Depth <0.2 cm or Clark levela I, II, or III ≥0.2 cm or Clark levela IV or V
Differentiation Well or moderately differentiated; Broder gradeb 1 or 2 Poorly differentiated; Broder Gradeb 3 or 4
Etiology Ultraviolet radiation Other/td>
Host immunosuppression Negative Positive
Perineural involvement Negative Positive
Recurrence Negative Positive
Rapid growth Negative Positive
Originating from chronic wound or scar Negative Positive
aClark level defines depth of invasion, with level I being confined to the epidermis as a carcinoma in situ and with all other levels being invasive tumours
that extend into the dermis. Clark level V tumours extend all the way through the dermis and have entered the subcutaneous fat layer.
bBroder grade reflects the proportion of poorly differentiated cells in the tumour biopsy.
Table 4: Recurrence risk of cutaneous SCC lesions.137

 

Sentinel Lymph Node Biopsies

  • Although SCC metastasis is rare, region lymph nodes (usually head and neck) are the most common site of disease spread.138
  • Prognosis of metastatic SCC is poor – 34.4% survival rate beyond 5 years.38
  • Thus, early detection of nodal involvement is important.
  • Sentinel lymph node biopsy is commonly used in breast cancer and cutaneous melanoma but its value in high risk SCC is not well established.

Surgical Treatments with Margin Control: The cornerstone of SCC management

  • Fixed-Margin Surgical Excision
    • Widely regarded as the treatment of choice for most cutaneous SCCs.139
    • Advantages – histologic verification of tumour margins, rapid healing, good cosmesis.140
    • SCC recurrence rates following surgical excision of primary invasive cutaneous SCC tumours: 5.7% for short term (follow up <5 years) and 8.1% for long term (follow up >5 years).38
    • Higher recurrence rates for recurrent tumours: 17.3% and 23.3% for short- and long-term, respectively.38
    • No consensus for acceptable surgical margin.141
      • 4-5mm for low-risk SCCs
      • 6-13mm for high-risk SCCs
  • Mohs Micrographic Surgery
    • Highest clearance rates, and allows normal tissue to be spared by offering complete control of the surgical margin.142-150
    • Thus, MMS should always be considered for SCC lesions with poorly defined borders, especially for cosmetically sensitive areas such as the face, hands, feet.

Destructive Treatments Without Margin Control

  • Electrodessication and Curettage (ED&C)
    • Generally, 1-3 cycles of ED&C are performed during a single visit.140
    • Cure rates for SCC in situ are 93-98%.151,152
    • Since reliable margin control is not achieved, the effectiveness is highly dependent on the skill and experience of the physician.
    • Because the tumour margin is lost, ED&C should not be used for recurrent or high-risk tumours, or for deeper lesions that extend to soft, subcutaneous fat.139,142
  • Cryosurgery
    • In low-risk SCC lesions, including SCC in situ and KAs, high short-term clearance (follow up <5 years; 96.8-100%) and 5 year cure rates (96.1%) have been reported following cryosurgery.63,113,114
    • May be inferior to ED&C in terms of patient pain, speed of healing, recurrent rate.153
    • Disadvantages – scarring, hypopigmentation,154 no established standards for optimal temperature, duration of treatment.

Radiation Therapy

  • Can be used to treat inoperable primary cutaneous SCC lesions.
  • High rates of short-term clearance (93.3%) and long-term cure (90-92.5%) are comparable to those achieved with surgical excision.38,155
  • Often suggested as an adjuvant to surgical management of high-risk SCC lesions, especially those with perineural involvement and positive surgical margins.141,142

Photodynamic Therapy

  • Currently, use of PDT in Canada is restricted to treatment of superficial BCCs and AKs.
  • May be effective for SCC in situ, especially in the lower leg (which generally has poorer healing in response to other therapies).156

Topical Regimens

  • No topical therapies approved by Health Canada for treating SCC.
  • Topical agents, such as 5-FU and imiquimod, have shown efficacy in the treatment of SCC in situ;157 short-term cure rates of 27-85% with 5FU and 73-88% with imiquimod.158
  • Adverse effects of 5FU – erythema, pain, dermatitis, pruritus.157
  • Adverse effects of imiquimod – erythema, edema, weeping, pruritus, hypopigmentation, erosion, burning, pain.157
  • 5-year cure rates are unknown so cannot be recommended, but anecdotal evidence suggests they may be used off-label to manage low-risk SCC.

Other Approaches

  • Laser
    • Argon, CO2 and Nd:YAG lasers have been studied in the treatment of SCC in situ in case reports and small series.
    • Mostly focusing on anogenital lesions, as well as SCC in situ of the digits.159
    • High cost and need for specialized equipment.
  • Intralesional therapy
    • Intralesional therapy with alpha-interferon or chemotherapeutics such as methotrexate, 5-FU, and bleomycin has produced cure rates of 91-100% for keratoacanthomas.151
    • Currently rarely used in practice.160

Treatment Recommendations137

  1. Suspected SCCs should be biopsied according to the criteria outlined in Chapter 1.
  2. Risk of recurrence should be established using the criteria in Table 4.
  3. Selected patients with high-risk SCCs may be considered for sentinel lymph node biopsy in consultation with a multidisciplinary skin cancer clinic.
  4. Primary low-risk SCC lesions of the skin, including SCC in situ and keratoacanthomas, may be treated with the following options:
    1. Surgical excision with 4-5mm margin (first line)
    2. ED&C
    3. Cryosurgery
    4. Radiation therapy
  5. The following off-label modalities can be also considered in the treatment of SCC in situ:
    1. Photodynamic therapy
    2. 5-FU
    3. Imiquimod
  6. Treatment options for recurrent or otherwise high-risk SCC lesions include the following:
    1. MMS
    2. Surgical excision with 6-13mm margin
    3. Radiation therapy
  7. Adjuvant radiation therapy may be added to the surgical treatment of high-risk SCCs, such as those with perineural invasion.
  8. Patients with select, high-risk SCCs may be considered for a referral to a multidisciplinary clinic.
Figure 6. Algorithm for management of SCCs.137

Conclusion

  • Complete removal of SCC along with preservation of function and cosmesis is best achieved through surgical methods allowing tumour margin assessment.
    • Fixed-margin surgical excision and MMS are the cornerstone treatments.
  • Treatment options for high-risk lesions are limited to MMS, fixed-margin surgical excision, and radiation therapy.
  • There are a number of second-line options for management of low-risk SCCs; while not currently approved, PDT and topical therapy may be especially useful for lesions in lower leg.

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