Squamous cell carcinoma

Introduction

  1. Cutaneous squamous cell carcinoma is a malignancy of the keratinocytes of the epidermis or hair follicles. It is a very common cancer, particularly in the population profile of the Alliance. It usually presents as a rapidly developing indurated area or nodular tumour that may be keratinising, crusted or ulcerative. It is locally invasive and has the potential to metastasise to other organs of the body.

  2. Alliance guidelines are based on experience, scientific literature, local patterns of practice and the British Association of Dermatologists guidelines (2020), to which Miss Carrie Newlands contributed.

  3. These guidelines are confined to treatment of squamous cell carcinoma of the skin and the vermillion border of the lip, and exclude SCC of the anogenital region, Bowen's disease, SCC arising from mucous membranes and keratoacanthoma.

  4. A cSCC care pathway diagram and OMFS postoperative skin cancer algorithm have previously been prepared.

Pretreatment

  1. In case of diagnostic uncertainty, a representative full thickness biopsy, ideally incorporating both the peripheral and deep margins, should be considered.

  2. Before any diagnostic or therapeutic procedure, the following should be recorded on the pathology submission form (RSH template here):

  • clinical diameter;

  • plane of deep excision margin;

  • whether the tumour is recurrent or in the field of previous radiotherapy;

  • the immune status of the patient.

  1. A photograph of the lesion should be obtained, especially in the context of multiple previous and current lesions, in order to limit the risk of wrong-site procedures, and importantly to guide any adjuvant radiotherapy.

  2. A full skin check should be considered, with clinical examination of the regional nodal basin as indicated. Ultrasound evaluation of the regional nodal basin may be considered in locally advanced disease.

Primary treatment

Non-metastatic resectable disease

  1. Surgical excision is considered the standard first-line treatment for patients with resectable primary cSCC.

  2. Peripheral tumour margins should be determined under bright lighting and magnification or dermoscopy. Target clinical margins are >= 4 mm for a low risk cSCC, >= 6 mm for a high risk cSCC and >= 10 mm for a very high risk cSCC (see Risk stratification, but recognising that risk categorisation may be informed only by clinical features at this stage). Final histological clearance should be at least 1 mm. For mobile lesions the deep margin should be within the next clear surgical plane, including galea for scalp tumours.

  3. For fixed or deeply infiltrating lesions, consideration should be given to cross-sectional imaging by CT or MRI. For scalp lesions this should include the neck as a screen for lymphadenopathy. Surgery may require inclusion of fascia, muscle, bone or other structures, and an orientated separate deep margin should be taken if there is concern at the security of the margin at resection.

  4. In most cases, immediate reconstruction will be required. However it is often desirable to confirm uninvolved histological margins prior to delayed defect repair, especially where complex reconstruction is required.

  5. The reconstruction technique should take into account a potential need for adjuvant radiotherapy.

  6. Mohs micrographic surgery should be considered in selected cases following SSMDT discussion, especially where tumour margins are indistinct or where functional tissue preservation is a factor.

Nodal disease

  1. Clinically suspicious nodal basins should be evaluated by ultrasound +/- fine needle aspiration cytology.

  2. In established stage III disease, the chest should be imaged by CT prior to any management decision for the regional nodes. Where the involved nodes are below the neck, the CT will also include this and adjacent nodal regions.

Locally advanced or metastatic disease, borderline or unresectable

  1. Cemiplimab is an option for locally advanced or metastatic cSCC. It is available through the Cancer Drugs Fund via NICE TAG [TA802]. Whilst the initial and subsequent registration trials found overall response rates of approximately 50%, Alliance experience is that the majority, perhaps 80%, of patients show major benefit from this treatment. CDF access to cemiplimab is limited to patients with performance status 0 or 1. Immunocompromised patients were not included in the original trials but are eligible for access. The Alliance recognises the importance of data collection in this patient group.

  2. In patients with contraindications to cemiplimab, or who otherwise do not qualify for access, palliative or radical radiotherapy may be considered. Occasional patients who are of good performance status, but unable to initiate or continue cemiplimab, may be treated with radical chemoradiation.

  3. Chemotherapy options include cisplatin-5-fluorouracil and capecitabine.

Pathology

  1. Pathology departments will adhere to guidelines on specimen handling and reporting as described in the Royal College of Pathology Minimum Data Set (MDS) for invasive squamous cell carcinoma.

  2. cSCC is staged according to the UICC8 system, rather than than AJCC8. TNM and aggregate stage grouping are given below.

Risk stratification

  1. The BAD guidelines assign three levels of risk according to multiple tumour and patient factors.

  2. Tumours are considered low risk when all the following apply:

    1. Well differentiated or moderately differentiated histology

    2. Tumour diameter <= 20 mm

    3. Tumour thickness <= 4 mm and no invasion beyond dermis

    4. No lymphovascular invasion or perineural invasion

    5. Clear pathology margins in all dimensions (>= 1 mm)

    6. Immune competence

  3. Tumours are considered high risk when any of the following apply:

    1. Poorly differentiated histology

    2. Diameter > 20 and <= 40 mm

    3. Thickness > 4 mm and <= 6 mm and/ or invasion into subcutaneous fat

    4. Asymptomatic perineural invasion present, dermal only, nerve diameter < 0.1mm

    5. Lymphovascular invasion

    6. Tumour site ear or lip

    7. Tumour arising within scar or area of chronic inflammaion

    8. One or more involved or close (< 1 mm) margins in a pT1 tumour. Close pathology margins (<1 mm) in a pT2 tumour.

    9. Iatrogenic immunosuppression or biological therapies; comorbidities likely to cause some degree of immune compromise; HIV infection stabilised on HAART

  4. Tumours are considered very high risk when any of the following apply:

    1. Metaplastic subtypes including adenosquamous, desmoplastic, spindle, sarcomatoid histology

    2. Diameter > 40 mm

    3. Thickness > 6 mm and/ or invasion beyond subcutaneous fat. Certain tumours with large exophytic components but limited depth of invasion may present less concern.

    4. Bone invasion

    5. Perineural invasion presented in named nerve; nerve >= 0.1 mm; nerve beyond dermis; symptomatic perineural invasion

    6. In transit metastasis

    7. One or more involved or close (< 1 mm) margins in a high risk tumour

    8. Major immunosuppression including solid organ transplant recipients, haematological malignancies such as chronic lymphocytic leukaemia or myelofibrosis

  5. Metastatic potential varies according to primary site, from lowest to highest: non-lip and ear sun-exposed skin; vermillion lip; ear; non-sun-exposed skin (eg perineum, sacrum, sole of foot); sites of radiation or thermal injury, chronic ulcers, chronic inflammation, chronic draining sinuses.

LSMDT and SSMDT discussion

  1. It is recognised that a variety of clinicians excise cutaneous squamous cell carcinomas. However clinicians who are not members of the LSMDT or SSMDT are strongly encouraged to refer cases to MDT members. In any case, all cSCC should be logged via a skin MDT.

  2. Low risk cSCC can be listed for tabling, not full discussion, as long as the following additional criteria are met:

    1. the histopathology has been reported by a substantive consultant histopathologist;

    2. the patient is under the care of a substantive consultant who regularly attends the SSMDT;

    3. the lesion has not been excised by curettage and cautery.

  3. All instances of medium or high risk cSCC, and recurrent cSCC, should be discussed in full at the SSMDT. This is asserted especially after discussion with HM Coroner's Officer for Surrey and Sussex 2022.

Second phase treatment

Where there is residual risk, patients may need further surgery and/ or adjuvant radiotherapy. Radiotherapy preserves anatomy in areas where there would otherwise be significant cosmetic or functional detriment. Some patients will require both further surgery and adjuvant radiotherapy, for example where major perineural invasion is present.

Further surgery to primary

  1. So long as a histologic margin of at least 1mm has been secured, and notwithstanding risk stratification, further marginal surgery is generally not pursued.

  2. In patients with one or more involved margins, close margins (< 1 mm) and where other tumour factors do not already prompt consideration of adjuvant radiotherapy, further surgery should be undertaken.

  3. This may be wider +/- deeper excision or Mohs micrographic surgery.

  4. In patients with symptomatic or radiologic perineural invasion, high resolution imaging should be performed and, where anatomically appropriate, joint discussion undertaken with the HNMDT or a skull base MDT (for example at St George's Hospital). Note that perineural invasion may be extensive, as far as the brainstem in rare cases. Aggressive surgical excision of the involved nerve should be undertaken where technically feasible.

Nodal disease

  1. Nodal dissection for metastatic cSCC will only be undertaken following a recommendation from the Specialist Skin Cancer MDT.

  2. Neck and parotid dissections are undertaken by SSMDT/ HNMDT members as required according to skill mix.

  3. Axillary dissections are undertaken by Miss Elizabeth Clayton (RSH), Mr Raouf Daoud (FPH) and Mr Farrokh Pakzad (RSH).

  4. Inguinal and ilioinguinal dissections are undertaken by Mr Raouf Daoud (FPH) and Mr Farrokh Pakzad (RSH).

Adjuvant radiotherapy

  1. The role of adjuvant radiotherapy after excision of cutaneous squamous cell carcinoma remains undefined and is a priority area for clinical trial evaluation.

  2. Alliance policy is that adjuvant radiotherapy should be considered if any two of the following parameters are present:

    • poorly differentiated histology

    • tumour diameter > 20 mm

    • tumour depth of invasion > 4 mm

    • lymphovascular invasion

    • perineural invasion, of a nerve >= 0.1mm in diameter

    • involved margin (which will typically indicate a definitive, rather than adjuvant, dose of radiation)

  1. In addition, clinical judgments will apply in relation to patient frailty and comorbidity and skin health, and immunocompromise.

  2. Radiation fields will be usefully guided by SSMDT discussion with the operating surgeon and histopathologist about the anatomy of risk. If the treating surgeon or radiotherapist are not both present in the meeting, photographs should be conveyed illustrating the position of the primary lesion and its relation to reconstructed skin.

  3. Full, and particularly split, thickness skin grafts are less likely to withstand radiotherapy than skin flaps. The length of time required for grafts to take may negate any potential benefits from adjuvant radiotherapy, in which case observation, with treatment reserved for relapse, may be more risk-adapted.

  4. In resected stage III disease, adjuvant radiotherapy to the regional nodal station should be considered on a case-by-case basis. Typically this will be if two or more lymph nodes are involved, any deposit is greater than 3 cm, or if there is extranodal extension.

  5. Radiotherapy protocols are curated internally by St Luke's Cancer Centre.

Other options

  1. Symptom-led management. A significant proportion of squamous cell carcinomas will not recur even in the presence of positive margins after initial excision.

  2. Cryotherapy/ cryosurgery.

  3. Curettage and cautery.

Follow up

Low risk cSCC, complete excision, no other previous skin cancers

  1. Ensure that a full skin check has been offered and the regional nodal basin examined.

  2. Inform the patient of their results. Educate patient about sun protection and skin surveillance. Inform the patient of a 40% risk of further keratinocyte cancer within 5 years. A specimen letter is provided.

  3. The patient can be discharged, and the GP can re-refer via the TWR system if needed in future. If the patient has had multiple non-melanoma skin cancers then active follow up may be retained in secondary care.

High risk cSCC, incompletely excised low risk cSCC and multiple skin cancers

  1. Patients should be offered four monthly follow up for twelve months, and six monthly follow up during the second year.

  2. Follow up should comprise a full skin check and examination of regional nodal basins, together with advice to the patient about sun protection and skin surveillance.

  3. Patients with more than one prior keratinocyte carcinoma have an 80% risk of a further keratinocyte cancer within five years. Consider secondary chemoprevention.

Very high risk cSCC

  1. Patients should be offered four monthly follow up for two years and six monthly follow up for a third year. No more than 5% of local and metastatic recurrences occur after three years.

  2. Follow up should comprise a full skin check and examination of regional nodal basins, together with advice to the patient about sun protection and skin surveillance. Previous Alliance guidance for ultrasound surveillance of regional nodal basins has been removed.

  3. Patients with more than one prior keratinocyte carcinoma have an 80% risk of a further keratinocyte cancer within five years. Consider secondary chemoprevention.

Secondary chemoprevention

  1. A randomised trial found that in patients who had had at least two non-melanoma skin cancers in the previous five years, nicotinamide was associated with a 20-30% reduction in the rate of new cSCC and BCC at twelve months. Nicotinamide was taken as 500 mg twice a day for a year. A systematic review and metaanalysis found nicotinamide to be associated with an approximate halving of the risk of subsequent cSCC and BCC.

  2. Patients need to self-source nicotinamide and counselled about small risks of nausea, diarrhoea and other gastrointestinal adverse effects, which may be attenuated by dose reduction to 500 mg daily.

Patient information and self-directed care

  1. Patient information is available from BAD (UK), the Skin Cancer Foundation (US) and DermNet (NZ).

Follow up after immunotherapy for advanced disease

  1. Follow up will typically be tailored to individual patients, taking into account risk of further cutaneous tumours, toxicity management, degree of response, and patient fitness and ability to attend for scans and clinic appointments.

  2. A suggested schedule is six-monthly cross-sectional imaging for up to three years following initiation of systemic therapy, acknowledging that not all patients complete two years of immunotherapy. This can reasonably be followed by return of care to the patient's dermatologist or primary clinician.

Horizon scanning and additional approaches

  1. Neoadjuvant cemiplimab in resectable cSCC was associated with a 51% pathological complete response and 13% pathological major response. Whilst this indication for cemiplimab is currently not NHS-funded, these data are relevant to discussions in cases of borderline operability.