8.4 Radiotherapy for regional (nodal) metastatic disease (non-distant)
Unless stated otherwise, tumour stage is according to edition American Joint Committee on Cancer (AJCC) cancer staging manual 8th edition  and Union for International Cancer Control (UICC) TNM classification of malignant tumours 8th edition.
Radiotherapy (RT) has been used in the treatment of metastasis to lymph nodes, lymph channels (in-transit disease in dermal lymphatics) or via perineural invasion (PNI).
Lymph node metastases[edit source]
Nodal disease is associated with poor prognosis in patients with cutaneous squamous cell carcinoma (cSCC) or basal cell carcinoma (BCC). The prevalence of nodal disease is higher for cSCC than for BCC. Radiotherapy increases regional control rates in both cSCC and BCC.
Basal cell carcinoma[edit source]
Basal cell carcinomas rarely metastasise to lymph nodes. Most commonly, the patient has a long history of multiple recurrences, extending over many years, or an uncontrolled primary lesion. Other risk factors have been reported, including a history of prior radiotherapy, a large primary tumour, and head and neck site.
Cutaneous squamous cell carcinoma[edit source]
- at sites of mucosal–squamous cell junction, including lip, anus and vulva
- at head and neck sites
- in a patient with immunosuppression
- within chronically inflamed/irritated lesions.
- size – lesions greater than 2cm in diameter are twice as likely as smaller lesions to develop regional recurrence
- site – lesions located on the ear and lip have a higher rate of local recurrence than cSCC elsewhere
- grade – poorly differentiated cSCCs have double the metastasis rate of well-differentiated lesions
- thickness – cSCCs >6mm in thickness recur three times more commonly than thinner lesions
- recurrence – recurrent cSCC is twice as likely to metastasise than primary cSCC
- PNI – PNI is the strongest predictor of regional recurrence (up to 50% risk).
The time to development of regional disease is short, usually within 12–24 months after initial treatment of the primary lesion.
Spread of cSCC to regional lymph nodes is uncommon, but is associated with metastasis to distant sites and a poorer outcome. Survival after lymph node metastasis is poor, with only one-third of patients surviving 5 years. Half of these patients die of uncontrolled regional disease without distant metastases. For patients with regional spread from cSCC of the lip, survival rates may be twice as high.
Any clinical suspicion of node metastases warrants referral to a multidisciplinary head and neck or skin clinic and further staging investigations. The diagnosis of nodal metastases should be confirmed by fine needle aspiration cytology (FNAC). Occasionally, image-guided FNAC or core biopsy may be necessary. Open incision biopsy of a suspicious lymph node for diagnosis is not advised because it potentially increases the risk of dermal lymphatic involvement, compromises further management, reduces the efficacy of subsequent lymphadenectomy and usually requires an avoidable general anaesthetic.
In Australia the most common malignancy of the parotid gland is metastatic cSCC to intraparotid nodes from a cutaneous malignancy. In many cases these patients have had multiple skin cancers of the head and neck treated and the index lesion may not be known. In this situation, metastatic cSCC arising from a mucosal site needs to be excluded in the first instance.
An Australian retrospective series of patients with metastatic cSCC in the parotid gland observed a low rate (< 15%) of pathological involvement of cervical nodes among patients with clinically negative cervical nodes, comparable to the low rate reported in a US study.
For cervical lymph nodes, most authorities recommend a selective neck dissection. The extent of the lymphadenectomy is determined by the site of the primary lesion, the involved node(s) and the extent of the disease. Generally, the facial nerve, accessory nerve and sternomastoid muscle can be preserved, which reduces the morbidity of the procedure. Occasionally lymph node metastases occur at unusual sites, including the epitrochlear region and popliteal fossa.
Perineural invasion[edit source]
Perineural invasion is uncommon. In the past, it was thought to spread as skip lesions but new data suggest this observation was due to specimen processing and that PNI is actually contiguous.
Perineural invasion may be incidental or, more rarely, symptomatic. The vast majority occur in head and neck cutaneous cSCC. Incidental PNI implies early spread, is asymptomatic and is recognised only after complete pathological examination of the specimen.
Perineural invasion is associated with a poor prognosis. Cohort studies reported that perineural invasion involving nerves with a diameter 0.1mm or greater 0.1mm was associated with increased risk of disease-specific mortality. 
In patients with PNI of cSCC or BCC, magnetic resonance imaging (MRI) should be considered to map macroscopic extent for further therapy. Intracranial macroscopic disease on MRI carries a poor prognosis and a palliative approach is suitable. Previously PNI was thought to predispose to increased nodal involvement but new data do not support this.
Overview of evidence (non-systematic literature review)[edit source]
Radiotherapy for lymph node metastasis of basal cell carcinoma[edit source]
Post-lymphadenectomy radiotherapy (BCC)[edit source]
Regional control can usually be achieved with lymphadenectomy. Postoperative RT may be indicated for patients with a high risk of recurrence (i.e. extensive disease, multiple involved nodes, extracapsular extension, or close/involved surgical margins).
Radiotherapy as an alternative to surgery[edit source]
Radiotherapy alone is a reasonable alternative to surgery for patients who are poor candidates for surgery or the those requiring palliation.
Radiotherapy for lymph node metastasis of squamous cell carcinoma[edit source]
Post-lymphadenectomy radiotherapy (SCC)[edit source]
- parotid node metastases
- ≥ two nodes positive in the neck
- ≥ three nodes positive in the axilla or groin
- ≥3cm node
- significant extra nodal extension
- close or involved surgical margins
- skin infiltration
- major nerve involvement (e.g. facial nerve)
- recurrent nodal metastases, salvaged surgically
- node metastases in unusual sites (posterior triangle neck, supraclavicular fossa, occipital nodes from primary cutaneous cSCC of posterior scalp or upper trunk, epitrochlear nodes or popliteal nodes)
- nodal metastases accompanied by local relapse
Some centres use one modality to manage parotid node metastases of cSCC: either irradiation or surgical lymphadenectomy  of the clinically negative ipsilateral neck, but not both. An Australian retrospective consecutive case series study reported that the addition of tissue equivalent bolus to adjuvant RT for intraparotid metastatic head and neck did not reduce local skin failure in the parotid region.
The role of postoperative chemoradiotherapy for high-risk cSCC of the head and neck has been resolved by a prospective randomised controlled trial (RCT) phase III conducted by the Trans-Tasman Radiation Oncology Group (TROG). The investigators reported that postoperative RT achieved high rates of locoregional control, and that this was not significantly improved by the addition of postoperative concurrent chemoradiotherapy.
In an observational cohort study in patients with parotid-area lymph node metastases, the combination of surgery and postoperative RT improved locoregional control, compared with RT alone.
Whether postoperative RT increases survival is controversial, based on low-level evidence. A retrospective multicentre study reported adjuvant RT was associated with improved overall survival in patients with cSCC of the head and neck, and improved disease-free survival in a subset of patients with PNI and regional disease. An Australian retrospective study of patients with neck node-positive cSCC of the head and neck reported adjuvant RT was associated with improved disease-free survival and overall survival, compared with surgery alone.
Postoperative RT for cSCC of the groin and axilla increases locoregional control. Modern RT techniques, such as volumetric modulated arc therapy, achieves better dosimetry than three-dimensional conformal RT for regionally metastatic cSCC of groin and axilla, and can be used to assist in reducing significant treatment-related adverse events.
Curative radiotherapy as an alternative to lymphadenectomy for nodal metastases of squamous cell carcinoma[edit source]
If lymphadenectomy is not possible in a patient with nodal metastases of cSCC because the patient is unfit for surgery or declines surgery, curative radiotherapy alone for is indicated.
Salvage surgery is sometimes possible if complete or durable control is not achieved with radiotherapy alone.
Palliative radiotherapy[edit source]
Palliative radiotherapy is appropriate for inoperable, advanced regional metastases to treat pain, stave off skin ulceration, and reduce bleeding. It is unlikely to prolong survival.
Radiotherapy for dermal lymphatic spread (in-transit metastases) of keratinocyte cancers[edit source]
Dermal lymphatic spread (in-transit metastasis) of BCC or cSCC is a very uncommon condition and may be seen in association with regional spread and/or locally recurrent disease.
Wide surgical excision is indicated, followed by adjuvant RT. Further recurrence is not uncommon.
Radiotherapy for perineural invasion of basal cell carcinoma or squamous cell carcinoma[edit source]
A 2009 systematic review comparing surgical monotherapy with surgery plus adjuvant RT in patients with high-risk cutaneous squamous cell carcinoma found no controlled trials. In 74 cases of PNI reported in included observational studies, there was no statistically significant difference in outcomes between groups. Clear surgical margins were associated with better outcomes, while involvement of larger nerves was associated with worse outcomes. The benefit of adjuvant RT could not be determined on the data analysed A 2011 narrative review reached the same conclusion.
For symptomatic PNI, the involved nerve must be treated with RT back to the base of skull.
The use of adjuvant RT following Mohs micrographic surgery in cases with incidental PNI is controversial. Positive margins on PNI are associated with worse survival despite RT. Surgical resection of the involved nerve, which is usually followed by adjuvant RT, can be associated with long term remission. Alternatively, high-dose RT with palliative or curative intent covering the entire course of the nerve back to its origin from the central nervous system is acceptable. Relief of symptoms occurs in more than 50% of cases, with variable durability.
Practice Points[edit source]
PP 8.4.2. Modern radiotherapy techniques should be considered as the modality of choice for treating the regional lymph node basin, to limit rates of significant adverse events.
Clinically suspected lymph node metastases of keratinocyte cancer should be confirmed by fine needle aspiration cytology (under radiological guidance, if required). Open surgical biopsy should be avoided.
Symptoms of perineural invasion should be elicited at the time of patient assessment of cutaneous squamous cell carcinoma, especially in cases of persistent, recurrent or locally advanced lesions. A positive response should prompt referral to a specialist clinic for further investigations, which may include magnetic resonance imaging.
- Radiotherapy – Introduction
- Radiotherapy with or without surgical treatment for keratinocyte cancer
- Radiotherapy for basal cell carcinoma
- Radiotherapy for squamous cell carcinoma
- Radiotherapy for actinic keratosis and cutaneous squamous cell carcinoma in situ
- Radiotherapy for keratoacanthoma
- Recent advances in the radiotherapy of skin cancer
- Management of side effects of radiotherapy
- Radiotherapy – health system implications and discussion
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