Cutaneous squamous cell carcinoma of the head and neck (CSCCHN) represents 25% of all nonmelanoma skin cancers and is reaching epidemic proportions in many countries. The annual incidence directly relates to proximity to the equator, ranging from 16/100 000 in central Europe to 300/100 000 in Australia . Within Australia, the highest incidence is seen in Northern Queensland, where the rate exceeds 1300/100 000 men [2,3]. Risk factors include Caucasian background, male sex, age above 65 years, sun exposure, and immunodeficiency. With the current ozone depletion, an ageing world population and the increasing number of organ transplant recipients, the incidence is expected to increase [1–5].
High-risk squamous cell carcinoma and metastases to regional lymph nodes
In most patients with CSSCHN, the prognosis is good, with cure rates exceeding 95% where the primary tumour can be completely excised [4,6,7]. A recent systematic analysis reported the risk of local recurrence, regional metastases, distant metastases, and disease-specific death as 5, 5, 1, and 1%, respectively . The low rate of nodal metastases contrasts with that of mucosal squamous cell carcinoma (SCC), and management of lymph nodes has been restricted to the small subset of patients who develop regional disease. However, the rate of metastases may exceed 20% in patients with selected high-risk features, with overall survival declining to between 46 and 70% at 5 years [4,6,7,9,10].
Table 1 provides a list of clinicopathological factors that have been associated with an increased risk of nodal metastases [4,10]. Unfortunately, most data is based on retrospective studies where patients had already developed metastases. This tends to overestimate the effect of any particular factor, and makes determining their relative importance difficult. The largest prospective study comes from Germany , where 4% of 615 patients developed metastases, and this was associated with increased tumour thickness (hazard ratio 4.8 for tumours 2–6 mm thick compared with <2 mm), tumour size (hazard ratio 2.2 for tumours 2–5 cm diameter compared with <2 cm), location on the ear (hazard ratio 3.6), and immunosuppression (hazard ratio 4.3). Despite this very large series of patients, the small number of events (n = 26) makes reliable statistical modelling difficult and partially explains the variable results reported. Other studies have shown poor differentiation, desmoplasia, perineural invasion, and lymphovascular invasion to be potentially important predictors [11,12]. Immunosuppression, although uncommon, predisposes to aggressive and poorly differentiated tumours, with increased risk of nodal involvement and poor outcome. In the presence of immunosuppression, metastases may occur with smaller lesions, and at lesser depth of invasion. These patients are a major challenge due to extensive lesions with a high mortality, and the increasing rate of organ transplantation suggests the problem is likely to increase [13–17].
A feature of CSCCHN that contrasts with mucosal SCC is the high rate of extracapsular spread (ECS) in lymph nodes and soft-tissue deposits. Overall, approximately 70% of patients with regional metastases exhibit ECS or soft-tissue deposits, and these features have an important impact on survival due to their adverse association with regional failure and distant metastases [3,18,19,20•].
Patterns of lymph node metastases
The most common sites of nodal metastases from CSCCHN are the parotid gland, in particular the parotid tail/external jugular lymph node junction, and upper cervical nodes [11,12,21–23]. In patients with parotid metastases, it is standard practice to treat the neck due to the high rate of both clinical (26%) and occult neck disease (35%) .
There is considerable data indicating that the location of the primary predicts the site of nodal disease (Fig. 1). The commonest site of the index lesion is the lateral aspect of the head, and these tumours mostly metastasize to the parotid and level II nodes [22,24,25]. Retrospective data from three Australian cancer centres , including the Sydney Head and Neck Cancer Institute [26•], demonstrated that the parotid was involved in 75%, and level II in approximately 40% of patients. However, it should be remembered that the external jugular node may be reported as being part of either the parotid or level II. It is essential to ensure that this node is removed at the time of parotidectomy or neck dissection [22,23].
Therapeutic management of the neck in the absence of parotid metastases (P0N+)
Current recommendations are to perform a comprehensive neck dissection in the presence of cervical metastases from CSCCHS as shown in Table 2. It appears to be safe to perform more selective neck dissections when the primary is known, particularly where postoperative radiotherapy is planned (e.g., a level I–III neck dissection for anterior primaries and II–IV dissection for posterior scalp primaries). Other superficial nodes, such as facial, occipital and retro-auricular, are less frequently involved, but are important because they are not routinely removed in comprehensive neck dissections. Consideration should be given to removing these, and we routinely include the perifacial nodes in a level I dissection . Tumours arising from midline structures such as the nose, lip, and glabellar region are more likely to metastasize to level I nodes [24,27,28].
Elective management of the neck in the presence of parotid metastases (P+N0)
Whilst the high rate of cervical nodal involvement in patients with clinical parotid metastases mandates some form of treatment, there is considerable variation in approaches used. Treatment plans include parotidectomy with comprehensive parotid/neck irradiation, parotidectomy with selective neck dissection, and parotidectomy with comprehensive neck dissection. In those patients undergoing neck dissection, radiotherapy is usually administered but may also be selective or comprehensive.
The Sydney Head and Neck Cancer Institute has recently published its treatment philosophy based on a retrospective review of 295 neck dissections carried out for CSCCHN, summarized in Table 2 [26•]. This data demonstrated that, in patients with parotid metastases, levels II and III are crucial to predicting the presence of disease in other nodal groups depending on the location of the primary. Level I involvement in the absence of levels II or III only occurred in patients with anterior facial primaries (6%). There were no nodal metastases to levels IV or V in the absence of level II or III involvement, compared with a 4% risk when levels II or III were pathologically positive. Therefore, in the majority of patients with parotid metastases and a clinically negative neck, a combination of parotidectomy and selective levels II/III neck dissection will allow accurate staging of the neck. This has allowed a more selective approach to radiotherapy fields in these patients without the morbidity of routine comprehensive neck dissection, but requires a multidisciplinary approach, as shown in Fig. 2. It should be noted that, overall, 15% of patients with posterior primaries had metastases in levels IV–V without involvement of levels II–III; therefore, we do not extend this recommendation to posterior primaries in patients without parotid disease, where levels II–V dissection is more appropriate.
Elective management of the neck in the absence of parotid metastases (P0N0)
It is an accepted practice in mucosal SCC to treat N0 neck with elective neck dissection if the risk of occult metastases is greater than 20% . This principle should be applied with caution in CSCCHN, since the lymphatic drainage patterns are less predictable, with discordance in up to 80% of cases [29,30]. Accurately predicting patients at high risk of developing nodal metastases, the role of elective neck dissection and sentinel node biopsy are areas of ongoing research . The survival benefit of elective neck dissection must be balanced with the morbidity of the procedure, and there are very few studies to support its use in CSCCHN [31–33]. There may, however, be a role for sentinel node biopsy, as discussed below.
Nodal staging systems and implications of staging
One of the major advances in CSCCHN has been the development of prognostic models that allow stratification of patients according to risk of disease-related death and recurrence. Such prognostic models are crucial, for both treatment planning and clinical trials.
TNM staging system
Previously, the TNM staging system was not specific for CSSCHN and has had minimal clinical applicability and limited prognostic value. Excluding T4 disease, the only variable considered in T classification was horizontal dimension. N status did not discriminate between the number, size, and location of the nodes [34–37]. This has prompted a number of studies aimed at designing a staging system that could be applied in a similar manner to that of mucosal SCC. Fortunately, the latest edition (2010) of the American Joint Committee on Cancer (AJCC) staging manual  has taken a substantial amount of recent data into consideration.
O'Brien P/N system
The independent effect of lymph nodes in the parotid and neck was suggested by various studies [18,19,21,27]. O'Brien therefore proposed the P/N staging system (Table 3), to allow better assessment of the prognostic factors and treatment outcomes . Initially, this system was applied to a cohort of 72 patients, finding that increasing P stage, positive margins, and failure to give adjuvant radiotherapy were associated with decreased local control, and advanced neck disease had a negative impact on survival. These findings were validated in a different cohort of patients treated at the Westmead Cancer Centre, Sydney . The P/N system was then applied to 322 patients with metastatic CSCCHN in a multiinstitutional international trial, concluding that advanced P stage (P3) and neck disease (N1/2) were independently associated with reduced survival . Although the staging system was a major step forward, the model was complex and did not stratify risk well within P and N groups. However, the discrimination between parotid and neck metastases is still important, as it underlies our current treatment philosophies.
In an attempt to simplify the O'Brien P/N system and by incorporating the parotid as one of the regional nodal levels, we carried out a further analysis of clinical and pathological information from 215 patients treated with primary surgery for metastatic CSCCHN [20•]. N1S3 refers to the number (one or more) and size of nodes (<3 cm or >3 cm), which were found to be significant predictors of survival along with ECS. This system demonstrates significant predictive capacity for loco-regional control, disease-specific survival and overall survival. The findings were externally validated in a cohort of 250 patients treated at Westmead Cancer Centre. The N1S3 system shown in Table 3 is easily applied to both clinical and pathological data.
ITEM prognostic score
The ITEM prognostic score moves away from traditional models that can be applied clinically to include pathological information only available in the postoperative setting and separates patients into three (low, medium, and high) risk groups [39•]. It takes into account four variables (immunosuppression, treatment, extranodal spread and margin) that are significantly associated with survival to calculate the ITEM score. In the cohort of patients tested, the 5-year risk of dying from disease for patients with high-risk (>3.0), moderate-risk (>2.6–3.0), and low-risk (2.6) ITEM scores was 56%, 24%, and 6%, respectively. An inherent problem with the ITEM score is that untreated patients cannot be staged and the staging system cannot be used to select patients at low risk of recurrence who may be suitable for less intensive treatment regimens.
New TNM staging system
The seventh edition of the AJCC staging manual, as already mentioned before (Table 3), has incorporated current information available to make substantial changes to the T and N staging criteria. The T stage incorporates size, bone invasion and several pathological high-risk criteria (thickness, perineural invasion, site, and differentiation). The N staging criteria are identical to those of mucosal head and neck SCC, thus using extent of disease (nodal size and number), but introduces criteria that have not been validated, such as laterality of nodes.
Application of staging systems
The newer staging systems allow risk stratification in the management of CSCCHN (Fig. 2).
Low-risk metastatic cutaneous squamous cell carcinoma of the head and neck
The high rates of subclinical neck disease and ECS/soft tissue deposits make this a relatively small group of patients. We identified 168 N1S3 stage I patients from a total cohort of 465 patients with nodal metastases. In the stage I group, disease-specific survival at 5 years was 92%. In a small subset of patients treated with surgery alone (n = 33), regional control and survival at 5 years were 91% and 97%, respectively, indicating that selected low-risk patients may be suitable for single modality or de-intensification of therapy [26•].
Combined surgery and adjuvant radiotherapy is standard therapy for patients with metastatic CSCCHN, based on several studies showing improved loco-regional control and survival with radiotherapy [18,31,40].
There is little evidence at present for treatment intensification in metastatic CSCCHN; however, groups eligible are becoming more clearly defined [20•,39•]. N1S3 stage III (large >3 cm and multiple nodes) is associated with 42% disease-specific survival at 5 years. Immunosuppression and positive margins, as indicated by the ITEM score, represent other high-risk features, particularly in combination. Soft tissue deposits are associated with a worse prognosis when compared with patients with ECS and represent a high-risk group of patients.
Options for treatment intensification
The role of postoperative chemoradiation is being investigated by the Trans-Tasman Radiation Oncology Group . The primary objective of the trial is to determine whether there is a difference in time to loco-regional relapse between patients treated with postoperative concurrent chemo-radiotherapy, consisting of Carboplatin, and adjuvant radiotherapy alone. If the addition of chemotherapy is shown to be beneficial and safe, then these results are likely to be translated into standard practice quite rapidly. It will be important to ascertain whether any improvement in loco-regional control due to the addition of chemotherapy is also associated with improvement in quality of life compared with the control arm.
Epidermal growth factor receptor (EGFR) gene amplification and protein overexpression are common in several cancers. This gene, located on chromosome 7p12, codes for a member of the C-erbB receptors of the tyrosine kinase family. Responses triggered through EGFR signalling include epithelial tissue development, cell proliferation and promotion of tumour cell motility. EGFR numerical aberrations and amplifications are frequent in CSCCHN, and are associated with poor clinical outcomes [42–45]. EGFR signalling could be considered as a potential therapeutic target to inhibit the progressing of unresectable and metastatic CSCCHN . A recent study has highlighted the role of matrix metalloproteinase-7 and heparin-binding growth factor-like factor in progression of cutaneous SCC . The combination of radiotherapy with targeted EGFR therapy using Cetuximab for mucosal SCC of the head and neck has known efficacy; however, skin toxicity appears to be exaggerated in patients with extensive prior sun exposure, which may limit its utility in the CSCCHN population. Preclinical studies have demonstrated potentiation of radiotherapy with Erlotinib, but safety and efficacy in the clinical setting remain unknown .
Research and future direction
There is ongoing research pertaining to sentinel nodes and second echelon nodes.
Sentinel node biopsy and SNIC trial (phase I study)
Detection of early metastases by sentinel node biopsy (SNB) and early intervention might improve treatment outcomes, and have cost–benefit advantages compared with more extensive surgery for delayed, advanced lymphatic disease. Although SNB is an accurate, cost-effective and reproducible tool in the staging of N0 disease, survival benefit remains unproven and the role of SNB remains investigational [14,47]. The published studies are from small nonrandomized studies and with imprecise description of high-risk factors [48–53].
The SNIC trial will be conducted on patients with high-risk CSCCHN. The primary aim is to analyse disease-free and overall survival for patients who undergo wide excision and SNB with immediate completion lymph node clearance in case of a positive sentinel node versus patients who undergo wide excision of the primary lesion and postoperative serial ultrasound observation of the regional lymphatic basin. The secondary aims are to monitor the morbidity, detect genetic profiles corresponding to metastatic patterns, and evaluate quality of life and cost-effectiveness in both groups. A pilot study has commenced and, if feasible, the major phase III international, multicentre, randomized trial will proceed. Information on the trial can be obtained from http://www.shnci.org/Pages/research01.html.
The better understanding of the predictors and patterns of nodal metastases supports a more selective approach to the neck in the treatment of CSCCHN. The status of the parotid and level II/III nodes has important implications for management of the neck, and therefore dissection of level I and level IV/V nodes is required in selected cases only. Newer staging systems allow better prognostication, and intensification or de-intensification of treatment in selected cases, hence influencing treatment outcomes.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 139–140).
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