Available online at www.sciencedirect.com
British Journal of Oral and Maxillofacial Surgery 52 (2014) 294–300
Invited review
Management of regional metastatic disease in head and neck cutaneous malignancy.1. Cutaneous squamous cell carcinoma Ben Gurney, Carrie Newlands ∗ Royal Surrey County Hospital, United Kingdom Accepted 24 January 2014 Available online 20 February 2014
Abstract This overview is the first of 2 articles on the current evidence for management of the neck and parotid in cutaneous cancers of the head and neck. In this paper we discuss cutaneous squamous cell carcinoma (SCC) and review the latest evidence for management of the regional nodes. © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Keywords: Cutaneous squamous cell carcinoma; Neck dissection; Lymphatic metastasis; Radiotherapy
Introduction In this first paper of 2 giving an overview of the current evidence for management of the neck and parotid in cutaneous cancers of the head and neck, we discuss regional management of cutaneous squamous cell carcinoma (SCC); in the second we discuss cutaneous malignant melanoma.1 The single most important prognostic determinant in both diseases is nodal status.2 In both papers we outline the risk factors for metastasis from the primary tumour and discuss controversies over prognostic staging. Much of the understanding about lymphatics in the head and neck relates to mucosal SCC (SCC of the head and neck), whereas skin cancer has different patterns of spread through the superficial lymphatics, including the parotid nodes.
∗ Corresponding author at: Royal Surrey County Hospital, Egerton Road, Guildford GU2 7RF, United Kingdom. Tel.: +44 1483 571122; fax: +44 1483406647. E-mail address: [email protected] (C. Newlands).
We present current evidence for the roles of imaging and sentinel node biopsy in patients with no sign of metastasis, and discuss imaging and tissue sampling of those with suspected clinical involvement of regional nodes. We also outline evidence for the surgical and adjuvant management of patients with some metastases with reference to ongoing research in this field. It is interesting to note that much of the current research on skin cancer relates to populations not in the UK, and particularly in cutaneous malignant melanoma, to sites of disease that are not in the head and neck. Non-melanoma skin cancer The incidence of non-melanoma skin cancer is rising and is estimated to do so until 2040.3 This group of malignant skin tumours includes basal cell carcinoma (BCC) which is the most common human cancer to affect white people globally, cutaneous SCC which accounts for 20% of deaths from skin cancer,4 and the much rarer Merkel cell carcinoma. Metastatic BCC is exceedingly rare with roughly 300 cases reported, and most arise from neglected giant BCC or
0266-4356/$ – see front matter © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bjoms.2014.01.015
B. Gurney, C. Newlands / British Journal of Oral and Maxillofacial Surgery 52 (2014) 294–300 Table 1 High risk factors in cutaneous squamous cell carcinoma (SCC). Size: >2 cm Depth: >2 mm Primary site: Scalp, ear, or lip Recurrence Histological findings: Poorly differentiated, perineural spread, lymphovascular spread Immunosuppression
basosquamous carcinoma.5 Merkel cell carcinoma has high rates of recurrence and metastasis; it is not considered further in this article. Over 80% of cutaneous SCC affects the head and neck, and around 10 000 cases are estimated to occur annually in the UK.6 However, this figure may be considerably higher because of regional and historical variations in the inclusion of non-melanoma skin cancer in cancer registries.
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Table 2 American Joint Committee on Cancer (AJCC) 2009. Staging of cutaneous squamous cell carcinoma and other cutaneous carcinomas. Primary tumour (T): cutaneous SCC or basal cell carcinoma: Primary tumour cannot be assessed TX No evidence of primary tumour T0 Carcinoma in situ Tis Tumour up to 2 cm in greatest dimension T1 with less than 2 high-risk features Tumour 2 cm or more in greatest T2 dimension or any size of tumour with 2 or more high-risk features* T3 Tumour with invasion of maxilla, mandible, orbit or temporal bone Tumour with invasion of skeleton (axial T4 or appendicular) or perineural invasion of base of skull N and M staging follow the same AJCC Regional lymph nodes (N) Distant metastasis (M) categories as head and neck SCC ∗ High-risk features: >2 mm thickness, Clark level ≥ IV, perineural invasion, ear or non-hair-bearing lip, poorly differentiated or undifferentiated.
Primary tumours: risk factors (Table 1) Over the last decade there has been a move to subdivide primary cutaneous SCC into low and high-risk types, as they behave differently in terms of regional metastasis, and this affects prognosis.7 Most cutaneous SCC are small (less than 2 cm), thin (less than 2 mm), well differentiated, and previously untreated, and nodal metastasis is rare. They can be considered low risk and local treatment is curative.6 Treatment is often given by dermatologists, and as large numbers of cases have been excluded from head and neck surgical practice, considerably higher rates of recurrent and metastatic disease are being reported in series from surgical institutions. Several large pathological studies have shown that there are specific high risk factors for metastasis to regional lymph nodes, and the associated prognosis for 5-year survival deteriorates to 46% in patients with regional nodal involvement.8 Overall, cutaneous SCC may metastasise in up to 5% of patients in the UK,9 but in high risk types the rates have been shown to be much higher: 33% in those with poorly differentiated lesions, 45% in those with lesions more than 4 mm thick, and 47% in cases of perineural invasion.10 Immunosuppression after transplant, and concurrent haematological malignancies are well known to increase the incidence and risk of cutaneous SCC,4,6 and recently, biological treatment with anti-tumour necrosis factor (TNF) has been shown to have a similar effect. 11 Staging (Table 2) The 7th edition of the staging classification by the American Joint Committee on Cancer (AJCC) now incorporates risk in the T-staging for cutaneous SCC.12 The presence of 2 or more high risk factors gives a T1 tumour a T2 designation.13 However, immunosuppression is not included, although it is widely recognised to be a poor prognostic factor.14 Efforts have been made in this edition to create greater compatibility
between the staging of cutaneous SCC and that of SCC of the head and neck. Nodal burden has been shown to be an important factor in decreasing survival in patients with cutaneous disease,15 and nodal staging now takes account of the number and the size of nodal disease to correlate with staging in other head and neck cancers. The main omission is the status of the parotid. Cutaneous SCC commonly metastasises to the parotid, as the first echelon nodes are often located here, and the scalp and pinna are the commonest sites for primary lesions. Patients with involved parotid nodes have a high incidence of clinical (26%) or occult (35%) neck disease,16 and this has led to a call for an alternative classification which takes parotid status into account, and uses P0 and P+ to denote whether the parotid nodes are involved.16,17 In both these papers, N+ is used to denote nodal involvement in the neck.
Superficial lymphatics of the head and neck Much of the evidence regarding lymphatic drainage of the skin of the head and neck comes from studies of sentinel node biopsy in cutaneous malignant melanoma. Drainage patterns can vary, and in over 30% of cases they can differ from the classic anatomical understanding of the area.18 It is likely, but not well established, that this could also apply in cutaneous SCC. Superficial lymphatic pathways from the skin can drain to facial, parotid, postauricular, and occipital nodes, and nodes superficial to the sternocleidomastoid, particularly the external jugular node. Connections between the superficial lymphatics and between the superficial and deeper lymphatics are unpredictable. Cutaneous SCC of the external pinna in particular has been shown to have variable and unpredictable patterns of regional spread, but despite this variability, some common patterns are recognised (Fig. 1).10
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Elective lymph node dissection There is no role for elective lymph node dissection in P0/N0 cutaneous SCC of the head and neck as morbidity is high, and nodes involved in occult disease may be missed because of the complex patterns of lymphatic drainage.21,22 The role of sentinel node biopsy
Fig. 1. Cutaneous squamous cell carcinoma: patterns of metastasis to the external jugular node and the superficial lymphatics.
Site predilection of cutaneous SCC Cutaneous SCC of the head and neck most commonly spreads to the parotid nodes (67–82%) as the parotid is the drainage basin for the anterior scalp, temple and forehead, and pinna, where most primary tumours are located. Involved nodes are found mostly within the superficial lobe, but some are deep to the facial nerve and can be superficial to parotid fascia.19 Tumours of the posterior scalp (around 5% of cutaneous SCC of the head and neck) commonly spread to the occipital nodes, and facial skin is most likely to have first echelon nodes around the facial or parotid nodes. The lower lip in contrast, has oral mucosa that is embryologically keratinised on eversion. It drains to the deep system level I nodes of the neck, and behaves like other oral mucosal SCC in relation to lymphatic spread.10
Investigation of P0/N0 disease: the role of imaging, elective lymph node dissection, and sentinel node biopsy Imaging Modifications of the staging systems (2009 AJCC) have shown that the accurate staging of clinically detectable nodal metastases of the parotid or neck, or both, has prognostic benefits. However, in patients with a clinical classification of P0/N0, radiological imaging is not beneficial, so patients are educated and a policy of watchful waiting is adopted.20 In common with SCC of the head and neck, radiological examination of the regional nodes is not highly sensitive or specific in the absence of clinically detectable disease.
Sentinel node biopsy is increasingly becoming the worldwide standard of care in cutaneous malignant melanoma. Its application in cutaneous SCC has yet to be established, but a systematic review of a small case series published in 2006 showed that it can be used in high risk cutaneous SCC.23 Future research is likely to focus on establishing indications for its use in cases of clinically P0/N0 cutaneous disease, and to establish whether completion lymph node dissection in cases with a positive result, benefits survival. Early studies have shown it to have a high sensitivity, particularly in the head and neck, and a review of 130 cases of cutaneous SCC showed no false negatives in the head and neck, but 22% in other primary sites.24 A false negative result is recorded when the initial finding of sentinel node biopsy is negative, but the patient subsequently develops regional nodal disease. The results of MSLT-I, a randomised controlled trial designed to assess the role of sentinel node biopsy in cutaneous malignant melanoma, have caused controversy, and it remains to be seen whether the procedure improves overall survival.25 With regard to cutaneous SCC, its role in the early detection of occult metastatic disease continues to be explored (see section “Areas of ongoing research”).
Investigation of suspected nodal disease (P+ or N+, or both) (Table 3) Fine needle aspiration cytology (FNAC), core, and open biopsy If a clinically enlarged regional node is found in a patient with cutaneous SCC, FNAC is recommended; if it is not diagnostic it should be repeated, ideally with ultrasound guidance. As an alternative to FNAC, ultrasound-guided core biopsy can give a more representative histological specimen, and has been shown to have high diagnostic yield and accuracy in metastatic SCC.26 If these investigations fail to give a diagnosis twice and suspicion remains, the node should be excised through an incision that takes into account the possibility of a future neck dissection.20 Imaging Radiological imaging in patients with P+ or N+ disease, or both, may help to identify nodal involvement in other sites and can modify decisions regarding surgical and adjuvant treatment. Computed tomography (CT) and magnetic resonance
B. Gurney, C. Newlands / British Journal of Oral and Maxillofacial Surgery 52 (2014) 294–300
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Table 3 Summary of appropriate investigations in cutaneous squamous cell carcinoma (SCC).
Table 4 Indications for radiotherapy in cutaneous squamous cell carcinoma (SCC) with parotid status taken into consideration.
Clinical P/N status
Investigations
Site of radiotherapy
Indications
Neck
P0/N0
No imaging No elective lymph node dissection Consider sentinel node biopsy if high risk with or without clinical trial Fine needle aspiration with or without ultrasound guidance – repeat if negative Open biopsy through considered incision if negative and suspicious Computed tomography or magnetic resonance imaging skull base to clavicles for confirmed or obvious nodal involvement
More than 1 neck node involved Single neck node >3 cm (>N1 as per TNM head and neck SCC staging) Extracapsular spread More than 1 parotid node involved Single parotid node >3 cm Extracapsular spread P0/N+ with primary site on anterolateral scalp or pinna P+/N+ any number of nodes involved
P+/N+
imaging (MRI) have similar sensitivity (81%) in detecting neck disease, although CT shows better specificity.22 Ultrasound shows higher sensitivity in parotid (80%) and neck disease (87%) than other methods; ultrasound-guided FNAC has up to 98% specificity for diagnosis of metastatic SCC.22,24
Management of established nodal disease (P+ or N+, or both) Operation is the primary treatment for established nodal involvement in cutaneous SCC. Dissection should include involved parotid tissue and levels in the neck, and extend to nodal levels where there is a high risk of occult disease.20 Extra care should be taken with the superficial lymphatics, not usually considered in SCC of the head and neck. Of note, in contrast to disease of the head and neck, up to 70% of patients with cutaneous SCC and nodal metastasis have extracapsular spread.27 Involvement of more than a single node is also common, and many patients require adjuvant radiotherapy (Table 4).
Management of the parotid gland in patients with P+/N0 disease As the superficial lobe of the parotid is the commonest site for nodal metastasis, “therapeutic” parotid surgery is usually superficial parotidectomy. Involvement of the skin, deep lobe, or facial nerve, will require more extensive resection.21 In patients with clinical metastatic disease deep to the plane of the facial nerve, and preoperative facial nerve palsy, radical total parotidectomy with frozen section of the proximal stump of the facial nerve is the therapeutic parotid operation of choice.16 Those with disease involving the facial nerve but normal preoperative function can be treated successfully with a nerve-sparing approach and timely adjuvant radiotherapy. 28
Parotid
Neck and parotid
Management of the neck in patients with P+/N0 disease Studies have shown that involvement of the parotid gland correlates with a high incidence of occult involved neck nodes (36%).10 Recommendations based on 295 neck dissections in patients with cutaneous SCC of the head and neck from The Sydney Head and Neck Cancer Institute have recently been published.29 Primary sites are mostly lateralised to the lateral aspect of the head including the external ear (anterolateral primary sites). The pattern of occult neck involvement in these patients, and therefore the commonest pattern seen in those with P+/N0 disease, is for positive nodes in level II including the external jugular node, and in level III. Cutaneous SCC of the facial skin with P+/N0 nodal status may show occult disease in the facial nodes and in level I, while disease in the posterolateral scalp or neck usually involves occipital or postauricular nodes and levels IV and V. A selective regional approach for elective neck dissection in these patients may therefore be appropriate (in addition to therapeutic parotid dissection), with neck dissection of levels I–III for facial primaries, levels II–III for primaries of the anterior scalp and external ear, and levels II–V for primaries of the posterior scalp and neck. Level I can be safely omitted except for midline facial primaries.29,30 Management of the parotid gland in patients with P0/N+ disease If the primary site and likely drainage (Fig. 1) suggest a risk of occult metastasis in the parotid, elective superficial parotidectomy can be considered. However, it is worth remembering that postoperative adjuvant radiotherapy to the neck is likely to be required in this group, so irradiation of the parotid gland could also be included to address occult disease and to reduce the risk of surgical morbidity to the facial nerve (Table 5). Management of the neck in patients with P0/N+ disease Previously, comprehensive therapeutic neck dissection of levels I-V has been recommended for patients with P0/N+
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Table 5 Summary of management for established nodal involvement in the parotid (P) or neck (N), or both, in cutaneous squamous cell carcinoma (SCC). For indications for radiotherapy see Table 4. Parotid or neck involvement
Primary site
Operation
Adjuvant radiotherapy
P+/N0
Anterior face and neck Anterior scalp, posterior face and pinna Posterior scalp and neck Anterior face and neck Anterior scalp, posterior face, and pinna Posterior scalp
Therapeutic parotidectomy and levels I–III including facial and external jugular nodes Therapeutic parotidectomy and levels II–III including facial and external jugular nodes
To parotid or neck if indicated
To parotid or neck if indicated
Posterior neck
Therapeutic parotidectomy and levels II–V including occipital and post-auricular nodes Levels I–V including facial and external jugular nodes, or consider I–III Superficial parotidectomy if radiotherapy unlikely and levels I–V including facial and external jugular nodes, or consider II–V Superficial parotidectomy if radiotherapy unlikely and levels I–V including occipital and post-auricular nodes, or consider II–V Levels II–V including occipital and post-auricular nodes
Any site
Therapeutic parotidectomy and levels I–V
P0/N+
P+/N+
disease. More recently, opinion has supported super-selective neck dissection when the site of the primary is known, particularly when postoperative radiotherapy is planned – for example, level I–III neck dissection for an anterior primary, and II to V for a posterior primary.22 Adjuvant radiotherapy is then given accordingly.
Management of the parotid and neck in patients with P+/N+ disease In patients with involvement of the parotid gland and the neck, therapeutic parotidectomy and comprehensive neck dissection are recommended, as the rate of level V involvement in this group is 30%.10
Adjuvant therapy in metastatic cutaneous SCC Radiotherapy Cutaneous SCC is radiosensitive and several different types of therapeutic methods of radiotherapy are used worldwide, including external beam, low voltage X-rays, and electrons. Retrospective studies suggest that adjuvant radiotherapy improves locoregional control and survival when the neck is staged higher than N1, or when there is extracapsular spread.27,31 The status of the parotid and site of the primary tumour should also be considered (Table 4). Chemotherapy The addition of postoperative platinum-based chemotherapy has shown benefit but has limitations in terms of toxicity.31
To parotid or neck if indicated
To neck if indicated To parotid if not electively dissected or neck, or both, if indicated To parotid if not electively dissected or neck, or both, if indicated To neck if indicated To parotid and neck if indicated
Biological treatments One of the main recent advances in the management of cutaneous malignancy is the development of targeted therapy: anti-patched/sonic hedgehog for BCC,32 anti-epidermal growth factor receptor (EGFR) for cutaneous SCC,33 and anti-BRAF for cutaneous malignant melanoma.34 The potential of the monoclonal antibody cetuximab against EGFR is increasingly being studied. Patients with cutaneous SCC have been shown to have an over expression of EGFR in metastatic disease. Current evidence of the efficacy of cetuximab in non-melanoma skin cancer comes from a phase II trial and case reports.35,36 Cetuximab combined with radiotherapy results in a complete response rate of 50%, which seems to be superior to its use alone,37 but further controlled trials are needed. Other studies have shown a clinical response in patients to the EGFR tyrosine kinase inhibitors, gefitinib38 and erlotinib (Read WL. Squamous carcinoma of the skin responding to erlotinib: three cases. Paper presented at the Annual Scientific Meeting of the American Society of Clinical Oncology (ASCO), Chicago, June 2007).
Areas of ongoing research Prospective randomised trial of sentinel node biopsy for high risk non-melanoma skin cancer (SNIC) The SNIC trial is a randomised multicentre trial in which patients with high-risk cutaneous SCC and clinical P0/N0 nodal status will be allocated to standard watch-and-wait management or staging by sentinel node biopsy. If the biopsy shows evidence of metastatic disease they will have a
B. Gurney, C. Newlands / British Journal of Oral and Maxillofacial Surgery 52 (2014) 294–300
completion neck dissection of the area around the lymph nodes. Phases I and II are currently underway.39 3.
Study of cetuximab in SCC of the skin in patients expressing EGFR (CTXSCC) As a first-line treatment in patients with unresectable cutaneous SCC who express EGFR, cetuximab has achieved 69% disease control in phase II of this French multicentre trial. A randomised phase III trial is now warranted.35
4.
5.
6.
N1S3 staging study 7.
The aim of this study was to produce a staging system that incorporates parotid status and enables better prognostic discrimination between subgroups of patients with metastatic disease. The N1S3 system shows significant predictive capacity for locoregional control, and disease-specific and overall survival, but is yet to be adopted widely.40
8.
9.
10.
Conclusion 11.
Cutaneous SCC continues to cause death when it metastasises, but predisposing high-risk factors for this are now better defined and recognised in staging systems. The anatomical site of the primary tumour and the first involved nodes, although not always consistent, can be used to predict the pattern of spread, but the status of the parotid gland is important in planning treatment. Staging systems and guidelines require further improvement so that treatment can be tailored to the individual patient. The role of sentinel node biopsy in the staging process continues to evolve and promises to aid management in patients with high-risk disease, but its benefits have yet to be proved. Research into chemoradiotherapy regimens and the role of targeted treatment for non-melanoma skin cancer is continuing, but they will have to show a benefit in survival before being adopted into practice.
12. 13.
14.
15.
16.
17.
Conflict of interest There is no conflict of interest.
Ethical approval No ethical approval is required.
18.
19.
20.
References 21. 1. Newlands C, Gurney B. Management of regional metastatic disease in head and neck cutaneous malignancy. 2. Cutaneous malignant melanoma. Br J Oral Maxillofac Surg 2014;52:301–7. 2. National Institute for Health and Care Excellence. Improving outcomes for people with skin tumours including melanoma; February
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2006. Available from: http://guidance.nice.org.uk/CSGSTIM/Guidance/ Standard2006/pdf/English The British Association of Dermatology. Available from: http://www. bad.org.uk Rowe DE, Carroll RJ, Day Jr CL. Prognostic factors for local recurrence, metastasis and survival rates in squamous cell carcinoma of the skin, ear and lip. Implications for treatment modality selection. J Am Acad Dermatol 1992;26:976–90. Ting PT, Kasper R, Arlette JP. Metastatic basal cell carcinoma: report of two cases and literature review. J Cutan Med Surg 2005;9: 10–5. Motley RJ, Preston PW, Lawrence CM. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma; 2009. Available from: http://www.bad.org.uk Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. Part one. J Cutan Pathol 2006;33:191–206. Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol 2008;9:713–20. Mourouzis C, Boynton A, Grant J, et al. Cutaneous head and neck SCCs and risk of nodal metastasis – UK experience. J Craniomaxillofac Surg 2009;37:443–7. Vauterin TJ, Veness MJ, Morgan GJ, et al. Patterns of lymph node spread of cutaneous squamous cell carcinoma of the head and neck. Head Neck 2006;28:785–91. Le Blay P, Mouterde G, Barnetche T, et al. Risk of malignancy including non-melanoma skin cancers with anti-tumor necrosis factor therapy in patients with rheumatoid arthritis: meta-analysis of registries and systematic review of long-term extension studies. Clin Exp Rheumatol 2012;30:756–64. Edge SB, Byrd DR, Compton CC, et al., editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. Lardaro T, Shea SM, Sharfman W, et al. Improvements in the staging of cutaneous squamous-cell carcinoma in the 7th edition of the AJCC Cancer Staging Manual. Ann Surg Oncol 2010;17:1979–80. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999;40:177–86. Andruchow JL, Veness MJ, Morgan GJ, et al. Implications for clinical staging of metastatic cutaneous squamous carcinoma of the head and neck based on a multicenter study of treatment outcomes. Cancer 2006;106:1078–83. O’Brien CJ, McNeil EB, McMahon JD, et al. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous cell carcinoma of the parotid gland. Head Neck 2002;24:417–22. Ch’ng S, Maitra A, Allison RS, et al. Parotid and cervical nodal status predict prognosis for patients with head and neck metastatic cutaneous squamous cell carcinoma. J Surg Oncol 2008;98: 101–5. Agnese DM, Maupin R, Tillman B, et al. Head and neck melanoma in the sentinel lymph node era. Arch Otolaryngol Head Neck Surg 2007;133:1121–4. Veness MJ, Porceddu S, Palme CE, et al. Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes. Head Neck 2007;29:621–31. Roland NJ, Paleri V, editors. Head and neck cancer: multidisciplinary management guidelines. 4th ed. London: ENT UK; 2011. p. 199–209. Available from: http://www.bahno.org.uk/docs/head and neck cancer.pdf Martinez JC, Cook JL. High-risk cutaneous squamous cell carcinoma without palpable lymphadenopathy: is there a therapeutic role for elective neck dissection? Dermatol Surg 2007;33:410–20. D’Souza J, Clark J. Management of the neck in metastatic cutaneous squamous cell carcinoma of the head and neck. Curr Opin Otolaryngol Head Neck Surg 2011;19:99–105.
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23. Ross AS, Schmults CD. Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature. Dermatol Surg 2006;32:1309–21. 24. Kwon S, Dong ZM, Wu PC. Sentinel lymph node biopsy for high-risk cutaneous squamous cell carcinoma: clinical experience and review of literature. World J Surg Oncol 2011;9:80. 25. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355:1307–17. 26. Saha S, Woodhouse NR, Gok G, et al. Ultrasound guided core biopsy, fine needle aspiration cytology and surgical excision biopsy in the diagnosis of metastatic squamous cell carcinoma in the head and neck: an eleven year experience. Eur J Radiol 2011;80:792–5. 27. Veness MJ, Palme CE, Smith M, et al. Cutaneous head and neck squamous cell carcinoma metastatic to cervical lymph nodes (nonparotid): a better outcome with surgery and adjuvant radiotherapy. Laryngoscope 2003;113:1827–33. 28. Iyer NG, Clark JR, Murali R, et al. Outcomes following parotidectomy for metastatic squamous cell carcinoma with microscopic residual disease: implications for facial nerve preservation. Head Neck 2009;31: 21–7. 29. Ebrahimi A, Moncrieff MD, Clark JR, et al. Predicting the pattern of regional metastases from cutaneous squamous cell carcinoma of the head and neck based on location of the primary. Head Neck 2010;32: 1288–94. 30. O’Hara J, Ferlito A, Takes RP, et al. Cutaneous squamous cell carcinoma of the head and neck metastasizing to the parotid gland – a review of current recommendations. Head Neck 2011;33:1789–95.
31. Apisarnthanarax S, Dhruva N, Ardeshirpour F, et al. Concomitant radiotherapy and chemotherapy for high-risk nonmelanoma skin carcinomas of the head and neck. Int J Surg Oncol 2011;2011:464829. 32. Lupi O. Correlations between the Sonic Hedgehog pathway and basal cell carcinoma. Int J Dermatol 2007;46:1113–7. 33. Ch’ng S, Low I, Ng D, et al. Epidermal growth factor receptor: a novel biomarker for aggressive head and neck cutaneous squamous cell carcinoma. Hum Pathol 2008;39:344–9. 34. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:707–14. 35. Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol 2011;29:3419–26. 36. Miller K, Sherman W, Ratner D. Complete clinical response to cetuximab in a patient with metastatic cutaneous squamous cell carcinoma. Dermatol Surg 2010;36:2069–74. 37. Wollina U. Cetuximab in non-melanoma skin cancer. Expert Opin Biol Ther 2012;12:949–56. 38. Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res 2012;18:1435–46. 39. SNIC trial. Available from: http://www.shnci.org/snic-trial.html 40. Forest VI, Clark JJ, Veness MJ, et al. N1S3: a revised staging system for head and neck cutaneous squamous cell carcinoma with lymph node metastases: results of 2 Australian Cancer Centers. Cancer 2010;116:1298–304.
British Journal of Oral and Maxillofacial Surgery 52 (2014) 294–300
Invited review
Management of regional metastatic disease in head and neck cutaneous malignancy.1. Cutaneous squamous cell carcinoma Ben Gurney, Carrie Newlands ∗ Royal Surrey County Hospital, United Kingdom Accepted 24 January 2014 Available online 20 February 2014
Abstract This overview is the first of 2 articles on the current evidence for management of the neck and parotid in cutaneous cancers of the head and neck. In this paper we discuss cutaneous squamous cell carcinoma (SCC) and review the latest evidence for management of the regional nodes. © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Keywords: Cutaneous squamous cell carcinoma; Neck dissection; Lymphatic metastasis; Radiotherapy
Introduction In this first paper of 2 giving an overview of the current evidence for management of the neck and parotid in cutaneous cancers of the head and neck, we discuss regional management of cutaneous squamous cell carcinoma (SCC); in the second we discuss cutaneous malignant melanoma.1 The single most important prognostic determinant in both diseases is nodal status.2 In both papers we outline the risk factors for metastasis from the primary tumour and discuss controversies over prognostic staging. Much of the understanding about lymphatics in the head and neck relates to mucosal SCC (SCC of the head and neck), whereas skin cancer has different patterns of spread through the superficial lymphatics, including the parotid nodes.
∗ Corresponding author at: Royal Surrey County Hospital, Egerton Road, Guildford GU2 7RF, United Kingdom. Tel.: +44 1483 571122; fax: +44 1483406647. E-mail address: [email protected] (C. Newlands).
We present current evidence for the roles of imaging and sentinel node biopsy in patients with no sign of metastasis, and discuss imaging and tissue sampling of those with suspected clinical involvement of regional nodes. We also outline evidence for the surgical and adjuvant management of patients with some metastases with reference to ongoing research in this field. It is interesting to note that much of the current research on skin cancer relates to populations not in the UK, and particularly in cutaneous malignant melanoma, to sites of disease that are not in the head and neck. Non-melanoma skin cancer The incidence of non-melanoma skin cancer is rising and is estimated to do so until 2040.3 This group of malignant skin tumours includes basal cell carcinoma (BCC) which is the most common human cancer to affect white people globally, cutaneous SCC which accounts for 20% of deaths from skin cancer,4 and the much rarer Merkel cell carcinoma. Metastatic BCC is exceedingly rare with roughly 300 cases reported, and most arise from neglected giant BCC or
0266-4356/$ – see front matter © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bjoms.2014.01.015
B. Gurney, C. Newlands / British Journal of Oral and Maxillofacial Surgery 52 (2014) 294–300 Table 1 High risk factors in cutaneous squamous cell carcinoma (SCC). Size: >2 cm Depth: >2 mm Primary site: Scalp, ear, or lip Recurrence Histological findings: Poorly differentiated, perineural spread, lymphovascular spread Immunosuppression
basosquamous carcinoma.5 Merkel cell carcinoma has high rates of recurrence and metastasis; it is not considered further in this article. Over 80% of cutaneous SCC affects the head and neck, and around 10 000 cases are estimated to occur annually in the UK.6 However, this figure may be considerably higher because of regional and historical variations in the inclusion of non-melanoma skin cancer in cancer registries.
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Table 2 American Joint Committee on Cancer (AJCC) 2009. Staging of cutaneous squamous cell carcinoma and other cutaneous carcinomas. Primary tumour (T): cutaneous SCC or basal cell carcinoma: Primary tumour cannot be assessed TX No evidence of primary tumour T0 Carcinoma in situ Tis Tumour up to 2 cm in greatest dimension T1 with less than 2 high-risk features Tumour 2 cm or more in greatest T2 dimension or any size of tumour with 2 or more high-risk features* T3 Tumour with invasion of maxilla, mandible, orbit or temporal bone Tumour with invasion of skeleton (axial T4 or appendicular) or perineural invasion of base of skull N and M staging follow the same AJCC Regional lymph nodes (N) Distant metastasis (M) categories as head and neck SCC ∗ High-risk features: >2 mm thickness, Clark level ≥ IV, perineural invasion, ear or non-hair-bearing lip, poorly differentiated or undifferentiated.
Primary tumours: risk factors (Table 1) Over the last decade there has been a move to subdivide primary cutaneous SCC into low and high-risk types, as they behave differently in terms of regional metastasis, and this affects prognosis.7 Most cutaneous SCC are small (less than 2 cm), thin (less than 2 mm), well differentiated, and previously untreated, and nodal metastasis is rare. They can be considered low risk and local treatment is curative.6 Treatment is often given by dermatologists, and as large numbers of cases have been excluded from head and neck surgical practice, considerably higher rates of recurrent and metastatic disease are being reported in series from surgical institutions. Several large pathological studies have shown that there are specific high risk factors for metastasis to regional lymph nodes, and the associated prognosis for 5-year survival deteriorates to 46% in patients with regional nodal involvement.8 Overall, cutaneous SCC may metastasise in up to 5% of patients in the UK,9 but in high risk types the rates have been shown to be much higher: 33% in those with poorly differentiated lesions, 45% in those with lesions more than 4 mm thick, and 47% in cases of perineural invasion.10 Immunosuppression after transplant, and concurrent haematological malignancies are well known to increase the incidence and risk of cutaneous SCC,4,6 and recently, biological treatment with anti-tumour necrosis factor (TNF) has been shown to have a similar effect. 11 Staging (Table 2) The 7th edition of the staging classification by the American Joint Committee on Cancer (AJCC) now incorporates risk in the T-staging for cutaneous SCC.12 The presence of 2 or more high risk factors gives a T1 tumour a T2 designation.13 However, immunosuppression is not included, although it is widely recognised to be a poor prognostic factor.14 Efforts have been made in this edition to create greater compatibility
between the staging of cutaneous SCC and that of SCC of the head and neck. Nodal burden has been shown to be an important factor in decreasing survival in patients with cutaneous disease,15 and nodal staging now takes account of the number and the size of nodal disease to correlate with staging in other head and neck cancers. The main omission is the status of the parotid. Cutaneous SCC commonly metastasises to the parotid, as the first echelon nodes are often located here, and the scalp and pinna are the commonest sites for primary lesions. Patients with involved parotid nodes have a high incidence of clinical (26%) or occult (35%) neck disease,16 and this has led to a call for an alternative classification which takes parotid status into account, and uses P0 and P+ to denote whether the parotid nodes are involved.16,17 In both these papers, N+ is used to denote nodal involvement in the neck.
Superficial lymphatics of the head and neck Much of the evidence regarding lymphatic drainage of the skin of the head and neck comes from studies of sentinel node biopsy in cutaneous malignant melanoma. Drainage patterns can vary, and in over 30% of cases they can differ from the classic anatomical understanding of the area.18 It is likely, but not well established, that this could also apply in cutaneous SCC. Superficial lymphatic pathways from the skin can drain to facial, parotid, postauricular, and occipital nodes, and nodes superficial to the sternocleidomastoid, particularly the external jugular node. Connections between the superficial lymphatics and between the superficial and deeper lymphatics are unpredictable. Cutaneous SCC of the external pinna in particular has been shown to have variable and unpredictable patterns of regional spread, but despite this variability, some common patterns are recognised (Fig. 1).10
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Elective lymph node dissection There is no role for elective lymph node dissection in P0/N0 cutaneous SCC of the head and neck as morbidity is high, and nodes involved in occult disease may be missed because of the complex patterns of lymphatic drainage.21,22 The role of sentinel node biopsy
Fig. 1. Cutaneous squamous cell carcinoma: patterns of metastasis to the external jugular node and the superficial lymphatics.
Site predilection of cutaneous SCC Cutaneous SCC of the head and neck most commonly spreads to the parotid nodes (67–82%) as the parotid is the drainage basin for the anterior scalp, temple and forehead, and pinna, where most primary tumours are located. Involved nodes are found mostly within the superficial lobe, but some are deep to the facial nerve and can be superficial to parotid fascia.19 Tumours of the posterior scalp (around 5% of cutaneous SCC of the head and neck) commonly spread to the occipital nodes, and facial skin is most likely to have first echelon nodes around the facial or parotid nodes. The lower lip in contrast, has oral mucosa that is embryologically keratinised on eversion. It drains to the deep system level I nodes of the neck, and behaves like other oral mucosal SCC in relation to lymphatic spread.10
Investigation of P0/N0 disease: the role of imaging, elective lymph node dissection, and sentinel node biopsy Imaging Modifications of the staging systems (2009 AJCC) have shown that the accurate staging of clinically detectable nodal metastases of the parotid or neck, or both, has prognostic benefits. However, in patients with a clinical classification of P0/N0, radiological imaging is not beneficial, so patients are educated and a policy of watchful waiting is adopted.20 In common with SCC of the head and neck, radiological examination of the regional nodes is not highly sensitive or specific in the absence of clinically detectable disease.
Sentinel node biopsy is increasingly becoming the worldwide standard of care in cutaneous malignant melanoma. Its application in cutaneous SCC has yet to be established, but a systematic review of a small case series published in 2006 showed that it can be used in high risk cutaneous SCC.23 Future research is likely to focus on establishing indications for its use in cases of clinically P0/N0 cutaneous disease, and to establish whether completion lymph node dissection in cases with a positive result, benefits survival. Early studies have shown it to have a high sensitivity, particularly in the head and neck, and a review of 130 cases of cutaneous SCC showed no false negatives in the head and neck, but 22% in other primary sites.24 A false negative result is recorded when the initial finding of sentinel node biopsy is negative, but the patient subsequently develops regional nodal disease. The results of MSLT-I, a randomised controlled trial designed to assess the role of sentinel node biopsy in cutaneous malignant melanoma, have caused controversy, and it remains to be seen whether the procedure improves overall survival.25 With regard to cutaneous SCC, its role in the early detection of occult metastatic disease continues to be explored (see section “Areas of ongoing research”).
Investigation of suspected nodal disease (P+ or N+, or both) (Table 3) Fine needle aspiration cytology (FNAC), core, and open biopsy If a clinically enlarged regional node is found in a patient with cutaneous SCC, FNAC is recommended; if it is not diagnostic it should be repeated, ideally with ultrasound guidance. As an alternative to FNAC, ultrasound-guided core biopsy can give a more representative histological specimen, and has been shown to have high diagnostic yield and accuracy in metastatic SCC.26 If these investigations fail to give a diagnosis twice and suspicion remains, the node should be excised through an incision that takes into account the possibility of a future neck dissection.20 Imaging Radiological imaging in patients with P+ or N+ disease, or both, may help to identify nodal involvement in other sites and can modify decisions regarding surgical and adjuvant treatment. Computed tomography (CT) and magnetic resonance
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Table 3 Summary of appropriate investigations in cutaneous squamous cell carcinoma (SCC).
Table 4 Indications for radiotherapy in cutaneous squamous cell carcinoma (SCC) with parotid status taken into consideration.
Clinical P/N status
Investigations
Site of radiotherapy
Indications
Neck
P0/N0
No imaging No elective lymph node dissection Consider sentinel node biopsy if high risk with or without clinical trial Fine needle aspiration with or without ultrasound guidance – repeat if negative Open biopsy through considered incision if negative and suspicious Computed tomography or magnetic resonance imaging skull base to clavicles for confirmed or obvious nodal involvement
More than 1 neck node involved Single neck node >3 cm (>N1 as per TNM head and neck SCC staging) Extracapsular spread More than 1 parotid node involved Single parotid node >3 cm Extracapsular spread P0/N+ with primary site on anterolateral scalp or pinna P+/N+ any number of nodes involved
P+/N+
imaging (MRI) have similar sensitivity (81%) in detecting neck disease, although CT shows better specificity.22 Ultrasound shows higher sensitivity in parotid (80%) and neck disease (87%) than other methods; ultrasound-guided FNAC has up to 98% specificity for diagnosis of metastatic SCC.22,24
Management of established nodal disease (P+ or N+, or both) Operation is the primary treatment for established nodal involvement in cutaneous SCC. Dissection should include involved parotid tissue and levels in the neck, and extend to nodal levels where there is a high risk of occult disease.20 Extra care should be taken with the superficial lymphatics, not usually considered in SCC of the head and neck. Of note, in contrast to disease of the head and neck, up to 70% of patients with cutaneous SCC and nodal metastasis have extracapsular spread.27 Involvement of more than a single node is also common, and many patients require adjuvant radiotherapy (Table 4).
Management of the parotid gland in patients with P+/N0 disease As the superficial lobe of the parotid is the commonest site for nodal metastasis, “therapeutic” parotid surgery is usually superficial parotidectomy. Involvement of the skin, deep lobe, or facial nerve, will require more extensive resection.21 In patients with clinical metastatic disease deep to the plane of the facial nerve, and preoperative facial nerve palsy, radical total parotidectomy with frozen section of the proximal stump of the facial nerve is the therapeutic parotid operation of choice.16 Those with disease involving the facial nerve but normal preoperative function can be treated successfully with a nerve-sparing approach and timely adjuvant radiotherapy. 28
Parotid
Neck and parotid
Management of the neck in patients with P+/N0 disease Studies have shown that involvement of the parotid gland correlates with a high incidence of occult involved neck nodes (36%).10 Recommendations based on 295 neck dissections in patients with cutaneous SCC of the head and neck from The Sydney Head and Neck Cancer Institute have recently been published.29 Primary sites are mostly lateralised to the lateral aspect of the head including the external ear (anterolateral primary sites). The pattern of occult neck involvement in these patients, and therefore the commonest pattern seen in those with P+/N0 disease, is for positive nodes in level II including the external jugular node, and in level III. Cutaneous SCC of the facial skin with P+/N0 nodal status may show occult disease in the facial nodes and in level I, while disease in the posterolateral scalp or neck usually involves occipital or postauricular nodes and levels IV and V. A selective regional approach for elective neck dissection in these patients may therefore be appropriate (in addition to therapeutic parotid dissection), with neck dissection of levels I–III for facial primaries, levels II–III for primaries of the anterior scalp and external ear, and levels II–V for primaries of the posterior scalp and neck. Level I can be safely omitted except for midline facial primaries.29,30 Management of the parotid gland in patients with P0/N+ disease If the primary site and likely drainage (Fig. 1) suggest a risk of occult metastasis in the parotid, elective superficial parotidectomy can be considered. However, it is worth remembering that postoperative adjuvant radiotherapy to the neck is likely to be required in this group, so irradiation of the parotid gland could also be included to address occult disease and to reduce the risk of surgical morbidity to the facial nerve (Table 5). Management of the neck in patients with P0/N+ disease Previously, comprehensive therapeutic neck dissection of levels I-V has been recommended for patients with P0/N+
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Table 5 Summary of management for established nodal involvement in the parotid (P) or neck (N), or both, in cutaneous squamous cell carcinoma (SCC). For indications for radiotherapy see Table 4. Parotid or neck involvement
Primary site
Operation
Adjuvant radiotherapy
P+/N0
Anterior face and neck Anterior scalp, posterior face and pinna Posterior scalp and neck Anterior face and neck Anterior scalp, posterior face, and pinna Posterior scalp
Therapeutic parotidectomy and levels I–III including facial and external jugular nodes Therapeutic parotidectomy and levels II–III including facial and external jugular nodes
To parotid or neck if indicated
To parotid or neck if indicated
Posterior neck
Therapeutic parotidectomy and levels II–V including occipital and post-auricular nodes Levels I–V including facial and external jugular nodes, or consider I–III Superficial parotidectomy if radiotherapy unlikely and levels I–V including facial and external jugular nodes, or consider II–V Superficial parotidectomy if radiotherapy unlikely and levels I–V including occipital and post-auricular nodes, or consider II–V Levels II–V including occipital and post-auricular nodes
Any site
Therapeutic parotidectomy and levels I–V
P0/N+
P+/N+
disease. More recently, opinion has supported super-selective neck dissection when the site of the primary is known, particularly when postoperative radiotherapy is planned – for example, level I–III neck dissection for an anterior primary, and II to V for a posterior primary.22 Adjuvant radiotherapy is then given accordingly.
Management of the parotid and neck in patients with P+/N+ disease In patients with involvement of the parotid gland and the neck, therapeutic parotidectomy and comprehensive neck dissection are recommended, as the rate of level V involvement in this group is 30%.10
Adjuvant therapy in metastatic cutaneous SCC Radiotherapy Cutaneous SCC is radiosensitive and several different types of therapeutic methods of radiotherapy are used worldwide, including external beam, low voltage X-rays, and electrons. Retrospective studies suggest that adjuvant radiotherapy improves locoregional control and survival when the neck is staged higher than N1, or when there is extracapsular spread.27,31 The status of the parotid and site of the primary tumour should also be considered (Table 4). Chemotherapy The addition of postoperative platinum-based chemotherapy has shown benefit but has limitations in terms of toxicity.31
To parotid or neck if indicated
To neck if indicated To parotid if not electively dissected or neck, or both, if indicated To parotid if not electively dissected or neck, or both, if indicated To neck if indicated To parotid and neck if indicated
Biological treatments One of the main recent advances in the management of cutaneous malignancy is the development of targeted therapy: anti-patched/sonic hedgehog for BCC,32 anti-epidermal growth factor receptor (EGFR) for cutaneous SCC,33 and anti-BRAF for cutaneous malignant melanoma.34 The potential of the monoclonal antibody cetuximab against EGFR is increasingly being studied. Patients with cutaneous SCC have been shown to have an over expression of EGFR in metastatic disease. Current evidence of the efficacy of cetuximab in non-melanoma skin cancer comes from a phase II trial and case reports.35,36 Cetuximab combined with radiotherapy results in a complete response rate of 50%, which seems to be superior to its use alone,37 but further controlled trials are needed. Other studies have shown a clinical response in patients to the EGFR tyrosine kinase inhibitors, gefitinib38 and erlotinib (Read WL. Squamous carcinoma of the skin responding to erlotinib: three cases. Paper presented at the Annual Scientific Meeting of the American Society of Clinical Oncology (ASCO), Chicago, June 2007).
Areas of ongoing research Prospective randomised trial of sentinel node biopsy for high risk non-melanoma skin cancer (SNIC) The SNIC trial is a randomised multicentre trial in which patients with high-risk cutaneous SCC and clinical P0/N0 nodal status will be allocated to standard watch-and-wait management or staging by sentinel node biopsy. If the biopsy shows evidence of metastatic disease they will have a
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completion neck dissection of the area around the lymph nodes. Phases I and II are currently underway.39 3.
Study of cetuximab in SCC of the skin in patients expressing EGFR (CTXSCC) As a first-line treatment in patients with unresectable cutaneous SCC who express EGFR, cetuximab has achieved 69% disease control in phase II of this French multicentre trial. A randomised phase III trial is now warranted.35
4.
5.
6.
N1S3 staging study 7.
The aim of this study was to produce a staging system that incorporates parotid status and enables better prognostic discrimination between subgroups of patients with metastatic disease. The N1S3 system shows significant predictive capacity for locoregional control, and disease-specific and overall survival, but is yet to be adopted widely.40
8.
9.
10.
Conclusion 11.
Cutaneous SCC continues to cause death when it metastasises, but predisposing high-risk factors for this are now better defined and recognised in staging systems. The anatomical site of the primary tumour and the first involved nodes, although not always consistent, can be used to predict the pattern of spread, but the status of the parotid gland is important in planning treatment. Staging systems and guidelines require further improvement so that treatment can be tailored to the individual patient. The role of sentinel node biopsy in the staging process continues to evolve and promises to aid management in patients with high-risk disease, but its benefits have yet to be proved. Research into chemoradiotherapy regimens and the role of targeted treatment for non-melanoma skin cancer is continuing, but they will have to show a benefit in survival before being adopted into practice.
12. 13.
14.
15.
16.
17.
Conflict of interest There is no conflict of interest.
Ethical approval No ethical approval is required.
18.
19.
20.
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