CUTANEOUS SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK METASTASIZING TO THE PAROTID GLAND A REVIEW OF CURRENT RECOMMENDATIONS

CLINICAL REVIEW David W. Eisele, MD, CUTANEOUS SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK METASTASIZING TO THE PAROTID GLAND A REVIEW OF CURRENT RECOMMENDATIONS James O Hara, FRCS, 1 Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP, 2 Robert P. Takes, MD, PhD, 3 Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg, 2 Primož Strojan, MD, 4 Ashok R. Shaha, MD, 5 Juan P. Rodrigo, MD, PhD, 6,7 Vinidh Paleri, MS, FRCS (ORL-HNS) 1 1 Department of Otolaryngology Head and Neck Surgery, Newcastle upon Tyne Hospitals, Newcastle, United Kingdom 2 Department of Surgical Sciences, ENT Clinic, University of Udine, Udine, Italy. E-mail: a.ferlito@uniud.it 3 Department of Otolaryngology Head and Neck Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands 4 Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia 5 Head and Neck Service, Memorial Sloan Kettering Cancer Center, New York, New York 6 Department of Otolaryngology, Hospital Universitario Central de Asturias, Oviedo, Spain 7 Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain Accepted 21 July 2010 Published online 10 November 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21583 Abstract: Cutaneous squamous cell carcinoma (SCC) of the head and neck may metastasize in up to 5% of patients, with the parotid lymph nodes the most frequent site for spread. Metastases frequently show delayed presentation after the primary cancer had been treated. The optimum treatment should be surgery followed by adjuvant radiotherapy, with an appropriate parotidectomy, and preservation of the facial nerve if not involved by tumor and treatment to the neck. In a clinically N0 neck, levels I to III should be cleared for facial primaries, levels II to III for anterior scalp and external ear primaries, and levels II to V for posterior scalp primaries. Approximate 5-year disease-specific survival (DSS) after treatment was 70% to 75%. Patients with immunosuppression, in particular transplant recipients, are at high risk of developing aggressive metastatic cutaneous SCC. Modifications of the staging systems have demonstrated the prognostic benefits of accurately staging parotid and/or neck nodal disease. VC 2010 Wiley Periodicals, Inc. Head Neck 33: 1789 1795, 2011 Keywords: cutaneous squamous cell carcinoma; lymph node metastases; parotid gland; surgery; radiotherapy Whereas metastatic disease to the parotid lymph nodes is relatively rare in the northern hemisphere, cutaneous squamous cell carcinoma (SCC) of the head and neck is the most common tumor to metastasize to Correspondence to: A. Ferlito This article was written by members and invitees of the International Head and Neck Scientific Group. VC 2011 Wiley Periodicals, Inc. the parotid region. In contrast, the incidence of this disease is far higher in Australia and New Zealand, where metastatic cutaneous SCC is the most common malignant neoplasm to affect the parotid lymph nodes. In a series of 232 patients treated in Sydney for malignant parotid neoplasms, 1 54 were primary parotid cancers, 101 were metastatic cutaneous SCC, 69 were metastatic melanoma, and 8 were other metastases (7 Merkel cell carcinomas and 1 small cell carcinoma). Because skin cancer is known to be induced by sunlight exposure, the high incidence of primary skin cancer of the head and neck in this region is felt to be a consequence of the influx of an Anglo-Celtic population to these countries in the 1700s and 1800s. As such, a wealth of knowledge can be gained from the experience in dealing with such tumors in these countries. Whereas basal cell carcinomas are the most common skin cancers, cutaneous SCC has a far greater metastatic potential and makes up 20% of nonmelanotic skin cancers in the head and neck area. 2 The true incidence of metastases from cutaneous SCC is not known but is felt to be in the region of 2% to 5%. The parotid lymph nodes are the most common site for metastatic spread from a head and neck cutaneous SCC and its involvement has significant implications with regard to management and prognosis. In this article, we review the risk factors and patterns of spread, staging, prognosis, and therapeutic implications of metastatic spread of cutaneous SCC to the parotid lymph nodes. Cutaneous Carcinoma Metastasizing to the Parotid Gland HEAD & NECK DOI 10.1002/hed December 2011 1789

Risk Factors for Cutaneous Squamous Cell Carcinoma of the Head and Neck. In general, the risk of developing cutaneous SCC is higher in fair-skinned patients exposed to more than average sunlight, for example because of their occupation outdoors or because of the climate they live in. An additional risk factor is immunosuppression. Immunosuppressed patients are at a higher risk of developing skin cancer than the general population, with the sun-exposed head and neck region the most common site for primary lesions. Whereas in the general population, basal cell carcinoma is more common than cutaneous SCC, this trend is reversed in immunocompromised patients with cutaneous SCC being more prevalent. 3 Cutaneous SCC is felt to be more immunogenic than basal cell carcinoma and, as such, more susceptible in immune deficient conditions. Patients with organ transplantation form the majority of those affected but, in addition, patients with chronic lymphocytic leukemia, hairy cell leukemia, and non-hodgkin lymphoma have been identified as being susceptible. 4,5 Immunosuppressed individuals tend to develop cutaneous SCC at a younger age and often develop recurrent primary lesions, a risk factor in itself for metastatic disease. As with immunocompetent patients, the risk of developing cutaneous SCC is far higher for immunosuppressed patients in Australia and New Zealand than it is in the Northern Hemisphere. 6 Risk Factors for Metastasis. Given the high incidence of cutaneous SCC to low metastatic rate, the majority of head and neck cutaneous SCC are not investigated or treated for occult metastases but rather treated based on positive clinical examination. However, there are certain characteristics to a primary lesion that imply a higher risk of metastasis: primary lesion >2 cm in diameter; tumor thickness >4 to 5 mm; tumor on or around the ear; recurrent lesions; poorly differentiated grade; microvascular, lymphatic, or perineural invasion; advanced age; and a cutaneous SCC in an immunocompromised host. 3,7 9 The role of molecular factors, especially epidermal growth factor receptor, in the lymphatic dissemination of cutaneous SCC has also been studied. In multivariate analysis of 54 patients with head and neck cutaneous SCC, patients with lymph node metastases significantly overexpress epidermal growth factor receptor in comparison with those patients without lymphatic metastases. 10 Primary Sites. The majority of patients with metastatic parotid disease present after the primary cutaneous SCC has been treated, usually up to 12 months but it can be up to 2 to 3 years. 3 Vauterin et al 11 found the most common primary tumor sites metastasizing to the parotid and/or neck were the cheek (22%), pinna (20%), forehead (16%), and temple (16%). However, Hinerman et al 12 stated that the most common scenario in their series was an unknown primary site in 38% with the identifiable tumors found in the temple/lateral scalp (26%), helix/ conchal bowl (20%), and forehead/vertex (15%). Patterns of Regional Spread to Lymph Nodes. The parotid gland has a rich lymphatic network which drains the temple area and the cheek region. Any tumor in this area is likely to metastasize to the parotid region and subsequently to the upper cervical lymph nodes. There are approximately 15 to 20 periparotid lymph nodes and approximately 4 to 5 lymph nodes in the deeper portion of the parotid gland. Any of these lymph nodes could be directly involved with metastatic disease generally from the temple region. Some intraparotid lymph nodes may be adherent to the facial nerve, which always raises considerable risk and concerns in the management of the facial nerve. Occasionally, the metastatic disease may involve the substance of the parotid gland, which is generally quite difficult to evaluate and also to manage surgically. Metastatic cutaneous SCC of the head and neck most commonly involves the parotid gland and, as such, the parotid gland has been termed the basin for these cancers. 13 In a multicenter series of 322 such tumors, 80% involved the parotid gland (67% alone and 13% involving the parotid and neck nodes) with 19% metastasizing to the cervical lymph nodes only. 14 With known parotid metastasis and a clinical N0 neck, the incidence of occult nodal disease in the neck can be as high as 35% to 50%. 9,15,16 Among pathologically positive neck dissections, 11 level II was involved in 79%. In particular, the external jugular lymph node was frequently involved. This node lies outside the current classification of neck levels and can be found superficial and anterior to the sternocleidomastoid muscle at the inferior border, but separate to the parotid gland itself. Levels IV and V were only involved in extensive nodal disease, except for primary lesions affecting the posterior scalp where level V was occasionally the sole level involved. In a more recent analysis of 295 neck dissections performed for patients with clinically evident regional metastases from cutaneous SCC of the head and neck between 1987 and 2009, the metastatic involvement of the separate levels of the neck was determined depending on the site of the primary tumor. 17 It seemed that level I involvement in the absence of level II or III only occurred in patients with facial primaries. In patients with clear nodes in levels II to III, no involvement at all was found of levels IV to V in patients with a primary tumor of the external ear, 2.7% for tumors arising in the face and anterior scalp, and 15.8% for the posterior scalp and neck. The authors concluded that, based on their findings, in patients undergoing parotidectomy for metastatic 1790 Cutaneous Carcinoma Metastasizing to the Parotid Gland HEAD & NECK DOI 10.1002/hed December 2011

cutaneous SCC with a clinically negative neck, selective neck dissection including levels I to III should be performed for facial primaries, levels II to III for anterior scalp and external ear primaries, and levels II to V for posterior scalp and neck primaries. Investigations. In the absence of any clinical metastatic disease, there is little evidence to suggest that routine imaging has a role in the management of patients with head and neck cutaneous SCC. 3 Identifying those at risk of metastases is clearly challenging, given the low rate of metastatic disease from these lesions and the usual delayed presentation of metastases after treatment of the primary lesion. Options seem limited, other than to use the high-risk characteristics discussed above as a guide to those at risk of metastases. Evaluation of the parotid and neck may be considered in high-risk patients using CT or MRI scans, or ultrasound-guided fine-needle aspiration, in centers with experience with this procedure. Sentinel lymph node (SLN) biopsy is advocated in the investigation of melanoma, but its role has not been defined for cutaneous SCC. In a review of the literature, Ross and Schmults 18 found no controlled trials, with the majority performed on patients with anogenital cutaneous SCC. For non-anogenital sites, the rate of positive SLN biopsies was 21% in highrisk lesions, using similar criteria to those mentioned above. While acknowledging the deficiency in controlled trials, the authors do feel that an SLN biopsy has the potential to enhance survival in the high-risk group. Patients with clinically metastatic cutaneous SCC of the head and neck should undergo staging imaging before treatment. The choices range from ultrasonography, CT, and MRI, usually of the head and neck, chest, and abdomen, to positron emission tomography-ct (PET-CT). Treatment Modality. The published evidence suggests that the optimum treatment for metastatic cutaneous SCC of the head and neck should be surgical resection with adjuvant radiotherapy. 19 The extent of surgery needs to be tailored to the extent of disease. The most common type of parotidectomy performed in a series of 31 patients with metastatic cutaneous SCC, 9 was a superficial parotidectomy in 22 patients, total parotidectomy with facial nerve preservation in 1 patient, extended parotidectomy with preservation of the main trunk of the nerve and sacrifice of at least 1 peripheral branch in 5 patients, and a radical parotidectomy with sacrifice of the main trunk in only 3 patients. The extent of surgery for metastatic disease to the parotid region always generates considerable debate. The major controversy revolves around issues related to the facial nerve. The facial nerve is rarely sacrificed if it is functioning preoperatively. However, if there is gross disease likely to be left behind in an effort to preserve the facial nerve or the tumor is encircling the facial nerve, then it would be most appropriate to sacrifice the facial nerve with immediate or delayed facial reanimation. The majority of these patients will require postoperative radiation therapy, which is not a negative prognostic factor for restoration of facial nerve function. 20 For obvious metastatic disease in the parotid region, a superficial parotidectomy is generally performed with identification and preservation of the facial nerve. However, every attempt should be made to evaluate the deeper lobe and the possibility of metastatic disease to the deep parotid lymph nodes. If such abnormalities are present, appropriate clearance of the disease deeper to the facial nerve should be performed. Veness et al 3 feel that the nerve should only be sacrificed in the presence of a malignant facial palsy or if the nerve is found to be directly involved by the tumor during surgery. They also argue that surgery rarely achieves oncologically clear margins (>5 mm) and, as such, adjuvant radiotherapy is recommended. Using this policy, Iyer et al 21 looked at the outcomes for patients with involved margins where a tumor had been resected off the nerve. Of these 15 patients treated with nerve-sparing surgery and adjuvant radiotherapy, from a series of 176, no difference was noted in terms of disease-specific survival (DSS) when compared to patients with clear or close margins. Three patients developed recurrence in the parotid bed that was salvaged with further radical surgery and nerve sacrifice. The other 2 patients had residual palsies despite nerve-sparing surgery. Hence, 10 of 15 patients had normal facial nerve function posttreatment. For radical surgery with facial nerve sacrifice, some authors do not use frozen sections, 21 whereas others routinely take them from the facial nerve stump to ensure complete excision before immediate facial nerve reconstruction. 4 As outlined above, roughly one-third of patients with metastatic cutaneous SCC have neck node involvement, either alone or in conjunction with parotid disease. Of the patients with metastatic disease to the parotid lymph nodes, those with clinically positive neck nodes should be treated as for any mucosal head and neck SCC with an appropriate modified radical neck dissection. The options for those with parotid metastasis who are clinically N0 are to undergo a selective neck dissection along with a parotidectomy, or to receive radiotherapy to the neck, assuming postoperative radiotherapy will be given after the parotidectomy. Either would suffice, but a pathologically clear neck dissection would avoid subsequent radiotherapy to the neck, limiting the field to the parotid. In the series of Chen et al, 16 none of the patients with clinically N0 necks who underwent either ipsilateral neck dissection (7 patients) or elective Cutaneous Carcinoma Metastasizing to the Parotid Gland HEAD & NECK DOI 10.1002/hed December 2011 1791

neck irradiation (15 patients) developed neck recurrence, whereas 7 of 14 patients who did not receive any treatment to the neck experienced nodal failure. Given the evidence detailed above, the majority of nodal disease being at level II, with levels IV and V only involved in advanced neck disease, it would seem reasonable to treat an anterolateral primary tumor with parotid metastases with a level I to III selective neck dissection. 3 Because level V may be the only nodal group involved by a posterior scalp primary, this area should be included for such disease. Patients with metastatic disease in the posterior triangle, especially with a primary involving the scalp or suboccipital area, will require posterolateral neck dissection of levels II, III, IV, and V. Identification and preservation of the accessory nerve is important in these individuals for better shoulder function. Even in patients undergoing selective node dissection for the upper neck, careful dissection of the accessory nerve and level II lymph nodes should be undertaken to avoid any long-term disability related to accessory nerve dysfunction. Elective parotidectomy for clinically and radiologically N0 cutaneous SCC disease is an area of debate. Osborne et al 22 looked at 19 parotidectomies performed for advanced auricular cutaneous SCCs in immunocompetent patients who were deemed clinically and radiologically N0 and found no evidence of metastatic disease. However, Veness et al 3 feel that elective clearance of the parotid gland should be considered in high-risk individuals with external ear malignancies, cartilage invasion, poor differentiation, or deep invasion. This argument may be more applicable to immunosuppressed organ transplant recipients with recurrent or thick primary tumors in the head and neck region draining to the parotid gland. 6 Treatment of cutaneous SCC metastatic to the parotid gland in immunosuppressed patients should be as for any other operable patient; parotidectomy and neck dissection with adjuvant radiotherapy. 4 However, due to their potentially poor outcome, O Brien 13 felt that these patients should be considered as a separate group, for whom their immune status required optimization. For some organ transplant recipients, there is the option of reducing immunosuppression. Transplant rejection may be offset by a return to dialysis in renal transplantation, but there are no other alternatives for patients with cardiac or liver transplants. As such, a balance must be struck between the reduction in immunosuppression and the potential benefits that would confer in terms of control of metastatic disease with the risks of organ transplant rejection. 6 Radiotherapy. In a recent review of the role of radiotherapy in the treatment of basal cell and cutaneous SCC of the head and neck, Mendenhall et al 19 stated that, for metastatic cutaneous SCC to the parotid gland, treatment should be as for any other high-grade parotid malignancy, with surgery and adjuvant radiotherapy. Preoperative radiation may be considered for borderline resectable cases and radiotherapy considered as the sole treatment modality for unresectable cases. In the case of metastatic neck nodes in the neck dissection specimen, postoperative radiotherapy should be offered as for any other head and neck mucosal SCC, for more than 1 involved node or for the presence of extracapsular spread. 19 Radiotherapy protocols use an appositional mixed photon-electron beam or photons alone, a wedge pair technique of beam orientation or intensitymodulated radiation therapy to limit the dose given to the cerebellum or temporal lobe. 19 Doses of 60 Gy in 30 once daily fractions are used for negative margins. For positive margins, doses of 66 to 70 Gy are recommended at 2 Gy daily fractions, or 74 Gy at 1.2 Gy twice daily fractions. 19 Irradiation of the parotid bed is sufficient when adequate and pathologically N0 neck dissection is done. 19 Accordingly, in a recent report from the University of California, 3 of 4 patients who experienced parotid recurrence after treatment in the postoperative setting received a radiation dose <60 Gy and none of the 22 patients, all with clinically N0 necks treated electively, developed neck failure. 16 The benefit of adjuvant radiotherapy is generally agreed upon in the literature. Veness et al 15 looked at 167 patients undergoing surgery for metastatic cutaneous SCC. Twenty-one were treated with surgery alone, locoregional recurrence occurred in 20% of the combined treatment group and 43% of the surgery alone group. DSS was significantly reduced in the surgery alone group (54%) compared with those receiving adjuvant radiotherapy (73%; p ¼.004). Also, in a multicenter review from New Zealand, patients who received adjuvant radiotherapy had a significant survival advantage over the patients treated only with surgery. 23 At the University of Florida, 12 121 parotid glands were treated for metastatic cutaneous SCC; 17 with preoperative radiotherapy, 87 with postoperative radiotherapy, and 17 with radiotherapy alone. Locoregional control was 59%, 87%, and 41%, respectively (p ¼.008). However, this study does not contain a comparison group of patients treated with surgery alone, and the results may be a reflection of the extent of disease on presentation. Chemotherapy. The role of systemic chemotherapy in the treatment of metastatic cutaneous SCC is yet to be defined. Moore et al 9 found that 17% of their patients treated for metastatic cutaneous SCC developed distant metastases, leading them to question whether systemic therapy in addition to surgery and radiotherapy would have been beneficial. 1792 Cutaneous Carcinoma Metastasizing to the Parotid Gland HEAD & NECK DOI 10.1002/hed December 2011

Table 1. A summary of the evidence for metastatic cutaneous squamous cell carcinoma. Authors (y of publication/country) Period of study Sample size No. receiving adjuvant radiotherapy 5-y disease-specific survival (%) 5-y locoregional control (%) Bron et al (2003/Australia) 1 1988 1999 101 86 65 75 Moore et al (2005/USA) 9 1996 2001 40 31 75 83 Veness et al (2005/Australia) 15 1980 2002 167 146 58 77 Andruchow et al (2006/Multicentre data) 14 1960 2003 322 267 74 77 Ch ng et al (2006/New Zealand) 4 1990 2004 58 39 54 48 Ch ng et al (2008/Multicentre data) 23 1990 2005 170 131 69 Not reported Hinerman et al (2008/USA) 12 1969 2005 121 87 54 74 Targeted Therapy. There is emerging evidence from phase II trials that targeted therapy (epidermal growth factor inhibitors) may have a greater role to play in the management of cutaneous SCC in the future. 24 Over 20 trials are in progress worldwide that are pursuing these avenues of investigation. Follow-Up Schedules. Although there is no agreed follow-up schedule for patients with head and neck cancer, most clinicians would see patients at intervals of 1 to 2 months for the first year. For a patient with a high-risk primary cutaneous SCC, or any cutaneous SCC in an immunocompromised patient, such close surveillance for the first 12 months would seem prudent because most nodal metastases will occur in this time period. Follow-up at intervals of 3 months for the second and third years would seem appropriate. Outcomes. Table 1 displays some of the DSS and locoregional control data from the literature. 1,4,9,12,14,15,23 Comparing one retrospective case series with another is inappropriate given the heterogeneity of samples and the varied inclusion criteria. Immunosuppression has been shown to be an independent prognostic indicator for reduced survival after cutaneous SCC metastasizing to the parotid gland. 4,23 Approximately 2-year survival figures of 50% are quoted after definitive surgery and adjuvant radiotherapy. 4 Although from different populations, this compares to a 5-year survival of 70% to 75% in immunocompetent patients with metastatic cutaneous SCC. 6 patients to whom this staging system was applied, the P stage was not found to have a significant correlation with survival. Patients with N2 disease had a significantly worse 5-year survival of roughly 30% compared with the 65% to 70% for patients with N0 and N1 disease. This study paved the way for a retrospective multicenter trial of the staging system, including 322 patients treated in 3 Australian and 3 North American institutions 14 ; 217 patients had parotid metastases alone, 43 had parotid and neck metastases, and 62 had neck metastases alone. Disease recurred in 105 patients: 42 in the parotid, 33 in the neck, and 30 at distant sites. Overall 5-year DSS was 74%. Advanced P stage disease (P2 or P3) had a DSS of 69% compared to 82% for P1 disease (p ¼.02). Patients with combined parotid and neck metastases had a significantly worse DSS of 61% compared to 79% for patients with only parotid metastases (p ¼.027). Patients with N0 also had a significantly higher DSS than patients with either N1 or N2 disease (p ¼.026). Similar results were reported by Ch ng et al 23 applying O Brien s staging system to a cohort of 170 patients treated in 4 major head and neck surgical oncology centers in New Zealand. The value of corrected staging was confirmed in a smaller Canadian series of 56 patients with significantly worse prognosis of stage P3 disease. 26 These studies, therefore, concluded that a review of the current TNM classification for head and neck cutaneous SCC was merited and that the separation of metastatic disease into P and N disease adds prognostic information to cancer outcomes. Revised Staging System. In 2002, O Brien et al 25 proposed a revised staging system for patients with head and neck cutaneous SCC. It was felt that the current TNM classification, comprising N0 and N1 to denote the absence or presence of metastases for all sites of skin SCC, was limited in its prognostic capabilities. This system is unable to differentiate between a small volume single parotid metastasis and large/ multiple parotid and/or neck metastases with facial nerve involvement. Table 2 shows the proposed staging system. 14,23 In the first study, 25 for the 87 P0 P1 P2 P3 N0 N1 N2 Table 2. Clinical staging system for metastatic cutaneous squamous cell carcinoma to the parotid and/or neck. 14,23 No clinical disease in parotid. Metastatic node up to 3 cm in diameter. Metastatic node >3 cm and up to 6 cm in diameter, or multiple nodes. Metastatic node >6 cm in diameter or disease involving the facial nerve or skull base. No clinical neck disease. Single ipsilateral node up to 3 cm in diameter. Single ipsilateral node >3 cm or multiple nodes or contralateral nodes. Cutaneous Carcinoma Metastasizing to the Parotid Gland HEAD & NECK DOI 10.1002/hed December 2011 1793

NX N0 N1 N2 N3 Table 3. Seventh edition of the American Joint Committee on Cancer staging for nodal disease from cutaneous squamous cell carcinoma. 28 Regional lymph nodes cannot be assessed. No regional lymph node metastasis. Metastasis in a single lymph node, 3 cm or less in greatest dimension. Metastasis in a single lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in multiple lymph nodes, none more than 6 cm in greatest dimension. Metastasis in a lymph node, more than 6 cm in greatest dimension. In 2010, Forest et al 27 reported on a new staging system for metastatic head and neck cutaneous SCC, entitled N1S3. These authors retrospectively reviewed 215 patients, treated with up-front surgery with postoperative irradiation in 81% of them; on Cox regression analysis and after exclusion of extracapsular spread (because it cannot be applied to a clinical staging system), the number of nodes (single vs multiple, p ¼.001) and size (3 cmvs>3 cm, p ¼.025) seemed statistically significant. In an N1S3 staging system, which incorporates the parotid gland as 1 of the regional levels, these 2 factors from the parotid and the neck were combined. Accordingly, patients were classified into 3 groups: (1) single lymph node <3 cm; (2) single lymph node >3 cm or multiple nodes <3 cm; and (3) multiple nodes measuring >3 cm. The N1S3 seemed predictive for locoregional control (p <.001), DSS (p <.0001), and overall survival (p <.0001). Good discrimination between the 3 groups was confirmed on an independent dataset consisting of a cohort of 250 patients. Taking the above evidence into account, the recent seventh edition of the American Joint Committee on Cancer 28 staging manual has altered the nodal staging classification for cutaneous SCC (Table 3). Although it does not divide nodal disease into separate parotid and neck groups, the expanded nodal classification should improve prognostic information. CONCLUSIONS Regional metastasis of cutaneous SCC of the head and neck is not frequently encountered. However, in case of risk factors like immunosuppression and certain features of the primary tumor (>2 cm in diameter, thickness >4 5 mm, tumor on or around the ear, recurrent lesions, poorly differentiated grade, microvascular or perineural invasion) the risk increases. The parotid gland is a major site for regional metastasis of cutaneous SCC of the head and neck, of tumors arising in the temple and the cheek area in particular. Elective treatment of the parotid gland for cutaneous SCC is not recommended but may be considered in (very) high-risk patients with multiple risk factors. Determination of the presence of parotid and neck nodal metastases in the clinically negative neck remains a challenge. The spectrum of approaches goes from watchful waiting to SLN biopsy to selective lymphadenectomy. Comparisons of the diagnostic and therapeutic efficacy of these approaches have not been prospectively studied in head and neck cutaneous SCC. Evidence over the past 2 decades has defined how patients with cutaneous SCC to the parotid and/or neck should be managed. It is now evident that surgery followed by adjuvant radiotherapy should be the preferred treatment modality with preservation of the facial nerve when not involved by tumor. With known parotid metastasis and a clinical N0 neck, the incidence of occult nodal disease in the neck is reported to be ranging between 35% and 50%, with predominantly involvement of level II and, in particular, the external jugular lymph node. Levels IV and V seem to be only involved in extensive nodal disease, except for primary lesions affecting the posterior scalp and exclusive level I involvement may occur in patients with facial primaries. Therefore, in patients undergoing parotidectomy for metastatic cutaneous SCC with a clinically negative neck, selective neck dissection including levels I to III should be performed for facial primaries, levels II to III for anterior scalp and external ear primaries, and levels II to V for posterior scalp and neck primaries. In large series, it has been found that patients who received adjuvant radiotherapy had a significant survival advantage over the patients treated with surgery alone and, therefore, parotid treatment should consist of surgery and postoperative radiotherapy. Irradiation of the parotid bed is sufficient when adequate and pathologically N0 neck dissection is done. We recommend that a future updated TNM classification should include separate staging for both parotid and neck nodal disease. REFERENCES 1. Bron LP, Traynor SJ, McNeil EB, O Brien CJ. Primary and metastatic cancer of the parotid: comparison of clinical behavior in 232 cases. Laryngoscope 2003;113:1070 1075. 2. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001;344:975 983. 3. Veness MJ, Porceddu S, Palme CE, Morgan GJ. Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes. Head Neck 2007;29:621 631. 4. Ch ng S, Maitra A, Lea R, Brasch H, Tan ST. 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