ORIGINAL ARTICLE OUTCOMES FOLLOWING PAROTIDECTOMY FOR METASTATIC SQUAMOUS CELL CARCINOMA WITH MICROSCOPIC RESIDUAL DISEASE: IMPLICATIONS FOR FACIAL NERVE PRESERVATION N. Gopalakrishna Iyer, MBBS (Hons), PhD (Cantab), FRCSEd (Gen), 1,2 Jonathan R. Clark, MBBS (Hons), FRACS, 1 Rajmohan Murali, MBBS, FRCPA, 3,4 Kan Gao, BSc, 1 Christopher J. O Brien, AM, MS, MD, FRACS 1 1 Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia 2 Department of Surgical Oncology, National Cancer Centre, Singapore. E-mail: gopaliyer@yahoo.com 3 Department of Anatomical Pathology, Royal Prince Alfred Hospital, Sydney, Australia 4 Discipline of Pathology, University of Sydney, Sydney, Australia Accepted 19 May 2008 Published online 2 September 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20912 Abstract: Background. Metastatic cutaneous squamous cell carcinoma (SCC) of the parotid is an aggressive disease, requiring combined modality treatment of surgery and adjuvant radiotherapy to achieve cure. This study aims to determine whether facial nerve preservation followed by radiotherapy is a reasonable option in patients with microscopic residual disease involving the facial nerve. Methods. One hundred seventy-six patients with metastatic cutaneous SCC involving the parotid were analyzed. Results. In this cohort, 15 patients who underwent nervesparing surgery and adjuvant radiotherapy were found to have involved margins adjacent to the facial nerve. Comparing this group to patients with clear margins showed no difference in local recurrence or survival. Only 3 patients in this group developed local recurrence, and all successfully salvaged by further surgery. Conclusion. This study suggests that patients with metastatic cutaneous SCC to the parotid with microscopic residual disease involving the facial nerve and normal function can be successfully treated with a facial nerve sparing approach and Correspondence to: N. G. Iyer VC 2008 Wiley Periodicals, Inc. timely postoperative radiotherapy. Inc. Head Neck 31: 21 27, 2009 VC 2008 Wiley Periodicals, Keywords: parotid; margins; radiotherapy; nerve-sparing Metastatic cutaneous carcinoma is the commonest malignant tumor involving the parotid gland in Australia. 1 The majority of these originate from primary squamous cell carcinomas (SCCs) arising from the skin of the head and neck region. 2 Whilst the metastatic potential of these cancers is generally low (approximately 5%), parotid gland involvement has been shown to have important adverse prognostic implications. 3,4 It is well recognized that this is an aggressive disease entity with a propensity for extracapsular spread, local invasion, and concomitant cervical lymph node metastases. 5,6 Consequently, recommendations have been made to incorporate parotid metastases as a stage-modifying factor. 7,8 Parotidectomy with Facial Nerve Preservation in Metastatic Cutaneous SCC HEAD & NECK DOI 10.1002/hed January 2009 21
As such, management requires a multimodality approach, with the majority of patients undergoing surgery and postoperative radiotherapy. Importantly, the surgeon needs to balance the principles of aggressive resection to achieve clear margins with facial nerve preservation to retain form and function. Radical parotidectomy with facial nerve sacrifice is the treatment of choice in patients with preoperative facial nerve palsy. However, the majority of patients were seen with disease amenable to resection with clear margins while preserving the facial nerve. Unfortunately, the distribution of intra-parotid lymph nodes is such that metastatic tumor is often in close proximity to the nerve and the basic oncologic principle requiring a wide margin of normal tissue is often compromised in order to maintain facial nerve function. 9 The addition of postoperative radiotherapy improves both local control and overall survival and is used routinely in patients with both clear and close pathological margins. 3,4,10,11 However, controversy persists as to the best management of patients with either microscopic or limited macroscopic nerve involvement, where the facial nerve is functionally intact. Treatment options range from a facial nerve sparing surgery followed by adjuvant radiotherapy, to aggressive radical parotidectomy, and vary depending on the treatment philosophies of the clinicians involved. Although a conservative approach has been shown to be a reasonable option in selected primary parotid malignancies, the efficacy of a facial nerve sparing approach for metastatic SCC remains unknown. 12 The primary aim of this study was to determine whether facial nerve preservation followed by postoperative radiotherapy is a reasonable option in patients with microscopic residual disease involving the facial nerve and normal preoperative facial nerve function. To address this question, we analyzed recurrence and survival rates in patients treated with this technique and compared their outcome with those with clear margins managed with surgery and postoperative radiotherapy. The secondary aim was to determine whether recurrence following a more conservative approach presents as extensive perineural disease or remains within the parotid where it is amenable to salvage by radical parotidectomy. FIGURE 1. Flowchart showing patient categories used in this study. Dashed boxes indicate the groups of patients used for comparison. PATIENTS AND METHODS This study included all patients with clinically evident and pathologically proven metastatic cutaneous SCC involving the parotid gland, and who had a minimum of 2 years follow-up. Patients were assessed in the multidisciplinary Head and Neck Cancer Service at Royal Prince Alfred Hospital, Sydney, and underwent either surgery alone or surgery and adjuvant radiotherapy. Clinical and pathologic data were accessioned prospectively onto the computerized database of the Department of Head and Neck Surgery, Royal Prince Alfred Hospital, Sydney. The study was approved by the hospital IRB committee, and informed consent was obtained from all patients involved in the study. Only patients treated with curative intent and with complete pathologic data were included from the 302 patients who underwent parotidectomy for metastatic SCC during this period. We identified 176 patients who fulfilled these criteria (Figure 1). The extent of parotidectomy was based on the clinical extent of disease. Patients with mobile tumors and no neurologic evidence of facial nerve involvement were treated with facial nerve sparing parotidectomies. In contrast, radical paroti- 22 Parotidectomy with Facial Nerve Preservation in Metastatic Cutaneous SCC HEAD & NECK DOI 10.1002/hed January 2009
FIGURE 2. Definition of histologic margin status: (A) Clear: Tumor completely excised with a rim of normal parotid surrounding it; (B, C) Close: Tumor completely excised (B) with only focal extension to the margin (C); (D) Involved: Tumor extends to margin over a broad front. Hematoxylin-eosin stain; (A, B) 312.5, (C) 320, (D) 340 (original magnification); black arrows: surgical margin; white arrows: invasive front of tumor; SCC, squamous cell carcinoma. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] dectomy was the procedure of choice in patients with large, fixed tumors or with evidence of facial nerve involvement. The presence of gross tumor extending deep to the plane of the facial nerve was also an indication for radical excision and facial nerve sacrifice. Frozen sections were not routinely employed to determine radial margins and hence did not affect the extent of surgery with regard to the facial nerve. The majority of patients (n 5 136) also underwent some form of concurrent neck dissection. 13 Postoperative radiotherapy was recommended in all cases unless there were contraindications to radiotherapy. Treatment was directed to the parotid bed in all cases and to the ipsilateral neck if it was pathologically involved or if neck dissection was omitted. All patients were reviewed by the primary surgical team at 3 monthly intervals, with imaging (CT or MRI) performed only when there is a suspected recurrence. Histologic margins (Figure 2) were defined as being clear if the tumor was completely excised with a definite margin of normal parotid tissue around the parotid tumor, and close if the tumor was excised with no more than focal extension of tumor to the margin. Margins were defined as involved if there was a broad front of invasive carcinoma extending to the excision margin; this rigorous definition is important to ensure that this group comprised patients who have a high likelihood of residual microscopic disease. Patients with operative reports describing gross residual disease were excluded from analysis. In the subsequent analyses, only patients who underwent facial nerve sparing surgery, and postoperative radiotherapy with pathologically involved margins adjacent to the facial nerve were considered. Statistical analyses were carried out using E- Stat statistical software (Macquarie University, Sydney, Australia). Cumulative local control and survival were calculated using the Kaplan Meier method and compared using the log rank test. RESULTS The cohort that was analyzed (n 5 176) comprised 159 men and 17 women, with a median age of 72.5 years (range, 37.5 99.6 years). One hundred thirty-six patients underwent parotidectomy and neck dissection, whereas the remainder underwent Parotidectomy with Facial Nerve Preservation in Metastatic Cutaneous SCC HEAD & NECK DOI 10.1002/hed January 2009 23
FIGURE 3. Kaplan Meier plot showing margin status correlates with local control, but this is not statistically significant (p 5.399). These include all patients who underwent parotidectomy, regardless of whether they received postoperative radiotherapy. parotidectomy alone. Adjuvant radiotherapy was carried out in 138 patients, with median dose of 54 Gy in 27 fractions (range, 45 66 Gy). Histologic margins were clear and close in 85 (48.3%) and 57 (32.4%) patients, respectively. Thirty-four (19.3%) patients had microscopically involved excision margins. In this group, 18 patients had facial nerve preserving procedures with involved margins adjacent to the facial nerve, and 15 of these underwent adjuvant postoperative radiotherapy. Three patients did not undergo immediate postoperative radiotherapy: 2 refused radiotherapy and 1 developed recurrent disease soon after surgery, requiring reexcision. Kaplan Meier plots for local control and disease-free survival were generated according to margin status for all 176 patients (Figures 3 and 4, respectively). In this analysis, all patients were included regardless of whether they underwent postoperative radiotherapy. Local control and disease-free survival were decreased when margins were involved, compared with patients with clear and close margins; however, this was not statistically significant (p 5.399 and p 5.063, respectively). To assess the impact of facial nerve preserving surgery in patients with residual microscopic disease on local control and survival, we compared this group with all patients with clear and close margins combined who received postoperative radiotherapy. Disease-free survival rates were similar between the 2 groups (p 5.937) (Figure 5), and there was no statistically significant difference in the local recurrence rates between the 2 groups (p 5.090) (Figure 6). Recurrent disease affecting the parotid bed alone was diagnosed in 3 (of 15) patients with involved margins at 5, 8, and 24 months, respectively. All 3 patients subsequently underwent salvage radical parotidectomy, with no further recurrence. Hence, ultimate local control was achieved in all patients who underwent nerve-sparing resection with residual disease, and normal facial nerve function was preserved in 10 of 15 patients (3 patients underwent radical parotidectomy and 2 had permanent paresis despite facial nerve preservation). DISCUSSION Optimal treatment strategies for metastatic cutaneous SCC are largely based on retrospective studies and best-practice guidelines. 10 As with most malignancies of the head and neck region, locoregional failure is the predominant pattern of recurrence and the main cause of mortality. Several factors have been shown to predict local failure, of which margin status and postoperative radiotherapy have been the most 24 Parotidectomy with Facial Nerve Preservation in Metastatic Cutaneous SCC HEAD & NECK DOI 10.1002/hed January 2009
FIGURE 4. Kaplan Meier plot showing margin status correlates with survival, but this is not statistically significant (p 5.063). These include all patients who underwent parotidectomy, regardless of whether they received postoperative radiotherapy. reproducible. 3,4,11,14 We have previously shown that radical surgery does not necessarily correlate with improved outcome, because extensive surgery does not negate the biological behavior of more aggressive underlying disease. 3 Data presented here suggest that margin status is an important factor in disease-specific mortality, although its impact on local control is limited due to the routine use of adjuvant radiotherapy. Furthermore, margin status alone does not take into account the heterogenous range of tumors within each group. For example, the involved margin group includes patients with massive tumors with extensive skull base involvement as well as patients with minimal residual disease along isolated facial nerve branches. FIGURE 5. Kaplan Meier plot showing no difference in survival between patients with clear or close margins and those with residual disease, facial nerve sparing surgery, and postoperative radiotherapy (p 5.937). Parotidectomy with Facial Nerve Preservation in Metastatic Cutaneous SCC HEAD & NECK DOI 10.1002/hed January 2009 25
FIGURE 6. Kaplan Meier plot showing a small difference in local failure rates between patients with clear or close margins and those with residual disease, facial nerve sparing surgery, and postoperative radiotherapy, but this is not statistically significant (p 5.090). When we restricted our analysis to patients with microscopic positive margins but no gross residual disease treated with nerve-sparing surgery and postoperative radiotherapy alone, we found that there was no difference in local recurrence and disease-free survival rates when compared with patients with clear margins undergoing the same treatment. Importantly, of the 15 patients with residual disease on the facial nerve, there were only 3 recurrences, and all 3 were successfully salvaged by radical surgery and facial nerve function was intact in the majority of these patients. There are several limitations in our study that need to be considered. First, the number of patients in our analysis was small because most patients found to have macroscopic tumor invasion of the nerve intraoperatively underwent radical parotidectomy. Therefore, we were limited predominantly to patients who were found to have involved margins postoperatively on pathological assessment. It is difficult to extrapolate these data to the clinical question that we aimed to address, ie, patients with minimal macroscopic nerve involvement. However, these data suggest that further prospective analysis is reasonable. Moreover, although there was not a statistically significant difference in local recurrence rates between the 2 groups in question, there was a trend to increased local recurrence in the group with involved margins treated with nerve-sparing surgery and radiotherapy. We have to acknowledge that the lack of statistical significance may be a reflection of a small cohort size. Also the usual deficiencies of a retrospective analysis on a relatively heterogenous group of patients apply. Nonetheless, this is the first study to date that has addressed the issue of nerve-sparing surgery in patients with minimal nerve involvement secondary to metastatic cutaneous SCC. Importantly, although there were more local recurrences in the nerve-sparing group, the fact that ultimate local control was achieved in all of these patients is encouraging. Hence, no death was directly attributable to local failure secondary to a relatively conservative approach, and patients did not recur with extensive perineural disease that was unsalvageable. Based on the results of this study, we suggest that patients with metastatic cutaneous SCC involving the parotid gland, with microscopic involvement of the facial nerve, may be treated with facial nerve sparing procedures and postoperative radiotherapy. Timely postoperative radiotherapy is critical in this treatment paradigm. REFERENCES 1. O Brien CJ. The parotid gland as a metastatic basin for cutaneous cancer. Arch Otolaryngol Head Neck Surg 2005;131:551 555. 2. Vauterin TJ, Veness MJ, Morgan GJ, Poulsen MG, O Brien CJ. Patterns of lymph node spread of cutaneous 26 Parotidectomy with Facial Nerve Preservation in Metastatic Cutaneous SCC HEAD & NECK DOI 10.1002/hed January 2009
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