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ORIGINAL ARTICLE SQUAMOUS CELL CARCINOMA OF THE PAROTID GLAND Yu-Lan Mary Ying, MD, Jonas T. Johnson, MD, Eugene N. Myers, MD Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Eye & Ear Institute; 203 Lothrop Street, Suite 500, Pittsburgh, PA 15213 Accepted 24 August 2005 Published online 10 February 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20360 Abstract: Background. Our objective was to evaluate the outcome of patients treated for squamous cell carcinoma (SCC) of the parotid gland. Methods. We conducted a retrospective chart review of the tumor registry from 1982 through 2003 at a tertiary referral medical center. Patients with SCC of the parotid gland were identified and followed for a minimum of 2 years after therapy. Results. SCC involving the parotid was identified in 66 patients. The tumor was a metastasis from a known primary site in 41 patients (62%). In 16 patients (24%), no other primary site was identified, and the tumor may have originated in the parotid gland. Nine patients (14%) were undetermined. Therapy frequently included surgery. The integrity of the facial nerve was preserved in 92% of surgical patients. Only eight patients initially had clinical evidence of cervical metastasis; however, cervical metastasis was identified in 25 patients (44%), changing the course of therapy. Conclusion. SCC of the parotid gland was metastatic from a known primary tumor in more than half of the patients. The most common site of the primary tumor was a cutaneous malignancy of the head and neck. The high incidence of cervical lymph node involvement underscores the diagnostic and therapeutic imporC tance of neck dissection with parotidectomy. V 2006 Wiley Periodicals, Inc. Head Neck 28: 626–632, 2006 Keywords: squamous cell carcinoma; parotid gland; parotidectomy; primary; metastasis Correspondence to: J. T. Johnson C V 2006 Wiley Periodicals, Inc. 626 Squamous Carcinoma of Parotid Tumors of the parotid gland are a histologically diverse group of neoplasms that exhibit a wide spectrum of biologic behaviors. Primary squamous cell carcinoma (SCC) originating in the parotid is rare. The reported incidence of SCC of the salivary gland is only 0.3% to 1.5%.1 More commonly, SCC is metastatic to the intraparotid and periparotid lymph nodes from cutaneous malignancy of the face and scalp. In patients with SCC of the skin, the overall risk of metastasis to regional lymph nodes is reported to be 1% to 2%.2 Direct invasion of the parotid gland from carcinoma of the external ear or preauricular skin also occurs. Metastatic cancer accounts for less than 10% of the malignancies found in the parotid gland. Of these metastases to the parotid lymph nodes, 40% are SCC.3 The purpose of this report is to review our experience in the management of primary and metastatic SCC of the parotid gland. PATIENTS AND METHODS This study is a retrospective analysis of all patients treated by the Department of Otolaryngology at University of Pittsburgh between 1982 and 2003. A total of 224 patients with cancer of the parotid were identified. Of these, 66 patients (29%) had SCC. Patients ranged in age from 41 to 96 years (mean, of 71.3 years; median, 73 years). HEAD & NECK—DOI 10.1002/hed July 2006 There were 49 men and 17 women. Overall, all patients except for one patient were white. Metastasis to the parotid gland from a known primary site was identified in 41 of 66 patients (62%). In 37 of these patients, the metastasis came from cutaneous malignancy. The most commonly identified site was the skin of the auricle. Four patients had a history of multiple cutaneous cancers on the head, but the actual primary site was unknown. There were also four patients with a mucosal primary tumor. Sixteen of the 66 patients (24%) had SCC of the parotid gland without a known primary lesion. In these patients, the cancer may have been primary in the parotid gland or may have been a metastasis from an unknown primary site. However, after careful review of the charts and pathology reports, it was convincing that they were primary SCC of the parotid gland. These patients had tumors in the parotid parenchyma, in contrast to intraparotid nodal disease alone, and did not have another tumor site. The remaining nine of 66 patients (14%) were undetermined to have either metastatic or primary SCC of the parotid gland despite careful review. For the purpose of this study, they were not included in the data analysis. All patients were treated and followed for a minimum of 2 years or until recurrence or death from the date of primary treatment. Statistical analysis was carried out using Statistix software for Windows. Statistical comparisons were made using the twosample t test for age and the chi-square method for the remainder variables. Two by two table test was also performed when appropriate. The following assumptions were made to simply the data. For disease status, patients with no evidence of disease were grouped with those who died of other conditions, and patients alive with disease were grouped with those dead of disease. A p value of less than .05 was considered to be statistically significant. Statistical Methods. was surgery only (25 of 32, 71%); some patients received both surgery and radiotherapy (7 of 32, 22%). In each case, cancer of the parotid gland was identified as a metastasis. At the initial presentation, one patient had palpable metastasis in the neck only (the parotid metastasis was occult), 35 patients had parotid gland metastasis only, and five patients had metastases to both the parotid gland and the neck. Treatment prescribed for the 41 patients were surgery alone in 14 patients (34%), surgery plus adjuvant therapy, including postoperative radiation, brachytherapy and/or chemotherapy in 25 patients (61%), radiotherapy only in one patient (2.4%), and one untreated patient (2.4%) who died of disease shortly after discovery of SCC metastasis to the parotid gland (Table 1). Parotidectomy alone was carried out in six patients, and parotidectomy plus neck dissection was carried out in 33 patients. Disease status was determined by following the patient for a minimum of 2 years after treatment. One patient treated only with surgery died of other causes before the minimum of 2 years and was excluded from analysis. The adjusted survival rates were 62% for surgery only and 64% for surgery plus adjuvant therapy (Table 1). In 16 patients with primary SCC of the parotid gland, three patients (19%) underwent surgery only; 11 patients (63%) were treated with surgery plus adjuvant therapies, including radiation, brachytherapy and/or chemotherapy; and two patients (10%) were treated nonsurgically with radiotherapy only (Table 2). Parotidectomy alone was carried out in five patients, and nine patients had parotidectomy and neck dissection. Patients with Primary Squamous Cell Cancer. Table 1. Metastatic squamous cell cancer to the parotid gland. Treatment Surgery Initial control Salvaged/ attempted Lost FU or DOC Adjusted survival– cured Adjusted survival– DOD 8/14 0/1 1 16/25 0/2 0 8/13 (62%) 16/25 (64%) 5/13 (38%) 8/25 (32%) 0/1 0 0 0 1/1 (100%) RESULTS In 41 patients with metastatic SCC to the parotid gland, 32 of 41 patients (78%) had undergone prior treatment for cutaneous SCC. Among these patients, the most common previous treatment Patients with Metastatic Squamous Cell Cancer. Squamous Carcinoma of Parotid Surgery þ adjuvant therapy Radiation only Abbreviations: FU, follow-up; DOC, died of other causes; DOD, died of disease. HEAD & NECK—DOI 10.1002/hed July 2006 627 Table 2. Primary squamous cell cancer of parotid gland. Treatment Surgery Surgery þ adjuvant therapy Radiation only Lost Initial Salvaged/ FU or control attempted DOC Adjusted survival– cured Adjusted survival– DOD 2/3 6/11 0 0/1 0 2 2/3 (67%) 1/3 (33%) 6/9 (67%) 3/9 (33%) 1/2 0 0 1/2 (50%) 1/2 (50%) Abbreviations: FU, follow-up; DOC, died of other causes; DOD, died of disease. Eighteen of 41 patients (44%), including those previously mentioned who were initially seen with a mass in the neck, were identified as having positive nodes on histologic examination. The clinical outcomes were as follows: eight patients died of disease, eight patients without evidence of disease, and two patients died of another condition. Seven of the eight patients without evidence of disease had received postoperative adjuvant therapy. Recurrence in the neck was observed in two patients within 5 months after parotidectomy and neck dissection (Table 3). Patients with Primary Squamous Cell Cancer. Two patients were treated with surgery and postoperative adjuvant therapy, and they died of other conditions in less than the 2-year follow-up period. The adjusted 2-year disease control rate was identical at 67% for surgery alone and for surgery plus adjuvant therapies (Table 2). No statistically significant difference was found in local control when comparing the different treatments with surgery alone, surgery plus adjuvant therapies, or radiation therapy and chemotherapy in either patient group. Salvage surgery was attempted for some patients in both groups, but the results were dismal (Tables 1 and 2). Overall, 53 of 57 patients (93%) underwent parotidectomy and three of 57 patients (5%) were treated with nonsurgical modalities because of their poor general medical condition. As part of their surgical therapy, 49 (92%) had facial nerve preservation. Two patients (3.8%) in the surgical group had a biopsy of the facial nerve. Sacrifice of the entire facial nerve was required in four of 53 patients (8%), with most patients (75%) in the metastatic SCC group. Nerve reconstruction was performed in two patients. The 2-year disease control rate with facial nerve preservation was 61%. Facial Nerve Preservation. In patients with primary SCC of the parotid gland, two of 16 patients (13%) initially were seen with cancer in the parotid gland and metastases to the neck. One patient was treated with surgery only and was disease free at the 2-year follow-up. The other patient received radiotherapy only but died of disease a year after starting treatment. Occult cervical metastasis was observed in seven other patients. Overall, nine of 16 patients (56%) had regional neck metastases. The clinical outcomes were as follows: four patients died of disease and five patients without evidence of disease. Three of the five (60%) patients free of disease had received postoperative adjuvant therapy. Recurrence in the neck was observed in two patients from the group of 16 patients within an average of 5 months after treatment (Table 3). Site of Recurrent Cancer. Patients with Metastatic Squamous Cell Cancer. In the group of patients with metastatic SCC to the parotid gland, 12 patients had documented local or regional recurrences and/or distant metastases. Four patients had multiple (>1) sites of local recurrences, regional recurrences, and/or distant metastases. Specifically, there were three local recurrences, nine regional recurrences, and four distant metastases. The median times for local/ Cervical Node Involvement. Patients with Metastatic Squamous Cell Cancer. In patients with SCC metastases to the parotid gland, six of 41 patients (15%) were initially seen with a clinically palpable mass in the neck. All six patients underwent parotidectomy and neck dissection and postoperative radiation therapy. Four patients had good disease control. Two patients succumbed to distant metastasis. 628 Squamous Carcinoma of Parotid Table 3. Cervical nodal involvement. Group Metastatic Primary On presentation Occult nodes Neck metastasis/ recurrence Total regional disease 6 2 12 7 2 2 20/41 (49%) 11/16 (69%) HEAD & NECK—DOI 10.1002/hed July 2006 Table 4. Site of disease recurrence in metastatic squamous cell cancer to parotid gland. Table 6. P values for disease outcome. Disease outcome (NED/DOD) On presentation Recurrent site No. of patients Neck and parotid Local Regional Distant Multiple sites Local Regional Distant Multiple sites 0 1 1 1 (RþD) 0 5 1 3 (LþR, LþR, LþD) Parotid Abbreviations: R, regional (head and neck); D, distant (beyond head and neck, ie, lungs); L, local (parotid gland). Multiple refers to >1 site of concurrent cancer recurrences. regional recurrence and distant metastasis were 7.5 months and 5 years, respectively (Table 4). p value Age Tumor group Sex Distant metastasis Treatment group (S vs S þ adj) Perineural involvement Margins Lymph node involvement Cranial nerve VII preservation .79 1.0 .51 .001 .75 .76 .13 .14 1.0 Abbreviations: NED, no evidence of disease; DOD, died of disease; S, surgery; S þ adj, surgery þ postoperative adjuvant therapy. SCC of the parotid gland, no variable was found to be statistically significant between the two tumor groups (Table 7). Patients with Primary Squamous Cell Cancer. In the group with primary SCC of the parotid, five patients had documented local recurrences, regional recurrences, and/or distant metastases. Two patients had multiple (>1) sites of local recurrences, regional recurrences, and/or distant metastases. Specifically, there was one local recurrence, five regional recurrences only, and one distant metastasis. The median time for local/regional recurrence metastasis was 7 months. This observed local recurrence rate is similar to the findings of Lee et al4 for primary SCC of the parotid gland to occur within 8 months of definitive treatment (Table 5). Variables found to be clinically significant to disease outcome were surgical margins of the parotidectomy and lymph node involvement. However, only the presence of distant metastasis was found to be a statistically significant (p .05) poor prognostic factor in the disease outcome for these patients (Table 6). Comparing the groups of metastatic SCC to unknown primary Statistical Analysis. Table 5. Site of recurrence in primary squamous cell cancer of parotid gland. On presentation Recurrent site No. of patients Neck and parotid Parotid None Local Regional Distant Multiple sites 0 0 3 0 2 (LþR, RþD) Abbreviations: L, local (parotid gland); R, regional (head and neck); D distant (beyond head and neck, ie, lungs). Multiple refers to >1 site of concurrent cancer recurrences. Squamous Carcinoma of Parotid DISCUSSION When SCC is identified in the parotid gland, an effort must be made to identify the etiology. When no other primary lesion exists, it seems logical to consider the cancer a primary tumor in the parotid gland. Primary SCC of the parotid gland is unusual. Therefore, when SCC is identified in the parotid gland, one must consider all possibilities so that the proper treatment plan for a particular setting is selected. After therapy, all patients require lifelong follow-up. In both metastatic and primary SCC of the parotid, near total parotidectomy with facial nerve dissection and preservation was the operation performed most commonly at our institution. The number of patients with cancer in the parotid gland and concurrent palpable metastasis to the neck at initial presentation was low for both groups: five and two patients in metastatic and primary SCC group, respectively. Others have reported that elective neck dissection is not routinely recommended for primary cancer of the parotid gland.5 In our series, 33 of 41 patients (80%) with metastatic cutaneous SCC and nine of 16 patients (56%) with primary SCC underwent neck dissection, irrespective of the physical finding at presentation. Of the 42 patients who had neck dissections, 25 patients (60%) had positive occult lymph nodes. The rationale for doing neck dissection is based on the observation that most patients with SCC in the parotid gland do, in fact, have metastatic disease to the neck and that the lymph nodes in the parotid area represent just one metastatic site for cutaneous SCC of the head and neck region. When the parotid HEAD & NECK—DOI 10.1002/hed July 2006 629 Table 7. Variable distribution frequency and p values comparing the two tumor groups: metastatic versus primary squamous cell carcinoma of the parotid gland. Age Sex, M:F Distant metastasis, Y:N Treatment group, S:SþAdj Perineural involvement, Y:N Margin involvement, Y:N Lymph node involvement, Y:N Cranial nerve VII preservation, Y:N Disease outcome, NED:DOD Metastatic Primary p value 2.9:1 1 (30.8%):2.3 (69.2%) 1 (35.9%): 1.8 (64.1%) 1 (35.9%): 1.8 (64.1%) 1 (35.9%): 1.8 (64.1%) 1 (43.6%): 1.3 (56.4%) 37.5 (97.4%):1 (2.6%) 2.3 (69.2%):1 (30.8%) 2.5:1 1 (28.6%):2.5 (71.4%) 1 (21.4%):3.7 (78.6%) 1 (50%): 1 (50%) 1 (50%): 1 (50%) 1 (50%): 1 (50%) 13 (92.9%): 1 (7.1%) 2.5 (71.4%): 1 (28.6%) .79 1.00 1.00 .51 .53 .53 .76 1.0 1.0 Abbreviations: M, male; F, female; Y, yes; N, no; S, surgery; SþAdj, surgery plus postoperative adjuvant therapy; NED, no evidence of disease; DOD, died of disease. gland is clinically involved, other nodes in the neck at risk should also be removed.2 Our data only verify the potential metastatic sites of head and neck cutaneous SCC. The incidence of occult metastases in the neck, as supported by positive histologic findings of lymph nodes and/or extracapsular spread, was observed in 18 of 44 patients (44%) with metastatic SCC and in seven of 16 patients (44%) with primary SCC of the parotid. The percentage of patients with metastases to the neck was similar in both groups, despite the worse disease status often observed in patients with metastatic cutaneous SCC to the parotid gland. This seems to suggest that patients in whom no other primary site was found may, in fact, have primary cancer arising in the parotid gland. The incidence of distant metastasis is increased in patients with metastasis to the neck compared with those with parotid gland SCC alone.6 The clinical outcome was similar between patients with metastatic SCC and primary SCC of the parotid gland, regardless of the treatment plan. Death from cancer occurred in 14 of 40 patients (35%) and five of 14 patients (36%) in the metastatic and primary SCC patient groups, respectively. In our relatively small group of patients with primary SCC of the parotid gland, follow-up visits failed to reveal new primary tumors. The disease control rate for patients with metastatic SCC to the parotid gland or primary SCC of the parotid gland treated with surgery alone was not statistically different from those treated with surgery and postoperative radiotherapy. This finding is consistent with the results of Khurana et al.6 In a retrospective study such as this, treat- 630 Squamous Carcinoma of Parotid ment bias is to be expected, because patients with the worst prognosis were treated with postoperative radiation. No comparison of efficacy is possible on the basis of our data. A prospective randomized trial would be required to address this issue. Past studies have shown that involvement of clinically palpable nodes in the neck worsened prognosis in the primary SCC of the parotid gland. In our sample, an equally sensitive negative prognostic factor in both groups is the histologic evidence of occult metastasis in the neck. Positive occult lymph nodes on histologic examination were found in 60% of patients who underwent neck dissection. Although by statistical analysis only distant metastasis was identified as a statistically significant variable, lymph node involvement and surgical margin are important clinical prognostic factors that are present in cases with distant metastasis. Prognostic Factors. The goal of any treatment is to cure with the least morbidity. In the setting of parotidectomy, this implies an attempt to preserve the facial nerve in resection of the parotid gland. In our experience of 53 parotidectomies, there were only four patients whose facial nerve had to be resected. Resection of the facial nerve did not result in improved outcome. Similarly, preservation of the nerve with close margins, including peeling the nerve off tumor, did not result in increased recurrence. Of those patients who underwent facial nerve preservation in both primary and metastatic SCC of parotid gland, 61% was the 2-year disease control rate. The extent of parotidecFacial Nerve Function. HEAD & NECK—DOI 10.1002/hed July 2006 tomy (ie, partial vs total) or sacrificing the facial nerve for better disease control did not seem to make any significant difference in either patient group. Therefore, we concur with Audet et al7 that the treatment approach in patients with metastatic cutaneous SCC to the parotid gland is a nerve-sparing parotidectomy when possible; although in cases with evidence of facial nerve involvement, a radical parotidectomy with facial nerve sacrifice is usually necessary despite the similar disease state outcome found in our study. The retrospective nature of these data introduces physician bias that cannot be eliminated. The number of patients with either local recurrence, regional recurrence, or distant metastasis was higher in the group with metastatic SCC (12 patients) than in the group with primary SCC of the parotid (five patients). The percentage of recurrent and distant metastatic rates (31%) for primary SCC of the parotid gland are in accordance with the recurrence rates reported in the literature, ranging from 8% to 55% for similarly treated patients with primary parotid cancer.8–11 In our series, local/regional recurrences were more commonly encountered than development of distant metastases during the follow-up period for both patient groups. Local recurrence in the area of the parotid gland was the most important site of failure in both groups of patients with SCC of the parotid. Among patients with primary SCC of the parotid gland, the skin of the auricle was the most common site of local recurrence. The neck and lungs were the sites for regional and distant metastases, respectively, common to both primary and metastatic SCC patient groups. Despite the comprehensive treatments received or the origin of SCC in the parotid, patients who had local or regional recurrence and distant metastases all died of disease. In our series, the average median time of local and regional recurrences for both patient groups averaged 7 months. On the basis of prior studies, the tendency for primary SCC of the parotid gland for distant spread has generally been low compared with cervical neck metastases.12 Our data supported this finding, with only one patient in the primary SCC of the parotid gland group who had distant metastasis. Recurrence. CONCLUSIONS This review of 57 patients with either primary or metastatic SCC to the parotid gland suggests that Squamous Carcinoma of Parotid an effective treatment is available for approximately 58% of patients with SCC in the parotid gland. A comprehensive treatment approach consisting of surgery and adjuvant therapy may increase disease control in those individuals with metastatic SCC to the parotid gland. The similar clinical course between the two groups of patients in our series leads us to hypothesize that some of the patients with primary SCC of the parotid gland may have had metastatic SCC to the parotid gland. Elderly patients are potentially poor historians, and it could be a challenge for them to recount all of their cutaneous lesions and treatments. The pattern of disease failure was dependent on neck metastasis associated with local recurrence and distant metastases, even when postoperative radiation was administered. Occult metastases to the cervical nodes are frequently encountered, suggesting that treatment should include neck dissection, as well as the excision of the parotid mass. Elective neck dissection has the benefit of providing additional pathologic information with low morbidity that will direct the physician regarding management of the disease and is also an effective treatment for limited metastatic cancer in the neck. The aggressive clinical behavior of metastatic cutaneous SCC underscores the importance of elective treatment of regional lymphatics, including the parotid gland. The goal is a greater chance of cure with a conservative approach to the parotid gland. Acknowledgments. We thank the Tumor Registry Staff, Dr. Carl H. Snyderman for statistical analysis, and Stout Family Fund for Head and Neck Cancer Research at the Eye & Ear Foundation of Pittsburgh. REFERENCES 1. Batsakis JG, McClatchey KD, Johns M, et al. Primary squamous cell carcinoma of the parotid gland. Arch Otolaryngol 1976;102:355–357. 2. O’Brien CJ, Malka VB, Mijailovic M. Evaluation of 242 consecutive parotidectomies performed for benign and malignant disease. Aust N Z J Surg 1993;63:870–877. 3. Guillamondegui OM. Salivary gland cancers, surgery and irradiation therapy. Arch Otolaryngol Head Neck Surg 1982;108:709–715. 4. Lee K, McKean ME, McGregor IA. Metastatic patterns of squamous carcinoma in the parotid lymph nodes. Br J Plast Surg 1985;38:6–10. 5. Bron LP, Traynor SJ, McNeil EB, O’Brien CJ. Primary and metastatic cancer of the parotid: comparison of clini- HEAD & NECK—DOI 10.1002/hed July 2006 631 cal behavior in 232 cases. Laryngoscope 2003;113:1070– 1075. 6. Khurana VG, Mentis DH, O’Brien CJ, Hurst TL, Stevens GN, Packham NA. Parotid and neck metastases from cutaneous squamous cell carcinoma of the head and neck. Am J Surg 1995;170:446–450. 7. Audet N, Palme CE, Gullane PJ, et al. Cutaneous metastatic squamous cell carcinoma to the parotid gland: analysis and outcome. Head Neck 2004;26:727–732. 8. Charabi S, Balle V, Charabi B, Nielsen P, Jens Thomsen. Surgical outcome in malignant parotid tumours. Acta Otolaryngol Suppl 2000;543:251–253. 632 Squamous Carcinoma of Parotid 9. Frankenthaler RA, Luna MA, Lee SS, et al. Prognostic variables in parotid gland cancer. Arch Otolaryngol Head Neck Surg 1991;117:1251–1256. 10. Malata CM, Camilleri IG, McLean NR, et al. Malignant tumors of the parotid gland. Br J Plast Surg 1997;50: 600–608. 11. Spiro RH. Salivary neoplasms: overview of a 35 year experience with 2807 patients. Head Neck Surg 1986;8:177–184. 12. Rice DH, Becker TS. Neoplastic disorders. In: Hanafee WN, Ward PH, editors. Clinical correlations in the head and neck series: the salivary glands. New York: Thieme; 1994. p 37–52. HEAD & NECK—DOI 10.1002/hed July 2006