ORIGINAL ARTICLE. Multivariate Analysis of Risk Factors for Neck Metastases in Surgically Treated Parotid Carcinomas

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1 ORIGINAL ARTICLE Multivariate Analysis of Risk Factors for Neck Metastases in Surgically Treated Parotid Carcinomas Izandro Régis de Brito Santos, MD; Luiz P. Kowalski, MD, PhD; Vera Cavalcante de Araujo, DDS, PhD; Angela Flávia Logullo, MD, PhD; José Magrin, MD, PhD Objective: To analyze risk factors for neck metastases in patients with parotid s. Design: Cohort of patients followed up from 1 to months at a single institution. Setting: Referral center, private or institutional practice, hospitalized care. Patients: A total of 145 patients with parotid s with complete clinical and pathological information. The histological diagnosis was reviewed according to the World Health Organization classification for salivary gland tumors. Intervention: Patients were treated by surgery alone (62 cases) or with postoperative radiotherapy (83 cases). A neck dissection was performed in 80 patients. Main Outcome Measure: Rates of neck lymph node metastasis. Univariate and multivariate analyses were carried out using logistic regression evaluating the significance of demographic, clinical, and pathological data. Results: The following variables were significantly associated to the risk of lymph node metastasis by univariate analysis: histological type (P), T stage (P), desmoplasia (P=.001), facial palsy (P=.02), perineural invasion (P=.01), extraparotid tumor extension (P=.02), and necrosis (P=.003). By multivariate analysis, histological type (P), T stage (P=.03), and desmoplasia (P=.006) had the highest correlation with lymph node metastasis. Conclusion: The significant risk factors for neck metastasis in parotid were histological type (ie, adeno, undifferentiated, highgrade mucoepidermoid, squamous cell, and salivary duct ), T stage (T3 and T4), and desmoplasia (severe). Arch Otolaryngol Head Neck Surg. 2001;127:56-60 From the Medical School (Drs Régis de Brito Santos and Flávia Logullo) and the Department of Oral Pathology, School of Dentistry (Dr Cavalcante de Araujo), University of São Paulo, and the Department of Head and Neck Surgery and Otorhinolaryngology, Centro de Tratamento e Pesquisa Hospital do Câncer A. C. Camargo (Drs Kowalski and Magrin), São Paulo, Brazil. SALIVARY GLAND tumors are rare and represent 0.3% of all malignant neoplasias. The vast majority have epithelial origin. 1 Seventy percent of all salivary gland neoplasias are at the parotid gland with a reported percentage of malignancy varying from 17% to 34%. The heterogeneity and great diversity in histological types along with the rarity of malignant subtypes have lead to the individualized and controversial treatment of these patients. 2,3 Tumor extent, neck metastases, pain at presentation, aged older than 55 to 60 years, and being male have all been considered poor prognostic indicators, 4-6 as well as the microscopic features of cellular atypia, desmoplasia, and a high mitotic index. 7 Patients with acinic cell and mucoepidermoid have a better prognosis when compared with patients with adeno, malignant mixed tumor, adenoid cystic, squamous cell, and undifferentiated. 7 Surgery is the main treatment modality and the type of resection, whether partial or total parotidectomy, with preservation or sacrifice of the facial nerve, depends on tumor location, size, and extent. 8,9 The incidence of lymph node metastases in parotid s at the time of initial presentation varies from 12.4% to 24%. 1,6,7,10 There is no doubt regarding the indications of neck dissection in clinically positive lymph nodes of the neck. However, the question does remain for patients with stage N0 neck. Indications for elective neck treatment (neck dissection or radiotherapy) are unclear. 11 Patients with neck recurrences have a poor prognosis, since treatment in this group is inefficient and relapse is unlikely to be salvaged. The specific point of interest in this article is to analyze demographic, clini- 56

2 PATIENTS AND METHODS All cases of malignant parotid neoplasias treated at the Department of Head and Neck Surgery and Otorhinolaryngology, Centro de Tratamento e Pesquisa Hospital do Câncer A. C. Camargo, São Paulo, Brazil, from November 30, 1965, to March 21, 1992, were reviewed. One hundred fortyfive patients with the diagnosis of primary malignant epithelial tumors of the parotid gland were eligible for this study. Melanomas, lymphomas, sarcomas, and metastatic s were excluded. We also included previously operated on patients whenever enough demographic, pathological, therapeutic, and clinical information were recovered. The patients were retrospectively staged according to American Joint Committee on Cancer classification (1997 version) 12 (Table 1). Hematoxylin-eosin stained slides were analyzed and histopathological diagnoses reviewed by 2 pathologists (V.C.A. and A.F.L.) adopting the World Health Organization classification for salivary gland tumors. 13 Whenever there was disagreement between diagnoses, the slides were analyzed by a third pathologist. There were 80 male (55.2%) and 65 female patients (44.8%), ranging in age from 2 to 82 years (median age, 53 years). The presence of a mass in the parotid region, the most frequent complaint, was reported for 141 patients (97.2%). Duration of complaint ranged from 1 to 480 months. Regarding tumor staging, 9 (6.3%) were classified as T1; 28 (19.3%), T2; 47 (32.4%), T3; 36 (24.8%), T4; and 25 (17.2%). TX. Clinical lymph node involvement was present in 38 (23.5%) of the 145 patients as follows: 18 (12.4%) N1, 15 (10.4%) N2, 1 (0.7%) N3, and 4 (2.7%)NX. All patients underwent surgical treatment. Total parotidectomy was the most common resection performed (91 cases [62.8%]), followed by partial parotidectomy in 37 patients (25.5%) and wider resections (total parotidectomy encompassing adjacent structures as bone, skin, and muscle), whenever the tumor extended beyond the parotid confines, in 17 patients (11.7%). Sixty-four patients (44.1%) submitted to radical (classic or modified) unilateral neck dissection. Supraomohyoid neck dissection was performed in 15 patients (10.3%) and bilateral radical neck dissection in 1 (0.7%). Surgical treatment was followed by external beam radiation therapy in 83 cases (57.2%), with a total dosage ranging from 30 Gy to 70 Gy. The lymphatic drainage was included in the radiation portals in 50 cases (34.5%) and only the parotid region in 33 cases (22.8%). The follow-up period ranged from 1 to months (median follow-up, 66.2 months) with 77 (53.1%) of the 145 patients being followed up for 60 months and 45 (31.0%) for at least 120 months. Local recurrence alone was observed in 20 patients (13.8%). Homolateral neck lymph node metastases occurred in 9 patients (6.2%), within a median period of 37.8 months (range, months), while contralateral neck nodes were the site of recurrence in only 3 patients (2.0%). Distant metastases were found in 17 patients (11.7%) and were associated with local recurrence in 2 patients (1.4%) and with neck metastases in another 2 patients (1.4%). The following variables were evaluated as candidate risk factors for lymph node metastases in parotid s: sex, age, race, T stage, facial paralysis, extraglandular tumor extent, histological type, vascular and lymphatic invasion, necrosis, peritumoral lymphocytes, and desmoplasia (inflammatory reaction). Regarding desmoplasia, we designated the following 3 different grades based on the proportion of such histopathological features in the tumor slides reviewed: grade 1, light (14 cases); grade 2, moderate (32 cases); and grade 3, severe (27 cases) when the proportion of tumor composed of desmoplastic stromal reaction was less than 25%, between 25% and 50%, and more than 50%, respectively. Surgical margins were not evaluated in view of the impossibility to get a precise assessment in a retrospective study like this one. Logistic regression was used to perform univariate and mulivariate analysis to build models representing the most parsimonious subset of variables with an independent predictive value for neck metastases. cal, and histopathological data to determine which were the N0-staged patients at a high risk for occult metastasis who could potentially benefit from elective neck treatment. RESULTS Mucoepidermoid was the most common histological type (20.0%) followed by undifferentiated (12.4%), malignant mixed tumor (11.?%), and squamous cell (9.7%). Occult metastases were detected in 17 (37.0%) of 46 N0-staged patients who underwent elective neck dissection. Thirteen patients (76.5%) among the 17 with occult neck metastases had T3 or T4 tumors. 12 The histological types observed in such cases were mucoepidermoid, salivary duct, squamous cell, undifferentiated, malignant mixed tumor, and adenoid cystic. Nine patients had ipsilateral neck recurrences within a median period of 39.6 months. Seven of these patients were initially staged as N0 and elective neck dissection was performed in 4 of them, followed by radiotherapy in 2 cases. The histological types were categorized according to the risk of neck metastases into 3 groups low, moderate, and high risk, when the percentage of lymph node involvement by histological type reached, respectively, 0% to 20%, 21% to 50%, and more than 50%. Histological types with a total number of cases equal to or smaller than 6 were classified as others (Table 2). The risk for neck metastases was significantly associated with the following variables by univariate analysis: histological type (P), T stage (P), desmoplasia (P=.001), necrosis (P=.003), facial paralysis (P=.02), perineural infiltration (P=.01), and extraparotid tumor extent (P=.02) (Table 3). There was a trend toward lymph node metastases in male patients that, however, failed to achieve statistical significance. Multivariate analysis identified the following as independent predictors for neck involvement: the histopathological type (P), T stage (P=.033), and desmoplasia (P=.006) (Table 4). 57

3 Table 1. Staging Systems for Major Salivary Gland Malignancy* Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor 2 cm or less in greatest dimension without extraparenchymal extension T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension without extraparenchymal extension T3 Tumor having extraparenchymal extension without seventh nerve involvement and/or more than 4 cm but not more than 6 cm in greatest dimension T4 Tumor invades base of skull, seventh nerve, and/or exceeds 6 cm in greatest dimension Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension N2 Metastasis in a single ipsilateral lymph node, more than 3 cm but no more than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension or in bilateral or in contralateral lymph nodes, none more than 6 cm in greatest dimension N2a Metastasis in a single ipsilateral lymph node more than 3 cm but no more than 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N3 Metastasis in a lymph node more than 6 cm in greatest dimension Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis *Staging classifications adapted from Fleming. 12 COMMENT Table 2. Histological Types and the Risk for Neck Metastases Risk Group Histological Types Risk, % Low ( 20%) Adenoid cystic 9.1 (Group 1) Low-grade mucoepidermoid 11.1 Intermediate-grade mucoepidermoid 16.7 Moderate (20%-50%) Acinic cell 23.1 (Group 2) Malignant mixed tumor 35 Mioepitelial 33.3 Other 21.1 High ( 50%) Adeno 54.6 (Group 3) Undifferenciated 55.6 High-grade mucoepidermoid 57.1 Squamous cell 78.6 Salivary duct 85.7 The treatment of the neck in patients with parotid is indicated whenever there is clinical evidence of lymph node metastases. This is the only situation in which there is no discussion on the therapeutic approach usually a radical neck dissection followed by postoperative external beam radiation. 9 The approach of the N0 neck, however, remains controversial; there is no consensus regarding the need for elective neck dissection or elective radiotherapy. 11 The addition of neck dissection, to the surgical treatment increases the time required for the surgical procedure, the risk of postoperative complications, treatment costs, and aesthetic and functional sequelae. Therefore, it should be avoided in N0-staged patients, whenever possible. In this series, 25 (31.3%) of 80 patients who underwent neck dissection had pn0-staged stage. However, clinically N0-staged patients, with occult metastases who did not undergo treatment of the neck, may evolve with detrimental outcome, and salvage treatment is frequently inefficient in such situations. 14 The overall incidence of lymph node metastases in our experience was 23.5% and the main histological type was the mucoepidermoid (20%), in accord with the data published in the literature. 1,6,7,10,15,16 The reported percentage of neck metastases at the time of patients admission for undifferentiated, squamous cell, adeno, mucoepidermoid, and malignant mixed tumor is more than 20%. 9,17,18 In this series, we observed that most of these histological types belong to the high-risk group for neck spread, ie, undifferentiated, high-grade mucoepidemoid, salivary duct, adeno, and squamous cell. Metastasis in patients with those histological types were seen in 68%. The question about N0-staged patients is: what is the exact percentage of such patients with occult metastases? Or how many patients will have recurrences in the neck? Are there indications for elective neck dissection in parotid? Several authors have different answers to these questions, nevertheless, the problem still remains. Fu et al 19 observed the preponderance of undifferentiated s (3 of 4 patients) in cases of neck recurrence. All patients had T3 tumors. Frankenthaler et al 10 by multivariate analysis showed that extraglandular tumor extent, being older than 54 years, and lymphatic invasion were significantly associated with the risk for neck metastasis. In their series, occult metastases were observed in cases of adeno, salivary duct, squamous cell, undifferentiated, and mucoepidermoid. Kelley and Spiro 2 consider clinical stage and tumor grading as the best predictive factors. Armstrong et al 9 have also shown that patients with high-grade tumors, advanced T stage, and undifferentiated (6 of 7 patients), squamous cell (6 of 28 patients), adeno (11 of 49 patients), and mucoepidermoid (30 of 209 patients) present high-risk for neck metastases and should be considered candidates to an elective neck dissection. Spiro et al 6 reported metastases in 40% and 16% of squamous cell and high-grade mucoepidermoid, respectively. The authors suggest elective neck dissection to be performed in patients with highgrade tumors. Spiro et al 6 stated that at least 58% of the patients with undifferentiated or squamous cell s will have neck metastases and could benefit from elective neck dissection. In their series, about 50% of the neck 58

4 metastases were detected by this procedure. Califano et al 20 found occult lymph node metastases in 17% of the patients with mucoepidermoid and suggested benefit effects of elective neck dissection in such cases, as well as in undifferentiated and squamous cell s. In a follow-up period of 4 years, Poulsen et al 16 registered neck metastases in 24.4% of 237 parotid s, showing that patients older than 60 years, with clinically positive lymph nodes at the time of first presentation and with positive surgical margins, squamous cell, and poorly differentiated tumors, have a higher percentage of neck metastases. High-risk histological types were observed in 13 (76.5%) of 17 patients with metastases detected by elective neck dissection in this series, and 13 (76.5%) of those cases had T3 or T4 tumors. The association of high-risk histological type and T3 or T4 was registered for 9 patients. These figures probably underestimate the actual percentage of T3 or T4 tumors in this subset of patients because T stage was undetermined (TX) in 4 of the 13 patients who had high-risk histological types with occult metastases. Neck recurrences were diagnosed in 7 patients (4.8%). The advanced T stage (T3 or T4) and the high-risk histological types were observed in 5 cases (71.4%) and 4 of them were dead of disease at the end of this study, demonstrating the remarkable and detrimental prognostic influence of neck recurrence. Considering that the identification of risk factors for lymph node metastases, including preoperative and pathological, could be significant to indicate elective neck dissection or elective postoperative radiotherapy, with possible prognostic significance, we decided to undertake this study. Frankenthaler et al, 10 analyzing 11 preoperative and postoperative variables, found patient s age, extraparotid tumor extent, and perilymphatic invasion to be the most significant predictive factors for occult lymph node metastases by multivariate analysis. In our series, histological type, T stage, facial palsy, extraglandular tumor extent, perineural invasion, necrosis, and desmoplasia reached statistical significance in univariate analysis. Of the several candidate prognostic factors, multivariate analysis revealed histological type, T stage, and severe desmoplasia as the most significant independent predictors of the risk of neck involvement. Lewis et al 3 studied a group of 90 patients with acinic cell of the parotid gland to determine clinical and histological features that consistently predicted disease progression. The presence of desmoplastic reaction (desmoplasia) was 1 of 3 microscopic features significantly correlated with poor outcome (P.01). In different tumors, parenchymal cells stimulate the formation of an abundant collagenous stroma, characterized by the growth of fibrous tissue, refered to as desmoplasia, 21 which is a fairly common finding in parotid. We tried, however, to estabilish not only a quantitative but also a qualitative relationship between this finding and the risk for lymph node metastases, estimating 3 different grades based on the proportion of the histopathological feature in the tumor slides that were reviewed. As we have shown, only severe desmoplasia was significantly associated with the risk for lymph node metastases (P=.001). Table 3. Univariate Analysis of Risk Factors for Neck Metastases in Parotid Carcinomas No. (%) of Patients With Neck Metastases Total No. of Patients Variable No Yes Age, y (64.6) 29 (35.4) (55.6) 28 (44.4) 63 Sex Male 43 (53.7) 37 (46.3) 80 Female 45 (69.2) 20 (30.8) 65 Histological type Low risk 23 (88.5) 3 (11.5) 26 Intermediate risk 42 (76.4) 13 (23.6) 55 High risk 23 (35.9) 41 (64.1) 64 Facial paralysis No 83 (63.8) 47 (36.2) 130 Yes 5 (33.3) 10 (66.7) 15 T stage T1 + T2 31 (83.8) 6 (16.2) 37 T3 + T4 39 (47.8) 44 (52.2) 83 TX 18 (72.0) 7 (28.0) 25 Extraparotid extension No/focal 66 (67.3) 32 (32.7) 98 Yes 22 (46.8) 25 (53.2) 47 Vascular invasion No 77 (59.7) 52 (40.3) 129 Yes 11 (68.7) 5 (31.3) 16 Perineural infiltration No 73 (66.4) 37 (33.6) 110 Yes 15 (42.9) 20 (57.1) 35 Desmoplasia None, light, 79 (66.9) 39 (33.1) 118 and moderate Severe 9 (33.3) 18 (66.7) 27 Necrosis None and light 67 (69.1) 30 (30.9) 97 Moderate or severe 21 (43.7) 27 (56.3) 48 Peritumoral lymphocytes No 71 (63.4) 41 (36.6) 112 Yes 17 (51.5) 16 (48.5) 33 Table 4. Multivariate Analysis of Risk Factors for Neck Metastases in Parotid Carcinomas Variable Odds Ratio 95% Confidence Interval* Histological type Low risk 1.0 Reference Moderate risk High risk T stage T1 + T2 1.0 Reference T3 + T TX Desmoplasia Absent and moderate 1.0 Reference Severe P P *Reference indicates reference category used for comparison with the confidence interval obtained for the other categories

5 Unfortunately, some of this information may be unavailable at the time of surgical treatment, restricting its applicability to decide on elective neck dissection or irradiation following primary tumor ressection. Tumor stage is easily known preoperatively, and histological type is generally known by intrasurgical evaluation of a tumor specimen (frozen section). Both types of information can be incorporated in the surgical treatment plan. This is not the case for desmoplasia. However, all of this information is valuable to decide whether postoperative radiotherapy should include the lymphatic drainage area because there is no proven benefit of elective neck dissection over radiotherapyin treating parotid. 11 Elective neck dissection is considered in the management of superior aerodigestive squamous cell s whenever the percentage of occult lymph node metastases is between 15% and 20%. 22 These figures are not yet established for parotid s. Our findings showed occult metastases in 22.2% of the subset of patients with T3 or T4 and a high-risk histological type. Gallo et al, 23 studying the expression of p53 in parotid tumors, observed the association of neck metastases and decreased survival in patients with high expression of this suppressor gene. However, as stated by Kelly and Spiro: the search for factors at the subcellular level holds much promise for the future, but as of this writing, the selection of patients for elective lymphadenectomy involves a judgment based on the relevant clinical findings. 2(p697) Our experience suggests that in the management of parotid s, patients with high-risk histological types (ie, adeno, undifferentiated, salivary duct, squamous cell, and high-grade mucoepidermoid ) and advanced T stage (T3 or T4) could benefit from elective neck treatment. In this series, there was neck metastases in 100% of the patients with tumors at advanced T stage, severe desmoplasia, and high-risk histological types. Results of retrospective published series regarding the risk factors for cervical metastases in parotid varies widely. Prospective randomized trials, however, are virtually infeasible as this is a rare tumor and long-term follow-up is required. Accepted for publication June 29, Reprints: Luiz P. Kowalski, MD, PhD, Department of Head and Neck Surgery and Otorhinolaryngology, Centro de Tratamento e Pesquisa Hospital do Câncer A. C. Camargo, R. Professor Antonio Prudente, 211, São Paulo-SP, Brazil ( lp_kowalski@uol.com.br). REFERENCES 1. Eveson JW, Cawson RA. Salivary gland tumors: a review of 2410 cases with particular reference to histological types, site, age and sex distribution. J Pathol. 1985;146: Kelley DJ, Spiro RH. Management of the neck in parotid. Am J Surg. 1996;172: Lewis JE, Oslen KD, Weiland LH. 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