PROGNOSTIC FACTORS IN PATIENTS WITH MINOR SALIVARY GLAND CARCINOMA OF THE ORAL CAVITY AND OROPHARYNX

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1 ORIGINAL ARTICLE PROGNOSTIC FACTORS IN PATIENTS WITH MINOR SALIVARY GLAND CARCINOMA OF THE ORAL CAVITY AND OROPHARYNX José F. Carrillo, MD, 1 Federico Maldonado, MD, 5 Liliana C. Carrillo, BSc, 1 Margarita C. Ramirez-Ortega, PhD, 4 Juan G. Gómez Pizano, MD, 1 C. Melo, 1 José G Chanona, MD, 3 K. Luna-Ortiz, 1 Luis F. Oñate Ocaña, MD 2 1 Head and Neck Department, Instituto Nacional de Cancerología, Mexico City, Mexico. josecarr@prodigy.net.mx 2 Division of Surgery, Instituto Nacional de Cancerología, Mexico City, Mexico 3 Pathology Department, Instituto Nacional de Cancerologia, México City, Mexico 4 Instituto Nacional de Cardiologia, Ignacio Chavez, Mexico City, Mexico 5 Division of Radiotherapy. Instituto Nacional de Cancerología, Mexico City, Mexico Accepted 6 September 2010 Published online 15 December 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed Abstract: Background. This study was performed to define prognostic factors and management of minor salivary gland carcinoma of the oral cavity and oropharynx. Methods. Retrospective analyses of patients with salivary gland carcinoma of the oral cavity or oropharynx, treated in 1989 to Statistics included univariate analyses to identify prognostic factors associated with disease-free survival (DFS) and disease-specific survival. A multivariate analysis model was constructed by the Cox method. Results. Seventy-seven patients constituted our cohort. Significant prognostic factors regarding DFS and disease-specific survival in univariate analyses comprised tumor size, surgical margins, grade, lymph node status, and Karnofsky status and T classification. A multivariate model identified tumor size, grade, surgical margins, and lymph node status significant regarding DFS. Conclusions. Tumor size, grade, surgical margins, and lymph node status could be used for a rational design of treatment strategies in these rare tumors. VC 2010 Wiley Periodicals, Inc. Head Neck 33: , 2011 Keywords: minor salivary gland carcinoma; oropharynx salivary gland carcinoma; oral cavity salivary gland carcinoma Minor salivary gland carcinomas of the oral cavity and oropharynx are infrequent neoplasms, represent 10% of malignant salivary gland neoplasms, and are difficult to diagnose because of their clinical presentation and the lack of familiarity of many pathologists with pathologic classification and grading except in referral centers. 1 3 Consequently, their biological behavior and treatment are heterogeneous and controversial. Correspondence to: J. F. Carrillo VC 2010 Wiley Periodicals, Inc. At present, few series exist regarding these malignancies, and most of these include a mixture of primary sites from the parotid gland to minor salivary glands. 4 Additionally, most studies report only epidemiologic and histopathologic data or are limited to univariate analyses because of the small number of cases. 5 Clinical data of these malignancies are elusive and frequently do not present at physical examination with ulceration or bleeding, which renders them difficult to detect by health care personnel. 6,7 The staging system for minor salivary gland cancer of the oral cavity and oropharynx at present follows the American Joint Committee on Cancer (AJCC) guidelines for squamous cell carcinoma of the oral cavity, with failure to determine in most instances the prognosis and guidelines for treatment of these patients. 8 This analysis was conducted to define prognostic factors of minor salivary gland carcinoma located in the oral cavity and oropharynx, the biology (including histopathologic and grade characterization), and consequently to define basic treatment strategies and the role of combined management in these neoplasms. MATERIALS AND METHODS This was a retrospective analysis of patients who presented to the Head and Neck Department in the Instituto Nacional de Cancerología at Mexico City with a diagnosis of minor salivary gland carcinoma of the oral cavity and oropharynx from January 1989 to December Inclusion criteria comprised, aside from histopathologic confirmation, complete medical records, absence of distant metastases, and treatment completion with curative intent. All patients included in our series with partial or no response to treatment were monitored until death or hospital discharge. Cases analyzed had a complete 1406 Minor Salivary Gland Cancer HEAD & NECK DOI /hed October 2011

2 clinical history and laboratory workup, complete ear, nose, and throat and extensive intraoral examinations, as well as image evaluation with computed tomography and ortopanthomography when indicated because of mandible proximity. MRI was performed as well in all cases from 2002 to date. Clinical staging was performed according to the AJCC 2002 system modifications as used in oral cavity and oropharynx for squamous cell carcinoma. 8 Histopathologic study definition was performed by 2 pathologists by consensus according to the 2005 World Health Organization classification. 9 Grade was determined by consensus between 2 pathologists, with guidelines established by the World Health Organization 9 and Luna et al 9 13 for cell structure (tumor necrosis, mitosis number by 10 high-power fields, [0 5, 5 10 and 10], and nuclear pleomorphism), and architecture (capsule and adjacent tissue invasion, neural and vascular invasion, presence of mucin-producing cells, acini, cribiform, or solid pattern and cysts). In addition, we considered an undifferentiated (epithelial malignancies or areas whose light-optic histopathologic features including sarcomatoid areas in adenocarcinoma are not sufficient to place them in other defined classes of carcinoma), high-grade category as has been described by Seethala et al, 13 Luna, 14 Batsakis and Luna, 15 and Cheuk and Chan. 16 When an undifferentiated neoplasia or areas of undifferentiation were found, the malignancy grade assigned was undifferentiated, and a better differentiated area was sought, with immunohistochemistry and electron microscopy performed to ascertain the epithelial salivary gland origin of the neoplasm. These criteria are supported as well by the MD Anderson grading system and other reports on grading and undifferentiation of minor salivary gland carcinomas Surgery is the primary treatment of choice in our institution for minor salivary gland carcinomas of the oral cavity and oropharynx. Laser was used in two T1, N0, M0 cases. Surgical margins were classified as positive, negative, or borderline. (Surgical margins in our institution are assessed in the specimen and the surgical bed. Specimen: surgical borders are evaluated with frozen section, as well as the area facing the surgical bed [tridimensional evaluation]. Pieces of tissue are excised of the surgical bed as well and frozen section assessed considering those critical areas as judged by the operating surgeon where tumor was specially invasive macroscopically, or where nerves, vessels, or major functional structures excision would produce prohibitive morbidity rates and in some cases death. The pathologic report after formalin fixation defined the final assessment of surgical margins in these cases.) When the tumor was observed macroscopically or microscopically either in the surgical specimen or surgical bed, margins were considered positive. Negative margins were obtained when a distance of 1 cm was obtained from the primary malignancy in the surgical specimen and ascertained with samples obtained from surgical bed. When distance from primary tumor was 1 cm with no tumor observed in the surgical bed samples, the margin was classified as borderline. Patients with T3, T4, N0 tumors because salivary gland malignancies have been reported with a 23% frequency of positive pathologic lymph nodes in these stages 4 and those with clinically positive lymph node metastasis underwent neck dissection. Supraomohyoid neck dissection was performed in N0 lesions and a modified type III comprehensive neck dissection in clinically positive necks. Cases with T4b lesions or regionally unresectable neoplasms, surgically unfit patients, and cases in which surgery would cause prohibitive functional or aesthetic derangements were taken to radiotherapy upfront. Adjuvant radiation therapy was administered in patients with borderline or positive surgical margins, high-grade malignancies (lesions with 2 or more of these parameters: tumor necrosis, 10 mitosis by 10 high-power fields, nuclear pleomorphism, vascular or neural invasion), in T3 and T4 tumors, and in cases with positive cervical lymph nodes (Nþ). Radiotherapy was initiated within 4 to 8 weeks after surgery. Doses administered in these cases were 60 to 75.6 Gy (mean dose, 66.6 Gy; median dose, 66 Gy), to primary lesion. The neck dose was 45 to 50 Gy (median dose, 48 Gy). The initial target volume included the primary tumor or surgical bed for small or low-grade cancers with indications for radiation therapy. The primary tumor or surgical bed and lymph nodes were included in the target volume for high-grade malignancies, T3 and T4 tumors, and in cases with lymph node metastases. When radiation therapy was administered up-front, patients received 1 dose daily, and the median external-beam dose was 74 Gy (range, Gy). A conventional parallel opposed field technique was used in all cases. The prescribed dose was 1.8 to 2 Gy per fraction, per day, administered 5 days a week. All patients underwent photon therapy, with energies from 1.25 to 6 MV. Statistics. Outcomes in our study included recurrence frequency, disease-free survival (DFS) and disease-specific survival (DSS). The association of clinical, pathologic, and therapeutic factors with the outcome were analyzed with the Student t test, chisquare, and Kaplan-Meier methods 19 for continuous, categorical, or survival data, respectively. Differences between survival curves were calculated employing the log-rank test. Variables with a plausible association and with probability values of 0.2 or less were included in multivariate survival analysis using the Cox proportional hazards model. Proportionality requirements, as well as interaction terms, were analyzed in the final model. 20 Probability values of.05 or less were considered statistically significant. SPSS for Windows version 10.0 (1999) software (SPSS, Inc., Chicago, IL) was used for all computations. Minor Salivary Gland Cancer HEAD & NECK DOI /hed October

3 Table 1. Histopathologic and staging characteristics of patients with minor salivary gland carcinoma of oral cavity and oropharynx. Characteristic No. % Site Oral cavity Hard palate Floor of mouth 7 9 Retromolar trigone 7 9 Mobile tongue 6 8 Gingivae 4 5 Lip 3 4 Oropharynx Soft palate 9 12 Base of tongue 6 8 Tonsillar fossae 3 4 Posterior wall 2 3 Histopathology Adenoid cystic carcinoma Mucoepidermoid carcinoma Adenocarcinoma Acinic cell carcinoma 3 4 Myoepithelial cell carcinoma 3 4 Clear cell carcinoma 1 1 Grade Well differentiated Moderately differentiated Poorly differentiated Undifferentiated 4 5 T classification T T T T4a T4b N classification N N N2 4 5 N3 3 4 RESULTS One hundred five patients were identified with salivary gland carcinoma of the oral cavity and oropharynx. Twenty-eight patients had incomplete clinical charts or refused treatment and therefore were not included in our study. Seventy-seven patients complied with the aforementioned requirement criteria and were included in the final analyses. There were 44 (57%) men and 33 (43%) women, and mean age was 49.8 years (standard deviation [SD], 16.6; range, years). Most common clinical presentation data were presence of a tumor mass in 76 (99%) of cases, pain in 26 (34%), ulceration in 7 (9%), and bleeding in 5 patients (6%). Fifty-seven (74%) cases were located in the oral cavity, and 20 (26%), in the oropharynx. Median follow-up time was 3.84 years. In Table 1, epicenter tumor location, histopathologic study, and T and N classification for patients in this case series are depicted, in which the most frequent histopathologic conditions were adenoid cystic and mucoepidermoid carcinoma. Treatment strategies were as follows: 34 (44%) patients received surgery plus adjuvant radiation therapy; 18 (23%) had surgery alone; 22 (29%) were administered radiotherapy alone; and 3 patients (4%) had radiotherapy plus salvage surgery. Recurrence patterns in this series were as follows: local in 11 cases (14%), regional in 6 (8%), lung metastases in 10 cases (13%) 8 of these corresponding to adenoid cystic carcinoma and bone metastasis in 1 case (1%). Median DFS was 11.5 years (95% CI, ), and median DSS, 15.6 years (95% CI, years). DFS and DSS rates at 5 years were 57.4% and 81.6%, respectively. The association of clinical, pathologic, and surgical variables with recurrence frequencies is depicted in Table 2. By univariate analyses, significant Table 2. Association between clinical and pathologic factors and the outcome of recurrence. No. (%) No recurrence Recurrence p value Sex.63 Female 22 (43) 11 (39) Male 27 (55) 17 (61) Age, mean (SD) 49.5 (18) 49.8 (14).1 Hemoglobin, mean (SD) 14.3 (2) 13 (2).4 Albumin, mean (SD) 3.65 (1) 3.54 (1).8 Tumor size, mean (SD) 3.46 (2) 6.06 (3).05 Tumor size <.0001 <2 cm 15 (31) 2 (7) 2 4 cm 24 (49) 6 (21) 4 6 cm 6 (12) 5 (18) >6 cm 4 (8) 15 (54) Karnofsky % 24 (50) 6 (21) <100% 25 (50) 22 (79) Histopathology.18 Mucoepidermoid 15 (31) 8 (29) Adenoid cystic 24 (49) 11 (40) Adenocarcinoma, NOS 5 (10) 7 (25) Acinic 3 (6) 0 Myoepithelial 1 (2) 2 (7) Clear cell 1 (2) 0 Grade.18 Well 16 (33) 10 (36) Moderately 23 (47) 9 (32) Poorly 8 (16) 7 (25) Undifferentiated 2 (4) 2 (7) Treatment.21 Surgery 13 (26) 5 (18) SurgeryþRt 24 (49) 10 (36) Rt 10 (20) 12 (43) RtþSurgery 2 (4) 1 (3) Surgical margins.1 Negative or 46 (94) 22 (79) undefined (up-front RT) Positive 3 (6) 6 (21) T classification.001 T1 10 (20) 0 T2 18 (37) 7 (25) T3 6 (12) 4 (14) T4a 11 (22) 9 (32) T4b 4 (8) 8 (29) Lymph node status.03 Negative 34 (69) 12 (43) Positive 15 (31) 16 (57) Abbreviations: SD, standard deviation; Rt, radiotherapy; NOS, not otherwise specified Minor Salivary Gland Cancer HEAD & NECK DOI /hed October 2011

4 prognostic factors regarding DFS and DSS were Karnofsky status, tumor size, T and N classification, grade, and histologic and surgical margins. Survival curves for DFS in terms of tumor size, grade, histology, and surgical margins are shown in Figure 1. In Figure 2, a DFS curve by N classification is shown in which high statistical significance was found for this prognostic factor. Figure 3 depicts DFS in our cohort, according to T classification. When we dichotomized the factor grade in high-grade to lowgrade, grouping together as low-grade lesions the well- and moderately differentiated tumors and excluding the other categories as high-grade lesions, in the DFS curve obtained a higher statistical significance was found: p ¼ Mean DFS of patients treated with surgery alone was 9.95 years (95% CI, years) and of those treated with surgery and adjuvant radiotheraphy 8.7 years (95% CI, years), p ¼.7, for patients available for follow-up. Multivariate analyses by Cox method identified a model that included tumor size, grade, surgical margins and N classification as independent prognostic factors for DFS (Table 3). The dichotomy mentioned regarding grade was applied (high- and low-grade lesions) in the multivariate analyses, and a higher significance than in the previous model was found (p <.001). In our study, no independent prognostic factors were identified regarding DSS. DISCUSSION This was a retrospective case series of patients with minor salivary gland carcinoma of oral cavity and oropharynx. We identified the following 4 independent DFS-associated clinicopathologic factors by multivariate analyses: tumor size, surgical margins, N classification, and grade. No significant DSS prognostic factors were identified by this method, probably because of lack of association of tumor recurrences with death, because most of them continue to have a feasible rescue treatment with good possibilities of disease control. Advantages of our series are that it includes a large sample size, that cases are derived from a single institution with homogeneous treatment and pathologic assessment strategies, and the inclusion of patients with primary site location in the oral cavity and oropharynx only. Potential pitfalls of our analysis are the study s retrospective nature and a median follow-up period of 3.84 years. Our follow-up, however, was sufficient to reach the median DFS in most calculations and is similar to follow-up reported in most series until FIGURE 1. Disease-free survival curves of the cohort of 77 patients according to tumor size (p ¼.0001) (A), grade (p ¼.037) (B), histopathology (p ¼.021) (C), and surgical margins (p ¼.073) (D). InC, the total sum of cases is 76, because 1 patient only had a clear cell carcinoma and was not included in the graphic. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Minor Salivary Gland Cancer HEAD & NECK DOI /hed October

5 FIGURE 2. Disease-free survival curves according to presence or absence of lymph node metastases (p ¼.0082). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] now. Ours, however, is a cohort in which most patients have low socioeconomic status, and low compliance is frequent. Other pitfalls could be the possible occurrence of institutional reference bias and inherent difficulties regarding histopathologic study and grade determination, which we tried to avert with final diagnoses obtained by means of the consensus of 2 pathologists. Finally, and although there could be a concern for overfitting in the multivariate analyses (77 patients with 28 events and a 4-term model), the guidelines are not quite as rigid regarding this issue, and the Cox model used has the advantage of considering not only the number of events, but time and censoring. Moreover, some authors 21 suggest that 5 events for each FIGURE 3. Disease-free survival curves according to tumor classification (p <.0001). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] variable is a good general recommendation for multivariate models. Clinical characteristics in our series are in agreement with the existing although scarce literature. 5 A nonulcerated and painful tumor mass should alert physicians and health care personnel devoted to oral diseases to the possibility of a minor salivary gland carcinoma and the need to perform an incisional biopsy. Because histopathologic study of these lesions is complicated, it is preferable that evaluation via consensus between 2 or more pathologists be performed. Of note is that the association of histopathologic classification with recurrence had no statistical significance in our bivariate or multivariate analysis, which has also been reported previously, 22 probably because histopathologic diagnosis is not necessarily related to tumor aggressiveness except in very specific varieties of minor salivary gland carcinomas such as ductal and acinic cell carcinoma. Regarding tumor grade, and although some authors 5 consider this factor as subjective, the parameters pointed out by Batsakis et al and Luna et al, 23,24 were considered regarding tumor architecture and cell structure. The significance of grade by multivariate analysis has been highlighted by our group in carcinoma of the parotid gland. 25 Otherwise, and although some reports suggest the significance of grade in minor salivary gland carcinomas, 26,27 to our knowledge this is the first study that finds prognostic significance and good stratification regarding grade in multivariate analyses for minor salivary gland carcinomas of oral cavity and oropharynx. Although the definition of grade has been considered subjective in these malignancies, the already established criteria (at the present time in a continued state of evolution) will probably incorporate it as a major prognostic factor for salivary gland carcinoma. Moreover, when we regrouped the lesions into lowand high-grade neoplasms, a higher statistical significance was found in the univariate and multivariate analyses. However, we believe that the 4 categories division is more stringent and less subjective than a dichotomization of grade. Tumor size cut-offs have been described in the present AJCC classification of squamous cell malignancies of oral cavity and oropharynx as 2 and 4 cm. However, our analysis allows differentiation of 2 other tumor size categories (4 6, and >6 cm), independently of invaded structures, probably related with lower biologic aggressiveness of salivary malignancies in general compared with squamous cell carcinoma. Surgical margin for minor salivary gland carcinomas was also found by our group as an independent prognostic factor by multivariate analysis. It is noteworthy that the margin is assessed not only in the specimen but also in the surgical bed in our unit. Other authors have also confirmed the importance of obtaining negative margins in treatment of minor salivary gland carcinomas of the oral cavity Minor Salivary Gland Cancer HEAD & NECK DOI /hed October 2011

6 Table 3. Estimators of recurrence-free survival-associated prognostic factors defined by Cox s method. Factor ß SE Exp, ß 95% CI p value Surgical margins Negative* 1 Positive <.001 Tumor diameter <.001 <2 cm* cm cm >6 cm <.001 Node status Negative* 1 Positive Grade.001 Well- differentiated* 1 Moderately differentiated Poorly differentiated Undifferentiated Abbreviations: RR, relative risk ;Exp (ß), relative risk; 95% CI, 95% confidence interval of RR; SE, standard error. Final model p <.05. The p value is the probability value of the relative risk or prognostic factor. *Reference category. Radiation therapy administration as adjuvant treatment was nonsignificant, probably because of the retrospective nature of the study and the known tendency to administer it to patients with more advanced and aggressive lesions or when surgical margins could be compromised. Considering that the survival rate of patients who underwent postoperative radiation therapy (who had more unfavorable prognostic factors) was comparable to that of patients treated with surgery only, the possibility of a benefit from adjuvant radiotherapy exists. Other retrospective studies 31,32 have found improved DFS in patients with advanced stages, as well as high-grade tumors when treated with adjuvant radiotherapy. Although it appears that available data would support combined treatment in high-grade, big-sized tumors and compromised surgical margins malignancies, the routine use of postoperative radiation therapy in oral cavity and oropharyngeal carcinoma has not reached consensus as suggested by reports like the ones from Spiro and Loh. 26,33 Although our study was not designed to discern whether lymph-node basins of the neck should comprise part of primary management, the significance of N classification by multivariate analysis suggests the need to investigate its inclusion as part of the initial therapy, especially in the large or high-grade minor salivary gland carcinomas, because 40% of patients in our series (with >50% of T3 T4 malignancies) presented with positive lymph nodes, and 5 cases had regional recurrences during follow-up. 28 In this way, patients with T1 T2 malignancies, and N0 necks could be subjected to observation, and those with T3 T4, N0 lesions should have elective neck dissection. Recurrence patterns of these neoplasms are to be mentioned at this point, with 17 cases presenting locorregional recurrence and 11 metastases (predominantly in lung). The metastatic pattern was associated with adenoid cystic histology (which has been reported previously). 34 Of interest is that Karnofsky performance status was found significant in univariate analyses but not in multivariate analysis. However, the importance of this factor, as well as of age in salivary gland malignancies, is being repeatedly reported in recent studies. 35 We believe that small tumors 2 cm, N0, with low to intermediate grade and in which negative surgical margins are obtained, are candidates for treatment with surgery only (even with laser resection) and reconstruction if needed. Low-grade tumors, >2 to4 cm in size, N0, resected with negative margins could receive surgical treatment with no adjuvant radiotherapy. Patients with >4 to 6 cm, N0 tumors, should be treated with surgery, probably with concomitant elective neck dissection and adjuvant treatment with radiotherapy according to the definitive pathology report. Tumors >6 cm in size and T4 lesions, with possibly compromised margins, require a multidisciplinary approach, with extensive negative margin-aimed surgery that encompasses even use of free flaps, radical neck lymph-node dissection, and adjuvant radiation therapy. 36 In unfit or unresectable cases, and in patients unwilling to undergo surgical treatment, upfront radiotherapy with surgical salvage in cases with partial and significant responses could be offered, 21,36 because this therapeutic modality is potentially curative for nonresectable (T4b) cases (33% DFS at 5 years), as is shown in Figure 3. Further studies should confirm this finding, which has also been reported by Cianchetti et al. 37 In conclusion, this study defines tumor size, grade, surgical margins, and lymph node status as significant prognostic factors in a multivariate model for minor salivary gland carcinomas of oral cavity and oropharynx. Minor Salivary Gland Cancer HEAD & NECK DOI /hed October

7 Acknowledgments. The authors wish to acknowledge Ms. Maggie Brunner for her assistance in translation and style editing of the manuscript. REFERENCES 1. Eveson JW, Cawson RA. Salivary gland tumors: a review of 2,410 cases with particular reference to histological types, site, age, and sex distribution. J Pathol 1985;146: Lopes MA, Santos GC, Kowalski LP. Multivariate survival analysis of 128 cases of oral cavity minor salivary gland carcinomas. Head Neck 1998;20: Loyola AM, de Araújo VC, de Sousa SO, de Araújo NS. Minor salivary gland tumours. A retrospective study of 164 cases in a Brazilian population. Eur J Cancer B Oral Oncol 1995;31: Terhaard CH, Lubsen H, Van der Tweel I, et al. Dutch Head and Neck Oncology Cooperative Group. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch Head and Neck Oncology Cooperative Group. Head Neck 2004;26: Vander Poorten VL, Balm AJ, Hilgers FJ, Tan IB, Keus RB, Hart AA. Stage as major long term outcome predictor in minor salivary gland carcinoma. Cancer 2000;89: Subhashraj K. Salivary gland tumors: a single institution experience in India. Br J Oral Maxillofac Surg 2008;46: Chou C, Zhu G, Luo M, Xue G. Carcinoma of the minor salivary glands: results of surgery and combined therapy. J Oral Maxillofac Surg 1996;54: Greene FL, Page DL, Fleming ID, et al. Editors. AJCC Cancer Staging Handbook. 6th ed. NewYork: Springer; p WHO classification of tumors. Pathology and genetics of head and neck tumors. Lyon, France: IARC Press; Batsakis JG, Luna MA. Histopathologic grading of salivary gland neoplasms: I. Mucoepidermoid carcinomas. Ann Otol Rhinol Laryngol 1990;99: Batsakis JG, Luna MA, El-Naggar AK. Histopathologic grading of salivary gland neoplasms: II. Acinic cell carcinomas. Ann Otol Rhinol Laryngol 1990;99: Batsakis JG, Luna MA, El-Naggar A. Histopathologic grading of salivary gland neoplasms: III. Adenoid cystic carcinomas. Ann Otol Rhinol Laryngol 1990;99: Seethala RR, Hunt JL, Baloch ZW, Livolsi VA, Leon Barnes E. Adenoid cystic carcinoma with high-grade transformation: a report of 11 cases and a review of the literature. Am J Surg Pathol 2007;31: Luna MA. Pathology of tumors of the salivary glands. In: Thawley SE, Panje WR, Batsakis JG, Lindberg RD. Comprehensive management of head and neck tumors. Philadelphia: WB Saunders; p Batsakis JG, Luna MA. Undifferentiated carcinomas of salivary glands. Ann Otol Rhinol Laryngol 1991;100: Cheuk W, Chan JK. Advances in salivary gland pathology. Histopathology 2007;51: Cheuk W, Chan JK: Salivary Gland Tumors. In: Fletcher CDM, editor. Diagnostic histopathology of tumors. 3rd ed. Philadelphia: Churchill Livingstone-Elsevier; Ganly I, Patel SG, Coleman M, Ghossein R, Carlson D, Shah JP. Malignant minor salivary gland tumors of the larynx. Arch Otolaryngol Head Neck Surg 2006;132: Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: Cox DR. Regression models and life tables series B (methodological). J R Stat Soc 1972;34: Tabachnik BJ, Fidell LS. Using multivariate statistics. London: Harper & Row; Parsons JT, Mendenhall WM, Stringer SP, Cassisi NJ, Million RR. Management of minor salivary gland carcinomas. Int J Radiat Oncol Biol Physiol 1996;35: Luna MA. Salivary mucoepidermoid carcinoma: revisited. Adv Anat Pathol 2006;13: Brandwein MS, Ivanov K, Wallace DI, et al. Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 2001;25: Carrillo JF, Vázquez R, Ramírez-Ortega MC, Cano A, Ochoa-Carrillo FJ, Oñate-Ocaña LF. Multivariate prediction of the probability of recurrence in patients with carcinoma of the parotid gland. Cancer 2007;109: Spiro RH, Thaler HT, Hicks WF, Kher UA, Huvos AH, Strong EW. The importance of clinical staging of minor salivary gland carcinoma. Am J Surg 1991;162: Beckhardt RN, Weber RS, Zane R, et al. Minor salivary gland tumors of the palate: clinical and pathologic correlates of outcome. Laryngoscope 1995;105: Copelli C, Bianchi B, Ferrari S, Ferri A, Sesenna E. Malignant tumors of intraoral minor salivary glands. Oral Oncol 2008;44: Anderson JN Jr, Beenken SW, Crowe R, et al. Prognostic factors in minor salivary gland cancer. Head Neck 1995;17: Bianchi B, Copelli C, Cocchi R, Ferrari S, Pederneschi N, Sesenna E. Adenoid cystic carcinoma of intraoral minor salivary glands. Oral Oncol 2008;44: Armstrong JG, Harrison LB, Spiro RH, Fass DE, Strong EW, Fuks ZY. Malignant tumors of major salivary gland origin: a matchedpair analysis of the role of combined surgery and postoperative radiotherapy. Arch Otolaryngol Head Neck Surg 1990;116: North CA, Lee DJ, Piantadosi S, Zahurak M, Johns ME. Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy. Int J Radiat Oncol Biol Physiol 1990;18: Loh KS, Barker E, Bruch G, O Sullivan B, et al. Prognostic factors in malignancy of the minor salivary glands. Head Neck 2009;31: Garden AS, Weber RS, Ang KK, Morrison WH, Matre J, Peters LJ. Postoperative radiation therapy for malignant tumors of minor salivary glands. Outcome and patterns of failure. Cancer 1994;73: Terhaard CH, van der Schroeff MP, van Schie K, et al. The prognostic role of comorbidity in salivary gland carcinoma. Cancer 2008;113: Mendenhall WM, Morris CG, Amdur RJ, Mendenhall NP, Siemann DW. Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer 2005;103: Cianchetti M, Sandow PS, Scarborough LD, et al. Radiation therapy for minor salivary gland carcinoma. Laryngoscope 2009; 119: Minor Salivary Gland Cancer HEAD & NECK DOI /hed October 2011