Malignant Minor Salivary Gland Tumors in Quito, Ecuador. Clinical Aspects and Prognostic Factors

Salivary gland tumors include a group of uncommon heterogeneous neoplasms that represent 3% to 6% of all head and neck malignancies [1,2]. Approximately 70% of these tumors are located in the parotid gland and most of them are benign. However, gland tumors may also originate in the submandibular, sublingual and minor salivary glands [3,4]. There are about 550 to 1000 lobules of minor glands located throughout the submucosa of the mouth and upper aerodigestive tract, including the lips, gingiva, palate, tonsils, tongue, oropharynx, paranasal sinuses and parapharyngeal space. Minor glands are either primarily mucous, primarily serous or both [3-5]. Other extremely rare sites include lymph nodes, thyroid glands, facial bones and the hypophysis. The wide variability of locations challenges diagnosis, hinders staging and delays proper treatment [5]. Salivary gland carcinomas carry an unparalleled histological diversity in comparison with any other organ systems [6]. Despite minor salivary gland tumors account for less than 25% of salivary neoplasms, 50 to 75 percent of them are malignant [2-4,7-9].

The incidence and mortality of malignant minor salivary gland tumors (MMiSGT) in a specific population is difficult to know because these tumors are registered within the lesions of each anatomic site. The aim of this study was to review the clinical presentation, management and results of treatment of a series of patients with MMiSGT tumors treated at a third-level hospital.

From 1980 to 2020, 639 patients were surgically treated for salivary gland tumors at the Social Security Hospital, a third level hospital, in Quito, Ecuador. Among them, 578 were located in major salivary glands, 54 in minor salivary glands, 19 benign and 35 malignant and 7 in ectopic salivary tissue. The clinical records of 35 patients with MMiSGT were reviewed. A university ethics committee permission was obtained. All these patients underwent a surgical resection, by a single surgeon and adjuvant therapy was given at the same institution. All of them signed an informed consent before surgery. The anatomical sites were determined by clinical examination and radiological imaging and were categorized as follows: nasal cavity and paranasal sinuses, oral cavity, oropharynx, larynx and trachea. The World Health Organization classification of head and neck tumors was used for histological classification and for definitions of grades within pathological groups. Staging was recorded according to the eighth edition of the American Joint Committee (AJCC) Staging Manual. MMiSGT were staged, by convention, with the mucosal tumor staging classification according to the anatomical site of the tumor.

The clinical information of the patients was organized in a database. For later tabulation and analysis, non-parametric statistics and maximum likelihood, we used the Kaplan-Meier method to calculate estimates of overall survival and to compare the different variables The expected results at 5 and 10 years were calculated. Elaboration and organization of the database was processed in Excel (version 1682 [24021116].2024 Microsoft) and the statistical analysis was carried out in SPSS (version 25; IBM).

The mean age of patients was 51 (26-77) years (s.d.51 [±14.5] years); 23 were females and 12 were males. One patient was simultaneously treated for a papillary thyroid carcinoma and another developed breast cancer later. Nineteen tumors were located on the left side, eleven on the right side and 5 in the midline. The mean duration of symptoms was 15 (1-60) months (s.d.15 [±17.34] months). The mean size was 4.1cm (1-10) (s. d. 4.1 [±1.99] cm). Among 31 patients with tumor consistency description, 22 had hard and 9 had soft lesions. Thirty-two patients had fixed tumors and 3 mobiles. In 4 patients, lesions were ulcerated. Anatomic tumor location and histologic type appears on table 1. Imaging studies were performed in most of them, according to the hospital availability and included Computed Tomography (CT) in 21, Magnetic Resonance Imaging (MRI) in 6 and Ultrasound (US) in one. An angiography was performed in patient with adenoid cystic carcinoma of the nasal cavity who presented with epistaxis during 5 months. A patient, who was initially treated with limited surgery due to an adenoid cystic carcinoma of the palate in another institution, came to our clinic with a previous Positron Emission Tomography (PET) requested by his clinical oncologist. There were no patients with initial distant metastasis. TNM distribution appears on tables 2&3. All patients underwent a surgical procedure for removal of the tumor. Three patients with clinically positive neck nodes underwent a modified neck dissection in 2 and a suprahyoid neck dissection in one. These 3 patients (8.6%) had pathological positive nodes. Three additional patients, underwent suprahyoid neck dissection, one for PET suspicious nodes and 2 because a combined neck and intraoral approach was performed. Finally, a patient with a cricotracheal adenoid cystic carcinoma whose thyroid was attached to the tumor, underwent a lateral paratracheal node dissection. All of these last 4 patients had pathologically negative nodes. Only two patients had been treated initially elsewhere: one patient with radiotherapy for an adenoid cystic carcinoma of the nasal cavity, who underwent a maxillectomy in our service and was lost to follow up; and another patient, a young woman initially treated with both radio and chemotherapy for a myoepithelial carcinoma of the base of the tongue and persistent tumor, who underwent a wide resection and is currently free of disease 2 years later. Surgical modalities appear on table 4. Postoperative complications occurred in 5 patients and were mostly minor.

Table 1: Anatomic location and histology of tumors.

Table 2: TNM staging. 

Table 3: Stage distribution.

Table 4: Surgical modalities according anatomic location of tumors. 

The report of surgical margins was available in 24 patients and were positive in 15 cases. All tumors arising in the nasal fossa had positive margins and those arising in the oropharynx, clear or close. Adjuvant treatment was given to 16 patients mainly based on aggressive histology and positive surgical margins. Radiotherapy was used in 12 patients and both radio and chemotherapy in 4 patients. Mean follow up was 6 years 5 months (s.d. 86.9 [± 83.4] months; range 3-326 months). Only 2 patients were lost to follow up. Overall five-year and ten-year survival rates were 75.8 % and 55.8%, respectively (Figure 1). Prognostic factor overall survival by univariate analysis appears on table 5. As there is not an available staging classification for minor salivary gland tumors, they were staged similar to squamous cell carcinoma according to the anatomic site of origin [10].  Local recurrence occurred in 10 patients, regional recurrence in 2 and distant metastasis in 8. Location of these metastases was lung in 8 patients, liver in one and brain in one. Patient conditions at last follow up appear on table 6. Age (< 60 versus ≥60 years), tumor histology and surgical margins were found to be significant prognostic factors by univariate analysis (Figures 2-4).

Table 5: Univariate analysis for overall survival. * No patients at risk **Described in 24 patients.

Table 6: Clinical condition at last follow up. 

Figure 1: Overall Survival.

 Figure 2: Overall survival according to age.

 Figure 3: Overall survival according to histological type.

Figure 4: Overall survival according to margin.

The most remarkable studies on MMiSGT have been the Baddour’s report [11] on 5,334 patients from the Surveillance, Epidemiology and End Results (SEER) database and the Memorial Sloan Kettering Cancer Center’s series of 450 patients reported by Hay [6]. In Latin America, only few studies have been published and most of them described demographic, clinical and pathological data [8,12-16]. In only one study current patient status at the last follow up visit was described [17]. No survival results appeared in any of these reports. Age and gender distribution still have discrepancies among literature, possibly due to referral bias and/or ethnic variations [1-2,12,17-18]. Most patients are middle aged and sex distribution seems approximately similar, according to Baddour’s and Hay’s reports [6,11]. Clinical presentation varies according to the location and the degree of invasion to nearby structures. They usually present as painless submucosal masses or ulcers in the palate, lips, or mucosa. On counterpart, advanced disease is more likely to manifest with nasal obstruction, vision changes, trismus and other symptomatology related to the possibility of skull base invasion, intracranial extension, or cranial nerves impairment [19]. The assessment of location, incidence and natural evolution of MMiSGT is difficult because most studies analyze all minor salivary gland neoplasms together [1-4,7-8,17,20-24]. Site distribution for malignant SG tumors were the oral cavity (59%), followed by  the oropharynx (21%), the sinonasal cavity (16%) and the larynx (4%), according to Baddour’s study [10],  and 68%, 21%, 8% and 4%, for the same sites, according to Hay’s series [6]. This distribution was 57%, 20%, 20% and 3% in our series, respectively. The palate is the most common oral cavity site [25,26]. Sinonasal lesions usually have more advanced T-stage at diagnosis, more invaded resection margins and a higher local recurrence rate [27]. 

The most common MMiSGT are Adenoid Cystic Carcinoma (ACC) (32% to 69%) and Mucoepidermoid Carcinoma (MEC) (15% to 35%) [2,6,8,17,23,28-31]. Other less common tumors are acinic cell carcinoma, polymorphic adenocarcinoma, myoepithelial carcinoma and carcinoma from pleomorphic adenoma [32]. ACC is a slow growing, but aggressive, tumor which tends to present perineural and lymphatic extension and distant metastasis [33]. MEC was the most common histological type in both Baddour and Hay’s series. However, adenocarcinoma was the second most common in Baddour’s study and ACC in Hay’s report [6,11]. ACC was the most common in our study. There may be tumor histology frequency variation when classified by site. Our patients had larger tumors and more advanced stages. In Hay’s report, T size was ≤4cm in 81% of patients while it was 67% in our study; and almost half of the patients (49.6%) had stage I disease, but only 14.3% in our series. Any modality of wide excision of the primary tumor is the treatment of choice. In Baddour’s study, 67% of patients received a form of surgical therapy [11]. In the other reports [6,34,35],  all patients were treated with a curative intent. Neck dissection is indicated in the presence of clinical or cytologically positive nodes. A neck dissection was performed in 29% of patients in Hay’s series [6] and in 23% in ours. Lymph node examination was performed in 15% of patients of the SEER program [11]. Forty-nine per cent of patients in our study received postoperative radiation treatment, but ACC patients were more likely to receive it (66%). 

Interestingly, Baddour [11] reported an 8.35 of Distant Metastasis (DM) at the time of diagnosis which was higher than in head and neck squamous cell carcinoma and major salivary gland malignancies. Of 152 patients from the SEER database with MMiSGT and DM at presentation, 50 (32.9%) who underwent Primary Tumor Surgery (PTS) had >20% increase in 1- and 2-year Overall Survival (OS) and Cancer-Specific Survival (CSS) compared with their counterparts without PTS [36]. Positive surgical margins have been described in 19.6% to 40% of patients [6,7,37-39]. In the present study, we had 37.5% of patients with positive surgical margins.  In our study, the 5- and 10-year OS rates were 75.8 % and 55.8%, respectively, approximately similar to other reports [6,34,35,39]. A higher size of tumors, a higher percentage of stage III and IV cases (40%) and a highest frequency of distant metastases in this study should be considered in the analysis of these figures. In Hay’s series, factors predictive of failure for overall survival on univariate analysis were as follows: age greater than or equal to 60 years, male sex, history of tobacco use, history of serious comorbidity, Perineural Invasion (PNI), Lymphovascular Invasion (LVI), close/positive margins, histology risk group, postoperative radiation, pathological T and N stages and AJCC oncological overall stage [6]. In Baddour’s study, patients with tumor location in the larynx and nasal cavity and paranasal sinuses, as well as age older than 75 years, had significant worse 5- and 10-year cause specific survival; while race, sex and postoperative radiotherapy were not significant prognostic factors. Additionally, MEC subtype histology and local disease patients had better survival than ACC and adenocarcinoma as well as regional or distant disease [11]. Age [39], sex [34,39],  site of occurrence [34,39], grade of tumor [34,39], vascular invasion [34,39], nerve invasion [40], stage [34,39,41], surgical margins [18,38] and postoperative radiotherapy [35] have been found to be significant prognostic factors in other series. Age, tumor histology and surgical margins were found to be significant prognostic factors by univariate analysis in the present series. Nasal cavity tumors had a poorer overall survival when comparing to oral cavity or oropharyngeal tumors, but it did not reach a significant value. This fact could be explained by the fact that all tumors arising in the nasal fossa had more frequent positive margins than those arising in the other locations. Other described predictive factors, such as sex, stage and adjuvant treatment were not significant in our series, probably due to the smaller size of our series. On multivariate analysis, age greater than or equal to 60 years, male sex, larynx/trachea location, high risk histology group, advanced clinical stages and no adjuvant radiotherapy treatment were associated with poorer outcome in Hay’s series [6]. In ACC, solid histological subtype and positive surgical margins have been described as important predictors of poor outcome while postoperative radiation has provided better OS and CSS compared with surgery alone [42]. In patients with ACC of the oral cavity, neck node metastases have been found to have a significant negative impact on OS and CSS [43]. Patients with low- or intermediate-grade MEC exhibit satisfactory survival after surgery, but patients with high-grade tumors, survival rates are poor and do not improve following adjuvant therapy [44]. In a study of sinonasal MMiSGT, isolated from the National Cancer Database (2004-2014), no difference in survival was found among treatment modalities: surgery alone, surgery with radiotherapy and surgery with chemoradiotherapy (CRT), with the exception of RT alone. Positive margins were prognostic in this tumor location. In this subset of patients, CRT did not provide survival benefit over surgery and RT and surgery alone was associated with decrease survival [45]. However, the National Comprehensive Cancer Network (NCCN) guidelines has recommended Chemotherapy (CT) only in the most concerning cases. Pathogenesis of minor salivary gland carcinoma is still not completely elucidated. Factors like smoking, poor hygiene or alcohol seem not to play a significant role as in oral squamous cell carcinoma [41]. However, history of tobacco use has been found to be a predictive factor of failure on univariate analysis in the series of the MSKCC [6]. In Hay’s series, there were 21.6% failures: distant, local and regional in frequency order. They occurred in 13 out of 35 cases (37.1%), in the present report; we had distant and local failures but no regional recurrences [6]. Distant metastases occurred in 13.6% of cases in Hay’ report and in 22.9% in our series. One strength in this short series could be that surgical treatment was performed by one surgeon and overall management was homogeneous.

MMiSGT are certainly very uncommon neoplasms so homogeneous institutional studies are occasionally published. We have reviewed the clinical and therapeutic features of our institutional patients over a long-time span and, to our knowledge, this is the only report with analysis of prognostic factors of MMiSGT carried out in Latin America. As younger patients, adenoid cystic carcinoma histology and positive surgical margins were found to be significant prognostic factors, in patients with these features, a more aggressive multimodality treatment should be warranted.

1. Spiro RH (1986) Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 8: 177–184.
2. Toida M, Shimokawa K, Makita H, Kato K, Kobayashi A, et al. (2005) Intraoral minor salivary gland tumors: a clinicopathological study of 82 cases. Int J Oral Maxillofac Surg 34: 528–32.
3. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (2017) WHO Classification of Head and Neck Tumours. 4th ed. Lyon: IARC 2017.
4. Guzzo M, Locati LD, Prott FJ, Gatta G, McGurk M, et al. (2010) Major and minor salivary gland tumors. Crit Rev Oncol Hematol 74:134-48.
5. Strick MJ, Kelly C, Soames JV, McLean NR (2004) Malignant tumours of the minor salivary glands - a 20-year review. Br J Plast Surg 57: 624–31.
6. Hay AJ, Migliacci J, Karassawa Zanoni D, McGill M, et al. (2019) Minor salivary gland tumors of the head and neck-Memorial Sloan Kettering experience: Incidence and outcomes by site and histological type. Cancer 125: 3354-66.
7. Copelli C, Bianchi B, Ferrari S, Ferri A, Sesenna E (2008) Malignant tumors of intraoral minor salivary glands. Oral Oncol 44: 658-63.
8. Rivera-Bastidas H, Ocanto RA, Acevedo AM (1996) Intraoral minor salivary gland tumors: a retrospective study of 62 cases in a Venezuelan population. J Oral Pathol Med 25: 1-4.
9. WHO Classification of tumors. Pathology and genetics of head and neck tumors. IARC 2005.
10. Amin MB, Gress DM, Vega LMR, Edge SB, Greene FL, et al. (2018) AJCC Cancer Staging Manual, Eighth Edition (8th ed.). American College of Surgeons.
11. Baddour HM, Fedewa SA, Chen AY (2016) Five- and 10-Year Cause-Specific Survival Rates in Carcinoma of the Minor Salivary Gland. JAMA Otolaryngol Head Neck Surg 142: 67–73.
12. Loyola AM, de Araújo VC, de Sousa SO, de Araújo NS (1995) Minor salivary gland tumours. A retrospective study of 164 cases in a Brazilian population. Eur J Cancer, B, Oral Oncol 31: 197-201.
13. Frias-Mendivil M, Isabel ZG, Laura SB, Fransico OC (1997) Epidemiolgía descriptiva del cáncer de cavidad oral en el Instituto Nacional de Cancerología. Revista del Instituto Nacional de Cancerología 43: 80-5.
14. Lendesma-Montes C, Garces-Ortiz M (2000) Malignant salivary gland tumors. Revista del Instituto Nacional de Cancerología. 2000;46(3):167-170.
15. Conceição B, Gurgel S, Gomes C, Agra G, Kruschewsky de, et al. (2010) Minor salivary gland tumors in a south American population. Arch Oncol 18: 56-59.
16. Fonseca FP, Carvalho M de V, de Almeida OP, Rangel ALCA, Takizawa MCH, et al. (2012) Clinicopathologic analysis of 493 cases of salivary gland tumors in a Southern Brazilian population. Oral Surg Oral Med Oral Pathol Oral Radiol 114: 230239.
17. Lopes MA, Kowalski LP, da Cunha Santos G, Paes de Almeida O (1999) A clinicopathologic study of 196 intraoral minor salivary gland tumours. J Oral Pathol Med 28: 264-7.
18. Mücke T, Robitzky LK, Kesting MR, Wagenpfeil S, Holhweg-Majert B, et al. (2009) Advanced malignant minor salivary glands tumors of the oral cavity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 108: 81-9.
19. Schramm VL, Imola MJ (2001) Management of nasopharyngeal salivary gland malignancy. Laryngoscope 111: 1533-44.
20. Bell RB, Dierks EJ, Homer L, Potter BE (2005) Management and outcome of patients with malignant salivary gland tumors. J Oral Maxillofac Surg 63: 917-28.
21. Terhaard CHJ, Lubsen H, Van der Tweel I, Hilgers FJM, Eijkenboom WMH, et al. (2004) 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 26: 681-92.
22. Jansisyanont P, Blanchaert RH, Ord RA (2002) Intraoral minor salivary gland neoplasm: a single institution experience of 80 cases. Int J Oral Maxillofac Surg 31: 257-61.
23. Yih W-Y, Kratochvil FJ, Stewart JCB (2005) Intraoral minor salivary gland neoplasms: review of 213 cases. J Oral Maxillofac Surg 63: 805-10.
24. Pires FR, Pringle GA, de Almeida OP, Chen SY (2007) Intra-oral minor salivary gland tumors: a clinicopathological study of 546 cases. Oral Oncol 43: 463-70.
25. Wang X, Meng L, Hou T, Zheng C, Huang S (2015) Frequency and Distribution Pattern of Minor Salivary Gland Tumors in a Northeastern Chinese Population: A Retrospective Study of 485 Patients. J Oral Maxillofac Surg 73: 81-91.
26. Poletto AG, Mello FW, Melo G, Rivero ERC (2020) Prevalence of mucoepidermoid carcinoma among intraoral minor salivary gland tumors: A systematic review and meta-analysis. J Oral Pathol Med 49: 720-726.
27. Lee SY, Shin HA, Rho KJ, Chung HJ, Kim SH, et al. (2012) Characteristics, management of the neck and oncological outcomes of malignant minor salivary gland tumours in the oral and sinonasal regions. Br J Oral Maxillofac Surg 51: e142-e147.
28. Xiao CC, Zhan KY, White-Gilbertson SJ, Day TA (2016) Predictors of nodal metastasis in parotid malignancies: A national cancer data base study of 22,653 patients. Otolaryngol Head Neck Surg 154: 121-130.
29. Dillon PM, Chakraborty S, Moskaluk CA, Joshi PJ, Thomas CY (2016) Adenoid cystic carcinoma: A review of recent advances, molecular targets and clinical trials. Head Neck 38: 620-627.
30. Wang D, Li Y, He H, Liu L, Wu L, et al. (2007) Intraoral minor salivary gland tumors in a Chinese population: a retrospective study on 737 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104: 94-100.
31. Buchner A, Merrell PW, Carpenter WM (2007) Relative frequency of intra-oral minor salivary gland tumors: a study of 380 cases from northern California and comparison to reports from other parts of the world. J Oral Pathol Med 36: 207-214.
32. Savera AT, Sloman A, Huvos AG, Klimstra DS (2000) Myoepithelial carcinoma of the salivary glands: a clinicopathologic study of 25 patients. Am J Surg Pathol 24: 761-774.
33. Fordice J, Kershaw C, El-Naggar A, Goepfert H (1999) Adenoid cystic carcinoma of the head and neck: predictors of morbidity and mortality. Arch Otolaryngol Head Neck Surg 125: 149-152.
34. Loh KS, Barker E, Bruch G, O'Sullivan B, Brown DH, et al. (2009) Prognostic factors in malignancy of the minor salivary glands. Head Neck 31: 58-63.
35. Salgado LR, Spratt DE, Riaz N, Romesser PB, Wolden S, et al. (2014) Radiation therapy in the treatment of minor salivary gland tumors. Am J Clin Oncol 37: 492-497.
36. Shi X, Huang NS, Shi RL, Wei WJ, Wang YL, et al. (2018) Prognostic value of primary tumor surgery in minor salivary-gland carcinoma patients with distant metastases at diagnosis: first evidence from a SEER-based study. Cancer Manag Res 10: 2163-2172.
37. Ampil FL, Misra RP (1987) Factors influencing survival of patients with adenoid cystic carcinoma of the salivary glands. J Oral Maxillofac Surg 45: 1005-1010.
38. da Cruz Perez DE, de Abreu Alves F, Nobuko Nishimoto I, de Almeida OP, Kowalski LP (2006) Prognostic factors in head and neck adenoid cystic carcinoma. Oral Oncol 42: 139-146.
39. Vander Poorten VL, Balm AJ, Hilgers FJ, Tan IB, Keus RB, et al. (2000) Stage as major long term outcome predictor in minor salivary gland carcinoma. Cancer 89: 1195-1204.
40. Cianchetti M, Sandow PS, Scarborough LD, Morris CG, Kirwan J, et al. (2009) Radiation therapy for minor salivary gland carcinoma. Laryngoscope 119: 1334-1338.
41. Kakarala K, Bhattacharyya N (2010) Survival in oral cavity minor salivary gland carcinoma. Otolaryngol Head Neck Surg 143: 122-126.
42. He S, Li P, Zhong Q, Hou L, Yu Z, et al. (2017) Clinicopathologic and prognostic factors in adenoid cystic carcinoma of head and neck minor salivary glands: A clinical analysis of 130 cases. Am J Otolaryngol 38: 157-162.
43. Moratin J, Ledermann A, Schulz A, Metzger K, Ristow O, et al. (2021) Neck involvement and disease recurrence in adenoid cystic carcinoma of the minor salivary glands: the role of surgery in primary and progressive disease. Int J Oral Maxillofac Surg 50: 423-430.
44. Terauchi M, Michi Y, Hirai H, Sugiyama K, Wada A, Harada H, et al. (2021) Prognostic factors in mucoepidermoid carcinoma of the minor salivary glands: A single-center retrospective study. Oral Pathol Oral Radiol 131: 209-216.
45. Torabi S, Spock T, Cardoso B, Chao J, Manes R, et al. (2020) Multi-modality Treatment and Survival in Sinonasal Minor Salivary Gland Tumors. J Neurol Surg B Skull Base 81: 198-205.