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Salivary gland tumors in a Brazilian population: A 20-year retrospective and multicentric study of 2292 cases
Journal of Cranio-Maxillo-Facial Surgery 46 (2018) 2227e2233
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Salivary gland tumors in a Brazilian population: A 20-year retrospective and multicentric study of 2292 cases* Leorik Pereira da Silva a, Marianna Sampaio Serpa a, Stephanie Kenig Viveiros b, urea Adília Co be Sena a, Rodrigo Finger de Carvalho Pinho b, Da vio de Sousa Andrade c, ~es b, Emanuel Sa Letícia Drumond de Abreu Guimara c rcia Maria Fonseca da Silveira c, Ana Paula Veras Sobral c, Ricardo Dias Pereira , Ma Jose lia Batista de Souza a, * Suzana Cantanhede Orsini Machado de Sousa b, Le a
Postgraduate Program in Oral Pathology, Federal University of Rio Grande do Norte-UFRN, Av. Senador Salgado Filho, 1787-Lagoa Nova, Natal, RN, 59056-000, Brazil b ~o Paulo, Av. Prof. Lineu Prestes, 2227-Butanta ~, Sa ~o Paulo, SP, Department of Oral Pathology and Special Care Patients, School of Dentistry, University of Sa 05508-900, Brazil c School of Dentistry, University of Pernambuco, Av. Gal. Newton Cavalcanti, 1650-Tabatinga, Camaragibe, PE, 54756-220, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 24 June 2018 Accepted 24 September 2018 Available online 26 September 2018
Purpose: Neoplasms of the salivary glands comprise more than thirty subtypes of lesions with various clinical behaviors. The present study aimed to describe the incidence and main features of salivary gland tumors in Brazil. Material and methods: A retrospective descriptive cross-sectional study was performed (1997e2017). A total of 88,430 biopsy records of oral and maxillofacial lesions from 5 pathology referral centers were analyzed. All cases of salivary gland tumors were reviewed and data such as gender, age, skin color, anatomical location, symptomatology, tumor size and histopathological diagnosis were collected. Results: Among all lesions, there were 2,292 (2.6%) cases of salivary gland tumors. The most frequent benign and malignant neoplasm was pleomorphic adenoma (n ¼ 1,086; 47.4%) and mucoepidermoid carcinoma (n ¼ 322; 14.0%), respectively. The majority of the patients were white (n ¼ 757; 33%) and female (n ¼ 1,391; 60.7%), and most cases involved the parotid gland (n ¼ 933; 40.7%; p < 0.001). Age ranged from 1 to 101 years, occurring more in the fourth decade of life. Tumor size varied from 0.3 to 15 cm and the presence of symptomatology (pain/swelling) occurred more in patients with malignant tumors (p < 0.001). Conclusion: The incidence profile and clinical findings of salivary gland tumors were similar to those described worldwide; nevertheless, multicenter studies are valuable to better characterize these neoplasms. © 2018 Published by Elsevier Ltd on behalf of European Association for Cranio-Maxillo-Facial Surgery.
Keywords: Salivary gland Neoplasm Epidemiology Head and neck pathology
1. Introduction The parotid, submandibular and sublingual glands are the three major salivary glands. Minor salivary glands are numerous and located in the oral cavity, especially on the palate, lips, buccal mucosa and tongue. The duct-acinar system of the salivary glands is complex, being morphologically and physiologically similar in both
*
No funding source for this study e No conflict of interest to be disclosed. * Corresponding author. E-mail address: [email protected] (L.B. de Souza).
major and minor glands (ductal, myoepithelial and acinar cells) (Tian et al., 2010; Wang et al., 2015; El-Naggar et al., 2017). This leads to a vast and diverse potential for the development of primary tumors independently of the anatomical site. Recently, the World Health Organization (WHO) has published some changes in the classification of salivary gland tumors, recognizing 31 primary epithelial neoplasms. Despite this large number of subtypes, these lesions account for about 3e6% of all head and neck tumors, with an annual estimated global incidence of 0.4e13.5 per 100,000 people (Tian et al., 2010; El-Naggar et al., 2017). Considering their wide histological variety and diverse
https://doi.org/10.1016/j.jcms.2018.09.028 1010-5182/© 2018 Published by Elsevier Ltd on behalf of European Association for Cranio-Maxillo-Facial Surgery.
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In this retrospective study (1997e2017), approximately 88,430 cases of oral and maxillofacial lesions were analyzed. Biopsies and histopathological data were obtained from the archives of 5 surgical pathology centers in Brazil: Department of Oral Pathology of the School of Dentistry of Pernambuco (northeastern region), Laboratory of Surgical Pathology of the University of Pernambuco (northeastern region), Oral Pathology Service of the Federal University of Rio Grande do Norte (northeastern region), Laboratory of Surgical Pathology, Norte-Riograndense League Against Cancer (northeastern region), and Department of Oral and Maxillofacial Pathology of the University of S~ ao Paulo (southeastern region). The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee (UFRN e Approval No. 1.714.150).
anatomical site (n ¼ 933; 40.7%). The palate was the second most frequent site (n ¼ 631; 27.5%) being the most common location of the malignant neoplasms (n ¼ 324; 51.3%). Among the benign tumors, pleomorphic adenoma (PA) was the most frequent one (n ¼ 1.086; 82.2%) followed by basal cell adenoma (BCA) (n ¼ 77; 5.9%) and cystadenoma (CA) (n ¼ 44; 3.3%). The benign tumors were diagnosed mainly between the fourth and seventh decades of life; however, the age ranged from 2 to 99 years, with a mean age of 47 years (SD ± 14) (Table 1). Most cases occurred in the parotid with 641 cases (48.5%) (Table 2). Mucoepidermoid carcinoma (MEC) was the most common malignant neoplasm (n ¼ 322; 33.3%), followed by adenoid cystic carcinoma (ACC) (n ¼ 218; 22.5%) and polymorphous adenocarcinoma (PAC) (n ¼ 165; 17.1%). The age of the patients ranged from 1 to 101 years, with most cases occurring between the fifth and eighth decades of life, with a mean of 55 years (SD ± 16) (Table 1). The most frequent anatomical location was the palate (n ¼ 324; 33.4%), followed by the parotid gland (n ¼ 292; 30.2%) (Table 3). Malignant salivary gland tumors were also found within the gnathic bones (n ¼ 25; 2.6%), with 13 cases in the mandible and 12 cases in the maxilla/maxillary sinus. The majority of the patients did not report any symptoms (pain/ swelling) (n ¼ 1,292; 56.4%). The size of the tumors at the time of diagnosis ranged from 0.3 to 15 cm, although the mean sizes were higher in malignant tumors when compared with the benign tumors (Table 4). When the behavior of the lesions (malignant versus benign tumors) was evaluated, the parotid was the most affected gland mainly by benign tumors (p < 0.001) and the presence of symptoms was more common in malignant tumors (p < 0.001). Benign and malignant salivary gland tumors were more common in older patients of white color; results were statistically significant (Table 5).
2.2. Sample
4. Discussion
All cases of salivary gland tumors were retrieved and data such as gender, age, skin color, anatomical location, symptomatology, tumor size and histopathological diagnosis were collected and analyzed. The lesions were categorized into: benign and malignant tumors in accordance with the current WHO classification of the head and neck tumors (El-Naggar et al., 2017). Immunohistochemical analysis was performed when routine staining (hematoxylin-eosin) was not sufficient to establish the final diagnosis.
In the last 10 years (2008e2018) some studies have been published on the incidence and characteristics of salivary gland tumors in Brazil (de Oliveira et al., 2009; Fonseca et al., 2012; Bittar et al., 2015; Vasconcelos et al., 2016) and other countries as shown in Table 6. However, in few studies more than three diagnostic centers participated and some only reported the incidence in a specific group of salivary glands. In addition, data regarding the symptomatology or size of malignant and benign lesions are necessary for a better knowledge of the clinical characteristics of these tumors. In the present study, 57.7% of the tumors were benign, similar to other reports in which these tumors comprised 53e86% of all salivary gland tumors (Table 6). On the contrary, studies conducted in Africa (Lawal et al., 2013) and Asia (Tilakaratne et al., 2009; Bussari et al., 2016; Taghavi et al., 2016) showed a higher incidence of malignant tumors. In this study, PA was the most common tumor, representing 82.2% of the benign neoplasms, agreeing with all previous studies described in Table 6. Furthermore, BCA was the second most frequent benign tumor (5.9%) in the present study. Other authors observed the same in studies conducted in the United Kingdom and India (Jones et al., 2008; Bussari et al., 2016). Nevertheless, most studies show Warthin's tumor (WT) as the second most common tumor as described in Table 6. Some other benign tumors were very rare, such as oncocytomas and ductal papillomas, as already observed in prior large samples studies. The most common malignant tumor was MEC, representing 33.3% of the cases, followed by ACC which represented 22.5%. Several studies are in accordance with these findings (Li et al., 2008; Jones et al., 2008; Tilakaratne et al., 2009; Atarbashi et al.,
biological behavior, knowing their characteristics and incidence profile is extremely relevant for scientific and clinical purposes. Regardless of the incidence variation of these neoplasms, large series reviews show more than 50% of all primary salivary gland tumors occur in the major salivary glands, mainly in the parotid gland, and are rare in the sublingual gland (1%). Regarding biological behavior, most studies indicate 50e79% of the cases are benign (Tian et al., 2010; Wang et al., 2015; Gao et al., 2017). The objective of this study was to describe the incidence and clinicopathological features of salivary gland tumors diagnosed in several pathology centers of Brazil. We hope these data contribute to the understanding of the current profile of these tumors in Brazil as compared with other countries. 2. Materials and methods 2.1. Study design and ethical aspects
2.3. Data analysis Descriptive and quantitative data analysis was performed using the Statistical Package for the Social Sciences for Windows 20.0 (SPSS, Inc., Chicago, IL, USA). Pearson's chi-square test and Fisher's exact test evaluated differences between the biological behavior of the tumors and their clinical and demographic characteristics, adopting a p-value of 0.05 and a 95% confidence interval. 3. Results In 20 years, there were 2,292 cases of primary salivary gland neoplasms diagnosed in the five centers studied, accounting for 2.6% of all oral and maxillofacial lesions. According to the estimated population of the cities that participated in this study, the incidence was approximately 13 salivary gland tumors per 100,000 inhabitants. Most patients were white (n ¼ 757; 33%) and female (n ¼ 1,391; 60.7%), with a female:male ratio of 1.5:1. Benign tumors were more common (n ¼ 1,322; 57.7%), with a benign:malignant ratio of 1.4:1. Most cases involved major salivary glands (n ¼ 1,178; 51.4%) and the parotid was the most common
L.P. da Silva et al. / Journal of Cranio-Maxillo-Facial Surgery 46 (2018) 2227e2233
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Table 1 Age group distribution (decade of life) of benign salivary gland tumors. Salivary gland tumors
Age Range
Benign tumors Pleomorphic adenoma Basal cell adenoma Cystadenoma Myoepithelioma Warthin's tumor Canalicular adenoma Sialadenoma papilliferum Inverted ductal papilloma Oncocytoma Malignant tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous adenoc Adenocarcinoma NOS Acinic cell carcinoma Carcinoma ex-PA Squamous cell carcinoma Myoepithelial carcinoma Basal cell adenocarcinoma Epithelial-myo carcinoma Salivary duct carcinoma Clear cell carcinoma Carcinosarcoma Cystadenocarcinoma Oncocytic carcinoma Secretory carcinoma Mucinous adenocarcinoma Sebaceous adenocarcinoma Total
Mean Age
Age groups
Total
0e19
20e29
30e39
40e49
50e59
60e69
70
NI
n
%
2e92 6e99 12e80 8e84 17e77 39e89 13e66 35e59 57e75
45 57 54 40 56 60 46 47 66
64 1 1 6 1 0 2 0 0
148 1 2 6 0 0 0 0 0
211 5 4 8 0 2 1 1 0
187 12 6 9 6 2 2 2 0
197 21 10 1 10 5 5 2 1
137 21 14 2 8 5 2 0 0
77 12 6 7 3 8 0 0 1
65 4 1 2 0 4 1 0 0
1,086 77 44 41 28 26 13 5 2
47.4 3.4 1.9 1.8 1.2 1.1 0.6 0.2 0.09
1e92 22e89 2e87 9e101 9e85 20e84 33e87 27e77 23e73 39e85 44e87 22e73 14e87 55e82 65e84 27 52 34 1e101
49 54 56 57 50 58 63 53 62 59 68 46 65 66 74 27 52 34 49 (SD ± 18)
22 0 4 5 3 0 0 0 0 0 0 0 1 0 0 0 0 0 110
45 10 4 4 10 1 0 1 1 0 0 1 0 0 0 1 0 0 235
54 28 17 8 3 3 1 1 0 1 0 1 0 0 0 0 0 1 350
40 37 20 17 3 7 2 1 0 2 1 1 0 0 0 0 0 0 357
42 49 38 20 5 5 2 3 1 3 2 2 0 1 0 0 1 0 426
50 50 39 18 5 11 2 2 2 1 1 0 0 1 1 0 0 0 372
56 36 31 28 12 8 5 2 5 3 6 1 3 1 1 0 0 0 312
13 8 12 5 6 0 2 3 2 0 0 2 0 0 0 0 0 0 130
322 218 165 105 47 35 14 13 11 10 10 8 4 3 2 1 1 1 2,292
14.0 9.5 7.2 4.6 2.1 1.5 0.7 0.6 0.5 0.4 0.4 0.3 0.2 0.1 0.09 0.04 0.04 0.04 100
n ¼ Number; NI ¼ Not informed; % ¼ Percentage; SD ¼ standard deviation; myo ¼ myoepithelial; ex-PA ¼ ex-pleomorphic adenoma; NOS ¼ Not otherwise specified; Polymorphous adenoc ¼ Polymorphous adenocarcinom.
Table 2 Distribution by anatomic site of benign salivary gland tumors. Benign tumors
Pleomorphic adenoma Basal cell adenoma Cystadenoma Myoepithelioma Warthin's tumor Canalicular adenoma Sialadenoma papilliferum Inverted ductal papilloma Oncocytoma Total (%)
Major Glands
Minor Glands
Total
Parotid
Subm
Subl
Palate
Buccal mucosa
Upper lip Lower lip Floor of mouth Retromolar Tongue NI
n
%
538 64 2 10 22 3 1
148 3 4 3 3 0 0
4 0 0 0 0 0 0
270 3 6 22 1 0 5
37 4 10 3 0 4 3
60 2 14 3 2 18 2
7 0 4 0 0 0 0
3 0 3 0 0 1 1
3 0 0 0 0 0 0
2 0 1 0 0 0 1
14 1 0 0 0 0 0
1,086 77 44 41 28 26 13
82.2 5.9 3.3 3.1 2.1 1.9 1.0
0
0
0
0
0
0
4
1
0
0
0
5
0.4
1 641 (48.5%)
1 162 (12.2%)
0 0 4 (0.3%) 307 (23.2%)
0 61 (4.6%)
0 101 (7.6%)
0 0 15 (1.1%) 9 (0.7%)
0 3 (0.2%)
0 0 2 0.1 4 (0.3%) 15 (1.1%) 1,322 100
Subm ¼ Submandibular; Subl ¼ Sublingual; n ¼ Number; NI ¼ Not informed; % ¼ Percentage.
2010; Wang et al., 2012, 2015; Bradley and McGurk, 2013; Saghravanian et al., 2013; Torabinia and Khalesi, 2014; Al Sarraj et al., 2015; Taghavi et al., 2016; Gao et al., 2017); although some have shown ACC as the most frequent malignant tumor (Subhashraj, 2008; de Oliveira et al., 2009; Kara et al., 2010; Tian et al., 2010; Shishegar et al., 2011; Bello et al., 2012; Luksic et al., 2012; Mejía-Vel azquez et al., 2012; Kızıl et al., 2013; Lawal et al., 2013; Jaafari-Ashkavandi et al., 2013; Fomete et al., 2015; Sando et al., 2016; Vasconcelos et al., 2016). In general, as shown in Table 6, the four most frequent malignant tumors are: MEC, ACC, acinic cell carcinoma (AcCC) and adenocarcinoma not otherwise specified (AcNOS). In the present study PAC was the third most common
malignant tumor. In a similar manner, other authors also reported PAC as one of the three most common malignant tumor in salivary glands (Ochicha et al., 2009). According to the literature (Table 6) and our results, the prevalence profile of salivary gland tumors may be different within the same country or between other countries. This emphasizes that multicentric studies contribute to the understanding of epidemiological differences in the population, better characterizing the heterogeneity of tumors in extensive territories, like Brazil, and globally. Histopathological diagnosis of salivary gland tumors is a challenge for pathologists due to the large number of subtypes and
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Table 3 Distribution by anatomic site of malignant salivary gland tumors. Malignant tumors
Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous adenocarcinoma Adenocarcinoma NOS Acinic cell carcinoma Carcinoma ex pleomorphic adenoma Squamous cell carcinoma Myoepithelial carcinoma Basal cell adenocarcinoma Epithelial-myoepithelial carcinoma Salivary duct carcinoma Clear cell carcinoma Carcinosarcoma Cystadenocarcinoma Oncocytic carcinoma Secretory carcinoma Mucinous adenocarcinoma Sebaceous adenocarcinoma Total (%)
Major Glands
Minor Glands
Total
Parotid
Subm
Subl
Palate
Buccal mucosa
Upper lip
Lower lip
Floor of mouth
Retromolar Tongue IO
NI
n
%
100 44 5 49 27 14
18 28 4 4 2 5
3 6 1 2 0 0
108 82 91 19 7 10
25 10 23 12 7 5
4 9 17 0 2 0
4 1 5 2 0 0
6 8 0 2 0 0
26 6 2 2 1 0
10 13 2 5 0 0
12 4 4 5 0 0
6 7 11 3 1 1
322 218 165 105 47 35
33.3 22.5 17.1 10.9 4.8 3.6
14 9 6 7
0 0 1 0
0 0 0 0
0 1 1 1
0 2 0 1
0 0 1 0
0 0 1 0
0 0 0 0
0 0 0 0
0 0 1 0
0 0 0 0
0 1 0 1
14 13 11 10
1.4 1.3 1.1 1.0
9 2 3 1 2 0 0 0 292 (30.2%)
1 0 1 1 0 0 1 1 67 (6.9%)
0 0 0 0 0 0 0 0 12 (1.2%)
0 3 0 0 0 1 0 0 324 (33.4%)
0 1 0 0 0 0 0 0 86 (8.9%)
0 0 0 0 0 0 0 0 33 (3.4%)
0 0 0 1 0 0 0 0 14 (1.4%)
0 0 0 0 0 0 0 0 16 (1.6%)
0 1 0 0 0 0 0 0 38 (3.9%)
0 1 0 0 0 0 0 0 32 (3.3%)
0 0 0 0 0 0 0 0 25 (2.6%)
0 0 0 0 0 0 0 0 31 (3.2%)
10 8 4 3 2 1 1 1 970
1.0 0.8 0.4 0.3 0.2 0.1 0.1 0.1 100
NOS ¼ Not otherwise specified; Subm ¼ Submandibular; Subl ¼ Sublingual; n ¼ Number; IO ¼ intraosseous; NI ¼ Not informed; % ¼ Percentage.
different classifications. Particularly, PAC can be difficult to diagnose, especially in centers without an experienced pathologist in oral and maxillofacial lesions, as this tumor has some confusing morphological characteristics that are present in other tumors. However, this tumor has a strong predilection for minor salivary glands, especially on the palate. In previous editions of the WHO
classification, PAC was named “polymorphous low-grade adenocarcinoma” since it has an indolent behavior in most cases. Nonetheless, 10e33% of the patients develop local recurrences, 9e15% present nodal metastases and some cases are extremely aggressive, characterizing a high-grade tumor with imprecise clinical behavior (El-Naggar et al., 2017; Seethala and Stenman, 2017; Mariano et al.,
Table 4 Clinical characteristics of benign and malignant salivary gland tumors. Salivary gland tumors
Benign tumors Pleomorphic adenoma Basal cell adenoma Cystadenoma Myoepithelioma Warthin's tumor Canalicular adenoma Sialadenoma papilliferum Inverted ductal papilloma Oncocytoma Malignant tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous adenocarcinoma Adenocarcinoma NOS Acinic cell carcinoma Carcinoma ex pleomorphic adenoma Squamous cell carcinoma Myoepithelial carcinoma Basal cell adenocarcinoma Epithelial-myoepithelial carcinoma Salivary duct carcinoma Clear cell carcinoma Carcinosarcoma Cystadenocarcinoma Oncocytic carcinoma Secretory carcinoma Mucinous adenocarcinoma Sebaceous adenocarcinoma Total
Size (cm)
Symptomatology
Total
Min
Max
Mean size
Yes
No
NI
n
%
0.5 0.8 0.3 0.5 0.8 0.5 0.5 0.4 1.0
14.0 5.5 6.0 11.0 5.5 5.0 4.0 2.0 2.0
3.0 2.5 1.5 2.7 2.8 1.5 1.0 1.0 1.5
21 1 9 3 0 1 0 1 0
657 61 32 28 22 23 10 4 2
408 15 3 10 6 2 3 0 0
1,086 77 44 41 28 26 13 5 2
47.4 3.5 1.9 1.8 1.2 1.1 0.6 0.2 0.1
0.5 0.4 0.4 0.8 0.8 1.0 0.5 0.9 1.3 0.8 2.0 1.0 1.2 1.0 2.0 0.8 2.0 1.7 -
13.0 15.0 10.0 14.0 12.0 8.0 5.5 4.5 5.0 6.5 10.0 5.5 11.0 6.5 3.5 0.8 2.0 1.7 -
4.5 3.8 3.4 4.0 3.2 4.0 3.0 2.9 2.8 2.7 4.9 3.0 5.9 3.4 2.8 0.8 2.0 1.7 -
93 107 49 35 14 16 7 3 4 3 7 2 0 0 1 0 0 0 377
172 69 85 51 21 16 5 8 3 6 2 5 4 2 1 1 1 1 1,292
57 42 31 19 12 3 2 2 4 1 1 1 0 1 0 0 0 0 623
322 218 165 105 47 35 14 13 11 10 10 8 4 3 2 1 1 1 2,292
14.0 9.5 7.2 4.6 2.0 1.5 0.6 0.6 0.5 0.4 0.4 0.3 0.2 0.15 0.1 0.05 0.05 0.05 100
NOS ¼ Not otherwise specified; Min ¼ Minimum; Max ¼ Maximum; n ¼ Number; NI ¼ Not informed; % ¼ Percentage.
L.P. da Silva et al. / Journal of Cranio-Maxillo-Facial Surgery 46 (2018) 2227e2233
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Table 5 Anatomic site, symptomatology, gender, age group and skin color distribution of benign and malignant salivary gland tumors. Benign
Anatomic site
Symptomatology
Gender Age
Skin color
Parotid Submandibular Sublingual Palate Buccal mucosa Lip Floor of the mouth Retromolar Tongue Intraosseous NI No Yes NI Male Female 19 years 20 years NI White Black Other NI
Malignant
n
%
n
%
641 162 4 307 61 116 9 3 4 0 15 839 36 447 513 809 75 1,170 77 406 202 110 604
68.7 70.7 25.0 48.7 41.5 71.2 36.0 7.3 11.1 0.0 32.6 64.9 9.5 71.7 60.5 62.8 68.2 57.0 59.2 59.2 61.1 40.4 71.1
292 67 12 324 86 47 16 38 32 25 31 453 341 176 388 582 35 882 53 351 173 192 254
31.3 29.3 75.0 51.3 58.5 28.8 64.0 92.7 88.9 100.0 67.4 35.1 90.5 28.3 39.5 37.2 31.8 43.0 40.7 40.8 38.9 59.6 28.9
Total (%)
p-value
933 (40.7) 229 (10.0) 16 (0.7) 631 (27.5) 147 (6.4) 163 (7.1) 25 (1.1) 41 (1.8) 36 (1.6) 25 (1.1) 46 (2.0) 1,292 (56.4) 377 (16.4) 623 (27.2) 901 (39.3) 1,391 (60.7) 110 (4.8) 2,052 (89.5) 130 (5.7) 757 (33.0) 375 (16.4) 302 (13.2) 858 (37.4)
<0.001a
<0.001b
0.333b 0.002b
<0.001b
n ¼ Number; NI ¼ Not informed; % ¼ Percentage. a Pearson's chi-square test. b Fisher's exact test.
2017). Considering the variation of this tumor behavior, the new edition (2017) of the WHO classification abandoned the term “lowgrade,” and renamed these tumors simply as polymorphous adenocarcinoma (PAC). This modification helps to avoid possible terminology confusion and facilitates the treatment choice for the more unusual cases (El-Naggar et al., 2017). Other malignant salivary tumors were very uncommon, such as oncocytic carcinoma and sebaceous adenocarcinoma. These entities are well recognized but also rarely reported. In the new WHO classification, cystadenocarcinoma was considered a synonym for intraductal carcinoma and mucinous adenocarcinoma as a variant of AcNOS (El-Naggar et al., 2017). For this study, it was preferred to maintain these tumors separately as they have specific features. In the present study, a case of AcCC was reclassified as secretory carcinoma. This tumor was recently recognized by the WHO; however, it was first described in 2010 as a mammary analog secretory carcinoma (MASC) (El-Naggar et al., 2017). The secretory carcinoma represents a salivary gland malignancy that was differentiated from AcCC and AcNOS because it shows a great similarity with the mammary-secreting carcinoma, besides presenting a specific translocation t (12; 15) (p13; q25) that results in an ETV6NTRK3 gene fusion. According to the WHO, to standardize international nomenclature, the official designation for this entity is simply “secretory carcinoma.” This tumor has an indolent clinical course such as AcCC but presents a higher probability to metastasize to cervical lymph nodes (up to 25%) (El-Naggar et al., 2017; Seethala and Stenman, 2017). Most of the tumors in this study were diagnosed in the parotid gland, followed by the minor salivary glands of the palate. In general, this result was also reported by other epidemiological studies (Jones et al., 2008; Li et al., 2008; Tian et al., 2010; Shishegar et al., 2011; Bello et al., 2012; Fonseca et al., 2012; Luksi c et al., 2012; Kızıl et al., 2013; Lawal et al., 2013; Jaafari-Ashkavandi et al., 2013; Araya et al., 2015; Wang et al., 2015; Vasconcelos et al., 2016; Gao et al., 2017). However, some authors describe the submandibular gland as the second most common anatomical site (de Oliveira et al., 2009;
zquez et al., 2012; Ochicha et al., 2009; Kara et al., 2010; Mejía-Vela Wang et al., 2012; Bittar et al., 2015; Fomete et al., 2015; Sando et al., 2016). On the other hand, studies conducted in Iran (Saghravanian et al., 2013) and Sri Lanka (Tilakaratne et al., 2009) have shown that salivary gland tumors are more common in the palate and rare in parotid glands. Interestingly, we observed that major salivary glands are mainly affected by benign tumors (69%; n ¼ 807). In contrast, malignant neoplasms accounted for 53.2% (n ¼ 568) of the minor gland tumors, similar to other authors (Tilakaratne et al., 2009). We emphasize to clinicians and surgeons that although benign tumors are more common, there is a greater chance (1.6:1) of diagnosing a malignant tumor in minor salivary glands. Therefore, a thorough examination of the oral cavity is essential to establish an early diagnosis avoiding morbidity and mortality. From a clinical point of view, salivary gland neoplasms usually are asymptomatic nodules of firm consistency (El-Naggar et al., 2017; Fomete et al., 2015). In our analysis, the presence of symptomatology occurred mainly in malignant tumors and patients usually complained of a swelling that may or not be painful. Benign tumors have an asymptomatic slow growth, unlike malignant tumors that show a faster growth which can lead to the appearance of symptoms (Jaber, 2006; Lin et al., 2008). The size of benign tumors is more limited (<3 cm), except for PA, which can reach large dimensions, while malignant tumors are larger (4e6 cm) (El-Naggar et al., 2017), as observed in this study. Larger malignant tumors (>4 cm) in the parotid gland are associated with an increased risk of facial paralysis (Lin et al., 2008). Although there are several reports in Brazil and in other countries, continuous studies that state the incidence and clinical characteristics of salivary tumors are important to keep clinicians and surgeons updated, especially when their classification undergoes some change. We emphasize that conducting multicenter studies facilitates the knowledge of the real data and covers the heterogeneity of the population, especially in countries with continental dimensions such as Brazil.
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Table 6 Worldwide distribution of salivary gland tumors published in the last 10 years (2008e2018). Continent/Country South America Brazil
Chile North America Mexico Europe Croatia UK Finland Africa Cameroon Nigeria
Asia China
India Iran
Israel Sri Lanka Turkey United Arab Emirates
Authors
n
Benign (%)
Malignant (%)
Most common benign tumors
Present study, 2018 (Multicentric) Vasconcelos et al., 2016 (Southern) Bittar et al., 2015 (Southern) Fonseca et al., 2012 (Southern) de Oliveira et al., 2009 (Central) Araya et al., 2015
2,292 109 271 493 599 259
57.7 78.0 79.3 74.8 78.3 72.6
42.3 22.0 20.7 25.1 21.7 27.4
PA PA PA PA PA PA
Mejía-Vel azquez et al., 2012
346
79.2
20.8
PA > WT
ACC > MEC
Luksi c et al. 2012 Bradley and McGurk, 2013 Jones et al. 2008 Bello et al.2012
779 1,060 741 1888
64.2 86.4 64.9 85.1
35.8 13.6 35.1 14.9
PA PA PA PA
> > > >
ACC > MEC MEC > ACC MEC > ACC ACC > MEC
Sando et al., 2016 Lawal et al., 2013 Ochicha et al., 2009 Fomete et al. 2015
200 413 76 135
71.8 46.5 56.6 28.9
28.2 53.5 43.4 71.1
PA PA > Myo PA PA > Onc
Gao et al., 2017 (Northern) Wang et al., 2015 (Northeast) Wang et al., 2012 Tian et al. 2010 (East) Li et al. 2008 (West) Subhashraj, 2008 Bussari et al., 2016 Taghavi et al., 2016 Torabinia et al., 2014 Jaafari-Ashkavandi et al., 2013 Shishegar et al. 2011 Atarbashi Moghadam et al., 2010 Saghravanian et al.2013 Bello et al.2012 Tilakaratne et al. 2009 Kızıl et al., 2013 Kara et al. 2010 Al Sarraj et al., 2015
7,190 2,508 1,154 6,982 3,461 684 82 184 229 366 392 112 165 330 713 500 121 314
64.73 77.1 76.9 68.0 59.8 62.0 46.3 35.3 55.5 67.8 68.2 75.0 51.5 66.7 49.9 70.8 75.2 74
35.27 22.9 23.1 32.0 40.2 38.0 53.7 64.7 44.5 32.2 31.8 25.0 48.5 33.3 50.1 29.2 24.8 26
PA PA PA PA PA PA PA PA PA PA PA PA PA PA PA PA PA PA
> > > > > >
> > > > > > > > > > > > > > > > > >
BCA WT WT WT WT WT
WT WT BCA WT
WT WT WT WT WT WT BCA Myo Myo WT WT WT Myo WT WT WT WT WT
Most common malignant tumors MEC > ACC ACC > MEC ¼ AcCC MEC > SCC MEC > AcNOS ACC > AcNOS MEC > ACC ¼ AcNOS
ACC > MEC ACC > MEC MEC > PAC ¼ ACC ACC > MEC MEC > ACC MEC > ACC MEC > ACC ACC > MEC MEC > ACC ACC > MEC MEC > ACC MEC > ACC MEC > ACC ACC > MEC ACC > MEC MEC > ACC MEC > ACC ACC > MEC MEC > ACC ACC > MEC ACC > AcNOS MEC > ACC
Abbrev.: ACC ¼ adenoid cystic carcinoma; AcCC ¼ acinic cell carcinoma; AcNOS ¼ adenocarcinoma not otherwise specified; BCA ¼ basal cell adenoma; MEC ¼ mucoepidermoid carcinoma; Myo ¼ myoepithelioma; PA ¼ pleomorphic adenoma; PAC ¼ polymorphous adenocarcinoma; SCC ¼ squamous cell carcinoma; WT ¼ Warthin's tumors; Onc ¼ Oncocytoma.
5. Conclusion Overall, the results of this study were similar to those found by other authors worldwide, namely that pleomorphic adenoma and mucoepidermoid carcinoma were the most common tumors in the salivary glands. We emphasize that the presence of symptomatology and larger tumor dimensions were more frequent in malignant tumors. Furthermore, malignant tumors occurred more in minor salivary glands. Declarations of interest All authors declare that they have no conflict of interest. Acknowledgements This work was supported by the Brazilian National Council for Scientific and Technological Development (CNPq) and Coordination for the Improvement of Higher Education Personnel (CAPES). References Al Sarraj Y, Nair SC, Al Siraj A, AlShayeb M: Characteristics of salivary gland tumours in the United Arab Emirates. Ecancermedicalscience 9: 583, 2015 Araya J, Martinez R, Niklander S, Marshall M, Esguep A: Incidence and prevalence of salivary gland tumours in Valparaiso, Chile. Med Oral Patol Oral Cir Bucal 20: e532ee539, 2015
Atarbashi Moghadam S, Atarbashi Moghadam F, Dadfar M: Epithelial salivary gland tumors in ahvaz, southwest of Iran. J Dent Res Dent Clin Dent Prospects 4: 120e123, 2010 Bello IO, Salo T, Dayan D, Tervahauta E, Almangoush A, Schnaiderman-Shapiro A, et al: Epithelial salivary gland tumors in two distant geographical locations, Finland (Helsinki and Oulu) and Israel (Tel Aviv): a 10-year retrospective comparative study of 2,218 cases. Head Neck Pathol 6: 224e231, 2012 Bittar RF, Ferraro HP, Moraes Gonçalves FT, Couto da Cunha MG, Biamino ER: Neoplasms of the salivary glands: analysis of 727 histopathological reports in a single institution. Otolaryngol Pol 69: 28e33, 2015 Bradley PJ, McGurk M: Incidence of salivary gland neoplasms in a defined UK population. Br J Oral Maxillofac Surg 51: 399e403, 2013 Bussari S, Shedam TM, Debta P, Shaikh NA, Yeli NR, Jeergal PA, et al: A retrospective clinicopathological study of salivary gland tumors with particular reference to histological types, site, age, and sex distribution. J Int Oral Health 8: 1082e1088, 2016 ximo AA, de Aquino EC, Alencar Rde C, et al: de Oliveira FA, Duarte EC, Taveira CT, Ma Salivary gland tumor: a review of 599 cases in a Brazilian population. Head Neck Pathol 3: 271e275, 2009 El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ: WHO classification of head and neck tumours. Lyon: IARC Press, 159e202, 2017 Fomete B, Adebayo ET, Ononiwu CN: Management of salivary gland tumors in a Nigerian tertiary institution. Ann Afr Med 14: 148e154, 2015 Fonseca FP, Carvalho Mde V, de Almeida OP, Rangel AL, Takizawa MC, Bueno AG, et al: Clinicopathologic analysis of 493 cases of salivary gland tumors in a Southern Brazilian population. Oral Surg Oral Med Oral Pathol Oral Radiol 114: 230e239, 2012 Gao M, Hao Y, Huang MX, Ma DQ, Chen Y, Luo HY, et al: Salivary gland tumours in a northern Chinese population: a 50-year retrospective study of 7190 cases. Int J Oral Maxillofac Surg 46: 343e349, 2017 Jaafari-Ashkavandi Z, Ashraf MJ, Moshaverinia M: Salivary gland tumors: a clinicopathologic study of 366 cases in southern Iran. Asian Pac J Cancer Prev 14: 27e30, 2013
L.P. da Silva et al. / Journal of Cranio-Maxillo-Facial Surgery 46 (2018) 2227e2233 Jaber MA: Intraoral minor salivary gland tumors: a review of 75 cases in a Libyan population. Int J Oral Maxillofac Surg 35: 150e154, 2006 Jones AV, Craig GT, Speight PM, Franklin CD: The range and demographics of salivary gland tumours diagnosed in a UK population. Oral Oncol 44: 407e417, 2008 € ze F, Ezirganli S, Polat S, Muderris S, Elagoz S: Neoplasms of the salivary Kara MI, Go glands in a Turkish adult population. Med Oral Patol Oral Cir Bucal 15: e880ee885, 2010 €ybas¸ıog lu A, Düzlü M, et al: Salivary gland tuKızıl Y, Aydil U, Ekinci O, Dilci A, Ko mors in Turkey: demographic features and histopathological distribution of 510 patients. Indian J Otolaryngol Head Neck Surg 65: 112e120, 2013 Lawal AO, Adisa AO, Kolude B, Adeyemi BF, Olajide MA: A review of 413 salivary gland tumours in the head and neck region. J Clin Exp Dent 5: e218ee222, 2013 Li LJ, Li Y, Wen YM, Liu H, Zhao HW: Clinical analysis of salivary gland tumor cases in West China in past 50 years. Oral Oncol 44: 187e192, 2008 Lin CC, Tsai MH, Huang CC, Hua CH, Tseng HC, Huang ST: Parotid tumors: a 10-year experience. Am J Otolaryngol 29: 94e100, 2008 Luksi c I, Virag M, Manojlovi c S, Macan D: Salivary gland tumours: 25 years of experience from a single institution in Croatia. J Craniomaxillofac Surg 40: e75ee81, 2012 Mariano FV, Varanda RF, Schultz L, Correa MB, de Almeida OP, Altemani A, et al: Cribriform adenocarcinoma of the soft palate with multiple lymph node metastasis and long-term follow-up. Oral Surg Oral Med Oral Pathol Oral Radiol 123: e117ee122, 2017 n-Padilla MA, Go mez-Apo E, Quezada-Rivera D, Gait Mejía-Vel azquez CP, Dura anCepeda LA: Tumors of the salivary gland in Mexicans. A retrospective study of 360 cases. Med Oral Patol Oral Cir Bucal 17: e183ee189, 2012 Ochicha O, Malami S, Mohammed A, Atanda A: A histopathologic study of salivary gland tumors in Kano, northern Nigeria. Indian J Pathol Microbiol 52: 473e476, 2009 Saghravanian N, Ghazi N, Saba M: Clinicopathologic evaluation of salivary gland neoplasms: a 38-year retrospective study in Iran. Ann Diagn Pathol 17: 522e525, 2013
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Sando Z, Fokouo JV, Mebada AO, Djomou F, NDjolo A, Oyono JL: Epidemiological and histopathological patterns of salivary gland tumors in Cameroon. Pan Afr Med J 23: 66, 2016 Seethala RR, Stenman G: Update from the 4th edition of the World Health Organization classification of head and neck tumours: tumors of the salivary gland. Head Neck Pathol 11: 55e67, 2017 Shishegar M, Ashraf MJ, Azarpira N, Khademi B, Hashemi B, Ashrafi A: Salivary gland tumors in maxillofacial region: a retrospective study of 130 cases in a southern Iranian population. Patholog Res Int 934350: 2011, 2011 Subhashraj K: Salivary gland tumors: a single institution experience in India. Br J Oral Maxillofac Surg 46: 635e638, 2008 Taghavi N, Sargolzaei S, Mashhadiabbas F, Akbarzadeh A, Kardouni P: Salivary gland tumors: a 15- year report from Iran. Turk Patoloji Derg 32: 35e39, 2016 Tian Z, Li L, Wang L, Hu Y, Li J: Salivary gland neoplasms in oral and maxillofacial regions: a 23-year retrospective study of 6982 cases in an eastern Chinese population. Int J Oral Maxillofac Surg 39: 235e242, 2010 Tilakaratne WM, Jayasooriya PR, Tennakoon TM, Saku T: Epithelial salivary tumors in Sri Lanka: a retrospective study of 713 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 108: 90e98, 2009 Torabinia N, Khalesi S: Clinicopathological study of 229 cases of salivary gland tumors in Isfahan population. Dent Res J (Isfahan) 11: 559e563, 2014 € r F, Meurer L, Salvadori G, Souza LB, Vargas PA, et al: ClinicoVasconcelos AC, No pathological analysis of salivary gland tumors over a 15-year period. Braz Oral Res 30, 2016 pii:S1806-83242016000100208 Wang XD, Meng LJ, Hou TT, Huang SH: Tumours of the salivary glands in northeastern China: a retrospective study of 2508 patients. Br J Oral Maxillofac Surg 53: 132e137, 2015 Wang YL, Zhu YX, Chen TZ, Wang Y, Sun GH, Zhang L, et al: Clinicopathologic study of 1176 salivary gland tumors in a Chinese population: experience of one cancer center 1997e2007. Acta Otolaryngol 132: 879e886, 2012
Contents lists available at ScienceDirect
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Salivary gland tumors in a Brazilian population: A 20-year retrospective and multicentric study of 2292 cases* Leorik Pereira da Silva a, Marianna Sampaio Serpa a, Stephanie Kenig Viveiros b, urea Adília Co be Sena a, Rodrigo Finger de Carvalho Pinho b, Da vio de Sousa Andrade c, ~es b, Emanuel Sa Letícia Drumond de Abreu Guimara c rcia Maria Fonseca da Silveira c, Ana Paula Veras Sobral c, Ricardo Dias Pereira , Ma Jose lia Batista de Souza a, * Suzana Cantanhede Orsini Machado de Sousa b, Le a
Postgraduate Program in Oral Pathology, Federal University of Rio Grande do Norte-UFRN, Av. Senador Salgado Filho, 1787-Lagoa Nova, Natal, RN, 59056-000, Brazil b ~o Paulo, Av. Prof. Lineu Prestes, 2227-Butanta ~, Sa ~o Paulo, SP, Department of Oral Pathology and Special Care Patients, School of Dentistry, University of Sa 05508-900, Brazil c School of Dentistry, University of Pernambuco, Av. Gal. Newton Cavalcanti, 1650-Tabatinga, Camaragibe, PE, 54756-220, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 24 June 2018 Accepted 24 September 2018 Available online 26 September 2018
Purpose: Neoplasms of the salivary glands comprise more than thirty subtypes of lesions with various clinical behaviors. The present study aimed to describe the incidence and main features of salivary gland tumors in Brazil. Material and methods: A retrospective descriptive cross-sectional study was performed (1997e2017). A total of 88,430 biopsy records of oral and maxillofacial lesions from 5 pathology referral centers were analyzed. All cases of salivary gland tumors were reviewed and data such as gender, age, skin color, anatomical location, symptomatology, tumor size and histopathological diagnosis were collected. Results: Among all lesions, there were 2,292 (2.6%) cases of salivary gland tumors. The most frequent benign and malignant neoplasm was pleomorphic adenoma (n ¼ 1,086; 47.4%) and mucoepidermoid carcinoma (n ¼ 322; 14.0%), respectively. The majority of the patients were white (n ¼ 757; 33%) and female (n ¼ 1,391; 60.7%), and most cases involved the parotid gland (n ¼ 933; 40.7%; p < 0.001). Age ranged from 1 to 101 years, occurring more in the fourth decade of life. Tumor size varied from 0.3 to 15 cm and the presence of symptomatology (pain/swelling) occurred more in patients with malignant tumors (p < 0.001). Conclusion: The incidence profile and clinical findings of salivary gland tumors were similar to those described worldwide; nevertheless, multicenter studies are valuable to better characterize these neoplasms. © 2018 Published by Elsevier Ltd on behalf of European Association for Cranio-Maxillo-Facial Surgery.
Keywords: Salivary gland Neoplasm Epidemiology Head and neck pathology
1. Introduction The parotid, submandibular and sublingual glands are the three major salivary glands. Minor salivary glands are numerous and located in the oral cavity, especially on the palate, lips, buccal mucosa and tongue. The duct-acinar system of the salivary glands is complex, being morphologically and physiologically similar in both
*
No funding source for this study e No conflict of interest to be disclosed. * Corresponding author. E-mail address: [email protected] (L.B. de Souza).
major and minor glands (ductal, myoepithelial and acinar cells) (Tian et al., 2010; Wang et al., 2015; El-Naggar et al., 2017). This leads to a vast and diverse potential for the development of primary tumors independently of the anatomical site. Recently, the World Health Organization (WHO) has published some changes in the classification of salivary gland tumors, recognizing 31 primary epithelial neoplasms. Despite this large number of subtypes, these lesions account for about 3e6% of all head and neck tumors, with an annual estimated global incidence of 0.4e13.5 per 100,000 people (Tian et al., 2010; El-Naggar et al., 2017). Considering their wide histological variety and diverse
https://doi.org/10.1016/j.jcms.2018.09.028 1010-5182/© 2018 Published by Elsevier Ltd on behalf of European Association for Cranio-Maxillo-Facial Surgery.
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L.P. da Silva et al. / Journal of Cranio-Maxillo-Facial Surgery 46 (2018) 2227e2233
In this retrospective study (1997e2017), approximately 88,430 cases of oral and maxillofacial lesions were analyzed. Biopsies and histopathological data were obtained from the archives of 5 surgical pathology centers in Brazil: Department of Oral Pathology of the School of Dentistry of Pernambuco (northeastern region), Laboratory of Surgical Pathology of the University of Pernambuco (northeastern region), Oral Pathology Service of the Federal University of Rio Grande do Norte (northeastern region), Laboratory of Surgical Pathology, Norte-Riograndense League Against Cancer (northeastern region), and Department of Oral and Maxillofacial Pathology of the University of S~ ao Paulo (southeastern region). The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee (UFRN e Approval No. 1.714.150).
anatomical site (n ¼ 933; 40.7%). The palate was the second most frequent site (n ¼ 631; 27.5%) being the most common location of the malignant neoplasms (n ¼ 324; 51.3%). Among the benign tumors, pleomorphic adenoma (PA) was the most frequent one (n ¼ 1.086; 82.2%) followed by basal cell adenoma (BCA) (n ¼ 77; 5.9%) and cystadenoma (CA) (n ¼ 44; 3.3%). The benign tumors were diagnosed mainly between the fourth and seventh decades of life; however, the age ranged from 2 to 99 years, with a mean age of 47 years (SD ± 14) (Table 1). Most cases occurred in the parotid with 641 cases (48.5%) (Table 2). Mucoepidermoid carcinoma (MEC) was the most common malignant neoplasm (n ¼ 322; 33.3%), followed by adenoid cystic carcinoma (ACC) (n ¼ 218; 22.5%) and polymorphous adenocarcinoma (PAC) (n ¼ 165; 17.1%). The age of the patients ranged from 1 to 101 years, with most cases occurring between the fifth and eighth decades of life, with a mean of 55 years (SD ± 16) (Table 1). The most frequent anatomical location was the palate (n ¼ 324; 33.4%), followed by the parotid gland (n ¼ 292; 30.2%) (Table 3). Malignant salivary gland tumors were also found within the gnathic bones (n ¼ 25; 2.6%), with 13 cases in the mandible and 12 cases in the maxilla/maxillary sinus. The majority of the patients did not report any symptoms (pain/ swelling) (n ¼ 1,292; 56.4%). The size of the tumors at the time of diagnosis ranged from 0.3 to 15 cm, although the mean sizes were higher in malignant tumors when compared with the benign tumors (Table 4). When the behavior of the lesions (malignant versus benign tumors) was evaluated, the parotid was the most affected gland mainly by benign tumors (p < 0.001) and the presence of symptoms was more common in malignant tumors (p < 0.001). Benign and malignant salivary gland tumors were more common in older patients of white color; results were statistically significant (Table 5).
2.2. Sample
4. Discussion
All cases of salivary gland tumors were retrieved and data such as gender, age, skin color, anatomical location, symptomatology, tumor size and histopathological diagnosis were collected and analyzed. The lesions were categorized into: benign and malignant tumors in accordance with the current WHO classification of the head and neck tumors (El-Naggar et al., 2017). Immunohistochemical analysis was performed when routine staining (hematoxylin-eosin) was not sufficient to establish the final diagnosis.
In the last 10 years (2008e2018) some studies have been published on the incidence and characteristics of salivary gland tumors in Brazil (de Oliveira et al., 2009; Fonseca et al., 2012; Bittar et al., 2015; Vasconcelos et al., 2016) and other countries as shown in Table 6. However, in few studies more than three diagnostic centers participated and some only reported the incidence in a specific group of salivary glands. In addition, data regarding the symptomatology or size of malignant and benign lesions are necessary for a better knowledge of the clinical characteristics of these tumors. In the present study, 57.7% of the tumors were benign, similar to other reports in which these tumors comprised 53e86% of all salivary gland tumors (Table 6). On the contrary, studies conducted in Africa (Lawal et al., 2013) and Asia (Tilakaratne et al., 2009; Bussari et al., 2016; Taghavi et al., 2016) showed a higher incidence of malignant tumors. In this study, PA was the most common tumor, representing 82.2% of the benign neoplasms, agreeing with all previous studies described in Table 6. Furthermore, BCA was the second most frequent benign tumor (5.9%) in the present study. Other authors observed the same in studies conducted in the United Kingdom and India (Jones et al., 2008; Bussari et al., 2016). Nevertheless, most studies show Warthin's tumor (WT) as the second most common tumor as described in Table 6. Some other benign tumors were very rare, such as oncocytomas and ductal papillomas, as already observed in prior large samples studies. The most common malignant tumor was MEC, representing 33.3% of the cases, followed by ACC which represented 22.5%. Several studies are in accordance with these findings (Li et al., 2008; Jones et al., 2008; Tilakaratne et al., 2009; Atarbashi et al.,
biological behavior, knowing their characteristics and incidence profile is extremely relevant for scientific and clinical purposes. Regardless of the incidence variation of these neoplasms, large series reviews show more than 50% of all primary salivary gland tumors occur in the major salivary glands, mainly in the parotid gland, and are rare in the sublingual gland (1%). Regarding biological behavior, most studies indicate 50e79% of the cases are benign (Tian et al., 2010; Wang et al., 2015; Gao et al., 2017). The objective of this study was to describe the incidence and clinicopathological features of salivary gland tumors diagnosed in several pathology centers of Brazil. We hope these data contribute to the understanding of the current profile of these tumors in Brazil as compared with other countries. 2. Materials and methods 2.1. Study design and ethical aspects
2.3. Data analysis Descriptive and quantitative data analysis was performed using the Statistical Package for the Social Sciences for Windows 20.0 (SPSS, Inc., Chicago, IL, USA). Pearson's chi-square test and Fisher's exact test evaluated differences between the biological behavior of the tumors and their clinical and demographic characteristics, adopting a p-value of 0.05 and a 95% confidence interval. 3. Results In 20 years, there were 2,292 cases of primary salivary gland neoplasms diagnosed in the five centers studied, accounting for 2.6% of all oral and maxillofacial lesions. According to the estimated population of the cities that participated in this study, the incidence was approximately 13 salivary gland tumors per 100,000 inhabitants. Most patients were white (n ¼ 757; 33%) and female (n ¼ 1,391; 60.7%), with a female:male ratio of 1.5:1. Benign tumors were more common (n ¼ 1,322; 57.7%), with a benign:malignant ratio of 1.4:1. Most cases involved major salivary glands (n ¼ 1,178; 51.4%) and the parotid was the most common
L.P. da Silva et al. / Journal of Cranio-Maxillo-Facial Surgery 46 (2018) 2227e2233
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Table 1 Age group distribution (decade of life) of benign salivary gland tumors. Salivary gland tumors
Age Range
Benign tumors Pleomorphic adenoma Basal cell adenoma Cystadenoma Myoepithelioma Warthin's tumor Canalicular adenoma Sialadenoma papilliferum Inverted ductal papilloma Oncocytoma Malignant tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous adenoc Adenocarcinoma NOS Acinic cell carcinoma Carcinoma ex-PA Squamous cell carcinoma Myoepithelial carcinoma Basal cell adenocarcinoma Epithelial-myo carcinoma Salivary duct carcinoma Clear cell carcinoma Carcinosarcoma Cystadenocarcinoma Oncocytic carcinoma Secretory carcinoma Mucinous adenocarcinoma Sebaceous adenocarcinoma Total
Mean Age
Age groups
Total
0e19
20e29
30e39
40e49
50e59
60e69
70
NI
n
%
2e92 6e99 12e80 8e84 17e77 39e89 13e66 35e59 57e75
45 57 54 40 56 60 46 47 66
64 1 1 6 1 0 2 0 0
148 1 2 6 0 0 0 0 0
211 5 4 8 0 2 1 1 0
187 12 6 9 6 2 2 2 0
197 21 10 1 10 5 5 2 1
137 21 14 2 8 5 2 0 0
77 12 6 7 3 8 0 0 1
65 4 1 2 0 4 1 0 0
1,086 77 44 41 28 26 13 5 2
47.4 3.4 1.9 1.8 1.2 1.1 0.6 0.2 0.09
1e92 22e89 2e87 9e101 9e85 20e84 33e87 27e77 23e73 39e85 44e87 22e73 14e87 55e82 65e84 27 52 34 1e101
49 54 56 57 50 58 63 53 62 59 68 46 65 66 74 27 52 34 49 (SD ± 18)
22 0 4 5 3 0 0 0 0 0 0 0 1 0 0 0 0 0 110
45 10 4 4 10 1 0 1 1 0 0 1 0 0 0 1 0 0 235
54 28 17 8 3 3 1 1 0 1 0 1 0 0 0 0 0 1 350
40 37 20 17 3 7 2 1 0 2 1 1 0 0 0 0 0 0 357
42 49 38 20 5 5 2 3 1 3 2 2 0 1 0 0 1 0 426
50 50 39 18 5 11 2 2 2 1 1 0 0 1 1 0 0 0 372
56 36 31 28 12 8 5 2 5 3 6 1 3 1 1 0 0 0 312
13 8 12 5 6 0 2 3 2 0 0 2 0 0 0 0 0 0 130
322 218 165 105 47 35 14 13 11 10 10 8 4 3 2 1 1 1 2,292
14.0 9.5 7.2 4.6 2.1 1.5 0.7 0.6 0.5 0.4 0.4 0.3 0.2 0.1 0.09 0.04 0.04 0.04 100
n ¼ Number; NI ¼ Not informed; % ¼ Percentage; SD ¼ standard deviation; myo ¼ myoepithelial; ex-PA ¼ ex-pleomorphic adenoma; NOS ¼ Not otherwise specified; Polymorphous adenoc ¼ Polymorphous adenocarcinom.
Table 2 Distribution by anatomic site of benign salivary gland tumors. Benign tumors
Pleomorphic adenoma Basal cell adenoma Cystadenoma Myoepithelioma Warthin's tumor Canalicular adenoma Sialadenoma papilliferum Inverted ductal papilloma Oncocytoma Total (%)
Major Glands
Minor Glands
Total
Parotid
Subm
Subl
Palate
Buccal mucosa
Upper lip Lower lip Floor of mouth Retromolar Tongue NI
n
%
538 64 2 10 22 3 1
148 3 4 3 3 0 0
4 0 0 0 0 0 0
270 3 6 22 1 0 5
37 4 10 3 0 4 3
60 2 14 3 2 18 2
7 0 4 0 0 0 0
3 0 3 0 0 1 1
3 0 0 0 0 0 0
2 0 1 0 0 0 1
14 1 0 0 0 0 0
1,086 77 44 41 28 26 13
82.2 5.9 3.3 3.1 2.1 1.9 1.0
0
0
0
0
0
0
4
1
0
0
0
5
0.4
1 641 (48.5%)
1 162 (12.2%)
0 0 4 (0.3%) 307 (23.2%)
0 61 (4.6%)
0 101 (7.6%)
0 0 15 (1.1%) 9 (0.7%)
0 3 (0.2%)
0 0 2 0.1 4 (0.3%) 15 (1.1%) 1,322 100
Subm ¼ Submandibular; Subl ¼ Sublingual; n ¼ Number; NI ¼ Not informed; % ¼ Percentage.
2010; Wang et al., 2012, 2015; Bradley and McGurk, 2013; Saghravanian et al., 2013; Torabinia and Khalesi, 2014; Al Sarraj et al., 2015; Taghavi et al., 2016; Gao et al., 2017); although some have shown ACC as the most frequent malignant tumor (Subhashraj, 2008; de Oliveira et al., 2009; Kara et al., 2010; Tian et al., 2010; Shishegar et al., 2011; Bello et al., 2012; Luksic et al., 2012; Mejía-Vel azquez et al., 2012; Kızıl et al., 2013; Lawal et al., 2013; Jaafari-Ashkavandi et al., 2013; Fomete et al., 2015; Sando et al., 2016; Vasconcelos et al., 2016). In general, as shown in Table 6, the four most frequent malignant tumors are: MEC, ACC, acinic cell carcinoma (AcCC) and adenocarcinoma not otherwise specified (AcNOS). In the present study PAC was the third most common
malignant tumor. In a similar manner, other authors also reported PAC as one of the three most common malignant tumor in salivary glands (Ochicha et al., 2009). According to the literature (Table 6) and our results, the prevalence profile of salivary gland tumors may be different within the same country or between other countries. This emphasizes that multicentric studies contribute to the understanding of epidemiological differences in the population, better characterizing the heterogeneity of tumors in extensive territories, like Brazil, and globally. Histopathological diagnosis of salivary gland tumors is a challenge for pathologists due to the large number of subtypes and
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Table 3 Distribution by anatomic site of malignant salivary gland tumors. Malignant tumors
Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous adenocarcinoma Adenocarcinoma NOS Acinic cell carcinoma Carcinoma ex pleomorphic adenoma Squamous cell carcinoma Myoepithelial carcinoma Basal cell adenocarcinoma Epithelial-myoepithelial carcinoma Salivary duct carcinoma Clear cell carcinoma Carcinosarcoma Cystadenocarcinoma Oncocytic carcinoma Secretory carcinoma Mucinous adenocarcinoma Sebaceous adenocarcinoma Total (%)
Major Glands
Minor Glands
Total
Parotid
Subm
Subl
Palate
Buccal mucosa
Upper lip
Lower lip
Floor of mouth
Retromolar Tongue IO
NI
n
%
100 44 5 49 27 14
18 28 4 4 2 5
3 6 1 2 0 0
108 82 91 19 7 10
25 10 23 12 7 5
4 9 17 0 2 0
4 1 5 2 0 0
6 8 0 2 0 0
26 6 2 2 1 0
10 13 2 5 0 0
12 4 4 5 0 0
6 7 11 3 1 1
322 218 165 105 47 35
33.3 22.5 17.1 10.9 4.8 3.6
14 9 6 7
0 0 1 0
0 0 0 0
0 1 1 1
0 2 0 1
0 0 1 0
0 0 1 0
0 0 0 0
0 0 0 0
0 0 1 0
0 0 0 0
0 1 0 1
14 13 11 10
1.4 1.3 1.1 1.0
9 2 3 1 2 0 0 0 292 (30.2%)
1 0 1 1 0 0 1 1 67 (6.9%)
0 0 0 0 0 0 0 0 12 (1.2%)
0 3 0 0 0 1 0 0 324 (33.4%)
0 1 0 0 0 0 0 0 86 (8.9%)
0 0 0 0 0 0 0 0 33 (3.4%)
0 0 0 1 0 0 0 0 14 (1.4%)
0 0 0 0 0 0 0 0 16 (1.6%)
0 1 0 0 0 0 0 0 38 (3.9%)
0 1 0 0 0 0 0 0 32 (3.3%)
0 0 0 0 0 0 0 0 25 (2.6%)
0 0 0 0 0 0 0 0 31 (3.2%)
10 8 4 3 2 1 1 1 970
1.0 0.8 0.4 0.3 0.2 0.1 0.1 0.1 100
NOS ¼ Not otherwise specified; Subm ¼ Submandibular; Subl ¼ Sublingual; n ¼ Number; IO ¼ intraosseous; NI ¼ Not informed; % ¼ Percentage.
different classifications. Particularly, PAC can be difficult to diagnose, especially in centers without an experienced pathologist in oral and maxillofacial lesions, as this tumor has some confusing morphological characteristics that are present in other tumors. However, this tumor has a strong predilection for minor salivary glands, especially on the palate. In previous editions of the WHO
classification, PAC was named “polymorphous low-grade adenocarcinoma” since it has an indolent behavior in most cases. Nonetheless, 10e33% of the patients develop local recurrences, 9e15% present nodal metastases and some cases are extremely aggressive, characterizing a high-grade tumor with imprecise clinical behavior (El-Naggar et al., 2017; Seethala and Stenman, 2017; Mariano et al.,
Table 4 Clinical characteristics of benign and malignant salivary gland tumors. Salivary gland tumors
Benign tumors Pleomorphic adenoma Basal cell adenoma Cystadenoma Myoepithelioma Warthin's tumor Canalicular adenoma Sialadenoma papilliferum Inverted ductal papilloma Oncocytoma Malignant tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous adenocarcinoma Adenocarcinoma NOS Acinic cell carcinoma Carcinoma ex pleomorphic adenoma Squamous cell carcinoma Myoepithelial carcinoma Basal cell adenocarcinoma Epithelial-myoepithelial carcinoma Salivary duct carcinoma Clear cell carcinoma Carcinosarcoma Cystadenocarcinoma Oncocytic carcinoma Secretory carcinoma Mucinous adenocarcinoma Sebaceous adenocarcinoma Total
Size (cm)
Symptomatology
Total
Min
Max
Mean size
Yes
No
NI
n
%
0.5 0.8 0.3 0.5 0.8 0.5 0.5 0.4 1.0
14.0 5.5 6.0 11.0 5.5 5.0 4.0 2.0 2.0
3.0 2.5 1.5 2.7 2.8 1.5 1.0 1.0 1.5
21 1 9 3 0 1 0 1 0
657 61 32 28 22 23 10 4 2
408 15 3 10 6 2 3 0 0
1,086 77 44 41 28 26 13 5 2
47.4 3.5 1.9 1.8 1.2 1.1 0.6 0.2 0.1
0.5 0.4 0.4 0.8 0.8 1.0 0.5 0.9 1.3 0.8 2.0 1.0 1.2 1.0 2.0 0.8 2.0 1.7 -
13.0 15.0 10.0 14.0 12.0 8.0 5.5 4.5 5.0 6.5 10.0 5.5 11.0 6.5 3.5 0.8 2.0 1.7 -
4.5 3.8 3.4 4.0 3.2 4.0 3.0 2.9 2.8 2.7 4.9 3.0 5.9 3.4 2.8 0.8 2.0 1.7 -
93 107 49 35 14 16 7 3 4 3 7 2 0 0 1 0 0 0 377
172 69 85 51 21 16 5 8 3 6 2 5 4 2 1 1 1 1 1,292
57 42 31 19 12 3 2 2 4 1 1 1 0 1 0 0 0 0 623
322 218 165 105 47 35 14 13 11 10 10 8 4 3 2 1 1 1 2,292
14.0 9.5 7.2 4.6 2.0 1.5 0.6 0.6 0.5 0.4 0.4 0.3 0.2 0.15 0.1 0.05 0.05 0.05 100
NOS ¼ Not otherwise specified; Min ¼ Minimum; Max ¼ Maximum; n ¼ Number; NI ¼ Not informed; % ¼ Percentage.
L.P. da Silva et al. / Journal of Cranio-Maxillo-Facial Surgery 46 (2018) 2227e2233
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Table 5 Anatomic site, symptomatology, gender, age group and skin color distribution of benign and malignant salivary gland tumors. Benign
Anatomic site
Symptomatology
Gender Age
Skin color
Parotid Submandibular Sublingual Palate Buccal mucosa Lip Floor of the mouth Retromolar Tongue Intraosseous NI No Yes NI Male Female 19 years 20 years NI White Black Other NI
Malignant
n
%
n
%
641 162 4 307 61 116 9 3 4 0 15 839 36 447 513 809 75 1,170 77 406 202 110 604
68.7 70.7 25.0 48.7 41.5 71.2 36.0 7.3 11.1 0.0 32.6 64.9 9.5 71.7 60.5 62.8 68.2 57.0 59.2 59.2 61.1 40.4 71.1
292 67 12 324 86 47 16 38 32 25 31 453 341 176 388 582 35 882 53 351 173 192 254
31.3 29.3 75.0 51.3 58.5 28.8 64.0 92.7 88.9 100.0 67.4 35.1 90.5 28.3 39.5 37.2 31.8 43.0 40.7 40.8 38.9 59.6 28.9
Total (%)
p-value
933 (40.7) 229 (10.0) 16 (0.7) 631 (27.5) 147 (6.4) 163 (7.1) 25 (1.1) 41 (1.8) 36 (1.6) 25 (1.1) 46 (2.0) 1,292 (56.4) 377 (16.4) 623 (27.2) 901 (39.3) 1,391 (60.7) 110 (4.8) 2,052 (89.5) 130 (5.7) 757 (33.0) 375 (16.4) 302 (13.2) 858 (37.4)
<0.001a
<0.001b
0.333b 0.002b
<0.001b
n ¼ Number; NI ¼ Not informed; % ¼ Percentage. a Pearson's chi-square test. b Fisher's exact test.
2017). Considering the variation of this tumor behavior, the new edition (2017) of the WHO classification abandoned the term “lowgrade,” and renamed these tumors simply as polymorphous adenocarcinoma (PAC). This modification helps to avoid possible terminology confusion and facilitates the treatment choice for the more unusual cases (El-Naggar et al., 2017). Other malignant salivary tumors were very uncommon, such as oncocytic carcinoma and sebaceous adenocarcinoma. These entities are well recognized but also rarely reported. In the new WHO classification, cystadenocarcinoma was considered a synonym for intraductal carcinoma and mucinous adenocarcinoma as a variant of AcNOS (El-Naggar et al., 2017). For this study, it was preferred to maintain these tumors separately as they have specific features. In the present study, a case of AcCC was reclassified as secretory carcinoma. This tumor was recently recognized by the WHO; however, it was first described in 2010 as a mammary analog secretory carcinoma (MASC) (El-Naggar et al., 2017). The secretory carcinoma represents a salivary gland malignancy that was differentiated from AcCC and AcNOS because it shows a great similarity with the mammary-secreting carcinoma, besides presenting a specific translocation t (12; 15) (p13; q25) that results in an ETV6NTRK3 gene fusion. According to the WHO, to standardize international nomenclature, the official designation for this entity is simply “secretory carcinoma.” This tumor has an indolent clinical course such as AcCC but presents a higher probability to metastasize to cervical lymph nodes (up to 25%) (El-Naggar et al., 2017; Seethala and Stenman, 2017). Most of the tumors in this study were diagnosed in the parotid gland, followed by the minor salivary glands of the palate. In general, this result was also reported by other epidemiological studies (Jones et al., 2008; Li et al., 2008; Tian et al., 2010; Shishegar et al., 2011; Bello et al., 2012; Fonseca et al., 2012; Luksi c et al., 2012; Kızıl et al., 2013; Lawal et al., 2013; Jaafari-Ashkavandi et al., 2013; Araya et al., 2015; Wang et al., 2015; Vasconcelos et al., 2016; Gao et al., 2017). However, some authors describe the submandibular gland as the second most common anatomical site (de Oliveira et al., 2009;
zquez et al., 2012; Ochicha et al., 2009; Kara et al., 2010; Mejía-Vela Wang et al., 2012; Bittar et al., 2015; Fomete et al., 2015; Sando et al., 2016). On the other hand, studies conducted in Iran (Saghravanian et al., 2013) and Sri Lanka (Tilakaratne et al., 2009) have shown that salivary gland tumors are more common in the palate and rare in parotid glands. Interestingly, we observed that major salivary glands are mainly affected by benign tumors (69%; n ¼ 807). In contrast, malignant neoplasms accounted for 53.2% (n ¼ 568) of the minor gland tumors, similar to other authors (Tilakaratne et al., 2009). We emphasize to clinicians and surgeons that although benign tumors are more common, there is a greater chance (1.6:1) of diagnosing a malignant tumor in minor salivary glands. Therefore, a thorough examination of the oral cavity is essential to establish an early diagnosis avoiding morbidity and mortality. From a clinical point of view, salivary gland neoplasms usually are asymptomatic nodules of firm consistency (El-Naggar et al., 2017; Fomete et al., 2015). In our analysis, the presence of symptomatology occurred mainly in malignant tumors and patients usually complained of a swelling that may or not be painful. Benign tumors have an asymptomatic slow growth, unlike malignant tumors that show a faster growth which can lead to the appearance of symptoms (Jaber, 2006; Lin et al., 2008). The size of benign tumors is more limited (<3 cm), except for PA, which can reach large dimensions, while malignant tumors are larger (4e6 cm) (El-Naggar et al., 2017), as observed in this study. Larger malignant tumors (>4 cm) in the parotid gland are associated with an increased risk of facial paralysis (Lin et al., 2008). Although there are several reports in Brazil and in other countries, continuous studies that state the incidence and clinical characteristics of salivary tumors are important to keep clinicians and surgeons updated, especially when their classification undergoes some change. We emphasize that conducting multicenter studies facilitates the knowledge of the real data and covers the heterogeneity of the population, especially in countries with continental dimensions such as Brazil.
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L.P. da Silva et al. / Journal of Cranio-Maxillo-Facial Surgery 46 (2018) 2227e2233
Table 6 Worldwide distribution of salivary gland tumors published in the last 10 years (2008e2018). Continent/Country South America Brazil
Chile North America Mexico Europe Croatia UK Finland Africa Cameroon Nigeria
Asia China
India Iran
Israel Sri Lanka Turkey United Arab Emirates
Authors
n
Benign (%)
Malignant (%)
Most common benign tumors
Present study, 2018 (Multicentric) Vasconcelos et al., 2016 (Southern) Bittar et al., 2015 (Southern) Fonseca et al., 2012 (Southern) de Oliveira et al., 2009 (Central) Araya et al., 2015
2,292 109 271 493 599 259
57.7 78.0 79.3 74.8 78.3 72.6
42.3 22.0 20.7 25.1 21.7 27.4
PA PA PA PA PA PA
Mejía-Vel azquez et al., 2012
346
79.2
20.8
PA > WT
ACC > MEC
Luksi c et al. 2012 Bradley and McGurk, 2013 Jones et al. 2008 Bello et al.2012
779 1,060 741 1888
64.2 86.4 64.9 85.1
35.8 13.6 35.1 14.9
PA PA PA PA
> > > >
ACC > MEC MEC > ACC MEC > ACC ACC > MEC
Sando et al., 2016 Lawal et al., 2013 Ochicha et al., 2009 Fomete et al. 2015
200 413 76 135
71.8 46.5 56.6 28.9
28.2 53.5 43.4 71.1
PA PA > Myo PA PA > Onc
Gao et al., 2017 (Northern) Wang et al., 2015 (Northeast) Wang et al., 2012 Tian et al. 2010 (East) Li et al. 2008 (West) Subhashraj, 2008 Bussari et al., 2016 Taghavi et al., 2016 Torabinia et al., 2014 Jaafari-Ashkavandi et al., 2013 Shishegar et al. 2011 Atarbashi Moghadam et al., 2010 Saghravanian et al.2013 Bello et al.2012 Tilakaratne et al. 2009 Kızıl et al., 2013 Kara et al. 2010 Al Sarraj et al., 2015
7,190 2,508 1,154 6,982 3,461 684 82 184 229 366 392 112 165 330 713 500 121 314
64.73 77.1 76.9 68.0 59.8 62.0 46.3 35.3 55.5 67.8 68.2 75.0 51.5 66.7 49.9 70.8 75.2 74
35.27 22.9 23.1 32.0 40.2 38.0 53.7 64.7 44.5 32.2 31.8 25.0 48.5 33.3 50.1 29.2 24.8 26
PA PA PA PA PA PA PA PA PA PA PA PA PA PA PA PA PA PA
> > > > > >
> > > > > > > > > > > > > > > > > >
BCA WT WT WT WT WT
WT WT BCA WT
WT WT WT WT WT WT BCA Myo Myo WT WT WT Myo WT WT WT WT WT
Most common malignant tumors MEC > ACC ACC > MEC ¼ AcCC MEC > SCC MEC > AcNOS ACC > AcNOS MEC > ACC ¼ AcNOS
ACC > MEC ACC > MEC MEC > PAC ¼ ACC ACC > MEC MEC > ACC MEC > ACC MEC > ACC ACC > MEC MEC > ACC ACC > MEC MEC > ACC MEC > ACC MEC > ACC ACC > MEC ACC > MEC MEC > ACC MEC > ACC ACC > MEC MEC > ACC ACC > MEC ACC > AcNOS MEC > ACC
Abbrev.: ACC ¼ adenoid cystic carcinoma; AcCC ¼ acinic cell carcinoma; AcNOS ¼ adenocarcinoma not otherwise specified; BCA ¼ basal cell adenoma; MEC ¼ mucoepidermoid carcinoma; Myo ¼ myoepithelioma; PA ¼ pleomorphic adenoma; PAC ¼ polymorphous adenocarcinoma; SCC ¼ squamous cell carcinoma; WT ¼ Warthin's tumors; Onc ¼ Oncocytoma.
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