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Dental considerations in diagnosis of maxillary sinus carcinoma
Original Contributions
Dental considerations in diagnosis of maxillary sinus carcinoma A patient series of 24 cases Natalia Martínez-Rodríguez; Cristina Barona Dorado; Jorge Cortés-Bretón Brinkmann; María Martín Ares; Javier Sanz Alonso; José Maria Martínez-González ABSTRACT Background. Maxillary sinus carcinoma is a rare entity with an incidence of 0.2% and a low patient survival rate due to the frequency of late diagnosis. Methods. In this multicenter, transversal, retrospective, observational study, the authors analyzed patients who had received a diagnosis of maxillary sinus carcinoma, registering their oral symptoms, histologic type, treatment efficacy, and survival rate. Results. Maxillary sinus carcinoma was diagnosed in 24 patients (15 men and 9 women), of which 75% were squamous cell carcinomas. All patients had dental mobility, and some had swelling, orosinus fistula, or some dental loss. Mean patient survival rate was 38.83 months. Conclusions. A history of pain or swelling of unknown origin, an unexplained widening of periodontal ligament space, or mobility of the teeth should be considered warning signs of maxillary sinus carcinoma. Practical Implications. Recognition of oral symptoms by the dentist would help in making an early diagnosis of maxillary sinus carcinoma, improving the patient’s chances of survival and quality of life. Key Words. Cancer; carcinoma; squamous cell; diagnosis; oral; dentist; head and neck neoplasms; imaging and oral cancer; neoplasms; oral cancer.
JADA 2018:149(11):976-982 https://doi.org/10.1016/j.adaj.2018.07.016
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Copyright ª 2018 American Dental Association. All rights reserved.
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ancers of the paranasal sinuses are an unusual entity, representing from 0.2% through 0.8% of all malignant tumors and approximately 3% of all tumors of the head and neck.1 From 50% through 80% of paranasal sinus carcinomas are located in the maxillary sinus, with an incidence of 0.2% of the population,2,3 the most common histologic type being squamous cell carcinoma. Incidence is twice as high among men than women, and the age at which it appears generally falls from 40 through 60 years.4-6 Regarding clinical manifestations, early symptoms are usually nonspecific. At more advanced stages, the cancer may erode bone tissue and invade the adjacent anatomic structures, the most frequently described symptoms being the presence of an ulcer or mass on the palate, nasal discharge (runny nose), nasal obstruction, epistaxis, pain, cranial neuropathies, abnormal vision, odontalgia, dental mobility, and even spontaneous dental loss.7,8 The tumor classification system was drafted by the American Joint Committee on Cancer on the basis of the TNM Classification of Malignant Tumours system9 and establishes 5 tumor stages (Table 1). There is no single treatment protocol for tumors of the paranasal sinuses that will meet all needs, and treatment planning must be individualized on the basis of clinical and histologic diagnosis to optimize local management, reduction of symptoms, and the patient’s chances of survival.10 Although survival rates have improved in recent years, they remain low probably due in most cases to late diagnosis. Various causes for the high rate of mortality have been put forward, including the similarity in presentation and symptoms to other benign pathologies (for example, sinusitis or benign polyps) and the ease with which the cancer can spread to neighboring structures.11,12 JADA 149(11)
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Table 1. Tumor staging according to the American Joint Committee on Cancer.* TUMOR CLASSIFICATION
DESCRIPTION
T1
Tumor limited to the maxillary sinus mucosa without erosion or destruction.
T2
Tumor that produces bone erosion or destruction, including affectation extending to the hard palate and/or middle meatus but not extending to the posterior wall of the maxillary sinus or the pterygoid processes.
T3
Tumor invading any of the following: posterior bone wall of the maxillary sinus, subcutaneous cell tissue, floor or mid-wall of the orbit, pterygoid fossa, or ethmoidal sinus.
T4a
Tumor invading the anterior orbit contents, skin of the cheek, pterygoid apophysis, infratemporal fossa, cribiform plate, or frontal or sphenoidal sinuses.
T4b
Tumor invading any of the following: orbital apex, dura, brain, middle cranial fossa, cranial canals, nasopharynx, or clivus.
* Source: Edge and colleagues.9
In this context, there is a clear need to improve knowledge and understanding of maxillary sinus carcinoma and its oral symptoms within dentistry. Our study hypothesizes that better understanding and awareness of maxillary sinus carcinoma and its oral symptoms would help early diagnosis, which in turn would improve the survival rate of these patients. For this reason, our objectives in this study were to register the most frequently occurring clinical manifestations of maxillary sinus carcinoma in the oral cavity, to evaluate clinical staging at the moment of diagnosis, and to evaluate treatment efficacy and patient survival rates. METHODS Study design and enrollment criteria This multicenter, transversal, retrospective, observational study followed guidelines established by Declaration of Helsinki13 for research involving human patients. The Clinical Research Ethics Committee of San Carlos Hospital in Madrid, Spain, approved the study design. The study included patients attending the oral and maxillofacial surgery service of the Faculty of Dentistry at the Complutense University in Madrid, Spain, and the Virgin de la Paloma Hospital in Madrid, Spain, all treated at the latter center for maxillary sinus carcinoma from 2010 through 2016. All patients were provided with information about the study design and objectives and gave their informed consent to take part in the study. Clinical variables We prepared an anamnesis for each patient recording his or her age and sex and the location of the carcinoma (left or right). We recorded the following clinical manifestations: the presence of orosinus fistula, dental mobility, dental loss or displacement, swelling and the location of any swelling (vestibule, hard palate, soft palate, skin), and the frequency of each manifestation. We also noted whether patients were cigarette smokers. Tumor staging We classified patients’ tumors according to the American Joint Committee on Cancer9 as stage T1, T2, T3, or T4. Histologic type We grouped patients according to the type of cancer: squamous cell carcinoma, adenoid cystic carcinoma, or adenocarcinoma. Treatment We assessed and classified the therapeutic approach adopted in each case as follows: surgical treatment by means of maxillectomy, surgical treatment in combination with radiotherapy, surgical treatment in combination with radiotherapy and chemotherapy, or radiotherapy and chemotherapy alone. JADA 149(11)
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ABBREVIATION KEY K: Chemotherapy. Rx: Radiotherapy.
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Survival We evaluated patient survival in months and as percentages of patients to assess the prognosis of the pathology. Statistical analysis We performed statistical analysis using SPSS software Version 22.0 (SPSS), calculating descriptive statistics for each of the following variables: mean values, standard deviations, ranges, and frequencies. We calculated inferential statistics applying c2 tests and analysis of variance to determine whether different variables such as age, sex, tumor staging, histologic pattern, or treatment type influenced patient survival. We set statistical significance at P < .05 in all tests (95% confidence intervals). RESULTS Among 4,650 patients attending the 2 maxillofacial and oral surgery units from 2010 through 2016, a total of 24 patients received a diagnosis of maxillary sinus carcinoma (15 men and 9 women). Their ages ranged from 36 through 72 years, and the mean (standard deviation) age at diagnosis was 62.20 (11.19) years. All patients were cigarette smokers. Patient characteristics (carcinoma location, histology, tumor stage, and oral signs and symptoms) are shown in Table 2. All the patients with squamous cell carcinoma were men, whereas adenocarcinoma and adenoid cystic carcinoma corresponded to women, showing a clear relation between patient sex and histologic type (P ¼ .01). However, there was no relation between age and type of carcinoma (P ¼ .298). At the time of diagnosis, no patient received a diagnosis of T1, and we found no statistically significant relation between age and tumor staging (P ¼ .875). With regard to oral symptoms, the most common was dental mobility or dental displacements, and 4 patients had orosinus fistula (Figure 1). As for tumor localization, 50% of patients had affectation in 2 regions, 29.2% in 3 regions, 12.5% in 1 region, and 8.3% in all regions (Figure 2). We did not find age to have any influence on the number of affected regions (P ¼ .06). Different treatment therapies were applied in relation to tumor staging as shown in Table 3. Mean (standard deviation) patient survival was 38.83 (13.61) months, ranging from 11 through 60 months. We found survival to be influenced by the tumor stage at diagnosis (P ¼ .04). In the same way, the presence of swelling in more than 1 region influenced survival negatively (P ¼ .02). We found no statistically significant relationships between histologic type and survival (P ¼ .23). The treatment type influenced patient survival significantly (P ¼ .01), whereby patients treated with surgery alone survived for longer than patients who were treated with radiotherapy and chemotherapy alone (Table 4). DISCUSSION Maxillary sinus carcinoma is an uncommon entity, representing 3% of all carcinomas of the head and neck and 80% of paranasal sinus carcinomas in the United States and Europe. 14 Maxillary sinus carcinoma usually appears during the fourth through sixth decades of life, as stated by Bristol and colleagues,4 figures that concur with our study in which patient age ranged from 36 through 72 years, the mean age at the time of diagnosis being 62.20 years. Authors such as Dubal and colleagues15 have found a higher incidence among men in a proportion of approximately 2:1, an observation that coincides with our study in which only 37.5% of the patients were women. Similarly, Ansa and colleagues16 reported that male (63.6%) and white (75.7%) patients in the seventh decade of life were the groups most affected. To our knowledge, there is unanimous agreement in the literature that most maxillary sinus carcinomas are diagnosed late and at advanced stages owing to their nonspecific symptoms. In our study, all carcinomas were diagnosed at stage T2 or higher, a fact that would influence patient survival. Researchers such as Dooley and Shah17 have reported that as many as 90% of patients are diagnosed at stages T3 and T4. The delayed diagnosis is due to the large air space that makes up the maxillary sinus, which allows the asymptomatic growth of the tumor. It is not until the tumor perforates 1 of the walls that it will start to provoke nasal, ocular, or oral symptoms.17-19 Moreover, the panoramic 978
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Table 2. Patient characteristics. VARIABLE
NUMBER
%
14
58.3
Right
9
37.5
Bilateral
1
4.2
15
62.5
9
37.5
Side Left
Sex Male Female Histology Squamous cell carcinoma
18
75
Adenocarcinoma
4
16.7
Adenoid cystic carcinoma
2
8.3
T1
-
-
T2
13
54.2
T3
8
33.3
T4
3
12.5
8
33.3
Tumor Classification*
Clinical Variables Dental loss Dental mobility
24
Orosinusal fistula Dental displacement
100
4
16.7
13
54.2
Tumor Localization Hard palate, vestibule
10
41.7
Hard palate, vestibule, skin
7
29.2
Hard palate, vestibule, skin, soft palate
2
8.3
Vestibule, skin
2
8.3
Vestibule
2
8.3
1
4.2
Hard palate * Source: Edge and colleagues.
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radiographic appearance of a malignant lesion developing in the maxillary sinus or extending into it from the alveolar process may be similar to that of a mucous-retention pseudocyst or sinusitis. In dental radiographs, superimposition of normal surrounding structures on the maxillary sinus can obscure details of the malignant lesion so that its true nature can be missed.20 In this context, symptoms such as the presence of ulcers, alveolar crest or palate enlargement, orosinus fistulas after a dental extraction, spontaneous dental loss, or apparently unexplained dental mobility should be considered alarm signals to the general dentist.8,12,19 For this reason, the dentist should always keep in mind the association of these symptoms with carcinoma and, when they appear, refer the patient for a cone-beam computed tomographic or nuclear magnetic resonance scan, which would help diagnose carcinoma earlier.19 All the patients in our study had dental mobility, 33.3% had some lost teeth, and 16.7% had orosinus fistula. Among the histologic varieties identified, the most frequent type of carcinoma among the patients in our study was squamous cell carcinoma (75%), followed by adenocarcinoma (16.7%) and adenoid cystic carcinoma (8.3%). This concurs with studies by Jeon and colleagues,14 Dubal and colleagues,15 and Turner and Reh,21 in which the histologic evaluation showed squamous cell carcinoma to be the most frequent type. JADA 149(11)
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Figure 1. Orosinus fistula after dental extraction.
Figure 2. Vestibule and hard palate tumor.
Table 3. Patient survival in relation to treatment type and tumor staging.* TUMOR CLASSIFICATION T2
T3
T4b
PATIENTS, NO. 9
TREATMENT
SURVIVAL, AVERAGE MO
Surgery
4
Surgery þ Rx
6
Surgery þ Rx
53.8 †
41.67 29.24 ‡
2
Surgery þ Rx þ K
1
Rx
14
2
Rx þ K
19.50
26.50
* Source: Edge and colleagues.9 † Rx: Radiotherapy. ‡ K: Chemotherapy.
Various different risk factors for maxillary sinus carcinoma have been put forward, including prolonged exposure to nickel, chlorophenol, formaldehyde, or asbestos; the presence of human papillomavirus; and smoking.18,21,22 All of the patients in our study were cigarette smokers (more than 15 cigarettes a day), which suggests that smoking could be a risk factor for maxillary sinus carcinoma. When it comes to treatment, this type of malignancy represents a clinical challenge because of its anatomic complexity, as well as the lack of consensus in the literature as to the best approach to treatment and management. Although it has been shown in several patient series that a multimodal 980
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Table 4. Patient survival in months (N ¼ 24). VARIABLE
MEAN (STANDARD DEVIATION)
Tumor Classification*
P VALUE .043
T2
50.05 (5.81)
T3
2.55 (1.26)
T4
17.67 (3.17)
Histology
.238
Squamous cell carcinoma
40.72 (19.18)
Adenocarcinoma
46.25 (13.72)
Adenoid cystic carcinoma
19.50 (6.36)
Tumor Localization
.027
1 region
51.33 (15.01)
2 regions
47.25 (16.67)
3 regions
28.14 (15.71)
4 regions
19.50 (6.36)
* Source: Edge and colleagues.
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approach achieves better survival results, the optimal combination of therapies and the sequence in which they are applied remain unclear.10,19,23 There is no doubt that early diagnosis of stage T1 carcinoma should be dealt with by surgery, which will have a positive influence on survival, and that radiotherapy and chemotherapy should be reserved for more advanced carcinomas in which tumor extension is greater and there is a risk that surgery may be incomplete. In this context, Dulguerov and colleagues24 found a poorer response among patients treated by means of radiotherapy alone compared with those who had been treated by means of surgery alone. In our study, 21 patients underwent surgical treatment alone or combined treatment, whereas the other 3 were treated by means of radiotherapy and chemotherapy because surgery was not a viable option. Unfortunately, in many cases this type of cancer is diagnosed only when severe dysfunctional symptoms appear, a situation that impacts negatively on prognosis. In our study, mean patient survival was 38.83 months, a relatively low figure compared with findings in studies such as that by Kreppel and colleagues25 in which 43% of patients survived for 5 years or more. Numerous studies have found a strong correlation between tumor-staging classification and patient survival.11,26 In spite of our study’s small sample size, a better prognosis was seen for patients with early stage carcinoma than those with more advanced stages, the latter treated with radiotherapy or chemotherapy but obtaining poorer survival. Although researchers such as Dulguerov and colleagues24 have observed longer survival in cases of adenocarcinoma at 5 years compared with undifferentiated carcinomas (suggesting that histology was an important factor for prognosis), we found no significant relations of this type. Further research is needed with much larger patient samples and longer follow-up periods than in our study to determine whether age, histologic type, and tumor staging could be determining factors for the survival of patients with maxillary sinus carcinoma. CONCLUSIONS A history of pain or swelling of unknown origin, an unexplained widening of periodontal ligament space, or dental mobility should be considered warning signs to the dentist and could play an important role in the early diagnosis of maxillary sinus carcinoma. n
Dr. Martínez-Rodríguez is an adjunct professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Madrid, Spain, e-mail hospinatmr@ hotmail.com. Address correspondence to Dr. Martínez-Rodríguez.
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Dr. Barona Dorado is an assistant professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain.
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Dr. Cortés-Bretón Brinkmann is an adjunct professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain. Dr. Martín Ares is an adjunct professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain.
Dr. Sanz Alonso is an adjunct professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain. Dr. Martínez-González is an associate professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain. Disclosure. None of the authors reported any disclosures.
1. Mirghani H, Hartl D, Mortuaire G, et al. Nodal recurrence of sinonasal cancer: does the risk of cervical relapse justify a prophylactic neck treatment? Oral Oncol. 2013;49(4):374-380. 2. Takes RP, Ferlito A, Silver CE, et al. The controversy in the management of the N0 neck for squamous cell carcinoma of the maxillary sinus. Eur Arch Otorhinolaryngol. 2014;271(5):899-904. 3. Rinaldo A, Ferlito A, Shaha AR, Wei WI. Is elective neck treatment indicated in patients with squamous cell carcinoma of the maxillary sinus? Acta Otolaryngol. 2002; 122(4):443-447. 4. Bristol IJ, Ahamad A, Garden AS, et al. Postoperative radiotherapy for maxillary sinus cancer: longterm outcomes and toxicities of treatment. Int J Radiat Oncol Biol Phys. 2007;68(3):710-730. 5. Gibson TN, McNaughton DP, Hanchard B. Sinonasal malignancies: incidence and histological distribution in Jamaica, 1973-2007. Cancer Causes Control. 2017; 28(11):1219-1225. 6. Kondo A, Kurose M, Obata K, et al. A clinical study of maxillary sinus squamous cell carcinoma. Adv Otorhinolaryngol. 2016;77:83-87. 7. Bhasker S, Mallick S, Benson R, Bhanuprasad V, Sharma A, Thakar A. A multimodality approach to sinonasal undifferentiated carcinoma: a single institute experience. J Laryngol Otol. 2017;131(1):19-25. 8. Park SY, Pi CY, Kim E, Lee Y. Adenoid cystic carcinoma of maxillary sinus misdiagnosed as chronic apical periodontitis. J Oral Maxillofac Surg. 2017;75(6):1303.e11303.e7. 9. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
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10. Robin TP, Jones BL, Gordon OM, et al. A comparative analysis of treatment modalities for sinonasal malignancies: a comprehensive, population-based approach. Cancer. 2017;123(16):3040-3049. 11. Shen W, Sakamoto N, Yang L. Prognostic models and nomograms for predicting survival of patients with maxillary sinus carcinoma. Int Forum Allergy Rhinol. 2017; 7(7):741-748. 12. Ramachamparambathu AK, Vengal M, Mufeed A, Siyo N, Ahmed A. Carcinoma of maxillary sinus masquerading as odontogenic infection. J Clin Diagn Res. 2016;10(9):ZD11ZD13. 13. World Medical Association. WMA Declaration of Helsinki: ethical principles for medical research involving human subjects. Available at: www.wma.net/ en/30publications/10policies/b3/index.html. Accessed October 13, 2016. 14. Jeon SH, Han DH, Won TB, Keam B, Kim JH, Wu HG. Implication of tumor location for lymph node metastasis in maxillary sinus carcinoma: indications for elective neck treatment. J Oral Maxillofac Surg. 2017; 75(44):858-866. 15. Dubal PM, Bhojwani A, Patel TD, et al. Squamus cell carcinoma of the maxillary sinus: a population-based analysis. Laryngoscope. 2016;126(2):399-404. 16. Ansa B, Goodman M, Ward K, et al. Paranasal sinus squamous cell carcinoma incidence and survival based on surveillance, epidemiology and end results data, 1973 to 2009. Cancer. 2013;119(14):2602-2610. 17. Dooley L, Shah J. Management of the neck in maxillary sinus carcinomas. Curr Opin Otolaryngol Head Neck Surg. 2015;23(2):107-114. 18. Santos MRM, Servato JPS, Cardoso SV, et al. Squamous cell carcinoma at maxillary sinus: clinicopathologic
data in a single Brazilian institution with review of the literature. Int J Clin Exp Pathol. 2014;7(12):88238832. 19. Ohja J, Kossak E, Mangat S, Kossak Z. Recurrent pain and swelling associated with impacted maxillary third molar: the diagnosisdsquamous cell carcinoma of the maxillary sinus. JADA. 2015;146(11):840-844. 20. Epstein JB, Waisglass M, Bhimji S, Le N, StevensonMoore P. A comparison of computed tomography and panoramic radiography in assessing malignancy of the maxillary antrum. Eur J Cancer. 1996;32B(3):191-201. 21. Turner JH, Reh DD. Incidence and survival in patients with sinonasal cancer: a historical analysis of population-based data. Head Neck. 2012;34(6):877-885. 22. Binazzi A, Ferrante P, Marinaccio A. Occupational exposure and sinonasal cancer: a systematic review and meta-analysis. BMC Cancer. 2015;15:49. 23. Danesh-Sani SA, Sarafraz A, Chamani M, Derakhshandeh H. Para-nasal sinuses malignancies: a 12-year review of clinical characteristics. Med Oral Patol Oral Cir Bucal. 2016;21(5):e626-e630. 24. Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T. Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer. 2001;92(12):3012-3029. 25. Kreppel M, Safi AF, Scheer M, et al. The importance of early diagnosis in patients with maxillary sinus carcinoma. Eur Arch Otorhinolaryngol. 2016;273(9):26292635. 26. Kuan EC, Arshi A, Mallen-St Clair J, Tajudeen BA, Abemayor E, St John MA. Significance of tumor stage in sinonasal undifferentiated carcinoma survival: a population based analysis. Otolaryngol Head Neck Surg. 2016; 154(4):667-673.
JADA 149(11)
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Dental considerations in diagnosis of maxillary sinus carcinoma A patient series of 24 cases Natalia Martínez-Rodríguez; Cristina Barona Dorado; Jorge Cortés-Bretón Brinkmann; María Martín Ares; Javier Sanz Alonso; José Maria Martínez-González ABSTRACT Background. Maxillary sinus carcinoma is a rare entity with an incidence of 0.2% and a low patient survival rate due to the frequency of late diagnosis. Methods. In this multicenter, transversal, retrospective, observational study, the authors analyzed patients who had received a diagnosis of maxillary sinus carcinoma, registering their oral symptoms, histologic type, treatment efficacy, and survival rate. Results. Maxillary sinus carcinoma was diagnosed in 24 patients (15 men and 9 women), of which 75% were squamous cell carcinomas. All patients had dental mobility, and some had swelling, orosinus fistula, or some dental loss. Mean patient survival rate was 38.83 months. Conclusions. A history of pain or swelling of unknown origin, an unexplained widening of periodontal ligament space, or mobility of the teeth should be considered warning signs of maxillary sinus carcinoma. Practical Implications. Recognition of oral symptoms by the dentist would help in making an early diagnosis of maxillary sinus carcinoma, improving the patient’s chances of survival and quality of life. Key Words. Cancer; carcinoma; squamous cell; diagnosis; oral; dentist; head and neck neoplasms; imaging and oral cancer; neoplasms; oral cancer.
JADA 2018:149(11):976-982 https://doi.org/10.1016/j.adaj.2018.07.016
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Copyright ª 2018 American Dental Association. All rights reserved.
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ancers of the paranasal sinuses are an unusual entity, representing from 0.2% through 0.8% of all malignant tumors and approximately 3% of all tumors of the head and neck.1 From 50% through 80% of paranasal sinus carcinomas are located in the maxillary sinus, with an incidence of 0.2% of the population,2,3 the most common histologic type being squamous cell carcinoma. Incidence is twice as high among men than women, and the age at which it appears generally falls from 40 through 60 years.4-6 Regarding clinical manifestations, early symptoms are usually nonspecific. At more advanced stages, the cancer may erode bone tissue and invade the adjacent anatomic structures, the most frequently described symptoms being the presence of an ulcer or mass on the palate, nasal discharge (runny nose), nasal obstruction, epistaxis, pain, cranial neuropathies, abnormal vision, odontalgia, dental mobility, and even spontaneous dental loss.7,8 The tumor classification system was drafted by the American Joint Committee on Cancer on the basis of the TNM Classification of Malignant Tumours system9 and establishes 5 tumor stages (Table 1). There is no single treatment protocol for tumors of the paranasal sinuses that will meet all needs, and treatment planning must be individualized on the basis of clinical and histologic diagnosis to optimize local management, reduction of symptoms, and the patient’s chances of survival.10 Although survival rates have improved in recent years, they remain low probably due in most cases to late diagnosis. Various causes for the high rate of mortality have been put forward, including the similarity in presentation and symptoms to other benign pathologies (for example, sinusitis or benign polyps) and the ease with which the cancer can spread to neighboring structures.11,12 JADA 149(11)
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Table 1. Tumor staging according to the American Joint Committee on Cancer.* TUMOR CLASSIFICATION
DESCRIPTION
T1
Tumor limited to the maxillary sinus mucosa without erosion or destruction.
T2
Tumor that produces bone erosion or destruction, including affectation extending to the hard palate and/or middle meatus but not extending to the posterior wall of the maxillary sinus or the pterygoid processes.
T3
Tumor invading any of the following: posterior bone wall of the maxillary sinus, subcutaneous cell tissue, floor or mid-wall of the orbit, pterygoid fossa, or ethmoidal sinus.
T4a
Tumor invading the anterior orbit contents, skin of the cheek, pterygoid apophysis, infratemporal fossa, cribiform plate, or frontal or sphenoidal sinuses.
T4b
Tumor invading any of the following: orbital apex, dura, brain, middle cranial fossa, cranial canals, nasopharynx, or clivus.
* Source: Edge and colleagues.9
In this context, there is a clear need to improve knowledge and understanding of maxillary sinus carcinoma and its oral symptoms within dentistry. Our study hypothesizes that better understanding and awareness of maxillary sinus carcinoma and its oral symptoms would help early diagnosis, which in turn would improve the survival rate of these patients. For this reason, our objectives in this study were to register the most frequently occurring clinical manifestations of maxillary sinus carcinoma in the oral cavity, to evaluate clinical staging at the moment of diagnosis, and to evaluate treatment efficacy and patient survival rates. METHODS Study design and enrollment criteria This multicenter, transversal, retrospective, observational study followed guidelines established by Declaration of Helsinki13 for research involving human patients. The Clinical Research Ethics Committee of San Carlos Hospital in Madrid, Spain, approved the study design. The study included patients attending the oral and maxillofacial surgery service of the Faculty of Dentistry at the Complutense University in Madrid, Spain, and the Virgin de la Paloma Hospital in Madrid, Spain, all treated at the latter center for maxillary sinus carcinoma from 2010 through 2016. All patients were provided with information about the study design and objectives and gave their informed consent to take part in the study. Clinical variables We prepared an anamnesis for each patient recording his or her age and sex and the location of the carcinoma (left or right). We recorded the following clinical manifestations: the presence of orosinus fistula, dental mobility, dental loss or displacement, swelling and the location of any swelling (vestibule, hard palate, soft palate, skin), and the frequency of each manifestation. We also noted whether patients were cigarette smokers. Tumor staging We classified patients’ tumors according to the American Joint Committee on Cancer9 as stage T1, T2, T3, or T4. Histologic type We grouped patients according to the type of cancer: squamous cell carcinoma, adenoid cystic carcinoma, or adenocarcinoma. Treatment We assessed and classified the therapeutic approach adopted in each case as follows: surgical treatment by means of maxillectomy, surgical treatment in combination with radiotherapy, surgical treatment in combination with radiotherapy and chemotherapy, or radiotherapy and chemotherapy alone. JADA 149(11)
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ABBREVIATION KEY K: Chemotherapy. Rx: Radiotherapy.
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Survival We evaluated patient survival in months and as percentages of patients to assess the prognosis of the pathology. Statistical analysis We performed statistical analysis using SPSS software Version 22.0 (SPSS), calculating descriptive statistics for each of the following variables: mean values, standard deviations, ranges, and frequencies. We calculated inferential statistics applying c2 tests and analysis of variance to determine whether different variables such as age, sex, tumor staging, histologic pattern, or treatment type influenced patient survival. We set statistical significance at P < .05 in all tests (95% confidence intervals). RESULTS Among 4,650 patients attending the 2 maxillofacial and oral surgery units from 2010 through 2016, a total of 24 patients received a diagnosis of maxillary sinus carcinoma (15 men and 9 women). Their ages ranged from 36 through 72 years, and the mean (standard deviation) age at diagnosis was 62.20 (11.19) years. All patients were cigarette smokers. Patient characteristics (carcinoma location, histology, tumor stage, and oral signs and symptoms) are shown in Table 2. All the patients with squamous cell carcinoma were men, whereas adenocarcinoma and adenoid cystic carcinoma corresponded to women, showing a clear relation between patient sex and histologic type (P ¼ .01). However, there was no relation between age and type of carcinoma (P ¼ .298). At the time of diagnosis, no patient received a diagnosis of T1, and we found no statistically significant relation between age and tumor staging (P ¼ .875). With regard to oral symptoms, the most common was dental mobility or dental displacements, and 4 patients had orosinus fistula (Figure 1). As for tumor localization, 50% of patients had affectation in 2 regions, 29.2% in 3 regions, 12.5% in 1 region, and 8.3% in all regions (Figure 2). We did not find age to have any influence on the number of affected regions (P ¼ .06). Different treatment therapies were applied in relation to tumor staging as shown in Table 3. Mean (standard deviation) patient survival was 38.83 (13.61) months, ranging from 11 through 60 months. We found survival to be influenced by the tumor stage at diagnosis (P ¼ .04). In the same way, the presence of swelling in more than 1 region influenced survival negatively (P ¼ .02). We found no statistically significant relationships between histologic type and survival (P ¼ .23). The treatment type influenced patient survival significantly (P ¼ .01), whereby patients treated with surgery alone survived for longer than patients who were treated with radiotherapy and chemotherapy alone (Table 4). DISCUSSION Maxillary sinus carcinoma is an uncommon entity, representing 3% of all carcinomas of the head and neck and 80% of paranasal sinus carcinomas in the United States and Europe. 14 Maxillary sinus carcinoma usually appears during the fourth through sixth decades of life, as stated by Bristol and colleagues,4 figures that concur with our study in which patient age ranged from 36 through 72 years, the mean age at the time of diagnosis being 62.20 years. Authors such as Dubal and colleagues15 have found a higher incidence among men in a proportion of approximately 2:1, an observation that coincides with our study in which only 37.5% of the patients were women. Similarly, Ansa and colleagues16 reported that male (63.6%) and white (75.7%) patients in the seventh decade of life were the groups most affected. To our knowledge, there is unanimous agreement in the literature that most maxillary sinus carcinomas are diagnosed late and at advanced stages owing to their nonspecific symptoms. In our study, all carcinomas were diagnosed at stage T2 or higher, a fact that would influence patient survival. Researchers such as Dooley and Shah17 have reported that as many as 90% of patients are diagnosed at stages T3 and T4. The delayed diagnosis is due to the large air space that makes up the maxillary sinus, which allows the asymptomatic growth of the tumor. It is not until the tumor perforates 1 of the walls that it will start to provoke nasal, ocular, or oral symptoms.17-19 Moreover, the panoramic 978
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Table 2. Patient characteristics. VARIABLE
NUMBER
%
14
58.3
Right
9
37.5
Bilateral
1
4.2
15
62.5
9
37.5
Side Left
Sex Male Female Histology Squamous cell carcinoma
18
75
Adenocarcinoma
4
16.7
Adenoid cystic carcinoma
2
8.3
T1
-
-
T2
13
54.2
T3
8
33.3
T4
3
12.5
8
33.3
Tumor Classification*
Clinical Variables Dental loss Dental mobility
24
Orosinusal fistula Dental displacement
100
4
16.7
13
54.2
Tumor Localization Hard palate, vestibule
10
41.7
Hard palate, vestibule, skin
7
29.2
Hard palate, vestibule, skin, soft palate
2
8.3
Vestibule, skin
2
8.3
Vestibule
2
8.3
1
4.2
Hard palate * Source: Edge and colleagues.
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radiographic appearance of a malignant lesion developing in the maxillary sinus or extending into it from the alveolar process may be similar to that of a mucous-retention pseudocyst or sinusitis. In dental radiographs, superimposition of normal surrounding structures on the maxillary sinus can obscure details of the malignant lesion so that its true nature can be missed.20 In this context, symptoms such as the presence of ulcers, alveolar crest or palate enlargement, orosinus fistulas after a dental extraction, spontaneous dental loss, or apparently unexplained dental mobility should be considered alarm signals to the general dentist.8,12,19 For this reason, the dentist should always keep in mind the association of these symptoms with carcinoma and, when they appear, refer the patient for a cone-beam computed tomographic or nuclear magnetic resonance scan, which would help diagnose carcinoma earlier.19 All the patients in our study had dental mobility, 33.3% had some lost teeth, and 16.7% had orosinus fistula. Among the histologic varieties identified, the most frequent type of carcinoma among the patients in our study was squamous cell carcinoma (75%), followed by adenocarcinoma (16.7%) and adenoid cystic carcinoma (8.3%). This concurs with studies by Jeon and colleagues,14 Dubal and colleagues,15 and Turner and Reh,21 in which the histologic evaluation showed squamous cell carcinoma to be the most frequent type. JADA 149(11)
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Figure 1. Orosinus fistula after dental extraction.
Figure 2. Vestibule and hard palate tumor.
Table 3. Patient survival in relation to treatment type and tumor staging.* TUMOR CLASSIFICATION T2
T3
T4b
PATIENTS, NO. 9
TREATMENT
SURVIVAL, AVERAGE MO
Surgery
4
Surgery þ Rx
6
Surgery þ Rx
53.8 †
41.67 29.24 ‡
2
Surgery þ Rx þ K
1
Rx
14
2
Rx þ K
19.50
26.50
* Source: Edge and colleagues.9 † Rx: Radiotherapy. ‡ K: Chemotherapy.
Various different risk factors for maxillary sinus carcinoma have been put forward, including prolonged exposure to nickel, chlorophenol, formaldehyde, or asbestos; the presence of human papillomavirus; and smoking.18,21,22 All of the patients in our study were cigarette smokers (more than 15 cigarettes a day), which suggests that smoking could be a risk factor for maxillary sinus carcinoma. When it comes to treatment, this type of malignancy represents a clinical challenge because of its anatomic complexity, as well as the lack of consensus in the literature as to the best approach to treatment and management. Although it has been shown in several patient series that a multimodal 980
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Table 4. Patient survival in months (N ¼ 24). VARIABLE
MEAN (STANDARD DEVIATION)
Tumor Classification*
P VALUE .043
T2
50.05 (5.81)
T3
2.55 (1.26)
T4
17.67 (3.17)
Histology
.238
Squamous cell carcinoma
40.72 (19.18)
Adenocarcinoma
46.25 (13.72)
Adenoid cystic carcinoma
19.50 (6.36)
Tumor Localization
.027
1 region
51.33 (15.01)
2 regions
47.25 (16.67)
3 regions
28.14 (15.71)
4 regions
19.50 (6.36)
* Source: Edge and colleagues.
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approach achieves better survival results, the optimal combination of therapies and the sequence in which they are applied remain unclear.10,19,23 There is no doubt that early diagnosis of stage T1 carcinoma should be dealt with by surgery, which will have a positive influence on survival, and that radiotherapy and chemotherapy should be reserved for more advanced carcinomas in which tumor extension is greater and there is a risk that surgery may be incomplete. In this context, Dulguerov and colleagues24 found a poorer response among patients treated by means of radiotherapy alone compared with those who had been treated by means of surgery alone. In our study, 21 patients underwent surgical treatment alone or combined treatment, whereas the other 3 were treated by means of radiotherapy and chemotherapy because surgery was not a viable option. Unfortunately, in many cases this type of cancer is diagnosed only when severe dysfunctional symptoms appear, a situation that impacts negatively on prognosis. In our study, mean patient survival was 38.83 months, a relatively low figure compared with findings in studies such as that by Kreppel and colleagues25 in which 43% of patients survived for 5 years or more. Numerous studies have found a strong correlation between tumor-staging classification and patient survival.11,26 In spite of our study’s small sample size, a better prognosis was seen for patients with early stage carcinoma than those with more advanced stages, the latter treated with radiotherapy or chemotherapy but obtaining poorer survival. Although researchers such as Dulguerov and colleagues24 have observed longer survival in cases of adenocarcinoma at 5 years compared with undifferentiated carcinomas (suggesting that histology was an important factor for prognosis), we found no significant relations of this type. Further research is needed with much larger patient samples and longer follow-up periods than in our study to determine whether age, histologic type, and tumor staging could be determining factors for the survival of patients with maxillary sinus carcinoma. CONCLUSIONS A history of pain or swelling of unknown origin, an unexplained widening of periodontal ligament space, or dental mobility should be considered warning signs to the dentist and could play an important role in the early diagnosis of maxillary sinus carcinoma. n
Dr. Martínez-Rodríguez is an adjunct professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Madrid, Spain, e-mail hospinatmr@ hotmail.com. Address correspondence to Dr. Martínez-Rodríguez.
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Dr. Barona Dorado is an assistant professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain.
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Dr. Cortés-Bretón Brinkmann is an adjunct professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain. Dr. Martín Ares is an adjunct professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain.
Dr. Sanz Alonso is an adjunct professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain. Dr. Martínez-González is an associate professor, Department of Medicine and Buccofacial Surgery, Faculty of Dentistry, Complutense University of Madrid, Madrid, Spain. Disclosure. None of the authors reported any disclosures.
1. Mirghani H, Hartl D, Mortuaire G, et al. Nodal recurrence of sinonasal cancer: does the risk of cervical relapse justify a prophylactic neck treatment? Oral Oncol. 2013;49(4):374-380. 2. Takes RP, Ferlito A, Silver CE, et al. The controversy in the management of the N0 neck for squamous cell carcinoma of the maxillary sinus. Eur Arch Otorhinolaryngol. 2014;271(5):899-904. 3. Rinaldo A, Ferlito A, Shaha AR, Wei WI. Is elective neck treatment indicated in patients with squamous cell carcinoma of the maxillary sinus? Acta Otolaryngol. 2002; 122(4):443-447. 4. Bristol IJ, Ahamad A, Garden AS, et al. Postoperative radiotherapy for maxillary sinus cancer: longterm outcomes and toxicities of treatment. Int J Radiat Oncol Biol Phys. 2007;68(3):710-730. 5. Gibson TN, McNaughton DP, Hanchard B. Sinonasal malignancies: incidence and histological distribution in Jamaica, 1973-2007. Cancer Causes Control. 2017; 28(11):1219-1225. 6. Kondo A, Kurose M, Obata K, et al. A clinical study of maxillary sinus squamous cell carcinoma. Adv Otorhinolaryngol. 2016;77:83-87. 7. Bhasker S, Mallick S, Benson R, Bhanuprasad V, Sharma A, Thakar A. A multimodality approach to sinonasal undifferentiated carcinoma: a single institute experience. J Laryngol Otol. 2017;131(1):19-25. 8. Park SY, Pi CY, Kim E, Lee Y. Adenoid cystic carcinoma of maxillary sinus misdiagnosed as chronic apical periodontitis. J Oral Maxillofac Surg. 2017;75(6):1303.e11303.e7. 9. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
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10. Robin TP, Jones BL, Gordon OM, et al. A comparative analysis of treatment modalities for sinonasal malignancies: a comprehensive, population-based approach. Cancer. 2017;123(16):3040-3049. 11. Shen W, Sakamoto N, Yang L. Prognostic models and nomograms for predicting survival of patients with maxillary sinus carcinoma. Int Forum Allergy Rhinol. 2017; 7(7):741-748. 12. Ramachamparambathu AK, Vengal M, Mufeed A, Siyo N, Ahmed A. Carcinoma of maxillary sinus masquerading as odontogenic infection. J Clin Diagn Res. 2016;10(9):ZD11ZD13. 13. World Medical Association. WMA Declaration of Helsinki: ethical principles for medical research involving human subjects. Available at: www.wma.net/ en/30publications/10policies/b3/index.html. Accessed October 13, 2016. 14. Jeon SH, Han DH, Won TB, Keam B, Kim JH, Wu HG. Implication of tumor location for lymph node metastasis in maxillary sinus carcinoma: indications for elective neck treatment. J Oral Maxillofac Surg. 2017; 75(44):858-866. 15. Dubal PM, Bhojwani A, Patel TD, et al. Squamus cell carcinoma of the maxillary sinus: a population-based analysis. Laryngoscope. 2016;126(2):399-404. 16. Ansa B, Goodman M, Ward K, et al. Paranasal sinus squamous cell carcinoma incidence and survival based on surveillance, epidemiology and end results data, 1973 to 2009. Cancer. 2013;119(14):2602-2610. 17. Dooley L, Shah J. Management of the neck in maxillary sinus carcinomas. Curr Opin Otolaryngol Head Neck Surg. 2015;23(2):107-114. 18. Santos MRM, Servato JPS, Cardoso SV, et al. Squamous cell carcinoma at maxillary sinus: clinicopathologic
data in a single Brazilian institution with review of the literature. Int J Clin Exp Pathol. 2014;7(12):88238832. 19. Ohja J, Kossak E, Mangat S, Kossak Z. Recurrent pain and swelling associated with impacted maxillary third molar: the diagnosisdsquamous cell carcinoma of the maxillary sinus. JADA. 2015;146(11):840-844. 20. Epstein JB, Waisglass M, Bhimji S, Le N, StevensonMoore P. A comparison of computed tomography and panoramic radiography in assessing malignancy of the maxillary antrum. Eur J Cancer. 1996;32B(3):191-201. 21. Turner JH, Reh DD. Incidence and survival in patients with sinonasal cancer: a historical analysis of population-based data. Head Neck. 2012;34(6):877-885. 22. Binazzi A, Ferrante P, Marinaccio A. Occupational exposure and sinonasal cancer: a systematic review and meta-analysis. BMC Cancer. 2015;15:49. 23. Danesh-Sani SA, Sarafraz A, Chamani M, Derakhshandeh H. Para-nasal sinuses malignancies: a 12-year review of clinical characteristics. Med Oral Patol Oral Cir Bucal. 2016;21(5):e626-e630. 24. Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T. Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer. 2001;92(12):3012-3029. 25. Kreppel M, Safi AF, Scheer M, et al. The importance of early diagnosis in patients with maxillary sinus carcinoma. Eur Arch Otorhinolaryngol. 2016;273(9):26292635. 26. Kuan EC, Arshi A, Mallen-St Clair J, Tajudeen BA, Abemayor E, St John MA. Significance of tumor stage in sinonasal undifferentiated carcinoma survival: a population based analysis. Otolaryngol Head Neck Surg. 2016; 154(4):667-673.
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