|Year : 2020 | Volume
| Issue : 1 | Page : 28-33
Relevance of tumor node metastasis staging in salivary gland tumors – a retrospective analysis from a tertiary cancer center
Aswin A Nagarajan1, Rajaraman Swaminathan2, Ganesharajah Selvaluxmy1, Ramya Ravichandar3
1 Department of Radiation Oncology, Biostatistics and Cancer Registry, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Epidemiology, Biostatistics and Cancer Registry, Cancer Institute (WIA), Chennai, Tamil Nadu, India
3 Department of Pharmacology, Sree Balaji Medical College and Hospital, Chennai, Tamil Nadu, India
|Date of Submission||11-Jun-2019|
|Date of Decision||04-Feb-2020|
|Date of Acceptance||26-Mar-2020|
|Date of Web Publication||20-Apr-2020|
Dr. Aswin A Nagarajan
Department of Radiation Oncology, Cancer Institute (WIA), 38, Sardar Patel Road, Adyar, Chennai - 600 020, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Salivary gland malignancies are generally not appropriately staged and are treated based on the high-risk features. Prognosis is not routinely predicted based on the tumor node metastasis (TNM) staging. Aim of this Study: The aim of the study was to identify whether TNM staging is useful in the prognosis of salivary gland malignancies. Materials and Methods: The patients of salivary gland malignancies treated during the period of years 2010–2014 were analyzed retrospectively. Age, gender, location, histology, stage, treatment received, and survival were analyzed. Results: A total of 79 cases were analyzed. The median age at presentation was 45 years. The male-to-female ratio was 1.63:1. Mucoepidermoid (37.9%) and adenoid cystic carcinoma (31.6%) were the common histological types. The 5-year disease-free survival (DFS) was 73.4% and overall survival was 82.3%. The 5-year DFS was significantly higher in women, mucoepidermoid and adenoid cystic carcinomas histology types, T1 versus T4 (P = 0.027), and N0 versus N2 (P = 0.004) and significantly lower in age ≥55 years than age < 35 and 35–44. DFS for different sites and treatment groups did not show any significant differences. The factors with significant result on univariate analysis showed an increasing risk of recurrence with increasing T-status (P = 0.459), increasing age at diagnosis (P = 0.035), nodal status (P = 0.059), and histology type (P = 0.02). Conclusion: There is an increasing trend to differentiate 5-year DFS for salivary gland malignancies between different T- and N-status suggesting usefulness of TNM staging before treatment and needs further evaluation.
Keywords: Disease-free survival, overall Survival, prognosis, salivary gland malignancies, tumour node metastasis staging
|How to cite this article:|
Nagarajan AA, Swaminathan R, Selvaluxmy G, Ravichandar R. Relevance of tumor node metastasis staging in salivary gland tumors – a retrospective analysis from a tertiary cancer center. Oncol J India 2020;4:28-33
|How to cite this URL:|
Nagarajan AA, Swaminathan R, Selvaluxmy G, Ravichandar R. Relevance of tumor node metastasis staging in salivary gland tumors – a retrospective analysis from a tertiary cancer center. Oncol J India [serial online] 2020 [cited 2020 May 28];4:28-33. Available from: http://www.ojionline.org/text.asp?2020/4/1/28/282834
| Introduction|| |
Salivary glands are divided anatomically into two major divisions such as major and minor. Three pairs of parotid, submandibular, and sublingual glands constitute major salivary glands. Six hundred to 1000 glands distributed in the upper aerodigestive tract constitute the minor salivary glands.
Although most of the tumors arising from the salivary glands are benign, around 6% of the tumors are malignant. The parotid gland is the most common site of origin of salivary gland tumors, but the incidence of malignancy is higher with the submandibular and submental glands and minor salivary glands. The incidence of cancer of the major salivary glands in Chennai during 2012–2014 was 0.5 per 100,000 population. The most common benign tumor is pleomorphic adenoma and the most common malignant tumor is mucoepidermoid carcinoma, followed by adenoid cystic carcinoma. Surgery is usually the mainstay of treatment of both benign as well as malignant tumors, but the extent and the type of surgery vary depending on the histology. Radiotherapy is indicated as an adjuvant treatment in high-risk patients, definitive treatment in unresectable patients, and palliative treatment to primary or metastatic foci. Chemotherapy is usually given in high-risk patients and metastatic disease. Targeted therapies may be useful in specific histology type such as adenoid cystic carcinoma.
Salivary gland malignancies are generally not appropriately staged and are treated based on the high-risk features such as T3–T4 stages, bone invasion, perineural invasion, major nerve involvement, close margins, high histologic grade, intermediate-grade mucoepidermoid, incomplete resection, and pathologic lymph node metastases. Prognosis is not routinely predicted based on tumor node metastasis (TNM) staging. With this background, the present study was conducted to identify whether TNM staging is useful in the prognosis of salivary gland malignancies.
| Materials and Methods|| |
The present study was conducted in the Cancer Institute (W. I. A), Chennai, during the period from January 2010 to December 2014. Ninety-seven patients with salivary gland tumors received treatment in the institute during the period. The malignant cases were retrieved and were analyzed as the study population. These cases were followed up until 2017 with 5 years' complete follow-up r ate of 90%. Data on factors such as age at diagnosis, gender, location, histology, comorbidities, investigations, stage, and treatment received were abstracted retrospectively from patients' case records. The relevance of TNM staging with respect to prognosis, the disease-free survival (DFS), and the overall survival (OS) were analyzed.
The staging was done by scrutinizing patients' clinical examination findings, imaging (computed tomography [CT], magnetic resonance imaging [MRI] or positron-emission tomography [PET]) reports, and postoperative histopathological examination regarding tumor size, margin status, nodal status, perineural involvement, perinodal spread, and the presence or absence of metastasis. As the staging was not done upfront, all the above details in the patients' case records were analyzed and stage was assigned based on the TNM edition VII. Patients underwent surgery, radiotherapy, and chemotherapy either as monotherapy or in combination depending on the stage of the disease.
Kaplan–Meier method was employed to estimate the survival probabilities in terms of OS and DFS. Log rank test was used to test the statistical significance between the survival curves. Cox proportional hazard model was utilized in univariate and multifactorial settings to elicit the independent prognostic factors for DFS. The data were analyzed using SPSS Statistics 17.0. Manual of the SPSS for Windows, Release 17.0.1 December 1, 2008, Chicago, Illinois, USA.
| Results|| |
Out of 97 case records analyzed, 79 (81.4%) of the tumors were malignant and the remaining 18 (18.6%) were benign. The most common benign tumor was pleomorphic adenoma followed by Warthin's tumor. As the TNM staging and survival would be of specific interest in malignant tumors, patients with malignant tumors were further analyzed.
The common age of presentation was <34 years followed by ≥55 years consisting of 30.4% and 29.1% [Table 1]. The median age of presentation was 45 years with the range between 10 and 75 years. There was a male preponderance in the ratio of 1.63:1. The common sites of involvement were the parotid consisting of 65 (82.28%) cases followed by the submandibular gland and others.
|Table 1: Descriptive statistics of factors analyzed, malignant salivary gland, 2010|
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Different types of malignant tumors with their incidence are mentioned in [Table 1]. The most common malignant tumor was mucoepidermoid carcinoma (37.9%) followed by adenoid cystic carcinoma (31.6%), which were the common histological types. The solitary case of non-Hodgkin's lymphoma (NHL) was not staged using TNM and excluded from the analysis of DFS with respect to the T- and N-status.
[Table 2] gives the number of patients in various tumor, nodal, and distant metastasis categories determined by the basis of staging. As NHL could not be staged in TNM classification, one case of NHL was excluded from the TNM staging. Clinical TNM staging was based on MRI in 47 (60.3%) patients, 15 (19.2%) were based on CT, 5 (6.4%) by PET, and 11 (14.1%) were clinically staged. Majority of patients were found to be T2 accounted for 32 cases (40.5%) followed by T3, T1, and T4 orderly. Majority cases were found to be node negative consisting of 46 cases (59.0%). Seventy-five of 79 cases (94.9%) were pathologically staged as the surgery was not feasible in the remaining four patients such as three patients received chemotherapy which includes the NHL case and one patient received chemoradiation.
|Table 2: Distribution of cases for clinical tumour, node, and metastasis status clinicoradiologically|
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Combined modality of treatment was received by 60 (76%) patients, i.e., surgery and radiotherapy by 58 (73.4%), one of whom received preoperative radiotherapy followed by surgery, one patient received chemoradiation, and one patient received chemoradiation followed by surgery. Surgery alone was performed on 16 (20.2%) patients and chemotherapy alone was performed in three cases.
The overall 5-year OS and 5-year DFS were 73.4% and 82.3%, respectively. [Figure 1], [Figure 2], [Figure 3] showed the DFS for the parameters such as sex, age group, and histology type, respectively. Women had significantly better 5-year DFS (82.8%) than men (54.7%) with P = 0.06 [Figure 1]. Patients aged 55 years or more experienced the least 5-year DFS (42.6%) and was statistically significant from those aged <35 (79.5%; P = 0.009) and 35–44 years (60.6%; P = 0.019) and not for those 45–54 years of age (72.7%; P = 0.315) [Figure 2]. The 5-year DFS for mucoepidermoid was 93.3% and adenoid cystic carcinoma was 91.7% and the both were found to be significantly better in comparison to the remaining histological types together (52.3%) with P = 0.009 for the former and P = 0.017 for the latter [Figure 3].
The 5-year DFS for T1 was highest (87.5%) and the least for T4 (60.0%) and the difference was statistically significant with P = 0.027 [Figure 4]. The 5-year DFS for node-negative patients was higher (71.7%) than N2 status (22.2%) and the difference was statistically significant with P = 0.004 [Figure 5]. DFS by site and treatment did not show any statistically significant differences between respective group categories.
The factors that exhibited significant survival differences were further analyzed in univariate and multifactorial settings [Table 3]. An increasing risk of recurrence with increasing T-status and N-status was forthcoming but was not statistically significant with P = value of 0.459 and 0.059, respectively. The risk of recurrence increased with an increasing age at diagnosis and was statistically significant (P = 0.035). Histology type (P = 0.02) also exhibited marked differences in the risk of recurrence within subcategories in a univariate setting. However, on multifactorial analysis, no factor emerged as an independent risk factor for DFS [Table 3].
|Table 3: Univariate and multifactorial analysis of prognostic factors for disease-free survival|
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| Discussion|| |
The majority of salivary tumors are benign consisting of 70% cases. Among the parotid gland tumors, 75%–80% of cases are benign, whereas around 50% of the submandibular gland tumors are benign. Sublingual gland tumors are very rare, but if present, they are most likely to be malignant. Since our hospital is a tertiary cancer center, majority of the cases already diagnosed with malignancy came to us for the treatment. Hence, a majority of salivary tumors (81.4%) were malignant in our study. Pinkston et al. analyzed the incidence of salivary gland tumors in a population-based study and found that mucoepidermoid carcinoma is the most common malignant tumor, which is coinciding with our study.
The high-risk features for the local recurrence of salivary gland malignancies include T3–T4, close margins, incomplete resection, bone invasion, perineural invasion, major nerve involvement, high histologic grade, intermediate-grade mucoepidermoid, and pathologic lymph node metastases. The high-risk features for nodal relapse in N0 neck include squamous cell carcinoma, undifferentiated carcinoma, adenocarcinoma, mucoepidermoid carcinoma (intermediate and high grade), tumors >4 cm in size, and high-grade tumors.
All these high featured patients receive adjuvant radiotherapy to avoid locoregional recurrence. Preoperative staging and postoperative staging are not done properly in case of salivary gland malignancies. The usual treatment followed is surgery followed by adjuvant radiotherapy in high-risk patients and chemotherapy in certain patients. Targeted therapy such as imatinib is used in adenoid cystic carcinoma for patients who are C-Kit positive. Terhaard et al. showed that postoperative radiotherapy at least 60 Gy is indicated for patients with T3 and T4 tumors, incomplete or close resection, bone invasion, perineural invasion, and positive nodes. Our study has shown that radiotherapy is useful in the above-mentioned indications, but the dose of radiotherapy ranged from 54 to 60 Gy.
Our study has shown that age, gender, comorbidities, and site did not show any significance, as shown in other studies. Hocwald et al. analyzed age, gender, tumor site, T-stage, facial paralysis, histologic neck involvement, perineural invasion, and cancer grade with respect to DFS and found that the presence of positive lymph nodes and perineural invasion are important independent predictors of DFS. Hocwald et al. also showed that positive lymph nodes and perineural invasion were important histologic predictors of shorter DFS. The receipt of both adjuvant radiation and cisplatin-based chemotherapy was an independent predictor of longer DFS. In our study, negative lymph node is associated with a longer DFS.
High-risk features both in primary and nodes received postoperative radiotherapy and had increased locoregional control which is consistent with other studies. Feinstein et al. evaluated patients with Stage III/IV salivary gland cancers who underwent curative resection followed by postoperative radiotherapy with respect to the recurrence free survival and OS. Patients had several high-risk features, including positive margins (51%), extracapsular spread (64%), perineural invasion (81%) and salivary duct carcinoma histology (24%). They concluded that despite standard treatment with curative intent, the 5-year recurrence-free survival in their patients was only 49%. The single factor associated with both higher risk of recurrence and death was the advanced nodal stage.
Anderson et al. showed that Stage I or II cancer and the absence of cervical lymph node metastases and surgical margins which were free of cancer were predictive of increased 4-year DFS in minor salivary gland tumors which is consistent with our study. DFS for node-negative patients was higher (5-year: 71.7%) than N2 status (22.2%) and was statistically significant (P = 0.004) in our study in univariate analysis. Lima et al.so showed that five factors influenced negatively the prognosis for salivary gland tumors such as T-stage, grade, positive lymph nodes, facial nerve dysfunction, and age. Patients with high-grade tumors and high-stage tumors had the worst prognosis. Our study has shown high-stage tumors had a shorter DFS. Eneroth showed that the prognosis for a given type of malignant tumor was most favorable when the primary tumor was located in the palate region, less favorable when it was in the parotid gland, and least favorable in the submandibular gland. The site is not statistically significant in our study.
Szanto et al. showed that important prognostic features of the adenoid cystic carcinoma were its grade, primary site, its presence or absence at surgical margins, and the anatomic structures it involved, which is not consistent with our study. Salgado et al. showed that higher T-stage and adenocarcinoma histology are the prognostic factors for local and locoregional recurrence in minor salivary gland tumors. We also found a poor DFS with higher stage and significantly better DFS for T1 in comparison to T4 although which on further univariate analysis found to be statistically insignificant. In our study, mucoepidermoid and adenoid cystic carcinoma histological types performed significantly better prognosis in comparison to other histological types together.
Armstrong et al. showed that postoperative radiotherapy significantly improves the outcome for patients with Stages III and IV disease and for patients with lymph node metastases, which is consistent with our data. In our study, three patients underwent preoperative radiotherapy followed by the reassessment for surgery due to inoperability, of which one patient has stable disease and is on regular follow-up. Another patient underwent surgery. Postoperative histopathology was suggestive of downstaging of tumor. The third patient had disease progression and lost follow-up.
| Conclusion|| |
There is an increasing trend of recurrence for salivary gland malignancies with the higher tumor and nodal status of TNM staging. The mucoepidermoid and adenoid cystic carcinoma histological types perform better DFS in comparison to other types, whereas older age group, i.e., ≥55 years shows poor outcomes. Hence, pretreatment pathological diagnosis and TNM staging could be useful for salivary gland malignancies. As only one case found with distant metastasis, the significance of M-status needs further evaluation with longer follow-up. Further larger studies are necessary to evaluate all the risk factors for their outcomes.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Sood S, McGurk M, Vaz F. Management of salivary gland tumours: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130 Suppl 2:S142-9.
Swaminathan R, Shanta V, Sampath P. Technical Report: Cancer incidence in Chennai, India, 2015. Chennai: National Cancer Registry Program, Indian Council of Medical Research; 2018.
Sobin LH, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours. 7th
ed. Geneva: International Union Against Cancer (UICC), Wiley-Blackwell; 2011.
Kaplan EL, Meier P. Non parametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457-81.
Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163-70.
Cox DR. Regression models and life tables. J R Statistic Soc 1972;34:187-220.
SPSS Statistics 17.0. Manual of the SPSS for Windows, Release 17.0.1 SPSS Inc.; 2008.
Pinkston JA, Cole P. Incidence rates of salivary gland tumors: Results from a population-based study. Otolaryngol Head Neck Surg 1999;120:834-40.
Terhaard CH, Lubsen H, Rasch CR, Levendag PC, Kaanders HH, Tjho-Heslinga RE, et al
. The role of radiotherapy in the treatment of malignant salivary gland tumours. Int J Rad Oncol Bio Phys 2005;61:103-11.
Hocwald E, Korkmaz H, Yoo GH, Adsay V, Shibuya TY, Abrams J, et al
. Prognostic factors in major salivary gland cancer. Laryngoscope 2001;111:1434-9.
Feinstein M, Lai SY, Lenzner D, Gooding W, Ferris RL, Grandis JR, et al
. Prognostic factors in patients with high-risk locally advanced salivary gland cancers treated with surgery and postoperative radiotherapy. Head Neck 2011;33;318-23.
Anderson JN Jr., Beenken SW, Crowe R, Soong SJ, Peters G, Maddox WA, et al
. Prognostic factors in minor salivary gland cancer. Head Neck 1995;17:480-6.
Lima RA, Tavares MR, Dias FL, Kligerman J, Nascimento MF, Barbosa MM, et al
. Clinical prognostic factors in malignant parotid gland tumours. Otolaryngol Head Neck Surg 2005;133:702-8.
Eneroth CM. Salivary gland tumours in the parotid gland, submandibular gland, and the palate region. Cancer 1971;27:1415-8.
Szanto PA, Luna MA, Tortoledo ME, White RA. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer 1984;54:1062-9.
Salgado LR, Spratt DE, Riaz N, Romesser PB, Wolden S, Rao S, et al
. Radiation therapy in the treatment of minor salivary gland tumours. Am J Clin Oncol 2014;37:492-7.
Armstrong JG, Harrison LB, Spiro RH, Fass DE, Strong EW, Fuks ZY. Malignant tumours of major salivary gland origin. Arch Otolaryngol Head Neck Surg 1990;116:290-3.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]