Tumor Thickness and Cervical Nodal Metastasis in N0 Oral Tongue Squamous Cell Carcinoma Patients: A Prospective Study

Keywords

Oral Tongue Cancer; Lymph Node Metastasis; Tumor Thickness.

Introduction

The majority of oral cavity cancers affects the lower parts of mouth and especially tongue margins and the neighboring floor of mouth extending backwards to oropharynx. Oral tongue squamous cell carcinoma (OTSCC) is one of the most common types of oral cancers. It represents 25- 50% of oral cavity cancers and includes only the lesions of the anterior tow thirds of tongue. [1, 2].

Tongue SCC (TSCC) is considered one of the most aggressive types of OSCC. It tends to develop regional lymph node metastasis earlier and with more incidence compared with the most other kinds of OSCC,[3-6] also it has in its early stages the larger mortality rates among various kinds of OSCC. [7]

TNM classification system for tumors staging has been founded on for many decades. It has formed the reference for clinicians and pathologists in determining the disease stage and prognosis and has provided the standard guidelines for tumors treatment. [8] Clinical practice has demonstrated some deficiency in this classification. There were many failure cases that were encountered when the suggested TNM treatment plan was applied, in addition to that there were some N0 cases of OSCC which did not respond -as expected- to the standard treatment plan determined according to this classification. This opinion was supported by many clinical studies which have confirmed the TNM classification deficiency in predicting cervical node metastasis, disease recurrence and survival. [9-15] and have concluded the presence of many other prognostic factors - other than tumor size - that influence the disease progression and prognosis such as tumor thickness (TT) or depth of invasion (DOI), tumor differentiation grade, perineural invasion, and many other factors.[16-20] Many recent studies have confirmed on the role of tumor thickness or depth of invasion in predicting OSCC regional lymph node metastasis [21-24]. According to these studies the increase in tumor thickness is associated with higher incidence of regional lymph node metastasis. The minute knowledge of the role of tumor thickness in predicting nodal metastasis in TSCC patients could be resulted in much more control of the disease and as a result much more survival for those patients by revising the TNM suggested treatment plan which could be included in some cases more additional prophylactic procedures and a modified followup regime, so that in cases of large thickness TSCC tumors the treatment plan may include an elective neck dissection or irradiation or at least more close follow-up procedures.[10, 25] The relation between tumor thickness and nodal metastasis in OSCC patients has been explored in many studies. [21, 23, 24] Concerning tongue SCC, most of this studies have evaluated tongue SCC as a part of a sample population based on OSCC patients, and few studies evaluated tongue SCC in particular, so that the relation between tumor thickness and nodal involvement in TSCC patients still need more studying as every subtype of OSCC has its specific characteristics related to tumor nature, clinical behavior, and disease development and prognosis. This aforementioned reason makes the studying of each subtype of OSCC separately an issue of great importance.[20, 25]

Materials And Methods

A prospective study was carried out on patients with initial diagnosis of stage I/II oral tongue SCC who were accepted for treatment at Al Moasat Hospital - Damascus University – in the period between 2016 and 2020. Initially all patients suspected to have Oral Tongue SCC had the routine clinical and radiological examination for tumor diagnosis and staging.

There were forty patients with OTSCC who had met our inclusion criteria and were included in our prospective study sample. All patients included in the study underwent a radiological examination consisted of plain radiographs, sonography, CT scan and -when needed- MRI.

All patients underwent a surgical procedure for tumor excision (partial glossectomy) and an excisional biopsy was obtained and studied by the same pathology lab. The histological grade and the maximum tumor thickness were determined by the pathologist depending on the followed standard histological criteria. Initially we excluded all patients suffering from recurrent or previously treated tumors or suffering from tumor metastasis that had affected the regional nodes or extended beyond it such as patients with distant organs metastasis or patients with end-stage tumors. Patients with predictive factors –other than tumor thickness- that known to influence the incidence of regional lymph nodes metastasis were also excluded of our sample such as patients with T3, T4 tumors, patients with histological grade III tumors, and patients with pathologically confirmed perineural or angiolymphatic vessels invasion because of the high probability of these types of tumors to develop regional lymph node metastasis.

On the other hand, all patients with exophytic type tumors and all cases that had been diagnosed as carcinoma in situ were also excluded because of the low probability of these tumors to develop regional lymph node metastasis.

The study sample was divided into two groups depending on the presence of regional lymph node metastasis:

1-Patients with positive lymph node metastasis (N+).

2-Patients with negative lymph node metastasis (N-).

Also, the study sample was divided into three groups according to the maximum tumor thickness:

1-Group 1: Patients with tumor thickness <3 mm.

2-Group 2: Patients with tumor thickness 3-6 mm.

3-Group 3: Patients with tumor thickness >6 mm.

Regional lymph nodes status was determined depending on either neck dissection and consequent pathological study performed on the surgically obtained nodes specimen or on consequent radiological and pathological findings obtained during the follow-up period. The regional lymph nodes were considered positive (N+) if the pathological result of neck dissection was positive or if there was a new radiologically or pathologically confirmed lymph node metastasis that had occurred during the follow- up period. All patients included in our study were followed–up clinically and radiologically and when needed histologically for a minimum period of 16 months. During the follow-up period all patients suffered from new regional lymph node metastasis were classified in the positive nodal group (N+), on the other hand all patients who did not suffer from new regional lymph node metastasis were classified in the negative nodal group (N-).

When the clinical and radiological and histological examinations were accomplished the TNM staging was established and the standard therapy was offered for all study patients which contained the surgical therapy alone or accompanied by one or more one kind of treatments (radio or chemo therapy).

Statistical analysis was performed using computed program SPSS Statistics software (Ver 23: IBM, Armonk, NY, USA). T-test was used to analyze the difference in tumor thickness values between the two studied nodal groups, with all statistics were considered significant at p value<0.05.

Results

40 patients with stage I/II OTSCC were included in our study (23 male, 17 female) with a mean age 65.3 years (range: 42 - 80 years). All patients underwent a surgical procedure for tumor excision with or without neck dissection and were followed-up for a mean period of 28 months (range:16.- 38 months).

The surgical procedure consisted of partial glossectomy, and the decision of associated neck dissection was taken depending on patient's clinical and histological findings. Neck dissection was performed if there was an evident risk of subclinical nodal involvement such as some large T2 tumors or rapidly growing tumors, on the other hand when there was no evident risk of nodal metastasis neck dissection was not performed and nodes status was determined depending on adjunctive findings obtained during the follow-up procedures.

According to the size of tumor there were 21 patients with T1 tumor (52.5%), and 19 patients with T2 tumor (48.5%). According to the histological grade there were 27 cases of grade I tumors (71%) and 13 cases of grade II tumors (29%).

Regional lymph node metastasis was discovered in 14 patients of our complete sample (35%), 9 cases (22.5 %) of them were discovered histologically after elective neck dissection, and 5 cases (12.5%) were discovered later during the follow-up period. Tumor Thickness in our whole sample ranged between 1 and 14 mm (mean: 6.05 mm), with a range of (2- 14 mm) in the positive lymph nodal group (mean: 8.07 mm), and a range of (1 - 11 mm) in the negative lymph nodal group (mean: 4.96 mm).

The positive lymph nodal group was characterized by higher values of tumor thickness compared with the negative nodal group and the difference in TT values was statistically significant (t-test, p value= 0.006). These results demonstrated that increased tumor thickness values were associated with more incidence of nodal involvement in our OTSCC sample.

Table (1) Nodal status and patients' statistics are illustrated in table 1.

Eleven patients were included in Group 1 of thickness (<3mm), twelve patients in group 2 (3-6mm), and seventeen patients in group 3 (>6mm). Two cases of the 11 patients included in group 1 had regional node metastasis (18.18%), 4 cases in group 2 (33.33%), and 8 cases in group 3 (47.05%). There was a progressive increase in the incidence of regional nodal metastasis from the thinner tumors’ groups to the thicker tumors’ groups which was an expected result because of the aforementioned statistical relation between regional nodal involvement and the increased tumor thickness values.

Table (2) Tumor thickness groups and the related nodal metastasis incidence are illustrated in table 2.

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Table 1:

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Table 1. Nodal status and statistics related to patients’ number and mean tumor thickness.

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Table 2:

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Table 2. Tumor thickness groups and related nodal metastasis incidence.

Discussion

TNM tumor classification system depends on tumor size in determining disease stage and expected prognosis and in establishing the standard treatment plan. [8, 9] Many recent studies have demonstrated the presence of other prognostic factors that influence tumors’ progress in general and oral squamous cell carcinoma in particular such as tumor thickness or tumor depth of invasion, tumor’s histological grade, perineural invasion, and many other risk factors. [21-33]

Tumor thickness is considered an important risk factor for regional lymph node involvement. [21-24] It may be of superior influence when compared with tumor maximum dimension as many recent trials have concluded. [10, 23, 30]

We evaluated in our study the role of tumor thickness (TT) of oral tongue SCC in the incidence of late regional lymph node metastasis by analyzing TT values in both studied nodal groups (positive lymph node metastasis group and negative lymph node metastasis group) and then statistically comparing the tumor thickness values in our two nodal groups.

Also, we analyzed the incidence of regional nodal metastasis in three different ranges of tumor thickness in order to detect the thickness range that is associated with higher probability to develop regional lymph node metastasis.

In order to lessen the misdirection in our study we exclude all cases that is characterized with high or low tendency for nodal involvement such T3, T4 tumors which were excluded due to the high probability of these tumors to develop lymph node metastasis, also we exclude the tumors of histological grade III, tumors with histologically confirmed perineural or Angio vascular invasion and the recurrent tumors for the same aforementioned reason. On the other hand, all cases that were diagnosed as carcinoma in situ or exophytic type cancers were also excluded because of the low incidence of regional nodes involvement in these kinds of tumors.

Ultimately our study sample included 40 patients whose neck were negative in clinical and radiological examination. Tumor thickness in the positive nodal metastasis group ranged between 2 and 14 mm with a mean thickness of 8.96 mm, and between 1 mm and 11 mm in the negative nodal metastasis group with a mean thickness of 4.96 mm. TT values were larger in the positive nodal group with a significant difference as resulted in statistical study (p value=0.006).

These results conducted with our attempt to exclude the known risk factors that may affect regional nodal metastasis make us conclude that thicker tongue tumors have the tendency to develop regional nodal metastasis more than thinner tumors. Regional nodal metastasis occurred in 14 patients of our whole sample (35%). This percentage varies in previous studies on OTSCC patients for many reasons relating to the inclusion criteria of each study and the range of thickness values for their included tumors. In a review of the incidence of late cervical nodal metastasis in these studies, we find that the rate was 14% in the study of Kurokawa, 28.88% in Sparano study, 47.7% in Asakage study, 19.3% in Shin study, and 43% in Yuen study. [31-35] In our study there was a progressive increase in the rate of late regional nodal involvement from groups of lesser thickness to groups of larger thickness. In the group of tumor thickness <3mm there was 18.18% of regional lymph node metastasis, with this percentage increased to 33.33% in the group of thickness 3-6mm and 47.05% in the group>6mm thick. This increase in the nodal metastasis incidence was expected because of the aforementioned statistical relation between regional nodal metastasis incidence and the increased tumor thickness values in our study sample.

Yuen et al had recorded 8% of regional nodal metastasis for tumors’ thickness less than 3mm, 44.6% for tumors of thickness between 3 and 9mm, and 53% for tumors’ thickness >9mm. [35] The thickness range between 3 and 9mm was here large and needed an equal distributions of thickness values to reach the real percentage of metastasis incidence related to this group, because this percentage is affected directly by the prevalent values of thickness whether it is high or low values, in other words if high thickness values are the dominant there will be a bias in results to more incidence of regional node metastasis in this group, and if low thickness values are the dominant there will be a bias in results to less incidence of regional node metastasis in this group. Shin et al had also studied the influence of tumor’s deep of invasion in OTSCC patients and had recorded 7.4% of regional nodal metastasis for tumors DOI of less than 3mm, and 23.2% for tumors DOI of more than 3mm, [34] also here the group (>3mm) was of large range of DOI values and again the nodal metastasis percentage will be affected by the prevalent DOI values of the group whether it is high or low values.

There was an agreement in previous studies that when occult nodal involvement exceeds the percentage 20%, then neck therapy with elective neck dissection or irradiation is indicated. [10, 20, 21] Concerning to tumors of thickness <3mm we have 18.18% nodal involvement, this rate exceeded the critical value of 20% in the thickness group of 3-6mm and the group >6mm with nodal involvement rate 33.33% and 47.05% respectively, and according to these results elective neck dissection or irradiation should be considered for tumors of more than 3 mm thick.

Conclusion

Tumor Thickness is a predictor for regional lymph node metastasis in oral tongue SCC patients. There was a significant incidence of nodal metastasis in OTSCC tumors of more than 3mm thick in comparison with tumors of less 3mm thick.

We recommend –within limits of this study- prophylactic neck dissection or prophylactic neck irradiation and close follow-up procedures for patients with more than 3mm thick oral tongue SCC tumors.

Acknowledgment

Damascus University funded this study.