Squamous cell carcinoma is the commonest pathology of head and neck cancers and represents at least 90% of oral malignancies.1 The World Health Organization expects a worldwide rising oral squamous cell carcinomas incidence in the next decades.2 Most important risk factors including tobacco smoking, alcohol consumption and Human papilloma virus infection (HPV).1, 2, 3 Squamous cell carcinoma of the tongue is one of the most critical issue due to rich vascular and lymphatic supply of the tongue.4 High morbidity is associated regarding speech, swallowing and mastication with subsequent life upset.5, 6
Multiple parameters are responsible for patient survival including tumour thickness, para-lingual distance and metastatic cervical lymph nodes that should be well assessed as an informative prognostic parameters for local recurrence and survival.7, 8, 9, 10 Tongue carcinoma is strongly associated with regional lymph nodes metastases. Therefore, it is crucial to improve cervical lymph nodes management as much as possible.11, 12, 13
Imaging is superior to clinical neck examination for detection of clinically occult subclinical metastatic lymph nodes. The incidence of occult metastases varies from 20% to 50% and represents a big unsolved issue as a clinically negative patient.14, 15, 16, 17, 18 MRI is considered the widespread imaging modality in assessment of carcinoma of the tongue due to its high soft tissue capability and it can define the true extent, loco-regional involvement and tumour depth. The role of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) in differentiation of benign from malignant lesions and grading of malignancies is under investigation.19, 20, 21, 22
In this study, we attempted to detect potential accuracy and cut-off values for MRI tumour thickness and para-lingual distance as well as DWI/ADC values associated with positive cervical lymph nodes spread for better pre-operative evaluation of tongue cancer patients.
The study included 50 patients who were diagnosed as squamous cell carcinoma of the tongue by histopathological examination. The hospital’s ethics committee approved the protocol of the study and all patients enrolled in this study signed the informed consent. The patients underwent MRI examination prior to surgery. MR examinations were performed using a 1.5-T system (Avanto, Siemens, Germany). Head/Neck 20 coil was used. The patient’s head was secured using relaxing cushion; ensuring that the shoulders touch the lower part of the coil. The protocol included axial, sagittal and coronal T1-weighted turbo spin echo (TSE), axial and coronal T2-weighted turbo spin echo (TSE) and gadolinium enhanced axial and coronal T1-weighted sequences with fat suppression (FS) as well as diffusion-weighted (DW) sequences. T1-weighted images were done with the following parameters; TR/TE: 550/18 ms; slice thickness/in-terslice gap: 5/2 mm; mean field of view: 250 mm; slices number: 23; matrix: 320 X 288. T2-weighted turbo spin-echo (TSE) images were done with the following parameters; TR/TE: 4000/41 ms, slice thickness/interslice gap: 5/2 mm; mean field of view: 250 mm; slices number: 23; matrix: 512 X 460. Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA, Magnevist, Schering, Berlin, Germany) was administered intravenously at a rate of 2 mL/s (total dose, 0.1 mmole/kg of body weight) using a power injector, followed by a 20-mL saline flush.
DWI was done by using the spin echo single-shot by using the spin echo single-shot echo-planar sequence. The parameters were as follows: TR/TE of 3200/70 ms, Slice thickness/inter-slice gap: 5/2 mm, mean field of view of 240mm, slices number: 23, matrix of 192X 192. DWI was done with b-values of 500 and 1000 smm-2. Apparent diffusion coefficient (ADC) maps were then automatically generated. As ADC maps suffer from relatively poor resolution, delineation of the tumour is typically performed on T2 or post-contrast (T1)-weighted images and the region of interest (ROI) is then overlaid on ADC maps.
ROIs were measured from the most representable part of the tumour. The tumour thickness, para-lingual distance and ADC values were measured at coronal MR images separately by the two radiologists shared in the study and inter-observer variability was calculated. The tumour depth and para-lingual distance were measured at post contrast T1 coronal FS. The tumour thickness was defined by the distance from the deepest point of invasion to the tumour surface. At first, a vertical line joining the maximum length between tumour-mucosa junctions was drawn as a reference line. The tumour thickness was determined by summation of two lines drawn perpendicular from the reference line to the point of maximum tumour extension. The para-lingual distance was defined as the distance measured between the para-lingual space and the tumour. The patients in whom tumour invasion extended beyond the midline, the para-lingual distances were expressed as a minus (examples of how the representative lines were drawn are shown on Figures 4 and 5).
Descriptive statistics were shown as mean ± SD. The differences between positive and negative nodes metastases groups were detected using two tail Student
This study included 50 patients with proved cancer tongue, their mean age was 61 ± 10 years, 34/50 (68%) were males. They all underwent MRI examination for detection of MR tumour thickness and para-lingual distance; including post-contrast study as well as diffusion-weighted imaging with corresponding measurement of ADC values of tumour tissue. According to tumour site, 42/50 (84%) were in oral tongue, while 8/50 (16%) of patients had tongue base tumour. MRI tumour thickness ranged between 5.5 mm and 43.2 mm (16.62 ± 9.45). Para-lingual distances ranged between -15 and 12.4 mm (3.8 ± 5.15). Regression analysis revealed that tumour thickness had a very strong negative association with para-lingual distance (p-value < 0.001 and R2 = 0.578) (Figure 1). Most of the patients had either T1 stage or T2 stage disease. They were 36/50 (72%) patients who had T1 stage and 12/50 (24%) patients who had T2 stage disease. This is while 2/50 patients (4%) had T3 stage disease. The ADC values for tumour tissue of studied population ranged between 0.724 and 1.310 (0.944 ± 0.124). No significant correlation could be detected between T stage of the tumours and their ADC values (p-value = 0.744). The Kappa value for inter-observer agreement was 0.80 indicating substantial to perfect agreement. The patients (either clinically positive or occult for lymph nodes) were classified according to lymph nodes spread as detected by MRI into two groups Table 1 shows absolute values of the three parameters (tumour thickness, para-lingual distance and ADC value) for patients with (N1) and those without (N0) lymph nodes spread.
Absolute values for TT, PLD and ADC for (N0) and (N1) LN spread
N0 | ||
---|---|---|
TT (mm) | PLD (mm) | ADC |
10 | 9.5 | 0.899 |
8.4 | 5.3 | 0.937 |
15 | 6.7 | 0.815 |
8.7 | 8.9 | 0.953 |
10.1 | 3.8 | 1.051 |
5.5 | 10.5 | 0.875 |
6.2 | 6.6 | 0.988 |
9 | 12 | 0.836 |
13 | 4.7 | 0.864 |
8.5 | 7.2 | 0.955 |
9.8 | 10 | 0.832 |
9 | 7.8 | 0.968 |
12.3 | 6.3 | 0.843 |
7.6 | 9.2 | 0.915 |
10.7 | 4.3 | 1.31 |
6.3 | 10.8 | 0.864 |
6.4 | 6.7 | 0.978 |
9.3 | 12.4 | 0.834 |
9.1 | 7.9 | 0.869 |
10 | 9.5 | 0.899 |
8.4 | 5.3 | 0.937 |
8.7 | 8.9 | 0.953 |
19 | 5.8 | 1.18 |
17.8 | 3.3 | 0.928 |
10 | 4.5 | 1.16 |
15.5 | 0.8 | 0.795 |
13.8 | 2.7 | 0.961 |
18 | 5.6 | 0.793 |
16.9 | 3.1 | 0.874 |
12.3 | 4.7 | 1.17 |
13.7 | 0.5 | 0.778 |
14.8 | 3.7 | 0.959 |
19 | 5.8 | 1.18 |
17.8 | 3.3 | 0.928 |
15 | 6.7 | 0.815 |
13.8 | 4.4 | 0.83 |
35 | -10 | 0.987 |
27.2 | 3.1 | 1.03 |
30 | -5 | 0.976 |
25.6 | 0 | 0.892 |
34 | -8 | 0.984 |
25 | 7 | 1.21 |
23.2 | 3.2 | 1.07 |
29.7 | -3 | 0.938 |
22.8 | 0 | 0.792 |
21.4 | 5.8 | 0.724 |
27.8 | -7 | 0.852 |
23.9 | 0 | 0.897 |
42.7 | -15 | 0.893 |
43.2 | -12 | 1.051 |
The 1st group included those patients with positive MRI nodes metastases (N1); they were 28/50 (56%) patients, of which 23/28 (82%) had unilateral lymph nodes metastases; while 5/28 (18%) had bilateral lymph nodes on both sides of the neck. MRI tumour thickness of this group ranged between 10 mm and 43.2 mm (19.8 ± 8.8). The para-lingual distance ranged between -15 mm and 7 mm (0.9 ± 5.5). The ADC values ranged between 0.724 and 1.212 (0.952 ± 0.112). The 2ndgroup included those patients with negative MRI nodes metastases (N0); they were 22/50 (44%) patients. MRI tumour thickness of this group ranged between 6.2 and 15 mm (9.9 ± 2.6). The para-lingual distance ranged between 3.8 mm and 12 mm (7.2 ± 2.5). The ADC values ranged between 0.793 and 1.161 (0.928 ± 0118). Table 2 shows summary of descriptive statistics for the two groups of the study.
Summary of descriptive statistics for studied population
N | N1 | N0 | P value | |
---|---|---|---|---|
61 ± 10 | 61 ± 11 | 60 ± 9 | 0.794 | |
34/50 (68%) | 20/28 (71%) | 14/22 (64%) | _ | |
16.62 ± 9.45 | 19.8 ± 8.8 | 9.9 ± 2.6 | 0.008* | |
3.8 ± 5.12 | 0.9 ± 5.5 | 7.2 ± 2.5 | 0.003* | |
0.944 ± 0.124 | 0.952 ± 0.112 | 0.928 ± 0.118 | 0.518 |
* = significant p value
Significant differences between the two groups were observed regarding tumour thickness and para-lingual distance (p-values 0.008 and 0.003 respectively) (Figure 2); while ADC values were not significantly different between patients with and without lymph nodes metastases (p-value 0.518). Logistic regression analyses (Table 2) showed that MRI tumour thickness and para-lingual distance were significant strong predictors for positive nodes metastases (p-values < 0.0001, 0.0001 and R2 0.755, 0.697 respectively). This is while ADC value does not seem to be useful for prediction of lymph nodes metastases (p-value = 0.472). ROC curve analyses (Figure 3) revealed cut-off value > 13.8 mm for tumour thickness for prediction of positive nodes metastases; which achieved 72% sensitivity and 88% specificity (AUC = 0.864, p-value = 0.0001 and 95% confidence interval 0.637 to 0.974). For para-lingual distance, the detected cut-off value for prediction of positive nodes metastases was ≤ 3.3 mm, which resulted in best sensitivity (64%) and specificity (89%) (AUC = 0.848, p-value = 0.0002 and 95% confidence interval 0.619 to 0.967). Representative example for T1N0 patient who showed MRI negative lymph nodes spread is shown at (Figure 4) and another T4N1 patient who had MRI positive lymph nodes spread is shown at (Figure 5).
Lymph nodes metastasis in many cancers including head and neck cancers is an important clinically accepted prognostic factor; either reflecting tumour aggressiveness or invasiveness or being an indicator for further tumour dissemination.23
Logistic regression analysis for independent variables predicting LN spread
P value | R2 | Odds Ratio | 95% CI | |
---|---|---|---|---|
0.926 | 0.0005 | 1.004 | 0.917 to 1.099 | |
<0.0001** | 0.755 | 1.756 | 1.075 to 2.866 | |
0.0001** | 0.697 | 0.325 | 0.107 to 0.982 | |
0.472 | 0.023 | 1.003 | 0.995 to 1.015 |
** = highly significant p value; CI: confidence Interval
Therefore; an accurate preoperative assessment of lymph nodes spread is essential to provide an appropriate management strategy for head and neck cancer patients.8 The lymphatic system serves as a primary escape route for cancer. Lymphatic capillaries have a thin discontinuous basement membrane, and contain endothelial gaps that can be invaded by cancer cells. In addition, tumour cells secrete factors that stimulate lymphangiogenesis.24 Cancer cells commonly metastasize through these lymphatic vessels to regional lymph nodes. The presence of metastatic cells in the sentinel lymph nodes is a prognostic indicator for many types of cancer, and the degree of dissemination determines the therapeutic course of action.24
In this study, we found that both tumour thickness and para-lingual distance which measured at pre-treatment MRI were significantly different between patients who had positive versus negative cervical lymph nodes spread. Tumour thickness and para-lingual distance were important predictors for cervical lymph nodes spread in tongue cancer patients in our study. This may be a logic relation which can be easily explained by that with deeper local invasion, tumour cells may come close to deep blood vessels and lymphatics which would carry tumour emboli to regional lymph nodes.25 This relation is supported by that therapeutic strategies which target both tumour -associated blood and lymphatic vessels can lead to a decrease in tumour size and decrease incidence of local/distant spread.24
There are several studies which tested the reliability of MRI in measuring tongue tumour thickness, and correlated it well with histologic tumour thickness.26, 27, 28 Spiro
Recent research is directed at establishing important prognostic pre-operative cut-off values for cancer tongue. Some investigators have attempted to define a cut-off point for oral cavity cancer thickness that correlates well with positive lymph nodes spread.30, 31, 32, 33 Yuen
Multiple pulse sequences had been used in previous works to detect small tongue cancers and accurately identify tumour margins, including T2WI, STIR and T1-weighted fat-suppressed contrast-enhanced sequences. Lam
In this study ADC value does not seem to be an important predictor of metastatic cervical lymph nodes spread. We did not find any significant differences between positive and negative nodes groups regarding tumour ADC values. Curvo-Semedo
Whether ADC values of tumours can be helpful for predicting tumour aggressiveness is a matter of debate that may require further justification. Sun
The preoperative decision of the extent of neck dissection based on ADC value measurements alone might be useless in daily clinical practice. Moreover, it may offer false impression to clinicians about the chance of lymph nodes spread. This is unlike the information derived from simple measurements of tumour dimensions and depth of the primary tumour, which can give more reliable data to take an appropriate management plan decisions.
The limitations of our study include the relative small number of cases pertaining to each group and errors caused by manual measurement of tumour thickness and para-lingual distances. Additionally, artifacts due to tongue motion or dental fillings were a limiting factor and the patients had to be well sedated and in most comfortable position during examination. The inevitable individual difference of manual ADC measurements, ROI size and shape is another limitation, which may result in different outcomes.
Tumour thickness and para-lingual distance are important prognostic factors that motivate the search for metastatic cervical lymph nodes to better tailor pre-operative judgment and management plan of cancer tongue patients. ADC value of the tumour itself is not a reliable index that could be useful in daily clinical practice to pinpoint to the stage of cancer progression. Further long term large scale studies are recommended for assessment of relation between tumour ADC value and anticipated nodes spread in cancers as well as influence upon survival rate.