1. Introduction
Three to six percent of tumors within the head and neck arise in the salivary glands [
1], the majority within the parotid glands. Up to 80% of tumors within the parotids are benign with the two most common types being Warthin tumors (WTs) and pleomorphic adenomas (PAs). Despite both being benign lesions, they present with different clinical course if left untreated. Malignant transformation is reported in 1.9–23.3% of untreated PAs, whereas it is less than 1% for WTs [
1,
2]. Thus, WTs can be surveilled if asymptomatic, while surgery is a method of treatment for pleomorphic adenomas. The aim of surgery is to obtain a complete resection with clear histopathological margins, as recurrence rate after enucleation in up to 50% [
2,
3]. Additionally, special attention should be given to lesions within the deep lobe as they are not only difficult to diagnose in cytology due to accessibility issues but also demand special caution during operation in order to preserve surrounding structures, especially facial nerves. Hence, a precise pre-treatment diagnosis is essential.
Reported overall sensitivity of salivary gland fine needle aspiration cytology (FNAC), which usually serves as a first-line diagnostic procedure, ranges from 86% to 100%, with specificity from 90% to 100% [
4]. Sensitivity and specificity of FNAC, however, depend on technical experience of both person performing the biopsy and the evaluating pathologist, quality of cytologic preparations, morphological heterogeneity of the lesions, presence of cystic components and lesion location (with limited access when the lesion is in the deep lobe) [
4].
Multiparametric magnetic resonance imaging (mpMRI) gains recognition in the diagnostic algorithm of salivary gland tumors, providing data from different diffusion-weighted imaging (DWI) models and dynamic contrast enhanced sequences (DCE-MRI) [
5,
6,
7,
8,
9]. Diffusion-weighted imaging reflects the cell density of the tissue. The most used quantitative parameter of DWI, apparent diffusion coefficient (ADC), relates to the microscopic diffusion of the water molecules and is assessed in a mono-exponential model; its role seems to be well established in radiological clinical practice [
5]. The intravoxel incoherent motion (IVIM) model proposed by LeBihan separates the perfusion-related parameters (pseudo-diffusion coefficient D* and perfusion fraction FP) and the diffusion-related parameters (pure diffusion coefficient D) by employing a bi-exponential analysis [
10,
11,
12]. Previous studies proved the utility of IVIM in head and neck tumors’ differentiation [
13,
14,
15,
16,
17,
18], evaluating lymph nodes [
19,
20,
21,
22], monitoring outcome and/or treatment response [
23,
24], in the assessment of radiation-induced changes [
25], and evaluating inflammatory processes, such as Sjögren’s syndrome [
26,
27]. Additionally, the potential role of IVIM analysis in parotid gland oncology seems to be increasing [
5]. Semi-quantitative analysis of the contrast enhancement pattern in DCE-MRI reflected as time intensity curves is widely employed in salivary gland tumor differentiation [
5,
28]. The utility of quantitative data derived from DCE-MRI such as Ktrans (transfer constant), Kep (reflux constant), Ve (extra-vascular extra-cellular volume fraction), and iAUC (initial area under curve in 60 s) is now under ongoing research [
29,
30,
31,
32,
33].
The aim of this prospective study is to identify quantitative IVIM and DCE-MRI parameters of the most frequent benign parotid tumors and compare the utility and diagnostic accuracy of those parameters. We believe that assessment of well-established features such as ADC values and time intensity curves together with novel quantitative parameters derived from IVIM and DCE-MRI will reveal tumor biology and hence provide significant information on tumor characteristics.
3. Results
ICCs of tumor derived features presented with excellent inter-rater reliability except for D*—good agreement;
p value < 0.001—
Table 3.
Values of magnetic resonance derived features of the most common benign parotid gland tumors and of contralateral healthy parotid parenchyma are gathered in
Table 4. The ADC values of WTs were significantly lower than that of PAs. Pleomorphic adenomas showed significantly higher D and Ve values than Warthin tumors (
p < 0.001). D* values and Kep values of Warthin tumors were significantly higher than that of PAs (
p < 0.001).
Kruskal–Wallis test for independent samples proved that statistically significant (
p < 0.001) inter-group differences exist between PAs and WTs in all tested parameters but iAUC, pleomorphic adenomas differ from healthy parotid gland in all aspects while the values of D* and FP of Warthin tumors and healthy parotid glands are very similar—
Table 5. The significance level was obtained at 0.05.
ROC curves were constructed to determine the optimal cut-off levels of the most significant parameters allowing differentiation between WT and PA—
Figure 1. The area under the curve (AUC) values and thresholds were for ADC: 0.931 and 1.05, D: 0.896 and 0.9, Kep: 0.964 and 1.1 and Ve: 0.939 and 0.299, respectively.
Lesions presenting with combination of ADC, D, and Ve values superior to the cut-off and Kep values inferior to the cut-off are classified as pleomorphic adenomas. A representative case of PA is presented in
Figure 2.
Lesions presenting with combination of ADC, D, Ve values inferior to the cut-off and Kep values superior to the cut-off are classified as Warthin tumors.
Figure 3 highlights the imaging features of WTs.
AUC for the rest of analyzed features presented as follows: Ktrans 0.692, D* 0.763, FP 0.773 and iAUC 0.576. The correlation between the area under the ROC curve and diagnostic accuracy is interpreted as 0.9–1.0 excellent, 0.8–0.9 very good, 0.7–0.8 good, 0.6–0.7 sufficient, 0.5–0.6 bad, respectively; with a value less than 0.5 representing that the test is not useful. Due to bad diagnostic accuracy value of AUC for the iAUC further analysis was not performed for that selected parameter.
Lesions presenting with combination of ADC, D, and Ve values superior to cut-off and Kep values inferior to cut-off are classified as pleomorphic adenomas.
Lesions presenting with combination of ADC, D, and Ve values inferior to cut-off and Kep values superior to cut-off are classified as Warthin tumors.
Diagnostic accuracy of IVIM- and DCE-derived parameters are shown in
Table 6.
When a combination of parameters (ADC, Kep and D) underwent analysis, we obtained diagnostic accuracy of 94.8% (95%CI 85.59–98.91), sensitivity of 92.59% (95%CI 75.71–99.09), specificity of 96.77% (95%CI 83.30–99,92), PPV 96.22% (95%CI 78.49–98.25) and NPV of 93.64% (95%CI 79.49–98.25).
Diagnostic accuracy increased to 96.55% (95%CI 88.09–99.58) when we analyzed a combination of ADC, Kep and D*; sensitivity—96.30% (95%CI 81.03–99.91), specificity—96.77% (95%CI 83.30–99.92), PPV 96.36% (95%CI 79.36–99.45) and NPV of 96.72% (95%CI 81.13–99.51).
However, we did not observe a further increase in diagnostic accuracy after including the fourth parameter (Ve) in the analysis. Accuracy in fact dropped to 91.33% (95%CI 80.95–97.11%) with sensitivity of 85.19% (95%CI 66.27–95.81), specificity of 96.77% (95%CI 83.30–99.92), PPV 95.90% (95%CI 77.19–99.39) and NPV of 88.05% (95%CI 74.84–94.80).
4. Discussion
Characterization of parotid focal lesions is crucial, as treatment differs accordingly to histopathological type of the tumor. Clinical findings provide limited information and FNAC is not always conclusive. Thus, pre-operative magnetic resonance imaging gains recognition in a pre-treatment diagnostic algorithm. Interpreted in conjunction with conventional morphological sequences, dynamic contrast-enhanced MRI and diffusion-weighted MRI have high potential for the characterization of parotid tumors [
37], according to research comparable to that of FNAC [
7,
38]. Nowadays, novel advanced DWI analysis techniques are under ongoing research with the aim to identify characteristic features of different histopathological types of parotid tumors in order to further increase diagnostic accuracy [
39]. In our study DWI, IVIM and quantitative analysis of DCE-MRI derived parameters demonstrated distinctive features of pleomorphic adenomas and Warthin tumors as confirmed with a Kruskal–Wallis test for independent samples. The test proved that statistically significant (
p < 0.001) inter-group differences exist between pleomorphic adenomas and Warthin tumors in all tested parameters but iAUC.
Pleomorphic adenomas presented with mean ADC value of 1.32 × 10
−3 mm
2/s which is in concordance to previous studies reporting a cut-off ADC value between 1.267 × 10
−3 mm
2/s and 1.60 × 10
−3 mm
2/s [
40,
41]. The ADC values of Warthin tumors were significantly lower than that of PAs. In our study the ADC cut-off value distinguishing between WTs and PAs was established at the level of 1.05 × 10
−3 mm
2/s (AUC 0.931) with diagnostic accuracy of 94.8%, sensitivity 88.9%, specificity 100%, PPV 100% and NPV 91%. A similar ADC value was obtained by Nada et al. with a cut-off 1.16 ± 0.31 (SD) × 10
−3 mm
2/s [
42].
IVIM, allowing separate evaluation of perfusion and diffusion-related features of salivary gland tumors, may help discriminate parotid gland tumors with good and excellent accuracy. Warthin tumors presented with significantly lower D values than pleomorphic adenomas with a threshold value equal or less than 0.9 × 10
−3 mm
2/s. Previously, Sumi et al. [
43] in their prospective study including 12 pleomorphic adenomas and 8 Warthin tumors evaluated the D cut-off value at the level of 1.1 × 10
−3 mm
2/s allowing differentiation of WT from PAs with 100% accuracy, specificity and sensitivity. As the authors imply these results may be attributed to large areas of densely packed small lymphocytes in Warthin tumors, which greatly limit pure diffusion. D* values of WTs were significantly higher than in case of PAs. D* reflects tumor vascularity being proportional to the average blood velocity and mean capillary segment length [
8].
The role of quantitative parameters of DCE-MRI reflecting the microvascular density of the lesion is less studied than IVIM. Warthin tumors showed significantly higher Kep values than pleomorphic adenomas (the median value was 2.49 min
−1). This is in concordance with results obtained by Yabuuchi et al. [
30] In their study on the added value of permeability imaging Kep, representing a rate constant between the extravascular space and the blood plasma, proved to be the only significant feature derived from DCE-MRI. Further the authors interpolated the results on TIC pattern, speculating that high Kep values correspond to a high wash-out rate, typically seen in case of WTs [
30]. Additionally, in our study 93.5% (29 tumors out of 31 total WTs) of Warthin tumors showed a type B time intensity curve, characterized by an early enhancement (T
peak prior to 120 s) and high washout pattern (WR over 30% at 5 min). In addition, the Ve values of WTs was significantly lower that than of pleomorphic adenomas. Taking that into consideration, we agree with Yabuuchi et al. that further analysis of Kep and Ve parameters may prove them feasible for precise evaluation of the contrast agent movement between extravascular extracellular space and blood pool [
28]. Furthermore, in the light of recent research by Xu et al., Ve seems to have a discriminative potential between benign and malignant lesions [
39].
The ROC analysis allowed us to propose the following thresholds allowing to differentiate WTs from PAs: ADC 1.05 (AUC 0.931), D 0.9 (AUC 0.896), Kep 1.1 (AUC 0.964) and Ve 0.299 (AUC 0.939). Lesions presenting with combination of ADC, D, and Ve values superior to the cut-off and Kep values inferior to the cut-off are classified as pleomorphic adenomas. Lesions presenting with combination of ADC, D, and Ve values inferior to the cut-off and Kep values superior to the cut-off are classified as Warthin tumors.
Similarly to Patella et al. [
33], we found that a combination of analyzed parameters increases diagnostic accuracy and its indices, however the optimal combination included no more than three features (with the best values obtained with ADC, Kep and D or ADC, Kep and D*).
The authors are aware of the following limitations. Firstly, it was a single-center study. Secondly, the sample size calculation has not been conducted as we recruited all consecutive patients within certain time period about inclusion and exclusion criteria. Additionally, due to a small number of lesions as well as group heterogeneity malignant lesions needed to be excluded from the study. However, we are now collecting cases for a validation study and researching parotid malignancies. At this point we have not yet analyzed different histopathological subgroups of PAs and WTs; however, as this study is a part of an ongoing prospective research, we will hopefully be able to investigate if and at to what extend the analyzed features may be dependent on pathological subtype of the tumor.