Clinical application of diffusion-weighted magnetic resonance imaging in radiotherapy for nasopharyngeal carcinoma

Abstract

OBJECTIVE:

To explore the clinical application of diffusion-weighted magnetic resonance imaging (DWI) in nasopharyngeal carcinoma (NPC) diagnosis, detection of lymph node metastasis, radiotherapy and prognosis.

METHODS:

Twenty patients with diagnosed NPC in an early stage of radiotherapy were enrolled in our department between May 2010 and May 2013. T1 and T2 weighted magnetic resonance imaging and DWI of the nasopharynx and neck were performed 1 week before radiotherapy, during radiotherapy at a dose of 60 Gy, and 1 month after radiotherapy. Pertinent measurements and related data were recorded.

RESULTS:

In comparison with that before radiotherapy, the ADC value of the nasopharyngeal primary lesion increased significantly during radiotherapy at a dose of 60 Gy and at 1 month after radiotherapy (F = 187.160, P = 0.000). When the dose of radiotherapy reached 60 Gy, the DWI signals from both the neck and the retropharyngeal lymph nodes were significantly lower than those before radiotherapy.

CONCLUSION:

DWI can be used for sensitive and accurate diagnosis of lymph node metastasis in the neck and retropharyngeal space, monitoring of the radiotherapy effect in early stages of NPC and development of new medical treatment strategies.

Keywords

Magnetic resonance imaging nasopharyngeal cancer radiotherapy

1. Introduction

Nasopharyng1eal carcinoma (NPC) is a malignant cancer that occurs at the top of the nasopharyngeal cavity and the lateral walls. NPC is a high-risk malignant tumor that has the highest incidence rate amongst malignant head and neck tumors in China. Because of its unique biological characteristics, radiotherapy-based comprehensive treatment is the current standard treatment for patients with NPC. Accurate determination of the extent of NPC invasion and lymph node metastasis and evaluation of therapeutic efficacy are key factors for individualized therapy. Recently, functional imaging techniques, especially 18F-FDG PET/CT, have drawn much attention for the detection of primary tumors and lymph node metastasis, therapeutic monitoring and prognosis in NPC. Although 18F-FDG PET/CT is a highly sensitive imaging method to detect lymph node metastasis and to predict therapeutic efficacy in NPCs [1], the clinical application of functional PET/CT has been greatly restricted due to high cost, limited resources, radiation, and false positive and false negative results. With the development of imaging technologies, magnetic resonance imaging (MRI) has played a key role in tumor diagnosis, treatment and prognosis determination. The MRI technique diffusion-weighted imaging (DWI) is the only non-invasive method that can detect the diffusion of water molecules in living tissues. It can also be used to determine restrictions in water motion in tissues and lesions, and it indirectly reports on biological information such as cell density and tissue structures. Relevant studies have shown that DWI-MRI can detect early pathological changes in diseased tissues [2 –4].

Through measurement of the apparent diffusion coefficient (ADC) of the lesions, DWI-MRI can be used in quantitative diagnosis and assessment for tumorous lesions, and it provides a new sensitive approach to determine the prognosis of cancer patients [5, 6]. In our previous studies, we have found that ADC values are useful in differential diagnosis among residual tumor, fibrotic plaque formation and tumor recurrence after radiotherapy for NPC [7]. However, to date, the dynamic changes and clinical merits of ADC measurement during radiotherapy in NPC remain unclear. In this paper, the DWI-MRI technique was used to monitor the dynamic changes in ADC values. Furthermore, we investigated the potential clinical application of DWI in the diagnosis of NPC, detection of lymph node metastasis and evaluation of therapeutic efficacy.

2. Materials and methods

2.1. Clinical data

20 patients, including 16 males and four females 17–67 years of age, with a median age of 46 years, were admitted to our department between May 2010 and May 2013. These patients were diagnosed on the basis of the examination of the electronic nasopharyngoscopy and biopsy before the radiation treatment. All patients underwent regular MRI and DWI scans before radiotherapy.

These patients were categorized in 4 T stages namely, T1 includes 2 cases, T2 has 7 cases, T3 has 8 cases, and T4 includes 3 cases, respectively. According to NCCN (National Comprehensive Cancer Network Guidelines) recommendations: Patients with T1, N0, M0 nasopharyngeal tumors were treated with definitive radiotherapy alone, and locoregionally advanced NPC patients (T1, N1–3; T2–T4, any N) were treated with concurrent chemo-radiotherapy followed by adjuvant chemotherapy.

2.2. Equipment and MRI scanning method

A superconducting magnetic resonance scanner (3.0 T Signa HDxt, GE, USA) and a head coil were used. All patients underwent conventional plain axis T1WI and T2WI scanning, coronal fat suppression T2WI scanning and axial DWI scanning. The scan range was from the skull base to the clavicle. The parameters were as follows: T1WI: TR 660 ms, TE 8 ms; T2WI: TR3 600 ms, TE 87 ms. Thickness/layer spacing: 3 mm/1.0 mm, number of excitations: two, matrix 384×256. DWI scan parameters: TE: 75 ms; TR: 5600 ms; FOV: 22.00 cm×22.00 cm; layer thickness/layer distance = 3 mm/1 mm; matrix: 160×160; b value = 0, 1000 s/mm²; single shot. Owing to the complex anatomy of the skull base, images in DWI are likely to have magnetic sensitivity artifacts. During the scan, an oil pillow was used under the patient’s neck to increase the local magnetic field uniformity and reduce image distortion.

2.3. Image analysis and ADC measurements

The resulting DWI images were automatically analyzed and processed in the Functool 2 software of the GE ADW 4.4 workstation. Data measurement was independently performed by a senior radiologist. During the measurement, the necrotic lesions were avoided as much as possible by using the regular MRI images as a reference. The region of interest where the solid part was located was selected to be as large as possible and was not less than half of the maximum area of the target lesion. The values of the lateral pterygoid were selected and averaged. If one side of the lateral pterygoid was invaded, only the normal side of the lateral pterygoid was selected. The longest and shortest diameters of lymph nodes were measured in axial T2WI fat-suppressed images. The longest diameter was defined as the longest diameter of the lymph nodes displayed in the axial images, and the shortest diameter was defined as the longest path of the lymph nodes perpendicular to the longest diameter in the axial images.

2.4. Characteristics of extracapsular invasion of lymph nodes in this study

The characteristics of extracapsular invasion of lymph nodes were as follows: coarse and uneven rough margins at the lymph nodes; enhanced irregular lymph nodes; blurriness or absence of fat around the lymph nodes; and mutually fused lymph nodes with adjacent tissue matrix.

2.5. Statistical methods

SPSS 13.0 statistical analysis software was used for the statistical analysis. ADC values are shown as $\bar{x}$ ±s. T-test and ANOVA were used for comparisons between groups, and P < 0.05 was considered statistically significant.

3. Results

3.1. The diagnostic value of DWI in nasopharyngeal carcinoma primary lesions

The 20 patients in the nasopharyngeal primary lesion group were diagnosed on the basis of the examination of the electronic nasopharyngoscopy and biopsy before the radiation treatment. This group included 19 cases of keratinizing squamous cell carcinoma and one case of non-keratinized carcinoma. The nasopharyngeal regions of the 20 patients showed soft tissue masses in the regular MRI scans, and the lesions showed abnormally high signals in the DWI scans, with ADC value (0.775±0.060)×10^-3 mm²/s, which was significantly lower than the ADC value ((1.459±0.089)×10^–3 mm²/s) of the normal lateral pterygoid (Table 1). These results indicated that the ADC value of nasopharyngeal tumor tissue has an auxiliary diagnostic value for NPC.

Table 1
Changes in ADC values of primary and lateral pterygoid of NPC before radiotherapy, radiation at a dose of 60 Gy and 1 month after radiotherapy

ADC (×10^-3mm²/s)

Group Primary $\bar{x}$ ±S.D. (Range) Lateral pterygoid $\bar{x}$ ±S.D. (Range)

Before radiotherapy 0.775±0.060 (0.680–0.890) 1.459±0.089 (1.300–1.620)

Radiation at 60 Gy 1.735±0.21 (1.140–1.970) 1.475±0.097 (1.300–1.650)

1 month after radiotherapy 1.837±0.220 (1.210–2.260) 1.468±0.096 (1.300–1.670)

P value 0.000 0.866

F value 187.163 0.144

	ADC (×10^-3mm²/s)
Before radiotherapy	0.775±0.060 (0.680–0.890)	1.459±0.089 (1.300–1.620)
Radiation at 60 Gy	1.735±0.21 (1.140–1.970)	1.475±0.097 (1.300–1.650)
1 month after radiotherapy	1.837±0.220 (1.210–2.260)	1.468±0.096 (1.300–1.670)
P value	0.000	0.866
F value	187.163	0.144

Comparison of before radiotherapy with radiation at a dose of 60 Gy and 1 month after radiotherapy, P < 0.05; comparison of radiation at a dose of 60 Gy with 1 month after radiotherapy, P > 0.05.

3.2. The value of DWI scan in detection of lymph nodes metastasis in the neck and retropharyngeal space

The 20 patients had routine MRI and DWI scans of the neck and nasopharynx before treatment. Ninety-seven lymph nodes with abnormally high signals were found in DWI scanning in conjunction with T1WI and T2WI MRI. There were 21 cases with the shortest diameter <10.0 mm, 46 cases with the shortest diameter 10 to <20 mm, 18 cases with the shortest diameter 20 to <30 mm, and 12 cases with the shortest diameter≥30 mm. The ADC values of the four lymph node groups were not significantly different from those of the nasopharyngeal primary lesions. The respective t and P values were t = 0.607, P = 0.547; t = 1.727, P = 0.089; t = 2.054, P = 0.148; and t = 1.297, P = 0.205 (Table 2).

Table 2
Comparison of ADC values between primary NPC and lymph nodes in DMI-MR

ADC value (×10^-3mm²/s) t value P value

Group Range Mean

Primary lesion 0.680–0.890 0.775±0.060

Lymph nodes <10 mm 0.570–0.900 0.788±0.75 0.607 0.547

10 to <20 mm 0.640–0.970 0.742±0.070 1.727 0.089

20 to <30 mm 0.630–0.880 0.752±0.065 2.054 0.148

≥30 mm 0.630–0.860 0.741±0.080 1.297 0.205

		ADC value (×10^-3mm²/s)	t value	P value
Primary lesion	0.680–0.890	0.775±0.060
Lymph nodes	<10 mm	0.570–0.900	0.788±0.75	0.607	0.547
	10 to <20 mm	0.640–0.970	0.742±0.070	1.727	0.089
	20 to <30 mm	0.630–0.880	0.752±0.065	2.054	0.148
	≥30 mm	0.630–0.860	0.741±0.080	1.297	0.205

3.3. The value of DWI in therapy monitoring and prognosis determination

To further evaluate the importance of ADC in evaluating the therapeutic efficacy of NPC treatment, we monitored the dynamic changes in ADC values before radiotherapy, during radiotherapy at a dose of 60 Gy and 1 month after radiotherapy for primary nasopharyngeal lesions and lymph node metastasis. When radiotherapy (radiotherapy or a combination of radiotherapy and chemotherapy) was performed at a dose of 60 Gy, regular MRI examination of the nasopharyngeal site showed that the nasopharyngeal primary lesion had decreased to varying extent after radiotherapy. In addition, DWI scanning showed normal or unevenly high signals. After measurement of ADC values in conjunction with regular MRI as the reference, we found that the mean value of ADC had increased by 124% after radiotherapy. One month after radiotherapy, the follow-up examination showed that the mean value of ADC in the radiotherapy area for nasopharyngeal primary lesions was slightly higher than that during radiotherapy at the dose of 60 Gy. In one case, the patient’s ADC value was not significantly higher at the radiation dose of 60 Gy in comparison with that after radiotherapy.

During the follow-up visit, this patient was diagnosed with multiple liver metastases at five months after the end of radiotherapy and a single metastatic lesion occurred in the brain 8 months after radiotherapy. In all patients, the ADC values of the lateral pterygoid were not significantly different in the three therapeutic stages (F = 0.144, P = 0.866; Table 1). These results indicated that radiotherapy did not affect the ADC values of normal human tissues. The regular MRI and DWI scans of the nasopharyngeal and neck regions were performed to examine patients treated with radiotherapy at a dose of 60 Gy.

The results indicated four lymph node groups in the neck and retropharyngeal space with high signal intensity in DWI before radiotherapy: 21 cases with the shortest diameter <10 mm, 46 cases with the shortest diameter 10 to <20.00 mm, 18 cases with the shortest diameter 20.00 to <30.00 mm, and 12 cases with the shortest diameter≥30.00 mm. The disappearance rates of lymph nodes metastasis were 100%, 100%, 95% and 90%, respectively. The lymph nodes appearing in DWI scans showed significantly lower signal than that before radiotherapy. These results suggested that during the dynamic monitoring process of the ADC value, a marginal increase in the ADC value or a decrease in the ADC value may indicate a residual tumor, which poses a high risk of cancer recurrence and metastasis.

4. Discussion

The main approach used for NPC diagnosis is electronic nasopharyngoscopy and histopathological examination. Because of its good soft tissue resolution and multi-dimensional imaging, MRI has substantial advantages in diagnosis, staging, radiotherapy design, therapeutic evaluation and prognosis determination for NPC; it has consequently become a favorable imaging method for NPC [8 –14]. DWI is currently the only non-invasive imaging method for the detection of microscopic movement of water molecules in living tissue [15, 16]. It can detect early changes in morphology and physiology associated with alterations in tissue water content. Additionally, DWI indicates the composition of the tumor cells and changes in the integrity of the cell membrane. MRI has high sensitivity and specificity for the diagnosis of malignant and benign tumors, as well as malignant lymph node metastasis [17 –21]. MRI can be used to monitor therapeutic efficacy in early stages of cancer [22 –27].

The 20 patients in this group were staged according to the 8th edition (2017) of the AJCC (The American Joint Committee on Cancer) staging standard: T staging: T1 (2 cases), T2 (7 cases), T3 (8 cases), T4 (3 cases); clinical staging: II stage (3 cases), III stage (12 cases), IVa (5 cases). DWI scans of the 20 patients indicated that the nasopharyngeal primary lesions showed significantly abnormal signals, according to the black background signal. The lowest ADC value was 0.680×10^-3 mm²/s, and the highest was 0.890×10^-3 mm²/s (Fig. 1).

Fig.1

Patient before radiotherapy: (A). T2WI had larger soft tissue shadows on the left nasopharynx, (B). Abnormally high signal on DWI (arrows); the ADC value was 0.713×10^-3 mm²/s. Biopsy pathology confirmed (on the left side of the nasopharynx) poorly differentiated squamous cell carcinoma.

A total of 97 lymph nodes with abnormally high signals were found in DWI scans before radiotherapy in this study. The smallest size was 4.60 mm×3.90 mm, with an ADC value of 0.829×10^-3 mm²/s. The largest size was 35.80 mm×27.60 mm, with an ADC value of 0.864×10^-3 mm²/s. One case was diagnosed with highly noticeable necrosis with a size of 13.60 mm×8.50 mm, with an ADC value of 1.090×10^-3 mm²/s. The ADC values in the extracapsular invasion and necrosis free groups were lower than those in the extracapsular invasion group (Table 3). The reason for this finding was that the growth density of the cells in the former groups were higher than that in the latter group, and the diffusion condition in the former groups was lower than that in the latter group.

Table 3

Comparison of ADC values in primary lesions of NPC and extracapsular invasion and necrotic lymph nodes, and non-extracapsular invasion and non-necrotic lymph nodes

	ADC value (×10^-3mm²/3)
Group	Range	Mean	F value	P value
Primary lesion	0.680–0.890	0.775±0.060	2.579	0.080
Extracapsular invasion and necrotic lymph nodes	0.630–1.090	0.770±0.833
Non-extracapsular invasion and non-necrotic lymph nodes	0.570–0.970	0.738±0.070

One-way ANOVA P > 0.05.

In this study, we found no significant differences in the ADC values between the nasopharyngeal primary lesions and the lymph nodes with abnormally high signal intensity in DWI, regardless of lymph node size, extracapsular invasion or necrosis conditions. These results indicate similarities in biological behaviors, structural features and the diffusion of water molecules between primary and metastatic lesions, in agreement with the basic principles of DWI imaging and the factors affecting ADC value. DWI imaging and ADC values are related only to the cell density of malignant tumors. The vigorous proliferation of malignant tumor cells results in a high cell density, which is reflected by a low ADC value and a high DWI signal. In contrast, the imaging results and measured ADC values are not associated with tumor characteristics such as size, shape, primary lesion or metastatic lesion.

Furthermore, DWI can allow for semi-quantitative analysis of lesions through the measurement of ADC values, and it can distinguish the presence and absence of necrotic status of tumors. Proliferating tumor tissue is seen as a clear high signal on a black background, whereas necrotic tumor tissue is seen as a low signal on a high background signal. The results of this study provide a new approach for diagnosing metastasis according to lymph node size and morphology, conditions of extracapsular invasion and tumor necrosis, which are mainly evaluated with CT and regular MRI at present. Owing to the background body signal suppression in DWI, the signals from muscle, fat, blood vessels, and most tissues and organs are suppressed and present low signals, whereas lymph node lesions show a distinctly high signal on a dark background; moreover, smaller lymph nodes can be detected sensitively and seen clearly. This method facilitates quantitative analysis of lesions and diagnosis of tumor positions through merging images with regular T2 and T2 MRI images.

When the radiotherapy reached a dose of 60 Gy, nasopharyngeal primary lesions disappeared in one of the 20 patients, and ADC values were not measurable. The nasopharyngeal tumors of the remaining 19 patients decreased in size to various degrees. The DWI showed unevenly high signals or normal signals with ADC values ranging from 1.14 to 1.97×10^-3 mm²/s. The ADC values were significantly higher than those before radiotherapy (Fig. 2). One month after radiotherapy, the follow-up examination indicated that the nasopharyngeal tissues of these 19 patients still showed soft tissue masses or thickened nasopharyngeal walls, with ADC values ranging from 1.210×10^-3 mm²/s to 2.260×10^-3 mm²/s. In comparison with values during the radiation at a dose of 60 Gy, the ADC values 1 month after radiotherapy did not differ significantly (Fig. 3).

Fig.2

The same patient during radiotherapy at a dose of 60 Gy: (A). T2WI; the left nasopharyngeal soft tissue shadow was significantly smaller than that before radiotherapy. (B). DWI showed an unevenly high signal (arrow). The ADC value was 1.89×10^-3 mm²/s.

Fig.3

The same patient 1 month after radiotherapy: (A): T2WI; the left nasopharyngeal soft tissue shadow was similar to that during radiotherapy at a dose of 60 Gy; (B): The signal in DWI returned to normal level (arrow). The ADC value was 1.94×10^-3 mm²/s.

The pathophysiological process analysis indicated that an effective anti-cancer treatment in the initial stage led to shrinkage of the tumor volume, loss of cell membrane integrity, necrosis and lysis of tumor cells, and increased extracellular space, all of which resulted in enhanced diffusion of water molecules and correspondingly elevated ADC values. After the end of treatment with radiotherapy at a dose of 60 Gy, the tumor cells had almost completely disappeared, and the necrosis and lysis of tumor cells gradually ceased. Some smaller tumors completely disappeared. In large tumor tissues, the radiation resulted in both tumor cell necrosis and blood vessel damage. The originally large tumor tissues gradually developed mature fiber hyperplasia or scar formation, thus leading to nearly unchanged ADC values. Furthermore, the small lymph nodes in the neck and parapharyngeal space subsided after radiotherapy up to 60 Gy, and the larger lymph nodes were significantly smaller in T1WI and T2WI than they were before radiotherapy, with normal DWI signals.

For one patient, The ADC value of the nasopharyngeal primary lesion was 0.732×10^-3 mm²/s before radiotherapy. When radiotherapy reached a dose of 60 Gy, the nasopharyngeal lesion showed unsatisfactory shrinkage. The DWI showed unevenly high signal with an ADC value of 1.140×10^-3 mm²/s. In the follow-up examination at 1 month after radiotherapy, the nasopharyngeal lesion appeared generally similar to that in radiotherapy at the dose of 60 Gy. The ADC value was 1.210×10^-3 mm²/s, which was significantly lower than the ADC value of the lateral pterygoid. In the follow-up visit, the changes in the nasopharyngeal primary lesion were not significantly different between 1 month and 3 months after radiotherapy. The patient was then diagnosed with a nasopharyngeal residual tumor through a combination of regular MRI and biopsy. The patient was diagnosed with multiple liver metastases 5 months after radiotherapy, and a single brain metastasis 8 months after radiotherapy. Of the remaining 19 patients, during radiotherapy at a dose of 60 Gy through 1 month after radiotherapy, 18 patients had nasopharyngeal soft tissue masses or thickened nasopharyngeal walls. However, the ADC values were higher than those in the lateral pterygoid. No recurrence or metastasis was found in the 19 cases in the follow-up visits. We suggest that if the ADC value does not increase significantly or decrease after the treatment, it may indicate residual tumors, which pose a high risk of tumor recurrence and metastasis. Therefore, follow-up visits should be performed.

5. Conclusion

In summary, this study revealed that MRI can play an important role in NPC diagnosis, radiotherapy, evaluation of lymph node metastasis, monitoring the therapeutic effects of radiotherapy and determining prognosis. Regular T1WI and T2WI MRI can clearly reveal the local morphological manifestations of the tumor before, during and after radiotherapy, and DWI can identify changes in the biological activities of tumor tissues at the molecular level. It is a comprehensive evaluation method combining the assessment of both biological activities and tumor size by imaging, and it may revolutionize the commonly accepted method of using changes in tumor size change as an evaluation criterion. For patients with disappearance of incomplete original nasopharyngeal lesions or with abnormal soft tissue shadows after radiotherapy, if the ADC value of the lesion is higher than that at the lateral pterygoid, the tumor can be considered to have been eliminated. Even if there are local residual tumors, the residual tumor metabolism is in a suppressive state, thus leading to a low recurrence and metastasis rate. Thus, patients can achieve considerably longer survival times. For patients with moderate increases in ADC value after therapy, and a lower signal than that in the lateral pterygoid, even if the volume of the tumor significantly shrinks after radiotherapy, the residual tumor may have a high proliferation rate and insensitivity to subsequent treatments. Therefore, the prognosis may be poor. Owing to the small number of cases and the short follow-up period in this study, our conclusions will be further validated during the patients’ follow-up visits. Additional studies are needed to confirm the relationship between ADC values and tumor metastasis and prognosis after treatments.

Footnotes

Acknowledgments

The authors thank Dr. Zhuting Tong (Anhui Medical University, China) for his valuable comments and extensive edit for the manuscript. The authors also thank International Science Editing () for its linguistic assistance during the preparation of this manuscript.

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	ADC (×10^-3mm²/s)
Group	Primary $\bar{x}$ ±S.D. (Range)	Lateral pterygoid $\bar{x}$ ±S.D. (Range)
Before radiotherapy	0.775±0.060 (0.680–0.890)	1.459±0.089 (1.300–1.620)
Radiation at 60 Gy	1.735±0.21 (1.140–1.970)	1.475±0.097 (1.300–1.650)
1 month after radiotherapy	1.837±0.220 (1.210–2.260)	1.468±0.096 (1.300–1.670)
P value	0.000	0.866
F value	187.163	0.144