Whole body diffusion-weighted MRI in detection of metastasis and lymphoma: a prospective longitudinal clinical study

Whole-body diffusion-weighted magnetic resonance imaging (WB-DWI-MRI) is an emerging tool that has an increasing role in the diagnosis of metastasis and lymphoma. This is a longitudinal study in actual clinical settings designed to assess WB-DWI-MRI in detection of tumor spread. The study included all patients who were referred to Radiology Department, during the period from June 2016 till May 2018, with either a known primary tumor (either laboratory, radiologically, or histologically proven, of any type, affecting any organ) or with biopsy-proven lymphoma of any subtype, affecting any organ. All patients underwent WB coronal T1-weighted, STIR, axial T2-weighted, and DWI-MRI examinations before commencing any treatment with curative intent. The body was divided into lymph nodes (LNs), skeletal system, and organs (brain, lung, and liver). Patients were followed up till the nature of the lesion(s) was confirmed (clinically, radiologically, or histologically). The study included 46 patients; 27 patients had metastases and 19 had lymphomas. Sensitivities, specificities, and accuracies for LN detection were 77%, 85%, and 83%; for skeletal metastasis were 88%, 94%, and 92%; for brain lesions were 78%, 95%, and 91%; and for lung lesion were 64%, 88%, and 76%, respectively. As for the liver, all lesions were correctly identified and did not miss any lesion with accuracy of 100%. Overall, 1739 lesions were discovered in 1271 regions out of 3818 examined regions with overall sensitivity, specificity, and accuracy of 86%, 92%, and 90% respectively. The diagnostic performance of WB-DWI-MRI is variable among different anatomical sites. It has good performance in diagnosis of some organs as liver, bone marrow, and some LNs regions as porta-hepatis. It has a less diagnostic performance in the lung, and LNs located in cervical, mediastinum, supraclavicular, and mesenteric regions.


Background
Metastatic lesions are common manifestations of advanced cancers with very high prevalence in current practice. It is becoming an everyday clinical question [1]. Malignant lymphoma is another relatively common tumor that requires accurate staging at initial presentation that is essential for treatment planning and prognostication. Clinicians are highly dependent upon different imaging procedures for staging that takes into account the number of involved sites and the type of lesions (nodal or extra-nodal) [2].
Whole-body diffusion-weighted magnetic resonance imaging (WB-DWI-MRI) is an emerging tool that has been developed to assess tumor spread. Combining MRI's unique power of characterizing tissues, based on water and fat content, with DWI's ability to assess tissue water motion, provides a unique tool to both detect and characterize lesions within tissues. Positron emission/ computed tomography (PET/CT) is considered the preferred investigation in secondaries detection in clinical guidelines [3]. WB-DWI-MRI is probably the closest competitor to PET/CT scanning. As PET/CT, it covers the whole body and gives exquisite anatomical identification as it is always done in association with other MRI sequences and has the capability to be considered "functional" scanning. But unlike PET/CT, it avoids ionizing radiation, of lower cost, and does not require radioactive tracers. Also, PET/CT has low sensitivity in detecting metastasis in the brain and liver, due to the high physiological tracer uptake in these organs [3].
In this study, we tried to explore the value of WB-DWI-MRI in detecting metastases, in clinical settings, by including different types of malignancies and lymphomas in a single study.

Methods
The study was prospective. Written informed consents were obtained from all patients for their data to be included in the study. Institutional ethical committee approval was obtained. The study included all patients referred to Radiology Department, during the period from June 2016 till May 2018, with a known primary or lymphoma, that were laboratory, radiologically, or histologically proven, of any type, affecting any organ. All patients underwent WB-DWI-MRI before commencing any treatment of the primary lesion (surgery, radiotherapy or chemotherapy). All included patients had no contraindication for MRI examination. The study excluded patients in whom a confirmatory method of the nature of the possibly metastatic lesion was not available. Patients who did not show any metastatic lesion in the scans were also excluded.

Confirmation of the nature of the lesion
The identified lesion(s) was considered a metastasis if it was confirmed histologically by a diagnostic biopsy that was done for clinical needs. Alternatively, if this was not available, clinical and radiological progress were followed till identification of the true nature of the lesion. All radiological investigations done during the follow-up period were requested for the clinical needs of patients, and at the discretion of the responsible physician.

MRI technique
All patients had MRI according to the study protocol. The machine used was Gyroscan Philips 1.5 Tesla strength ACS-NT synergy coil, Holland. No contrast media was used. The patients lied supine on MRI table with hands beside his body. Conventional techniques used were coronal T1-weighted images (WI), coronal STIR, axial T2-WI images, and sagittal STIR of the spine. Then, WB-DWI-MRI was obtained. Parameters are summarized in Table 1. Images were acquired with a built-in body coil for signal reception, from head to toes, under free breathing. The total acquisition time for WBconventional and DWI-MRI was approximately 40-45 min including 20-25 min for WB-DWI. Axial images were reconstructed on a coronal plane; then the reconstructed images in the coronal plane for each station were merged to obtain a coronal WB images. Colorcoded fused T1-DWI images and apparent diffusion coefficient (ADC) maps were generated by Phillips workstation software.

Image interpretation
The images for MRI were prospectively assessed for each patient by two radiologists who have more than 5 years' experience in MRI imaging. For the purpose of the research, the body was divided into three groups: lymph nodes (LNs), skeletal system, and organs. Then, LN groups were further divided into 16 regions and skeletal system was divided into 63 regions. Organs considered in the study are the three organs commonly involved which are the brain, lungs, and liver, and a fourth group that includes the other organs. Criteria for involvement were either local or diffuse hypo intensities in T1-WI or hyper intensities in T2-WI and STIR images or restricted diffusion in DWI or hypo-intensity on ADC maps or their combinations. Post-processing ADC values and maps were done separately for each anatomical location through the workstation software. Lowest ADC values were measured using a region of interest in the center of the lesion avoiding necrotic and cystic areas. A cut-off value of 1 × 10 −3 mm 2 /s was used to differentiate restricted areas from non-restricted areas. A LN was considered positive if its short diameter was equal to or more than 10 mm, loss of fatty hilum, irregular margins or apparent speculation, diffusion restriction, and low ADC value where a cut-off value of 0.8 × 10 −3 mm 2 /s was used.

Statistical analysis
Analysis will be performed using SPSS 18.0 software (SPSS Chicago, IL, USA). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated and expressed per region not per patient.

Results
This study included 46 patients; (25 males and 21 females, median age was 49, range 16 to 79 years); 27 patients had metastases of a known primary tumor and 19 had lymphomas. Distribution according to primary site is shown in Table 2.
Methods of confirmation of the nature of the lesions Radiological follow-up by different imaging techniques was the method of confirmation of the nature of the lesion in most of the occasions. Follow-up ranged from 6 to 12 months. Table 3 shows the number of scans done in patients in this study that were used for confirmation. Most patients had underdone more than one imaging modality during follow-up. Only 4 lesions had been biopsied; 2 from liver, 1from lung, and 1 from a neck LN.

Diagnostic performance of WB-MRI
Results are shown in Tables 4 and 5. Regarding LN detection, WB-DWI-MRI detected 233 out of all 736 possible LN regions in all patients. Sensitivity, specificity, and accuracy for LN detection were 77%, 85%, and 83%, respectively. WB-DWI-MRI showed highest sensitivity in femoral groups of LNs followed by inguinal and porta-hepatis groups of LN's. On the other hand, it was the lowest in the supraclavicular and mediastinal groups of LNs. The highest false-positive results were in axillary and inguinal LNs, while the mediastinal, supraclavicular, and cervical LNs showed the highest false-negative results (Fig. 1).
For skeletal metastasis, WB-DWI-MRI detected lesions in 984 out of 2898 regions in all patients. Sensitivity, specificity, and accuracy were 88%, 94%, and 92%, respectively. In all regions, sensitivity ranged between 80 and 92% except for pubic bones where it was 60% (Fig. 2). For brain lesions, sensitivity, specificity, and accuracy were 78%, 95%, and 91%, respectively. In 46 patients, 9 patients had 13 brain lesions; of them, 2 were falsepositive and 2 were false-negative. For lung lesions, sensitivity, specificity, and accuracy were 64%, 88%, and 76% respectively. Fifty-four lesions were identified in 17 patients; of them, 3 were false-positive and 8 were falsenegative ( Fig. 3 and 4). As regards the liver, WB-DWI-MRI detected correctly all 52 lesions in 16 patients and did not miss any lesion with accuracy of 100% in this study (Fig. 5).
Overall, 1739 lesions were discovered by WB-DWI-MRI in 1271 regions out of 3818 examined regions; 1069 regions were true-positive and 176 regions were missed and were later proved to be malignant, whereas 202 regions were false-positive. Overall sensitivity, specificity, and accuracy were 86%, 92%, and 90%, respectively.

Discussion
This research was intended to be an exploratory research of the applicability of WB-DWI-MRI. It was a prospective clinical study, in which the patients were followed up till a clarification of the nature of the lesion had been reached. So, the researchers are naturally blind to the actual nature of the lesion. In most similar studies, comparisons are made with other concurrently done scans that have their own inherent accuracies. Additionally, for this study to be as beneficial and reproducible as possible, we tried to simulate the actual clinical scenario that the radiographer is exposed to in his/her daily activities. So, we combined the data from the conventional MRI to that of DWI-MRI and did not try to compare       them to each other, which does not happen in the clinical scenarios. We did not restrict our inclusion to a specific disease or organ, either primary or secondary. Also, to get the highest yield from our limited research, we deliberately did not investigate the role of WB-MRI in assessment of tumor response.
In this study, to get the most accurate calculations, we divided the LN and skeletal groups to the smallest possible segments or regions. For example, ribs, we divided in 24 ribs; so every single rib is an independent region. Meanwhile, we did not divide organs into further smaller segments.

LN lesions
Regarding evaluating malignant metastatic or lymphomatous LNs, the relatively low sensitivity of WB-DWI-MRI in detection of regional nodal metastases in this study can be explained by the fact that metastases can be present in non-enlarged LN and not all enlarged nodes are malignant. Changing the size criteria towards larger or smaller cut-offs will influence sensitivity and specificity as a low threshold for cut-off values would increase the sensitivity, but specificity would decrease. This can explain the variation in the sensitivity of WB-DWI-MRI in other studies which ranges from 60 to 90% [4,5]. The most accepted criterion for malignant LN involvement in conventional MRI sequences is that a short diameter greater than 8-10 mm [6]. A normal LN already has a relatively long T2 relaxation time and a restricted diffusion, due to their high cellularity, thus adding ADC values enhanced the discrimination between malignant and benign LNs. In this study, the combined usage of WB-DWI-MRI with the conventional sequences improved the detectability of LN metastasis. Seber et al. [7] in their study on differentiating benign from malignant LN infiltration from wide range of tumor types involving different body locations, found that adding DWI (utilizing an ADC cut-off value of 0.8 × 10 −3 mm 2 /s) to conventional MRI findings increased the accuracy from 80.6 to 91.6%. There is a wide variability of accuracies within different sites in the study. The highest accuracy was found in porta-hepatis LNs. Whereas the lowest accuracy was found in mediastinal LNs where image quality may be affected by pulsation artifacts. The later finding was contrary to Sigovan et al.'s findings [8] where they showed high sensitivity, specificity, and accuracy (90.9%, 83%, and 85%, respectively) for DWI in differentiating benign from malignant enlarged mediastinal LNs.
One of the confusing pitfalls is splenic hilar lymphadenopathy with an accessory spleen, as both may be hyper-intense on STIR and DWI sequences. The same issue was reported by Massani et al. [9].
In our study, there were no differences in DWI values between Hodgkin disease and non-Hodgkin's lymphoma. Interestingly, Sabri et al. [10], in their study on malignant mediastinal LN involvement, detected a significant difference between the ADC values of Hodgkin disease and non-Hodgkin lymphoma.

Skeletal system lesions
In this study, WB-DWI-MRI identified 1137 bony lesions in 984 regions. The sensitivity, specificity, and accuracy were 88%, 94%, and 92%, respectively. Similar to other studies, we noted that the sole evaluation of bone lesions by DWI, STIR, or T2-WI makes high falsepositive results of non-tumor lesions as in anemia, smoking, spondylodiscitis, osteomyelitis, bone infarctions, hemangiomas, and fractures which cause increased signal due to bone marrow edema [11][12][13]. The use of ADC maps and T1-WI in these occasions could decrease the false-positive results. Sagittal STIR of whole spine was included for evaluation of all the vertebrae to improve the accuracy of lesion localizations due to a higher spatial resolution [14]. False-negative results were found in the areas prone to motion artifacts as the sternum and clavicles. They were more obvious in conventional sequences than in WB-DWI [15,16].

Brain lesions
WB-DWI-MRI only provide information about tumor cellularity, and this may explain its low sensitivity of 78% and high specificity 95% in this study as it could correctly identify 13 lesions of the brain in 9 patients. This was evident in other studies as well and is believed to be due to inherent high signal of the brain [17]. In suspected brain lesions, FLAIR sequence was exceptionally added to confirm the diagnosis, which is capable to elucidate areas of vasogenic edema around the tumor [18]. Ahmed and Mokhtar [19] reported similar finding to ours in their study on cerebral lesions. They found that there are mixed diffusion changes in most of the lesions in their study, and there was overlap in the measured ADC values between neoplastic and nonneoplastic lesions. On the other hand, Berghoff et al. [20] reported that ADC values correlated with survival and recurrence after surgical resection. Additionally, Lee et al. [21] reported that it correlated with survival after radiosurgery. Another interesting finding was reported by Zakaria et al. [22], that ADC changes at the tumor edge may indicate a more aggressive phenotype.

Pulmonary lesions
WB-MRI identified 54 lesions in 17 patients. Sensitivity, specificity, and accuracy were 64%, 88%, and 76%, respectively. This was lower than that of other conventional imaging as CT in many studies [23]. This can be attributed to difficulties in detection of small metastatic lung nodules (less than 8 mm). Free-breathing DWI acquisition in this study led to reduced accuracy of lesion detection (especially lung bases) due to respiratory movements and cardiac motion [23]. Also, lesions located at air-tissue interfaces were more difficult to be identified. Similarly, Regier et al. [24] reported sensitivity of 97% for nodules larger than 10 mm, but for 6-9 mm nodules, the sensitivity decreased to 86%, and for nodules 5 mm or smaller, it decreased to 43.8%. Similar finding was reported by Liu et al. [25] in assessing pulmonary metastases in patients with renal cell carcinoma. The use of ADC mapping added a value of discrimination between benign and malignant nodules [26]. A recent meta-analysis reported sensitivity and specificity of DWI to be 82.8% and 80.1%, respectively [27].

Liver lesions
Regarding hepatic metastases, WB-MRI had an accuracy of 100%. Thanks to the use of combined DWI with ADC together with anatomical localization by conventional MRI, the detection rate of malignant focal hepatic lesion was high. These results were also reported in another study [28]. Another explanation to these high results in this study as whole organ is considered a single region.
As there was usually more than one lesion in the liver, if only one of them was correctly detected, the researchers would consider this scan a true-positive; the others will not be reported. WB-MRI is comparable with contrastenhanced CT or contrast-enhanced MRI but with advantage that it does not require contrast medium [29].
Of particular interest, Abou-Khadrah and Bedeer [30] in a prospective study showed that DWI is beneficial in small hepatocellular carcinomas smaller than 2 cm where they reported high sensitivity, specificity, and accuracy of combined conventional MRI and diffusion (92.8%, 71.4%, and 93.3%, respectively).

Study limitations
There are some limitations to the study. It included a heterogenous group of patients with different pathologies, so, each pathology was represented by a small number of patients. Our aim was to do an exploratory study for the value of WB-DWI-MRI in detecting metastases, by including different types of malignancies and lymphomas in a single study. To minimize the effect of small study size, we deliberately did not investigate the role of WB-MRI in assessment of tumor response. Another limitation to the study is that histological examination to confirm the nature of the lesion was possible in only a small number of lesions. This study was conducted in clinical setting, and biopsies were requested by the treating physicians for the clinical requirements not for the sake of the study. This study was prospectively conducted and included only those patients who could be followed up by different radiological examinations for periods that were deemed sufficient to prove that a specific radiological finding is metastatic or not base upon its biological behavior.

Conclusion
The diagnostic performance of WB-DWI-MRI combined with conventional MRI and ADC mapping is variable among different anatomical sites. It has good performance in diagnosis of some organs as liver, bone marrow, and some LNs as porta-hepatis. It has a less diagnostic performance in the lung, and LNs located in cervical, mediastinum, supraclavicular, and mesenteric regions.