Correlation between apparent diffusion coefficients on diffusion-weighted MRI and standardized uptake value on FDG-PET/CT in pancreatic adenocarcinoma

Abstract

Background

Diffusion-weighted magnetic resonance imaging (DW-MRI) and 2-deoxy-2-[18F]fluoro-D-glucose–positron emission tomography/computed tomography (PET/CT) is increasingly recognized as important for assessing tumor malignancy in oncology. Apparent diffusion coefficient (ADC) and standardized uptake value (SUV) are negatively correlated in some types of cancer based on tumor aggressiveness.

Purpose

To evaluate relationships between ADC of magnetic resonance imaging and SUV of PET/CT in pancreatic adenocarcinomas.

Material and Methods

Twenty-nine patients histopathologically diagnosed with pancreatic adenocarcinomas were evaluated. ADC maps were generated from 3 T-MRI using b values (b = 0, 800 s/mm²). PET/CT was performed 60 min after intravenous injection of FDG (3.7 MBq/kg). The margins of tumors on DW-MRI and PET/CT were assessed to measure ADC and SUV of tumor appropriately. For tumors considered well-marginated, minimal and mean ADC as well as maximal and mean SUV were measured. The correlation of ADC and SUV were statistically evaluated and survival period stratified on ADC and SUV also evaluated.

Results

Twenty-two tumors on DW-MRI and 25 on PET/CT were deemed well-marginated. Minimal ADC was significantly and negatively correlated with maximal and mean SUV (r = −0.61, P = 0.0040; r = −0.66, P = 0.0015), and mean ADC also showed significantly and negatively correlation with maximal and mean SUV (r = −0.50, P = 0.024; r = −0.54, P = 0.012). There was no significant difference on overall survival stratified on ADC and SUV.

Conclusion

ADC and SUV were significantly correlated in pancreatic adenocarcinomas, although no significant findings were observed in overall survival.

Keywords

Apparent diffusion coefficient diffusion-weighted imaging (DWI)magnetic resonance imaging (MRI)standardized uptake value PET/CT pancreatic adenocarcinoma

Introduction

Pancreatic cancer is the ninth most common cause of cancer with 277,000 new cases diagnosed worldwide (1,2). It accounts for around 2.2% of all cancer cases and is currently the sixth major cause of cancer-related mortality due to its very low 5-year survival rate (3). 2-deoxy-2-[18F]fluoro-D-glucose–positron emission tomography/computed tomography (FDG-PET/CT) can be used to evaluate metabolic activity in a variety of tissues and tumors (2). Most malignant tumors show increase of FDG uptake and high standardized uptake value (SUV) associated with an increased rate of glycolysis and glucose transport, and PET/CT is also generally accepted as a useful examination for tumor staging and treatment monitoring in pancreatic cancer (4 –7). The clinical use of PET/CT has been demonstrated to contribute for initial staging and prognostic prediction of patients with pancreatic cancer (8).

The apparent diffusion coefficient (ADC), a parameter of magnetic resonance imaging (MRI) measured on diffusion-weighted imaging (DWI), has received attention as an approach to evaluate tumor cellularity and aggressiveness (9,10). ADC is also applied for detection and differentiation of lesions in the pancreas (11,12). Both ADC and SUV are quantitative parameters to evaluate tumor malignancy, and several studies have attempted to demonstrate that ADC and SUV are negatively correlated in some types of cancers with high cellularity (13 –15). However, the relationship between ADC and SUV is not revealed in pancreatic cancer, which is known not only for its high malignancy, but also for tumor-induced fibrous changes, inflammatory reaction, and obstruction of pancreatic duct behind the scene. This relationship has a possibility to utilize ADC for evaluation of grade of malignancy of a tumor and patient prognosis as well as SUV in pancreatic cancer. The aim of this study was to investigate the correlation between ADC and SUV in patients with pancreatic adenocarcinoma. When significant correlations were identified, the relationship of ADC and SUV was also reviewed for patient prognosis.

Material and Methods

Patient population

Our institutional review board approved this retrospective study and waived the requirement for informed consent. This retrospective study comprised patients who were examined by MRI and PET for pancreatic malignancy. All patients had a preoperative examination with a single 3 T-MRI scanner and sequential PET/CT scanner at our institution between April 2008 and March 2012. A total of 68 patients with an initial diagnosis of pancreatic malignancy were identified within the period from the hospital database. Twelve patients who had treatment before image examinations and seven patients who had hyperglycemia (blood glucose concentration >8.3 mmol/L (150 mg/dL)) were excluded from the study. Six patients were deemed ineligible because they had been examined with MRI and PET/CT with an interval of more than 15 days (mean delay, 5 days; range, 1–13 days). Nine patients were excluded from the final analysis because they were clinically or pathologically diagnosed with benign pancreatic lesions (mass forming pancreatitis, n = 4; solid pancreatic hamartoma, n = 1; focal fatty replacement of the pancreas, n = 1) and other malignancies (acinar cell carcinoma of the pancreas, n = 1; extrahepatic biliary tract cancer, n = 1; lymph node metastases, n = 2). Of the residual patients, three patients with clinically apparent pancreatitis were excluded by symptom, blood examination, and initial CT. Consequently, the remaining 29 patients (20 men, 9 women; mean age, 72 years; age range, 44–84 years) were appropriately tested and had pathologically confirmed invasive ductal pancreatic adenocarcinoma by cytological examination (n = 16) or surgical specimens (n = 13). Median serum amylase and CA 19-9 were 81 IU/L (range, 32–355 IU/L) and 127 IU/L (range, 5–47,800, IU/L), respectively.

MRI protocol

MRI examinations were performed with a 3 T scanner (Signa HDxt; GE Healthcare, Milwaukee, WI, USA) with patients in the supine position. An 8-element body-phased array coil was placed around the patient in order to cover the upper abdomen. The MRI protocol included axial T1-weighted (T1W) in- and out-of-phase 3D dual-echo fast spoiled gradient-recalled echo (FSPGRE) sequences, an axial T2-weighted (T2W) fast spin echo (FSE) sequence, a coronal true fast imaging with steady precession (FISP) sequence, and an axial T1W 3D liver acceleration volume acquisition (LAVA) sequence with fat suppression before the administration of contrast media. Multi-slice respiratory-triggered and breath-hold MRCP images were obtained using a three-dimensional (3D) fast-recovery fast-spin echo sequence. Respiratory-triggered diffusion-weighted imaging (DWI) was acquired using a spin-echo echo-planar sequence with fat suppression in the axial plane (with two diffusion sensitivity coefficient [b] values of 0 and 800 s/mm²; four orthogonal directions; repetition time [TR] [ms] /echo time [ms], TR = R – R /65.9; flip angle, 90 degrees; image matrix, 128 × 128; field of view [FOV], 340 mm; slice thickness/gap, 5 mm/2 mm; and 4 NEX). In addition, dynamic LAVA with fat suppression imaging for clinical use was also performed in the arterial, portal venous, and equilibrium phases after injection of contrast material (0.2 mL/kg; Magnescope, Terumo, Tokyo, Japan) to identify the tumor localization accurately. MR images were transferred to a computer workstation (Advantage Windows 4.2; GE Healthcare). Workstation software was applied to calculate the ADC maps, and the ADC values were measured by manually drawing the region of interest (ROI) on the tumor. ADC maps were automatically created on the basis of two sets of DWI images using the following equation: ADC = [ln (S₁) – ln (S₀)]/(b₁ - b₀), where b₀ was 0 s/mm², S₀ was the signal intensity for this value, b₁ was 800 s/mm², and S₁ was the signal intensity of b₁.

PET/CT data acquisition

Patients underwent PET/CT examination on a clinical PET/CT scanner (Gemini GXL; Philips Healthcare, Cleveland, OH, USA). Blood glucose levels (6.6 ± 1.8 mmol/L [median ± standard deviation]) were checked before administration of FDG. PET scans were performed about 1 h (55 ± 6.8 min) after intravenous injection of FDG (3.7 MBq/kg body weight, total 199 ± 33 MBq). Sixteen row-detector spiral CT was then performed, and subsequent whole-body emission data were acquired with 120 kVp, 50 effective mA, and a 5.0 mm slice thickness/4.0 mm interval from the brain to pelvis. Attenuation-corrected PET images using CT data of sequentially achieved low-dose CT were obtained with an axial FOV of 60 cm, 2 min scan/bed position × 11 positions, and a 4.0 mm slice thickness/interval in the 3D emission scan mode without contrast material. PET/CT images were then transferred to a computer workstation.

Tumor evaluation and quantitative measurements

Tumor size and localization were evaluated by dynamic CT and MRI, which was performed for clinical use. TNM classification according to the Union for International Cancer Control (UICC), follow-up period, and overall survival were documented from the medical database.

Image evaluation was performed at the same workstation that had been used to create the ADC map by a radiologist with 8 years of experience in the abdominal field. First, the margins of tumor on DWI and SUV were assessed to measure ADC and SUV of the tumor appropriately. DWI was separated into well-marginated tumors and poorly-marginated tumors depending on intensity in tumor or signal increase of the tail of the pancreas. PET/CT image was also divided into well-marginated tumors and poorly-marginated tumors depending on FDG uptake by tumor or FDG uptake increase in the tail of the pancreas. Second, quantitative measurements were performed in all well-marginated tumors. DWI and ADC maps were displayed side by side with an application on the workstation. When a ROI was placed at tumor on DWI, the ROI was automatically reflected in the ADC map. The PET images were also displayed side by side with DWI, and ROIs were manually drawn on the image. If the tumor was spanned several continuous images of an ADC map or PET image, ROIs were placed on the tumor region of each image and the slice with the lowest mean ADC or the highest mean SUV were selected as the representative images. The ROIs were placed as large as possible in the tumor (mean area of ROI, 1.89 cm² [range, 0.70–3.93 cm²]). The lowest ADCs were recorded from these ROIs on ADC map as the minimum ADC (ADC_min) of tumor. The mean ADC (ADC_mean) was also recorded in order to minimize the effect of tumor heterogeneity on the same image. Similarly, the highest and mean SUVs were recorded from these ROIs from the PET images as the maximum SUV (SUV_max) and mean SUV (SUV_mean), respectively. Third, patients were divided to two groups dependent on SUV_mean and ADC_mean to evaluate survival period. Patients with higher ADC compared to ADC_mean were defined as high ADC group, and the residual patients were defined as low ADC group. In a similar way, patients were divided to high and low SUV group.

Statistical analysis

All statistical analyses were performed with commercially available software (JMP version 9.2; SAS Institute Inc., Cary, NC, USA). To estimate the statistical relationship between SUV_max or SUV_mean and ADC_min or ADC_mean of the pancreatic tumors, Pearson’s correlation analysis was performed. P values less than 0.05 were considered to represent statistical significance. Overall survival was compared using Kaplan-Meier method.

Results

Tumor evaluation and patient follow-up

Mean tumor diameter of 29 cases pathologically diagnosed as invasive ductal pancreatic adenocarcinomas was 29 mm (range, 13–50 mm). The tumors were located in the head of the pancreas (n = 19) or the body and tail (n = 10). The clinical extent of tumors (T) were subdivided into T1 (n = 1), T2 (n = 2), T3 (n = 22), and T4 (n = 4) based on the TNM staging system. Five patients had lymph node metastases and seven patients had metastatic lesions at initial diagnosis (liver, n = 5; liver and lung, n = 1; para-aortic lymph nodes, n = 1). Median follow-up period was 408 days (range, 32–1220 days).

Evaluation of tumor margin on DWI and PET/CT

The margins of tumors on DWI were assessed, and 7/29 cases were deemed as poorly-marginated tumors. The margins of tumors on PET/CT were also evaluated, and four cases of 29 were deemed as poorly-marginated. Two cases were deemed poorly-marginated on both of DWI and PET/CT (Fig. 1). Finally, 20 residual cases with well-marginated tumors on both modalities proceeded to quantitative measurement.

Fig. 1.

Correlations between ADC and SUV in a 65-year-old man with pancreatic adenocarcinoma proven by transesophageal endoscopic ultrasound-guided fine-needle aspiration. (a) Contrast-enhanced MRI on arterial phase shows a hypovascular tumor with massive invasion to retroperitoneum in the body of the pancreas (arrow). (b) Fusion image of PET with plain CT showed that the FDG-avid tumor (SUV_mean, 6.8) was difficult to be marginated from the atrophic tail-side because of the increased uptake with obstructive change. (c) DWI also depicted that the tail of tumor was difficult to differentiate from the tumor. Thus, this patient was excluded from the correlation analysis between ADC and SUV.

Correlation between ADC and SUV

The averaged ADC_min and ADC_mean values of the tumors were 1.10 (95% confidence interval [CI], 98.5–122) × 10⁻³ mm²/s and 1.44 (CI, 1.33–1.54) × 10⁻³ mm²/s. The averaged SUV_max and SUV_mean values were 4.0 (CI, 3.3–4.6) and 3.3 (CI, 2.7–3.8). ADC_min was significantly and negatively correlated with SUV_max and SUV_mean (r = −0.61, P = 0.0040; r = −0.66, P = 0.0015) according to Pearson’s correlation analyses. ADC_mean was also significantly and negatively correlated with SUV_max and SUV_mean (r = −0.50, P = 0.024; r = −0.54, P = 0.012). (Fig. 2a–d). A typical case of pancreatic adenocarcinoma demonstrating a trend of higher SUV_mean and lower ADC_mean values is shown in Fig. 3.

Fig. 2.

Correlations between ADC and SUV. (a–d) Scatter plots show the significant negative correlations between ADC and SUV. The central-linier lines indicate the regression lines and the curved lines upper and under the regression line show 95% confidence intervals. ADC_min was significantly and negatively correlated with SUV_max and SUV_mean (r = −0.61, P = 0.0040; r = −0.66, P = 0.0015) according to Pearson’s correlation analyses. ADC_mean was also significantly and negatively correlated with SUV_max and SUV_mean (r = −0.50, P = 0.024; r = −0.54, P = 0.012).

Fig. 3.

A 67-year-old man with histologically proven pancreatic adenocarcinoma. (a) Contrast-enhanced MRI on arterial phase shows a hypovascular tumor in the body of the pancreas (arrow). (b) Fusion image of PET with plain CT shows high accumulation of FDG in the tumor (SUV_mean, 4.4). (c, d) DWI depicts the tumor as a high signal intensity lesion, and ADC maps show the reduced ADC of the tumor (ADC_mean, 1.59 × 10^–3 mm²/s).

Overall survival stratified on ADC and SUV

Thirteen out of 22 patients who had well-marginated lesions on DWI were grouped in a low ADC group and 13 out of 25 patients who had well-marginated lesions on PET/CT were grouped in a high SUV group. The mean overall survival of patients with low and high ADC were 610 and 340 days, respectively (P = 0.40), and the mean overall survivals of patients with high and low SUV were 527 and 533 days, respectively (P = 0.92). For the 20 patients with well-marginated tumor on both modalities, the mean overall survival of 10 patients with low ADC and high SUV was 622 days, and it was longer than the survival period (407 days) of the residual 10 patients (P = 0.47).

Discussion

The present results showed that ADC_min and ADC_mean were significantly and negatively correlated with SUV_max and SUV_mean in cases of invasive ductal pancreatic adenocarcinoma, although there was no significant change in overall survival by stratifying patients with ADC_mean and SUV_mean. Several investigators have previously reported a significant inverse correlation between ADC and SUV of abdominal tumors primarily due to tumor cellularity (15). However, pancreatic cancer is histologically characterized by a dense fibrosis of tumor-associated stroma with intermediating neoplastic cell (16 –19). Muraoka et al. demonstrated that the fibrotic change of pancreatic cancer may be also responsible for water-diffusion abnormalities, and the viable cells residing within extracellular matrix might be supposed to contribute to increase FDG uptake (17 –19). In addition, the highly invasive nature of pancreatic cancer often leads to tumor-related reactions in surrounding structures. Therefore it was thought that the correlation between SUV and ADC of pancreatic adenocarcinoma might be based not only on tumor cellularity, but also whole tumor-related reactions caused by pancreatic cancers, and it is slightly different in principle from previously described high-cellularity tumors. Even under these conditions, a mild correlation between SUV and ADC still existed as a consequence on MRI and PET/CT.

DWI and PET/CT still require technological improvement in order to provide better diagnostic performance and adequate lesion-to-background contrast for imaging of the pancreas (20 –23). Previous reports have demonstrated that DWI was an important diagnostic tool for evaluating pathologic conditions in the pancreas, although tumor-associated pancreatitis appears hyperintense on DWI with reduced ADCs, and 47% of pancreatic adenocarcinoma had been reported to be indistinguishable from pancreatic parenchyma distal to the cancer on DWI (24,25). With respect to FDG-PET, pancreatic adenocarcinoma is known to be generally FDG-avid because of the low glucose utilization in normal pancreas, although the poor-spatial resolution of FDG-PET limits local tumor staging in pancreatic adenocarcinoma (26). PET/CT also has difficulties with regards to differentiation of pancreatic malignancy from various inflammatory states caused by tumor and obstruction of the pancreatic duct. This is thought to be due to accumulation of leukocytes with metabolic activity. In the present study, patients with clinically-apparent obstructive pancreatitis were initially excluded from evaluation, although there were still several patients with poorly-marginated tumors difficult to be distinguished from obstructive change of pancreatic duct especially in the tail-side of pancreas. PET-CT tended to be more sensitive to circumscribe the tumors than DWI, although current technology cannot separate completely inflammatory reaction from tumor both on DWI and PET-CT. Advances within these technologies are expected to open the way to resolve these issues, for example, parallel transmit or focused excitation with MRI and combination PET-MRI scanners (27 –29).

While pancreatic adenocarcinoma is widely recognized having a poor prognosis, chemoradiotherapy and surgery are currently considered promising in improving the prognosis (1,30 –32). The metabolic activity of the pancreatic tumor, measured by FDG-PET seems to be useful in evaluating the prognosis of pancreatic adenocarcinoma (8). PET scan parameters can generally predict shorter survival for patients with higher SUV_max in in patients with advanced pancreatic cancer (33 –35). Low ADC values correlate with tumor size, number of metastatic lymph nodes and local invasion at initial evaluation, furthermore it is related to a significantly high rate of progression after chemotherapy (11,36). Our study showed a seemingly counterintuitive result that patients with low ADC and high SUV had better prognosis, although not significant. As a possible cause for this, it has been reported that patients with higher SUV_max before chemoradiotherapy have better pathologic response for treatment and better prognosis (37,38). Additionally, several investigators also showed that high pre-treatment ADC was related to a poor response to chemotherapy in adenocarcinomas of the abdomen (39,40). It was supposed that most of our patients were treated with chemoradiotherapy in the course of treatment, and patients with low ADC and high SUV could had better treatment response as mentioned in the previous literature. Although still controversial because of the heterogeneity of patient background and treatment, further studies are needed with post-treatment MRI and PET examination.

The present study has some limitations. First, this was a retrospective study with a small number of patients and a variety of backgrounds and treatments. A further prospective trial with more cases and new imaging techniques is thus warranted to confirm the present results. Second, PET imaging were performed without breath holding technique and it might lead to a slight systematic bias. Use of combination PET-MRI scanners with motion correction that enables precise superposition of ROI is expected to validate these preliminary results. Third, we employed b = 0 s/mm² for a lesser b value. As shown in the previous literature, ADC is overestimated with b = 0 s/mm² using a 2-point monoexponential regression model, because the effect of perfusion is also incorporated in the calculation. So investigators should be careful in adopting the present results for clinical practice (41). Fourth, the present study could not evaluate pathological correlation in order to prove differences in parameters. Therefore, the mechanism of correlation between two parameters remains an issue that must be investigated further.

In conclusion, the present study demonstrated that ADC_min and ADC_mean and had a significantly negative correlation with SUV_max or SUV_mean in pancreatic adenocarcinoma. The correlation between SUV and ADC were supposed to exist as a consequence of histopathological characteristics in pancreatic adenocarcinoma. There was no significant change in overall survival by stratifying patients with ADC_mean and SUV_mean. Further studies are needed to clarify if the combination of SUV and ADC has a relevant role in clinical situations.

Footnotes

Conflict of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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