Differentiating metastatic disease from primary hepatic malignancy is critical for therapeutic decision-making. Conventional imaging may be limited when lesions are atypical or heterogeneous. DW-MRI offers a functional approach to tissue characterization but quantitative validation is required.​

Diffusion-weighted MRI was first used for the early diagnosis of stroke in neuroradiology.¹ Currently, DWI is increasingly used for evaluation of extracranial organs like breast, liver, kidneys, pelvic organs (prostate) as well as whole body imaging in cancer patients. The use of DWI is very promising for the detection and differentiation of benign and malignant lesions, imaging in oncological patients before treatment and for follow-up after treatment.^2,3 DWI measurements are quick to perform and do not require administration of exogenous contrast medium.⁴

As a non-contrast-enhanced technique, DW-MRI is crucial in patients with severe renal dysfunction at risk of developing nephrogenic systemic fibrosis (NSF) after administration of gadolinium-based contrast medium. Although dynamic contrast enhanced examinations have become a routine component of abdominal imaging, high cost/benefit ratio and risk of contrast media side effects remain an issue. Moreover, sometimes it is not possible to distinguish between highly vascular metastases and haemangiomas, even using dynamic examinations.^1,5

With recent advances in technology, DW MR imaging is reaching a potential for clinical use in the liver imaging. Restricted diffusion is seen in tissues with high cellularity, e.g. tumors, abscesses, fibrosis and cytotoxic edema whereas unimpeded diffusion is seen in tissues with low cellularity or tissues with disrupted cell membranes, e.g. cysts and necrotic tissues. 

To our knowledge, most of the studies are retrospective in design where selection bias is inevitable. Till date very few Indian studies are available and results are not in consensus. Till date no Indian study is available on usefulness of DWI in differentiation of liver metastasis from primary liver lesions. Some studies are not followed up by histopathological correlation.

This project is a prospective type of observational study, designed to evaluate the contribution of diffusion-weighted imaging (DWI) towards the confident diagnosis and evaluation of liver lesions reducing the need of contrast agents and obviate the use of invasive diagnostic modalities like FNAC or biopsy.

Total 64 patients were evaluated with diffusion-weighted MR imaging at tertiary hospital in Central India. Informed consent was obtained from patients. The final diagnosis was confirmed by histopathological examination or follow up. Multiple liver lesions of similar morphology in a single patient was considered as a single lesion in the study. Clinical history, diagnostic modalities like biopsy, laboratory findings (AFP level  etc),  and  other  imaging  modalities  like USG,  CT  Scan;  wherever  applicable  were  taken  into  consideration.

INCLUSION CRITERIA

• Patients referred for MRI with clinically suspected liver lesions.
• Patients referred for MRI with focal liver lesions detected on USG or CT.

EXCLUSION CRITERIA

• Patients having cardiac pacemakers, MRI incompatible prosthetic heart valves, cochlear implants or any incompatible metallic implants.
• Claustrophobic patients.
• Patients who cannot lie down- dyspnoeic patients/ Un-co-operative patients.
• Postoperative cases and recently biopsied cases and recurrent cases are excluded from the study.
• Patients who do not give informed consent to take part in this study.

TECHNIQUE AND TOOLS

Machine: 1.5 Tesla Philips Achieva MRI machine.     

Coil: Body Surface coil

Scan parameters:

Table 1: Scan parameters

RECOMMENDED SEQUENCES

Respiratory triggered fat suppresses single shot echo-planar diffusion-weighted imaging (DWI) was performed in axial plane with tri-directional diffusion gradients by using three b values (b=0 s/mm, b=500 s/mm and b=1000 s/mm). The ADC value of each FLL was calculated within a region of interest (ROI) placed in the centre of the assessed FLL, covering more than 50% of its surface. In cases of necrotic FLLs, measurements were taken only in the solid part, trying to avoid inclusion within the ROI of any necrotic part, covering area   > 1 cm.^7,16  T2 weighted  images  were obtained.

DATA ANALYSIS 

Qualitative analysis of hepatic lesions was done by visual assessment of their signal intensity on diffusion-weighted images at three b values & comparing them with ADC map. Signal intensities of T2WI were also observed for comparison with DWI.  For quantitative analysis, ADC values were recorded for liver lesions. 

Imaging analysis: a lesion was considered¹⁰

• Benign: Hyperintense on T2WI and DWI at b = 0 sec/mm2 with a strong signal intensity decreases at b=500 sec/mm² and ADC subjectively higher than liver parenchyma.
• Malignant: mildly to moderately hyperintense on T2WI and on DW images at b=0 sec/mm² and remained hyperintense compared with liver parenchyma at b=500 sec/mm², with an ADC qualitatively lower than that of the surrounding liver.

For statistical calculations,

For statistical calculations, independent sample t-test and independent sample Welch-test for unequal variances were used. ROC curve anal ysis was done to evaluate the utility of ADC measures for the prediction of malignancy. 

Pvalue of 0.05 or less was considered statistically significant. 

A total of 64 patients with focal liver lesions were studied and based on the MRI findings, the observations are as below:

MALIGNANT vs BENIGN LESION CHARACTERIZATION DEPENDING ON DWI AND ADC SIGNAL INTENSITY

Table 2: Malignant vs benign lesion characterization depending on

DWI and ADC signal intensity

In current study population, out of total 40 malignant lesions, all lesions showed hyperintense/heterogeneous hyperintense signal intensity on DWI at higher ‘b’ values and showed hypo/heterogeneous hypointense signal intensity on ADC map which is suggestive of restricted diffusion. 

In case of total 24 benign lesions, 12(50%) lesions showed hyperintense or heterogeneous hyperintense signal intensity at b=1000sec/mm² on DWI. 12(50%) lesions disappeared at higher b values (b=500sec/mm² and/or b=1000sec/mm²) on DWI. 3(12.5%) lesions showed heterogeneous hypointense signal intensity on ADC map which correspond to 3 abscesses showing restricted diffusion. Rest of benign lesions (~87.5%) showed hyperintense/heterogeneous hyperintense signal intensity on ADC map; suggestive of facilitated diffusion.

MALIGNANT    vs           BENIGN              LESION              CHARACTERIZATION DEPENDING ON DIFFUSION RESTRICTION

Table 3: Malignant vs benign lesion characterization depending on diffusion restriction

All malignant lesions showed restricted diffusion. 12.5% of benign lesions                     (3 abscesses) showed restricted diffusion. Rest 87.5% benign lesions did not show restricted diffusion.

MALIGNANT    vs           BENIGN              LESION              CHARACTERIZATION DEPENDING ON T2WI

Table 4: Malignant vs benign lesion characterization depending onT2WI signal intensity

All malignant lesions showed mild to moderate hyperintensity on T2WI. 8.3% of benign lesions (2 hemangiomas) showed mild hyperintensity. Rest 91.6% benign lesions showed hyperintense signal.

Table 5: Correctly characterized FLLS by DW and T2WI

Out of 64 FLLs, 62 lesions were characterised accurately by T2WI (two false positive hemangioma). DWI was able to characterise 61 out of 64 FLLs (3 abscesses were restricting on diffusion).

MEAN ADC VALUES FOR LIVER LESIONS

Table 6: Mean ADC values for liver lesions

In the current study with total 64 lesions, it was observed that benign lesions had highest mean ADC value. Hydatid cyst had max mean ADC value of 2.16×10^-3mm²/sec followed by simple cyst having 2.09×10^-3 mm²/sec. Among malignant lesions HCC had the lowest mean ADC value of 0.94×10^-3mm²/sec while metastases had mean ADC value of 1.14×10^-3mm²/sec.

A total of 64 patients with focal liver lesions were studied and based on the MRI findings, the observations are as below:

MALIGNANT vs BENIGN LESION CHARACTERIZATION DEPENDING ON DWI AND ADC SIGNAL INTENSITY

Table 2: Malignant vs benign lesion characterization depending on

DWI and ADC signal intensity

In current study population, out of total 40 malignant lesions, all lesions showed hyperintense/heterogeneous hyperintense signal intensity on DWI at higher ‘b’ values and showed hypo/heterogeneous hypointense signal intensity on ADC map which is suggestive of restricted diffusion. 

In case of total 24 benign lesions, 12(50%) lesions showed hyperintense or heterogeneous hyperintense signal intensity at b=1000sec/mm² on DWI. 12(50%) lesions disappeared at higher b values (b=500sec/mm² and/or b=1000sec/mm²) on DWI. 3(12.5%) lesions showed heterogeneous hypointense signal intensity on ADC map which correspond to 3 abscesses showing restricted diffusion. Rest of benign lesions (~87.5%) showed hyperintense/heterogeneous hyperintense signal intensity on ADC map; suggestive of facilitated diffusion.

MALIGNANT    vs           BENIGN              LESION              CHARACTERIZATION DEPENDING ON DIFFUSION RESTRICTION

Table 3: Malignant vs benign lesion characterization depending on diffusion restriction

All malignant lesions showed restricted diffusion. 12.5% of benign lesions                     (3 abscesses) showed restricted diffusion. Rest 87.5% benign lesions did not show restricted diffusion.

MALIGNANT    vs           BENIGN              LESION              CHARACTERIZATION  DEPENDING ON T2WI

Table 4: Malignant vs benign lesion characterization depending on

T2WI signal intensity

All malignant lesions showed mild to moderate hyperintensity on T2WI. 8.3% of benign lesions (2 hemangiomas) showed mild hyperintensity. Rest 91.6% benign lesions showed hyperintense signal.

Table 5: Correctly characterized FLLS by DW and T2WI

Out of 64 FLLs, 62 lesions were characterised accurately by T2WI (two false positive hemangioma). DWI was able to characterise 61 out of 64 FLLs (3 abscesses were restricting on diffusion).

MEAN ADC VALUES FOR LIVER LESIONS

Table 6: Mean ADC values for liver lesions

In the current study with total 64 lesions, it was observed that benign lesions had highest mean ADC value. Hydatid cyst had max mean ADC value of 2.16×10^-3mm²/sec followed by simple cyst having 2.09×10^-3 mm²/sec. Among malignant lesions HCC had the lowest mean ADC value of 0.94×10^-3mm²/sec while metastases had mean ADC value of 1.14×10^-3mm²/sec

REPRESENTATIVE IMAGES

CASE OF HEPATOCELLULAR CARCINOMA

Figure 1: (case no in Master chart) A) Hyperintense lesion on b=0 sec/mm² B) Htrg-hyperintense lesion on b=500 sec/mm² C) Htrg-hyperintense lesion on b=1000 sec/mm² D) Htrg-hypointense lesion on ADC map, ADC=1.000 x 10^-3 mm²/sec E) Mild Hyperintense on T2WI. Final diagnosis was confirmed by FNAC, IHC.

CASE OF HEPATIC METASTASIS

Figure 2: (A) Htrg-hyperintense lesions on b=0 sec/mm²B) Htrg-hyperintense lesions on b=500 sec/mm² C) Htrg-hyperintense lesions on                           b=1000 sec/mm² D) Htrg-hypointense lesions on ADC map, ADC=0.1064 x 10^-3 mm²/sec E) mild hyperintense on T2W images. FNAC proven case of hepatic metastases of ca cervix

DW-MRI enabled clear quantitative distinction between liver metastases and primary hepatic tumors.

LESION DETECTION ON DWI

In the current study, all focal liver lesions showed higher signal intensity compared to surrounding liver parenchyma, predominantly on lower b value DWI images, enabling lesion detection.

Out of 64 patients, 40 patients (62.5%) had malignant lesions and 24 patients (37.5%) population had benign lesion/s. In the study most common diagnosis of patients was metastases 26(40.63%) followed by HCC 11 (17.19%) and simple cyst 9(14%). 

In the study 53.13% lesions were observed in right hepatic lobe, 17.19% in left lobe and 29.69% lesions in both the lobes.

In the current study 54.5% of HCCs, 100% Cholangiocarcinoma and                            100% abscesses were seen in male patients.61.5% of metastases and 88.8% of simple cysts were seen in female patients. Haemangioma and hydatid cysts were equally seen in males and females. Among 64 lesions, 26 lesions were metastases followed by HCC                (11 lesions) and simple cyst (9 lesions).

All liver lesions (64) were classified into three groups based on their size                       (in cm). 46 lesions (71.8%) were <5cm, among which 21 were metastases. 9 lesions were greater than10cm in size. Average size of lesions was 4.6cm.

Table 13: Comparison of number & size of focal liver lesions between current study & other similar studies

Table 13 depicts that current study closely matches with similar studies in literature studied.

MALIGNANT LESION CHARACTERIZATION ON DWI & ADC MAP: QUALITATIVE ANALYSIS

In the     present study, all malignant lesions showed hyperintense/heterogeneous hyperintense signal intensity on DWI at all ‘b’ values and hypointense/heterogeneous hypointense signal intensity on ADC map. Thus, all HCCs, cholangiocarcinoma and metastatic lesions in the study showed restricted diffusion due to high cellularity.

These results are comparable with Badawy et al¹³, who concluded that all malignant solid lesions showed increased signal intensity on higher b values with low signal on corresponding ADC maps. Hosny et al⁵ also demonstrated persistent hyperintense signal of solid tumors on high b value on DWI. Haradome et⁹ al and Parikh et al¹⁰ demonstrated that lesion is considered as malignant if it showed hyperintense signal at b=500sec/mm² & an ADC qualitatively lower than that of surrounding liver. Current study results concur with the same.

BENIGN LESION CHARACTERIZATION ON DWI AND ADC MAP: QUALITATIVE ANALYSIS

In this study, all 8 hemangiomas showed hyperintense/heterogeneous hyperintense signal intensity on ADC map (no restricted diffusion). Persistence of hyperintense signal on higher ‘b’ values could be due to T2 shine through effect (validated by signal intensity on ADC map).^{4,11,18,19,20}

All simple cysts disappeared at b=1000sec/mm² on DWI and showed hyperintense signal intensity on ADC map. Current study results are comparable with Hosny.⁵                             All the hydatid cysts (2 lesions) disappeared at b=1000 sec/mm² and showed hyperintense signal intensity on ADC map (no restricted diffusion).

All abscesses (3 lesions) showed heterogeneous hyperintense signal intensity at b=500 sec/mm² and b=1000 sec/mm² and showed heterogeneous hypointense signal intensity on corresponding ADC map represented restricted diffusion. This is due to high viscosity in the abscess core. Chan et al¹⁸ showed that all abscesses showed hyperintensity on DWI and hypointensity on ADC maps. Current study results concur with the same.

MALIGNANT VS BENIGN LESION DIFFERENTIATION BASED ON DWI AT THREE ‘b’ VALUES

All 40 malignant lesions, 8 hemangiomas and all abscesses (3 lesions) showed persistent hyperintense/heterogeneous hyperintense signal intensity on DWI at higher ‘b’ values. Rest of the benign lesions disappeared at higher ‘b’ values (b=500 sec/mm² and/or b=1000 sec/mm²).These results are similar to those obtained by Hosny⁵, Haradome H⁹ and Parikh et al.¹⁰

MALIGNANT VS BENIGN LESION DIFFERENTIATION BASED ON DWI AND ADC MAP

Comparing DWI images and ADC map, all malignant lesions showed restricted diffusion. 3(12.5%) of benign lesions (3 abscesses) showed restricted diffusion. Rest 87.5% benign lesions did not show restricted diffusion.

These results are comparable with Kilickesmez et al¹⁹ who demonstrated that lesions with high cellularity like tumors show diffusion restriction whereas those with low cellularity like cysts show facilitated diffusion (no diffusion restriction). Similar results were also obtained in study done by Hosny⁵, Haradome et al⁹ and Parikh et al¹⁰ also demonstrated that lesion is considered as malignant if it showed persistent hyperintense signal on higher b value & hypointensity than that of surrounding liver on corresponding ADC map qualitatively.

LESION CHARACTERISATION ON T2WI AND COMPARISON WITH DWI

All malignant lesions and 2 hemangioma lesions were showing mild-moderate hyperintensity. Rest of the benign lesions showed hyperintense signal. All malignant lesions were correctly characterised on T2WI and DWI. Two hemangioma lesions were false positively characterised as malignant lesion on T2WI. All the FLLs except abscesses (known to show diffusion restriction) were accurately characterised into malignant and benign on DWI. The overall accuracy of DWI was better than T2WI, however there was no statistically significant difference (p=>0.05). Similar results were also obtained in study done by Haradome et al⁹ and Parikh et al.¹⁰

ROLE OF ADC VALUE:  QUANTITATIVE ANALYSIS

For the statistical calculations --was used in current study. Among total                        64 lesions, it was observed that benign lesions had highest mean ADC value. Hydatid cyst had maximum mean ADC value of 2.16×10^-3mm²/sec followed by simple cysts and hemangioma having mean ADC 2.09×10^-3mm²/sec and 2.03×10^-3mm²/sec respectively. Among malignant lesions, HCC had the lowest mean ADC value of 0.94×10^-3 mm²/sec, cholangiocarcinoma had mean ADC value of 0.95×10^-3 mm²/sec while metastases had mean ADC value of 1.14×10^-3 mm²/sec. Although being benign lesions, abscesses had mean ADC value of 1.02×10^-3mm²/sec.

Demir et al³ showed that mean ADC value for abscess was                               1.09±0.32×10^-3 mm²/sec. He explained that this low value could be related to dense viscous content of abscess. According study by Chan et al¹⁸ mean ADC value was significantly lower for hepatic abscess compared to necrotic tumors and simple cyst (0.67±0.35×10^-3 mm²/sec). Current study shows comparable results with literature studies. According to Demir et al³ mean ADC value of hydatid cysts was                       2.99±0.24×10^-3 mm²/sec. This value was not significantly different from simple cyst.  According to Kilickesmez et al¹⁹ mean ADC value of hydatid cysts was                       2.58±0.53×10^-3 mm²/sec. This value was not significantly different from simple cyst. Current study results concur with mean ADC value of hydatid cysts mentioned in above literature studies.

Mean ADC value for benign lesions was 1.95×10^-3mm²/sec and for malignant 1.08×10^-3mm²/sec. Using Independent sample t-test, statistical significant difference between mean ADC values for malignant lesions and benign lesions was observed with p-value 0.0087(< 0.05) in the studied samples.

Above observations are similar with findings of Hosny⁵, Rao UMM⁶, and                 Emara DMM⁸ who showed that cysts and hemangiomas had highest ADC values while malignant masses had the lowest.

Similarly. using Independent sample Welch-test for unequal variances; statistical significant difference between mean ADC values for HCC and metastases was also seen (p-value < 0.05). In the study done by Sun X J et al²⁰, showed that HCCs and metastases had significant differences between mean ADC values. Mean ADC value of HCC was 0.95±0.11×10^-3 mm²/sec and that of metastases was 1.13±0.21×10^-3mm²/sec. Similar results were obtained in current study.

SENSITIVITY AND SPECIFICITY OF    ADC VALUE FOR DIFFERENTIATING BETWEEN BENIGN AND MALIGNANT LESIONS

ROC curve analysis was used to determine sensitivity and specificity.                        ADC cut-off value of 1.39x10^-3mm²/s was obtained by normal distribution (mean±2SD) with area under cover 0.902. Sensitivity of 100%, specificity of 83.3% (20/24), positive predictive value of 90.6% (39/43) and negative predictive value of 100% were obtained.

Excluding abscesses, ADC cut-off value of 1.501x10^-3 mm²/s was obtained by normal distribution (mean±2SD) with sensitivity, specificity, positive predictive value and negative predictive value of 100%.

Table 14: ADC cut-off, sensitivity & specificity comparison of current study with selected studies

Table 14: Mean ADC values of liver lesions, ADC cut-off, sensitivity & specificity comparison of current study with selected studies

*Represents ADC values determined excluding abscesses.

Table 30 shows that Cut-off ADC value in current study is in concurrence with literature studied, however slight difference in sensitivity and specificity results are seen  from ours study. This is mostly due to the absence of solid benign FLLs in our study. Lack of solid benign lesions (except) hemangioma  such as FNH, hepatic adenoma outweighed the differences of ADC values between malignant and benign, due to the fact that solid benign lesion being a hypercellular lesion, expected to present with low ADC values.^13,14,15

The study with similar sensitivity and specificity with our study is that of Gourtsoyianni et al.²² evaluated series of 39 patients with 37 FLLs, the benign lesions were mainly biliary cysts (15 out of 22 FLL) with significantly higher ADC than any other FLL.

These findings support use in preoperative staging and tailored therapy. Methodological strengths include prospective ADC measurement and blinded analysis.

Limitations of current study

Sample size and duration of study was small. Being oncology setup, number of malignant lesions was more than benign lesions. Solid benign FLLs (hemangioma) not encountered in this study. Paediatric population was excluded from study.

Qualitative and quantitative assessment of liver lesions was done based on only diffusion-weighted MR imaging and T2WI. Comparison with contrast enhanced MR imaging was not done

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