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Published online before print August 9, 2007, 10.1148/radiol.2443061355
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(Radiology 2007;244:776-783.)
© RSNA, 2007

Gastrointestinal Imaging

Hepatocellular Carcinoma with Indeterminate or False-Negative Findings at Initial MR Imaging: Effect on Eligibility for Curative Treatment—Initial Observations1

Dongil Choi, MD 2, Donald G. Mitchell, MD, Sachit K. Verma, MD 3, Diane Bergin, MD, Victor J. Navarro, MD, Aarati B. Malliah, MD, Christopher McGowan, MD, Hie-Won L. Hann, MD, and Steven K. Herrine, MD

1 From the Departments of Radiology (D.C., D.G.M., S.K.V., D.B.) and Medicine (V.J.N., A.B.M., C.M., H.L.H., S.K.H.), Thomas Jefferson University Hospital, 132 S 10th St, 1094 Main Bldg, Philadelphia, PA 19107. From the 2006 RSNA Annual Meeting. Received August 4, 2006; revision requested October 10; final revision received October 31; accepted December 6; final version accepted January 16, 2007. Address correspondence to D.G.M. (e-mail: donald.mitchell{at}jefferson.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Purpose: To retrospectively evaluate the effect of indeterminate or false-negative findings at magnetic resonance (MR) imaging on eligibility for curative treatment of hepatocellular carcinoma (HCC).

Materials and Methods: This HIPAA-compliant retrospective study was approved by the institutional review board; the need for informed consent was waived. Of 166 patients with cirrhosis in whom HCC was detected with MR imaging, 21 (13 men, eight women; mean age, 60 years) had 33 proved HCCs that were not detected on previous MR images obtained 6–24 months earlier. MR imaging included T1-weighted, T2-weighted, and dynamic contrast material–enhanced T1-weighted imaging. Serial MR images and treatment records were reviewed to evaluate nodule growth and the effect of delayed diagnosis on treatment eligibility.

Results: Of 33 HCCs in 21 patients, 24 corresponding nodules (73%) were described on previous MR images as benign or indeterminate. Five additional nodules were visible at retrospective evaluation, but only on arterial phase images. The diameters of these 29 visible but indeterminate nodules were initially 0.6–1.9 cm (mean, 1.1 cm) and increased to 0.9–4.5 cm (mean, 1.9 cm) at HCC diagnosis (mean follow-up, 378 days). The mean doubling time was 856 days for diameter and 285 days for volume. All nine HCCs with a delayed diagnosis of less than 1 year were smaller than 3 cm at diagnosis, and the patients had undergone liver transplantation (n = 3) or technically successful ablation or embolization (n = 6). All 10 subcentimeter indeterminate nodules were smaller than 2 cm at HCC diagnosis, and none progressed to untreatable HCC.

Conclusion: Indeterminate nodules smaller than 2 cm did not become untreatable HCC with delayed HCC diagnosis of 6–12 months.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Magnetic resonance (MR) imaging is widely used for diagnosing hepatocellular carcinomas (HCCs), which are often seen best as nodules that enhance during the hepatic arterial phase of dynamic MR imaging (1,2). However, arterial-portal venous shunt, aberrant venous drainage, hemangioma, focal nodular hyperplasia, and other nodules also enhance during the hepatic arterial phase, so this finding is not specific for malignancy (3–6). Results of several previous reports (5,7,8) noted that 72%–93% of small (<2 cm) indeterminate enhancing nodules are benign, particularly in the absence of low signal intensity on delayed contrast material–enhanced images and high signal intensity on T2-weighted MR images. Because some of these indeterminate enhancing nodules are indeed HCCs, however, decisions regarding the appropriate management or interval for imaging follow-up are not clear. Thus, the purpose of our study was to retrospectively evaluate the effect of indeterminate or false-negative findings at MR imaging on eligibility for curative treatment of HCC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Patients
This retrospective study was compliant with the Health Insurance Portability and Accountability Act and was approved by our institutional review board; the need for patient informed consent was waived. Patients with HCC were identified by querying the billing databases of a university-based tertiary liver center in the United States from January 2000 to December 2005. Chart reviews were conducted for all patients whose records contained the International Classification of Diseases, ninth revision, billing codes 155.0 (malignant neoplasm of liver, primary), 155.2 (malignant neoplasm of liver, not specified as primary or secondary), or 211.5 (benign neoplasm of liver and biliary).

A physician (C.M.) identified 166 patients with HCCs who had undergone MR imaging of the liver, and a radiologist (D.C.) reviewed their radiology reports and medical records. The indications for MR imaging included evaluation of underlying liver disease, screening for HCC on the basis of high risk, and characterization of nodules detected with other imaging modalities. Of the 166 patients with HCC, 30 had undergone at least two MR imaging examinations at our facilities before HCC was diagnosed. The time between MR examinations ranged from 6 to 24 months. Six patients were excluded because they had undergone chemoembolization or ablation therapy before their second MR examination, and three were excluded because dynamic images obtained in the hepatic arterial phase did not show minimal hepatic enhancement, enhancement of the hepatic veins, intense enhancement of the pancreas and renal cortex, minimal enhancement of renal pyramids, or serpiginous enhancement of spleen. No selected patient had undergone multiphasic computed tomography (CT) during the interval between MR examinations, consistent with our institutional practice of relying on MR imaging in this patient population.

The final study group included 21 patients with 33 HCCs. There were 13 men and eight women (age range, 44–75 years; mean age, 60 years) with cirrhosis due to hepatitis C (n = 16), hepatitis B (n = 2), or alcoholism (n = 2). In one patient, the cause of cirrhosis was unknown. Eight patients had previously undergone only one MR examination, and 13 patients had undergone multiple (up to seven) MR examinations.

Confirmation of Diagnosis
Thirteen patients had one HCC, four patients had two HCCs, and four patients had three HCCs. Diagnosis was confirmed in six patients with six HCCs at explantation for liver transplantation, including two Edmondson-Steiner grade I HCCs and four grade II HCCs. The remaining 27 HCCs in 15 patients were confirmed with the presence of at least two of the four following criteria: (a) focal lesion greater than 2 cm, (b) MR enhancement showing hypervascularity during the hepatic arterial phase and a washout pattern during the delayed phase, (c) elevated {alpha}-fetoprotein level of more than 400 ng/mL (400 µg/L), or (d) interval diameter doubling within 1 year or 50% diameter increase within 6 months (7,9).

MR Imaging Technique
All MR examinations were performed during suspended respiration with a 1.5-T system and a phased-array coil (Signa; GE Medical Systems, Milwaukee, Wis). The sequences included two-dimensional coronal and transverse single-shot fast spin-echo T2-weighted MR imaging (echo time, 180–200 msec), transverse fat-suppressed fast spin-echo T2-weighted MR imaging (repetition time msec/echo time msec, 2000–4000/70–90), and spoiled dual gradient-echo T1-weighted in- and out-of-phase MR imaging (120–200/2.3 and 4.6, 90° flip angle). Parameters for two-dimensional images included 5–8-mm-thick sections with a 0–1-mm intersection gap, 256 x 160–192 matrix, 32-cm by 24-cm field of view (width by anteroposterior dimensions), and one or less signal acquired. Three-dimensional (3D) dynamic contrast-enhanced spoiled dual gradient-echo dynamic fat-suppressed MR images were obtained at 2.5-mm increments by using zero-fill interpolation, 3–6.1/0.9–2.1, a 12°–20° flip angle, and parameters otherwise similar to those of the two-dimensional images.

Twenty milliliters of contrast material (Magnevist; Berlex Laboratories, Wayne, NJ) was administered intravenously with a power injector (Optistar LE; Mallinckrodt, Hazelwood, Mo) at 2 mL/sec. This was followed by a 20-mL saline solution flush. First-pass arterial enhancement was optimized by using a timing bolus sequence or by observing enhancement on images reconstructed in real time. Dynamic imaging was performed during breath holding before the injection (unenhanced), immediately after the injection (hepatic arterial phase), 30 seconds after the injection (early venous phase), and 1 minute after the injection (late venous phase). Additional images of the entire liver were acquired in the delayed phase with a two-dimensional single-section spoiled dual gradient-echo technique with 19–20/1.5–2.1 and a flip angle of 40°; in some patients, an additional 3D spoiled dual gradient-echo series was used in the delayed phase.

Review of Records and Images
The prospective interpretations were issued by four radiologists, each with 5–15 years of experience in the conventional interpretation of abdominal MR images. A radiologist (D.C.) first reviewed the prospective radiology reports from all MR examinations to assess the prospective detection and their primary diagnostic considerations. With knowledge of the location of the HCC based on the MR examination findings on which HCC was diagnosed, two radiologists (D.C. and S.K.V., with 3–5 years of experience after completing a fellowship in abdominal radiology) independently assessed the previously obtained MR images with a picture archiving and communication system workstation (Canon Medical Systems, Irvine, Calif). The appearance of the HCCs before diagnosis (indeterminate or missed nodules) was assessed with regard to signal intensity (hyperintense, isointense, or hypointense relative to liver parenchyma) and contrast enhancement on T1-weighted images. Indeterminate nodules were defined as small (<2 cm) nodules that could not be diagnosed yet as HCCs. Contrast enhancement was determined with direct comparison of tumor signal intensity between unenhanced and contrast-enhanced images, primarily on the basis of visual change of relative signal intensities. We frequently confirmed the visual impression of enhancement with the measurement of signal intensities on images with constant receiver gain, choosing the regions of interest on the picture archiving and communication system workstation. Disagreement between readers was resolved in conference along with a third radiologist (D.G.M., with 20 years of body MR imaging experience).

One of the initial readers (D.C.) measured the size of the nodules on images that provided the best delineation of margins, with preference given to unenhanced or delayed images when possible. The average size was calculated from the greatest two perpendicular dimensions, as measured on transverse images. The growth rate of nodules was expressed as diameter doubling time and volume doubling time (10). Subsequent medical records were reviewed to determine whether any HCC exceeded the criteria for curative treatment (criteria: single HCC <5 cm in diameter or multiple HCCs [up to three] <3 cm in diameter each) (9). Satisfactory outcome of MR imaging follow-up was defined when tumors were treated with technical success by means of transplantation, hepatic resection, or tumor ablation.

Statistical Analysis
HCC diameters in patients with a follow-up interval of less than 1 year versus more than 1 year were compared by using a two-tailed Student t test. A P value of less than .05 was indicative of a statistically significant difference. Data analyses were performed with commercially available software (SPSS for Windows, version 13.0, 2004; SPSS, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Prospective Radiology Reports
Of the 33 HCCs in 21 patients, 24 (73%) were noted at the same locations in the prospective radiology reports from the previous MR examinations but were considered indeterminate or benign (Fig 1). The primary diagnostic considerations for the 24 HCCs were possible HCC (n = 9, 38%), probable dysplastic nodule (n = 8, 33%), and arterial-portal venous shunt (n = 7, 29%). Radiology reports recommended short-term follow-up MR imaging in nine (43%) of the 21 patients. Among 13 patients who had previously undergone multiple MR examinations, five had repeated impressions of atypical or dysplastic nodules and four had arterial-portal venous shunts. In the remaining four patients, there was no mention of nodules.


Figure 1A
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  		Figure 1a: MR images in a 46-year-old woman with subcentimeter indeterminate nodule. Fat suppression was not used to reduce artifact from metallic transjugular intrahepatic portosystemic shunt. Prospective radiology report suggested dysplastic nodule and recommended follow-up. (a–c) Transverse T1-weighted 3D gradient-echo MR images (3/0.9). (a) Unenhanced image shows 0.9-cm indeterminate hyperintense nodule (arrow). (b) Image obtained in arterial phase shows minimal perilesional enhancement of nodule (arrow). (c) Image obtained in delayed phase shows no nodule. (d) Transverse fast spin-echo MR image (2000/78.9 [effective]) reveals hypointense indeterminate nodule (arrow). (e–g) MR images obtained at 7-month follow-up. Edmondson-Steiner grade II HCC was found at explantation for liver transplantation. (e) Transverse T1-weighted 3D gradient-echo MR image (3/0.9) obtained during hepatic arterial phase shows considerable growth of enhancing nodule (arrow), which now measures 1.7 cm. (f) T1-weighted transverse gradient-echo MR image (19/1.5) obtained during delayed phase reveals hypointense HCC (arrow) with washout enhancement pattern. (g) T2-weighted transverse fast spin-echo MR image (2000/71.6 [effective]) shows slightly hypointense HCC (arrow).

 

Figure 1B
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  		Figure 1b: MR images in a 46-year-old woman with subcentimeter indeterminate nodule. Fat suppression was not used to reduce artifact from metallic transjugular intrahepatic portosystemic shunt. Prospective radiology report suggested dysplastic nodule and recommended follow-up. (a–c) Transverse T1-weighted 3D gradient-echo MR images (3/0.9). (a) Unenhanced image shows 0.9-cm indeterminate hyperintense nodule (arrow). (b) Image obtained in arterial phase shows minimal perilesional enhancement of nodule (arrow). (c) Image obtained in delayed phase shows no nodule. (d) Transverse fast spin-echo MR image (2000/78.9 [effective]) reveals hypointense indeterminate nodule (arrow). (e–g) MR images obtained at 7-month follow-up. Edmondson-Steiner grade II HCC was found at explantation for liver transplantation. (e) Transverse T1-weighted 3D gradient-echo MR image (3/0.9) obtained during hepatic arterial phase shows considerable growth of enhancing nodule (arrow), which now measures 1.7 cm. (f) T1-weighted transverse gradient-echo MR image (19/1.5) obtained during delayed phase reveals hypointense HCC (arrow) with washout enhancement pattern. (g) T2-weighted transverse fast spin-echo MR image (2000/71.6 [effective]) shows slightly hypointense HCC (arrow).

 

Figure 1C
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  		Figure 1c: MR images in a 46-year-old woman with subcentimeter indeterminate nodule. Fat suppression was not used to reduce artifact from metallic transjugular intrahepatic portosystemic shunt. Prospective radiology report suggested dysplastic nodule and recommended follow-up. (a–c) Transverse T1-weighted 3D gradient-echo MR images (3/0.9). (a) Unenhanced image shows 0.9-cm indeterminate hyperintense nodule (arrow). (b) Image obtained in arterial phase shows minimal perilesional enhancement of nodule (arrow). (c) Image obtained in delayed phase shows no nodule. (d) Transverse fast spin-echo MR image (2000/78.9 [effective]) reveals hypointense indeterminate nodule (arrow). (e–g) MR images obtained at 7-month follow-up. Edmondson-Steiner grade II HCC was found at explantation for liver transplantation. (e) Transverse T1-weighted 3D gradient-echo MR image (3/0.9) obtained during hepatic arterial phase shows considerable growth of enhancing nodule (arrow), which now measures 1.7 cm. (f) T1-weighted transverse gradient-echo MR image (19/1.5) obtained during delayed phase reveals hypointense HCC (arrow) with washout enhancement pattern. (g) T2-weighted transverse fast spin-echo MR image (2000/71.6 [effective]) shows slightly hypointense HCC (arrow).

 

Figure 1D
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  		Figure 1d: MR images in a 46-year-old woman with subcentimeter indeterminate nodule. Fat suppression was not used to reduce artifact from metallic transjugular intrahepatic portosystemic shunt. Prospective radiology report suggested dysplastic nodule and recommended follow-up. (a–c) Transverse T1-weighted 3D gradient-echo MR images (3/0.9). (a) Unenhanced image shows 0.9-cm indeterminate hyperintense nodule (arrow). (b) Image obtained in arterial phase shows minimal perilesional enhancement of nodule (arrow). (c) Image obtained in delayed phase shows no nodule. (d) Transverse fast spin-echo MR image (2000/78.9 [effective]) reveals hypointense indeterminate nodule (arrow). (e–g) MR images obtained at 7-month follow-up. Edmondson-Steiner grade II HCC was found at explantation for liver transplantation. (e) Transverse T1-weighted 3D gradient-echo MR image (3/0.9) obtained during hepatic arterial phase shows considerable growth of enhancing nodule (arrow), which now measures 1.7 cm. (f) T1-weighted transverse gradient-echo MR image (19/1.5) obtained during delayed phase reveals hypointense HCC (arrow) with washout enhancement pattern. (g) T2-weighted transverse fast spin-echo MR image (2000/71.6 [effective]) shows slightly hypointense HCC (arrow).

 

Figure 1E
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  		Figure 1e: MR images in a 46-year-old woman with subcentimeter indeterminate nodule. Fat suppression was not used to reduce artifact from metallic transjugular intrahepatic portosystemic shunt. Prospective radiology report suggested dysplastic nodule and recommended follow-up. (a–c) Transverse T1-weighted 3D gradient-echo MR images (3/0.9). (a) Unenhanced image shows 0.9-cm indeterminate hyperintense nodule (arrow). (b) Image obtained in arterial phase shows minimal perilesional enhancement of nodule (arrow). (c) Image obtained in delayed phase shows no nodule. (d) Transverse fast spin-echo MR image (2000/78.9 [effective]) reveals hypointense indeterminate nodule (arrow). (e–g) MR images obtained at 7-month follow-up. Edmondson-Steiner grade II HCC was found at explantation for liver transplantation. (e) Transverse T1-weighted 3D gradient-echo MR image (3/0.9) obtained during hepatic arterial phase shows considerable growth of enhancing nodule (arrow), which now measures 1.7 cm. (f) T1-weighted transverse gradient-echo MR image (19/1.5) obtained during delayed phase reveals hypointense HCC (arrow) with washout enhancement pattern. (g) T2-weighted transverse fast spin-echo MR image (2000/71.6 [effective]) shows slightly hypointense HCC (arrow).

 

Figure 1F
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  		Figure 1f: MR images in a 46-year-old woman with subcentimeter indeterminate nodule. Fat suppression was not used to reduce artifact from metallic transjugular intrahepatic portosystemic shunt. Prospective radiology report suggested dysplastic nodule and recommended follow-up. (a–c) Transverse T1-weighted 3D gradient-echo MR images (3/0.9). (a) Unenhanced image shows 0.9-cm indeterminate hyperintense nodule (arrow). (b) Image obtained in arterial phase shows minimal perilesional enhancement of nodule (arrow). (c) Image obtained in delayed phase shows no nodule. (d) Transverse fast spin-echo MR image (2000/78.9 [effective]) reveals hypointense indeterminate nodule (arrow). (e–g) MR images obtained at 7-month follow-up. Edmondson-Steiner grade II HCC was found at explantation for liver transplantation. (e) Transverse T1-weighted 3D gradient-echo MR image (3/0.9) obtained during hepatic arterial phase shows considerable growth of enhancing nodule (arrow), which now measures 1.7 cm. (f) T1-weighted transverse gradient-echo MR image (19/1.5) obtained during delayed phase reveals hypointense HCC (arrow) with washout enhancement pattern. (g) T2-weighted transverse fast spin-echo MR image (2000/71.6 [effective]) shows slightly hypointense HCC (arrow).

 

Figure 1G
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  		Figure 1g: MR images in a 46-year-old woman with subcentimeter indeterminate nodule. Fat suppression was not used to reduce artifact from metallic transjugular intrahepatic portosystemic shunt. Prospective radiology report suggested dysplastic nodule and recommended follow-up. (a–c) Transverse T1-weighted 3D gradient-echo MR images (3/0.9). (a) Unenhanced image shows 0.9-cm indeterminate hyperintense nodule (arrow). (b) Image obtained in arterial phase shows minimal perilesional enhancement of nodule (arrow). (c) Image obtained in delayed phase shows no nodule. (d) Transverse fast spin-echo MR image (2000/78.9 [effective]) reveals hypointense indeterminate nodule (arrow). (e–g) MR images obtained at 7-month follow-up. Edmondson-Steiner grade II HCC was found at explantation for liver transplantation. (e) Transverse T1-weighted 3D gradient-echo MR image (3/0.9) obtained during hepatic arterial phase shows considerable growth of enhancing nodule (arrow), which now measures 1.7 cm. (f) T1-weighted transverse gradient-echo MR image (19/1.5) obtained during delayed phase reveals hypointense HCC (arrow) with washout enhancement pattern. (g) T2-weighted transverse fast spin-echo MR image (2000/71.6 [effective]) shows slightly hypointense HCC (arrow).

 
Nine (27%) of the 33 nodules were not described prospectively in radiology reports. Among these nine missed nodules, five (56%) could be seen retrospectively (Fig 2), although the reason for not mentioning the nodule in the prospective report could not be determined; four nodules (44%) were not visible even with careful retrospective review in locations where HCCs later were detected (Fig 3).


Figure 2A
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  		Figure 2a: MR images with image degradation from patient motion in a 53-year-old woman show subcentimeter indeterminate nodule. HCC was noted at MR imaging performed 17 months later. (a) Transverse T1-weighted 3D gadolinium-enhanced gradient-echo dynamic MR image (5/1.4) obtained during hepatic arterial phase shows subtle enhancement of 0.8-cm nodule (arrow). Prospective radiology report did not note this nodule, and it was not visible on any other image. (b) Transverse T1-weighted 3D gradient-echo MR image (4/1.4) obtained 17 months later during hepatic arterial phase shows interval growth of enhancing nodule (arrow), which now measures 1.3 cm. Nodule was slightly hyperintense on T2-weighted images (not shown).

 

Figure 2B
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  		Figure 2b: MR images with image degradation from patient motion in a 53-year-old woman show subcentimeter indeterminate nodule. HCC was noted at MR imaging performed 17 months later. (a) Transverse T1-weighted 3D gadolinium-enhanced gradient-echo dynamic MR image (5/1.4) obtained during hepatic arterial phase shows subtle enhancement of 0.8-cm nodule (arrow). Prospective radiology report did not note this nodule, and it was not visible on any other image. (b) Transverse T1-weighted 3D gradient-echo MR image (4/1.4) obtained 17 months later during hepatic arterial phase shows interval growth of enhancing nodule (arrow), which now measures 1.3 cm. Nodule was slightly hyperintense on T2-weighted images (not shown).

 

Figure 3A
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  		Figure 3a: MR images in a 61-year-old woman with HCC who had no visible nodule at MR imaging performed 14 months earlier. (a) Transverse T1-weighted 3D gadolinium-enhanced gradient-echo dynamic MR image (5/1.6) obtained during hepatic arterial phase shows early homogeneous enhancement of 1.6-cm nodule (arrow). (b) Transverse T1-weighted 3D gadolinium-enhanced gradient-echo dynamic MR image (5/1.6) obtained during venous phase reveals hypointense HCC (arrow) with washout enhancement pattern. (c) Transverse fast spin-echo MR image (2500/80.0 [effective]) shows slightly hyperintense HCC (arrow).

 

Figure 3B
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  		Figure 3b: MR images in a 61-year-old woman with HCC who had no visible nodule at MR imaging performed 14 months earlier. (a) Transverse T1-weighted 3D gadolinium-enhanced gradient-echo dynamic MR image (5/1.6) obtained during hepatic arterial phase shows early homogeneous enhancement of 1.6-cm nodule (arrow). (b) Transverse T1-weighted 3D gadolinium-enhanced gradient-echo dynamic MR image (5/1.6) obtained during venous phase reveals hypointense HCC (arrow) with washout enhancement pattern. (c) Transverse fast spin-echo MR image (2500/80.0 [effective]) shows slightly hyperintense HCC (arrow).

 

Figure 3C
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  		Figure 3c: MR images in a 61-year-old woman with HCC who had no visible nodule at MR imaging performed 14 months earlier. (a) Transverse T1-weighted 3D gadolinium-enhanced gradient-echo dynamic MR image (5/1.6) obtained during hepatic arterial phase shows early homogeneous enhancement of 1.6-cm nodule (arrow). (b) Transverse T1-weighted 3D gadolinium-enhanced gradient-echo dynamic MR image (5/1.6) obtained during venous phase reveals hypointense HCC (arrow) with washout enhancement pattern. (c) Transverse fast spin-echo MR image (2500/80.0 [effective]) shows slightly hyperintense HCC (arrow).

 
Signal Intensity
Among the 29 indeterminate nodules visible prospectively (n = 24) or retrospectively (n = 5), 20 (69%) were isointense on T1-weighted images, seven (24%) were hyperintense, and two (7%) were hypointense. During the hepatic arterial phase, 23 (79%) of the 29 indeterminate nodules enhanced more than adjacent parenchyma; however, no nodules were hypointense during the delayed phase. Neither perilesional enhancement nor a pseudocapsule appearance was seen in any lesion. Three nodules showed signal loss on opposed-phase compared with in-phase images, a finding that is indicative of lipid content. Slight hyperintensity on T2-weighted images was seen in only one nodule. All five nodules found at retrospective examination enhanced during the hepatic arterial phase but were not visible on any other images.

At diagnosis, all 33 HCCs enhanced more than parenchyma during the hepatic arterial phase. During the delayed phase, 24 (73%) of 33 HCCs were hypointense (washout pattern) and none were hyperintense. At T2-weighted imaging, 21 (64%) of the 33 HCCs were hyperintense; none were hypointense. At T1-weighted imaging, 18 (54%) of the 33 HCCs were isointense and 13 (39%) were hypointense. Two HCCs showed visible lipid on opposed-phase images.

Size and Doubling Time
The diameters of the 29 indeterminate nodules visible on previously obtained MR images ranged from 0.6 to 1.9 cm (mean, 1.1 cm). The diameters increased to 0.9–4.5 cm (mean, 1.9 cm) when the nodules were diagnosed as HCC (mean follow-up, 378 days) (Table). Ten subcentimeter indeterminate nodules became HCCs smaller than 2 cm (mean, 1.3 cm) and did not progress to untreatable HCC (Table). The diameters of four HCCs that were not visible on previously obtained MR images were smaller than 2 cm (mean, 1.4 cm) at diagnosis. Among the 14 indeterminate nodules in nine patients with delayed diagnosis of less than 1 year, three smaller than 1 cm became HCCs smaller than 2 cm (mean, 1.3 cm) and 10 larger than or equal to 1 cm (mean, 1.3 cm) became HCCs 2.5 cm or less (mean, 2.0 cm). Among the 19 indeterminate nodules in 12 patients with delayed diagnosis of more than 1 year, seven smaller than 1 cm became HCCs smaller than 2 cm (mean, 1.3 cm) and nine larger than or equal to 1 cm (mean, 1.3 cm) became HCCs up to 4.5 cm (mean, 2.5 cm). The size of the indeterminate nodules at initial MR imaging and the size of the HCC at diagnosis were not significantly different between patients with a follow-up interval of less than 1 year versus those in the more than 1 year follow-up (respectively, mean ± standard deviation = 1.7 cm ± 0.56 vs 1.9 cm ± 0.95, P = .574; 1.2 cm ± 0.35 vs 1.1 cm ± 0.33, P = .427).


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  		Size Changes of 33 HCCs

 
The mean doubling time was 856 days (range, 207–6127 days; median, 564 days) for diameter and 285 days (range, 69–2042 days; median, 188 days) for volume. The mean doubling times of indeterminate nodules initially smaller than 1 cm versus those that were at least 1 cm were 643 and 968 days for diameter and 214 and 323 days for volume, respectively (P > .05 for each).

Treatment Eligibility
None of the 21 patients in this series developed HCCs that were too large or numerous to satisfy the criteria for curative treatment (9). Two HCCs were larger than 3 cm, and both were solitary tumors. Three patients with a delayed diagnosis of less than 1 year underwent liver transplantation and two each underwent radiofrequency ablation, ethanol ablation, and transcatheter arterial chemoembolization. Three of 12 patients with a delayed diagnosis of more than 1 year underwent liver transplantation, two underwent radiofrequency ablation, and three underwent transcatheter arterial chemoembolization. Two patients with treatable tumors received only supportive treatment due to severe hepatic dysfunction and comorbidity. The remaining two patients were lost to follow-up after the diagnosis of HCC.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Several investigators have used their findings with regard to the growth rate of HCC to suggest 3–6 months as an appropriate interval for screening high-risk patients (11–15). These recommendations involve assuming a continuous geometric rate of volume doubling, although small well-differentiated HCCs often show slow initial growth (16). The basis for recommending short-interval follow-up is an assumption that a longer interval might result in HCC that cannot be cured; however, we are not aware of any previous study that addresses the eligibility for curative treatment of patients whose diagnosis of HCC was delayed because of indeterminate or false-negative findings at MR imaging. Despite diagnostic delays of 6–24 months, no patient developed HCC that exceeded eligibility for curative treatment, raising the question of whether aggressive short-term follow-up imaging for subcentimeter indeterminate nodules—even in patients at high risk for HCC—is necessary. Results of several previous reports (17–20) noted that incidental small HCCs detected only in the pathologic specimens after liver transplantation did not alter the survival.

Although small HCC is detected most frequently as a focus of enhancement during the hepatic arterial phase after the injection of contrast material (1), benign lesions often have a similar appearance. Even when small HCC is strongly suspected at MR imaging, it may be difficult to confirm the diagnosis by using other imaging modalities or even with biopsy (21). Among subcentimeter foci of transient enhancement that are not hyperintense on T2-weighted images, at least 80% are benign lesions such as arterial-portal venous shunts or dysplastic or hyperplastic nodules (5,7,8). Jeong et al (7) suggested that interval serial imaging was the most practical method for evaluating subcentimeter indeterminate enhancing nodules. Aggressive short-interval follow-up of these probably benign nodules, however, increases cost, complicates care, and is an obstacle to the cost-effective use of MR imaging to screen for HCC in high-risk patients. A patient with cirrhosis (especially if the cirrhosis is due to viral hepatitis) is at high risk for HCC, regardless of whether subcentimeter transient enhancing lesions are seen. Therefore, these nodules may not substantially change the patient's risk category and continued routine follow-up may remain sufficient. Shorter follow-up intervals, however, are probably best for indeterminate lesions that are larger than 1 cm; the likelihood of malignancy is higher for these lesions, and fewer tumor doublings are required before a large size (and poor prognosis) is reached.

Shah et al (22) reported that the presence of nonspecific nodules in a cirrhotic liver is a marker for an increased likelihood of HCC. Further study is needed to determine if this or other factors may help determine which patients might benefit from shorter intervals between imaging.

In our series, five (17%) of 29 indeterminate nodules visible at retrospective review were not described in the initial prospective report. All of these nodules were visible only during the hepatic arterial phase, similar to arterial-portal venous shunts. These lesions may have been omitted from the prospective report because they were not perceived or because they were attributed to small arterial-portal venous shunts.

Yu et al (23) recently reviewed previously obtained MR images in 152 patients in whom HCC was later diagnosed at imaging, finding visible nodules in only 36% of initial MR images (compared with 21 [73%] of 33 HCCs in our series). This difference might be related to their use of CT for eventual HCC diagnosis in 111 (73%) of the 152 patients. All of our eventual HCC diagnoses were made with MR imaging, so the retrospective visibility of HCC on an earlier MR image may be more likely.

Selection bias was a limitation of our study and the likely reason why several of our observations differ from those reported in previous studies. Previous investigators have found that hypointensity on delayed contrast-enhanced images (washout enhancement pattern) (24,25) or hyperintensity on T2-weighted images (1) is important in the differentiation of HCCs from many benign lesions. At prospective interpretations, nodules with either of the above findings were considered definite or probable HCC and were therefore managed more aggressively and not included in our series. Thus, only one indeterminate nodule in our series was hyperintense on T2-weighted images; none showed hypointensity on delayed contrast-enhanced images.

The mean volume doubling time of 285 days in our series is longer than that reported previously (74–204 days) (7,11–16). In our study, we did not estimate the growth rate of obvious (overt) HCC but selected only nodules that were indeterminate. Compared with previous studies, a higher proportion is likely to be early low-grade tumors, which grow slower than those with poor differentiation (12,26). All six HCCs with histologic correlation in our series were Edmondson-Steiner grade I or II. Some nodules in our series may in fact have initially been dysplastic nodules that later developed intranodular HCC, although we did not note the characteristic nodule-in-nodule appearance (10,27,28) in any lesions.

Our observations would have been strengthened if we could have included a larger population of patients, particularly including more with subcentimeter nodules and longer follow-up intervals—and an assessment of patients' survival. Many tumors were not pathologically proved but were considered HCC on the basis of characteristic imaging features combined with an elevated serum {alpha}-fetoprotein level or interval growth. These criteria are considered sufficient for clinical diagnosis at many institutions (9,17,29,30), including ours, so it was impractical to perform invasive biopsy of all small tumors. Finally, our result of no statistical difference in the size of the initial indeterminate nodule or HCC at diagnosis between patients with a follow-up interval of less 1 year and those with a follow-up interval of more than 1 year is intended to describe our study population rather than predict no difference in a later study with a larger size or different selection criteria.

In conclusion, when HCC initially appeared at MR imaging in patients with cirrhosis as an indeterminate nodule less than 2 cm, delayed diagnosis of 6–12 months due to indeterminate or false-negative findings at previous MR imaging did not lead to untreatable HCC. Our initial data do not support the need for short-term follow-up imaging (eg, <6 months) of indeterminate nodules smaller than 2 cm and raise the possibility that routine annual follow-up may be sufficient for subcentimeter indeterminate nodules. Larger studies, however, are needed for confirmation before such an approach can be recommended, because our results are initial observations in a small number of patients.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE
 References
 


   IMPLICATIONS FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
References
 


   FOOTNOTES
 

Abbreviations: HCC = hepatocellular carcinoma • 3D = three-dimensional

2 Current address: Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Back

3 Current address: Department of Radiodiagnosis, K.G. Hospital and Post Graduate Medical Institute, Coimbatore, India Back

Author contributions:Guarantors of integrity of entire study, D.C., D.G.M.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, D.C., D.G.M., A.B.M., S.K.H.; clinical studies, all authors; statistical analysis, D.C.; and manuscript editing, all authors

Authors stated no financial relationship to disclose.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 

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