The liver is both a principal site of primary malignancies and a major target of metastatic disease from almost any primary malignant neoplasm 1. In addition, the incidence of benign hepatic lesions is high in the adult population 2–4. With remarkable advances in diagnostic imaging of the liver, small hepatic hypovascular lesions are increasingly being detected. These include malignant lesions, such as intrahepatic cholangiocellular carcinoma (ICC) and hepatic metastases (HM), as well as benign lesions, such as atypical hepatic hemangiomas (HG), inflammatory pseudotumors (IPT), and solitary necrotic nodules (SNN) of the liver. It is important to differentiate these lesions because the carcinoma and metastases are considered potentially fatal diseases that require prompt surgical or therapeutic attention, whereas benign lesions do not often require any intervention 5–8. Therefore, the ability to accurately differentiate between benign and malignant hypovascular hepatic lesions is increasingly a clinically important issue.
On the basis of our experience, hepatic hypovascular tumors are not uncommon. These four entities need to be distinguished, especially hemangioma and metastasis. Motosugi et al. 9 reported that bright signals on T2WI could be detected in both hemangiomas and hepatic metastases in 94–98% and 13–25% of cases, respectively.
In earlier studies, characteristics of large lesions (>3 cm) and multiple lesions were reported 4,10–14. However, to the best of our knowledge, the MRI features of small solitary hypovascular hepatic nodules (HHN) (≤3 cm) have not been reported so far. This retrospective study aimed to describe the MRI findings of hypovascular hepatic lesions as well as the diagnostic performance of MRI in differentiating malignant from benign hepatic lesions.
Materials and methods
This retrospective study was approved by the institutional review board and informed consent was waived. Between January 2005 and January 2014, 145 consecutive patients with 145 solitary hypovascular hepatic lesions (≤3 cm) were admitted to two medical centers. Patients with cirrhosis and cysts without associated enhancement were excluded from the study.
Study inclusion criteria were as follows: (a) patients with precontrast and contrast agent enhancement at multiple phases (e.g. no contrast enhancement, arterial phase, portal venous phase, delayed venous phase), (b) solitary hepatic lesions, (c) maximum diameter of any hepatic nodules up to 3 cm, and (d) hypovascular nodules, defined as nodules with large areas of hypointensity on the arterial and portal venous phases of dynamic enhancement, which was the same as or less than that of adjacent liver.
Imaging criteria used for the diagnosis of atypical hemangioma were as follows: (a) nodules with typical unenhanced features (high T2 signal, low T1 signal, and sharp borders), but atypical enhancement (central or peripheral nodular enhancement with no filling, rim-like enhancement); (b) no change for more than 1 year during the follow-up 15.
The criteria used to determine metastases were as follows: (a) lesions without radiofrequency ablation, chemoembolization or radioembolization, or other similar; (b) lesions first detected or 20% larger than the previous images using the same technique; and (c) follow-up imaging with any other primary malignant tumors (mean follow-up period of 8.65±3.18 months, range 3–12 months).
Overall, 135 patients were included in the final study population (57 women and 78 men; age range 21–91 years; mean age 56±13 years). The hepatic lesions included IPT and SNN (n=48), atypical HG (n=32), ICC (n=29), and HM (n=26). Symptoms and laboratory test results are summarized in Table 1. All IPT and SNN (n=48) were confirmed by surgical resection (n=28) or percutaneous biopsy (n=20). Thirty-two atypical HG were confirmed by percutaneous biopsy (n=8) or surgical resection (n=4) and follow-up imaging (n=20). Twenty-nine ICC were confirmed by surgical resection (n=26) and percutaneous biopsy (n=3). All HM were confirmed by surgical resection (n=7) or percutaneous biopsy (n=8) and imaging follow-up (n=11). The longest follow-up duration was 5 years.
MRI was performed using a 3 T scanner (Magnetom Trio; Siemens, Erlangen, Germany) with an eight-channel body phased-array coil. Baseline MRI images were acquired with the following parameters: breath-hold T1-weighted gradient-echo images; repetition time (TR), 220 ms; echo time (TE), 5.1 ms; flip angle (FA), 66°; matrix, 320×256; number of signals acquired, one; section thickness, 6 mm; intersectional gap, 1.0 mm; and acquisition time, 28 s. Navigator-triggered, fat-suppressed, and T2-weighted turbo spin echo images were acquired using the following parameters: TR, 4781 ms; TE, 81 ms; FA, 140°; matrix, 256×256; number of signals acquired, one; section thickness, 7 mm; intersectional gap, 1.0 mm; and acquisition time ∼90 s. T2-weighted half-Fourier acquisition single-shot turbo spin echo sequence (TR/TE, 4500/78 ms; FA 150°; matrix, 256×256; 6 mm slice thickness); and a breath-hold T1-weighted fast low angle shot sequence [TR, 172 ms; TE, 2.50 (in-phase)/1.22 ms (out-phase)]; FA 65°; matrix, 208×256; average of 1 and 2 acquisitions; 5 mm slice thickness). Dynamic imaging with a three-dimensional volumetric interpolated breath-hold examination sequence was obtained before (precontrast) and 20 s (arterial phase), 50 s (portal venous phases), and 3–5 min (delayed phases) after an intravenous administration of a gadolinium (Gd)-based contrast medium Gd–diethyltriaminepentaacetic acid (Primovist; Bayer Schering Pharma, Leverkusen, Germany) at a dose of 0.1 mmol/kg and 3.0 ml/s using a contrast enhancement autoinjector, followed by a 20 ml saline flush. Some delayed images were acquired at 10 min. All images were acquired in the transverse plane with a field of view of 370 mm to cover the entire liver. The average interval between MRI and surgery was 10 days (range 1–30 days).
Two radiologists with 10 years of clinical experience in abdominal MRI, blinded to the pathologic and clinical findings, independently analyzed all images, described the characteristics, and then rated the likelihood of a malignant mass in each patient using a five-point scale as follows: 1, definitely benign; 2, probably benign; 3, indeterminate; 4, probably malignant; and 5, definitely malignant. Combined unenhanced and contrast-enhanced MRI images were randomly assigned to each observer. Each observer interpreted the MRI images independently and separately. All MRI images were evaluated on the picture archiving and communication system monitors.
All analyses were carried out by the location, margin (defined or ill-defined edge), signal intensity on T2WI, nodule homogeneity, capsular retraction, enhancement patterns and features, and vessel encasement. The enhancement patterns included globular or rim-like enhancement at the lesions’ edge, and patchy, septum-like linear or nodular enhancement in the center. The above-mentioned signs are evaluated for determining the nodules benign or malignant. The long diameter of each mass was also measured.
Either the χ 2-test or the Fisher exact test was used to compare MRI findings. The statistically significant variables of the qualitative imaging features obtained from univariate analysis were used to carry out multivariate logistic regression analysis to determine the most predictable findings. These findings were used to differentiate malignant from benign nodules. Diagnostic performance for differentiating malignant from benign lesions was then assessed using the area under the receiver operating characteristic curve (Az). A difference with a P less than 0.05 was considered statistically significant for all tests. The κ statistic was used to evaluate interobserver agreement. A κ value less than 0.20 was considered to be poor, 0.21–0.4 as fair, 0.41–0.60 as moderate, 0.61–0.80 as good, and 0.81–1.00 as excellent. SPSS, version 17.0 software (IBM SPSS, Inc., Chicago, Illinois, USA) was used for statistical analysis.
The mean diameter of the lesions examined was 1.8±0.7 cm (range 0.5–3.0 cm). The main imaging features are summarized in Tables 2–4. Univariate analysis indicated that there were significant differences between the malignant group and the benign group in terms of location, margin, T2-weighted signal intensity, nodule homogeneity, and type and degree of peripheral and intratumoral enhancement (P<0.05). Multivariate analysis showed that the statistically common findings for malignant hypovascular nodules were ill-defined borders (n=42, 76%, P<0.05); heterogeneity (n=29, 52%, P<0.05); rim-like enhancement at the periphery (n=51, 93%, P<0.05) with decreasing intensity on the delayed phase (n=47, 86%, P<0.05); and patchy enhancement centrally (n=24, 44%, P<0.05) with increasing intensity on delayed phase (n=27, 49%, P<0.05). The most common MRI finding for ICC (n=27) was peripheral enhancement in the arterial dominant phase with centripetal enhancement on delayed phases. Twenty-three ICC showed patchy enhancement on delayed phases and three showed patchy enhancement in the center with peripheral defects (Fig. 2e). Twenty of 26 hepatic metastases were because of colorectal carcinoma. The most common MRI finding for HM (n=23) was peripheral rim enhancement (Fig. 3d–f).
Statistically, the most common findings for benign nodules were subcapsular (n=39, 49%, P<0.05), defined borders (n=62, 78%, P<0.05), marked high-signal intensity on T2WI (n=49, 61%, P<0.05), mild hyperintensity on T2WI (n=22, 28%, P<0.05), HG (n=53, 66%, P<0.05), peripheral nodular enhancement (n=30, 38%, P<0.05) and increasing intensity (n=40, 51%, P<0.05) on delayed phase, and central septum-like linear enhancement (n=27, 34%, P<0.05) and persistence in the delayed phase (n=77, 96%, P<0.05). Large area of atypical HG was a persistent low signal intensity on the three routine phases, but the enhancing area was slightly enlarged like an enhancing dot even at 10 min of delay (n=24; Fig. 4d–f). Twenty-seven cases of IPT and SNN showed thin and rim-like enhancement at the periphery (Fig. 5c–e).
As Fig. 1 shows, the Az values for MRI diagnostic performance in differentiating malignant from benign nodules was 0.955, sensitivity was 96.4%, and specificity was 83.8%, which were determined using combined imaging features of poor-definition, heterogeneity, decreasing intensity of rim-like enhancement at the periphery, and increasing intensity of cloud-like enhancement centrally. The κ values for the two reviewers ranged from 0.72 to 1.00. The interobserver agreement was good.
HHN can be classified into benign and malignant in etiologies, including ICC, HM, HG, IPT, SNN, etc. 1–4,9,10,16–20. Malignant nodules usually appear with advanced age, immune liver disease, history of malignancy, etc. However, these clinical features may be insufficient indicators for differentiation. Therefore, MRI examination, because of its superior soft-tissue contrast, may play an important role in the diagnosis and differential diagnosis of solitary HHN.
Currently, ICC accounts for ∼15–20% of all primary liver cancers and is the second most common primary hepatic tumor worldwide 17,18. Histologically, ICC are adenocarcinomas emerging from the epithelial lining of the small intrahepatic bile ducts 19,20. When visualized by MRI, because of the similarity of ICC to some benign lesions, it may lead to delayed cholangiocarcinoma diagnosis. The most common enhancement feature of ICC was a peripheral rim enhancement pattern during the arterial phase, followed by progressive and concentric filling with contrast material and patchy enhancement on delayed phases. This pattern was observed in 23 cases, corresponding well with the results of Kim et al. 21.
The cancers from the gastrointestinal tract often metastasize to the liver by the portal vein. HM develop during the course of the disease in up to 50% of colorectal cancer patients 3,22. For surveillance of liver metastases, MRI plays a major role because of its superior diagnostic sensitivity and specificity when evaluating liver lesions 23,24. Yoon and Tanabe 25 and Choi et al. 26 reported that metastasis to the liver is the sole site of metastatic disease in 25–40% of colorectal cancer patients. In our study, 24 HM nodules showed peripheral enhancement such as HHN, which is in agreement with the report of Zech et al. 27.
Yun et al. 16 reported that 88% of HG smaller than 2 cm showed peripheral nodular enhancement with persistent hypodensity (even at 10 min) using two-phase spiral CT. Tiny enhancing dots in two-phase spiral CT corresponded well to the initial enhancing globules in dynamic MRI. Although the nodules were up to 3 cm, 75% of the nodules in this study showed the same enhancement pattern as described previously 16. In addition, central nodular enhancement, progressive range, and intensity of enhancement on delayed phase were observed in three HG, probably because of replacement of parts of the central sinusoids by fibrous tissue.
IPT and SNN can also present as HHN. Twenty-seven IPT and SNN in our study appeared to be heterogeneous, with mixed or patchy high signals on T2WI, which resulted from liquefaction or fibrosis in the nodule 11. In our study, mild hyperintensity appeared only in IPT and SNN. Diverse enhancement patterns for IPT and SNN following the administration of Gd–diethyltriaminepentaacetic acid have been reported. Most reported IPT and SNN have been hypovascular, with limited or no appreciable enhancement at the arterial phase. Peripheral enhancement with a central nonenhancing core is a commonly reported morphological enhancement pattern 28,29. Other morphological enhancement features may include nodular enhancement of the central core, thick irregular septations, and ‘stalactite’ marginal enhancement 30. In this study, peripheral rim-like enhancement with central septum-like enhancement was observed in 27 cases, which was the most common enhancement pattern. In 20 cases, no enhancement of the central core was observed.
In our study, subcapsular nodules were more commonly observed in the benign group with HG, 17 cases, whereas IPT and SNN were observed in 22 cases. These observations are consistent with previous reports 31,32. By contrast, smaller ICCs were located in the more central parts of the liver, whereas HM had no particular location preference.
As typically expected for HG, all 32 HGs showed markedly high signals on T2WI, whereas regional high T2WI signals appeared in nine HMs. Small solitary metastases were often misdiagnosed as HG. Motosugi et al. 9 reported that a bright signal on T2WI (94–98% in HG, and 13–25% in metastasis) and ring-like enhancement (4% in HG and 58–60% in metastasis) were the independent findings suggesting HG and metastasis, respectively.
According to our data, 24 HG showed peripheral nodular enhancement. Yun et al. 16 reported that persistently hypoattenuating small HG visualized by two-phase spiral CT should be considered tumors with large vascular spaces. In this study, 42 IPT and SNN showed peripheral enhancement, 38 cases of which had increasing enhancement in the delayed phase. Venkataraman et al. 33 used microscopy to show that this change in MRI appearance was because of expansion of the portal tracts by fibrosis and occlusive phlebitis of the large-sized and medium-sized veins caused by granulation tissue. These findings were visualized as periportal soft-tissue infiltration.
Kitajima et al. 34 found that HM contained central necrosis, an enhanced area of active tumor cells and a zone of peritumoral edema and congestion. These results explain the fact that HM nodules are often ill defined, with rim-like enhancement and decreased intensity of peripheral enhancement. In our study, a similar enhancement pattern appeared in 23 HM and 24 ICC. Several previous reports have described infiltration of the edges of lesions by tumor cells, resulting in the ICC enhancement pattern 6,8,13.
Zen et al. 31 reported that venous encasement in the nodule was frequently observed in SNN. Kim et al. 35 reported that 53% of ICC also showed venous encasement. We also found that two cases in the ICC group showed portal vein encasement. This encasement was likely because of infiltration of the tumor into hepatic vessels.
However, there are some limitations in our study. First, because it was a retrospective study, some inherent selection bias was present. Second, a precise correlation between imaging findings and histological composition was not made because of the lack of pathologic rereview and lack of surgical specimens from all patients. Third, surgical correlations were not available for all of our study patients. Many cases of benign nodules required no further invasive procedures or surgery. However, in these cases, we had a firm clinical diagnosis and imaging follow-up.
In conclusion, nodular lesions with imaging findings of subcapsularity, sharp margins, homogeneity, marked high signal intensity on T2WI, mild hyperintensity on T2WI, increasing intensity of peripheral globular enhancement, and persistence of central septum-like linear enhancement on delayed phase should be considered benign. The most common findings for malignant nodules were ill-defined margins, heterogeneity, decreasing intensity of peripheral rim-like enhancement, and centrally increasing intensity of patchy enhancement.
Authors contributions: Shihong Li contributed equally to this work as the co-first author with Haizhen Qian. Haizhen Qian, data collection and processing, manuscript writing; Shihong Li, data collection and statistical analysis, manuscript writing; Ming Ji, data collection; Guangwu Lin, supervisor, project development, manuscript revision and submission.
Conflicts of interest
There are no conflicts of interest.
1. Rummeny E, Weissleder R, Stark DD, Saini S, Compton CC, Bennett W, et al.. Primary liver tumors: diagnosis by MR imaging. Am J Roentgenol 1989; 152:63–72.
2. Baron RL. Detection of liver neoplasms: techniques and outcomes. Abdom Imaging 1994; 19:320–324.
3. Baker ME, Pelley R. Hepatic metastases: basic principles and implications for radiologists. Radiology 1995; 197:329–337.
4. Tajima T, Akahane M, Takao H, Akai H, Kiryu S, Imamura H, et al.. Detection of liver metastasis: is diffusion-weighted imaging needed in Gd–EOB–DTPA-enhanced MR imaging for evaluation of colorectal liver metastases? Jpn J Radiol 2012; 30:648–658.
5. Liu LX, Zhang WH, Jiang HC. Current treatment for liver metastases from colorectal cancer. World J Gastroenterol 2003; 9:193–200.
6. Lieser MJ, Barry MK, Rowland C, Ilstrup DM, Nagorney DM. Surgical management of intrahepatic cholangiocarcinoma
: a 31-year experience. J Hepatobiliary Pancreat Surg 1998; 5:41–47.
7. Roayaie S, Guarrera JV, Ye MQ, Thung SN, Emre S, Fishbein TM, et al.. Aggressive surgical treatment of intrahepatic cholangiocarcinoma
: predictors of outcomes. J Am Coll Surg 1998; 187:365–372.
8. Valverde A, Bonhomme N, Farges O, Sauvanet A, Flejou JF, Belghiti J. Resection of intrahepatic cholangiocarcinoma
: a Western experience. J Hepatobiliary Pancreat Surg 1999; 6:122–127.
9. Motosugi U, Ichikawa T, Onohara K, Sou H, Sano K, Muhi A, Araki T. Distinguishing hepatic metastasis from hemangioma using gadoxetic acid-enhanced magnetic resonance imaging. Invest Radiol 2011; 46:359–365.
10. Ijuin H, Ono N, Koga K, Yoshida T, Ohnishi H, Miyazaki S, et al.. Inflammatory pseudotumor of the liver – MR imaging findings. Kurume Med J 1997; 44:305–313.
11. Wang LX, Liu K, Lin GW, Zhai RY. Solitary necrotic nodules of the liver: histology and diagnosis with CT and MRI
. Hepat Mon 2012; 12:e6212.
12. Soyer P, Bluemke DA, Sibert A, Laissy JP. MR imaging of intrahepatic cholangiocarcinoma
. Abdom Imaging 1995; 20:126–130.
13. Choi BI, Han JK, Shin YM, Baek SY, Han MC. Peripheral cholangiocarcinoma
: comparison of MRI
with CT. Abdom Imaging 1995; 20:357–360.
14. Koh DM, Brown G, Meer Z, Norman AR, Husband JE. Diagnostic accuracy of rim and segmental MRI
enhancement of colorectal hepatic metastasis after administration of mangafodipir trisodium. Am J Roentgenol 2007; 188:W154–W161.
15. Bartolotta TV, Taibbi A, Galia M, Lo Re G, La Grutta L, Grassi R, Midiri M. Centrifugal (inside-out) enhancement of liver hemangiomas: a possible atypical appearance on contrast-enhanced US. Eur J Radiol 2007; 64:447–455.
16. Yun EJ, Choi BI, Han JK, Jang HJ, Kim TK, Kim AY, Lee KY. Hepatic hemangiomas: contrast enhancement patterns on two-phase spiral CT. J Korean Radiol Soc 1998; 38:93–98.
17. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma
in the United States. Hepatology 2001; 33:1353–1357.
18. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma
. Semin Liver Dis 2004; 24:115–125.
19. Vilgrain V. Staging cholangiocarcinoma
by imaging studies. HPB (Oxford) 2008; 10:106–109.
20. Huppertz A, Haraida S, Kraus A, Zech CJ, Scheidler J, Breuer J, et al.. Enhancement of focal liver lesions at gadoxetic acid-enhanced MR imaging: correlation with histopathologic findings and spiral CT – initial observations. Radiology 2005; 234:468–478.
21. Kim SH, Lee CH, Kim BH, Kim WB, Yeom SK, Kim KA, Park CM. Typical and atypical imaging findings of intrahepatic cholangiocarcinoma
using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging. J Comput Assist Tomogr 2012; 36:704–709.
22. Weiss L, Grundmann E, Torhorst J, Hartveit F, Moberg I, Eder M, et al.. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol 1986; 150:195–203.
23. Niekel MC, Bipat S, Stoker J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment. Radiology 2010; 257:674–684.
24. Martin DR, Danrad R, Hussain SM. MR imaging of the liver. Radiol Clin North Am 2005; 43:861–886.
25. Yoon SS, Tanabe KK. Surgical treatment and other regional treatments for colorectal cancer liver metastases. Oncologist 1999; 4:197–208.
26. Choi EA, Lei H, Maron DJ, Mick R, Barsoum J, Yu QC, et al.. Combined 5-fluorouracil/systemic interferon-beta gene therapy results in long-term survival in mice with established colorectal liver metastases. Clin Cancer Res 2004; 10:1535–1544.
27. Zech CJ, Herrmann KA, Reiser MF, Schoenberg SO. MR imaging in patients with suspected liver metastases: value of liver-specific contrast agent Gd–EOB–DTPA. Magn Reson Med Sci 2007; 6:43–52.
28. Yan FH, Zhou KR, Jiang YP, Shi WB. Inflammatory pseudotumor of the liver: 13 cases of MRI
findings. World J Gastroenterol 2001; 7:422–424.
29. Abehsera M, Vilgrain V, Belghiti J, Flejou J-F, Nahum H. Inflammatory pseudotumor of the liver: radiologic–pathologic correlation. J Comput Assist Tomogr 1995; 19:80–83.
30. Ganesan K, Viamonte B, Peterson M, Kono Y, Santillan C, Middleton M, Sirlin C. Capsular retraction: an uncommon imaging finding in hepatic inflammatory pseudotumour. Br J Radiol 2009; 82:e256–e260.
31. Zen Y, Fujii T, Sato Y, Masuda S, Nakanuma Y. Pathological classification of hepatic inflammatory pseudotumor with respect to IgG4-related disease. Mod Pathol 2007; 20:884–894.
32. Kim T, Federle MP, Baron RL, Peterson MS, Kawamori Y. Discrimination of small hepatic hemangiomas from hypervascular malignant tumors smaller than 3 cm with three-phase helical CT. Radiology 2001; 219:699–706.
33. Venkataraman S, Semelka RC, Braga L, Danet IM, Woosley JT. Inflammatory myofibroblastic tumor of the hepatobiliary system: report of MR imaging appearance in four patients. Radiology 2003; 227:758–763.
34. Kitajima K, Kuwata Y, Hayashi M, Imanaka K, Kaji Y, Sugimura K. Ring enhancement on T1-weighted GRE images after ferucarbotran administration for hepatic metastasis: comparison with pathological findings: case report. Radiat Med 2005; 23:75–79.
35. Kim YK, Han YM, Kim CS. Comparison of diffuse hepatocellular carcinoma and intrahepatic cholangiocarcinoma
using sequentially acquired gadolinium-enhanced and resovist-enhanced MRI
. Eur J Radiol 2009; 70:94–100.
Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
cholangiocarcinoma; hepatic hemangioma; hypovascular hepatic nodule; liver cancer; MRI