Liver/Bile Ducts| Volume 160, ISSUE 3, P654-660, September 2016

Natural history of nonenhancing lesions incidentally detected during the diagnosis of hepatocellular carcinoma


      Incidental detection of nonenhancing tumors during imaging studies for patients with classical hepatocellular carcinoma is not unusual. These tumors are considered to have a high potential of malignant transformation. The aim of this study was to clarify the natural history of such tumors.


      In 93 patients who underwent liver resection for hepatocellular carcinoma, 138 nonenhancing or enhancing nodules without washout were detected during dynamic computed tomography and observed without further treatments. We subsequently compared the cumulative occurrence of new hepatocellular carcinomas to that of the malignant transformation of these lesions. We additionally compared the appearance of new hepatocellular carcinomas between the patients with (n = 93) and without (n = 782) nonenhancing lesions or enhancing lesions without washout.


      After a median follow-up period of 0.7 years (range, 0.2–6.8), the median intervals from resection to the appearance of new classical hepatocellular carcinoma and malignant transformation of nonenhancing lesions or enhancing lesions without washout were 1.6 years (95% confidence interval, 1.2–1.9) and 2.3 years (1.9–6.8 years; P = .002), respectively. On the other hand, the median intervals from resection to the appearance of new lesions in patients with and without nonenhancing lesions or enhancing lesions without washout were 1.6 years (95% confidence interval, 1.2–1.9) and 2.1 years (1.9–2.1 years; P = .031), respectively.


      During the natural history of nonenhancing lesions and enhancing lesions without washout that coexist with hepatocellular carcinoma, new lesions often develop prior to the malignant transformation of these lesions. This should be considered a risk factor for the appearance of new hepatocellular carcinoma.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bolondi L.
        • Gaiani S.
        • Celli N.
        • Golfieri R.
        • Grigioni W.F.
        • Leoni S.
        • et al.
        Characterization of small nodules in cirrhosis by assessment of vascularity: The problem of hypovascular hepatocellular carcinoma.
        Hepatology. 2005; 42: 27-34
        • Matsui O.
        • Kobayashi S.
        • Sanada J.
        • Kouda W.
        • Ryu Y.
        • Kozaka K.
        • et al.
        Hepatocelluar nodules in liver cirrhosis: Hemodynamic evaluation (angiography-assisted CT) with special reference to multi-step hepatocarcinogenesis.
        Abdom Imaging. 2011; 36: 264-272
        • Rao P.N.
        Nodule in liver: Investigations, differential diagnosis and follow-up.
        J Clin Exp Hepatol. 2014; 4: S57-S62
        • Takayasu K.
        • Arii S.
        • Sakamoto M.
        • Matsuyama Y.
        • Kudo M.
        • Ichida T.
        • et al.
        Clinical implication of hypovascular hepatocellular carcinoma studied in 4,474 patients with solitary tumour equal or less than 3 cm.
        Liver Int. 2013; 33: 762-770
        • Ichikawa S.
        • Ichikawa T.
        • Motosugi U.
        • Sano K.
        • Morisaka H.
        • Enomoto N.
        • et al.
        Presence of a hypovascular hepatic nodule showing hypointensity on hepatocyte-phase image is a risk factor for hypervascular hepatocellular carcinoma.
        J Magn Reson Imaging. 2014; 39: 293-297
        • Maruyama H.
        • Takahashi M.
        • Ishibashi H.
        • Yoshikawa M.
        • Yokosuka O.
        Contrast-enhanced ultrasound for characterisation of hepatic lesions appearing non-hypervascular on CT in chronic liver diseases.
        Br J Radiol. 2012; 85: 351-357
        • Matsuda M.
        • Ichikawa T.
        • Amemiya H.
        • Maki A.
        • Watanabe M.
        • Kawaida H.
        • et al.
        Preoperative gadoxetic Acid-enhanced MRI and simultaneous treatment of early hepatocellular carcinoma prolonged recurrence-free survival of progressed hepatocellular carcinoma patients after hepatic resection.
        HPB Surg. 2014; 2014: 641685
        • Roncalli M.
        • Borzio M.
        • Di Tommaso L.
        Hepatocellular dysplastic nodules.
        Ann Ital Chir. 2008; 79: 81-89
        • Takayama T.
        • Makuuchi M.
        • Hirohashi S.
        • Sakamoto M.
        • Yamamoto J.
        • Shimada K.
        • et al.
        Early hepatocellular carcinoma as an entity with a high rate of surgical cure.
        Hepatology. 1998; 28: 1241-1246
        • Yamamoto M.
        • Takasaki K.
        • Otsubo T.
        • Katsuragawa H.
        • Katagiri S.
        • Yoshitoshi K.
        • et al.
        Favorable surgical outcomes in patients with early hepatocellular carcinoma.
        Ann Surg. 2004; 239: 395-399
        • Midorikawa Y.
        • Yamamoto S.
        • Tsuji S.
        • Kamimura N.
        • Ishikawa S.
        • Igarashi H.
        • et al.
        Allelic imbalances and homozygous deletion on 8p23.2 for stepwise progression of hepatocarcinogenesis.
        Hepatology. 2009; 49: 513-522
        • Cho Y.K.
        • Wook Chung J.
        • Kim Y.
        • Je Cho H.
        • Hyun Yang S.
        Radiofrequency ablation of high-grade dysplastic nodules.
        Hepatology. 2011; 54: 2005-2011
        • Kaji K.
        • Terada T.
        • Nakanuma Y.
        Frequent occurrence of hepatocellular carcinoma in cirrhotic livers after surgical resection of atypical adenomatous hyperplasia (borderline hepatocellular lesion): A follow-up study.
        Am J Gastroenterol. 1994; 89: 903-908
        • Midorikawa Y.
        • Takayama T.
        • Shimada K.
        • Nakayama H.
        • Higaki T.
        • Moriguchi M.
        • et al.
        Marginal survival benefit in the treatment of early hepatocellular carcinoma.
        J Hepatol. 2013; 58: 306-311
        • Borzio M.
        • Fargion S.
        • Borzio F.
        • Fracanzani A.L.
        • Croce A.M.
        • Stroffolini T.
        • et al.
        Impact of large regenerative, low grade and high grade dysplastic nodules in hepatocellular carcinoma development.
        J Hepatol. 2003; 39: 208-214
        • Toyoda H.
        • Kumada T.
        • Tada T.
        • Niinomi T.
        • Ito T.
        • Sone Y.
        • et al.
        Non-hypervascular hypointense nodules detected by Gd-EOB-DTPA-enhanced MRI are a risk factor for recurrence of HCC after hepatectomy.
        J Hepatol. 2013; 58: 1174-1180
        • Makuuchi M.
        • Hasegawa H.
        • Yamazaki S.
        Intra-operative ultrasonic examination for hepatectomy.
        Jpn J Clin Oncol. 1981; 11: 367-389
        • Takayama T.
        • Makuuchi M.
        • Hirohashi S.
        • Sakamoto M.
        • Okazaki N.
        • Takayasu K.
        • et al.
        Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma.
        Lancet. 1990; 336: 1150-1153
        • Oikawa T.
        • Ojima H.
        • Yamasaki S.
        • Takayama T.
        • Hirohashi S.
        • Sakamoto M.
        Multistep and multicentric development of hepatocellular carcinoma: histological analysis of 980 resected nodules.
        J Hepatol. 2005; 42: 225-229
        • Kobayashi M.
        • Ikeda K.
        • Hosaka T.
        • Sezaki H.
        • Someya T.
        • Akuta N.
        • et al.
        Dysplastic nodules frequently develop into hepatocellular carcinoma in patients with chronic viral hepatitis and cirrhosis.
        Cancer. 2006; 106: 636-647
        • Sato T.
        • Kondo F.
        • Ebara M.
        • Sugiura N.
        • Okabe S.
        • Sunaga M.
        • et al.
        Natural history of large regenerative nodules and dysplastic nodules in liver cirrhosis: 28-year follow-up study.
        Hepatol Int. 2015; 9: 330-336
        • Takayasu K.
        • Muramatsu Y.
        • Mizuguchi Y.
        • Moriyama N.
        • Ojima H.
        Imaging of early hepatocellular carcinoma and adenomatous hyperplasia (dysplastic nodules) with dynamic CT and a combination of CT and angiography: Experience with resected liver specimens.
        Intervirology. 2004; 47: 199-208