【摘要】肝細(xì)胞癌(hepatocellular carcinoma，HCC)的發(fā)生是一個多步驟、逐步癌變的過程，影像學(xué)技術(shù)對多步癌變結(jié)節(jié)的早期準(zhǔn)確診斷和鑒別診斷尤為重要。本文旨在總結(jié)肝硬化結(jié)節(jié)磁共振(magnetic resonance，MR)影像特征的特異性和規(guī)律性，實現(xiàn)肝硬化再生結(jié)節(jié)多步演變的早期診斷及鑒別診斷。

［doi: 10．3969/j．issn．1006-7795．2015．04．029］·轉(zhuǎn)化醫(yī)學(xué)研究·

基金項目:北京佑安醫(yī)院肝臟疾病與艾滋病研究項目(BJYAH-2011-067)。This study was supported by the Liver Disease and AIDS Research Fund of Youan Hospital(BJYAH-2011-067)．* Corresponding author，E-mail: lihongjun00113@ 126．com

網(wǎng)絡(luò)出版時間: 2015－07－16 23∶16網(wǎng)絡(luò)出版地址: http:∥www．cnki．net/kcms/detail/11．3662．r．20150716．2316．033．html

MR imaging research situation of HBV related multistep hepatocarcinogenesis and the latest progress

Zhang Yanyan，Li Hongjun *

(Department of Radiology，Beijing Youan Hospital，Capital Medical University，Beijing 100069，China)

【Abstract】The development of Hepatocellular carcinoma(HCC)is described either as de novo hepatocarcinogenesis or as a multistep process，and it is important to diagnosis accurately and differential diagnosis the multi-step hepatocarcinogenesis nodules using the imaging technology．The purpose of this paper is to summarize the specificity and regularity of the magnetic resonance(MR)imaging characteristics for the cirrhotic nodule，and to realize the early diagnosis and differential diagnosis of the cirrhotic regenerative nodules．

【Key words】hepatocellular carcinoma; multi-step hepatocarcinogenesis; hemodynamic changes

Hepatocellular carcinoma(HCC)is a major world health problem and the sixth most common malignancy worldwide，ranking as the third most common cause of death from cancer．The majority of HCCs develop in cirrhotic livers，with approximately 80% of cases of HCC developing in a cirrhotic liver．The development of HCC is described either as de novo hepatocarcinogenesis or as a multistep process in the following: from regenerative nodule(RN)，to low-grade dysplastic nodule(LGDN)，high-grade dysplastic nodule(HGDN)，early HCC，welldifferentiated HCC，nodule-in-nodule HCC，and finally，to moderately differentiated HCC ［1-2］．Of course，carcinoma may also occur independently from regenerative nodules or dysplastic nodules．HCC is a devastating cancer with a five-year survival rate of＜5% when diagnosed at an advanced stage ［3］．Patients with high-grade dysplastic nodules are at a high risk for HCC．So the early detection and characterization of this entity is very important，which may in turn improve prognosis．Based on recent clinical practice guidelines，imaging is largely replacing pathology as the preferred diagnostic method for determination ［4］．With the progress of imaging modality，MRI is becoming the most sensitive tool in the differentiation of premalignant/borderline lesions and early HCC，because it provides better soft-tissue contrast and a more naunced depiction of different tissue properties，without ionizing radiation．As is known to all，HGDN is precancerous lesion and malignant transformation rate is higher; so the diagnosis and the differential diagnosis between early HCC and HGDN have been the focus and the difficult debate ［5-6］．In this review，we aimed at analyze the characteristics of nodules in different stages through the control study of the magnetic resonance(MR)imaging and pathologic feature，on the other hand，we devoted toimprove the sensitivity of MR imaging for detection of these nodules and decrease the mortality．

1　Intranodular hemodynamic changes

Hemodynamic change is an important accompanying symptom during the progression from regeneration nodules to cancer and hemodynamic features of nodules remain the main diagnostic criterion．Research displays that the pathologic findings and grade of malignancy are closely related to the intra-and peri-nodular hemodynamics of HCC and the imaging features can be largely explained by the changes of the blood supply in the nodules ［7］．The blood supply of a RN continues to be largely from the portal vein，with minimal contribution from the hepatic artery．As dedifferentiation progresses within these nodules，angiogenic pathways are activated that induce new vessel formation，which manifests as an increased density of unpaired arteries and sinusoidal capillary units ［8-10］．Intranodular portal venous supply gradually decreases as the grade of malignancy of the nodules evolves and finally disappears，on the other hand，the arterial supply first decreases at the early stage and then acutely increases，and finally，the entire nodule is fed only by the abnormal hepatic artery ［11-12］and is usually seen as a hypervascular lesion on imaging studies．CT hepatic angiography and CT arterial portography can visualize the intranodular hemodynamic changes，but we can see the arterial enhancement patterns on contrast-enhanced MR imaging．

2　Intranodular composition changes

In the cancerization process of nodules，the component within nodules will be changed．Nodules are usually exhibit increased cell density and show cytoplasms with fatty/eosinophilic modifications，iron or copper accumulation．Intralesional fatty infiltration is a feature of dysplastic nodules or well-differentiated HCCs in the cirrhotic liver．Diffuse fatty change is observed in 40% of tumors＜2 cm in diameter and the fatty content decreases along with an increase in tumor size．Fatty metamorphosis is attributed to a relative decrease in the blood supply caused by diminished portal supply and immature arterial neovascularization．Iron deposit in the nodules(siderotic nodules)is another problem in cirrhotic patients，researchers found that siderotic nodules in particular a diameter greater than 8mm，have a higher malignant transformation ［13］．

Some nodules show hyperintensity on T1 weighted images(T1WI)due to the presence of fatty，protein or copper in the intranodules，while reflecting the better differentiated．Gradient-recalled echo(GRE)with out-ofphase and in-phase image are helpful to evaluate hepatic or intralesional steatosis and the lipid-containing nodules display signal loss on out-of-phase GRE images in comparison with in-phase images．Moreover siderotic nodules usually have decreased signal intensity on both T1-and T2 weighted images(T2WI)owing to susceptibility．As a new MR imaging technique，SWI(susceptibility-weighted imaging)now is getting used to monitor iron deposit within the nodules due to having a higher sensitivity．Recently we introduce a Dixon technique，which can separate the fat and water signal using multi-echo acquisitions，the software has been tested internally but not yet in a clinical environment．Therefore a lot of images and pathologic datas are still needed，to confirm this technology can replace invasive examination in human to calculate the content of fat and water．

3　Nodule size

For nodules in a cirrhotic liver，it has been suggested that the malignant potential depends on the size of the lesion．Nodules with a benign lesion seldom exceeding 2 cm，if malignant，are usually well differentiated．Similarly，lesions with a diameter of more than 2 cm tend to be malignant and more likely to be moderated to poor differentiation．Although early HCCs are usually＜2 cm in diameter，unusually large regenerative nodules and dysplastic nodules can measure 5 cm or larger and mimic a mass，but they are rare．If the diameter of nodules gradually increase in continuous follow-up imaging，it suggests that the malignant degree is increasing．

4　Capsule

Capsule is a kind of thin and annular tissue in theedge of lesion，and has a difference with adjacent liver parenchyma in density or signal．Typical LGDN and HGDN have no real capsules，but there is a dense fibrous tissue surrounding the nodule，so you can see a clear or vague nodular structure in the cirrhotic background．A capsule may be present in regenerative nodules and dysplastic nodules．Psuedocapsule formation is an important feature of HCC，a tumor capsule composed of an inner layer of fibrous tissue and an outer layer of compressed vessels and bile ducts．MRI T1WI is the most sensitive method to display the capsule and characterize a complete or incomplete signal belt，T2WI shows low or high signal．Generally a well defined capsule predicts that there is no microvascular invasion．Some lesions without a capsule show quite marked early arterial enhancement in the peri-lesional liver parenchyma(corona enhancement)．

Previous studies showed that RN usually takes on low signal on plain T2WI and T2* WI and performance diversity on T1WI; The blood supply of RN mainly comes from the portal vein，so it is difficult to show on dynamic contrast-enhanced MRI．Typical DN display hypersignal on T1WI and iso-hypo-signal on T2WI，however the signal strength of majority DN has a overlap with RN and well-differentiated HCC; on T2WI，LGDN shows a lower signal contrast with the adjacent liver parenchyma，HGDN shows slightly increased signal，TIWI is no helpful for the identification of LGDN and HGDN; Most of the DN are mainly blooded by the portal vein，a few by the artery(mainly HGDN)，therefore DN often cannot display enhancing on dynamic contrast-enhanced T1WI．Typical findings for confirmed HCC are long T1 and T2 signal，high signal intensity in the arterial phase and a rapidly washout in the portal venous and equilibrium phases，which is fast in and out．

But some nodules with malignant transformation tendency may mimic the imaging pattern of HCC．So for the nodules that T2-weighted hyperintensity，arterial enhancement and portal venous washout，we highly suspect malignant; For the nodules whose imaging features are nonspecific，especially those small hypervascular nodules detected on contrast-enhanced images，follow up imaging become necessary to verify their nature．Intervals of follow-up are only dictated by the growth rate of the tumor，which on average takes six months to double its volume ［14］．In the long-term follow-up，we should be alert to some signs of nodules canceration，and the signs are as follows:①Interval growth≥3 mm /year;②Iso-and hyper-signal gradually transformed into slightly hypo-signal on T1WI;③Displayed nodule in nodule on T2WI; ④Arterial phase gradually enhancement;⑤Nodule strengthening in nodule．

In carcinogenesis，from the conversion of a normal cell to invasive cancer，the hallmarks of cancer are manifested from metabolic reprogramming ［15-16］．Therefore，functional imaging would be gradually introduced，the development of imaging techniques and the use of newly developed contrast agents have shown great possibilities for improving the diagnosis and may overcome the diagnostic dilemma associated with the hepatocellular lesions，particularly precancerous lesions．But for some lesions，using imaging method cannot identify，the fine needle puncture is necessary．

5 References

［1］　Kudo M．Multistep human hepatocarcinogenesis: correlation of imaging with pathology［J］．J Gastroenterol，2009，44(19): 112-118．

［2］　Choi B I，Takayasu K，Han M C．Small hepatocellular carcinomas and associated nodular lesions of the liver: pathology．pathogenesis，and imaging findings［J］．AJR Am J Roentgenol，1993，160(6): 1177-1187．

［3］　Davila J A，Morgan R O，Richardson P A，et al．Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States［J］．2010，52(1): 132-141．

［4］　Omata M，Lesmana L A，Tateishi R，et al．Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma［J］．2010，4(2): 439-474．

［5］　Kojiro M．Focus on dysplastic nodules and early hepatocellular carcinoma: an Eastern point of view［J］．Liver Transpl，2004，10(2 Suppl1): S3-S8．

［6］　Kojiro M，Roskams T．Early hepatocellular carcinoma and dysplastic nodules［J］．Semin Liver Dis，2005，25(2): 133-142．

［7］　Efremidis S C，Hytiroqlou P．The multistep process of hepatocarcinogenesis in cirrhosis with imaging correlation［J］．Eur Radiol，2002，12(4): 753-764．

［8］　Borzio M，F(xiàn)argion S，Borzio F，et al．Impact of large regenerative，low grade and high grade dysplastic nodules in hepatocellular carcinoma development［J］．J Hepatol，2003，39(2): 208-214．

［9］　Colli A，F(xiàn)raquelli M，Casazza G，et al．Accuracy of ultrasonography，spiral CT，magnetic resonance，and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review［J］．Am J Gastroenterol，2006，101(3): 513-523．

［10］Snowberger N，Chinnakotla S，Lepe R M，et al．Alpha fetoprotein，ultrasound，computerized tomography and magnetic resonance imaging for detection of hepatocellular carcinoma in patients with advanced cirrhosis［J］．Aliment Pharmacol Ther，2007，26(9): 1187-1194．

［11］Matsui O，Kobayashi S，Sanada J，et al．Hepatocelluar nodules in liver cirrhosis: hemodynamic evaluation(angiography-assisted CT)with special reference to multi-step hepatocarcinogenesis［J］．Abdom Imaging，2011，36(3): 264-272．

［12］Park Y N，Yang C P，F(xiàn)ernandez G J，et al．Neoangiogenesis and sinusoidal“capillarization”in dysplastic nodules of the liver［J］．Am J Surg Pathol，1998，22(6): 656-662．

［13］Ito K，Mitchell D G，Gabata T，et al．Hepatocellular carcinoma: association with increased iron deposition in the cirrhotic liver at MR imaging［J］．Radiology，1999，212(1): 235-240．

［14］Di Tonnaso L，Sanqiovanni A，Borzio M，et al．Advanced precancerous lesions in the liver［J］．Best Pract Res Clin Gastroenterol，2013，27(2): 269-284．

［15］Hanahan D，Weinberq R A．The hallmarks of cancer［J］．Cell，2000，100(1): 57-70．

［16］Gatenby R A，Gillies R J．A microenvironmental model of carcinogenesis［J］．Nat Rev Cancer，2008，8(1): 56-61．

(收稿日期: 2014-01-13)

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