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Diagnosis of Small Hepatocellular Carcinoma
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Hepatology
July 2005
Morris Sherman, M.B., B.Ch., Ph.D, FRCP(C) *§
Department of Medicine, University of Toronto and University Health Network, Toronto, ON, Canada
Abstract for study upon which Editorial is based. Editorial follows this abstract:
"Characterization of small nodules in cirrhosis by assessment of vascularity: The problem of hypovascular hepatocellular carcinoma"
Luigi Bolondi 1 *, Stefano Gaiani 1, Natascia Celli 1, Rita Golfieri 2, Walter Francesco Grigioni 3, Simona Leoni 1, Anna Maria Venturi 1, Fabio Piscaglia 1
1Division of Internal Medicine, Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy
2Division of Radiology, Policlinico S. Orsola Malpighi, Bologna, Italy
3Department of Pathology, Institute of Oncology F. Addarii, University of Bologna, Bologna, Italy
ABSTRACT
In a prospective study, we examined the impact of arterial hypervascularity, as established by the European Association for the Study of the Liver (EASL) recommendations, as a criterion for characterizing small (1-3 cm) nodules in cirrhosis. A total of 72 nodules (1-2 cm, n = 41; 2.1-3 cm, n = 31) detected by ultrasonography in 59 patients with cirrhosis were included in the study. When coincidental arterial hypervascularity was detected at contrast perfusional ultrasonography and helical computed tomography, the lesion was considered to be hepatocellular carcinoma (HCC) according to EASL criteria. When one or both techniques showed negative results, ultrasound-guided biopsy was performed. In cases with negative results for malignancy or high-grade dysplasia, biopsy was repeated when an increase in size was detected at the 3-month follow-up examination. Coincidental hypervascularity was found in 44 of 72 nodules (61%; 44% of 1-2-cm nodules and 84% of 2-3-cm nodules). Fourteen nodules (19.4%) had negative results with both techniques (hypovascular nodules). Biopsy showed HCC in 5 hypovascular nodules and in 11 of 14 nodules with hypervascularity using only one technique. All nodules larger than 2 cm finally resulted to be HCC. Not satisfying the EASL imaging criteria for diagnosis were 38% of HCCs 1 to 2 cm (17% hypovascular) and 16% of those 2 to 3 cm (none hypovascular). In conclusion, the noninvasive EASL criteria for diagnosis of HCC are satisfied in only 61% of small nodules in cirrhosis; thus, biopsy frequently is required in this setting. Relying on imaging techniques in nodules of 1 to 2 cm would miss the diagnosis of HCC in up to 38% of cases. Any nodule larger than 2 cm should be regarded as highly suspicious for HCC. THE REMAINDER OF THE FULL TEXT FOLLOWS THE EDITORIAL BELOW.
EDITORIAL
As radiological techniques used to screen patients for hepatocellular carcinoma (HCC) have improved, smaller and smaller liver nodules are being identified. The smaller the nodule seen, the more difficult it is to be certain of the relationship between the nodule and the development of HCC. Determining whether these small nodules are cancer is challenging. Deciding whether they should be treated or not is at present a matter of expert opinion, rather than evidence based.
Carcinogenesis is a process in which there is no clear morphological boundary between a lesion that is still subject to growth regulation and one that that is no longer subject to regulation and can proliferate independently of its neighbors. Thus, perhaps it should not come as a surprise that it is so difficult to make this distinction when we attempt to define the nature of small nodules seen on ultrasound screening for HCC. Further complicating the picture is the presence of numerous nodules that have nothing to do with malignancy, namely the cirrhotic nodule. Some of these nodules have arterial blood flow because the sinusoids are arterialized or because the portal veins have been damaged or destroyed.[1] On vascular imaging, such as triphasic computed tomography (CT) scanning, these may show arterial enhancement, but typically they do not show venous washout.
Like all other cancers, HCC evolves through series of steps in which clones of cells emerge that are less and less subject to growth regulation. Although there are probably many steps that occur at a genetic level, the only discrete morphological change that has been identified as an intermediate in the malignant pathway is the small cell dysplastic change.[2] This may occur as a focus a few cells in size, or enlarge into a nodule (high-grade dysplastic nodule). That at least some of these lesions become malignant seems clear from the finding of a nodule-in-nodule appearance. This occurs when a nodule that is morphologically neoplastic develops within a dysplastic nodule.[3][4] However, it is not clear that all dysplastic nodules inevitably become cancer. In fact, it is likely that some remain stable for some time, and others even regress completely.[5] Small cell dysplastic change is, in general, a marker of increased HCC risk. The HCC may develop in a focus of small cell change (dysplastic focus or nodule) or may develop elsewhere in the liver. Simply finding a dysplastic nodule does not mean that HCC will inevitably follow in that nodule.
In addition to these changes Japanese pathologists have described two morphological variants of liver nodule that they consider to be established but early malignancy.[6] The so-called early HCC is a nodule with poorly defined margins, in which the cells are morphologically close to normal but in which some features associated with malignancy can be found. Most often this is invasion of the portal space, and less often of vascular structures, by hepatocyte-like cells. The hepatocytes in the nodule often contain fat and are supplied by the portal vein rather than the hepatic artery.[7][8] On ultrasound these lesions are bright because they contain fat, and on CT they are hypoattenuating. Because they are fed by the portal vein, they do not show the typical arterial enhancement and venous washout that characterize HCC.[9] In contrast, the so-called small HCC, thought to be a more advanced form of HCC than the early HCC, is surrounded by a capsule and is fed by the hepatic artery.[9] The hepatocytes express many more features of malignancy, such as an altered nucleo-cytoplasmic ratio and nuclear atypia. The distinguishing features of these two lesions have been described from resected specimens. These lesions may show a halo effect on ultrasound, and on CT they show the typical arterial enhancement and venous washout. Needle biopsy of early HCC, however, rarely shows the typical features of the lesion, because the diagnostic features are very focal. Even small HCC can be missed on a biopsy. It should be emphasized that the natural history of these small lesions is unknown because they were described in resected specimens, so their natural history could not be observed. It is presumed (but not certain) that these lesions are malignant. It seems likely that the small HCC is indeed malignant based on its description, and invasion of the portal space in the early HCC would also suggest malignancy, when present.
In 2001 the European Association for Study of the Liver (EASL) convened a consensus conference on the management of hepatocellular carcinoma.[10] With regard to HCC diagnosis the consensus document states that lesions smaller than 1 cm do not need to be biopsied but can simply be observed to see whether they enlarge over time. In a liver with cirrhosis, lesions larger than 2 cm that were shown to be vascular using two imaging techniques can also be considered HCC and do not need to be biopsied. The group recommended that lesions between 1 and 2 cm should be biopsied. The authors recognized that these recommendations were based on expert opinion and that there were no studies to support these recommendations. Nonetheless, these seemed appropriate at the time. The recommendations were silent regarding what to do with nodules larger than 2 cm that did not meet the defined radiological criteria.
Bolondi and his colleagues have addressed this issue in their article published in this edition of HEPATOLOGY.[11] They examined the relationship between the radiological appearance of nodules found on HCC screening and their histological diagnosis. They stratified the results by lesion size according to the EASL criteria. All lesions that were larger than 2 cm turned out to be HCC. The majority (84%) exhibited typical radiology and were confirmed by biopsy. The other 16% did not meet the EASL radiological criteria and were diagnosed only by biopsy. Thus, the study confirms the EASL recommendations for lesions larger than 2 cm. If the lesion is hypervascular by 2 radiological techniques a biopsy is not necessary.However, if the lesion does not meet these criteria biopsy must be performed. For lesions between 1 and 2 cm in size only 71% were diagnosed as HCC on biopsy, either at the first biopsy, or, if the first biopsy was negative, a subsequent biopsy after interval growth confirmed the diagnosis. Again, this confirms the EASL recommendations that lesions between 1 and 2 cm should be biopsied. Note that in this study, as in others,[5] a negative biopsy did not exclude the diagnosis of HCC. The message is that all patients with a liver mass and a biopsy that is negative for HCC must be followed at frequent intervals to document a change in lesion size that might require another biopsy.
When the EASL consensus document was written the importance of the washout in the portal venous phase of a triphasic CT scan was perhaps not fully appreciated.[9][12] Washout is the appearance of a hypoattenuating area in the portal venous phase of a triphasic CT liver scan that was hyperattenuating compared with the rest of the liver in the arterial phase. During the arterial phase the HCC, which is fed by the hepatic artery only, enhances more strongly compared with the surrounding liver. This is because the blood in the liver is both arterial and portal, so that the contrast agent, which is being delivered exclusively by the hepatic artery at this stage, is diluted by the portal blood, while the arterial blood in the tumor is undiluted. During the venous phase the arterial blood feeding the tumor now contains diluted contrast or very little contrast, while the liver enhances more brightly that the tumor because it is fed by venous blood with a relatively high concentration of contrast, as well as arterial blood. Thus, in the arterial phase the lesion is hyperattenuating (bright) compared with the rest of the liver, and in the venous phase the tumor is hypoattenuating compared with the rest of the liver. This finding is highly specific for HCC. Even in lesions between 1 and 2 cm the presence of washout indicates HCC. Thus, the indications for biopsy can be extended further. A nodule found on screening of a liver with cirrhosis should be biopsied if it is larger than 1 cm, if it does not show features of arterial enhancement with washout, and if it is clearly not some other lesion, such as a hemangioma. It should be remembered, however, that context is important. A similar finding in a patient at low risk for HCC may require a different algorithm for investigation, and a more cautious approach may be warranted.
How important is it to identify HCC at such small sizes?
Does it matter if the HCC is identified at 1.5 cm in size or at 3 cm? There are few data to answer this question, but Sala et al.[13] have shown that the smaller the lesion that is treated by radiofrequency ablation, the more likely it is that complete radiological obliteration can be achieved. Survival was also better after ablation of smaller lesions, but lead-time bias was not accounted for. Thus, there would appear to be merit in finding HCC as small as possible.
However, the paradox is that the smaller the HCC, the more difficult it is to diagnose. There are fewer and fewer features of HCC as the lesions are smaller and smaller. It becomes more and more difficult to separate dysplasia from HCC. It may be argued that finding a high-grade dysplastic nodule is tantamount to finding HCC and that all these lesions should also be ablated. This argument depends on how many high-grade dysplastic nodules ultimately develop into HCC. If the proportion is high, and if a large proportion of nodules that are not HCC initially become HCC within a few years, a case can be made for obliterating all such nodules without the benefit of a biopsy. The counterargument is that imaging studies with CT scanning and magnetic resonance imaging have shown that up to 50% of lesions that are smaller than 2 cm and vascular but do not exhibit washout either disappear with time or become smaller and do not become HCC.[14][15] Thus, ablating all vascular nodules between 1 and 2 cm will result in ablation of numerous nonmalignant lesions.
The use of molecular tools may be helpful in the diagnosis of the small early lesions. If it is possible to identify genes expressed early in carcinogenesis in tissue samples it may be possible to make an early diagnosis of HCC. To date, however, there is insufficient information to assess any single marker. HCC has been shown to express beta-catenin,[16][17] p53,[18][19] glypican-3,[20][21] and many other markers. Beta-catenin seems to be expressed later in tumor development, as it is not present in dysplastic nodules.[16] The timing of upregulation of p53 expression may also be a later phenomenon, although some small HCCs also express p53.[18][19] Glypican-3 is expressed early in carcinogenesis and may be a serological marker as well as a molecular marker of early HCC.[20][21] Few of the studies of protein expression in HCC have carefully differentiated between early and later HCC. However, a recent study using microarray technology looked at various nodules, including nonmalignant nodules with cirrhosis, low- and high-grade dysplastic nodules, and early and later HCC, as well as normal liver.22 The investigators were able to identify genes that were differentially regulated in HCC compared with dysplastic nodules, and they were able to use this information to predict whether a nodule was dysplastic or neoplastic. This analysis was performed on resected specimens, so that the problem of sampling error on a needle biopsy may still reduce the accuracy of diagnosis, even if the changes in gene transcription are highly predictive of malignancy.
The challenge upon us now is to find noninvasive methods of distinguishing malignant and pre-malignant lesions from benign ones. Until these are available biopsy of small lesions will remain an important part of the investigation of lesions found on HCC screening.
References
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2 International Working Party. Terminology of nodular hepatocellular lesions. HEPATOLOGY 1995; 22: 983-989. Links
3 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. 4 Kojiro M. Nodule-in-nodule appearance in hepatocellular carcinoma: its significance as a morphologic marker of dedifferentiation. Intervirology 2004; 47: 179-183.
5 Borzio M, Fargion S, Borzio F, Fracanzani AL, Croce AM, 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.
6 Kojiro M. Focus on dysplastic nodules and early hepatocellular carcinoma: an Eastern point of view. Liver Transpl 2004; 10( Suppl 1): S3-S8.
7 Ogata R, Majima Y, Tateishi Y, Kuromatsu R, Shimauchi Y, Torimyra T, et al. Bright loop appearance; a characteristic ultrasonography sign of early hepatocellular carcinoma. Oncol Rep 2000; 7: 1293-1298.
8 Roncalli M, Roz E, Coggi G, Di Rocco MG, Bossi P, Minola E, et al. The vascular profile of regenerative and dysplastic nodules of the cirrhotic liver: implications for diagnosis and classification. HEPATOLOGY 1999; 30: 1174-1178.
9 Iannaccone R, Laghi A, Catalano C, Rossi P, Mangiapane F, Murakami T, et al. Hepatocellular carcinoma: role of unenhanced and delayed phase multi-detector row helical CT in patients with cirrhosis. Radiology 2005; 234: 460-467.
10 Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35: 421-430.
11 Bolondi L, Gaiani S, Celli N, Golfieri R, Grigioni WF, 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.
12 Marrero JA, Hussain HK, Nghiem HV, Umar R, Fontana RJ, Lok AS. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass. Liver Transpl 2005; 11: 281-289.
13 Sala M, Llovet JM, Vilana R, Bianchi L, Sole M, Ayuso C, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. HEPATOLOGY 2004; 40: 1352-1360.
14 O'Malley M, Takayama Y, Sherman M. The fate of arterial enhancing nodules seen on triphasic ct scan in patients with chronic liver disease. Am J Gastro , in press.
15 Shimizu A, Ito K, Koike S, Fujita T, Shimizu K, Matsunaga N. Cirrhosis or chronic hepatitis: evaluation of small (< or=2-cm) early-enhancing hepatic lesions with serial contrast-enhanced dynamic MR imaging. Radiology 2003; 226: 550-555. Links
16 Park JY, Park WS, Nam SW, Kim SY, Lee SH, Yoo NJ, et al. Mutations of beta-catenin and AXIN I genes are a late event in human hepatocellular carcinogenesis. Liver Int 2005; 25: 70-76.
17 An FQ, Matsuda M, Fujii H, Tang RF, Amemiya H, Dai YM, et al. Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cells proliferation, expression and mutation of p53 and beta catenin. Int J Cancer 2001; 93: 468-474.
18 Yano H, Nanashima A, Hidaka S, Haseba M, Tanaka K, Yamaguchi H, et al. Numerical aberrations of chroncsome 17 and the p53 locus in small hepatocellular carcinomas. Anticancer Res 2004; 24: 111-115.
19 Murakami Y, Hayashi K, Hirohashi S, Sekiya T. Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. Cancer Res 1991; 51: 5520-5525. Links
20 Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology 2003; 125: 89-97.
21 Hippo Y, Watanabe K, Watanabe A, Midorikawa Y, Yamamoto S, Ihara S, et al. Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma. Cancer Res 2004; 64: 2418-2423.
00 LLovet JM, Chen Y, Wurmbach E, Roayaie S, Fiel I, Schwartz M, et al. Comparison of gene transcriptional profiles in dysplastic nodules and earlu hepatocellular carcinoma in HCV cirrhosis: identification of molecular markers. J Hepatol 2005; 42( Suppl 2): 20.
REMAINDER OF TEXT FROM ORIGINAL ARTICLE
"Characterization of small nodules in cirrhosis by assessment of vascularity: The problem of hypovascular hepatocellular carcinoma"
Luigi Bolondi 1 *, Stefano Gaiani 1, Natascia Celli 1, Rita Golfieri 2, Walter Francesco Grigioni 3, Simona Leoni 1, Anna Maria Venturi 1, Fabio Piscaglia 1
1Division of Internal Medicine, Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy
2Division of Radiology, Policlinico S. Orsola Malpighi, Bologna, Italy
3Department of Pathology, Institute of Oncology F. Addarii, University of Bologna, Bologna, Italy
Article Text
The definitive diagnosis of a nodular lesion, detected by imaging techniques in a liver with cirrhosis, remains a critical challenge for clinicians. The issue is particularly complicated for small (1-3 cm) nodules, because many of these may be preneoplastic lesions with uncertain malignant potential,[1] such as macroregenerative nodules, low-grade dysplastic nodules (LGDN) or high-grade dysplastic nodules (HGDN), or more rarely, hemangiomas, which can be found altogether in up to 42% of cases in explanted livers.[2-4] It is accepted that a number of these may contain small foci of hepatocellular carcinoma (HCC)[5-7] and that most will evolve into HCC over a few years,[8-10] thus making critical the decision of whether to treat these nodules.
Arterial hypervascularization, detected at contrast-enhanced imaging techniques, is now regarded as a distinctive feature of HCC in cirrhosis, because nonneoplastic nodules still have a prevalent portal vascularization.[11][12] This feature was taken into account in the European Association for the Study of the Liver (EASL) document for the clinical management of HCC published in 2001,[13] where confirmation of the arterial hypervascular pattern by two imaging techniques, even in the absence of a significant (>400 ng/mL) rise in -fetoprotein, was suggested as diagnostic criteria for HCC in nodules larger than 2 cm in patients with cirrhosis, whereas histological confirmation plays a pivotal role in the diagnosis of nodules of 1 to 2 cm because of the potential inaccuracy of imaging techniques in such small nodules. The EASL document, however, did not comment on the problem of discordant vascularity, nor on the interpretation of the hypovascular lesions. Furthermore, these recommendations have not yet been tested and validated in a prospective study aimed not only at establishing the rate of small (<3 cm) HCCs that do not satisfy the proposed noninvasive diagnostic criteria, but also at testing the impact of the more recent techniques. Further, since the establishment of these recommendations, significant improvements have been forthcoming with the advent of contrast-enhanced harmonic ultrasonography (perfusional ultrasonography [US]),[14-16] and more experience has been achieved with multislice helical computed tomography (helical CT).[17][18] Magnetic resonance imaging also has evolved significantly, particularly with the use of reticuloendothelial and hepatospecific contrast agents. Therefore, it is important to establish the efficiency of the currently available advanced techniques (based on the EASL criteria) for the diagnosis of small HCC and whether the diagnostic approach to small nodules in livers with cirrhosis should be updated.
Following these considerations, we planned this prospective study, the primary aim of which was to validate the clinical impact of arterial hypervascularity as a criterion for the diagnosis of HCC in small nodules in cirrhosis detected by conventional US.
Secondary aims were: (1) to detect possible differences in the vascular pattern between nodules at first detection (incidental nodules) and those arising in patients previously submitted to curative treatment of HCC (recurrent nodules); (2) to obtain a pathological characterization of nodules appearing to be hypovascular both at perfusional US and helical CT to assess the true rate of small hypovascular HCC; and (3) to investigate the influence of the size of the nodule in the detection of arterial hypervascularity.
DISCUSSION
In a relevant number of nodules, up to 17.5%,[4][22][23] a diagnosis of malignancy is not achieved with the currently available diagnostic tools and a follow-up policy is undertaken or, alternatively, treatment is tailored individually. It is surprising how this problem, which is so common in clinical practice, has been neglected in most studies dealing with screening and surveillance.[24] The correct diagnostic characterization and staging of these lesions has become even more complicated, because liver transplantation may represent the treatment of choice for most of these patients if a diagnosis of HCC is definitely established. Furthermore, in many transplant centers adopting the Model for End-Stage Liver Disease-HCC scoring system, the presence of HCC significantly increases the priority on the waiting list,[25-27] thus making the precise definition of any nodular lesion mandatory.
The EASL recommendations for the management of HCC[13] provide a rational approach to this problem, but leave some areas of uncertainty, particularly concerning the interpretation of discordant vascularity, the use of imaging techniques in nodules between 1 and 2 cm, the meaning of truly hypovascular nodules, and the management of nodules diagnosed as LGDN or HGDN at guided biopsy. Furthermore, the EASL criteria remain to be validated in a prospective series of patients. The present study, therefore, was aimed at clarifying the vascular pattern of small HCC using imaging techniques and validating the clinical impact of arterial hypervascularity as a criterion for the diagnosis of HCC.
For this purpose, we used the state-of-the-art technologies in the field of US and CT. In accordance with the study protocol (Fig. 2), pathological confirmation was sought and obtained in nearly all cases not fulfilling the noninvasive criteria. Whether the addition of magnetic resonance imaging (possibly with new contrast agents assessing not only the vascular pattern) may modify the diagnostic approach before biopsy will be the subject of future studies.
Vascular Pattern of Small HCC and Its Impact on Noninvasive Diagnostic Criteria:
Histopathological studies have demonstrated a progressive increase in the arterial supply to nodules evolving toward malignancy,[28-30] providing the clues for the clinical diagnosis with imaging techniques.[20][31-35] To give a solid basis for the noninvasive diagnosis, the EASL panel of experts determined that this pattern must be confirmed by two different imaging techniques in nodules larger than 2 cm. No reference was made to vascularity for nodules between 1 and 2 cm, and it was pointed out that these lesions require histopathological investigation. Hence, the EASL criterion of vascularity seems to be applicable only for lesions larger than 2 cm.
Because this represents an important issue that was left open to individual interpretation, we decided to analyze the impact of arterial vascularity also in the group of nodules between 1 and 2 cm, and we were able to confirm that biopsy is required in most of these cases. Whether coincidental hypervascularity in these small lesions or even in nodules larger than 2 cm always correspond to HCC[36] was not addressed in this study and remains open to further investigation.
Data obtained from perfusional US and helical CT showed a coincidental arterial hypervascularity, satisfying the EASL noninvasive criteria, in 61% (44/72) of small (<3 cm) nodules in cirrhosis and in 73% (44/60) of small nodules with a final diagnosis of HCC, demonstrating that guided biopsy is frequently required in this setting. This is particularly true for nodules of 1 to 2 cm, where fulfillment of the criteria drops to 44%, making the need for biopsy quantifiable in more than half of the 1- to 2-cm nodules at first observation. Biopsy demonstrated HCC in 11 of 23 of these cases (48%). This high rate may still be an underestimation, because HCC was detected during a short-term (3-6 months) follow-up in a few other cases. Furthermore, we are aware that the gold standard for assessing diagnostic accuracy is the meticulous examination of the explanted liver, which might have detected foci of HCC in those nodules diagnosed as HGDN. However, this gold standard is not applicable for the purpose of the present study, aimed at validating the EASL noninvasive diagnostic criteria in current clinical practice, in which most patients are not candidate for transplantation and HGDN were immediately treated.
Because some studies have claimed that the analysis of later vascular phases with contrast US[37] may add a significant contribution to the characterization of HCC, we also analyzed these patterns. Our results confirm that a contrast washout leading to hypoattenuation in later phases is the most frequent and typical pattern of HCC with both techniques.
As far as hypovascular nodules at both techniques are concerned, 9 of 14 nodules (64%) proved to be nonmalignant lesions, whereas 5 nodules (all with a diameter between 1.5 and 2 cm; 36%), were truly hypovascular HCC. Hence, hypovascular HCC represents 8.3% of nodules in our series of small (<3 cm) HCCs (5/60), and 17% (5/29) in the subgroup of HCCs with a diameter of 1 to 2 cm. Hypovascular HCC were shown by other authors to be less invasive than the hypervascular type.[38]
In some nodules (14/72; 19.4%), the vascular pattern at perfusional US was different from that at helical CT (with more nodules being positive only at perfusional US). This discrepancy may be because of the different vascular distribution of the US and CT contrast agents, the capacity of perfusional US, by working in continuous real-time, to detect hypervascularity lasting for only a short time or occurring very early, or both. Perfusional US, however, can alsodisplay intranodular portal flow coming from the superior mesenteric vein in the following few seconds, thus making a false-positive result of early hypervascularity, and it has a limitation in depicting vascularity in deeply located small nodules. Apart from these considerations, the detectability of vascularity in small HCC was nearly identical between perfusional US and CT, as also reported by others.[39]
The problem of the recall policy for nodules arising in patients known to have had HCC in the past (recurrent nodules) is another issue which was not discussed in the EASL recommendations. Since this represents an important clinical challenge, due to the high number of non neoplastic nodules coexisting with HCC, as shown in explanted livers,[4] we also stratified nodules into incidental and recurrent and analyzed their vascular pattern separately which proved to be similar. This finding is consistent with the theory that the majority of new nodules arising in livers with cirrhosis and previous HCC are not metastases from the primary lesion, but rather new lesions and it implies that the diagnostic approach must be the same.
The Problem of Nodules Without Confirmation of Malignancy at US-Guided Biopsy:
In a number of cases of hypovascularity shown with both techniques or without coincidental arterial hypervascularity, a diagnosis of HCC was, nonetheless, confirmed, whereas others did not prove malignant even with US-guided biopsy. The latter cases, however, which are not so rare in clinical practice, remain an unsolved diagnostic challenge. Should the finding of hypervascularity with only one technique be regarded as false-positive results? This is difficult to accept if we consider that, in the present investigation, HCC was not confirmed at first biopsy in only 5 of 14 nodules with arterial hypervascularity using only one technique, and that 3 of these 5 were found to be HGDN and the remaining 2 nodules developed into HCC during the 6-month follow-up. When making a clinical decision concerning the management of these cases, we should also take into account the lack of knowledge about the early stages of the natural history of HCC and the limitations and pitfalls of guided biopsy, which may lead to a number of false-negative results as high as 10%.[40] Small foci of HCC may be present in at least one third of dysplastic nodules,[6][41] and these can be missed by biopsy. Different grades of dysplastic changes could also affect different parts of the nodule. Little is known about the possibility of correctly making a definite differential diagnosis of LGDN, HGDN, and HCC from a small biopsy specimen sampled from a part of a nodule.[9] To confirm this difficulty further, even on surgical specimens, a significant interobserver variability of interpretation among pathologists was recently reported.[42]
In our series, we decided to treat nodules diagnosed as HGDN at guided biopsy. We are aware that not all clinicians agree with this policy. However, from a clinical and ethical standpoint, we considered it debatable whether simply to leave these patients in a follow-up program, when curative techniques that carrying a low risk of complications, such as percutaneous ethanol ablation and thermoablation, are available. This policy was also proposed in a previous paper.[43]
The problem remains open for nodules of 1 to 2 cm that appear to be truly hypovascular (34% in our series), because in 5 of 14 (36%), a diagnosis of HCC nonetheless was established, thus corresponding to a rate of hypovascular HCC of 17% in nodules of 1 to 2 cm with cirrhosis in our series (5 of 29 nodules). To summarize, if a clinician were to exclude malignancy in a 1- to 2-cm liver nodule in a patient with cirrhosis merely on the basis of two completely negative contrast imaging findings, he or she would carry a risk of a false-negative diagnosis of more than 35%. This risk is even greater if we consider the possibility of false-negative results at biopsy. At present, however, there is no definite answer to whether a much earlier diagnosis would imply a better outcome, but again, in the perspective of liver transplantation, earlier diagnosis would probably lead to a better chance of being placed on the waiting list and being transplanted successfully.
In conclusion, results of this study show that a number of truly hypovascular HCCs do exist, as previously shown,[43][44] particularly in nodules of 1 to 2 cm, and a not insignificant number of nonmalignant hypovascular lesions may also be found in livers with cirrhosis.[4] These lesions, together with those nodules that appear to be hypervascular with only one technique, without a pathological diagnosis of malignancy, represent an area of clinical uncertainty that accounts for at least 39% of newly diagnosed small nodules in cirrhosis. These uncertainties cannot be easily solved within the EASL recommendations, especially if a biopsy does not yield a definite diagnosis of HCC. New diagnostic parameters based on different physical and pathological alterations, such as those provided by new technologies and nonvascular agents of magnetic resonance imaging, also should be considered in the diagnostic work-up of small HCC.[4][45-48] At present, an aggressive policy should, in our opinion, be considered if arterial hypervascularization with one technique is detected and other benign hypervascular lesions, such as hemangioma, angiomyolipoma, and focal nodular hyperplasia, are reasonably ruled out. Similarly, any new nodule in a liver with cirrhosis with a diameter of more than 2 cm should always be regarded as very suspicious for HCC, because the benign nature of nodules of this size (a situation not encountered in our series) is rare.[49]
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