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Contrast-enhanced ultrasound assessment of arterial vascularization of small nodules arising in the cirrhotic liver
Abstract
Background and aim:
Aim of this study was to compare contrast-enhanced ultrasound and multi-detector row computed tomography in detecting arterial hypervascularity in small cirrhotic nodules.
Patients and methods:
Sixty-two nodules (41 measuring 1.0-2.0 cm, 21 measuring 2.1-3.0 cm) found in 55 cirrhotic patients were examined with both methods. Lesions displaying arterial hypervascularity with washout in the portal/venous phase on both studies were considered hepatocellular carcinomas and treated; all other nodules were subjected to ultrasound-guided fine-needle biopsy.
Results:
The larger nodules (2.1-3.0 cm) included 19 hepatocellular carcinomas (90%), 1 macroregenerative nodule type I and 1 macroregenerative nodule type II; 35 (87%) of the smaller nodules were hepatocellular carcinomas, 2 were macroregenerative nodules type I, 2 macroregenerative nodules type II and 2 hemangiomas. The two studies yielded concordant findings for 54 nodules (87%), including 46 hypervascular on both examinations and 8 that were consistently hypovascular. Two of the latter nodules were hepatocellular carcinomas. The other eight nodules displayed arterial hypervascularity on only one of the studies. Six of these (75%) were hepatocellular carcinomas, including five that were negative in the contrast-enhanced ultrasound study.
Conclusion:
Computed tomography and contrast-enhanced ultrasound show high agreement in the vascular classification of small nodules detected by ultrasound in cirrhotic livers, although the former technique was slightly more sensitive in the detection of arterial hypervascularization.
... US studies were performed with a Philips iU22 system (Philips Ultrasound, Bothell, Washington, USA) in Milan, MyLab scanner (Esaote, Genova, Italy) in Bologna and Rome and Technos MPX, CnTI (Esaote, Genova, Italy) in Piacenza. The vascular pattern of focal liver nodules was assessed by CEUS with a second generation US blood pool contrast agent (Sonovue, Bracco, Milano, Italy), using a dedicated US technology as previously reported by each centre [9,[10][11][12]. All examinations were obtained and evaluated in real time and digitally stored and documented by a commercially available system or videotapes. ...
... Quadruple-phase CT scan (i.e., unenhanced, hepatic arterial, portal/venous and delayed phases) was performed with a P32-multidetector row CT (MDCT) in all four centers using the following equipments: Definition (Siemens Medical Systems, Erlangen, Germany) in Milan, HiSpeed Multislice (GE Medical Systems, Milwaukee, WI, USA) in Piacenza, Emotion 6 (Siemens Medical Systems, Erlangen, Germany) in Bologna and Light Speed VCT XT (GE Medical System, Milwaukee, WI, USA) in Rome, as previously described by each centre [9,[10][11][12]. ...
Background and aim
Although contrast-enhanced computed tomography (CT), dynamic magnetic resonance (MRI) and fine needle biopsy (FNB) are the standard of care to diagnose hepatocellular carcinoma (HCC), the clinical and economic benefits of the updated AASLD diagnostic algorithm, including the drop of contrast enhanced ultrasound (CEUS), have not been previously evaluated.
Patients/Methods
119 de-novo liver nodules detected during ultrasound (US) surveillance in 98 cirrhotics, 7 < 1cm, 67 1-2cm, 45 > 2cm in size, were sequentially examined by CEUS and CT, using MRI as a rescue approach in patients lacking a typical vascular pattern for HCC by one or both contrast techniques in the 1-2 cm nodules and by CT in the >2 cm nodules. A FNB was performed when required to meet both 2005 and 2010 AASLD criteria.
Results
Eighty-four (70%) nodules were HCC: the radiological diagnosis was done in 38 (88%) of those 1-2 cm and in 38 (95%) for those >2 cm HCCs according to 2010 AASLD criteria. CT or MRI detected 13 HCC nodules that were missed by unenhanced US. Despite an absolute specificity, CEUS failed to identify any HCC uncharacterized by CT or MRI. By updated AASLD criteria, 6 (17%) FNB procedures were spared in patients with 1-2 cm nodules (p=0.025), as compared to 2005 criteria. The 2010 vs 2005 AASLD per patient cost was similar in 1-2 cm nodules, 432€ vs 451€ (p=0.46), but lower in > 2cm nodules, 248€ vs 321€ (p<0.001).
Conclusions
A sequential study with either CT or MRI enhances the radiological diagnosis of HCC and reduces costs and liver biopsy need.
... CEUS using non-linear imaging modes has been used to improve sonographic visualization of hepatic tumor vascularity [96,97] . CEUS can give information about the nature of liver lesions that are not characterized with baseline US, and every lesion detected during US surveillance in patients with chronic liver disease, or in patients with past history of malignancy [96,98] . CEUS is safe and well tolerated. ...
... The authors concluded that CEUS is a dependable imaging tool for vascular characterization of small nodules (less than 2 cm) in patients with cirrhosis. CEUS gives equivalent accuracy to CT and MRI in the characterisation of focal liver lesions [98] and is probably the best alternative when there are contraindications to CT or MRI [97] . However, the performance of CEUS compared with CT or MRI, is highly affected by operator skill and experience, patient-related factors, such as body habitus and cooperativeness, and tumor-related factors, such as nodule location. ...
Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, particularly in parts of the developing world, and is increasing in incidence. This article reviews the current modalities employed for the diagnosis of HCC, including serum markers, radiological techniques and histological evaluation, and summarises international guidelines for the diagnostic approach to HCC.
... Ultrassonografia com contraste por microbolhas (CEUS) auxilia na avaliação da vascularização e perfusão tecidual, permitindo inferir sobre a viabilidade vascular [26] detectando lesões primárias ou metastáticas difíceis de serem percebidas pela ultrassonografia modo-B [3,19]. Na medicina, a CEUS é empregada na avaliação de melanoma uveal, melanoma coroidal e descolamento de retina [21,25,27]. ...
Background: Ocular lymphoma can affect the iris, conjunctiva, choroid, and retina and is mostly associated with multicentric disease. Elastography is an ultrasound technique that provides noninvasive, pain-free assessment of tissue stiffness. It has the ability to assess subtle changes throughout the organ as well as focal lesions. Microbubble contrast ultrasound enables the detection of incipient vascular flows, which are difficult to detect using traditional ultrasound methods. This study aimed to describe acoustic radiation force impulse (ARFI) elastography and microbubble contrast ultrasound findings in the eyes of two dogs diagnosed with intraocular T-cell lymphoma. Cases: Case 1. Physical examination revealed an exophytic mass in the left eye. Schirmer test revealed a secretion of 22 mm/min. Negative threat reflex, glare, direct pupillary light reflex, and consensual response were also noted. Biomicroscopy revealed hyperplasia of the third eyelid, overlapping with the affected eye. When the membrane was removed, moderate conjunctival hyperemia, mucoid secretion, and buphthalmia were observed. In addition, significant corneal edema was present, making it impossible to visualize the anterior chamber and perform fundus examination. The intraocular pressure, as measured with a rebound tonometer, was 39 mmHg. B-mode ultrasonography identified amorphous, hyperechoic, and heterogeneous structures throughout the anterior chamber, iris, and ciliary body. The elastogram showed that the mass had greenish tones and intermediate stiffness, and the mean SWV of the ciliary body and iris was 2 m/s. Contrast-enhanced ultrasound (CEUS) revealed vascularization of the neoformation region, with wash-in, peak, and wash-out values of 9.89 s, 24.56 s, and 107.87 s, respectively. Case 2. On physical examination, a change in the shape of the right pupil was observed. Schirmer test revealed a secretion of 20 mm/min, with negative threat, glare, and pupillary reflexes to direct and consensual light. Biomicroscopy revealed neoformation from 7 am to 11 am in the sclera, retina, and choroid complex, concomitant with dyscoria and conjunctival hyperemia. The intraocular pressure, as measured by rebound tonometry, was 33 mmHg. Fundoscopy revealed a mass in the temporal region and focal retinal detachment. No changes were observed in the contralateral eye. B-mode ultrasound revealed an increase in volume in the temporal region of the iris, ciliary body, and choroid with diffuse heterogeneity and partial retinal detachment. Elastographic examination revealed shades of green and yellow compatible with increased tissue stiffness. On quantitative examination, the mean SWVs of the ciliary body and iris were 3.14 m/s. On CEUS, the neoformation region presented wash-in, peak, and wash-out values of 8.67 s, 22.33 s, and 80.20 s. Discussion: B-mode ultrasonography established the tumor extent and evaluated echogenicity, verifying the involved ocular structures. The examination played an important role in the diagnosis as well as clinical management. ARFI elastography can detect small tissue changes, helping to define nodules and masses more reliably, in addition to allowing the verification of tissue stiffness. In both dogs, it was possible to verify that the masses presented greater rigidity than the adjacent tissues both qualitatively and quantitatively. In previous studies, it was found that cutaneous and breast lymphomas in humans were more rigid than adjacent tissues on elastography. This increase in rigidity and heterogeneity observed on elastograms can be explained by the extramedullary interactions of the matrix in T-cell lymphomas. Tumor growth is dependent on the blood supply, which was evaluated using CEUS in these cases. Furthermore, the ciliary body contrast filling times were longer than those described in normal dogs. Keywords: eye, surgery, diagnostic imaging, pain, veterinary ophthalmology, neoplasia. Título: Linfoma intraocular em cães - achados da ultrassonografia contrastada e elastografia ARFI Descritores: olho, cirurgia, diagnóstico por imagem, dor, oftlamologia veterinária, neoplasia.
... Hence, the results of separate individual study were unstable and can be affected by many confounding factors. [19] Therefore, [6] 2001 Italy 41 19 6 1 15 Giorgio et al. [3] 2007 Italy 73 37 1 11 24 Zhu et al. [7] 2010 China 45 31 7 10 27 Wei et al. [8] 2010 China 52 20 2 1 15 Zhou et al. [9] 2010 China 33 20 0 1 19 He et al. [10] 2008 China 68 31 13 2 29 Dai et al. [11] 2008 China 72 51 6 6 41 Forner et al. [12] 2008 Spain 89 37 1 23 28 Xu et al. [13] 2006 China 104 39 4 10 51 Jang et al. [4] 2009 Canada 59 22 0 4 33 Quaia et al. [14] 2009 Italy 106 64 15 8 34 Kan et al. [15] 2010 Japan 41 36 2 2 9 Leoni et al. [16] 2010 Italy 60 37 2 18 9 Pompili et al. [17] 2008 Italy 62 47 0 7 8 Wu et al. [18] 2010 China 85 73 1 1 10 ...
Objective: To discuss the efficacy of contrast-enhanced ultrasound (CEUS) for diagnosis of small hepatocellular carcinoma (HCC) by pooling the open published data.Methods: A comprehensive publication electronic search was performed by reviewers in the databases of PubMed, Embase, Web of Science, and China National Knowledge Infrastructure. The open published studies about CEUS for small HCC diagnosis were collected. The sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (–LR), and diagnostic odds ratio (DOR) were pooled by stata 12.0 software.
Results: A total of 16 studies were included in the present study. The sensitivity, specificity, +LR, and –LR were aggregated by random effects model because of significant heterogeneity (I2 >50.0%). However, DOR was pooled by fixed effects model without significant heterogeneity (I2
... Die Kontrastmittelsonographie kann bei der Dignitätsentscheidung von kleinen Herden von 1 bis 2 cm von Bedeutung sein. In diesen Fällen ist die alleinige Durchführung einer Sonographie im B-Mode oft nicht ausreichend, da hierdurch die Vaskularisierung der Raumforderung nicht dargestellt werden kann [4,57,90,148]. Bei der Kontrastmittelsonographie erfolgt eine kontinuierliche Messung des Enhancements während der arteriellen Phase (5-30 Sekunden post injectionem), der portalvenösen Phase (30-90, maximal 120 Sekunden post injectionem) sowie während der verzögerten Phase (120-180 Sekunden post injectionem). ...
Das Hepatozelluläre Karzinom (HCC) ist der fünfthäufigste Tumor und mit einer weltweit steigenden Inzidenz. Oft wird das HCC in fortgeschrittenen Stadien diagnostiziert und den Patienten können keine kurativen Therapiemöglichkeiten mehr angeboten werden. Als palliative Therapiemöglichkeiten sind die Durchführung einer transarteriellen Chemoembolisation (TACE) sowie die orale Gabe des Multikinaseinhibitors Sorafenib etabliert. Zur Evaluation des Therapieansprechens wird dabei in der Regel eine Schnittbildgebung durchgeführt. Zusätzlich kann der Tumormarker Alpha-Fetoprotein (AFP) als Verlaufsparameter herangezogen werden. Zur Diagnostik eines HCC ist die Bestimmung des AFP möglich. Aufgrund deutlicher Einschränkungen in der diagnostischen Wertigkeit hat es keinen Einfluss in der Klinik. Als weitere mögliche Tumormarker stehen das Lens culinaris-reaktive AFP (AFP-L3) und das Des-y-Carboxyprothrombin (DCP) zur Verfügung. Sie sind bislang nur unzureichend an einem einheitlichen Kollektiv untersucht.
Ziel dieser Arbeit war es die Verläufe des AFP, AFP-L3 und DCP nach einer TACE zu untersuchen. Dabei konnte festgestellt werden, dass der Einsatz dieser Marker nur bei initial erhöhten Werten sinnvoll ist. Für das DCP konnte eine Korrelation mit dem radiologischen Therapieansprechen gezeigt werden. Des Weiteren war das DCP am besten mit verschiedenen klinisch-pathologischen Parametern assoziiert. Bei der Untersuchung der Lebensqualität der in die Studie eingeschlossenen Patienten zeigten sich keine Unterschiede vor und nach TACE. Ebenfalls war kein Unterschied zu Patienten ohne HCC nachweisbar.
Im zweiten Teil der Arbeit wurde das Augenmerk auf die Nützlichkeit der Tumormarker in der Diagnostik des HCC gelegt. Es zeigte sich, dass die einzelnen Tumormarker deutliche Einschränkungen im Bezug auf die HCC-Diagnostik aufwiesen. Dies lag zum Beispiel daran, dass die Ätiologie der zugrunde liegenden Lebererkrankung einen Einfluss auf die Ergebnisse der Marker hatte. Die Kombination aller untersuchten Marker konnte die Limitation der einzelnen Marker kompensieren, so dass die Diagnostik des HCC verbessert wurde.
Eine weitere Untersuchung widmete sich der Betrachtung der AFP-Verläufe unter einer Therapie mit Sorafenib. Dabei zeigte sich, dass diese nicht mit dem Therapieansprechen korrelierten und das AFP als klinischer Verlaufsparameter ungeeignet war. Zudem konnte anhand dieses Patientenkollektivs gezeigt werden, dass sich die Daten aus den Zulassungsstudien zu Sorafenib im klinischen Alltag reproduzieren lassen. Darüber hinaus ließ sich zeigen, dass das Auftreten von Diarrhöen als positiver prognostischer Faktor bei den Patienten unter einer Sorafenib-Therapie anzusehen ist.
... CEUS has comparable diagnostic performance of CT and MRI in the characterization of hepatic focal lesions that are identified during US screening in patients with chronic liver disease or with a past history of prior malignancy [58] . CEUS is well tolerated, safe and may be the best choice when the CT or MRI are contraindicated [59] . However, a meta-analysis of 18 studies was unable to determine whether CEUS was adequate to exclude HCC lesions of size less than 30 mm [60] . ...
Hepatocellular carcinoma (HCC) is ranked as the 5(th) common type of cancer worldwide and is considered as the 3(rd) common reason for cancer-related deaths. HCC often occurs on top of a cirrhotic liver. The prognosis is determined by several factors; tumour extension, alpha-fetoprotein (AFP) concentration, histologic subtype of the tumour, degree of liver dysfunction, and the patient's performance status. HCC prognosis is strongly correlated with diagnostic delay. To date, no ideal screening modality has been developed. Analysis of recent studies showed that AFP assessment lacks adequate sensitivity and specificity for effective surveillance and diagnosis. Many tumour markers have been tested in clinical trials without progressing to routine use in clinical practice. Thus, surveillance is still based on ultrasound (US) examination every 6 mo. Imaging studies for diagnosis of HCC can fall into one of two main categories: routine non-invasive studies such as US, computed tomography (CT), and magnetic resonance imaging, and more specialized invasive techniques including CT during hepatic arteriography and CT arterial portography in addition to the conventional hepatic angiography. This article provides an overview and spotlight on the different diagnostic modalities and treatment options of HCC.
... Quanto à qualidade de imagem, a UCM é semelhante à TC e à RM com realce de contraste em muitos aspectos, incluindo a capacidade de demonstrar o padrão vascular e o grau de diferenciação de CHC (1618) . Além da capacidade de mostrar os padrões morfológico e vascular de lesões hepáticas focais, a UCM pode ser usada para detectar metástases (19,20) , guiar procedimen tos intervencionistas e caracterizar lesões em outros ór gãos, como intestino, pâncreas, mamas, rins, glândulas adrenais e próstata (21) . ...
To evaluate the efficacy of microbubble contrast ultrasound in diagnosis of hepatocellular carcinoma and to compare its results with those of magnetic resonance and histopathology.
A total of 29 patients suffering from chronic liver diseases and awaiting liver transplants at Hospital Israelita Albert Einstein were subject to magnetic resonance, microbubble contrast ultrasound, and excision liver biopsies.
Excellent agreement between magnetic resonance and microbubble contrast ultrasound was observed in this study. There was moderate agreement between both imaging methods and histopathology results.
Microbubble contrast ultrasound was as accurate as magnetic resonance to evaluate hepatocellular carcinoma. These results were confirmed by comparing both methods to histopathological diagnosis.
... The enhancement patterns in the early and middle phases have been used to reflect specific enhancement features and vascular structures. [11][12][13][14] However, because the brief total duration of the early and middle phases, approximately 2 minutes, limits the number of lesions that can be scanned, some of the lesions in patients with multiple lesions cannot be examined during the vascular phase; therefore, it is impossible to determine the distribution of the tumor vessels and early tumor enhancement in a single contrast imaging process. Usually, the contrast process has to be repeated by additional injection of the contrast agent to show tumor vascularity, which increases the cost of materials and requires a longer observation time. ...
The purpose of this study was to evaluate the enhancement patterns of focal liver tumors in the late phase of Sonazoid-enhanced ultrasonography by intermittent imaging with a high mechanical index (MI).
A total of 142 patients with 208 lesions, including 109 hepatocellular carcinomas (HCCs), 61 metastases, 30 hemangiomas, and 8 focal nodular hyperplasias (FNHs), were enrolled in this prospective study. Contrast-enhanced ultrasonography with intermittent scanning at 2 frames per second (MI, 0.7-1.2) was conducted in the late phase (>5 minutes after bolus intravenous injection of the perflubutane-based contrast agent Sonazoid; Daiichi Sankyo, Tokyo, Japan). Two blinded readers classified the enhancement patterns of the lesions. The sensitivity, specificity, and positive predictive value (PPV) of the dominant enhancement patterns and inter-reader agreement were assessed.
A combination of diffuse enhancement with intratumoral vessels and intratumoral vessels alone yielded sensitivity of 85% (average of both readers), specificity of 88%, and a PPV of 88% for HCC. For metastasis, a combination of peripheral ringlike enhancement with peritumoral vessels and peripheral ringlike enhancement with intratumoral vessels yielded sensitivity of 79%, specificity of 95%, and a PPV of 85%. For hemangiomas, a combination of peripheral nodular enhancement with peritumoral vessels and peripheral nodular enhancement without peritumoral vessels yielded sensitivity of 75%, specificity of 99%, and a PPV of 92%. Diffuse enhancement with spoked wheel arteries yielded sensitivity of 82%, specificity of 100%, and a PPV of 87% for FNHs. Good inter-reader agreement was achieved.
Sonazoid-enhanced ultrasonography using intermittent imaging with a high MI can potentially be used for evaluating the enhancement patterns of focal liver tumors in the late phase.
Background:
Hepatocellular carcinoma occurs mostly in people with chronic liver disease. Worldwide, it ranks sixth in terms of incidence of cancer, and fourth in terms of cancer-related deaths. Contrast-enhanced ultrasound (CEUS) is used as an add-on test to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma after prior diagnostic tests such as abdominal ultrasound or measurement of alpha-foetoprotein, or both. According to guidelines, a single contrast-enhanced imaging investigation, with either computed tomography (CT) or magnetic resonance imaging (MRI), may show the typical hepatocellular carcinoma hallmarks in people with cirrhosis, which will be sufficient to diagnose hepatocellular carcinoma. However, a significant number of hepatocellular carcinomas show atypical imaging features, and therefore, are missed at imaging. Dynamic CEUS images are obtained similarly to CT and MRI images. CEUS differentiates between arterial and portal venous phases, in which sonographic hepatocellular carcinoma hallmarks, such as arterial hyperenhancement and subsequent washout appearance, are investigated. The advantages of CEUS over CT and MRI include real-time imaging, use of contrast agents that do not contain iodine and are not nephrotoxic, and quick image acquisition. Despite the advantages, the use of CEUS in the diagnostic algorithm for HCC remains controversial, with disagreement on relevant guidelines. There is no clear evidence of the benefit of surveillance programmes in terms of overall survival as the conflicting results can be a consequence of an inaccurate detection, ineffective treatment, or both. Therefore, assessing the diagnostic accuracy of CEUS may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of CEUS for the diagnosis of hepatocellular carcinoma is needed for either diagnosing hepatocellular carcinoma or ruling it out in people with chronic liver disease who are not included in surveillance programmes.
Objectives:
1. To assess the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease, in a surveillance programme or in a clinical setting. 2. To assess the diagnostic accuracy of CEUS for the diagnosis of resectable hepatocellular carcinoma in people with chronic liver disease and identify potential sources of heterogeneity in the results.
Search methods:
We used standard, extensive Cochrane search methods. The last date of search was 5 November 2021.
Selection criteria:
We included studies assessing the diagnostic accuracy of CEUS for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross-sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver, and histology of resected or biopsied focal liver lesion with at least a six-month follow-up.
Data collection and analysis:
We used standard Cochrane methods to screen studies, extract data, and assess the risk of bias and applicability concerns, using the QUADAS-2 checklist. We used the bivariate model and provided estimates of summary sensitivity and specificity. We assessed the certainty of the evidence using GRADE. We presented uncertainty-of-the-accuracy estimates using 95% confidence intervals (CIs).
Main results:
We included 23 studies with 6546 participants. Studies were published between 2001 and 2021. We judged all 23 studies at high-risk of bias in at least one domain, and 13/23 studies at high concern for applicability. Most studies used different reference standards to exclude the presence of the target condition. The time interval between the index test and the reference standard was rarely defined. We also had major concerns on their applicability due to the characteristics of the participants. - CEUS for hepatocellular carcinoma of any size and stage: sensitivity 77.8% (95% CI 69.4% to 84.4%) and specificity 93.8% (95% CI 89.1% to 96.6%) (23 studies, 6546 participants; very low-certainty evidence). - CEUS for resectable hepatocellular carcinoma: sensitivity 77.5% (95% CI 62.9% to 87.6%) and specificity 92.7% (95% CI 86.8% to 96.1%) (13 studies, 1257 participants; low-certainty evidence). The observed heterogeneity in the results remains unexplained. The sensitivity analyses, including only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted with no knowledge of the results about the index test, showed no differences in the results.
Authors' conclusions:
We found that by using CEUS, as an add-on test following abdominal ultrasound, to diagnose hepatocellular carcinoma of any size and stage, 22% of people with hepatocellular carcinoma would be missed, and 6% of people without hepatocellular carcinoma would unnecessarily undergo further testing or inappropriate treatment. As to resectable hepatocellular carcinoma, we found that 23% of people with resectable hepatocellular carcinoma would incorrectly be unresected, while 8% of people without hepatocellular carcinoma would undergo further inappropriate testing or treatment. The uncertainty resulting from the high risk of bias of the included studies, heterogeneity, and imprecision of the results and concerns on their applicability limit our ability to draw confident conclusions.
Purpose:
To study the comparative performance of contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT or MRI (CECT/MR) in evaluating liver lesions using the LI-RADS guidelines.
Methods:
Retrospective analysis of radiology database from July 2010 to April 2017 revealed 228 patients who had CECT/MR and CEUS. Patients at risk of hepatocellular carcinoma (HCC), had contemporaneous CEUS and CECT/CEMR studies within 3 months and adequate follow up were included; reviewed (2 reviewers) and graded according to the 2017 CEUS and 2018 CECT/MR LI-RADS guidelines. Reference standard was multidisciplinary clinical decisions, histology or follow-up imaging.
Results:
The study cohort consisted of 45 patients with 46 lesions. HCC were significantly larger than non-malignant (mean sizes of 2.5 and 1.4 cm, respectively, p<0.001). Intraclass correlation coefficient for CEUS review (0.941) was higher than of CECT/MR review (0.643). Mean area-under-ROC curve (AUC) for CEUS (0.994) was significantly higher than of CECT/MR (0.760) for all lesions (p=0.01). For lesions scored LR-3 by CECT/MR, the AUC was significantly higher for CEUS (0.978) than CECT/MR (0.500) (p<0.001). Twenty-one (of 27) lesions, classified LR-3 or LR-4 by CECT/MR were upgraded by CEUS and 20 were found to be HCC. Six lesions that were LR-3 on both CECT/MR and CEUS were found to be non-malignant. There was good concordance for LR-5 lesions between both techniques.
Conclusion:
CEUS is useful for reassessment of lesions with intermediate probability (LR-3) or probable for HCC (LR-4) on CECT/MR. Lesions upgraded by CEUS tend to be HCC. Lesions that remain LR-3 on CEUS tend to be non-malignant.
Introduction: Positron Emission Tomography (PET) with ¹⁸F-fluorodeoxyglucose (FDG) presents some limitations for imaging of hepatocellular carcinoma (HCC), the most common primary hepatic malignancy.
Areas covered: The authors discuss the accuracy and limitations of FDG for HCC detection. Then, authors examine the recent advances in PET tracers other than FDG for the biological and prognostic characterization of HCC such as ¹¹C-acetate, ¹¹C-choline and its ¹⁸F-labeled derivatives.
Expert commentary: FDG PET can be helpful for the identification of the more aggressive and poorly differentiated HCC. ¹¹C-acetate is readily incorporated into intracellular phosphatidylcholine membranes and proved useful for the in vivo biological characterization of the more differentiated and less aggressive HCC. Nevertheless, the short half-life of ¹¹C- radionuclide limits the clinical application of this compound. ¹¹C-choline, another surrogate biomarker of cell membrane biosynthesis, has been demonstrated effective for HCC imaging. The availability of choline derivatives labelled with ¹⁸F-radionuclide (i.e. ¹⁸F-fluoroethylcholine, ¹⁸F-fluorocholine) has overcome the drawbacks due to ¹¹C, thus triggering the clinical applications of choline PET for HCC diagnosis and management. Further research needs to be conducted to better define the alternative or complementary role of these PET probes for the characterization of HCC, with particular regard to the dual-tracer PET-CT modality.
Purpose:
To compare contrast-enhanced ultrasonography (CEUS)-derived time-intensity (TI) curves with histological findings in kidneys of patients affected by chronic glomerulonephritides (GN) in the early stage of disease.
Methods:
Research ethics committee approval and patient written informed consent were obtained. Thirty-one patients who showed clinical and laboratory signs of GN, with preserved renal function, were consecutively enrolled. They underwent kidney CEUS, from which TI curves were obtained, and kidney biopsy. TI curves were compared with clinical data, ultrasound (US) Doppler, and histological parameters.
Results:
The persistence of contrast agent signal during the wash-out phase was found to be correlated with the degree of disease activity (p = 0.016) and in particular with the presence of mesangial hyperplasia (p = 0.008). No correlation was observed between TI curves and clinical or Doppler US-derived parameters.
Conclusions:
The persistence of contrast agent signal in the wash-out phase of CEUS appears to reflect a disturbance of perfusion in glomerular capillaries in the early stages of GN. We found that the histological element directly correlated with the prolonged wash-out was mesangial hyperplasia.
Purpose:
To compare the per-lesion sensitivity and positive predictive value (PPV) of ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) for the diagnosis of hepatocellular carcinoma (HCC).
Materials and methods:
The meta-analysis of sensitivity included 242 studies (15,713 patients); 116 studies (7492 patients) allowed calculation of PPV. Pooled per-lesion sensitivity and PPV for HCC detection were compared using empirical Bayes estimates of a beta-binomial model.
Results:
The pooled per-lesion sensitivity and PPV of contrast-enhanced CT (73.6%, 85.8%) and gadolinium-enhanced MRI (77.5%, 83.6%) are not significantly different (P = 0.08, P = 0.2). However, if the hepatobiliary agent gadoxetate is used, MRI has significantly higher pooled per-lesion sensitivity and PPV (85.6%, 94.2%) than CT (P < 0.0001) or than MRI with other agents (P < 0.0001). Non-contrast-enhanced US has the lowest overall sensitivity and PPV (59.3%, 77.4%). Pooled per-lesion sensitivity and PPV of contrast-enhanced US (84.4%, 89.3%) are relatively high, but no contrast-enhanced US study used the most rigorous reference standards.
Conclusion:
MRI utilizing the hepatobiliary agent gadoxetate has the highest overall sensitivity and PPV, and may be the single optimal method for diagnosis of HCC. Non-contrast-enhanced US has the lowest sensitivity and PPV. More rigorous reference standards are needed to compare the performance of contrast-enhanced US with CT and MRI. Differences in sensitivity and PPV between CT and conventional gadolinium-enhanced MRI are not statistically significant overall.
Objective: To evaluate the value of contrast-enhanced ultrasound in diagnosing small hepatocellular carcinoma with Meta-analysis. Methods: With 'ultrasonic imaging' and 'small hepatocellular carcinoma' as the key words, evidence was collected from Cochrane Library, Embase, CNKI(2006.1-2011.12) and so on according to search strategy. Methods of evidence-based medicine were used to calculate the specificity, sensitivity, and summary receiver operating curve (SROC), and the area under the curve (AUC) were calculated to evaluate the diagnosis value of contrast enhancement ultrasonic imaging technology for small liver cancer. According to the quality evaluation standard of evidence-based medicine evidence, QUADAS items were used to evaluate the quality of evidence. Results: A total of 9 studies were identified and the total number of case is 670. With the random effects pattern, the sensitivity and specificity of contrast-enhanced ultrasound in diagnosing small hepatocellular carcinoma were 83% and 86%, respectively. The AUC is 93.41%. Conclusion: The contrast-enhanced ultrasound will be helpful in diagnosing small hepatocellular.
Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, particularly in parts of the developing world, and is increasing in incidence. This article reviews the current modalities employed for the diagnosis of HCC, including serum markers, radiological techniques and histological evaluation, and summarises international guidelines for the diagnostic approach to HCC.
L’imagerie ultrasonore conventionnelle (US) joue un rôle essentiel dans le diagnostic et la prise en charge thérapeutique des hépatopathies chroniques.
Néanmoins, elle présente de multiples limites : caractère opérateur-dépendant et subjectif, visibilité des nodules variable selon leur accessibilité et leur contraste avec le parenchyme qui les entoure, caractérisation limitée.
L’imagerie US conventionnelle bénéficie d’avancées technologiques importantes comme l’imagerie US de contraste, l’élastographie et les techniques d’imagerie volumique et de fusion d’images.
L’échographie de contraste permet la détection du rehaussement en temps réel d’une lésion nodulaire et améliore l’identification de son caractère hypervasculaire, critère diagnostique essentiel du carcinome hépatoceullulaire. Cette cinétique est différente de celle des lésions bénignes (nodules de régénération, hémangiomes…).
L’échographie de contraste est une excellente technique pour la caractérisation d’un nodule (visible sur l’échographie conventionnelle ou une autre modalité d’imagerie), mais ces performances pour la détection du CHC sont plus limitées. La tolérance des agents de contraste ultrasonore est excellente en pratique clinique et il n’existe pas de contre-indications liées à la fonction hépatique ou rénale.
L’élastographie ultrasonore est une technique non invasive qui permet la détection et la quantification de la fibrose hépatique et son domaine d’application s’étend de plus en plus vers la caractérisation des nodules du foie.
L’échographie volumique et la fusion d’image devraient permettre d’améliorer la prise en charge thérapeutique des lésions malignes et en particulier le guidage percutané des procédures de destruction par hyperthermie (ablation radiofréquence…).
Hepatocellular carcinoma (HCC) is the commonest primary hepatic malignancy and the third most common cause of cancer-related death worldwide. Incidence remains highest in the developing world and is steadily increasing across the developed world. The majority of HCC occurs on a background of cirrhosis, principally caused by two major risk factors, chronic hepatitis B and hepatitis C infection. Current diagnostic modalities, of ultrasound and α-fetoprotein, are expensive and lack sensitivity in tumour detection. Early diagnosis is integral to improved survival rates and there have been recent advances in technology that have enabled early identification of the process of hepatocarcinogenesis. This review outlines the epidemiological trends and risk factors for HCC; diagnostic techniques and current guidelines for screening and surveillance; and newer methods of screening.
The purpose of this study was to examine the results of percutaneous radiofrequency ablation of both medium-sized hepatocellular carcinoma (HCC) and the accompanying main portal venous tumor thrombus in patients with cirrhosis.
From January 2005 to January 2008, among 1,837 consecutively registered patients with HCC seen at our institution, 412 had HCC and portal venous invasion; 27 of the 412 had a single HCC nodule accompanied by main portal venous tumor thrombus. Thirteen patients (10 men, three women; mean age, 70 years; range, 66-74 years) with 13 HCC nodules 3.7-5 cm in diameter extending into the main portal trunk underwent percutaneous radiofrequency ablation. Fourteen matched patients (10 men, four women; mean age, 69 years; range, 67-73 years) with 14 HCC nodules 3.6-4.8 cm in diameter extending into the main portal trunk refused radiofrequency ablation and composed the control group. Diagnosis of main portal venous tumor thrombus was made with fine-needle biopsy in all cases. Radiofrequency ablation was performed first on the main portal venous tumor thrombus and then on the HCC nodule. Efficacy of radiofrequency was defined as complete necrosis of HCC and complete recanalization of the main portal trunk and its branches. HCC necrosis was evaluated with enhanced CT. Recanalization of portal vessels was analyzed with color Doppler and contrast-enhanced ultrasound. Radiofrequency ablation was performed under ultrasound guidance with a perfused needle electrode.
Complete necrosis of the HCC associated with complete recanalization of the main portal vein and its branches was achieved in 10 patients (efficacy, 77%). In the other three patients, necrosis of the HCC ranged from 70% to 90%, and recanalization of the main portal trunk was not complete. No major complications occurred. In three cases, mild to moderate ascites and increased aspartate aminotransferase and alanine aminotransferase levels were found. The follow-up periods ranged from 3 to 36 months among the treated patients and 2 to 10 months among the untreated patients. The cumulative survival rate was 77% 6, 12, and 36 months after procedure in the treated group and 43% and 0% 6 and 12 months after diagnosis in the untreated group (p < 0.0001). All 10 successfully treated patients were alive and the portal system was patent at the end of the follow-up period. All three untreated patients died of progressive disease within 5 months of diagnosis.
Radiofrequency ablation can destroy both single intraparenchymal medium-sized HCCs and the accompanying main portal venous tumor thrombus with high efficacy and safety and a low rate of complications.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide and, owing to changes in the prevalence of the two major risk factors, hepatitis B virus and hepatitis C virus, its overall incidence remains alarmingly high in the developing world and is steadily rising across most of the developed world. Early diagnosis remains the key to effective treatment and there have been recent advances in both the diagnosis and therapy of HCC, which have made important impacts on the disease. This review outlines the epidemiological trends, risk factors, diagnostic developments and novel therapeutics for HCC, both in the developing and developed world.
According to the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), ultrasound (US) is the recommended tool for surveillance of patients at risk of developing hepatocellular carcinoma (HCC). Larger HCCs can be diagnosed with a high accuracy by conventional US. However, the differentiation of smaller malignant lesions in cirrhotic livers can be improved by contrast-enhanced ultrasound (CEUS). Second-generation contrast agents consisting of microbubbles enable us to visualize specific tumor vascularization patterns. With CEUS, it is not only possible to detect and characterize HCC nodules, but to control the effects of ablation techniques of HCC as well, evaluating the former lesion with respect to complete necrosis or residual viable tumor. Limitations of CEUS are its inability to characterize lesions distant to the applicator. Moreover, so far the use of contrast agents in US did not result in increased sensitivity in the detection of small HCCs (<1 cm). Thus, there is currently no indication to use contrast agents to increase the detection rate of HCC in patients undergoing US surveillance.
The aim of this study was to assess the added diagnostic value of contrast-enhanced US (CEUS) combined with 64-row multidetector CT (CT) in the assessment of hepatocellular nodule vascularity in patients with liver cirrhosis. One hundred and six cirrhotic patients (68 male, 38 female; mean age +/- SD, 70 +/- 7 years) with 121 biopsy-proven hepatocellular nodules (72 hepatocellular carcinomas, 10 dysplastic and 15 regenerative nodules, 12 hemangiomas, and 12 other benignancies) detected during US surveillance were prospectively recruited. Each nodule was scanned by CEUS during the arterial (10-40 s), portal venous (45-90 s), and delayed sinusoidal phase (from 100 s after microbubble injection to microbubble disappearance). Nodule vascularity at CEUS, CT, and combined CEUS/CT was evaluated side-by-side by two independent blinded readers who classified nodules as benign or malignant according to reference diagnostic criteria. The combined assessment of CEUS/CT provided higher sensitivity (97%, both readers) than did separate assessment of CEUS (88% reader 1; 87% reader 2) and CT (74% reader 1; 71% reader 2; P < 0.05), while no change in specificity was provided by combined analysis. The combined assessment of hepatocellular nodule vascularity at CT and CEUS improved sensitivity in the diagnosis of malignancy in patients with liver cirrhosis.
Hepatocellular carcinoma (HCC) is a major cause of death in cirrhotic patients. This neoplasm is associated with liver cirrhosis (LC) in more than 90% of cases. Early diagnosis and treatment of HCC are expected to improve survival of patients.
To assess the cost effectiveness of a surveillance programme of patients with LC for the early diagnosis and treatment of HCC.
A cohort of 313 Italian patients with LC were enrolled in the surveillance programme between March 1989 and November 1991. In the same period, 104 consecutive patients with incidentally detected HCC were referred to our centre and served as a control group.
Surveillance was based on ultrasonography (US) and alpha fetoprotein (AFP) determinations repeated at six month intervals. Risk factors for HCC were assessed by multivariate analysis (Cox model). Outcome measures analysed were: (1) number and size of tumours; (2) eligibility for treatment; and (3) survival of patients. Economic issues were: (1) overall cost of surveillance programme; (2) cost per treatable HCC; and (3) cost per year of life saved (if any). Costs were assessed according to charges for procedures at our university hospital.
Surveillance lasted a mean of 56 (31) months (range 6-100). During the follow up, 61 patients (19.5%) developed HCC (unifocal at US in 49 cases), with an incidence of 4.1% per year of follow up. AFP, Child-Pugh classes B and C, and male sex were detected as independent risk factors for developing HCC. Only 42 (68.9%) of 61 liver tumours were treated by surgical resection, orthotopic liver transplantation, or local therapy. The cumulative survival rate of the 61 patients with liver tumours detected in the surveillance programme was significantly longer than that of controls (p=0.02) and multivariate analysis showed an association between surveillance and survival. The overall cost of the surveillance programme was US$753 226, the cost per treatable HCC was US$17 934, and the cost for year of life saved was US$112 993.
Our surveillance policy of patients with LC requires a large number of resources and offers little benefit in terms of patient survival. The decision whether to adopt a surveillance policy towards HCC should rely on the prevalence of the disease in the population and on the resources of a particular country.
To evaluate the safety profile of SonoVue, a new echo-contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles, in healthy volunteers and in patients with chronic obstructive pulmonary disease (COPD).
Safety and tolerability of SonoVue were evaluated in 66 healthy volunteers during two placebo-controlled phase I studies (a single intravenous ascending-dose study in 36 volunteers given SonoVue doses of 0.003 to 0.12 mL/kg and a multiple-dose study in 30 subjects given cumulative doses of 0.15 to 0.6 mL/kg) and in 12 patients with COPD of various degrees of clinical severity, who were given SonoVue at a dosage of 4 mL (corresponding to 0.057 mL/kg in a 70-kg patient). Adverse events were monitored up to 48 to 72 hours after administration. All volunteers underwent extensive safety assessments (monitoring of vital signs, electrocardiogram, blood oxygen saturation, laboratory assessments, and Mini-Mental test) up to 24 to 72 hours after administration. In addition, patients with COPD underwent specific lung function tests, such as forced expiratory volume, forced vital capacity, and forced midexpiratory flow.
No serious adverse events occurred throughout the study. All nonserious adverse events were minor, mild, and rapidly self-resolving. No difference in the incidence of adverse events was observed among the various dosages of SonoVue and between SonoVue and placebo. There were no clinically significant changes in any of the safety assessments. No statistically significant differences between SonoVue and placebo were observed in mean forced expiratory volume, forced vital capacity, or forced midexpiratory flow levels. No substantial changes from baseline in blood oxygen saturation were observed for either study agent at any postinjection time point.
SonoVue showed a good safety profile both in healthy subjects and in patients with COPD.
To determine the potential application of contrast-enhanced ultrasound in the characterisation of focal liver lesions encountered in radiological practice at a district general hospital.
Retrospective analysis of 68 sequential patients undergoing contrast-enhanced ultrasound (CEUS) of liver. All patients were referred for CEUS following identification of 1 or more focal liver lesions on conventional ultrasound or CT imaging. After baseline US examination (Acuson), a bolus of 1.0-2.4 ml of SonoVue (Bracco, UK) was administered intravenously. CEUS images were obtained during arterial, portal venous and delayed phases. Patients were followed up for a mean period of 6 months. The CEUS diagnosis was compared to that indicated by other imaging modalities, histopathology, and clinical follow up.
CEUS correctly identified malignant liver lesions in 19 patients, with the final diagnosis confirmed by histopathology in 5 cases and clinico-radiological follow up in 14 cases. 47 patients were correctly identified with benign liver lesions on CEUS imaging, with all these cases confirmed on clinico-radiological follow up. In the detection of malignancy, the sensitivity was 95.0% and the specificity was 97.9%.
In our experience to date, contrast-enhanced ultrasound imaging is highly accurate in characterising malignant and benign focal liver lesions. It therefore has significant potential for utilisation in most general radiology departments.
BACKGROUND
Hepatocellular carcinoma (HCC) is a major cause of death in cirrhotic patients. This neoplasm is associated with liver cirrhosis (LC) in more than 90% of cases. Early diagnosis and treatment of HCC are expected to improve survival of patients.
AIMS
To assess the cost effectiveness of a surveillance programme of patients with LC for the early diagnosis and treatment of HCC.
PATIENTS
A cohort of 313 Italian patients with LC were enrolled in the surveillance programme between March 1989 and November 1991. In the same period, 104 consecutive patients with incidentally detected HCC were referred to our centre and served as a control group.
METHODS
Surveillance was based on ultrasonography (US) and α fetoprotein (AFP) determinations repeated at six month intervals. Risk factors for HCC were assessed by multivariate analysis (Cox model). Outcome measures analysed were: (1) number and size of tumours; (2) eligibility for treatment; and (3) survival of patients. Economic issues were: (1) overall cost of surveillance programme; (2) cost per treatable HCC; and (3) cost per year of life saved (if any). Costs were assessed according to charges for procedures at our university hospital.
RESULTS
Surveillance lasted a mean of 56 (31) months (range 6–100). During the follow up, 61 patients (19.5%) developed HCC (unifocal at US in 49 cases), with an incidence of 4.1% per year of follow up. AFP, Child-Pugh classes B and C, and male sex were detected as independent risk factors for developing HCC. Only 42 (68.9%) of 61 liver tumours were treated by surgical resection, orthotopic liver transplantation, or local therapy. The cumulative survival rate of the 61 patients with liver tumours detected in the surveillance programme was significantly longer than that of controls (p=0.02) and multivariate analysis showed an association between surveillance and survival. The overall cost of the surveillance programme was US$753 226, the cost per treatable HCC was US$17 934, and the cost for year of life saved was US$112 993.
CONCLUSION
Our surveillance policy of patients with LC requires a large number of resources and offers little benefit in terms of patient survival. The decision whether to adopt a surveillance policy towards HCC should rely on the prevalence of the disease in the population and on the resources of a particular country.
The blood supply of hepatocellular carcinoma (HCC) is primarily arterial. Recent studies reported differences of vascular, especially arterial, supply among low- and high-grade dysplastic nodules and HCC. We assessed arterialization using monoclonal antibody specific for smooth muscle actin as well as simultaneous changes in sinusoidal capillarization in cirrhotic nodules, dysplastic nodules, and HCC. We immunohistochemically stained 56 cirrhotic nodules, 20 low-grade dysplastic nodules, 27 high-grade dysplastic nodules, and 20 HCCs for alpha smooth muscle actin (to identify unpaired arteries (i.e., arteries not accompanied by bile ducts) and CD34 (indicating sinusoidal capillarization). Distribution and number of unpaired arteries and distribution of sinusoidal capillarization were graded semiquantitatively. Unpaired arteries were rare in cirrhotic nodules, significantly more common in dysplastic nodules of both types (p < 0.00001), and most common in HCC. Sinusoidal capillarization was least common in cirrhotic nodules, significantly more common in dysplastic nodules (p < 0.0035), and most common in HCC. No topographic relationship between unpaired arteries and sinusoidal capillarization was identified. These findings showed that (1) distributions of sinusoidal capillarization and unpaired arteries in dysplastic nodules are intermediate between those in cirrhotic nodules and HCC, supporting dysplastic nodules as premalignant lesions; (2) unpaired arteries are histologically useful for distinguishing dysplastic nodules from large cirrhotic nodules; and (3) areas of sinusoidal capillarization within dysplastic nodules are unrelated to location of arterialization.
The advances made by ultrasonography in the last decade, in parallel with the development of ultrasound contrast agents, have opened a wide range of potential breakthroughs in the field of ultrasound imaging. SonoVue™ is a new echocontrast agent made of microbubbles stabilized by phospholipids and containing sulphur hexafluoride (SF6), an innocuous gas. The suspension of the microbubbles is stable over the time following reconstitution. The bubble concentration of SonoVue™ is between 100 and 500 million per ml. The mean bubble diameter is 2.5 μm and more than 90% of the bubbles are smaller than 8 μm. Following intravenous injection, the bubble suspension is submitted to pressure increases. SF6, a high molecular weight gas with low solubility in water, was selected since laboratory tests showed that it confers to the bubbles a good resistance to pressure changes as those that occur in the left ventricle, in the pulmonary capillaries, or in the coronary circulation. The high bubble concentration, combined with a favorable size distribution profile, provides SonoVue™ with a strong echogenicity. SonoVue™ shows a peak in the backscatter coefficient at about 3 MHz. With regard to the gas contained in the bubbles, its pharmacokinetics have been assessed during a study in human volunteers. Following intravenous administration of 0.3 ml/kg of SonoVue™ (i.e., approximately ten times the imaging dose), the blood level curve showed a distribution half-life of about 1 minute and an elimination half-life of about 6 minutes. More than 80% of the administered gas is exhaled via the lungs after 11 minutes. Extensive studies in animals and humans have confirmed the outstanding safety profile of this second generation contrast agent and its capability in providing a clinically useful ultrasound signal enhancement for the evaluation of cardiac function and extracardiac vessel abnormalities. Thanks to the long persistence of SF6 microbubbles, SonoVue™ is also potentially useful in the assessment of myocardial perfusion, as well as microcirculatory disorders.
Percutaneous fine-needle aspiration biopsies of the liver were performed on 21 patients with a clinical suggestion of hepatic malignancy. Under the guidance of the liver scan, several aspirations at the suspect areas were made in each case, with an average of 3.4 punctures and 13.8 smears per case. The biopsies were positive in 13 cases: 12 metastatic carcinomas and 1 hepatocellular carcinoma. There were no false-positive or false-negative results in this series. On the 13 patients with proven hepatic malignancy, 47 punctures had been performed. Of these 47 punctures, 34 (72.3%) were positive for malignant cells. Neoplastic tissue or cells were found from at least one aspirate in these 13 biopsies. Liver biopsies by Menghini technique were also performed on five patients with proven hepatic malignancy in this series. Of these five biopsies, only two showed evidence of malignancy. Typing of the tumors and determination of the primary sites based on cytomorphologic features in all the malignant cases were attempted. Origins of neoplastic cells were suggested in 11 cases and all confirmed in the follow-ups. The punctures and aspirations of these 21 biopsies did not reveal any immediate complication. Multiple fine-needle liver aspirations under the guidance of liver scan are of great diagnostic value with high accuracy in detecting hepatic malignancy.
Liver nodules smaller than 25 mm in diameter (19 hepatocellular carcinomas [HCCs] and nine adenomatous hyperplastic nodules [AHNs]) were examined with color Doppler flow imaging and hepatic angiography. Angiography revealed a tumor vessel in eight (42%) of the 19 HCCs, while color Doppler flow imaging revealed an arterial pulsating afferent tumor vessel in 10 (53%) of the 19 HCCs but in none of the AHNs. In addition, color Doppler flow imaging revealed a constant-flow efferent tumor vessel continuing to a portal branch in 10 (53%) of the 19 HCCs but in none of the AHNs. In 15 (79%) of the 19 HCCs, a pulsating afferent tumor vessel or a constant-flow efferent tumor vessel or both were observed. Therefore, in this series, color Doppler flow imaging was of value in distinguishing between these two lesions.
The blood supplies of nodular lesions associated with liver cirrhosis were analyzed in vivo with various imaging modalities. The portal blood supply was evaluated with computed tomography (CT) during arterial portography (CTAP); the arterial blood supply was evaluated with hepatic angiography, CT angiography, CT following intraarterial injection of iodized oil, or ultrasound following intraarterial injection of carbon dioxide microbubbles. A total of 84 surgically confirmed hepatocellular carcinomas (HCCs) (less than or equal to 3 cm) and 25 areas of adenomatous hyperplasia (AH) were included in the study. At CTAP, a portal blood supply was seen in 96% of cases of AH and only 6% of HCCs (chi 2, P less than .005). In contrast, an arterial supply greater than that of the surrounding liver was verified in 94% of the HCCs and only 4% of the cases of AH (chi 2, P less than .005). The blood supply of areas of AH with atypical hepatocytes and the blood supply of well-differentiated HCCs (Edmondson grade 1) tended to be intermediate between that of AH without atypia and that of HCC that was Edmondson and Steiner grade 2 or greater. Evaluation of the blood supply of the nodular lesions associated with liver cirrhosis is considered to be useful in the differential diagnosis and treatment of early-stage HCC.
The livers of 345 autopsy cases of chronic liver disease were examined for macroregenerative nodule (MRN), a large nodular lesion more than 10 mm in diameter. A total of 86 lesions of MRN was found in 49 cases (14.2%): 32 were from 191 cases of hepatocellular carcinoma (HCC), 16 were from 148 cases of cirrhosis only, and one was from six cases of chronic hepatitis. The incidence (19.6%) and the size (12.1 mm) of MRN in macronodular type of cirrhosis were significantly higher and larger than those in other types of cirrhosis. Also, the average size of MRN lesions of cases with HCC (12 mm) was significantly larger than that of cases with cirrhosis only (10.5 mm). The incidence of liver cell dysplasia (LCD) in cases of MRN (67.3%) was significantly higher than that in cases without MRN (40.9%). The MRN lesions were divided into Type I and Type II, the latter having proliferative foci distinguishable from the surrounding tissue. Three of them contained atypical cells regarded as cancer. Type II lesions were larger in size, and cases with multiple MRN lesions were seen more frequently in cases of HCC. The average age of the patients with Type II lesion was 5 years older than those with Type I lesions. These findings suggest that MRN should not be ignored in the morphogenesis of HCC.
Ultrasonically guided fine needle biopsies were carried out in 84 patients with focal liver lesions and were subsequently evaluated histologically. A correct diagnosis of malignancy was made in 46 of 52 patients with proven hepatic malignancy, showing an overall accuracy of 93%. The specificity of the procedure was 100%. Such histological examination not only enables the differentiation between primary and secondary hepatic malignancy; it has the additional advantage of making a more precise tumour description and at the same time it pinpoints the primary site of the tumour.
The aims of this study were to evaluate the typing accuracy of smear cytology and microhistology and of their association in the diagnosis of hepatocellular carcinoma arising in liver cirrhosis, and to analyze the usefulness of smear cytology in the diagnosis of well-differentiated neoplasms.
One hundred sixty patients with hepatocellular carcinoma underwent an ultrasound-guided fine-needle biopsy, providing material for cytological and histological study. In 73 patients, a double biopsy with noncutting and cutting needles was performed (double-needle group), whereas in the remaining 87, a single biopsy with cutting needle was carried out (single-needle group).
In the whole population examined, smear cytology, microhistology, and their association, provided the diagnosis of hepatocellular carcinoma in 128 (80%), 98 (61%), and 144 (90%) cases, respectively. The double-needle and the single-needle groups did not differ significantly as to typing accuracy. Smear cytology correctly diagnosed 54 of 64 neoplasms classified histologically as well-differentiated.
Our results show that both smear cytology and microhistology should be applied immediately, when diagnosing hepatocellular carcinoma arising in liver cirrhosis, and that smear cytology is effective in the diagnosis of well-differentiated neoplasms.
To compare power Doppler ultrasound (US) with conventional color Doppler US for the assessment of tumor vascularity in hepatocellular carcinoma (HCC).
Fifty-one patients with 88 histologically proved HCCs were examined with power and color Doppler US according to a standardized examination protocol. Findings at Doppler studies of each lesion were correlated with findings at digital subtraction angiography.
Angiography revealed neovascularization or staining in 75 (85%) of 88 lesions. Intratumoral color signals with an arterial Doppler spectrum were detected in 69 (92%) of 75 angiographically hypervascular tumors at power Doppler US and in 55 (73%) of 75 at color Doppler US (P < .01). Blood flow signals with an arterial Doppler spectrum were not detected at power or color Doppler US in any of the 13 angiographically hypovascular tumors. The small size and the deep location of the lesion significantly reduced (P < .05) the detection rate of blood flow signals at color Doppler US but did not affect the results of power Doppler US.
Power Doppler US is superior to conventional color Doppler imaging in the depiction of tumor vascularity in HCC.
There is still debate over the relative merits of cytology and histology in diagnosing hepatocellular carcinoma in cirrhotic livers. Previous comparisons of the diagnostic accuracies of these two methods may have been biased by sampling errors due to multiple punctures. We compared the diagnostic accuracies of cytology and microhistology using tissue and cells from the same point in liver nodules subsequently proved to be hepatocellular carcinoma. A single ultrasound-guided liver-nodule biopsy was obtained with a 20- to 21-G cutting needle from 131 cirrhotic patients. The solid portion of samples was used for microhistology; the remainder was subjected to smear cytology. The results of each type of examination were expressed as true positive, nonspecific malignancy, false negative, or inadequate for diagnosis. No false-positive diagnoses were made in 13 benign lesions. In 118 HCC nodules (particularly those <30 mm in diameter), cytology provided a significantly higher percentage of correct diagnoses (85.6%) that was only slightly inferior to that based on results of both studies (89.8%). The single-biopsy technique generally provides adequate tissue for histology and cytology specimens with a high cellularity. It reduces both the cost and the risks of fine-needle biopsy diagnosis of hepatocellular carcinoma.
The aim of this study was to compare the ability of power Doppler sonography and color Doppler sonography to differentiate hepatocellular carcinoma (HCC) from adenomatous hyperplasia (AH).
In 48 patients with cirrhosis of the liver, color Doppler sonography and power Doppler sonography were performed on 53 hepatic nodules smaller than 20 mm in diameter (32 nodules were HCC; 21 nodules were AH). We evaluated the detectability of the pulsatile and continuous flows in the nodules at each hepatic segment.
Thirty-four percent of nodules produced color signal on color Doppler sonography; 77%, on power Doppler sonography (p < .01). The identification rate of nodules in the left lateral segment was significantly lower than in other segments. Continuous flow was seen in the nodules of both HCC and AH. However, only in HCC did we see pulsatile flow. For HCC, pulsatile flow was seen with color Doppler sonography in 25% of the nodules smaller than 10 mm in diameter and in 50% of the nodules between 10 and 20 mm. With power Doppler sonography, pulsatile flow was seen in 67% (p < .05) of the nodules smaller than 10 mm and in 90% (p < .01) of the nodules between 10 and 20 mm. Sensitivity and negative predictive value in the differentiation of HCC from AH were significantly higher with power Doppler sonography than with color Doppler sonography (81% versus 41%, respectively, for sensitivity and 78% versus 53%, respectively, for negative predictive value). Specificity, positive predictive value, and efficacy of both color Doppler sonography and power Doppler sonography were 100%, 100%, 60%, respectively.
On the basis of our results, power Doppler sonography is more sensitive than color Doppler sonography in revealing small HCC and in differentiating HCC from AH under physiologic hemodynamic conditions.
To assess in humans the pharmacokinetics of SonoVue, a new echo contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles and to provide additional safety and tolerability information on the compound.
The blood kinetics and pulmonary elimination of SF6 after intravenous bolus injection of two dosage levels (0.03 and 0.3 mL/kg) of SonoVue were evaluated in 12 healthy subjects (7 men, 5 women). In addition, safety and tolerability were evaluated by monitoring vital signs, adverse effects, discomfort, and physical examination and laboratory parameters associated with the SonoVue injection.
The blood kinetics of SF6 was not dose dependent. SF6 was rapidly removed from the blood by the pulmonary route, with 40% to 50% of the injected dose eliminated within the first minute after administration and 80% to 90% eliminated by 11 minutes after administration; the elimination was similar in men and women and independent of dose. Both dosages were well tolerated. No adverse effects were observed immediately or during the 24-hour follow-up period.
SonoVue was shown to be rapidly removed from the blood. The route of SF6 elimination was by means of the lungs in the expired air. SonoVue appeared to be safe and well tolerated in healthy subjects.
To characterize blood flow in focal hepatic lesions with harmonic ultrasonographic (US) imaging and a microbubble contrast agent.
Thirty patients with known hepatic masses were examined after injection of a perfluorocarbon microbubble agent. Tumor vascularity was assessed with continuous, harmonic gray-scale imaging with a low mechanical index (MI). Tumor vascular volume was assessed with brief, high-MI insonation called interval-delay imaging, which caused microbubble destruction. As the total contrast agent volume in the liver reflects the total vascular volume, quantitation of lesion enhancement relative to normal hepatic enhancement helped determine the vascular volume of the tumor relative to that of normal parenchyma.
Low-MI continuous harmonic imaging showed lesional vessels in hepatocellular carcinomas, minimal or no vessels in hemangiomas, and variable vascularization in metastases. High-MI interval-delay imaging showed greater enhancement in hepatocellular carcinomas than in normal liver (P <.02) and showed less enhancement in hemangiomas than in normal liver (P <.02). Enhancement in metastases was greater in the margins than in the center; as a result, the lesions appeared smaller (P <.03) and less well defined on the interval-delay images.
Contrast-enhanced harmonic imaging appears superior to conventional Doppler US for hepatic mass characterization. Low-MI continuous and high-MI interval-delay imaging can help assess tumor vascular pattern and microvascular volume.
Fatty change is frequently observed in small hepatocellular carcinoma (HCC) of the early stage. However, the mechanism of fatty change and its pathomorphological features in small HCC are not yet fully understood. These issues are addressed here.
Histological examinations were conducted on 260 HCC nodules (< or =3 cm in diameter) which were surgically obtained from 249 patients. According to the distribution pattern, fatty changes were classified into two types: 'diffuse type' when the change was found throughout the cancerous nodule; and 'focal type' when the change was localized in part of the nodule. To study the pathogenesis of fatty change in HCC in relation to angioarchitecture, the number of arterial tumor vessels and intratumoral portal tracts in 104 of the 260 nodules was counted.
Fatty change was found in 51 of the 260 nodules (19.6%), the frequency was highest (36.4%) in the nodules whose diameter was 1.1 to approximately 1.5 cm, and the frequency decreased with the increase in tumor diameter. Small well-differentiated HCCs were often associated with a diffuse type fatty change. With the increase in tumor diameter, moderately differentiated cancerous tissues without associated fatty change appeared, and the focal type was found more frequently. According to the angioarchitecture, in HCCs < or =1.5 cm, the number of intratumoral arteries was significantly smaller in HCCs with fatty change (p<0.05), though the number of intratumoral portal tracts was not significantly different compared with HCCs without fatty change.
These findings suggest that fatty change of small HCC is closely related to the tumor size, the histological grade and insufficient development of the arterial tumor vessels.
The number of dysplastic nodules detected clinically has increased since patients with hepatitis virus-associated cirrhosis, who are at increased risk for hepatocellular carcinoma (HCC), began to undergo regular cancer surveillance. Although it is potentially important to determine which type(s) of nodule may be prone to progress to HCC, outcomes of dysplastic nodules have not been fully investigated. This prompted us to examine the outcomes of dysplastic nodules in cirrhotic patients clinicopathologically. We studied 33 dysplastic nodules of <20 mm in maximum diameter, diagnosed by fine needle aspiration biopsy under ultrasonography (US). These nodules were clinically followed, mainly by US examination, for up to 70 months. When the nodules enlarged or exhibited changes on US, they were histologically reexamined by second biopsy. Surprisingly, 15 of the 33 nodules (45.5%) disappeared, 14 nodules (42.4%) remained unchanged, and only 4 nodules (12.1%) progressed to HCC. The latter 4 nodules were all hyperechoic on US and were composed of clear cells with fatty change or small cells with increased nuclear density, and in all 4 patients serum was positive for hepatitis C virus antibody. Univariate analyses revealed that, although not significant, the hyperechoic nodules or nodules with small cell change showed a higher HCC progression rate in comparison with the hypoechoic nodules or the nodules without small cell change. In summary, most of the dysplastic nodules we followed disappeared or remained unchanged, but some progressed to HCC. Hyperechoic nodules in patients with hepatitis C virus-associated cirrhosis, which show small cell change with increased nuclear density, may be prone to progress to HCC.
To quantify the risk of misdiagnosis of focal hepatic lesions manifesting at ultrasonography (US) as typical hemangiomas in a population at high risk for hepatocellular carcinoma (HCC) and to identify the most effective approach to their diagnostic evaluation.
A total of 1,982 patients with newly diagnosed cirrhosis underwent US and serum alpha-fetoprotein determinations for early detection of HCC. Focal lesions with typical features of hemangioma were evaluated with confirmatory findings of contrast material-enhanced dynamic or spiral computed tomography (CT) and/or single photon emission CT with technetium 99m-labeled red blood cells and, in the absence of confirmatory imaging findings, US-guided fine-needle biopsy. Patients whose initial US scan depicted no lesions or hemangiomas were enrolled in a US follow-up program. All hemangioma-like lesions detected during follow-up were evaluated, or biopsy was performed.
US depicted hemangioma-like lesions in 44 of 1,982 patients: 22 hemangiomas and 22 HCCs. Hemangioma-like lesions detected during follow-up in 1,648 patients were HCCs (n = 22) or dysplastic nodules (n = 4). Only 85 (22%) of 383 patients with HCC had alpha-fetoprotein levels suggestive of the diagnosis. The probability of a diagnosis of HCC (or preneoplastic lesion) is 100% for hemangioma-like lesions depicted on subsequent US scans.
If initial US examination of a cirrhotic liver depicts a hemangioma, confirmatory findings of imaging studies are necessary since 50% of hemangiomas in this study were hyperechogenic HCCs. US-guided biopsy can be safely performed, and its findings can be used to confirm the diagnosis.
Hepatocellular carcinogenesis in cirrhosis is a multistage process that includes large regenerative nodules, dysplastic nodules, and hepatocarcinoma. The aim of this study was to establish whether contrast-enhanced Doppler ultrasonography (US) is able to distinguish between early hepatocellular carcinoma (HCC) and small nonmalignant nodules in cirrhosis. Between January 1998 and December 1999, 500 cirrhotic patients with no previous history of HCC or evidence of hepatic focal lesions were enrolled and prospectively followed-up with US every 6 months until December 2000. Sixty-one patients developed focal lesions, 12 multifocal, and 49 monofocal. Biopsy of focal lesions, contrast-enhanced Doppler US, and spiral computed tomography (CT) were performed in 41 consecutive patients with small (<3 cm) monofocal lesions. Twenty nodules were diagnosed as HCC and 21 as nonmalignant (14 large regenerative nodules, 3 low-grade, and 4 high-grade dysplastic nodules) by liver biopsy. Intratumoral arterial blood flow was detected in 19 of 20 (95%) HCC and 6 of 21 (28%) nonmalignant nodules by contrast-enhanced Doppler US (P<.0001). The mean peak resistance and pulsatility indices were 0.82 +/- 0.09 and 1.56 +/- 0.2 in HCC and 0.62 +/- 0.08 and 0.82 +/- 0.08 in dysplastic lesions (P =.002 and.0001), respectively. Spiral CT revealed arterial perfusion in 19 of 20 HCC and in 4 of 21 nonmalignant nodules (high-grade dysplastic nodules). Four of the apparently false-positive nodules at enhanced Doppler US were high-grade dysplastic nodules and 2 evolved to HCC during follow-up. In conclusion, contrast-enhanced Doppler US is a noninvasive, very sensitive technique in differentiating malignant and premalignant lesions from nonmalignant focal lesions in the liver.
The purpose of our study was to determine the specificity of helical CT for depiction of hepatocellular carcinoma in a population of patients with cirrhosis.
Single-detector helical CT screening was undertaken in 1329 patients with cirrhosis who were referred for transplantation. The patients underwent one or more helical CT examinations over 30 months and were followed up for an additional 19 months or until transplantation. We predominantly used unenhanced and biphasic contrast-enhanced techniques with infusions of 2.5-5.0 mL/sec. Four hundred thirty patients underwent transplantation within this period. Liver specimens were sectioned at 1-cm intervals, with direct comparison of imaging and pathologic findings and histologic confirmations of all lesions. Prospective preoperative helical CT reports were used for the primary data analysis. A retrospective unblinded review was undertaken to determine characteristics of false-positive lesions diagnosed as hepatocellular carcinoma.
Thirty-five patients (8%) had false-positive diagnoses for hepatocellular carcinoma based on helical CT. Twenty of these patients (5%) showed hypoattenuating lesions seen during one of the three helical CT examination phases. Fifteen patients (3%) had hyperattenuating lesions seen during the arterial phase. Among the 15 hyperattenuating lesions, CT revealed the causes to be transient benign hepatic enhancement (n = 3), hemangiomas (n = 2), fibrosis (n = 2), peliosis (n = 1), volume averaging (n = 1), low-grade dysplastic nodule (n = 1), or undetermined (n = 5). Of the 20 hypoattenuating lesions, the causes were shown to be fibrosis (n = 8), focal fat (n = 4), infarcted regenerative nodules (n = 2), regenerative nodules (n = 1), fluid trapped at the dome of the liver (n = 1), hemangioma (n = 1), or undetermined (n = 3). Follow-up helical CT in 13 (72%) of 18 patients allowed a change in the diagnosis of hepatocellular carcinoma to a finding of no cancer present.
Helical CT screening for hepatocellular carcinoma in patients with cirrhosis has a substantial false-positive detection rate. Although most of lesions were hypoattenuating, a few hyperenhancing arterial phase lesions were proven not to be hepatocellular carcinoma. An awareness of imaging characteristics and follow-up imaging can help radiologists avoid a mistaken diagnosis in many patients.
The natural outcome of ultrasound-detected macronodules in cirrhosis is still poorly understood. In this study we assessed the incidence and predictors of malignant transformation in a prospective study of 90 consecutive ultrasound-detected macronodules in cirrhosis.
Macronodules classification was based on recently proposed histological criteria. Extranodular large (LCC) and small cell changes were also evaluated. The follow-up included ultrasound and serum alfa-fetoprotein determination every 3 months. Independent predictors of hepatocellular carcinoma were evaluated by Cox proportional hazards regression analysis.
During a mean follow-up of 33 months, 28 (31%) nodules transformed into hepatocellular carcinoma. The incidence of hepatocellular carcinoma per 100 person-years of follow-up was 11.3%, with a malignant transformation rate of 3.5, 15.5, 31 and 48.5% at 1, 2, 3, and 5 years respectively. High-grade dysplastic nodules (HGDN) (hazard risk=2.4; CI 95%=1.1-5.0) and LCC (hazard risk=3.1; CI 95%=1.2-7.8) were independent predictors of malignant transformation. Eight additional hepatocellular carcinomas developed outside the original lesions raising the overall malignant transformation rate to 40% while 15 macronodules (17%) became undetectable at ultrasound (US).
Macronodules characterize a cirrhotic subpopulation with high risk of hepatocellular carcinoma. HGDN and LCC are strong predictors of malignant transformation; subjects with simultaneous presence of both these two conditions are at highest risk of cancer development. The management of cirrhotics with macronodules should be based on morphologic features detected on liver microsamples.
Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer, and its incidence is increasing worldwide because of the dissemination of hepatitis B and C virus infection. Patients with cirrhosis are at the highest risk and should be monitored every 6 months. Surveillance can lead to diagnosis at early stages, when the tumour might be curable by resection, liver transplantation, or percutaneous treatment. In the West and Japan, these treatments can be applied to 30% of patients, and result in 5-year survival rates higher than 50%. Resection is indicated among patients who have one tumour and well-preserved liver function. Liver transplantation benefits patients who have decompensated cirrhosis and one tumour smaller than 5 cm or three nodules smaller than 3 cm, but donor shortage greatly limits its applicability. This difficulty might be overcome by living donation. Most HCC patients are diagnosed at advanced stages and receive palliative treatments, which have been assessed in the setting of 63 randomised controlled trials during the past 25 years. Meta-analysis shows that only chemoembolisation improves survival in well-selected patients with unresectable HCC.
Our purpose was to evaluate the value of contrast-enhanced coded phase-inversion harmonic imaging in showing the characteristic intranodular hemodynamics of hepatic tumors. SUBJECTS AND METHODS. Using a microbubble contrast agent we performed coded harmonic angio in 163 patients with 192 hepatic tumor nodules: 153 hepatocellular carcinomas, 13 metastases, 14 hemangiomas, eight dysplastic nodules, and four focal nodular hyperplasias. After injecting Levovist, we performed real-time scanning, interval-delay fast low-angle shot imaging, and sweep scanning in the early arterial phase, late vascular phase, and postvascular phase, respectively.
On contrast-enhanced coded harmonic angio, the typical hemodynamic pattern of hepatocellular carcinomas was shown as abundant tumor vessels supplied from the periphery to the center of the tumor and dense parenchymal tumor staining with fast washout (sensitivity, 92.8%; specificity, 92.3%). The characteristic hemodynamic pattern of metastases was peripheral tumor vessels with a rim parenchymal stain in the vascular phase followed by a perfusion defect in the postvascular phase (sensitivity, 69.2%; specificity, 100%). Hemangiomas were hypovascular in the early arterial phase with gradual spotty or cotton-wool pooling continuing to the late vascular phase (sensitivity, 92.9%; specificity, 100%). Dysplastic nodules were shown as having no early arterial supply with isovascularity in the late vascular phase (sensitivity, 75%; specificity, 100%). Focal nodular hyperplasias were shown to have a spoked wheel pattern of blood vessels accompanied by dense staining in interval-delay scanning (sensitivity, 100%; specificity, 100%).
Contrast-enhanced coded harmonic angio is a promising method to provide useful information for the differential diagnosis of hepatic tumors.
The objective of our study was to prospectively evaluate the results of helical CT in the detection of hepatocellular carcinoma (HCC) in patients with cirrhosis undergoing orthotopic liver transplantation. SUBJECTS AND METHODS. Eighty-five patients with cirrhosis were studied preoperatively with biphasic helical CT. Arterial, portal, and equilibrium phase images were obtained after injection of 170 mL of contrast material at 5 mL/sec. The prospective CT interpretation was compared with pathologic results on a lesion-by-lesion basis.
Pathologic examination found 85 cases of HCC in 51 patients. Helical CT enabled a correct diagnosis of HCC in 67 of 85 lesions for a sensitivity of 78.8%. HCC nodules were hypervascular in the arterial phase and hypovascular in the equilibrium phase in 63.5% (54/85) of patients. The false-negative rate was 21% (n = 18), and the positive predictive value was 88%. We had nine false-positive findings (11.8%) related to hemangiomas, transient hepatic attenuation differences, and regenerative nodules. Helical CT detected 61% (23/38) of lesions smaller than 2 cm and 93.6% (44/47) of lesions 2 cm or larger.
Helical CT is a useful preoperative imaging technique in cirrhotic patients who are candidates for orthotopic liver transplantation, although it is relatively insensitive for detection of small lesions (< 2 cm).
Significant improvements in management of hepatocellular carcinoma (HCC) have occurred in the last years, but their impact on surveillance outcome is unknown. To clarify this, we compared survival of HCC patients identified along 3 consecutive quinquennia of surveillance.
A cohort of 417 HCC-free outpatients with compensated cirrhosis was prospectively followed for 148 months (range, 1-213 months) with periodic ultrasound examinations.
HCC developed in 112 patients, at a 3.4% rate per year, and was the prime cause of death (n = 54). Forty-six (41%) patients had a single tumor, with a mean size of 3.7 cm, 3.0 cm, and 2.2 cm in the 3 quinquennia (first vs. second: ns; first vs. third: P = 0.017; second vs. third: P = 0.02), and 38 (44%) underwent radical therapy. Mortality rates in HCC patients fell from 45% in the first quinquennium to 37% in the second and 10% in the third (first vs. second: ns; first vs. third: P = 0.0009; second vs. third: P = 0.018) in parallel with a reduction in yearly mortality of treated patients (34%, 28%, and 5%, respectively; first vs. second: ns; second vs. third: P = 0.036; first vs. third: P = 0.0024). After stratification for quinquennium, tumor staging, according to Cancer of the Liver Italian Program (CLIP), was the only independent predictor of survival (P = 0.015).
Cirrhotic patients developing a HCC during the last 5 years of surveillance survived longer than previously, as a consequence of improved management of the tumor and complications of cirrhosis.
To determine the frequencies of various echogenicity patterns in 153 consecutive unifocal hepatocellular carcinomas (HCCs) <2 cm detected in cirrhotic livers and to identify their relationships with clinical, laboratory, and microscopic features.
The tumors were classified as hypoechoic, hyperechoic, isoechoic, or nodule-in-nodule. Correlation was evaluated between hypoechoic and hyperechoic patterns and the following variables: age, gender, serum alphafetoprotein (AFP), tumor size, ultrasound features of liver parenchyma, cirrhosis etiology, and cyto/histological tumor grading.
One hundred and seventeen tumors (76.4%) were hypoechoic, 26 (17.0%) were hyperechoic, 5 (3.3%) were isoechoic, and 5 (3.3%) had nodule-in-nodule patterns. The hyperechoic pattern was more common in patients under 69 years (25.0% vs. 11.3% in those under 69 years or older, P=0.033). Patients with a hyperechoic pattern displayed a trend towards lower AFP levels and higher prevalence of hepatitis C-related cirrhosis. The prevalence of well-differentiated tumors was identical (56.6% and 56.5%) in the hypoechoic and hyperechoic subgroups. AFP was higher than 400 ng/ml in only 11/153 cases (7.2%).
The hyperechoic pattern of HCC is by no means uncommon, particularly in patients under 70. Hyperechogenicity is not related to an increased frequency of well-differentiated tumors. AFP shows limited value as a confirmatory test of small HCC.
Diagnosis of hepatocellular carcinoma (HCC) relies strongly on the detection of hypervascularity in the arterial phase and, in this setting, spiral computed tomography (CT) is the most widely used method. This prospective study aimed to investigate the usefulness of low mechanical index harmonic ultrasound (US), using a second generation contrast-enhanced technique, in the assessment of vascular pattern of HCC shown to be hypervascular at spiral CT.
A total of 79 cirrhotic patients with 103 nodules (mean+/-SD 28+/-13 mm) with arterial hypervascularity at spiral CT were studied. US examination was performed by perfusional sonography, using a new dedicated technology (CnTI-Esaote trade mark ), operating at low mechanical index, after injection of a second generation contrast agent (SonoVue trade mark -Bracco), allowing detection of tumoral flow during arterial phase.
Selective arterial enhancement on perfusional sonography was observed in 94 /103 nodules (91.3%), with a sensitivity of 66.6, 87.5, 91.7, and 97.3% in nodules </=1 cm, >1</=2 cm, >2</=3 cm, and >3 cm respectively.
Perfusional sonography shows good diagnostic agreement with spiral CT in hypervascular HCC and may be proposed for the immediate vascular characterization of nodules detected at US and used as second imaging technique to confirm hypervascularity in cirrhotic nodules.
We evaluated the usefulness of Doppler ultrasonography (DUS) for the analysis of tumor hemodynamics in small hepatocellular carcinoma (HCC).
We compared Doppler ultrasound (DUS) findings with angiography-assisted computed tomography (Angio-CT) such as CT during arterial portography and during hepatic arteriography in the evaluation of the intratumoral hemodynamics, and with pathologic findings in 45 small HCC nodules (< or =3.0 cm in diameter) of 43 patients. DUS flow pattern of each nodule was categorized into three types: afferent continuous flow (Type 1), afferent pulsatile flow with afferent continuous flow (Type 2), and afferent pulsatile flow without afferent continuous flow (Type 3). Intratumoral blood supply was determined by Angio-CT, and pathologic findings were evaluated on resected or biopsied specimen.
Based on Angio-CT findings, Type 1 nodules showed decreased arterial blood supply (ABS) without decreased portal blood supply (PBS). Type 2 nodules showed unchanged ABS but decreased PBS. Type 3 nodules showed both increased ABS and decreased PBS. DUS findings well represented blood supply of HCC evaluated by Angio-CT. In addition, all Type 1 and 2 nodules were well-differentiated HCC, and all Type 3 nodules were moderately or poorly differentiated HCC; DUS findings well reflected differentiation of HCC.
DUS is a non-invasive imaging method and can be used for the evaluation of the stage of malignancy of small HCC.
We sought to investigate the efficacy of contrast-enhanced sonography using a second-generation contrast agent for the evaluation of hepatocellular carcinoma in patients with cirrhosis by comparing the results to those obtained with contrast-enhanced helical CT.
Between October 2002 and March 2003, 74 patients with cirrhosis (60 men and 14 women; age range, 47-80 years; mean age, 67 years) who had a single nodule of hepatocellular carcinoma were selected to be studied from a cohort of 437 patients with cirrhosis. The size range of the 74 nodules was 9-65 mm (mean, 28.2 mm). Twenty-eight (38%) were 20 mm smaller (range, 9-20 mm; mean, 16.6 mm), and 46 (62%) were larger than 20 mm (range, 21-65 mm; mean, 35.2 mm). Contrast-enhanced sonography was performed at a low mechanical index after IV administration of the contrast agent SonoVue. CT scans were obtained in all patients. The enhancement pattern related to tumor hypervascularity was analyzed. The chi-square test was used for statistical analysis.
For the 28 hepatocellular carcinomas 20 mm or smaller, contrast-enhanced sonography showed 15 (53.6%) as hypervascular and 10 (35.7%) as avascular; three (10.7%) carcinomas were missed. On CT, 12 (42.9%) of the 28 hepatocellular carcinomas appeared hypervascular, 13 (46.4%) appeared hypovascular, and three (10.7%) were missed. For the 46 hepatocellular carcinomas larger than 20 mm, contrast-enhanced sonography showed 42 (91.3%) as hypervascular and four (8.7%) as avascular. On CT, 35 (76.1%) hepatocellular carcinomas appeared hypervascular, eight (17.4%) appeared hypovascular, and three (6.5%) were missed. Differences between CT appearance of hepatocellular carcinomas and contrast-enhanced sonographic appearance of the carcinomas were not statistically significant. Concordance between contrast-enhanced sonographic and CT appearances was observed in 61 (82.4%) of 74 cases.
Contrast-enhanced sonography is similar to CT for detecting hepatocellular carcinoma hypervascularity. It could be complementary to conventional unenhanced sonography for evaluation of liver nodules.
To determine, by using multi-detector row helical computed tomography (CT), the added value of obtaining unenhanced and delayed phase scans in addition to biphasic (hepatic arterial and portal venous phases) scans in the detection of hepatocellular carcinoma (HCC) in patients with cirrhosis.
Local ethical committee approval and patient consent were obtained. One hundred ninety-five patients (129 men, 66 women; mean age, 61 years; age range, 39-78 years) with 250 HCCs underwent multi-detector row helical CT of the liver. A quadruple-phase protocol that included unenhanced, hepatic arterial, portal venous, and delayed phases was performed. Analysis of images from hepatic arterial and portal venous phases combined, hepatic arterial and portal venous phases with the unenhanced phase, hepatic arterial and portal venous phases with the delayed phase, and all phases combined was performed separately by three independent radiologists. Relative sensitivity, positive predictive value, and area under the receiver operating characteristic curve (A(z)) were calculated for each reading session.
Mean sensitivity and positive predictive values, respectively, for HCC detection were 88.8% (666 of 750 readings) and 97.8% (666 of 681 readings) for the combined hepatic arterial and portal venous phases, 89.2% (669 of 750 readings) and 97.8% (669 of 684 readings) for hepatic arterial and portal venous phases with the unenhanced phase, 92.8% (696 of 750 readings) and 97.3% (696 of 715 readings) for hepatic arterial and portal venous phases with the delayed phase, and 92.8% (696 of 750 readings) and 97.3% (696 of 715 readings) for all four phases combined. The reading sessions in which delayed phase images were available for interpretation showed significantly (P < .05) superior sensitivity and A(z) values.
Unenhanced phase images are not effective for HCC detection. Because of the significant increase in HCC detection, a delayed phase can be a useful adjunct to biphasic CT in patients at risk for developing HCC.
The diagnosis of hepatocellular carcinoma (HCC) is based on imaging examinations in combination with clinical and laboratory findings. Despite technological advances, imaging cirrhotic patients remains a challenging issue because nonmalignant hepatocellular lesions, such as dysplastic nodules, mimic a small HCC. One of the key pathologic factors for differential diagnosis that is reflected in imaging appearances is the vascular supply to the lesion. It is accepted that imaging techniques may establish the diagnosis of HCC in nodules larger than 2 cm showing characteristic arterial hypervascularization. In lesions ranging from 1 to 2 cm, biopsy is still recommended, although a negative response can never be used to rule out malignancy completely. Although ultrasonography is widely accepted for HCC surveillance, spiral computed tomography (CT) or dynamic magnetic resonance imaging is required for diagnostic confirmation and intrahepatic tumor staging. These examinations have replaced invasive procedures, such as lipiodol CT, but remain relatively insensitive for the detection of tiny HCC lesions and tumor vascular invasion into peripheral portal vein branches.
It has been established that small, equivocal nodular lesions such as dysplastic nodules (DNs) and small well-differentiated hepatocellular carcinomas (early HCCs) are frequently observed in noncancerous liver tissues resected along with HCCs and in explant cirrhotic livers. DNs are classified into low-grade DNs or high-grade DNs on the basis of cytological and architectural atypia; high-grade DNs show varying degrees of cytological or architectural atypia, or both. Early HCCs are indistinctly nodular and highly differentiated and are frequently difficult to differentiate from high-grade DNs. Although the pathological diagnosis of high-grade DNs and early HCCs is controversial, the presence of tumor cell invasion into the intratumoral portal tracts (stromal invasion) is a helpful clue for differentiating early HCC from high-grade DNs. It is highly suggested that many HCCs occurring in cirrhotic liver arise in DNs and develop to classical HCC in a multistep fashion.
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.
We aimed to characterise the vascularisation patterns of hepatocellular carcinomas in contrast-enhanced sonography in correlation to the histological differentiation of hepatocellular carcinomas (HCC), and we also compared the diagnostic value of contrast-enhanced sonography in addition to B-scan sonography and power Doppler sonography.
51 hepatocellular carcinomas (21 well differentiated, 27 moderately differentiated, 3 poorly differentiated) were examined: by B-scan sonography, power Doppler sonography and contrast-enhanced sonography using phase or pulse inversion harmonic imaging with a low mechanical index (< 0.3) and second generation microbubble contrast medium (Optison, Sonovue) as echo-enhancing agent. Lesion vascularity and the kinetics of contrast enhancement within the lesions in the early arterial phase, arterial phase, portal phase and late phase were analysed. The final diagnosis of a HCC was assessed after B-scan sonography, power Doppler sonography and contrast-enhanced sonography.
Hypervascularisation and/or irregular tumour vascularisation could be detected in 18/48 HCCs (37.5%) by power Doppler sonography. After contrast application, 46/51 HCCs (90.2%) were identified as hyperechoic lesions during the early arterial or arterial phase with no correlation to histological differentiation. In the portal phase and late phase, the echogenicity of HCCs after contrast application was variable. A hypoechoic appearance was noted in 17/51 HCCs (33.3%) in the portal phase and in 21/51 HCCs (41.2%) in the late phase. Moderately differentiated HCCs were more often hypoechoic than well differentiated HCCs (p = 0.04).
Contrast-enhanced sonography is highly efficient for the detection of tumour vascularity in HCCs. The majority of HCCs--regardless of histological differentiation--can be characterised as hypervascular lesions in the early arterial and arterial phase with irregular tumour vessels using contrast-enhanced sonography. In addition to B-scan sonomorphology, contrast-enhanced sonography may offer helpful information in patients with liver cirrhosis and focal liver lesions.
The aim of this study was to compare contrast-enhanced gray-scale harmonic ultrasound with multiphasic spiral computed tomography in the assessment of treatment efficacy of non-surgically treated HCC.
We studied 56 HCCs treated by percutaneous ethanol injection (31 cases), radiofrequency ablation (three cases), trans-arterial chemoembolization (12 cases), and combined treatment (10 cases). The efficacy of therapies was blindly assessed by multiphasic computed tomography and gray-scale harmonic ultrasound with a second-generation contrast agent (sulfur hexafluoride).
On computed tomography 30 tumors (53.6%) showed complete necrosis, while 26 lesions (45.4%) were still viable. On contrast-enhanced ultrasound examination 33/56 nodules (58.9%) had no contrast enhancement in the arterial phase, while 23/56 lesions (41.1%) were still vascularized. All the nodules assessed as completely necrotic on computed tomography did not show arterial enhancement on contrast-enhanced ultrasound and diagnostic agreement was found in 53/56 cases (94.6%) (P<0.001). Contrast-enhanced ultrasound demonstrated relative sensitivity and specificity of 87.0% and 98.4%.
Contrast-enhanced harmonic ultrasound is promising in the efficacy evaluation of ablation treatments for HCC. Nodules vascularized in the arterial phase on contrast harmonic ultrasound should be considered still viable and addressed to additional treatment without further evaluation.
The radiologic diagnosis of liver metastasis involves detection, characterization, and tumor staging. Knowledge of the histopathologic changes that occur with metastases provides the best approach to the accurate interpretation of radiologic imaging findings, and in particular, radiologists need to choose appropriate imaging methods based on such knowledge. Because the majority of metastases are hypovascular, the merits of the routine acquisition of hepatic arterial dominant-phase images by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) are disputable. Hepatic arterial dominant-phase images may be obtained when hypervascular tumors are suspected or three-dimensional CT angiography is necessary. And, imaging during the portal venous phase is essential for detecting metastases, evaluating intrahepatic vessel invasion, and for assessing intratumoral necrosis or fibrosis. Equilibrium- to delayed-phase imaging 3-5 min after contrast administration may improve the detection of intratumoral fibrosis, and occasionally lead to more accurate tissue characterization. MRI offers diagnostic information on vascularity, amount of free water, hemorrhage, fibrosis, necrosis, and water molecule diffusion in metastases. And, liver-specific contrast agents like superparamagnetic iron oxide, liposoluble gadolinium chelate, and manganese may improve the MRI-based diagnosis of liver metastases.
Current management guidelines for hepatocellular carcinoma (HCC) do not require biopsy to prove the diagnosis. We evaluated our experience of patients with liver disease and hepatic lesions suspicious for HCC who underwent both fine-needle aspiration and core biopsy and correlated the results with those from commonly used noninvasive approaches.
We retrospectively reviewed the outcomes of a series of patients undergoing biopsy because of a suspicion of HCC and compared sensitivity, specificity, and predictive value of biopsy with existing noninvasive methods for diagnosing HCC.
HCC was diagnosed by biopsy in 74 (63%) of 118 cases, and an additional 10 were found to have HCC on follow-up. Patients with positive biopsy results had significantly higher serum alpha-fetoprotein levels (median, 57 vs 12; P = .014) than those with negative biopsies, although these 2 groups were otherwise similar with regard to tests of liver function, lesion size on imaging, and Child-Pugh class. No patient developed evidence of tumor spread along the needle track after biopsy. We compared the diagnosis of HCC by biopsy with noninvasive diagnostic criteria advocated by the European Association for the Study of the Liver and those used by the United Network for Organ Sharing. Compared with criteria of the European Association for the Study of the Liver and the United Network for Organ Sharing, biopsy had greater sensitivity, specificity, and predictive value.
We recommend a greater role for image-guided biopsy of lesions greater than 1 cm clinically suspicious for HCC to allow adequate treatment planning because the risks of biopsy appear small and the potential benefits significant. Obtaining material for both cytologic and histologic examination at biopsy maximizes the diagnostic yield.
We compared the enhancement pattern of 98 hepatocellular carcinoma nodules in 92 patients on contrast-enhanced ultrasound (CEUS) and contrast-enhanced computed tomography (CECT). Contrast-enhanced ultrasound was performed with SonoVue and a low mechanical index method. In arterial phase, 98 nodules were hyperenhancing on CEUS and 94 on CECT. In portal phase, 82 nodules were hypoenhancing on CEUS and 83 on CECT. Peripheral thin-rim-like enhancement was exhibited in 30 nodules on CEUS and 31 on CECT. Intratumoral vessels were visualized in 94 nodules on CEUS and 36 on CECT.
The purpose of this study was to compare the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) with spiral computed tomography (SCT) for the characterization of focal liver lesions (FLL) and to determine the degree of correlation between the two techniques. Seventy-seven FLL (45 hepatocellular carcinomas; 12 metastases; ten hemangiomas; two regenerating/dysplastic nodules; eight focal nodular hyperplasias) detected with ultrasound (US) were prospectively evaluated by CEUS using a second-generation contrast agent and SCT (with an interval of no more than one month between the two techniques). Independent observers made the most probable diagnosis and the results were compared with the final diagnoses (histology n = 59; MRI n = 18). Statistical analysis was performed by the Chi-square and Kappa tests. CEUS provided a correct, specific diagnosis in 69/77 (90%) of the FLL, while SCT did so in 67/77 (87%). The sensitivity, specificity, and diagnostic accuracy for malignancy were 91%, 90%, and 91%, respectively, for CEUS and 88%, 89%, and 88%, respectively, for SCT. No statistically significant difference was found between CEUS and SCT in the characterization of FLL (p > 0.05). In addition, agreement between the two imaging techniques was good (k = 0.75). We conclude that CEUS and SCT provide a similar diagnostic accuracy in the characterization of FLL, with a good degree of correlation between the two techniques.
The introduction of second-generation microbubble ultrasound contrast agents and the development of contrast specific ultrasound techniques have improved the ability of contrast enhanced ultrasound in detecting and characterising liver lesions, offering new perspectives for its exploitation in clinical hepatology. Indeed, several studies have demonstrated a high diagnostic accuracy in focal lesion characterisation (85-96%) in patients either with or without underlying chronic liver disease. This review article describes the basic principles of contrast enhanced ultrasound, defines the different vascular features of benign and malignant liver lesions, and assesses its clinical impact in different clinical scenarios, according to the guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology, contrast enhanced ultrasound enables the characterisation of focal liver lesions, regardless of the presence or absence of underlying chronic liver disease. Contrast enhanced ultrasound is also useful in staging and follow-up of cancer patients and in monitoring local ablative treatment. Contrast enhanced ultrasound is expected to be considerably increased and replace many computed tomography and magnetic resonance imaging examinations in near future, according to the European Federation of Societies for Ultrasound in Medicine and Biology guidelines. Therefore, it is necessary to take measures in order to meet the demand for an increasing number of these procedures.