Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma.

BACKGROUND & AIMS: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs. METHODS: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling. RESULTS: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA ("Nestin High", >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies. CONCLUSION: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. LAY SUMMARY: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.

Evaluation of the Hepatorenal B-Mode Ratio and the "Controlled Attenuation Parameter" for the Detection and Grading of Steatosis.

PURPOSE: The aim of this study was to evaluate the hepatorenal index ratio of Supersonic Imagine (B-mode ratio) and the controlled attenuation parameter (CAP) of FibroScan for the noninvasive diagnosis and grading of steatosis. MATERIALS AND METHODS: Two centers prospectively included patients who underwent liver biopsy, B-mode ratio and CAP evaluation all on the same day between June 2017 and July 2019. MRI and histological morphometry were also performed in center 1. Histology (classic semiquantitative score and morphometry) was used as the reference. RESULTS: Concerning the B-mode ratio, the AUROCs for ≥ S1, ≥ S2 and ≥ S3 were respectively 0.896 ±â€Š0.20, 0.775 ±â€Š0.30 and 0.729 ±â€Š0.39 with the best cut-off values being 1.22 for ≥ S1 (Se = 76.4 %, Sp = 93.2 %), 1.42 for ≥ S2 (Se = 70.2 %, Sp = 71.2 %) and 1.54 for ≥ S3 (Se = 68.4 %, Sp = 69.8 %). The correlation between the B-mode ratio and morphometry was moderate (Rs = 0.575, p < 0.001) and the correlation between the B-mode ratio and MRI was good (Rs = 0.613, p < 0.001). Concerning the CAP, the AUROCs for ≥  S1, ≥ S2 and ≥ S3 were 0.926 ±â€Š0.18, 0.760 ±â€Š0.30 and 0.701 ±â€Š0.40, respectively, with the best cut-off values being 271 dB/m for ≥ S1 (Se = 84 %, Sp = 88.2 %), 331 dB/m for ≥ S2 (Se = 64.5 %, Sp = 74.7 %) and 355 dB/m for ≥ S3 (Se = 55.3 %, Sp = 75.1 %). The correlation between the CAP and morphometry and between the CAP and MRI was moderate in both cases (Rs = 0.526, p < 0.001 and Rs = 0.397, p < 0.001, respectively). The B-mode ratio was better at ruling in and the CAP was better at ruling out the disease. CONCLUSION: B-mode ratio and CAP show similar and good performance for the diagnosis of steatosis (≥ S1). However, both techniques are limited with respect to differentiating mild to moderate (≥ S2) or severe (≥ S3) steatosis.

Doppler ultrasonography devices, including elastography, allow for accurate diagnosis of severe liver fibrosis.

OBJECTIVES: Advanced chronic liver disease is frequent yet largely underdiagnosed. Doppler-US is a common examination and we recently identified three simple Doppler-US signs associated with severe liver fibrosis. Recent Doppler-US devices include elastography modules, allowing for liver stiffness measurement (LSM). Our aim was to assess whether the use of elastography following positive simple Doppler-US signs improves the detection of severe liver fibrosis in a single Doppler-US examination. METHODS: 514 patients with chronic liver disease who consecutively underwent percutaneous liver biopsy were included in the study. All patients had a Doppler-US examination and LSM with Virtual Touch Quantification (VTQ) on the same day as a liver biopsy. A subset of 326 patients also had LSM with 2D shear wave elastography (SSI). Severe fibrosis was defined as Metavir F ≥ 3 on liver biopsy. RESULTS: Multivariate analysis confirmed our three simple Doppler-US signs (liver surface irregularity, splenomegaly ≥110 mm, and demodulation of hepatic veins) as independently associated with severe fibrosis. The presence of at least one of these three signs showed 85.6% sensitivity and 36.1% specificity for the diagnosis of severe liver fibrosis. Using VTQ (≥1.59 m/s) where there was a positive Doppler-US sign increased the specificity to 80.8%, at the cost of a decrease in sensitivity (73.7%). Similar results were obtained with SSI (≥9.5 kPa), with 73.3% specificity and 81.5% sensitivity. CONCLUSION: Elastography improves the accuracy of Doppler-US in the detection of severe fibrosis. This two-step procedure will help radiologists to accurately identify patients who need to be referred to specialist hepatologists during routine Doppler-US examinations.

Screening for significant chronic liver disease by using three simple ultrasound parameters.

OBJECTIVES: Chronic liver diseases remain asymptomatic for many years. Consequently, patients are diagnosed belatedly, when cirrhosis is unmasked by lifethreatening complications. We aimed to identify simple ultrasound parameters for the screening of patients with unknown significant chronic liver disease. METHODS: Three hundred and twenty seven patients with chronic liver disease, liver biopsy, and ultrasound examination were included in the derivation set. 283 consecutive patients referred for ultrasound examination were included in the validation set; those selected according to the ultrasound parameters identified in the derivation set were then referred for specialized consultation including non-invasive fibrosis tests and ultimately liver biopsy if liver fibrosis was suspected. RESULTS: In the derivation set, three ultrasound parameters were independent predictors of severe fibrosis: liver surface irregularity, spleen length (>110mm), and demodulation of hepatic veins. The association of ≥2 of the three above parameters provided 49.1% sensitivity and 86.9% specificity. In the validation set, at ≥2 of the three parameters were present in 23 (8%) of the patients. Among these patients, 8 had liver fibrosis (F≥1), 5 had significant fibrosis (F≥2) and two cirrhosis. CONCLUSION: The generalized search of three simple ultrasound signs in patients referred for abdominal ultrasound examination may be an easy way to detect those with silent but significant chronic liver disease.

Fusion of COL1A1 exon 29 with PDGFB exon 2 in a der(22)t(17;22) in a pediatric giant cell fibroblastoma with a pigmented Bednar tumor component. Evidence for age-related chromosomal pattern in dermatofibrosarcoma protuberans and related tumors.

In contrast with classic dermatofibrosarcoma protuberans (DP), genetic information about the juvenile or pigmented variant forms of DP, so-called giant cell fibroblastoma (GCF) and Bednar tumor (BT), is limited. In the sole karyotyped case of BT a supernumerary ring containing chromosomes 17 and 22 sequences, similar to DP rings, was reported, whereas in three GCF cases, t(17;22) or der(22)t(17;22) with COL1A1-PDGFB fusion involving exons 11, 40, and 47, respectively, have been described. Here, we report the first cytogenetic and molecular analysis of a tumor from a 5-year-old child that contained both GCF and BT components. The karyotype and molecular analyses confirmed the common histogenetic origin between DP, GCF, and BT in showing the presence of a der(22)t(17;22) fusing the COL1A1 exon 29 to PDGFB exon 2. Because COL1A1 exon 29 has been involved previously in gene fusion with PDGFB exon 2 in several cases of adult or infantile DP presenting either t(17;22) or ring chromosomes, our results support the concept that DP, GCF, and BT are morphologic variants of a same entity, rather than distinct tumors. Of interest, our findings give prominence to the relation between patient age and the chromosomal rearrangement pattern in DP and related tumors. Whereas only a few adult DP cases presented with translocations, all the infantile cases, either DP, GCF, or mixed BT-GCF, as shown here, contained translocation derivatives but not ring chromosomes. All the ring chromosomes were observed in adult cases. With respect to cytogenetic studies, DP, GCF, and BT appear to be a unique model for age-related chromosomal rearrangement progression.

Fractal dimension can distinguish models and pharmacologic changes in liver fibrosis in rats.

Fractal analysis measures the complexity of geometric structures. The aim of this study was to evaluate the feasibility and accuracy of fractal analysis in liver fibrosis. A total of 77 rats were included: 10 sham, 46 with fibrosis secondary to bile duct ligation (BDL), and 21 with fibrosis due to CCl(4) intoxication. Measurements included the fractal dimension of Kolmogorov (D(k)), histologic lesions, the area of fibrosis by image analysis, liver hydroxyproline content, messenger RNA fibronectin, serum hyaluronate level, and portal pressure. Fibrotic rats were given placebo, octreotide, or O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO). Intraobserver agreement of D(k) was excellent with the intraclass (ic) correlation coefficient r(ic) = 0.91 (P <.0001) as well as the interobserver agreement with r(ic) = 0.88 (P <.001). D(k) was correlated with other measurements or markers of fibrosis: the area of fibrosis (r = 0.75; P <.0001), hydroxyproline content (r = 0.51; P <.001), serum hyaluronate level (r = 0.52; P <.001), and portal pressure (r = 0.52; P <.01). D(k) was significantly different between the 2 models of fibrosis (P <.0001), unlike the area of fibrosis, and this relationship was independent of other histologic lesions. The significant decrease in fibrosis observed with octreotide or V-PYRRO/NO was similarly reflected by D(k) or the area of fibrosis. The diagnostic accuracy for the fibrosis model was 97% with the 5 main measurements or markers of fibrosis studied, with D(k) isolated at the first step by stepwise analysis. In conclusion, fractal analysis is suitable for analyzing liver fibrosis and has excellent reproducibility. This is the only quantitative morphometric method that can discriminate among the models of fibrosis and is sensitive enough to detect pharmacologically induced changes in liver fibrosis.