Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis.

BACKGROUND & AIMS: Myeloproliferative neoplasms (MPNs) are the most frequent cause of non-tumoural non-cirrhotic splanchnic vein thrombosis (NC-SVT). Diagnosis of MPN is based on blood cell count alterations, bone marrow histology, and detection of specific gene mutations. Next-generation sequencing (NGS) allows the simultaneous evaluation of multiple genes implicated in myeloid clonal pathology. The aim of this study was to evaluate the potential role of NGS in elucidating the aetiology of NC-SVT. METHODS: DNA samples from 80 patients (75 with idiopathic or exclusively local factor [Idiop/loc-NC-SVT] and 5 with MPN and NC-SVT [SVT-MPN] negative for Janus kinase 2 gene [JAK2] [V617F and exon 12], calreticulin gene [CALR], and thrombopoietin gene [MPL] mutations by classic techniques) were analysed by NGS. Mutations involved in myeloid disorders different from JAK2, CALR, and MPL genes were categorised as high-molecular-risk (HMR) variants or variants of unknown significance. RESULTS: In 2/5 triple-negative SVT-MPN cases (40%), a mutation in exon 12 of JAK2 was identified. JAK2-exon 12 mutation was also identified in 1/75 patients with Idiop/loc-NC-SVT. Moreover, 28/74 (37.8%) of the remaining Idiop/loc-NC-SVT had at least 1 HMR variant. Sixty-two patients with Idiop/loc-NC-SVT were not receiving long-term anticoagulation and 5 of them (8.1%) had recurrent NC-SVT. This cumulative incidence was significantly higher in patients with HMR variants than in those without. CONCLUSIONS: NGS identified JAK2-exon12 mutations not previously detected by conventional techniques. In addition, NGS detected HMR variants in approximately one-third of patients with Idiop/loc-NC-SVT. These patients seem to have a higher risk of splanchnic rethrombosis. NGS might be a useful diagnostic tool in NC-SVT. LAY SUMMARY: Next-generation sequencing (NGS) performs massive sequencing of DNA allowing the simultaneous evaluation of multiple genes even at very low mutational levels. Application of this technique in a cohort of patients with non-cirrhotic non-tumoral portal vein thrombosis (NC-SVT) and a negative study for thrombophilic disorders was able to identify patients with a mutation in exon 12 not previously detected by conventional techniques. Moreover, NGS detected High Molecular Risk (HMR)-variants (Mutations involved in myeloid disorders different from JAK2, CALR and MPL genes) in approximately one third of patients. These patients appear to be at increased risk of rethrombosis. All these findings supports NGS as a potential useful tool in the management of NC-SVT.

Vascular diseases of the liver. Clinical Guidelines from the Catalan Society of Digestology and the Spanish Association for the Study of the Liver. / Enfermedades vasculares del hígado. Guías Clínicas de la Sociedad Catalana de Digestología y de la Asociación Española para el Estudio del Hígado.

Despite their relatively low prevalence, vascular diseases of the liver represent a significant health problem in the field of liver disease. A common characteristic shared by many such diseases is their propensity to cause portal hypertension together with increased morbidity and mortality. These diseases are often diagnosed in young patients and their delayed diagnosis and/or inappropriate treatment can greatly reduce life expectancy. This article reviews the current body of evidence concerning Budd-Chiari syndrome, non-cirrhotic portal vein thrombosis, idiopathic portal hypertension, sinusoidal obstruction syndrome, hepatic vascular malformations in hereditary haemorrhagic telangiectasia, cirrhotic portal vein thrombosis and other rarer vascular diseases including arterioportal fistulas. It also includes a section on the diagnostic imaging of vascular diseases of the liver and their treatment from a haematological standpoint (study of thrombotic diathesis and anticoagulation therapy). All recommendations are based on published studies extracted from PubMed. The quality of evidence and strength of recommendations were rated in accordance with the GRADE system (Grading of Recommendations, Assessment Development and Evaluation). In the absence of sufficient evidence, recommendations were based on the opinion of the committee that produced the guide.

Lack of arterial hypervascularity at contrast-enhanced ultrasound should not define the priority for diagnostic work-up of nodules <2 cm.

BACKGROUND & AIMS: Current guidelines recommend diagnostic work-up for nodules >1cm detected during screening for hepatocellular carcinoma (HCC). This implies that patients with benign conditions may undergo unnecessary evaluation and those with small nodules may be intervened too early, leading to overdiagnosis. Since increased arterial vascularization is the hallmark of malignancy, its detection by contrast-enhanced ultrasound (CEUS) could become the signal to proceed with diagnosis confirmation. The aim was to assess if HCCs <2 cm without arterial hyperenhancement by baseline CEUS have a benign evolutionary profile, suggesting that diagnosis and invasive treatment could be delayed until detection of an overt malignant profile, associated with increased vascularization. METHODS: We prospectively included 168 cirrhotic patients with a newly detected solitary nodule of 5-20mm by screening ultrasonography. MRI, CEUS and fine needle biopsy (FNB) were performed and if no confident diagnosis was obtained, patients were closely followed to rule out HCC. Final diagnosis was: HCC (n = 119), cholangiocarcinoma (n = 3), neuroendocrine tumour (n = 1) and benign lesions (n = 45). RESULTS: CEUS did not detect contrast hyperenhancement in the arterial phase in 55 cases (34%). Eighteen out of these 55 nodules were diagnosed as HCC. Non-CEUS hyperenhanced HCCs were more frequently well-differentiated than CEUS-hyperenhanced HCCs (p < 0.004). Fourteen patients were treated with ablation and 4 with resection. Ten (55.6%) patients experienced tumour recurrence after treatment, mostly distant, confirming their overt malignant profile. CONCLUSIONS: Absence of contrast hyperenhancement on CEUS during the arterial phase in nodules <2 cm in a cirrhotic liver does not predict a less malignant profile. Accordingly, priority for diagnostic work-up and treatment should not differ according to contrast profiles on CEUS.