Non-alcoholic steatohepatitis (NASH) is growing into global problem, mainly due to NASH-induced cirrhosis and hepatocellular carcinoma (HCC), that can develop either subsequently to cirrhosis or preceding it. In addition, NASH-induced cirrhosis constitutes a significant fraction of cases diagnosed as cryptogenic cirrhosis. Thus, there is a need for deeper understanding of the molecular basis, leading to liver steatosis, then—to the associated inflammation seen in NASH, loss of liver architecture and cirrhosis, followed or paralleled by carcinogenesis and HCC. Insulin resistance, increased hepatic iron level, and certain cytokines, including TNF-α and IL-6 derived from extrahepatic adipose tissues, can trigger the chain of events. The imbalance between leptin and adiponectin is important as well. These markers remain important during the whole course from NASH through liver cirrhosis to HCC. The molecular pathogenesis substantiates treatment: hypertriglyceridemia can be lowered by low calorie diet; mTOR complex can become inhibited by physical activity and metformin; cholesterol synthesis, RAF/MAPK1/ERK and p21 pathway by statins; inflammation by pentoxyfillin, and kinases (in HCC) by sorafenib. Bidirectional regulation of telomere attrition, senescence and p21 pathway, restoration of wild-type p53 activity and regulation of miRNA network represent attractive future treatment options. Focusing on relevant molecular pathways allows deeper understanding of NASH pathogenesis, leading to identification of predictive markers and treatment targets.
Part of the book: Liver Cirrhosis
Gastric cancer induces systemic inflammatory reaction (SIR) manifesting with changes in counts of white blood cell fractions and concentrations of acute phase proteins, clotting factors and albumins. Thus, protein-based scores or blood cell ratios (neutrophil to lymphocyte ratio (NLR); platelet to lymphocyte ratio (PLR)) are used to evaluate SIR. SIR tests are biologically justified by multiple clinically important and fascinating events including bone marrow activation, development of immune-suppressing immature myeloid cells, generation of pre-metastatic niches and neutrophil extracellular trap formation from externalised DNA network in bidirectional association with platelet activation. Despite biological complexity, clinical SIR assessment is widely available, patient-friendly and economically feasible. Here we present concise review on NLR, PLR, Glasgow prognostic score and fibrinogen – parameters that have prognostic role regarding overall, cancer-free and cancer-specific survival in early and advanced cases. Tumour burden can be predicted helping in preoperative detection of serosal or lymph node involvement. Practical consequences abound, including selection of surgical approach in respect to tumour burden, adjustments in treatment intensity by prognosis or evaluation of chemotherapy response. The chapter also scrutinises main controversies including different cut-off levels. Future developments should include elaboration of complex scores as described here. SIR parameters should be wisely incorporated in patients’ treatment.
Part of the book: Gastric Cancer
In the global cancer statistics, hepatocellular carcinoma (HCC) ranges sixth by incidence and second by oncological mortality. The risk factors comprise hepatitis B and C virus infection, non-alcoholic steatohepatitis, as well as long-lasting peroral exposure to alcohol or aflatoxins. Liver cirrhosis is the most important single predisposing factor. Ultrasonography once per 6 months is recommended for surveillance in cirrhotic patients. Computed tomography (CT) and magnetic resonance imaging (MRI) represent the gold standard of non-invasive diagnostics while core biopsy and/or immunohistochemistry (IHC) are indicated for controversial and non-cirrhotic HCC cases. Molecular classification is under development. At present, classics of HCC diagnostics is based on evaluation of risk factors, surveillance in cirrhotic patients, preference for CT or MRI-confirmed non-invasive diagnosis and biopsy proof in equivocal cases. Diffusion-weighted imaging and hepatobiliary phase contrasting represent significant recent developments in MRI. Contrast-enhanced ultrasonography is recommended by some but not all guidelines. Positron emission tomography is advocated before liver transplantation to detect extrahepatic metastases but has limited role in the initial diagnostic evaluation of liver nodule. Innovations are expected in the field of molecular diagnostics, including IHC panels and novel antigens, e.g. clathrin and bile salt export pump protein, and development of molecular classification.
Part of the book: Hepatocellular Carcinoma
Thyroid nodules are frequent in general population, found in 3.7–7% of people by palpation and 42–67% by ultrasonography (US). The differential diagnosis ranges from papillary (PC), follicular (FC) and medullary (MC) carcinomas to follicular adenoma (FA) and colloid goitre. Cancer risk in thyroid nodules varies: 5% in masses found by palpation, 1.6–15% by US, 3.9–11.3% by computed tomography (CT), 5–6% by magnetic resonance imaging (MRI) and 30–50% by positron emission tomography (PET). The final diagnosis depends on fine needle aspiration (FNA) findings and histopathology. The recent WHO classification (2017) is based on classic morphology, including assessment of invasion and nuclei. New entities are defined to designate tumours with doubtful invasion or controversial nuclear features. By immunohistochemistry, PC expresses HBME-1, TROP-2, CITED1 and CK19. Notably, PC can stain for CD20. MC is recognised by neuroendocrine differentiation. To distinguish FA vs. FC, evaluation of HBME-1, p27 and galectin has been suggested. Regarding miRNAs, miR-146b, miR-222, miR-221 and miR-181b are upregulated, while miR-145, miR-451, miR-613 and miR-137 are downregulated in PC. FC features downregulated miR-199a-5p and upregulated miR-197 and miR-346. In MC, miR-21 and miR-129-5p are downregulated. In addition, increased systemic inflammatory reaction can be poor prognostic factor in thyroid cancer. The aim of this chapter is to review classic and innovative histopathology of thyroid nodules for diagnostic pathology practice and research in multidisciplinary thyroid teams.
Part of the book: Histopathology
Hepatocellular carcinoma (HCC) is an aggressive tumour associated with dismal prognosis. To improve the outcome, early diagnostics is important. At present, classical HCC diagnostics is based on evaluation of risk factors, surveillance in cirrhotic patients, preference for non-invasive diagnosis by computed tomography or magnetic resonance imaging and biopsy confirmation in controversial cases. However, ambiguous radiological presentation, biopsy-related complications or insufficient representation of the pathology in the tissue core are well-known problems. Panel assessment of microRNAs has diagnostic and prognostic value; thus, in future, microRNA-based liquid biopsy could partially reduce the need for core biopsies. Systemic inflammatory reaction (SIR), characterised mainly by neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and Glasgow prognostic score, may have prognostic value and can be incorporated in criteria for certain treatment approaches, e.g., becoming an adjunct to Milan criteria. Thus, innovations in HCC diagnostics are expected in the field of miRNA-based liquid biopsy for diagnosis/prognosis and SIR for prognosis/selection of treatment.
Part of the book: Hepatocellular Carcinoma