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Conventional histopathology involves expensive and labor intensive processes that often consume tissue samples, rendering them unavailable for other analysis. We present a novel end-to-end workflow for pathology powered by hyperspectral microscopy and deep learning. First, we developed a custom hyperspectral microscope to non-destructively image the autofluorescence of unstained tissue sections. We then train a deep learning model to use the autofluorescence to generate virtual histological stains, which avoids the cost and variability of chemical staining procedures and conserves tissue samples. We showed that the virtual images reproduce the histological features present in the real stained images using a randomized nonalcoholic steatohepatitis (NASH) scoring comparison study where both real and virtual stains are scored by pathologists. The test showed moderate to good concordance between pathologists’ scoring on corresponding real and virtual stains. Finally, we developed deep learning-based models for automated NASH clinical research network (NASH CRN) score prediction. We showed that the end-to-end automated pathology platform is comparable to pathologists for NASH CRN scoring when evaluated against the expert pathologist consensus scores. This study provides proof of concept for this virtual staining strategy, which could improve cost, efficiency, and reliability in pathology, and enable novel approaches to spatial biology research.

AimsA survey of members of the UK Liver Pathology Group (UKLPG) was conducted, comprising consultant histopathologists from across the UK who report liver specimens and participate in the UK National Liver Pathology External Quality Assurance scheme. The aim of this study was to understand attitudes and priorities of liver pathologists towards digital pathology and artificial intelligence (AI). MethodsThe survey was distributed to all full consultant members of the UKLPG via email. This comprised 50 questions, with 48 multiple choice questions and 2 free-text questions at the end, covering a range of topics and concepts pertaining to the use of digital pathology and AI in liver disease. ResultsForty-two consultant histopathologists completed the survey, representing 36% of fully registered members of the UKLPG (42/116). Questions examining digital pathology showed respondents agreed with the utility of digital pathology for primary diagnosis 83% (34/41), second opinions 90% (37/41), research 85% (35/41) and training and education 95% (39/41). Fatty liver diseases were an area of demand for AI tools with 80% in agreement (33/41), followed by neoplastic liver diseases with 59% in agreement (24/41). Participants were concerned about AI development without pathologist involvement 73% (30/41), however, 63% (26/41) disagreed when asked whether AI would replace pathologists. ConclusionsThis study outlines current interest, priorities for research and concerns around digital pathology and AI for liver pathologists. The majority of UK liver pathologists are in favour of the application of digital pathology and AI in clinical practice, research and education. Funding Agencies|National Pathology Imaging Co-operative (NPIC); Data to Early Diagnosis and Precision Medicine strand of the Governments Industrial Strategy Challenge Fund [104687]; Leeds Hospitals Charity; National Institute for Health Research (NIHR); NPIC; National Institute For Health Research (NIHR) UCLH/UCL Biomedical Research Centre (BRC)

BackgroundNorthern England has been experiencing a persistent rise in the number of primary liver cancers, largely driven by an increasing incidence of hepatocellular carcinoma (HCC) secondary to alcohol-related liver disease and non-alcoholic fatty liver disease. Here we review the effect of the COVID-19 pandemic on primary liver cancer services and patients in our region.ObjectiveTo assess the impact of the COVID-19 pandemic on patients with newly diagnosed liver cancer in our region.DesignWe prospectively audited our service for the first year of the pandemic (March 2020–February 2021), comparing mode of presentation, disease stage, treatments and outcomes to a retrospective observational consecutive cohort immediately prepandemic (March 2019–February 2020).ResultsWe observed a marked decrease in HCC referrals compared with previous years, falling from 190 confirmed new cases to 120 (37%). Symptomatic became the the most common mode of presentation, with fewer tumours detected by surveillance or incidentally (% surveillance/incidental/symptomatic; 34/42/24 prepandemic vs 27/33/40 in the pandemic, p=0.013). HCC tumour size was larger in the pandemic year (60±4.6 mm vs 48±2.6 mm, p=0.017), with a higher incidence of spontaneous tumour haemorrhage. The number of new cases of intrahepatic cholangiocarcinoma (ICC) fell only slightly, with symptomatic presentation typical. Patients received treatment appropriate for their cancer stage, with waiting times shorter for patients with HCC and unchanged for patients with ICC. Survival was associated with stage both before and during the pandemic. 9% acquired COVID-19 infection.ConclusionThe pandemic-associated reduction in referred patients in our region was attributed to the disruption of routine healthcare. For those referred, treatments and survival were appropriate for their stage at presentation. Non-referred or missing patients are expected to present with more advanced disease, with poorer outcomes. While protective measures are necessary during the pandemic, we recommend routine healthcare services continue, with patients encouraged to engage.

Biopsy is still the gold standard for the diagnosis of nonalcoholic steatohepatitis but the definition may vary among pathologists, a drawback especially in evaluation of biopsies for clinical trials. We previously developed a scoring system (steatosis, activity, fibrosis [SAF]) allowing the use of an algorithm (fatty liver inhibition of progression [FLIP]) for the classification of liver injury in morbid obesity. The aim of this study was to determine whether the use of the SAF score and FLIP algorithm can decrease interobserver variations among pathologists. In a first session, pathologists categorized 40 liver biopsies of patients with nonalcoholic fatty liver disease (NAFLD) according to their own experience. In a second reading session, each pathologist reclassified the same slides by using the FLIP algorithm and SAF score, blinded to their first evaluation. The experiment was repeated with two different groups of pathologists at varying levels of training in liver pathology. The percentage of biopsy interpretation concordant with reference evaluation increased from 77% to 97% in Group 1 and from 42% to 75% in Group 2 after the use of the SAF score and FLIP algorithm. The strength of concordance in classification increased in Group 1 from moderate (κ = 0.54) to substantial (κ = 0.66) and from fair (κ = 0.35) to substantial (κ = 0.61) in Group 2 with application of the algorithm. With regard to the SAF score, concordance was substantial in Group 1 for steatosis (κ = 0.61), activity (κ = 0.75), and almost perfect for fibrosis (κ = 0.83 after pooling 1a, 1b, and 1c together into a single score F1). Similar trends were observed in Group 2 (κ = 0.54 for S, κ = 0.68 for A, and κ = 0.72 for F). Conclusion: The FLIP algorithm based on the SAF score should decrease interobserver variations among pathologists and are likely to be implemented in pathology practice. (Hepatology 2014;60:565–575)

Steatosis--accumulation of triacylglycerol in hepatocytes--is a common finding in liver biopsy specimens. The commonest form is macrovesicular change, which occurs in response to a wide range of insults. In the absence of other features, the pathologist cannot ascertain the likely cause on morphological features alone but can give an indication of the severity of steatosis. Close clinicopathological correlation is required to establish the cause. In most instances, macrovesicular steatosis is at least potentially reversible. Although it may be thought of as a benign condition, it may be associated with the development of necroinflammation and fibrosis--so-called steatohepatitis. The classic example of this is alcoholic hepatitis, but there is increasing awareness of steatohepatitis occurring in nonalcoholics: NASH. Distinction between alcoholic hepatitis and NASH on purely histological grounds may be impossible; careful clinicopathological discussion is mandatory. Microvesicular steatosis is generally a more severe disease than the macrovesicular form and is seen in a variety of conditions in which there is either an inherited or an acquired defect in beta-oxidation of fatty acids; the former includes mitochondrial cytopathies and disorders of ureagenesis, and the latter includes acute fatty liver of pregnancy and Reye's syndrome. This review describes the morphological features of steatosis and steatohepatitis, considers their pathogenesis, and outlines the clinical significance of the different patterns of injury.

Chronic liver disease has been reported to be an important cause of late morbidity and mortality in renal transplant recipients. We have examined the prevalence and nature of chronic liver disease among 538 patients with functioning renal allografts managed at the Western Infirmary, Glasgow, between 1980 and 1989. Thirty-seven patients (7 per cent) satisfied biochemical criteria for chronic liver dysfunction. Liver biopsies were obtained from 24 of these, and autopsy tissue was available from three other patients. Chronic hepatitis of variable severity was present in 15 patients, haemosiderosis in 12 patients and nodular regenerative hyperplasia in five patients. Nineteen patients (51 per cent) had serological evidence of infection with the hepatitis C virus, and one of these developed chronic hepatitis B and D infection as well. Although a variety of chronic liver diseases occurred in our transplant population, the frequency of serious sequelae from liver dysfunction was much lower than that reported from transplant centres in other countries.

The case of an unusual variant of breast carcinoma arising in an 80-year-old woman is presented. Fine needle aspiration (FNA) cytology of this carcinoma revealed sheets of cells showing apocrine differentiation and significant cellular atypia mixed with lymphocytes and plasma cells. At mastectomy, the neoplasm was found to have features of both apocrine carcinoma and medullary carcinoma, with a prominent lymphocytic infiltrate. This case underlines the difficulty in distinguishing between malignant apocrine cells and apocrine metaplastic cells by FNA cytology. The presence of an inflammatory component, as seen in this case, may compound such difficulties.

The relationship between survival and 25 clinical and histologic variables was studied in 195 patients (171 women, 24 men) who satisfied stringent criteria for the diagnosis of primary biliary cirrhosis. The mean duration of follow-up was 6 yr (range 0-17). One hundred and sixteen patients died, 84% as the result of liver disease and 16% from nonhepatic causes. Using the Kaplan-Meier estimate, we calculated the mortality from liver disease to be 40% after 5 yr and 60% after 10 yr. Ascites, serum bilirubin level, variceal hemorrhage, and age were identified as independent clinical risk factors, and extent of hepatic fibrosis, bilirubinostasis, and Mallory's hyalin were identified as independent histologic risk factors correlating with reduced survival.

We investigated the response of macrophages and perisinusoidal (Ito) cells (PSCs) during the development of secondary biliary cirrhosis after ligation and division of the common bile duct. Liver tissue was obtained from three groups of male Wistar rats: 1) untreated controls (n = 3); 2) common bile duct-ligated (CBDL) animals (n = 15); and 3) sham-operated controls (n = 15). Material from animal groups 2 and 3 was obtained on days 3, 7, 14, 21, and 28 after operation; in all animals 5-bromo-2-deoxyuridine was administered intraperitoneally before death. Monocytes and macrophages were detected using the monoclonal antibody ED1 and tissue macrophages using the antibody ED2. Cell proliferation within the macrophage population was demonstrated by double labeling for ED2 and incorporated 5-bromo-2-deoxyuridine. PSCs were demonstrated in tissue sections by immunolocalization of desmin; proliferating PSCs were identified by double labeling for desmin and incorporated 5-bromo-2-deoxyuridine. Evidence of phenotypic modulation of PSCs was sought using anti-alpha-smooth muscle actin (alpha-SMA) antibody. Increased numbers of ED1- and ED2-positive cells were seen in CBDL animals at all time points. Local proliferation of macrophages could be identified and reached a peak at day 3, thereafter falling toward control values. Compared with those of controls, livers of CBDL animals showed increased numbers of desmin-positive PSCs in periportal zones from day 3 on, reaching a peak at day 14 (127.8 +/- 10.99 cells/0.635 mm2) and followed by a plateau. PSC proliferation peaked at days 3 and 7 (labeling indices 11.2% and 11.2%, respectively) and thereafter fell toward control values; no expansion of the PSC population was seen in sham-operated rats. Increased alpha-SMA-positive cells were also noted from day 3, with a peak at day 21 (231.1 +/- 11.52 cells/0.635 mm2) and followed by a plateau. En face labeling experiments in days 14, 21, and 28 CBDL animals showed cells co-expressing alpha-SMA and desmin and cells expressing alpha-SMA alone. These results indicate that in response to chronic cholestatic liver injury, PSCs proliferate and undergo phenotypic modulation toward "myofibroblast-like" cells. The kinetics of the response are similar to those of the ED2-positive cell population in keeping with a hypothesis that PSC proliferation and activation may be mediated by factors released by macrophages in response to various forms of liver injury. We conclude that the responses of macrophages and PSCs to cholestatic injury are similar to those after toxin-induced hepatocyte necrosis.

Biliary tract dilatation without obstruction may result from sclerosing cholangitis, pyogenic cholangitis, or bile duct surgery. This case report describes a patient with AIDS whose biliary tract dilatation was due to cytomegalovirus infection. Such a diagnosis should now be considered in the immuno-suppressed patient who has dilated bile ducts.