Peter J. Scheuer

Histological grading and staging of chronic hepatitis

‘Armed Forces instifute of Pathology, Washington, USA, 2University of Lisbon. Lisbon, Portugal, -‘Hofstetten, Switzerland, 4Servizio di Anatomia e Istologia Patologica. Spedali Civili, Brescia, Italy, 5Department of Medicine, University of Leuven, Leaven, Belgium, 61nstitute for Pathology, University of Basel, Basel, Switzerland, 7Department of Pathology, University of Graz. Graz, Austria, 8Department of Pathology, University of Leuven, Leuven, Belgium. 9 Weiden, Germany, ‘ODepartment of Pathology, Western Infirmary, University of Glasgow, Glasgow, UK, “Department of Pathology, ~osp~talfor Sick Children, University of Toronto, Toronto, Canada, ~‘~nstitute of Liver Studies, King’s College Hospital, London, UK, 13Frederiksberg, Denmark, Is Watt, Switzerland, “Vienna, Austria

Nomenclature of the finer branches of the biliary tree: Canals, ductules, and ductular reactions in human livers

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field. (HEPATOLOGY 2004; 39:1739–1745.)

The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization.

This memorandum provides guidelines on the definition, nomenclature, and classification of cirrhosis, chronic hepatitis, and hepatic fibrosis. These are considered according to morphological characteristics and aetiology. It is hoped that this system will serve as a standard for diagnostic, research, and epidemiological purposes. The relationship of cirrhosis to liver cell carcinoma is briefly discussed and the possible morphological markers of an increased risk of malignancy are defined.

PROPOSAL FOR STANDARDIZED CRITERIA FOR THE DIAGNOSIS OF BENIGN, BORDERLINE, AND MALIGNANT HEPATOCELLULAR LESIONS ARISING IN CHRONIC ADVANCED LIVER-DISEASE

Although current literature contains many cases of putative premalignant hepatocellular proliferations and small hepatocellular carcinomas, no consistent nomenclature and diagnostic criteria have been put forward to describe them. These nodules, which are being detected by radiographic techniques in cirrhotic livers and removed during transplantation procedures, represent a new and challenging histologic spectrum of liver pathology. In this study, a multinational panel of five liver pathologists reviewed 23 such nodules and were able to reach a consensus on the diagnostic criteria and to devise a standard nomenclature to describe the histologic lesions. We recommend that benign nodules showing little histologic difference from cirrhotic nodules be classified as regenerative or macroregenerative, and nodules with atypical features not diagnostic of carcinoma be classified as borderline. Such standardization should facilitate further study of the pathologic features and clinical behavior of these lesions.

Partial nodular transformation of the liver with portal hypertension

Abstract Four patients with portal hypertension due to nodular transformation of the liver, but without cirrhosis, are described. The liver was not enlarged but up to two thirds of the perihilar region was replaced by nodules. The periphery of the liver was normal or atrophic. The portal hypertension was presumably due to obstruction to hepatic blood flow by the nodules. It is probably postsinusoidal in type and this was confirmed by detailed circulatory studies in one patient. Liver cell function remains fairly good and duration of life seems considerably longer than in cirrhosis. Diagnosis is difficult; it may be suggested by findings on wedge liver biopsy, but confirmation must await autopsy. A normal needle biopsy specimen of the liver does not exclude the condition.

Scoring of chronic hepatitis.

Grading of the severity of chronic hepatitis and staging of its structural consequences are widely used in clinical trials of therapy and in research. Simple and complex methods are available. Intra- and interobserver variation can be reduced but not eliminated, because grading and staging are essentially subjective. The data are categorical rather than numerical and must be treated accordingly. Morphometry of fibrous tissue offers a different approach to biopsy assessment.

The nomenclature of chronic hepatitis: time for a change

T” histological subdivision of chronic hepatitis into chronic persistent and chronic active forms was first advocated nearly 30 years ago (1,2). The underlying purposes of this classification were first to clarify the use of the term chronic active hepatitis, and secondly to distinguish between mild disease, chronic persistent hepatitis, with a low potential for cirrhosis, and more aggressive forms which might lead to cirrhosis by the process of piecemeal necrosis. Chronic lobular hepatitis was added to the classification shortly afterwards (3) to indicate a predominantly lobular (acinar) lesion, and the term chronic septal hepatitis was introduced to describe scarring without piecemeal necrosis (4). The classification was widely adopted by clinicians and pathologists alike. There are several good reasons why this simple histological classification no longer meets the needs of hepatologists. Foremost is the rapid increase in understanding of hepatitis virus infection, the main cause of chronic hepatitis. In 1968, when the histological classification was published, the hepatitis B virus had only recently been discovered (5) and little was known about its replication and behaviour in chronic infections. The hepatitis A virus was discovered a few years later (6). Testing for antibodies to the most important non-A, non-B virus followed in 1989 and enabled hepatitis C infection to be identified (7,8). All histological forms and degrees of severity of chronic hepatitis are found in both hepatitis B and C, but they sometimes have quite different clinical and prognostic implications. To give an example, in patients with hepatitis B in a phase of low viral replication (HBeAg negative, anti-HBe positive, low serum HBV-DNA) the histological appearances are typically those of chronic persistent hepatitis. For these patients the risk of developing cirrhosis is low, though not en-

HCV-associated hepatocellular carcinoma without cirrhosis

Abstract Background/Aims: Hepatocellular carcinoma is an aggressive malignancy and carriers a poor prognosis. Hepatitis B and C virus infection, cirrhosis and aflatoxin B 1 exposure are considered major risk factors. The role of hepatitis C virus in the causation of hepatocellular carcinoma has been debated. It is a positive, single-stranded RNA virus without a DNA intermediate in its replicative cycle, so that integration of hepatitis C virus nucleic acid sequences into the host genome seems unlikely. The most plausible explanation of hepatitis C virus-associated hepatocellular carcinoma so far is that the virus causes necroinflammatory hepatic disease with vigorous regeneration, fibrosis, and eventually cirrhosis. The aim of this study was to examine the relationship of hepatitis C, cirrhosis and hepatocellular carcinoma. Methods: Sixty-six consecutive patients with hepatocellular carcinoma undergoing resection or transplantation at the Royal Free Hospital were reviewed. A combination of serological data and polymerase chain reaction assay was used to assign hepatitis C virus and hepatitis B virus infection. Results: We found four HCV-RNA positive patietns with hepatocellular carcinoma without cirrhosis. All four cases were positive for HCV-RNA and negative for all markers of hepatitis B virus infection. Conclusions: These four cases show that hepatocellular carcinoma may develop in patients with hepatitis C virus without pre-existing cirrhosis. However, the precise role of hepatitis C virus in hepatocarcinogenesis, the carcinogenic potential of the different genotypes and whether this role is influenced by other risk factors still have to be clarified.

An immunohistochemical and ultrastructural study of the sinusoids of hepatocellular carcinoma

The sinusoids of 30 human hepatocellular carcinomas of various types were examined by electron microscopy and histochemically for binding to the Ulex europaeus lectin (UEA1). A population of sinusoidal macrophages was identified with an antibody to lysozyme (muramidase). The UEA1 binding was negative in normal sinusoids but positive in the tumor vessels. Macrophages resembling Kupffer cells were found within the tumor vessels but in smaller numbers than in either normal or cirrhotic liver tissue. Fibrolamellar and sclerosing carcinomas contained the smallest numbers. Ultrastructurally, endothelial cells of tumor vessels were thicker than normal, with fewer fenestrations. They contained bundles of microfilaments and showed basement membrane formation. Subendothelial myoid cells were found. These findings indicate that the sinusoidal vessels of hepatocellular carcinomas show features of true capillaries and precapillary blood vessels. The degree of this difference from normal hepatic sinusoids may reflect the relative immaturity of the cancer cells.

Histological demonstration of copper and copper-associated protein in chronic liver diseases.

Liver copper concentrations in percutaneous biopsy specimens were measured by neutron activation analysis and compared with histological staining for copper by rubeanic acid and rhodanine, and with copper-associated protein stained by orcein. Liver copper concentrations were elevated in 31 of 35 biopsies from patients with primary biliary cirrhosis (PBC), and discrimination between normal and elevated liver copper was correct in 32 of the 35 biopsies by staining with rubeanic acid, and 31 of the 35 by staining with rhodanine. Orcein staining of copper-associated protein was positive in 33 of the 35 biopsies. All 17 biopsy specimens from patients with Wilsons disease had high liver copper concentrations, but only nine had positive staining for copper, and six were orcein positive. Similarly, histological stains gave little indication of the liver copper concentrations in tissue from 16 patients with chronic active hepatitis. Staining of liver sections can be useful in detecting elevation of liver copper in PBC, but not in Wilsons disease, where the absolute concentration must be measured. Excess copper appears to accumulate in the liver in different chemical forms in PBC and Wilsons disease.