J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from Journal of Clinical Pathology, 1978, 31, 395-414 The morphology of cirrhosis' Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization P. P. ANTHONY, K. G. ISHAK, N. C. NAYAK, H. E. POULSEN, P. J. SCHEUER, AND L. H. SOBIN From the Bland-Sutton Institute ofPathology, Middlesex Hospital Medical School, London, the Armed Forces Institute ofPathology, Washington, the All India Institute ofMedical Sciences, New Delhi, Hvidovre Hospital, University of Copenhagen, The Royal Free Hospital School ofMedicine, London, and the Cancer Unit of the World Health Organization, Geneva SUMMARY 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. The aim of this paper is to provide guidelines for the morphological terms but, in spite of many attempts, pathologist on the definition, nomenclature, and no single definition exists that does not require classification of hepatic cirrhosis and related con- further elaboration or qualification. The essential ditions. The many systems of classification in current features are considered to be parenchymal necrosis, http://jcp.bmj.com/ use (Table 1) hinder rather than help comparisons of regeneration, and diffuse fibrosis, resulting in dis- published data and the evaluation of relationships organisation of the lobular architecture throughout between cirrhosis and liver cancer. Different words the whole of the liver. There are many who consider have been used to describe essentially similar features, that the altered vascular relationships are an equally and a single word is sometimes applied to a variety or even more important feature. All would agree, of forms. The terminology of many classifications is however, that cirrhosis is a chronic, progressive con- based on a mixture of pathogenesis, morphology, dition that results in liver cell dysfunction and portal on September 26, 2021 by guest. Protected copyright. and aetiology (for example, 'post-necrotic', 'portal', hypertension. Instances of regression from estab- and 'biliary' cirrhosis). There is, therefore, a need for lished cirrhosis to normal liver architecture are rare a logical and readily reproducible system. and open to doubt. In the preparation of these guidelines, comments In this article cirrhosis is defined as a diffuseprocess and criticisms from a number of other pathologists characterized by fibrosis and the conversion ofnormal and hepatologists throughout the world have been liver architecture into structurally abnormal nodules. taken into account. An attempt has been made to The process is diffuse in the sense that it involves study a wide variety of material from different the whole organ. Focal lesions, eg, focal nodular geographical areas. hyperplasia, do not constitute cirrhosis. Diffuse nodularity without fibrosis, eg, the nodular hyper- Cirrhosis plasia associated with Felty's syndrome or induced by drugs and chemicals, is not cirrhosis, nor is diffuse DEFINITION fibrosis without nodularity, eg, hepatoportal sclero- It is generally agreed that cirrhosis is best defined in sis. There are conditions in which both generalised 'This is an abbreviated version of the original published fibrosis and nodularity are present, eg, congenital in the Bulletin of the World Health Organization (4, 521- hepatic fibrosis, but which are not considered to con- 540, 1977). stitute cirrhosis because the lobular architecture is largely maintained. Received for publication 7 November 1977 It is generally assumed that fibrosis is the result of 395 J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from 396 P. P. Anthony, K. G. Ishak, N. C. Nayak, H. E. Poulsen, P. J. Scheuer, aud L. H. Sohin Table 1 An approximate comparison of tennis used to designate various types of cirrhosis Nutritional Septal Laennec's types Regular Micronodular Tspe C Laennec's, fatty, alcoholic, A, B, C, D portal, monolobular, diffuse, uniform, finely nodulai, florid Postnecrotic Postcollapse Postnecrotic Irregular Macronodtwlar Type A Nonalcoholic, toxic, multilobular, atrophic, trabecular, variform, coarsely\ nodular, healed yellow atiophs Posthepatitic Incomplete septal TIpe B necrosis, and some definitions of cirrhosis include appearances, sometimes in the same patient. The the presence of necrosis as a criterion. Whatever the complete characterisation ofcirrhosis in an individual mechanism of fibrosis and whatever the initial lesion case should take into account the morphological may have been, evidence of necrosis may no longer features, aetiology, stage of evolution, activity, and be apparent by the time a cirrhotic liver is examined. complications of the disease. Necrosis is, therefore, omitted from the mor- phological definition of cirrhosis. Fibrosis is general- Morphology ised throughout the liver, but it is variable in extent Subdivision of cirrhosis into different morphological and distribution, eg, focal, diffuse, multilobular (see categories is better described as characterisation Glossary, pages 411-412). rather than classification, for the reasons already The nodules of a cirrhotic liver lack normal lobular noted. These categories do not represent different organisation and are surrounded by fibrous tissue. diseases but are stages in the development of a single They are often referred to as 'regenerative' or 'hyper- disease process. The morphological characteristics of plastic', terms that imply concepts of pathogenesis any one cirrhotic liver result from the operation and rather than serve morphological definition. They can- interplay of a number of independent factors, such as not be truly regenerative in that restitution to normal liver cell necrosis, hyperplasia, and fibrosis. There is liver tissue does not occur. Histological evidence of thus a range of morphological patterns rather than a growth is commonly seen in the form of liver cell small number of rigid categories. plates more than one cell thick, and pressure on sur- There are nevertheless reasons for subdividing rounding structures may be evident. Some nodules cirrhosis on a purely morphological basis. It enables http://jcp.bmj.com/ may contain portal tracts and efferent veins abnor- patterns to be studied epidemiologically, and may mally related to each other. These structures may be allow their correlation with aetiological agents. either pre-existing or newly formed. It is not known Morphological patterns may reflect aetiology and for certain just how the nodules of cirrhosis do arise stage of evolution and prognosis, and also affect the but it is likely that several mechanisms take part. Re- ease or difficulty of histological diagnosis. This is growth after necrosis, dissection of lobules by fibro- usually easy when nodules are small, regular, and sis, and remodelling associated with altered vascular closely set but can be extremely difficult when the on September 26, 2021 by guest. Protected copyright. relationships are probably all operative. nodules are large in relation to the sample. Liver cancer is found more often in cirrhotic livers with CLASSIFICATION large nodules. In the past, cirrhosis has often been classified on the Among the systems of morphological categories basis of a mixture of pathogenesis, morphological currently in use, the division of cirrhosis into micro- appearances, aetiology, and eponyms (Table 1). Such nodular and macronodular forms is preferred. This mixtures are confusing and undesirable, and any one is a simple system, readily understood, and already classification should be restricted to a particular base used in many parts of the world. It can be applied at or axis. Pathogenetic terms (for example, post- both a macroscopic and microscopic level. hepatitic) are often difficult to apply because the pathogenesis of a particular cirrhosis may no longer (a) Micronodular pattern (Figs 1, 3, 6). A cirrhotic be evident at the time of examination. Morphological liver in which nearly all the nodules are less than 3 and aetiological classifications should be regarded as mm in diameter. This somewhat arbitrary figure has complementary rather than as alternative, and both been chosen deliberately in order to avoid forcing the should be separately applied to the individual majority of cirrhotic livers into a macronodular example, as outlined in the sections that follow. There category; this is what happens when a maximum is evidence that the same morphological pattern can diameter of I or 2 mm is chosen. A striking feature is be produced by a variety of causal agents and that a the regularity of the nodule size. Micronodules may single agent can produce a variety of morphological rarely contain portal tracts (for example, in cirrhosis J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from The morphology of clrrhosis 397 due to venous outflow obstruction) or efferent veins be a common pattern in the tropics and subtropics (for example, in biliary obstruction) but generally ('incomplete septal' or 'posthepatitic' pattern). In